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Pre-Conference Workshop Pre-Conference Workshop Document Transcript

  • TWENTY-FOURTH INTERNATIONAL NEUROTOXICOLOGY CONFERENCEEnvironmental Etiologies of Neurological Disorders NTX XXIV Abstracts
  • November 11-14, 2007 ABSTRACTS Page 1Opening darkest). The theme features those human diseases orSESSION I: WELCOME, ACKNOWLEDGEMENTS, AND disorders linked to environmental toxicants for which we haveOVERVIEW OF THE 24TH CONFERENCE the greatest human ⇒ animal model ⇒ translational research data.Conference Chair: Joan Cranmer Focus Topics comprise: Complex Disease or Disorder:1 Toxicant-Induced Cognitive Disorders, Parkinson’s disease,TWENTY-FOURTH INTERNATIONAL NEUROTOXICOLOGY Alzheimer’s disease, Autism Spectrum Disorder and ADHD.CONFERENCE: “ENVIRONMENTAL ETIOLOGIES OF The chemicals listed in column two have been linked in theNEUROLOGICAL DISORDERS” Joan M. Cranmer, peer-reviewed literature to the complex disease/disorder listedDepartment of Pediatrics and Department of Pharmacology and in column one. Data from animal models and studies ofToxicology, College of Medicine, University of Arkansas for humans exposed to Lead, Mercury, Pesticides or PCBs willMedical Sciences & Arkansas Children’s Hospital, Little Rock, AR. comprise the major Case Studies with which NEUROTOXICOLOGY 24 will explore “modifiers” of clinicalThe twenty-fourth meeting in this International Neurotoxicology outcome. For each of these Disease-Toxicant categoriesConference Series (NEUROTOXICOLOGY 24) convenes human and animal model data will be presented to elucidateNovember 11-14, 2007 at the Riverwalk Holiday Inn in San Modifiers of Toxic Effect including: Genetic susceptibility,Antonio, Texas. The theme of THE 2007 conference is Age, Gender, Nutrition, Extended EnvironmentEnvironmental Etiologies of Neurological Disorders. Scientists (Social/Political/Economic), and Simultaneous Chemicalfrom around the world will present state-of-the-science Exposures. Within each plenary session devoted to a specificresearch in a variety of venues including Plenary sessions, Disease-Toxicant-Modifier, speakers and topics were selectedSymposia, Roundtable Discussion/Open Forum, Platform to incorporate the following Research Approaches:Sessions, Workshops, a Poster Session with Pre- and Post- Translational, Integrated, Multifactorial, Interdisciplinary, andDoctoral Student Award Competitions, and focused Panel Clinician/Community Outreach.Discussions on controversial issues. NEUROTOXICOLOGY24 will wrap up with Roundtable Discussion aimed at Environmental Etiologies of Neurological Disorders will beconsensus building on “What We Don’t Know about a focus throughout the Conference especially in the PlenaryEnvironmental Etiologies of Neurological Diseases” focusing Sessions and selected Symposia. However, since this is the thon Alzheimer’s, Autism and Parkinson’s diseases. 24 meeting in a well-established conference series, it is also our objective to “build in” time for sessions related to other contemporary issues in neurotoxicology to allow greaterBackground on the Theme participation. Sessions on proposed mechanisms for neurotoxicant-linked neurodegenerative disease, riskThe overall organizational design for NEUROTOXICOLOGY assessment strategies, public health and policy, design and24 is summarized in the table below. In the table our interpretation of epidemiological studies for assessing risk andknowledge and level of understanding of the role a open sessions for talks and poster presentations selected fromneurotoxicant plays in the nervous system disorder is ranked submitted abstracts and Symposium proposals are also a keyhighest to lowest from top to bottom (and from lightest to part of the program. Organizational Design for Plenary Sessions in NEUROTOXICOLOGY 24 HUMAN DISEASE ENVIRONMENTAL ANIMAL MODELS MECHANISTIC RISK MODIFIERS OR DISORDER LINKS AND DATA DATA Gender, Genetic Cognitive Pb, Hg, PCBs, Rats, primates and predisposition SES, Dysfunction; Neurotransmitter Function pesticides operant schedules Nutrition, Prematurity, Learning Disabilities Low birth wt, Aging Dopamine, MRI, latent Genetic predisposition, Parkinson’s Disease; Primates and MPTP, Pesticides, Pb, Mn toxicity (FeBAD), Age, Gender, lifestyle Movement Disorders Rodents, transgenics α- synuclein, parkin (smoking) Type-2 Alkenes, Neurogenesis, APP Bisphenol A, epigenetics, Estrogen Neurodegenerative Endocrine disruptors, transgenics, lifespan FeBAD, Aβ aggregation Replacement, Diseases (Alzheimer’s Aluminum, exposure models, /clearance, oxidative stress, Genetics, Prevention, Disease, PD, ALS) Methylmercury, primates, guinea pigs, inflammation, altered APP Diet (cholesterol), Lead, Pesticides Aβ plaques expression, cell loss Age, Education >Hoxa1, serotonin, nutrition, Infections, Maternal Autism Thalidomide, Hg, Eye-blink, stereotypy, oxidative stress, calcium age Spectrum Disorders valproate circadian rhythm channels Genetic predisposition, Operant schedules, Prematurity, Low birth ADHD Pb, PCBs Dopamine RT wt Table by Bernard Weiss ~ University of Rochester School of MedicineNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 2Fourteen Sessions comprise NEUROTOXICOLOGY 24: important investment decisions without adequate forethought and planning at the national level; and (3) that we lackSunday Early Afternoon Opening Session adequate metrics to determine how our investments areSESSION I: Opening, Keynote Address and Theme Rationale performing. I will conclude (1) that the United States needs aSunday Afternoon Plenary Session National Commission to develop a rational science policy; (2)SESSION II: Cognitive Disorders Linked to Lead Exposure: Risk that we need a mechanism to analyze our investment portfolioModifiers with respect to impact; and (3) that translation of scientific discoveries into technologies to prevent or treat chronicSunday Evening Thought Provokers diseases will require community participation. Keywords:SESSION III: Cross-Cutting Issues: Hot New Topics strategic planning, priority setting, public participation.Monday Morning Plenary SessionSESSION IV. Cognitive Disorders Linked to Methymercury 3Exposure: Risk Modifiers RATIONALE FOR THEME. Deborah Cory-Slechta. Department of Environmental Medicine, University ofMonday Late Morning Roundtable DiscussionSESSION V. Translating Risk Assessment into the Real World Rochester School of Medicine & Dentistry, Rochester, NY14642Monday Early Afternoon Symposium It has become increasingly evident that many humanSESSION VI-A. Fetal Basis of Adolescent and Adult Disease neurological diseases and disorders arise from complex interactions of multiple risk factors, of which environmentalMonday Early Afternoon Roundtable chemical exposures may serve as one contributing risk. OtherSESSION VI-B. Cell Death in the Nervous System: Facts and Artifacts environmental and host factors, such as genetic background,Monday Late Afternoon Platform Session dietary status, immune status, obesity, stress, socioeconomicSESSION VII-A. Developmental Neurotoxicity; Neuroprotection status, gender, behavior, and intercurrent disease state, as well as other chemical exposures, can also contribute. ForMonday Late Afternoon Symposium example, Parkinson’s disease exhibits gender differences, andSESSION VII-B. The Olfactory System: An Often Forgotten Target protection is conferred by caffeine and smoking. The impact ofMonday Evening neurotoxicants like lead and methylmercury is heavilySESSION VIII. Poster Session. Pre- and Post-Doctoral Student influenced by developmental windows, with children showingAward Competition significantly greater vulnerability. Thus, a full understanding of the true risk posed by any environmental toxicant for humanTuesday Morning Plenary Session neurological diseases or disorders will ultimately requireSESSION IX. Modifiers of Disease Development in Parkinson’s assessments of its interaction with other relevantDisease: Role of Environmental Toxicants environmental, host and genetic risk factors.Tuesday Early Afternoon Platform Session Despite these complexities, the paradigms used toSESSION X. Environmental Links to Neurological Diseases understand the impact of environmental exposures as risk factors for human diseases continue to rely on approaches thatTuesday Late Afternoon Symposium fail to capture this reality. Instead, they focus on exposures toSESSION XI. An Ecosystem Approach to Exposure to Neurotoxic single chemicals in isolation from other risk factors. AnimalSubstances in Latin America studies often examine effects of a single chemical in youngWednesday Morning Plenary Session adult, mostly male rodents, ignoring, for instance, the potentialSESSION XII. Oxidative Stress in Autism: Cause or Consequence? importance of age and gender. Epidemiological and clinical studies generally focus on main effects of environmentalWednesday Early Afternoon Platform Session: exposures, since risk modification, as reflected in statisticalSESSION XIII. Autism Spectrum Disorders interactions, is considered inaccessible because of inadequateWednesday Late Afternoon Roundtable/Consensus Building sample sizes. Consequently, as models of diseases andSESSION XIV. What is the Weight of Evidence that disorders, current research approaches are distant from actualEnvironmental Contaminants and/or Genetic Factors Influence human conditions, constraining the ability to determinethe Etiologies of Neurological Disorders? pathophysiological mechanisms from which biomarkers and therapeutic strategies can be identified, thereby limiting theOn Tuesday evening the conference will host a dinner, award ability to protect human health.ceremonies and “Six Flags Over Texas – Neurotox Style” An understanding of the interactions of host andentertainment by the Jalapeño Honey band and some of the environmental risk factors with environmental chemicalNEUROTOX 24 conference participants! exposures in the etiology of neurological diseases and disorders allows the development of increasingly more realistic2 and valid animal models of disease, and more focused clinicalKeynote Address /epidemiological studies. Refined animal and human modelsSCIENCE AND THE PUBLIC INTEREST. Kenneth Olden. will expedite the discovery of pathophysiological mechanismsFormer Director of the National Institute for Environmental of environmentally-related diseases and disorders, and thusHealth Sciences and the National Toxicology Program. Yerby improve the ability to define biomarkers of disease onset andProfessor, Harvard University, School of Public Health, and progression, as well as potential targets for therapeuticChief, Metastasis Section, NIEHS/NIH. interventions, thereby leading to improved prevention and In this presentation, I will describe my views about how detection strategies. Understanding how risk factors interact isresearch and development priorities are established in the also critical in the context of global public health protection,United States Government. I will argue (1) that we have a since different populations and cultures bring different sets offragmented priority setting process; (2) that we are making risk factors into play.NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 3Plenary Session health implications. Our experimental studies in animal modelsSESSION II: COGNITIVE DYSFUNCTION LINKED TO have now evaluated the impact of maternal Pb exposure, andLEAD EXPOSURE: MODIFIERS OF EFFECT: of lifetime Pb exposure, with prenatal stress, and with stress toSocioeconomic Status, Stress, Gender, Genetic the offspring on measures of behavior and on neurochemicalBackground and Aging and corticosterone levels. These studies reveal that: 1) Pb can produce effects that resemble those associated with prenatalSession Chair: Deborah Cory-Slechta stress; 2) Pb alone, either maternal or lifetime exposure,Co-Chair: David Bellinger permanently alters HPA axis function and stress responsivity, 3) Pb can modulate the effects of stress, and, conversely,Theme and Rationale: After the removal of lead, a well stress can modulate the effects of Pb. Most notably, 4) in someknown neurotoxicant, from paint and gasoline in many cases potentiated effects of Pb+stress occur, i.e., effects ofcountries, blood lead levels of the general population combined risks in the absence of an effect of either Pb or stress alone consistent with a multiple hit model; and 5)declined, easing the burden of lead exposure in corresponding marked gender differences are observed, with our currentpopulations. However, new concerns have arisen over the investigations showing greater impact on behavioral outcomeresidual lower levels of exposure, as accumulating evidence in female offspring. Gender differences are seldom evaluateddocuments effects on cognitive function and other health in human cohort studies of Pb. Collectively, these findingsoutcomes even at levels below the currently defined level of suggest that human studies should more fully evaluate long-concern for children. Moreover, lead exposures remain a term behavioral consequences in girls. Permanent effects of Pb on the HPA axis suggest pregnant women should besignificant public health problem in particular for inner city screened, and also raise the possibility that Pb could contributeminority children living in old housing with residual lead as a risk factor to a broad array of diseases associated withpaint. Although much of the focus of research on lead has HPA axis dysfunction. ES02ES012712.concerned the confirmation of its impact on cognitive function,it is becoming increasingly evident that these effects can be 5significantly modified by other environmental and host risk SOCIOECONOMIC STATUS AS A MODULATOR OF THEfactors. Among these modifiers are socioeconomic status, BEHAVIORAL TOXICITY OF LEAD. David C. Bellinger, Department of Neurology, Harvard Medical School andgender, genetic background, nutrition and aging. Older Children’s Hospital Boston, Department of Environmentalmembers of the population had higher level exposures that Health, Harvard School of Public Health, Boston, MA, USAmay now impact the nervous system. In addition, new findings Consideration of the social, political, and economicsuggest that some effects of lead exposure may be contexts in which exposure occurs to environmental chemicalstransgenerational. Understanding how these other risk can produce a deeper understanding of individual susceptibilityfactors influence the impact of lead on the nervous system and patterns of disease occurrence. Most studies include measurement of individual-level factors, such as hostallows the development of more refined experimental animal characteristics or the immediate family, but rarely considermodels and more directed cohort studies. In addition, it should macro-level factors such as neighborhood, community, andprovide a sounder basis for the determination of behavioral or cultural characteristics. Even more rarely are such factorsother directed therapeutic strategies for attenuation of lead evaluated as risk modifiers as well as confounders, despiteeffects, as well as increasing precision and reducing evidence that contextual factors can sometimes influence theuncertainties related to redefining blood lead levels of manner in which neurotoxicities are expressed. Our analytical models must also address the fact that contaminant exposuresconcern. occur within a dynamic system, such that aspects of the system other than health outcomes can also be affected by the4 contaminants, creating complex, time-varying relationships.INTERACTIONS OF LEAD EXPOSURE, STRESS AND Thus, a systems approach to analysis is needed in order toGENDER: IMPLICATIONS FOR COGNITIVE DISORDERS. capture the possibility that contaminant-induced change inD.A. Cory-Slechta, M. Virgolini, A. Rossi-George and M. covariates mediates some portion of the association betweenThiruchelvam. Department of Environmental Medicine, early contaminant exposures and late outcomes. TheseUniversity of Rochester School of Medicine and Dentistry, hypotheses will be discussed within the context of the literatureRochester, NY, USA and Environmental and Occupational on the developmental neurotoxicity of lead.Health Sciences Institute, a joint Institute of Rutgers Universityand UMDNJ, Piscataway, NJ, USA. 6 Lead (Pb) exposure increases the risk for cognitive DEVELOPMENTAL LEAD AND LATE ONSETdysfunction and attention deficit, likely through its effects on ALZHEIMER’S DISEASE PATHOLOGY. Nasser H. Zawia,mesocorticolimbic systems. The highest Pb exposures, Ph.D., Department of Biomedical and Pharmaceuticalhowever, occur in low socioeconomic status populations, the Sciences, College of Pharmacy, University of Rhode island,same groups thought to chronically sustain high levels of Kingston, RI, 02881.stress and its associated hormones that also act through Alzheimer’s disease (AD) is a progressivemesocorticolimbic systems. In fact, prenatal stress itself has neurodegenerative disorder whose clinical manifestationslifetime consequences for offspring, including impairments in appear in old age. The hallmark pathological features of ADcognitive function and attention. Thus, Pb and stress are likely (amyloid plaques and associated proteins) are present into interact in influencing these behaviors. Yet virtually nothing normal aging indivduals suggesting that AD may result fromis known about the nature of such interactions, the the acceleration of normal age-related processes in the brain.mechanisms through which they occur, and their broader The sporadic nature of AD argues for an environmental linkNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 4that may drive AD pathogenesis; however, the triggering factor assessment process. Funded by NIH Grants RO1 ES012482,and the period of its action are unknown. Rodent studies from P30 EY07751 and T32 EY07024.our lab showed that exposure to lead (Pb) during braindevelopment pre-determined the expression and regulation of Panel Discussion and Q&A:the Amyloid Precursor Arotein (APP) and elevated beta-amyloid (Aβ) levels in old age. In order to link these molecular • Can gender differences in the behavioral consequences ofperturbations to pathological consequences associated with Pb exposure be used to assist in diagnosis of specificAD, we have acquired the brains of monkeys who have been behavioral disorders and in the development ofsimilarly exposed to Pb as infants in the 80’s. Primates are appropriate behavioral therapeutic strategies?among the few animal models that express amyloid plaques • Do permanent Pb-induced changes in HPA axis functionand other pathological features that are absent in normal non- from even maternal only Pb exposure mean that screeningtransgenic rodents. Here we report that the expression of AD- for Pb exposure should include pregnant women?related genes and their transcriptional regulator (SP1) wereelevated in aged monkeys exposed to Pb early in life. Infantile • How should future cohort studies and experimental animalPb-exposure altered the levels, intracellular distribution of Aβ models be refined in future studies to more preciselystaining and amyloid plaques in the frontal cortex. These latent estimate risks arising from even current levels of Pbeffects were accompanied by decrease in DNA- exposure?methyltransferase activity and increased oxidative DNA-damage indicating that epigenetic imprinting in early lifeinfluenced the expression of AD-related genes and promotedDNA damage and pathogenesis. These data suggest that AD Thought Provokerspathogenesis is influenced by early life exposures and argues SESSION III: CROSS-CUTTING ISSUES: HOT NEW TOPICSfor both an environmental trigger and developmental origin ofAD. Session Chair: Richard LoPachin Co-Chair: William Slikker7LOW-LEVEL HUMAN EQUIVALENT GESTATIONAL LEAD 8EXPOSURE PRODUCES GENDER-SPECIFIC MOTOR AND FROM TREES TO FOREST: USING BIBLIOMETRICS FORCOORDINATION ABNORMALITIES AND LATE-ONSET SYNTHESIZING AND PRIORITIZING BIOLOGY,OBESITY IN YEAR-OLD MICE. DA Fox, JL Leasure, A TOXICOLOGY AND EXPOSURE TOPICS IN THEGiddabasappa, S Chaney, JE Johnson, K Pothakos, YS Lau. RESEARCH LITERATURE ON AUTISM. Mark Corrales,College of Optometry and Departments of Biology & MPP1, Avi Ringer B.A.2, Martha Herbert MD, PhD2 1. Office ofBiochemistry, Psychology, Natural Sciences, and Policy, Economics and Innovation, EPA, Washington DC USA;Pharmacological and Pharmaceutical Sciences, University of 2. Pediatric Neurology, Mass Gen Hosp, Harvard Med School,Houston, Houston, TX, USA. Boston MA USA Low-level developmental lead exposure is linked to There is a growing awareness of the need for bettercognitive and neurological disorders in children. However, the approaches to setting strategic priorities across potentiallong-term effects of gestational lead exposure (GLE) have avenues of research. The rapidly expanding literature relatedreceived little attention. Our goals were to establish and to autism shows that a great deal of research is underway, butvalidate a murine model of human equivalent GLE and to keeping track of so much new literature is daunting. Autismdetermine dose-response effects on body weight, motor research seems to be expanding in emphasis beyond behaviorfunctions and dopamine neurochemistry in year-old offspring. and genetics to include more physiology and molecularFemale C57BL/6 mice were exposed to water containing 0, 27 biology. Objective metrics describing the areas of emphasis(low), 55 (moderate) or 109 ppm (high) of lead from two weeks and apparent shifts would be helpful. We will describe aprior to mating, throughout gestation and until postnatal day 10 bibliometric assessment of the research literature, highlighting(PN10). Maternal and litter measures, blood lead topics that have been heavily studied or understudied. Weconcentrations ([BPb]) and body weights were obtained focus here in particular on chemical substances, including riskthroughout the experiment. Locomotor behavior in the absence factors, markers of exposure, and markers of effect. We willand presence of amphetamine, running wheel activity, rotarod review the state of biological research in autism as revealed bytest and dopamine utilization were examined in year-old mice. these methods, identify horizons highlighted by this approach,Peak [BPb] were <1, ≤10, 27 and 42 µg/dL in control, low-, and discuss methodological challenges. Describing the state ofmoderate- and high-dose GLE groups, respectively. Year-old the literature through patterns of keywords and other usefulmale, but not female, GLE mice exhibited late-onset obesity. groupings can quickly summarize useful information andSimilarly, we observed male-specific decreased spontaneous generate new insights into areas needing further researchmotor activity, increased amphetamine-induced motor activity attention. For example, a greater emphasis on the exposureand decreased rotarod performance in year-old GLE mice. biology and intermediary metabolism domains may be criticalLevels of dopamine and its major metabolite were altered in for understanding this complex, heterogeneous set ofyear-old male mice, although only forebrain utilization conditions that appear to involve gene-environmentincreased. GLE-induced alterations were consistently larger in interactions. This could be helpful to individual researchers,low-dose GLE mice. Our novel results show that GLE research programs and the NIH, which is increasinglyproduced permanent male-specific deficits. The nonmonotonic expected to produce comprehensive research roadmaps thatdose-dependent responses showed that low-level GLE document plans and progress in various areas, including theproduced the most adverse effects. These data reinforce the autism research matrix.idea that lifetime measures of dose-response toxicantexposure should be a component of the neurotoxic riskNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 59 attention with respect to neurological disorders, andKETAMINE-INDUCED NEURONAL CELL DEATH IN neurodegenerative diseases than have these latterPERINATAL RHESUS MONKEYS. W. Slikker1*; X. Zou3; C. transmitters. Nonetheless, evidence is accumulating thatHotchkiss2; R. Divine3; N. Sadovova3; N. Twaddle4; D. glutamate, in addition to its’ well described role in stroke andDoerge4; A. Scallet5; T. Patterson5; J. Hanig6; M. Paule5; C. ischemic brain damage, also may contribute to Parkinson’s 5Wang 1. Office of the Director, 2. Bionetics, 3. Toxicologic and Alzheimer’s Disease, and it appears to play a dominantPathology Associates, 4. Division of Biochemical Toxicology, role in amyotrophic lateral sclerosis. Disruptions in GABAergicNCTR, Jefferson, AR, USA 5. Division of Neurotoxicology, transmission, in turn, are well recognized as playing crucialNCTR, Jefferson, AR, USA 6. OPS/OTR/DAPR, CDER/FDA, roles in seizurigenic disorders, but are increasingly recognizedRockville, MD, USA. william.slikker@fda.hhs.gov. as playing a significant role in Huntington’s disease, and may An increase (~20-150%) in the percentage of damaged also be important contributors to the actions of ethanol. Thebrain cells was observed in the frontal cortex of monkey dominant excitatory responses are glutamate-mediatedfetuses from ketamine-treated pregnant animals and five-day- excitatory postsynaptic potentials (EPSPs) which result fromold infant monkeys compared with non-treated controls. These activation of both kainate/AMPA receptors (fast EPSP) and N-findings are of interest because ketamine is used as a pediatric methyl,D-aspartate (NMDA) receptors (slow EPSP). Theseanesthetic in children. Previous studies have shown that result from influx of Na and Ca, and in some neurons, makeketamine is neurotoxic (causes brain damage) in the significant contributions to the intracellular calcium (Ca2+I).developing rat but these results needed to be confirmed or GABAergic inhibitory postsynaptic potentials (IPSPs) result -ruled out in an appropriate primate model with greater similarity from influx of Cl , however during development, activation ofto developing humans. Pregnant rhesus monkeys (pregnant for GABAA receptors is excitatory, due to lack of expression of a122 days which is 75% of term), and five- and 35-day-old K/Cl cotransporter. In some cells, distinct phenotypes ofinfants were continuously infused intravenously with ketamine glutamate or GABAA receptors confers distinct properties onto maintain a stable anesthetic condition for 3 and 24 hrs, the neuron. In ALS, the high Ca permeability of the AMPAfollowed by a 6-hr washout period during which no drug was receptors on motor neurons, makes them especially vulnerableadministered. Maternal blood oxygen, exhaled carbon dioxide, to glutamate-mediated, Ca-induced cytotoxicity. Similarly, inbody temperature, heart rate, blood pressure, and glucose cerebellar granule cells, GABAA receptors containing the Ύ6were all monitored and observed to be within normal ranges subunit play a critical role in granule cell excitability by gating athroughout ketamine administration. The deeply anesthetized tonic conductance. Interaction of these two receptor systemsfetuses (after Cesarean section delivery under anesthesia) or can contribute to excessive excitability. Such a situation hasinfant monkeys were injected with a tissue preservative and been hypothesized to contribute to vulnerability of cerebellarthe brain tissue was collected and processed for several types granule neurons to methylmercury-induced cytotoxicity.of highly specialized microscopic and biochemical analyses.The brains from monkey fetuses from pregnant control animals 11and from five and 35 day old control infant monkeys (no TYPE-2 ALKENE-INDUCED NERVE TERMINAL DAMAGEketamine treatment) were similarly processed and assessed. REPRESENTS A UNIFIED MECHANISM FORHistochemical techniques showed a modest (~20-150%) but NEURODEGENERATIVE DISEASES (ALZHEIMER’Sstatistically significant increase in the degree of brain cell death DISEASE, PARKINSON’S DISEASE, ALS AND OTHERS).as in the frontal cortices of fetuses and five-day-old infants but Richard M. LoPachin. Dept. of Anesthesiology, Montefiorenot in 35-day-old infants anesthetized with ketamine for 24 hr. Medical Center, Albert Einstein College of Medicine of YeshivaTUNEL (Terminal deoxynucleotidyl Transferase Biotin-dUTP University, Bronx, NY 10467.Nick End Labeling) and electron microscopic (EM) data Growing evidence indicates that Alzheimer’s disease (AD),indicated that enhanced cell death was apparent in the frontal amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD)cortex. EM observations showed typical nuclear condensation, and other neurodegenerative conditions (stroke, ischemia)fragmentation and cell body swelling after the 6-hr washout involve initial oxidative stress–induced lipid peroxidation andperiod. Interestingly, five-day-old infants anesthetized with subsequent generation of endogenous conjugated type-2ketamine for only 3 hours showed no increase in brain cell alkenes such as acrolein and 4-hydroxy-2-nonenal (HNE).death compared to controls. Many questions remain to be Indeed, acrolein, HNE and their protein adducts have beenanswered: 1) will the observed cell death affect overall brain identified in the brains of AD, ALS and PD patients and a rolefunction 2) can the injured brain tissue recover with no loss of for these chemicals in neuronal degeneration has beennormal function, and 3) are there preventive treatments that proposed. However, other research has suggested thatwill ameliorate the anesthetic-induced neuronal cell death? selective nerve terminal dysfunction precedes and, perhaps, initiates the onset of neurodegeneration in these diseases.10 Data from in vivo and in vitro studies have demonstrated theAMINO ACID NEUROTRANSMISSION: IT’S ROLE IN sensitivity of nerve terminal function to chemicals in the type-2NEURODEGENERATIVE DISEASES AND NEURO- alkenes class and, therefore, it is conceivable that endogenousTOXICITY. William Atchison. Dept. of Pharmacology production of acrolein and HNE mediates the primary nerve/Toxicology, Michigan State University, East Lansing, MI, terminal damage in AD, ALS and PD. The type-2 alkenes are48824. soft electrophiles and recent research has shown that these The amino acids glutamate and GABA are the chemicals can inhibit the function of many presynapticpredominant excitatiory and inhibitory transmitters, processes (e.g., neurotransmitter release and vesicularrespectively, in the mammalian brain. They each gate storage) by forming covalent adducts with soft nucleophilicionotropic (NMDA, AMPA; GABAA) as well as metabotropic sulfhydryl groups on functionally important proteins. Nerve(mGluR, GABAB) receptors. While they have a greater overall terminals are particularly vulnerable to type-2 alkene toxicityimpact in the brain than do other “canonical” transmitters, such since the resident proteins turnover slowly and are susceptibleas acetylcholine and dopamine, they have received less to cumulative adduction and inhibition, and because nerveNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 6terminals lack transcription-based antioxidant defense risk assessment and risk management. This session will focusmechanisms. The purpose of this symposium is to present on potential interactions between methyl mercury andevidence supporting the hypothesis that the early stages of potential protective nutrients in humans and an animal model,many neurodegenerative diseases are characterized byoxidative generation of type-2 alkenes in specific brain regions. as well as potential effect modification by other chemicals.We propose that cumulative protein adduction by thesechemicals inhibits neurotransmission and, thereby, causes 12synaptic toxicity and eventual nerve terminal degeneration. COGNITIVE DISORDERS LINKED TO METHYL MERCURYSince type-2 alkenes such as acrolein, acrylamide and EXPOSURE: MODIFIERS OF EFFECT. Deborah Rice, Mainemethylvinyl ketone are prevalent pollutants, it is possible that Center for Disease Control and Prevention, Augusta, MEenvironmental exposure to these and other electrophilic 04333.chemicals accelerates the onset of neurodegenerative It has been known for decades that methyl mercury is adiseases like AD and ALS. Understanding the molecular potent neurotoxicant, and that the developing brain is moremechanism of type-2 alkene-induced nerve terminal damage susceptible to impairment as a result of exposure than is thecould provide insight into the development of adult. Epidemiological and experimental studies documentedpharmacotherapeutic approaches to these debilitating the constellation of effects produced by environmentaldiseases. exposure to methyl mercury, including decreased cognitive function; deficits in attention, memory, and ability to inhibit inappropriate or non-adaptive behavior; and sensory and motorPanel Discussion and Q&A: deficits. Exposure to methyl mercury is exclusively through• How can primary nerve terminal damage lead to generalized consumption of fish and marine mammals. In recent years, the neurodegeneration? potential for protection against methyl mercury toxicity by nutrients present in fish, particularly omega-3 fatty acids and• How does the relative electrophilicity of the type-2 alkenes selenium, has received increasing attention. In addition, the determine nervous tissue vs. systemic toxicity? potential for methyl mercury to interact with other• What pharmacotherapeutic approaches can be developed environmental contaminants present in marine food, including based on the role of protein adduction in type-2 alkene PCBs and pesticides, is of vital importance. An understanding neurotoxicity? of the interactions of the multiple factors that determine the final behavioral outcome of exposure to methyl mercury is• Are type-2 alkene adducts other than cysteine relevant to crucial to risk assessment and risk management. The nerve terminal toxicity? presentations in this session will address the influence of nutritional elements present in abundance in fish in modifying methyl mercury neurotoxicity in children, the interaction of multiple chemicals present in fish and marine mammals andPlenary Session the social environment on neuropsychological outcome inSESSION IV. COGNITIVE DISORDERS LINKED TO METHYL children, and the interaction of methyl mercury and variousMERCURY EXPOSURE: MODIFIERS OF EFFECT: dietary constituents in an animal model of methyl mercuryChemical Co-Exposures and Nutrition neurotoxicity.Session Chair: Deborah C. Rice 13Co-Chair: M. Christopher Newland INTERACTIONS OF NEUROTOXIC CONTAMINANTS IN 1 1 THE ARCTIC. Joseph L. Jacobson, Sandra W. Jacobson,Theme and Rationale: It has been known for decades that 2 2 2 Gina Muckle, Eric Dewailly, and Pierre Ayotte . Wayne 1methyl mercury is a potent neurotoxicant, and that the 2 State University School of Medicine. Public Health Researchdeveloping brain is more susceptible to impairment as a result Unit, Laval University Hospital Centre, Quebecof methyl mercury exposure than is the adult. Many pollutants are transported into the ArcticEpidemiological and experimental studies documented the environment from the northern hemisphere, including mercury,constellation of effects produced by environmental exposure to PCBs and other halogenated pollutants, and pesticides. These may be bioconcentrated up the food chain and are consumedmethyl mercury. Developmental exposure may produce a by residents eating locally-caught fish and sea mammals.constellation of adverse effects, including decreased cognitive These chemicals may interact with each other in complex waysfunction; deficits in attention, memory, and ability to inhibit in analyses of associations between exposures and neurotoxicinappropriate or non-adaptive behavior; and sensory and effects, as well as with nutritional constituents of the foodsmotor deficits. Some of these effects may be mediated through containing these pollutants. Prenatal exposure to mercury wasinterference with dopaminergic neurotransmitter function. assessed in maternal hair samples and prenatal exposure to PCBs, lead, and selenium, in cord plasma samples obtainedExposure to methyl mercury is exclusively through from 110 Inuit infants in Northern Quebec, who were assessedconsumption of fish and marine mammals. In recent years, on neuropsychological tests of specific aspects of cognitivethe potential for protection against methyl mercury toxicity by function at 6 and 11 months postpartum. DHA, anutrients present in fish, particularly omega-3 fatty acids and polyunsaturated fatty acid that plays a critical role in third-selenium, has received increasing attention. In addition, the trimester neuronal development, was also assessed in cordpotential for methyl mercury to interact with other chemicals plasma. After adjustment for potential confounders, prenatal mercury exposure was associated with poorer performance onpresent in marine food, including PCBs and pesticides, is of the A-not-B Test, which assesses the ability to maintainvital importance. These issues have important implications for attention across a brief period of delay. Prenatal PCBNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 7exposure was associated with poorer recognition memory on regimen produced MeHg levels in the neonatal brain similar tothe Fagan Test of Infant Intelligence (FTII); cord lead, with those seen with other rodent models, including mice, andslower, less efficient information processing on the FTII. Two levels that were several-fold higher than seen in primates,of these effects were modulated by third-trimester DHA intake, suggesting that allometric considerations apply to thealbeit by apparently different processes. DHA provided relationship between exposure and brain mercury content.protection against the effect of mercury on A-not-B attentional Brain PUFA and Se content reflected dietary exposures but, inperformance; no adverse effect was seen at higher levels of neonates, did not modify MeHg content. Developmentalantenatal DHA intake. Controlling statistically for DHA exposure to methylmercury resulted in perseveration,increased the magnitude of the effect of PCBs on recognition behavioral rigidity, enhanced sensitivity to reinforcing stimuli,memory, indicating that co-exposure reduced the impact of the and enhanced sensitivity to dopamine agonists. The n-3contaminant in a linear fashion but did not provide increased PUFA-rich diet exerted behavioral effects of its own but didprotection with increasing levels of prenatal intake (i.e., no little to protect against the expression of developmentalstatistical interaction). The only synergistic effect among these exposure to methylmercury. Selenium can significantly protectexposures was an intensification of the effect of lead on against the severe consequences of adult-onset exposuresprocessing speed at higher levels of antenatal selenium intake. and interacted in complex ways with with developmental MeHgThese data illustrate the potential of DHA to mitigate the exposure. The developmental studies have identified aadverse effects of in utero neurotoxicological exposures and behavioral domain that appears to be especially sensitive toprovide one example of the exacerbation of a neurotoxic developmental MeHg. Overall, these studies suggest that inexposure with co-exposure to a second potential teratogen. utero MeHg exposure alters the impact of reinforcing events by producing a "reinforcement trap." This, in turn, results in14 behavioral perseveration and impaired adaptation to changingNEURODEVELOPMENTAL EFFECTS OF MATERNAL environments. (funded by ES 10865 from the NIH).NUTRITIONAL STATUS AND EXPOSURE TOMETHYLMERCURY FROM EATING FISH DURING Panel Discussion and Q&A:PREGNANCY. Phillip W. Davidson. Dept. of Pediatrics, • What is the evidence for protective effects of nutrients orUniversity of Rochester, Rochester, NY14627 additive effects of chemical co-exposure? We conducted a study to test the hypothesis thatbeneficial nutrients present in fish might mask possible • How do we use that information in risk assessment?adverse effects of prenatal MeHg exposure from fishconsumption. The longitudinal cohort study took place in theRepublic of Seychelles, an Indian Ocean archipelago with a Roundtable Discussionpopulation of high fish consumers. A total of 300 mothers were SESSION V. TRANSLATING RISK ASSESSMENT INTO THErecruited during pregnancy. Nutrients considered to be REAL WORLDimportant for brain development were measured duringpregnancy along with maternal dietary intake and prenatal Session Chair: Bernard WeissMeHg exposure. The children were evaluated four times to age Co-Chair: Kevin Crofton30 months. Cohort mothers consumed on average about 9 fishmeals per week. The average prenatal MeHg exposure was Theme and Rationale: Neurological diseases and disorders5.9 ppm in maternal hair. The results indicated that prenatal are rarely unidimensional or unifactorial. Even those whoseMeHg exposure and maternal dietary intake and nutrient status etiologies seem closely linked to genetic predispositions tendmay affect some developmental outcome measures in to be the product of multiple and intertwined risk factors, ofopposite directions. If confirmed, our findings indicate that theconfounding role of maternal nutrition is important to assess in which environmental chemical exposures may serve as oneany study examining the relationship of fish consumption to component. Factors such as genetic background, age, dietaryenvironmental toxicant exposures. status, immune status, obesity, stress, socioeconomic status, sex, and intercurrent disease state, as well as current and past15 chemical exposures, must also be considered.FISH NUTRIENTS AND METHYLMERCURY: THE VIEWFROM THE LAB. M. Christopher Newland, Department of Despite these complexities, traditional risk assessmentPsychology, Auburn University, Auburn, Alabama, USA 36849 practices fail to capture this reality. Instead, they focus on Fish are the main source of methylmercury (MeHg) and exposures to single chemicals in isolation from other riskare important sources for nutrients such as selenium and n-3 factors. Animal studies often examine effects of a singlefatty polyunsturated acids (PUFAs). We have been studyingwhether dietary levels of these nutrients modify the expression chemical in young adult, mostly male rodents, ignoring, forof methylmercurys neurotoxicity in a rodent model of low-level instance, the potential importance of age, sex, and earlydevelopmental and adult-onset exposure. Female rats were environment. Epidemiological and clinical studies tend toexposed to low- to moderate levels of methylmercury (0, 0.5, or emphasize main effects of environmental exposures, stripping5.0 ppm in drinking water). In one study, the rats consumed a away interactions by allegedly controlling for confounders.diet that was rich or marginal in n-3 polyunsaturated fatty acids The result is a wide gulf between current models of diseases(PUFAs) and, in another, a diet that was rich or marginal inselenium content. Dietary exposure began 2-3 weeks before and disorders and the actual conditions under which theyMeHg exposure, which began 2-3 weeks before mating. In the emerge.developmental studies, MeHg exposures ended at parturitionbut the diets continued throughout life. Brain mercury content The vulnerability of an organism to disease results from ain neonates fell in the low-to moderate range. This exposure combination of environmental stressors and modifiers.NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 8Advances in our ability to interdict threats to neurobehavioral Theme and Rationale: During the past 30 years, research onintegrity require us to take into account xenobiotic exposures, mechanisms of developmental neurotoxicity has focusedlife stage, socio-economic factors, nutritional status, and primarily on the impact on children’s health. However,genetics. We already possess substantial evidence of the compelling evidence from animal models published within thehealth impact of single environmental factors. We lack the past few years has shown that developmental exposures todata required to model the interactions between these risk neurotoxicants and other environmental stressors may alsomodifiers and to translate them into risk policy. This session adversely affect adult health and cognitive function duringis designed to examine the multifaceted nature of neurotoxic aging. Much less recognized is the vulnerability of therisk. adolescent to toxic exposures prior to the onset of puberty. Both topics deserve focused attention as neuroscientistsQuestions for the Roundtable Discussants: attempt to understand gene-environment interactions in• We are supposed to be part of a science whose lifelong health. This session will focus on recent progress in framework was constructed by the mantra that The Dose understanding how exposure to neurotoxicants early in life Makes the Poison. Is it now time to bid farewell to the may affect neural function in the adolescent and adult. NOAEL as it is currently applied? (Schettler, Rice) Examples include the effects of manganese on the onset of puberty through actions on the hypothalamic-gonadal axis• We agree that exposures take place in a complex societal setting whose features help determine how the and the association of early exposures to lead and pesticides consequences of those exposures will be expressed. So on neurodegenerative disease in aging. In addition, the what does all this mean for what is labeled as translational hypothesis that molecular targets, such as chaperones and research? Does it mean viewing disease as an astute cytokines, are the link between developmental exposures to clinician might see it? Such a clinician would not neurotoxicants and late-onset neurodegenerative disease will undertake to diagnose and treat a patient without knowing be examined. The speakers will discuss data obtained from in the patient’s home environment, his or her workplace, vivo and in vitro models by means of numerous techniques, dietary practices, family situation, economic status, and including, imaging, neurochemical and hormonal analysis, other components of the individual’s life. Is our situation immunocytochemistry, electrophysiology, and behavioral parallel? (Cory-Slechta, C. Miller) testing. This session would be of interest to neuroscientists• Conversely, despite the immense volume of literature who are investigating disease etiologies, particularly given the demonstrating connections between environmental increased emphasis in recent years on environmental factors exposures and clinical diseases and disorders, they still in the etiology of Parkinson’s and Alzheimer’s Diseases. are accorded a relatively minor role in diagnosis, treatment, and, especially, prevention. How do we 16 promote awareness of these connections among health EFFECTS OF MANGANESE ON PUBERTAL professionals and health agencies? (E. Miller, Gilbert) DEVELOPMENT. WL Dees , JK Hiney, MD Pine, B Lee and VK Srivastava. Dept. of Integrative Biosciences, College of• Finally, how do we embed these new perspectives into our Veterinary Medicine, Texas A&M University, College Station, research, especially for those of us whose primary efforts Texas, USA. lie in the laboratory? Who can we convince to pay for Manganese (Mn) is an essential element that is them? (Crofton, Newland) considered important for normal growth and reproduction, but has been shown in adults to be detrimental to reproductiveSpeakers and Roundtable Discussants: function at elevated levels. Because Mn can cross the blood brain barrier and accumulate in the hypothalamus, andDeborah Cory-Slechta ~ University of Rochester because it has been suggested that infants and children areKevin Crofton ~ US Environmental Protection Agency potentially more sensitive to Mn than adults, we assessed theSteven Gilbert ~ Inst. for Neurotoxicology and Neurological Disorders effects of Mn exposure on puberty related events. We haveDonna Mergler ~ University of Quebec at Montreal shown using in vivo and in vitro studies that MnCl2 acts doseElise Miller ~ Learning and Developmental Disabilities Initiative dependently at the hypothalamic level to enhance secretion ofClaudia Miller ~ Univ. of Texas Health Science Center at San Antonio pubertal hormones and advance the timing of puberty in bothM. Christopher Newland ~ Auburn University female and male rats, with the females being more sensitive toDeborah Rice ~ Maine Center for Disease Control the metal. More recently, we used an in vitro approach toTed Schettler ~ Science and Environmental Health Network investigate the mechanism by which Mn induces hypothalamicBernard Weiss ~ University of Rochester luteinizing hormone releasing hormone (LHRH) in prepubertal female rats. Specifically, we assessed the effects of the metal on the guanylyl cyclase (GC)-cGMP-protein kinase G (PKG)- LHRH releasing pathway. These experiments demonstratedSymposium that the principal action of Mn within the prepubertalSESSION VI-A. FETAL BASIS OF ADOLESCENT AND hypothalamus is to activate GC directly and/or as a co-factorADULT DISEASES with available nitric oxide; hence, generating cGMP and resulting in LHRH release. Taken together, these results areSession Chair: Evelyn Tiffany-Castiglioni the first to show Mn can stimulate specific puberty relatedCo-Chair: Pamela J. Lein hormones and suggest it may facilitate the normal onset ofNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 9puberty. Additionally, we also suggest Mn may contribute to progressive loss of nigral DA neurons, striatal DA andprecocious puberty of an individual if exposed to low but behavioral deficits evaluated over the period from 2 to 22elevated levels too early in development. This is a potential months of age following postnatal exposure to PQ+MB.child health issue of particular relevance to young females, Additionally, the progressive decline in DA function is onlysince over 65% of female precocious puberty cases are gender specific, with males more affected than females. Ouridiopathic. This work was supported by NIH/NIEHS grant data indicates that this progressive decline in DA function mayESO-13143. be attributed to sustained elevation of oxidative stress and proteasomal dysfunction, both implicated in the pathogenesis17 of PD. This not only identifies yet another susceptibleEXPOSURE OF THE DEVELOPING BRAIN TO population but may also generate an animal model of PD thatPOLYCHLORINATED BIPHENYLS INFLUENCES is more predictive of the human condition.SUSCEPTIBILITY OF THE ADULT BRAIN TO STRESS. PJLein1, KH Kim2, R Berman2 and IN Pessah2. 1Center for 19Research on Occupational and Environmental Toxicology, LEAD EFFECTS ON MOLECULAR CHAPERONES: A LINKOregon Health & Science University, Portland, OR, U.S.A.; and TO NEURODEGENERATIVE DISEASES? E. Tiffany-2 Department of Molecular Biosciences, School of Veterinary Castiglioni, Y. Zheng, and Y. Qian. Texas A&M University,Medicine, University of California, Davis, CA, U.S.A. College Station TX, USA. Perinatal exposure to polychlorinated biphenyls (PCBs) Molecular chaperones are highly conserved proteins thatimpairs cognition and behavior in children. Emerging evidence assist the folding of nascent proteins into their correctsuggests that developmental PCB exposure may also alter the conformations. Chaperones are sensitive to environmentalresponse of the mature brain to stress and injury. This stress, and a deficiency in their function may underliepresentation will provide data demonstrating that gestational neurodegenerative diseases that exhibit protein accumulationand lactational exposure of rats to PCBs in the maternal diet or misfolding. In earlier work, we found that >90% of totalalters their susceptibility as adults to ischemic brain injury and cellular Pb extracted from Pb-exposed C6 glial cells isseizures. Specifically, developmental exposure to Aroclor 1254 associated with a protein fraction having molecular weights ofhas been shown to decrease infarct volume in animal models above 14 kD, that Pb specifically binds to the chaperoneof focal cerebral ischemia induced by middle cerebral artery glucose regulated protein 78 (GRP78) in silico, and that Pbocclusion. In contrast, developmental exposure to the non- induces GRP78 aggregation intracellularly in human CCF-coplanar PCB 95 enhances susceptibility to flurothyl-induced STTG1 astrocytoma cells in culture. One of the proteinsseizures. While the mechanisms underlying the effects of chaperoned by GRP78 in astrocytes is interleukin-6 (IL-6).developmental PCB exposure on stroke remain unclear, Therefore, Pb binding to GRP78 may plausibly impair itssensitization of ryanodine receptors appears to mediate, in chaperone function. IL-6 is a pleiotropic cytokine involved inpart, the enhanced seizure susceptibility. Considered in disease progression and inflammatory responses toaggregate, these data suggest that developmental PCB environmental insults. We found that Pb (1-50 µM) significantlyexposure is a risk factor for diverse adult onset diseases. reduced IL-6 secretion by astrocytes in primary culture. Image analysis of fusion fluorescence proteins constructed for GRP7818 and IL-6 in co-transfected cells showed that IL-6 and GRP78DEVELOPMENTAL BASIS FOR PARKINSON’S DISEASE. J were co-localized in live astrocytes. IL-6 did not bind to Pb in aKochar, BK Barlow, B Buckley, DA Cory-Slechta, EK Richfield, Pb affinity column, indicating that Pb interacted with GRP78M Thiruchelvam. University of Medicine and Dentistry of New alone. Furthermore, GRP78 depletion with double strand RNAJersey - Robert Wood Johnson Medical School & interference technique (dsRNAi) increased IL-6 retention inEnvironmental and Occupational Health Sciences Institute astrocytes, indicating that Pb indirectly blocked IL-6 secretion The Parkinson’s disease (PD) phenotype is a complex by targeting GRP78. These data support the hypothesis thatdisease trait resulting from the interaction of an unknown Pb binding to GRP78 decreases IL-6 secretion and thusnumber of risk factors including genetic background, life-long provide evidence for a significant chaperone deficiency in Pb-environmental exposures, diet, life-style, and aging. Increasing exposed astrocytes in culture.evidence implicates environmental risk factors as contributoryto the etiology of PD, a disorder resulting from the death of 20nigrostriatal dopaminergic (DA) neurons. Although typically DEVELOPMENTAL PESTICIDE EXPOSURE: A NEW RISKonset is later in life, it has been suggested that insults incurred FACTOR FOR ADHD? Jason R. Richardson1,2, Michele M.developmentally could underlie PD. Data from our laboratory Taylor1,2, Deborah A. Cory-Slechta3, and Stuart L. Shalat1.now supports this assertion, implicating a role for 1 Environmental and Occupational Health Sciences Institutedevelopmental neurotoxicant exposure in the induction of and Department of Environmental and Occupational Medicine,neurodegenerative disorders such as PD. PD is a progressive Robert Wood Johnson Medical School; 2Joint Graduateneurodegenerative disorder that is characterized by loss of the Program in Toxicology, Rutgers University and Robert Woodnigrostriatal dopaminergic system. Thus, an ideal animal model Johnson Medical School; 3Department of Environmentalof PD should recapitulate this essential characteristic of the Medicine, University of Rochester Medical School.disease phenotype. Combined exposure from postnatal day Attention-deficit hyperactivity disorder (ADHD) is a(PND) 7-19 to the pesticides paraquat (PQ) + maneb (MB) clinically heterogeneous disorder characterized by coreproduces permanent and selective nigrostriatal dopamine (DA) features of impulsivity, hyperactivity, and attention deficits thatneurotoxicity, and markedly enhances vulnerability to is estimated to affect 8-12% of school-aged children worldwide.subsequent pesticide exposures later in adulthood, with While ADHD is a complex disorder with significant geneticstrikingly greater losses of nigrostriatal DA neurons than contributions, no single gene has been linked to a significantoccurs in response to postnatal or adult only exposures. More percentage of cases, suggesting that environmental factors orrecent findings suggest that the model produces a significant gene-environment interactions may contribute to the etiology orNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 10clinical manifestation of ADHD. Recent data from this Roundtable / Open Forum Discussants:laboratory have demonstrated that mice exposed during David Dorman ~ North Carolina State Universitydevelopment to low levels of the pyrethroid pesticide Hassan El Fawal ~ Mercy Collegedeltamethrin exhibit symptoms similar to those observed in Jack Harkema ~ Michigan State Universitychildren with ADHD, including elevated dopamine transporterlevels, hyperactivity, and a paradoxical calming response to Kenneth Reuhl ~ Rutgers University and UMDNJpsychostimulants. Furthermore, mice developmentally exposed Conference Participantsto deltamethrin exhibit impulsive-like behaviors on a fixed ratiowaiting for reward paradigm that are reversed withmethylphenidate treatment. To determine whether our Platform Sessionlaboratory findings were supported by observations in the SESSION VII-A. DEVELOPMENTAL NEUROTOXICITY;human population, we carried out a cross-sectional study of NEUROPROTECTIONpyrethroid pesticides as a risk factor of ADHD on U.S. childrenbetween the ages of 6 and 15 years. Data for this analysis was Session Chair: DMG DeGrootobtained from the 1999-2002 rounds of the National Health Co-Chair: Nikolay Filipovand Nutrition Examination Survey (NHANES) using parent-reported diagnosis of ADHD and urinary levels of 3- 21phenoxybenzoic acid, a metabolite of pyrethroid pesticides ROLE OF OXIDATIVE STRESS AND FREE RADICALS INincluding deltamethrin, as a measure of exposure. Parents of METHAMPHETAMINE, MPTP OR FESO4 -INDUCEDchildren aged 6-15 with detectable levels of pyrethroid NEUROTOXICITY. Eden Tarekea, Helen Duhartb, Glennmetabolites in their urine were more than twice as likely to Newportb, Beverly Lynn-Cooka, Mohamed, Rahmanb and Syedreport that a doctor or health professional had told them their Alib. a Division of Nutrition and Personalized Medicine,child had ADHD. The parallels between mice developmentally NCTR/FDA, Jefferson, AR 72079. b Division ofexposed to deltamethrin and individuals with ADHD reinforce Neurotoxicology, NCTR/FDA, Jefferson, AR 72079.the epidemiological data suggesting that developmental The neurotoxicity associated to Methamphetaminepesticide exposure may be a risk factor for ADHD. Supported (METH) and MPTP is believed to be related to the oxidativeby: NIEHS Grants R21ES013828, R01ES015991, stress and production of free radicals. In this study weR01ES012712, T32ES007148, P30ES005022, and NICHD investigate the role of oxidative stress and free radicals thatContract #: 0258-325-4609. may be responsible to produced dopaminergic neurotoxicity. Male adult C57 mice (n = 4/group) were treated (ip) with saline, METH, MPTP and FeSO4. Animals were sacrificed 24 and 48Roundtable / Open Forum hrs after treatment and brain tissues were collected forSESSION VI-B. CELL DEATH IN THE NERVOUS SYSTEM: neurochemical analysis using HPLC-ECD. METH and MPTPFACTS AND ARTIFACTS produced significant depletion of DA levels, significant increased in the formation of 3-NT but had no effects in5HTSession Chair: David Dorman levels in CN, where as treatment with FeSO4 show no effectsCo-Chair: Jack Harkema on the dopamine and 3-NT levels where as 5-HT production was significantly depleted. These results suggest that theTheme and Rationale: This round table discussion session neurotoxicity of METH and MPTP leading to the depletion ofwill address a number of key issues concerning the delineation DA are probably mainly mediated through the superoxide and NO generation while the depletion in 5-HT observed followingof neuronal cell death by histopathology. Specifically, FeSO4 exposure suggest that the depletion of 5HT is mediatedroundtable discussants will examine key questions related to by hydroxyl radical formation. (Supported by FORMAS and USthis important area of research. It is hoped that attendees of FDA/NCTR).this session with experience in these issues will alsoparticipate in an open discussion of these important topics. 22 IMPORTANT ROLE FOR THE EARLY GRWTH RESPONSETopics include: FACTOR 1 (EGR1) IN THE POTENTIATION OF• What are the accepted morphological, biochemical, and/or MICROGLIAL PROINFLAMMATORY CYTOKINE other cellular changes that may serve as criteria for PRODUCTION BY MANGANESE EXPOSURE. N. M. Filipov, neuronal cell death? R. B. Pringle, S-R. Lee, P. L. Crittenden, and L. M. Pinchuk. Center for Environmental Health Sciences, Department of• What types of stains / staining techniques are most Basic Sciences, College of Vet. Medicine, Mississippi State appropriate and reliable for directly or indirectly (e.g., glial University, Mississippi State, MS, USA. responses) recognizing neuronal cell death in in vivo Manganese (Mn) neurotoxicity resembles in many aspects studies Parkinson’s disease (PD). In earlier studies, we have• What are known morphological artifacts that may interfere demonstrated that Mn potentiates the production of with evaluating tissues for neuronal cell death? lipopolysaccharide (LPS)-induced proinflammatory cytokines, such as IL-6 and TNF- by microglial cells in vitro and that the• How do these artifacts occur, and how can they be increased proinflammatory cytokine production is associated minimized or avoided by tissue processing or staining with persistent activation of the mitogen activated protein techniques? kinase (MAPK) p38 (p38). Moreover, the inhibition of p38 eliminates the potentiating effect of Mn on cytokine production. In these studies, using a focused MAPK real time PCR arrayNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 11(in vitro) and a custom real time PCR array that includes 24important inflammatory, oxidative stress, and neuronal function DEVELOPMENTAL PHENCYCLIDINE (PCP) OR KETAMINEgenes (in vivo), we sought to determine (i) which other TREATMENT INCREASES THE FREQUENCY OFmolecules on the MAPK pathway, besides p38, are associated ABNORMAL ACTIVITY IN SPRAGUE-DAWLEY RAT PUPS. 1,2 3 2 2 2with the potentiating effect of Mn on microglial cytokine SY Boctor , N Sadovova , X Zou , C Wang , SA Ferguson ; 1production, and (ii) whether the changes that we observe after Dept. of Interdisciplinary Biomedical Science, UAMS, Little 2in vitro exposure to Mn are also apparent after exposure to this Rock, AR, USA; Div. of Neurotoxicology, National Center for 3metal in vivo. Early growth response factor 1 (Egr1), an Toxicological Research/FDA, Jefferson, AR, USA; Toxicologicimmediate early gene that has been associated with Pathology Associates, Jefferson, AR, USAinflammation, was affected the most by the combined in vitro Developmental treatment with the N-methyl-D-aspartateexposure to Mn and LPS. Thus, after 1 and 4 h exposures, (NMDA) antagonists, PCP or ketamine, can trigger apoptoticEgr1 mRNA levels in microglial cells exposed to Mn and LPS neurodegeneration in nonhuman primates and rodents. Suchincreased several-fold more that the increases caused by the ketamine-induced apoptotic neurodegeneration may beexposure to LPS alone. In experiments where microglial cells clinically relevant since ketamine is commonly administered towere exposed to a p38 inhibitor prior to the exposure to Mn pediatric patients. In this study, male and female Sprague-and LPS, Egr1 mRNA levels were still markedly increased by Dawley rats were subcutaneously treated with: saline; 10the Mn and LPS exposure, suggesting that the Egr1 increase mg/kg PCP (1x/day) on postnatal days (PNDs) 7, 9 and 11; 20is either independent of p38, or, more likely, that it is upstream mg/kg ketamine (6 injections every 2 hrs on PND 7 only); or aof p38. While the exact relationship between Egr1 and p38 in similar regimen of ketamine and 250 mg/kg L-carnitine on PNDthe Mn-caused enhanced production of proinflammatory 7 with a single daily injection of 250 mg/kg L-carnitine on PNDscytokines by microglial cells remains to be elucidated, in the in 8-11. Each litter (n=48) was culled to 8 pups (4/sex). Pupsvivo experiments where mice exposed to Mn were challenged were randomly assigned to the 4 treatment groups (saline,with LPS, similar to our in vitro data, Egr1 expression was PCP, ketamine, ketamine + L-carnitine) with 1markedly increased by Mn+LPS. Supported by NIEHS pup/sex/treatment/litter. Post-injection, the pups were returnedES11654 and by a grant from LSBI/USDA. Keywords: to the home cage with their dam and observed 4 times for themanganese, inflammation, gene expression next 32 minutes. Observations were conducted by testers blind to experimental treatment. At each observation, the behavioral23 state of each pup was categorized as normal activity (active,FUNCTIONAL IMAGING OF DEVELOPMENTAL grooming), abnormal activity (paddling, paresis, wall climbing),NEUROTOXICITY. EFJ de Vries1, A van Waarde1, ATM or normal inactivity (quiet, nursing). On PND 7, ketamine-Willemsen1, A. Wesselius2, A. Wolterbeek2, DMG de Groot2. treated pups exhibited significantly higher levels of abnormal1 Dept. of Nuclear Medicine & Molecular Imaging, University activity than the control or ketamine + L-carnitine-treated rats. 2Medical Center Groningen, Groningen, the Netherlands. TNO The ketamine- and ketamine + L-carnitine-treated pups wereQuality of Life, Zeist, the Netherlands. not significantly different from the control pups or from each Developmental neurotoxicity studies are not only laborious other on PNDs 8-11. PCP-treated pups displayed significantlyand time-consuming, but also require the sacrifice of many higher levels of abnormal activity on PNDs 7, 9 and 11laboratory animals. As an alternative approach, we compared to the other treatment groups. Thus, levels ofinvestigated the potential of functional imaging by Positron abnormal activity were elevated only on treatment days andEmission Tomography (PET) using the labeled glucose only for ketamine or PCP treatment groups. There were no sex 18molecule [ F]FDG as the tracer. In this pilot study, female rats differences. Thus, developmental PCP or ketamine treatmentwere exposed to methylazoxymethanol (MAM, 5 mg/kg/d) caused an acute increase in abnormal activity in Sprague-during day 13-15 of pregnancy. Brain glucose metabolism (i.e. Dawley rat pups. (This work was supported through anbrain activity) of the male offspring (n=4) and of controls (n=4) interagency agreement (IAG no. 244-93-001) between thewas repetitively and non-invasively monitored by FDG PET National Institute of Environmental Health Sciences/NIH, andduring the first 2 months of development. At day 18 after birth, the National Center for Toxicological Research/FDA, in supportregional brain glucose consumption in the MAM treated group of the activities of the National Toxicology Program.)was 24-32% lower than in the control group (t-test, p<0.05). Keywords: development, ketamine, behavior.This difference in cerebral glucose consumption graduallyreduced over time, with a residual discrepancy of only 10% at 25day 61 (p>0.2). Between day 18 and 35, glucose metabolism PARAQUAT INDUCES OXIDATIVE STRESS, NEURONALsignificantly increased in frontal cortex, striatum and thalamus LOSS AND PARKINSONISM IN RATS:in the MAM treated group (+18-28%), whereas no significantly NEUROPROTECTION BY WATER-SOLUBLE COQ10. 1 1* 2changes were observed in the control group at all (<10%). Mallika Somayajulu-Nitu ; T. S. Sridhar , Anca Matei, ; VeraBetween day 35 and 61, glucose consumption only 2 2 3significantly increased in frontal cortex in both groups. These Parameswarann ; Jerome Cohen ; Jagdeep Sandhu ;Henryk 3 3 1results demonstrate that the first generation neurotoxic and Borowy-Borowski ; Marianna Sikorska and Siyaram Pandey .developmental effects of MAM can be detected by FDG PET, 1. Chemistry & Biochemistry, University of Windsor, Windsor,even when only a very small number of animals are used. ON, Canada. 2. Psychology, University of Windsor, Windsor,These observations warrant further evaluation of the potential ON, Canada. 3. Institute for Biological Sciences, Nationalrole of function imaging techniques in guidelines for Research Council of Canada, Ottawa, ON, Canada. *Currentdevelopmental neurotoxicity studies. Keywords: address: St John’s Medical College, Bangaluru. India.Developmental neurotoxicity, Positron Emission Tomography, Parkinson’s disease (PD) is a progressive neurologicalRegulatory testing and animal 3R’s. disorder caused by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and consequently their projections to other brain areas. Present studies correlateNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 12exposure to herbicide paraquat (PQ) to an increased incidence prenatally exposed fetuses exhibited drastic reductions in THirof PD. Increased oxidative stress resulting from mitochondrial cell counts when compared to controls (F5,32=31.69, P<0.001).dysfunction has been implicated upon exposure to paraquat. In conclusion, given the reduced process extension andThis assertion is derived from previous findings from our reduced cell counts observed in the LPS-SN/SAL-ST, LPS-laboratory that PQ causes oxidative stress and apoptosis in SN/LPS-ST and SN monoculture conditions, LPS may mediatedifferentiated human neuroblastoma cells. Particularly its effect by altering striatal derived trophic interactions with DAimportant is the fact that pre-treatment with water soluble neurons. With an alteration in DA neuron process extension,Coenzyme Q10 (WS-CoQ10) protects cells against PQ toxicity. access to target derived trophic factors would also be altered,The present study was designed to investigate the in vivo leading to increased apoptotic culling of DA neurons. The dataeffects of PQ and the neuroprotective properties of WS-CoQ10. presented here are consistent with our previous observationsWe have successfully established a model of PD in Long in vivo. Further studies will access whether factors associatedEvans hooded male rats by injecting them with PQ. Both with the SN or ST are responsible for the prenatal LPS effectsbehavioral and biochemical parameters were studied to assess on developing DA neurons. Supported by DOD and thethe toxicity caused by PQ as well as the neuroprotective Richard Nopar Foundation.effects of WS-CoQ10. Results indicated the evidence of motorbalance dysfunction as observed by a drastically reduced Symposiumtendency to turn around and walk backwards on the rotorod SESSION VII-B: THE OLFACTORY SYSTEM: AN OFTENfollowing PQ injections. Lipid peroxidation and GSH FORGOTTEN TARGETmeasurements revealed that PQ induced oxidative stress,while lowered ATP production corresponded to mitochondrial Session Chair: Dave Dormandysfunction. Immunohistochemistry illustrated the loss of DAneurons and PD-like symptoms in the injected rats. Theme and Rationale: The olfactory system is unique in thatConsiderably, neuroprotection and amelioration of these PD- it forms a direct interface between the air and the centrallike symptoms were observed in rats fed with WS-CoQ10. nervous system (CNS). There is growing evidence that metalsAltogether, we present a novel model of sporadic PD causedby PQ and present an encouraging possibility for the inhibition and other xenobiotics deposited within the nose can beof progressive neuronal loss by the unique formulation of WS- absorbed at this site and then undergo transport along theCoQ10. olfactory nerve, thus bypassing the blood-brain-barrier. One metal of special concern to be discussed in this symposium is26 manganese, a neurotoxic metal shown to be able to crossPRENATAL LPS EXPOSURE ALTERS THE FATE OFDEVELOPING DOPAMINE PROJECTIONS. Angela synapses in the olfactory bulb and migrate via secondaryJ.Monahan, Zaodung Ling, and Paul M. Carvey. Rush olfactory neurons to more distant nuclei of the brain. ThisUniverisity Chicago, IL 60605 symposium will also discuss inter-species differences in nasal Numerous neurotoxiology studies have approached non- anatomy that may play a role in olfactory uptake andfamilial Parkinson’s disease from the standpoint of adult transport and responses. The olfactory neuron is also anexposure. Data from our lab, however, implicates prenatal important target for many xenobiotics with both functionalexposure as being as important to consider as adult exposure. and structural changes of concern and will be addressed byWhen gravid female rats were exposed to bacterotoxinlipopolysaccaharide (LPS) offspring exhibited reduced two speakers during the symposium.numbers of dopamine (DA) neurons, less striatal DA, anincrease in DA activity and an increase in pro-inflammatory 27cytokine release. The mechanism through which LPS THE OLFACTORY SYSTEM: ANATOMY AND OVERVIEWproduces this effect is unknown to date. Using in vitro DC Dorman, College of Veterinary Medicine, North Carolinatechniques, we hypothesize that prenatal LPS exposure alters State University, Raleigh, NC, USAthe early stages of DA process development, leading to The olfactory system is unique in that it forms a directunderdevelopment and loss of DA neurons in striato-nigral co- interface between the air and the central nervous systemcultures. Female rats at E9.5 were injected with 100,000 (CNS). The anatomy and physiology of the nose andendotoxin units of LPS or 0.9% saline (SAL). At E14.5, the accompanying epithelium are related to its primary functionsmesencephalic region (substantia nigra, (SN)) and lateral including conditioning and movement of air, odorant andganglionic eminence (striatum (ST)) were dissected from each pheromone detection, nociception, and immunosurveillance.fetus and pooled per animal. Single cells were plated as SN- Primates have relatively simple nasal anatomy in regions of theST co-cultures according to the following treatment scheme: nose lined by olfactory mucosa. In contrast, the rat has a highlySAL-SN/SAL-ST; SAL-SN/LPS-ST; LPS-SN/SAL-ST; LPS- complex set of ethmoid turbinates, as do the mouse, dog, andSN/LPS-ST. The co-cultures were incubated for 7 days at rabbit. In spite of considerable differences in nasal anatomy37˚C undisturbed, followed by fixation and analysis of cells for and airflow, the basic histologic structure of the olfactoryanti-tyrosine hydroxylase immunoreactivity (THir). Supernatant mucosa is similar among most mammals. The olfactorywas also collected from each co-culture condition to assess epithelium, a patch of cells in the dorsal regions of the nasaltrophic activity on SN primary cultures. The results cavity, contains the cell bodies of the olfactory sensory cellsdemonstrated two overt effects. First, co-cultures established and their supporting sustentacular cells. Olfactory neuronsfrom fetuses prenatally exposed to LPS had less process have short apical dendrites and a long, thin unmyelinated axonextension morphologically. Second, there were fewer DA cells that passes into the underlying lamina propria to form olfactoryin the LPS-SN/LPS-ST condition compared to the SAL- nerve bundles. The bundles of sensory axons, supported bySN/SAL-ST and SAL-SN/LPS-ST conditions (F3,26=19.5, Schwann cells, pass through the lamina propria toward thep<0.001). In addition, SN monocultures established from LPS cribiform plate, through which they penetrate the cranial cavityNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 13to synapse with the dendrites of mitral cells in the olfactory atrophy of OE and the outer layer of the olfactory bulb in thebulb. The olfactory bulb is the synaptic terminal of the olfactory brain. This presentation will focus on the kinetics and plausiblenerve. Further projections of axons from the olfactory bulb to mechanisms of toxicant-induced injury and regeneration of OEan area of associated neocortex occur. Unlike the other and OSN in laboratory rodents after acute or subchronicsensory systems, olfactory impulses reach the cerebral cortex exposures. The presentation will also address the relevance ofwithout relay through the thalamus. these findings from animal toxicology studies to human health and suggestions for future studies.28OLFACTORY TRANSPORT OF XENOBIOTICS. MF Struve, 30CIIT at The Hamner Institutes for Health Sciences, Research ODOR PERCEPTION. P Dalton, Monell Chemical SensesTriangle Park, NC, USA Center, Philadelphia, PA 19104 USA The axonal transport of chemicals in the olfactory system The human olfactory system contains the only primaryrepresents a mechanism for the direct delivery of chemicals to sensory neurons which are directly exposed to the ambientthe central nervous system (CNS). A variety of metals environment and thus has a unique potential to be impacted byincluding iron, lead, cadmium, mercury, thallium, silver, gold, daily exposure to a variety of organic and inorganiczinc, and manganese have been demonstrated to undergo compounds. Although the olfactory system exhibits remarkableaxonal transport. Recent experiments have used an animal regenerative capacity, some types of exposures may exceedmodel in which one nostril is occluded, thus restricting olfactory this capacity and lead to sensitivity loss or other dysfunction.transport of manganese to the side of the rat brain ipsilateral to While not directly life-threatening, olfactory dysfunction canthe patent nostril. In these studies, direct delivery along the reduce the impact of many warning signals (e.g., smoke,olfactory route accounted for nearly all the 54Mn found in the spoiled food and gas leaks) and may affect nutritional status,olfactory bulb and tract of the rat brain following acute 54Mn eating satisfaction, and many other issues related to quality ofinhalation. Data from longer-term rat inhalation studies with the life. Among individuals occupationally-exposed to chemicals,phosphate, sulfate, or tetroxide forms of manganese further moreover, loss of olfaction may lead to greater risk fromsupport the role olfactory uptake plays in brain manganese exposure-related injuries due to the loss of an early warningdelivery. Like rats, monkeys also develop markedly elevated system for chemical exposure. This presentation will serve toolfactory bulb manganese concentrations following manganese clarify the importance and functionality of the olfactory systeminhalation. Collectively, these findings suggest that the in humans and to summarize our knowledge about the adverseolfactory route may indeed be a significant pathway by which effects associated with exposure to occupational andinhaled manganese gains direct access to certain structures environmental toxicants on olfactory function and how thosewithin the mammalian brain. Since olfactory delivery of effects are evaluated.manganese has been observed in multiple animal species weanticipate that this route of delivery could also occur inhumans. SESSION VIII: POSTER SESSION29TOXICOLOGIC PATHOLOGY OF OLFACTORY SENSORY SEE PAGES 26 - 40 for abstracts presented fromNEURONS. JR Harkema, Department of Pathobiology and Poster. Poster abstracts are numbered from P-58 toDiagnostic Investigation, Michigan State University, East P-104.Lansing, MI, USA The nose often serves as an efficient scrubbing tower The poster session is a highlight of this conference series andremoving inhaled xenobiotic agents that may be harmful to provides an ideal opportunity for one-on-one personalsensitive pulmonary tissues in the lower respiratory tact. exchange of research information and ideas in an informalHowever, olfactory epithelium (OE) lining the nasal airwaysmay also be a prime target for toxicity caused by direct setting with a unique consortium of participants expert inexposure to an airborne toxicant(s). Numerous chemical various aspects of the theme and neurotoxicology in general.agents have been identified as olfactory toxicants that cause The General Poster Session has proven to be a wonderfuldegeneration of OE with cell injury and death to olfactory venue for informal, in-depth discussion, collaborationsensory neurons (OSN). The purpose of this invited building, and mentoring of young scientists. It is an importantpresentation is to provide an overview of the toxicologic networking opportunity for students. Judging and selection ofpathology of OE and OSN in laboratory animals experimentallyexposed to inhaled toxicants. Like other surface epithelia lining Pre – and Post-Doctoral Student Awardees will be madethe nasal airways, the pathologic responses of the OE to toxic during the session.insult could include cellular degeneration, necrosis, atrophy,regenerative hyperplasia, metaplasia (squamous orrespiratory), or even neoplasia. The type of morphologic Plenary Sessionalteration to OE is dependent on a number of factors including SESSION IX. MODIFIERS OF DISEASE DEVELOPMENT INthe mechanism of action of the toxic agent, specific exposure PARKINSON’S DISEASE: ROLE OF ENVIRONMENTALconditions (e.g., concentration, duration), local tissue dose, TOXICANTScellular susceptibility, and time after exposure. Though manycytotoxic chemical insults (e.g., cigarette smoke) to the OE of Session Chair: Donato A. Di Monterodents induce necrosis (oncotic cell death) of OSN and Co-Chair: Gary Milleradjacent epithelial support cells, a few toxic compounds (e.g.,macrocyclic trichothecene mycotoxins) induce apoptosis(programmed cell death) of OSN alone with subsequentNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 14Theme and Rationale: Investigations into factors and dopaminergic nigrostriatal system. The decreased incidencemechanisms that predispose to Parkinson’s disease (PD) are of PD in smokers, which has been reported by a large numberdirectly relevant to our understanding of the pathogenesis of of epidemiological studies and is not a mere consequence ofthe disease and provide important clues for the development of decreased life expectancy, could be mediated at least in partpreventive strategies and neuroprotective intervention. through neuroprotection by nicotine. Data suggest that injuryEpidemiological and clinical evidence points to an caused by environmental toxicants may be alleviated by co-unequivocal risk factor for PD, i.e. aging, as well as putative exposure with nicotine.predisposing and protective conditions. The former include These important modifiers of PD pathogenesis will bepesticide and metal exposure, inflammation and polymorphism discussed in this symposium with particular emphasis on (i)of the alpha-synuclein promoter, whereas an example of translational information from clinical/epidemiologicalprotective factors is cigarette smoking. Modeling PD in studies to laboratory research and vice versa, and (ii) howexperimental animals though toxic or genetic manipulation environmental toxicants may act as risk factors for PD andprovides a tool for validating the role of specific risk factors interact with other PD modifiers in disease pathogenesis. Forand studying the mechanisms underlying their action. Results this reason, the lectures and discussions should be ofof these studies support a role of environmental toxicants in significant interest to a broad audience of neurotoxicologists,the pathogenesis of PD and have suggested, for example, that: neuroscientists, epidemiologists, clinicians and patientAging is not associated per se with progressive dopaminergic advocates.cell degeneration, but it causes nigrostriatal dysfunction andincreased susceptibility to injury by environmental toxicants. 31 INTERACTIONS BETWEEN α-SYNUCLEIN ANDNeuromelanin accumulation and loss of tyrosine hydroxylase ENVIRONMENTAL TOXICANTS IN THE PATHOGENESISimmunoreactivity are markers of these age-related changes OF PD. DA Di Monte. The Parkinson’s Institute, Sunnyvale,within nigral dopaminergic neurons. Furthermore, recent California, USAwork has revealed increasing levels of alpha-synuclein with Increased expression of the protein α-synuclein isage in the substantia nigra of humans and non-human associated with familial parkinsonism in humans with genomicprimates, suggesting an additional mechanism for age-related multiplication of the α-synuclein gene. In sporadic (i.e. non-enhanced susceptibility to neurodegenerative processes. familial) Parkinson’s disease (PD), non-genetic factors could account for enhanced α-synuclein levels and augmentedPesticides such as paraquat, maneb, dieldrin and rotenone vulnerability to α-synuclein pathology, including exposure toreproduce pathological aspects of PD in animal models. environmental toxicants and aging. Observations in the non-Interesting features of these models include synergistic human primate brain reveal that treatments with the herbicideinteractions, the formation of alpha-synuclein-positive paraquat or the parkinsonism-inducing agent MPTP cause adeposits and signs of oxidative damage. Neuronal injury by marked increase in α-synuclein at both the mRNA and proteinputative environmental toxicants triggers an up-regulation of levels. This toxicant-induced up-regulation is accompanied by post-translational modifications of the protein in the form ofalpha-synuclein. This effect provides an intriguing mechanism phosphorylated and nitrated α-synuclein that resembleby which genetic (polymorphism within the gene promoter) changes seen in PD. Increased protein expression is alsoand environmental (toxic exposures) factors may cooperate to followed by the accumulation of insoluble α-synucleininduce alpha-synuclein-related pathology (a hallmark of PD). aggregates that are particularly evident within dystrophicPolychlorinated biphenyls (PCBs) are widespread neurites and are therefore reminiscent of PD Lewy neurites.environmental and occupational neurotoxicants. Although the Another factor associated with enhanced α-synuclein levels is normal aging. Both α-synuclein mRNA and protein aremajority of PCB research has dealt with the consequences of significantly elevated in the brain of old humans as well as olddevelopmental exposure, a growing body of literature has non-human primates. Interestingly, this finding contrasts withshown that the adult CNS is also a target. PCBs reduce: (i) the observations in rodents in which α-synuclein levels declinenumber of tyrosine hydroxylase positive neurons in the rather than increase with age. Taken together, evidencesubstantia nigra; (ii) dopamine (DA) concentrations in basal indicates that α-synuclein may be a critical target for PD-ganglia and (ii) in common with some pesticides, both relevant environmental toxicants and that aging may act as a risk modifier by enhancing α-synuclein expression in thevesicular monoamine and dopamine transporter function. The primate brain.putative role of PCBs as an etiologic factor in Parkinson’sDisease warrants further investigation. 32 A pre-existing inflammatory process and, in particular, ENVIRONMENTAL RISK FACTORS FOR PARKINSON’Smicroglial activation can dramatically enhance the DISEASE (PD) IDENTIFIED THROUGH EPIDEMIOLOGICALsusceptibility of dopaminergic cells to toxic injury. This STUDIES. CM Tanner, Director of Clinical Research, The“priming” effect could be mediated by oxidative reactions Parkinson’s Institute, Sunnyvale, CA, USA Epidemiological studies have identified many factorscatalyzed by enzymes such as NADPH-oxidase and inducible associated with Parkinson’s disease (PD) risk. Increasing agenitric oxide synthase. Early-in-life conditions, such as and male gender are the most frequently observed nongeneticincreased neonatal iron intake, can have long-term risk factors for PD. Many other risk factors have beenconsequences and lead to neurodegenerative changes in aged described inconsistently. These include certain occupations,animals. These changes appear to selectively affect the pesticide exposure, head injury and dietary factors. Lower riskNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 15of PD has also been associated with many factors, includingtobacco use, especially cigarette smoking, drinking coffee or 34tea and nonsteroidal anti-inflammatory drug use. Family CYCLODIENE INSECTICIDES AND PARKINSON’Shistory of PD is associated with increased risk, but purely DISEASE: EVIDENCE FROM MICE AND MEN. Gary W.genetic causes of PD likely constitute no more than 10% in Miller, Jaime M. Hatcher, Marla Gearing, Allan I. Levey, andmost populations. Twin studies, including a recent large Kurt D. Pennell. Center for Neurodegenerative Disease,prospective follow-up of twin pairs discordant for PD, do not Emory Universityfind greater concordance for PD in monozygotic twins with The pathogenic processes in Parkinson’s disease (PD)typical age at onset, suggesting that environmental occur over several decades ultimately leading to the loss ofdeterminants are of primary importance in typical-onset PD. dopamine neurons in the substantia nigra pars compacta.However, in twins with onset before age 50, concordance is Epidemiological studies support an association betweengreater in monozygotic twins, supporting a genetic cause in pesticide exposure and PD but have been unable to identifythis small young-age-at-onset group. The majority of specific compounds or classes associated with the disease.parkinsonism in the community most likely has complex Our laboratory has hypothesized that the compounds mostdeterminants, involving one or more environmental and/or one likely to be associated with PD are lipophilic compounds thator more genetic factors. Investigation of the pathophysiologic persist in the environment and bioaccumulate in brain tissue.mechanisms of the toxicants and genes known to cause To test this hypothesis we performed GC/MS analysis on theparkinsonism can provide insight into other likely candidates, brains of nearly 100 patients in the Emory University Brainalone or in combination. Endowment Bank, including controls and those with PD and Alzheimer’s disease. Our results show that there is a33 significant association between the concentration of cycldieneGENDER DIFFERENCES IN PCB-INDUCED CHANGES IN insecticides and the neuropathological diagnosis of PD.CENTRAL DOPAMINE TRANSPORTERS: RELEVANCE TO Furthermore, we have identified two plausible mechanisms by 1 2PARKINSON’S DISEASE. RF Seegal , SA Factor , EF which this class of compounds may contribute to theFitzgerald , RF Haase , DS Higgins , EA Hills , KL Marek6 and 3 4 5 3 development of PD, namely, increased expression of alpha- 5 1ES Molho . Wadsworth Center, New York State Dept. of synuclein and altered sequestration of dopamine. IncreasedHealth, Albany, NY; 2Dept. of Neurology, Emory University alpha-synuclein expression via gene duplication or triplication 3School of Medicine, Atlanta, GA; Dept. of Epidemiology and has been implicated in human cases of PD and we haveBiostatistics, School of Public Health, University at Albany, recently shown that reduced vesicular storage of dopamineRensselaer, NY; 4Dept. of Counseling Psychology, University causes progressive nigrostriatal dopamine neuronat Albany, Albany, NY; 5Neurology Dept., Neurosciences degeneration in mice. These data suggest that cyclodiene 6Institute, Albany Medical Center, Albany, NY; Institute for insecticides should be considered suspects in the continuedNeurodegenerative Disorders, New Haven, CT, USA mystery of environmental causation of Parkinson’s disease. Polychlorinated biphenyls (PCBs) are widespreadenvironmental and occupational neurotoxicants shown to 35reduce dopamine (DA) concentrations and the number of INFLAMMATION-MEDIATED DEGENERATION OFtyrosine hydroxylase positive neurons in the substantia nigra DOPAMINERGIC NEURONS: MECHANISMS,(SN) of both adult laboratory rodents and non-human primates. INTERVENTIONS AND RELEVANCE TO PARKINSON’STo determine whether PCB-induced changes in central DA are DISEASE. Jau-Shyong Hong, Ph.D. Neuropharmacologyalso seen in humans, we measured the density of dopamine Section, Lab. of Pharmacology & Chemistry, NIEHS/NIH,transporters (DAT) in the basal ganglia of male and female Research Triangle Park, NC USAformer capacitor workers using β-CIT imaging. The mean age Microglia, the predominant cell type in the central nervousof the workers at time of examination was 63.5 years. Women system expressing the major histocompatibility complex classconstituted approximately 44% of the population and were II molecule, play an important role in immune surveillance.exclusively postmenopausal. Although mean current serum However, during in certain pathological conditions, over-PCB concentrations were similar between men and women activated and dys-regulated microglia secrete neurotoxic(mean for men = 7.9 ppb; mean for women = 6.7 ppb; F=0.94, substances, such as proinflammatory cytokines or freep=0.336), a significant negative relationship was observed radicals, which kill neurons and have been proposed to be thebetween serum PCB concentrations and β-CIT measures of major causes of neurodegenerative diseases, such as 2DAT density for women (r =0.18, p<0.01, N=37), but not for Parkinsons disease. Because neurodegeneration is a common 2men (r =0.01, p=0.46, N=41). Control for potential confounders sequela for patients exposed to a variety of environment-including age, body mass index, smoking, alcohol related neurotoxins, information generated from this line ofconsumption, caffeine consumption, bone lead body burden research should further our understanding of the mechanismsand the use of cardiovascular medicines did not alter the of action for neurotoxicants. In this presentation, I will discussabove relationship. These results suggest that reductions in the following two aspects:circulating ovarian hormones following menopause may 1. Role of microglia in inflammation–relatedincrease the risk for reduction in central DA following exposure neurodegeneration. Using both primary midbrain neuron/gliato PCBs and similar neurotoxicants. Our findings gain further co-cultures and in vivo study, we have developed ansupport when one considers the recent findings of Steenland et inflammation-induced rodent Parkinson’s disease model byal. (2006) who reported increased PD mortality only in highly employing different inflammagens such as endotoxin, LPS, β-exposed female former capacitor workers. In summary, these amyloid peptides, and the pesticide, rotenone. We havefindings highlight the potential importance that ovarian studied the molecular mechanisms underlying microglia-hormones play in altering basal ganglia DA following toxic mediated neurotoxicity through the investigation of pro-insult. Supported by U.S. Army grant # DAMD17-02-0173 to inflammatory factors released from microglia and how theseRFS. factors exert their toxic effects on neurons.NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 16 2. Development of potential therapeutic interventions in with activation of astrocytes and microglia, the latter beinginflammation-related diseases. Based on our understanding of resident antigen-presenting cells. In addition, both astrocytesthe microglia-mediated neurotxic effects in inflammation- and microglia have been shown to elaborate cytokines thatrelated neurodegeneration, effort has been made to develop contribute to neuroinflammation and the recruitment ofnovel anti-inflammmatory drugs, which have potential peripheral macrophages and lymphocytes, thus contributing totherapeutic use for Parkinson’s disease. These compounds are the potential generation of a humoral immune response. Somedifferent from the current available anti-inflammatory drugs in neuroantibodies, tested in in vitro cultures and preparations, ortheir mode of action and safe for long-term clinical usage. by passive transfer have proven to be pathogenic. Whether as epiphenomena and potential biomarkers of nervous systemPanel Discussion and Q&A: degeneration, or as potential contributors to disease processes, the literature suggests a role for humoral• How strong is the association between toxicant exposure neuroimmunity in nervous system insult of various etiologies. and PD risk? Key Words: neuroimmunity, antibodies, biomarkers.• Is there a concordance between epidemiological and experimental findings related to environmental toxicants 37 and other modifiers of PD development? JNK MEDIATES LACTACYSTIN-INDUCED DOPAMINE• How well do animal models reproduce the “multiple hits” NEURON DEGENERATION. Xuping LI, PhD1; Weidong Le, hypothesis of PD pathogenesis involving environmental MD, PhD1,2. 1Neurogenomic Lab, Institute of Health Science, toxicants? Shanghai Institutes for Biological Sciences, Chinese Academy 2• What are the most relevant modifiers of the effects of of Sciences, Shanghai 200025, China; Department of neurotoxicants in PD? Neurology, Baylor College of Medicine, Houston, TX 77030, USA• How does knowledge of PD modifiers influence our view Parkinson’s disease (PD) is characterized by the of disease prevention and treatment? progressive loss of dopamine (DA) neuron in the substantia nigra pars compacta (SNc), a major pathology with unclear mechanisms and without cures available. It has been proposedPlatform that dysfunction of ubiquitin proteasome system (UPS) playsSESSION X: ENVIRONMENTAL LINKS TO NEURO- an important role in the pathogenesis of PD, but theLOGICAL DISEASES (PARKINSON’S, ALZHEIMER’S) mechanisms underlying the UPS dysfunction-induced DA neuron degeneration are largely unknown. In the presentSession Chair: Anumantha Kanthasamy study, we demonstrated that proteasome inhibition inducedCo-Chair: Syed Imam phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, release of cytochrome c, activation of both caspase-9 and36 caspase-3 as well as the sequential apoptosis of DA neuronsHUMORAL NEUROIMMUNITY IN NEUROLOGICAL in vitro. These effects were diminished by the specific JNKDISORDERS AND NEUROTOXICITY: PARALLELS, inhibitor SP600125. Furthermore, application of lactacystin inMECHANISMS AND BIOMARKERS. A REVIEW OF THE vivo by microinjection in nigra also led to phosphorylation ofLITERARURE. HAN El-Fawal. Neurotoxicology Laboratory, JNK prior to the nigral DA neuronal loss, which was effectivelyMercy College, Dobbs Ferry, NY. blocked by chronic administration of SP600125 Several neurological disorders, including Alzheimer’s, intracerebroventricularly. These results indicate that the JNK isParkinson’s, Amyotrophic Lateral Sclerosis, spongiform involved in the proteasome inhibition-induced DA neuronencephalopathy and autism, not considered autoimmune, have degeneration via the caspase-3-mediated cell intrinsicbeen reported to present with detectable antibodies in serum apoptotic machinery, suggesting this kinase as potentialand/or cerebral spinal fluid (CSF) of affected individuals. This therapeutic target in prevention of nigral DA neuronhas also been mirrored in animal models of several disorders. degeneration. Key Words: Apoptosis, c-Jun N-terminal kinase,Autoantigens to which these antibodies react include Dopamine neurodegeneration, Lactacystin, Parkinson’scytoskeletal proteins [e.g., neurofilament (NF), tau and glial disease, Ubiquitin proteasome pathway.fibrillary acidic proteins (GFAP)], synaptic proteins (e.g., α-synuclein), enzymes (e.g., acetylcholinesterase) ion channels, 38receptors and myelin components [e.g., myelin basic protein NEUROTOXIC INSULTS MODULATE OXIDATIVE STRESS-(MBP)]. With an increased interest in the development of SENSITIVE PKCΔ GENE PROMOTER ACTIVITY INbiomarkers of chemically-induced neurotoxicity and in NEURONAL CELLS: IMPLICATIONS FOR GENE-environmental agents as risk factors for neurological disorders, ENVIRONMENT INTERACTIONS INresearch in the detection of neuroantibodies in human and NEURODEGENERATION. Anumantha Kanthasamy, Huajunexperimental exposures has been ongoing for the last decade. Jin, Vellareddy Anantharam, and Arthi Kanthasamy.Antibodies to several neural (e.g., NF, GFAP and MBP) Department of Biomedical Sciences, Iowa Center for Advancedantigens have been detected in human and animal exposures Neurotoxicology, Iowa State University, Ames, IA 50011. e-to inorganic (e.g., lead, mercury and cadmium) and organic mail: akanthas@iastate.edu(methylmercury and trimethyltin) heavy metals, Recently, we demonstrated that protein kinase Cδ (PKCδ)organophosphorus compounds (metamidophos, chlorpyriphos is an oxidative stress-sensitive kinase that plays a causal roleand phenyl-saligenin-phosphate) and solvents (benzene and in apoptotic cell death in Parkinson’s disease models (Kaul ettoluene). An emerging mechanism contributing to neurological al., 2004, 2005; Yang et al., 2004; Kanthasamy et al., 2006).diseases and neurotoxicity that may result in autoantigen The objective of this study was to determine whetherpresentation and neuroantibody generation is oxidative stress environmental neurotoxicant exposure alters the regulatory mechanisms of PKCδ gene expression in neuronal cells. WeNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 17cloned the mouse PKCδ promoter and performed deletion scores correlated positively with their aluminum dose (rs =analysis to identify key regulatory elements underlying PKCδ 0.58, p> 0.01) and serum aluminum levels (rs = 0.41, p< 0.05).expression. Using various deletion PKCδ promoter-luciferase We propose that the propensity for rats to develop this slowly-constructs, we identified a core promoter region, nucleotide - progressing age-associated cognitive deterioration relates in a148 to +1 relative to transcription start site, required for dose-dependent manner to the amounts of aluminum theysufficient PKCδ transcription in NIE115, MN9D, and N-2a cells. consume and absorb throughout life. Interestingly, in theseComparative analysis of the core promoter resulted in rats, the lowest observed adverse effect level for aluminumidentification of some key evolutionarily conserved regulatory (0.49 mg/kg bw/day) was equivalent to less than half theelements including two potential candidate sites for NF-κB (κB tolerable aluminum intake level set for humans by the W.H.O.I, κB II). Subsequent functional studies using site-directed Keywords: aluminum, Alzheimer’s disease, animal model.mutation analysis revealed that κB I, but not κB II, is necessaryfor PKCδ expression. In addition, we investigated the possible 40involvement of DNA methylation in regulating PKCδ NEUROPROTECTIVE EFFECTS OF CANNABINOIDS INexpression. Using the bioinformatics method, we found a MPTP-TREATED MICE: ROLE OF CB1 AND CB2 1 1 1,2putative CpG island (+39 to +400 relative to transcription start RECEPTORS. D.A. Price , W. Koek , J.L. Roberts and A. 1site) that overlaps with the mouse PKCδ promoter. In vitro Giuffrida . 1. Dept. Pharmacol., 2. Audie L. Murphy VA Med.methylation studies further confirmed that PKCδ transcription is Ctr., UTSCSA, San Antonio, TX, USAindeed affected by methylation of the putative CpG island. By Parkinson’s disease (PD) is characterized by progressivemethylation-specific PCR, we found that the PKCδ promoter is loss of dopamine (DA) neurons residing in the substantia nigrapartially methylated in NIE115, MN9D, and N-2a cells, pars compacta (SNc). Current therapies aiming at alleviatingconsistent with the fact that PKCδ is expressed at low levels in PD symptoms fail to halt the underlying neurodegenerativethese cells as compared to other cell types. Furthermore, we process; therefore, there is an urgent need for neuroprotectiveexamined whether environmental neurotoxicant exposure agents that can be administered early in the course of thealters the PKCδ expression. Since manganese (Mn) exposure disease to stop or reverse PD progression.is associated with a Parkinsonian-like neurotoxic condition and Infiltration of microglia, the macrophage-like cells thatinduces NF-κB activation, we tested the effect of Mn exposure provide immune-surveillance in the brain, and the inflammatoryin mouse neuroblastoma (NIE115) cells. Western blot and response triggered by their activation, are increasinglyqRT-PCR analysis showed Mn exposure resulted in a robust recognized as prominent neuropathological features of PD.induction of PKCδ expression in a time-dependent manner. This scenario can be mimicked in animals using 1-methyl-4-PKCδ promoter-luciferase reporter and chromatin phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin thatimmunoprecipitation assays revealed that Mn exposure causes loss of midbrain DA neurons and microglia infiltration.increased both full-length and core promoter-luciferase activity, Cannabinoid drugs have anti-inflammatory properties and haveand increased NF-κB recruitment to PKCδ promoter, been extensively studied in different models ofrespectively. Collectively, these data suggest that both NF-κB neurodegeneration. In this study, we investigated theand promoter methylation play roles in the regulation of mouse protective effects of the non-selective cannabinoid receptorPKCδ gene expression, and that environmental neurotoxicant agonist WIN 55,212-2 (WIN) in mice treated with MPTP (4x 20exposure can alter expression of this important oxidative mg/kg, i.p.) using unbiased stereology and behavioralstress-sensitive kinase. (supported by NIH grants ES10586 measures. WIN (4 mg/kg, i.p.) protected against loss ofand NS 38644). Keywords: tyrosine hydroxylase positive (TH+) neurons from the SNc when administered over a 5-day period, beginning 24 hr after39 the last injection of MPTP. This effect was accompanied by aHUMAN RANGE DIETARY ALUMINUM EQUIVALENTS significant reduction of MPTP-induced motor deficits, asCAUSE COGNITIVE DETERIORATION IN AGED RATS. JR assessed by behavioral measures that are sensitive to nigro-Walton. Australian Institute for Biomedical Research, Sydney striatal degeneration (inverted screen test and gait dynamics).NSW, Australia Interestingly, CB1 knockout mice were more resistant to MPTP- The ubiquitous use of aluminum salts in modern life and induced DA cell loss than littermate controls, suggesting that:their effects on humans and the environment remain to be 1) WIN may exert its neuroprotective actions via targets otherquantified. A prospective human study on dietary aluminum than CB1 receptors and 2) stimulation of CB1 receptors mayover decades would be valuable but impracticable. Thus, we mask the “full” neuroprotective potential of WIN. On the otherused rapidly-aging rodents to mimic this exposure. From age hand, MPTP treatment promoted microglia infiltration in the12 months onwards, three groups of memory-trained rats were ventral midbrain and up-regulated CB2 receptors, which co-chronically given aluminum at equivalent levels ingested by localized with the microglia marker MAC-1. Sub-chronichumans living in contemporary urban society (0.36, 0.49, and treatment with WIN (4 mg/kg, i.p.) or with the selective CB21.68 mg aluminum/kg bodyweight/day). The rats were agonist JWH 015 (JWH; 4 mg/kg, i.p., 1 injection per day for 5memory-tested weekly during middle age (12-23 months) and days) reduced MPTP-induced elevation of MAC-1 in ventralold age (≥24 months) until their terminal condition became midbrain back to control levels, an effect that was reversed byapparent, their lifespans averaging 30 months. Their over-all the CB2 antagonist JTE 907 (JTE; 4 mg/kg, i.p.). In contrast,health was monitored with clinical tests. Of the rats that WIN did not affect the expression of the astrocyte markersurvived to at least 28 months, 0/10 (0%) on the lowest GFAP. Taken together our data indicate that CB2 receptorsaluminum dose, 2/10 (20%) on the intermediate dose, and 7/10 may represent a new pharmacological target to slow down the(70%) on the highest dose attained significantly lower mean neurodegenerative process observed in PD. NIH NS 050401-memory scores in old age than in middle age and displayed 03 (AG). American Parkinson Disease Association (AG).behaviours associated with dementia. Cognitively-damagedrats had significantly higher serum aluminum levels than thosethat remained cognitively-intact. Decline in the rats’ memoryNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 1841 controls. Red cell iron and copper were inversely related.CHEMO BRAIN: A TRANSLATIONAL CHALLENGE FOR The striking finding is that these changes were significantlyNEUROTOXICOLOGY. B Weiss. Department of associated with vasculopathic alleles of MTHFREnvironmental Medicine, University of Rochester School of (VV>AV>>AA), AAT (SS,SZ>MS,MZ<MM), APOE (tendencyMedicine and Dentistry, Rochester, New York, USA. E44>E34, E33). This supports the possible use of these Many cancer patients treated with adjuvant chemotherapy markers for disease activity and therapeutic effect. We willor radiation complain of diminished neurobehavioral function, a present cases that suggest that the elevation of red cell ironphenomenon that has become known as Chemo Brain. The and depression of copper are pathological and may respond toleading complaint is impaired cognitive ability. Patients report anti-oxidant therapies. These abnormalities may representmemory loss, learning problems, response slowing, and other an indicator of membrane and vascular pathology.difficulties. Only lately, however, have such complaintsreceived scrutiny with recognized neuropsychological andneurobehavioral assessment tools. Scientific investigations Symposiumhave established the validity of these patient observations. SESSION XI: AN ECOSYSTEM APPROACH TOLittle is known about their structural and functional correlates in EXPOSURE TO NEUROTOXIC SUBSTANCES IN LATINthe brain, however, except for the neuropathology induced by AMERICAhigh doses. Little is known, as well, of the extent of subtlemotor and sensory dysfunction arising from cancer therapy. Session Chair: Donna MerglerThe enormous gaps in our comprehension of the scope of Co-Chair: Maryse BouchardChemo Brain (which should not be confined to its cognitiveaspects) presents the discipline of neurotoxicology with a set of Theme and Rationale: Although exposure to neurotoxicchallenges it has largely ignored up to now, a task that directlyaddresses a major human disease, and an opportunity to exposure has been extensively studied in occupational andenlarge its scope and influence. The list of questions posed by environmental settings in industrialized societies, fewerChemo Brain embraces nearly every aspect of studies have been carried out in lesser industrialized countriesneurotoxicology. How do we design appropriate animal models where exposure profiles may be very different with respect toof Chemo Brain so that we can study it more effectively and, as source, pathways and effects, modulated by differentwell, provide a means for predicting neurotoxicity? What are biogeophysical, social, cultural and nutritional realities.the underlying cellular and molecular processes that underliesuch effects? What other factors need to be considered; for Using an ecosystem approach to human health, whichexample, age, sex, and hormonal status? To what degree does integrates research in the natural, social and health sciences,Chemo Brain foreshadow neurodegenerative disorders such with a view to proposing prevention intervention strategies,as Alzheimer’s disease? What kind of countermeasures, such several studies are currently being carried out in Latinas cognitive enrichment, stimulant medication, and physical America on neurotoxic agents and their effects on adults andactivity might prove useful in undertaking rehabilitation? This children.presentation reviews our current understanding of ChemoBrain, its array of features, its possible underlying 43mechanisms, potential countermeasures, and the opportunities NEUROTOXIC EFFECTS OF MERCURY EXPOSURE IN THEit presents to neurotoxicology. (Preparation supported in part BRAZILIAN AMAZON: AN ECOSYSTEM APPROACH TOby grants ES015509 and ES 013247.) Keywords: EXPOSURE REDUCTION AND EFFECTS. Donna Mergler,chemotherapy, cancer, cognitive function. CINBIOSE, University of Quebec in Montreal, CP 8888, Succ Centreville, Montréal, Québec, Canada42 Mercury (Hg) exposure has been well documented in fish-VASCULAR AND MEMBRANE PATHOLOGY IN eating populations in the Brazilian Amazon. ContaminationNEURODEGENERATIVE DISORDERS: RED CELLS AS arises from several sources, notably gold mining, hydro-electricTARGET AND BIOMARKER. Donald E. Schmechel, MD, reservoirs and widespread deforestation which results in soilAndy Ghio, MD, and Claude Piantadosi, MD. Falls Neurology erosion and lixiviation releasing Hg into the waterways. Hg inand Memory Center, Caldwell Memorial Hospital, Granite falls, the aquatic system is transformed into methylmercury, which isNC (DS); Department of Medicine, Duke University Medical then bioaccumulated and biomagnified through the trophicCenter, Durham, NC (DS, AG, CP); Human Health Effects chain, resulting in several-fold higher levels of Hg in carnivoresLaboratory, EPA, Chapel Hill, NC (AG). compared to non-carnivores. An initial study of neurotoxic Genes influencing cognitive impairment in older people effects of Hg exposure, carried out in 1995 among 98 adultsinclude apolipoprotein E (APOE), alpha-1-antitrypsin (AAT), living in a community on the Tapajós River, a major tributary ofand methylene tetrahydrofolate reductase (MTHFR). All three the Amazon, showed dose-related decreases in motorgenes are expressed in liver and influence inflammatory functions requiring coordination (Santa Ana test, Branchesresponse. One common feature of pathology in many Alternate Movement Task (BAMT)) and visual functions (nearneurodegenerative conditions is vascular pathology. We visual contrast sensitivity, color vision, peripheral vision). Aexamined peripheral markers of inflammation and acute phase village campaign, which sought to maintain fish consumptionresponse in controls and persons presenting with a variety of while reducing mercury exposure, adopted the slogan “Eatcognitive syndromes. Our new approach was to examine red more fish that don’t eat over fish”. In 2000, 47 persons werecells as a target, looking at washed red cell membranes for re-tested. Fish consumption frequency had not changed, butcopper, iron and zinc levels and red cell lysate for Cu,Zn-SOD fish species consumption patterns had changed over time fromenzyme and protein levels, and for copper chaperonin protein proportionally more carnivores to proportionally more non-levels. Our findings show that persons with MCI/dementia had carnivores; hair Hg levels diminished by almost 40%. Motorsignificantly higher red cell iron and lower red cell copper thanNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 19functions had improved, but visual functions continued to Neurocirugía Manuel Velasco Suárez de México, Mexico. 4diminish in relation to previous Hg exposure. Selenium levels Department of Occupational and Environmental Medicine,were found to be relatively high. These findings lead us to Lund University, Sweden. 5 CINBIOSE, Université du Québec 6carry out a large-scale study with 450 persons from 12 villages; à Montréal, Québec, Canada. Institute for Risk Assessmentblood and hair Hg were assessed in 2003 and 2004 and in Sciences, Utrecht University, The Netherlands.2006, we assessed motor functions (Santa Ana, Grip Strength, The objective was to study childrens environmentalGrooved Pegboard, BAMT), two-point discrimination and pesticide exposure and its neurological effects within a socialseveral visual functions, including an ocular examination. context. The study population consisted of two bananaBioindicators of Hg exposure (plasma and blood total Hg, hair communities with extensive pesticide use, and twoHg), plasma and blood selenium (Se) and blood lead (Pb) were communities without pesticide use (organic farmers). Focusanalyzed. Preliminary findings suggest that current Hg groups in parents, semi-structured interviews in key-actors, asexposure may be a better predictor of motor functions than well as informal interviews and observations were held to studypast exposure, while previous exposure is a better predictor for risk perceptions and qualitative exposure. Quantitativecertain visual functions. Selenium appears to affect some exposures and neurological effects were studied in 103visual functions. The findings of this study will serve to improve exposed and 70 non-exposed 6 to 9 year-old children, byour understanding of the effects of Hg in adults and factors that measuring pesticide metabolites in urine and by applying ainfluence these changes. neurological test-battery including: cognitive, motor and sensorial tests, inventories on psycho-behavioral disorders44 (ChIPS, Connor’s), and a medical examination. AdditionalAN ECOSYSTEM APPROACH TO NEURO- exposure sampling: skin exposure, air, dust, soil, surface andPSYCHOLOGICAL EFFECTS OF MANGANESE EXPOSURE drinking water, and soil sampling, was performed in 14ON CHILDREN LIVING IN COMMUNITIES NEAR TO children. Perceptions of pesticide risks differed between 1PROCESSING PLANTS IN MEXICO. Horacio Riojas , Yaneth communities, and between fathers and mothers, but principally 2 2 2Rodriguez , David Hernández , Rodolfo Solis , Sergio Montes, between working parents (emphasizing utility) and house- 1 1Sandra Rodriguez-Dozal . National Institute of Public Health . wives (emphasizing risks). Pesticide exposure pathways andNational Institute of Neurology and Neurosurgery Manuel patterns were different for children from communities where 2Velasco Suárez . bananas are produced on a large (constant exposure due to Mexico has one of the largest deposits of manganese living very nearby the plantations) versus small scale (children(Mn) in the world. Around 200,000 inhabitants live in this zone. join their parents when going to plantations, resulting inMn deposits have been exploited for the past 60 years. A incidentally high exposures. Preliminary analysis showed lowprevious study showed significant effects of Mn exposure on levels of Chlorpyrifos in hand- and foot wash samples: handsneuromotor performance in the adult exposed population. The (n 12), median 19 ng/both hands, range 0-67 ng/both hands;present project uses an ecosystem health approach that feet (n 12): median 30 ng/both feet, range 0 – 108 ng/both feet.includes community participation, environmental pathway ETU (Ethylene-Thiourea), the principal metabolite ofcharacterization and exposure and neuropsychological dithiocarbamates, was detected in urine samples (n 8), rangeoutcomes analysis. To evaluate the association between Mn 0.1 – 12 ng/ml urine. Preliminary results from the Conner’sexposure and neuropsychological effects in children, we parents rating scale showed that exposed children had moreselected 100 boys and girls from the elementary schools (age disruptive behavior disorders than non-exposed children. This8 to 11 years old); 100 more children living outside the Mn was seen in particular for boys (worse on all the four scales,basin, with similar age and socioeconomic conditions, were Mann-Whitney p<0.05), whereas for girls only differences wereselected as the non-exposed control group. Biomarkers of Mn seen for hyperactivity and attention deficit (Mann-Whitney,exposure were assessed (total blood Mn and hair Mn). A p<0.05). We conclude that children living nearby bananabattery to assess cognitive, motor and neuropsychiatric plantations are exposed to pesticides and have more disruptivedisorders was applied. Mean blood Mn concentrations were behavior disorders than non-exposed children, especially boys.significantly higher in exposed children compared to non Boys may be higher exposed to pesticides and/or be moreexposed (10.04 µg/L versus 8.3 µg/L p<0.05). Mean air Mn vulnerable for its toxic effects. The ecosystem health approachconcentration in the exposed population was 14.4 µg/g. helps to gain insight regarding the social, cultural, and gender(Significantly higher than those found in previous studies). aspects of exposure and health effects, which is essentialPreliminary analyses of neuropsychological test results will be when studying environmental etiologies of neurologicalpresented. The ecosystem approach has allowed us to well- disorders.characterize exposure and understand the social situation thatinfluences these communities relations with exposure. 46Keywords: manganese, children, neuropsychological battery. OCCPATIONAL EXPOSURE TO PESTICIDES DURING PREGNANCY AND NEUROBEHAVIORAL DEVELOPMENT45 IN INFANTS AND TODDLERS IN A FLOWER GROWING 1AN ECOSYSTEM APPROACH TO ENVIRONMENTAL REGION OF ECUADOR. Alexis J. Handal , Siobán D. 1 2 3PESTICIDE EXPOSURE AND NEUROLOGICAL EFFECTS Harlow , Jaime Breilh , Betsy Lozoff . 1 Department ofIN CHILDREN. B van Wendel de Joode1, A Mora1, M Epidemiology, University of Michigan School of Public Health,Gutiérrez1, L Córdoba1, D Villagra1, D Barraza,1,2 D Ann Arbor, MI. 2 Health Research and Advisory CenterHernández,3 C Lindh,4 M Morera,1 J García,1 L Sosa,5 M (CEAS), Quito, Ecuador. 3 Center for Human Growth and 1 1 6 5 1Rojas, E de la Cruz , H Kromhout, D Mergler, C Ruepert . Development and Department of Pediatrics and1 Central American Institute for Studies on Toxic Substances, Communicable Diseases, University of Michigan, Ann Arbor,Universidad Nacional, Heredia, Costa Rica. 2 Technology and MIAgrarian Development Group, Wageningen University, The Few studies have examined the effects of in utero 3Netherlands. Instituto de Investigación Neurología y exposure to organophosphate and carbamate pesticides onNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 20neurobehavioral development in infants and young children. by a movement disorder specialist who identified 1 probableThis preliminary study considers the potential effects of and 2 possible Parkinson disease cases, using the UPDRSmaternal occupation within the cut-flower industry during exam, different from the self-reported previously diagnosed PDpregnancy on neurobehavioral development in Ecuadorian cases. In addition, 13 confirmed or probable cases of essentialchildren. Data were collected over six months in the rural tremor were identified. Based on small numbers, our data of athighland region of Cayambe, Ecuador (2003-2004). Children least 3 but possibly more than 6 cases per 639 adults suggestages 3-23 months residing in three communities were a prevalence of PD between 450 and 900/100,000, withadministered the Ages and Stages Questionnaire and specific perhaps half previously undiagnosed. These figures are withindevelopmental tests targeting prehension and visual skills. the range reported from other countries. We conclude that itInformation was gathered on maternal health and work would be possible to extend the techniques developed in thecharacteristics, the home environment, and child health status. pilot study to detect cases and estimate PD prevalence on aGrowth measurements and a hemoglobin finger-prick blood larger scale in Costa Rica, but coverage of the targettest were obtained. Multiple linear and logistic regressions population by the ATAPs was low. Additional, more efficientwere conducted. Children whose mothers worked in the flower methods are been explored. Keywords: Parkinson disease,industry during pregnancy scored lower on communication (7.7 pesticide exposure, Costa Rica.% decrease, 95% Confidence Interval (CI): (-9.60, 0.31)) andfine motor skills (13.4% decrease, 95% CI: (-12.98, -3.10)),and had a higher odds of having poor visual acuity (Odds Ratio Plenary Session(OR): 4.7; 95% CI: (1.12, 19.60)), compared to children whose SESSION XII: OXIDATIVE STRESS IN AUTISM - CAUSEmothers did not work in the flower industry during pregnancy, OR CONSEQUENCE?after adjusting for potential confounders. These resultssuggest that maternal occupation in the cut-flower industry Session Chair: Isaac Pessahduring pregnancy may be associated with delayed Co-Chair: Jill Jamesneurobehavioral development of children ages 3-23 months.Unique hazards associated with working in the flower industryduring pregnancy may include pesticide exposure, exhaustion, Theme and Rationale: Autism is among the most complexand job stress. Keywords: Ecuador, neurobehavioral neurodevelopmental disorders with potential susceptibilitydevelopment, pesticides. genes spread across the entire genome. Concordance between monozygotic twins for autism is significantly less than unity47 and phenotypic presentation can vary broadly between sibs.FEASIBILITY FOR STUDYING PARKINSON DISEASE IN Autism therefore presents unique opportunities and challengesRELATION TO PESTICIDE EXPOSURE IN COSTA RICA. to study interactions among multiple susceptibility genes, andAM Mora1, K Steenland2, C Wesseling1. 1 Central American how epigenetic factors and exposure to environmentalInstitute for Studies on Toxic Substances, UniversidadNacional, Heredia, Costa Rica. 2 Department of Environmental modifiers may contribute to variable expression of autism, andand Occupational Health, Rollins School of Public Health, autism-related traits. Markers of oxidative stress have beenEmory University, Atlanta, United States recently detected at higher levels in autistic individuals Parkinson disease’s ethiology is unknown but compared to those that are not autistic. Whether oxidativeexperimental studies in animals and epidemiologic literature stress is an etiological determinant of autism, biomarker ofsuggest a consistent relationship between this environmental susceptibility, or simply and epiphenomenonneurodegenerative disease and pesticide exposure. In a has been hotly debated.population-based case-control study ascertainment of cases isdifficult, especially in a developing country like Costa Rica. The In the first presentation, Dr. James will discuss thepurpose of this study was to evaluate the feasibility of detecting metabolic pathways that have been found to be abnormal incases of Parkinson disease (PD) or parkinsonism in Costa many autistic children (and their parents) with focus on theRica through home visits by Primary Care Technical Assistants interdependent pathways of folate, methionine, and(ATAPs). During a two month period, the ATAPs of two Social glutathione metabolism and related genetic polymorphisms.Security Health Areas applied a short questionnaire to all the She will present evidence for plasma, intracellular andpeople over age 50 whose homes were visited as part of aroutine primary health care program. The questionnaire mitochondrial redox imbalance that suggests many autisticincluded, besides sociodemographic data, two questions on children may be under systemic oxidative stress with abalance and tremor, and a test for detecting Parkinson (either reduced capacity to buffer pro-oxidant environmentala parallel lines or a spiral drawing test). The ATAPs reached exposures.only 28% of the people over age 50 theoretically to be covered The second presentation (Pratico) will focus on newduring two months of home visits, equivalent to 5% of the total evidence that children with a clinical diagnosis of autism havetarget population ≥ 50. The ATAPs applied 639 questionnaires. significantly higher urinary levels of lipid peroxidationAmong these, three participants reported having beendiagnosed with PD but never having been treated and 59 (9%) biomarkers that correlate with markers of platelet andanswered yes to both the question on balance and on tremor. vascular endothelium activation. These imbalances in fattyBased on a positive answer to the tremor question and an acid metabolism, possibly mediated by oxidative stress, mayabnormal result on either of the two Parkinson detection tests, contribute to autism, since recent data indicates that28 (4.4%) persons were found to potentially have Parkinson supplementation with omega-3 fatty acids may be an effectivedisease, together with an additional 29 persons based only on treatment. Of particular importance to the etiology of autismabnormal detection tests. Of these, 24 patients were examined is identification of critical cellular signaling pathways thatNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 21may be common cell of the central nervous and immune in the autistic children suggesting that GSH synthesis may besystems that particularly sensitive to shifts in antioxidant inadequate. These new findings are of clinical concern because they indicate a significant decrease in cellulardefenses and redox signaling. methylation capacity (↓SAM/SAH) and in antioxidant/ One such redox sensitive receptor tyrosine kinase (RTK) detoxification capacity (↓GSH/GSSG), and an increase insignaling pathway is required for cell division in central oxidative stress (↑GSSG). Associated with the abnormalnervous system (CNS) progenitor cells. Local chemically metabolic phenotype, preliminary evidence suggests that manyinduced changes in redox status have been associated with autistic children exhibit an increased frequency of severalFyn kinase activation that leads to activation of c-Cbl genetic polymorphisms that negatively affect the flux throughubiquitin ligase. Sequential Fyn and c-Cbl activation, with these metabolic pathways. In cell culture experiments, lymphoblastoid cell lines derived from autistic childrenconsequent pathway-specific suppression of RTK signaling, is exhibited significant increases in situ free radical productioninduced by levels of methylmercury and paraquat. Dr. Noble and decreased intracellular and mitochondrial GSH/GSSG(3rd talk) will present results of studies that identify a novel ratio at baseline and after exogenous oxidative stress.regulatory pathway of oxidant-mediated Fyn/c-Cbl activation Impaired methylation and glutathione-dependent antioxidantas a shared mechanism of action of chemically diverse capacity would create a fragile metabolic homeostasis withtoxicants at environmentally relevant levels, and as a means reduced capacity to detoxify environmental exposures. These results suggest that some autistic behaviors may be aby which increased oxidative status may disrupt mitogenic neurologic manifestation of a genetically-basedsignaling. He will discuss a predictive framework of broad environmentally-sensitive metabolic imbalance. A metabolicpotential relevance to the understanding of pro-oxidant- and more systemic approach to autism beyond the brain wouldmediated disruption of normal development. encompass not only the neurologic manifestations but also the Dr. Ashwood will describe new evidence that NK and gastrointestinal and immunologic pathology associated withCD8+ immune cells isolated from autistic children exhibit autism. Moreover, individualized treatment strategies directedaltered patterns of activation and cytokine secretion compared toward correcting specific metabolic imbalance could potentially improve some autistic behaviors and offer insightsto those isolated from typically developing children and into the heterogeneity within the autism spectrum.discuss possible mechanisms leading to inflammation.Calcium is a universal signaling molecule in virtually all 49cellular systems that regulate activation, metabolism, growth, LIPID BIOMARKERS OF ENHANCED OXIDATIVE STRESS:and differentiation. RELATIONSHIP TO PLATELET AND VASCULAR The final talk by Dr. Pessah will describe molecular ENDOTHELIUM ACTIVATION. Domenico Pratico. Dept. of Pharmacology, Temple University, Philadelphia, PA 19140.mechanisms by which Ca2+ channels are deregulated in Background: Autism is a complex neurologic disorderautism and how such mutation can confer increased characterized by impaired communication and socialsusceptibility to chemically induced oxidative stress and interaction. Recent data showed that oxidative stress isabnormal Ca2+ signaling. The implications of Ca2+ channel present in autism, however no information is available on themutations in conferring susceptibility to environmental vascular phenotype of these subjects. Moreover, previoustriggers will be discussed. studies showed biochemical evidence for abnormal platelet reactivity and altered blood flow in autistic children. Objective:48 In the present study we evaluated the oxidative stress levels asREDOX IMBALANCE AND THE METABOLIC PATHOLOGY well as the vascular phenotype in children with autism. DesignOF AUTISM. S. Jill James. Department of Pediatrics, College and Main Outcome Measures: Urinary levels of theof Medicine, University of Arkansas for Medical Sciences, Little isoprostaneF2α-VI, marker of lipid peroxidation, 2,3-dinor-Rock, AR thromboxaneB2, which reflects platelet activation, and 6-keto- Research into the metabolic phenotype of autism has been prostaglandinF1α, a marker of endothelium activation, wereless explored compared to broad scale genomic approaches measured in autistic subjects and normal controls. Results:despite the fact that metabolic abnormalities have been Compared with controls, autistic children had significantlyimplicated in the pathogenesis of many other neurologic higher urinary levels of isoprostaneF2α-VI, 2,3-dinor-TxB2, anddisorders. We have used a targeted approach to autism 6-keto-PGF1α. Lipid peroxidation levels directly correlated with“metabolomics” by focusing on the dynamics of an integrated both vascular biomarkers ratios. Conclusions: These resultsmetabolic pathway that is important for the regulation of normal demonstrate that besides enhanced oxidative stress, plateletredox homeostasis and cellular methylation. In recent a case- and vascular endothelium activation could also contribute tocontrol study, we reported that the metabolic profile of children the development and clinical manifestations of autism.diagnosed with an autism spectrum disorder was severelyabnormal relative to that of unaffected control children. Briefly, 50the mean ratio of plasma S-adenosylmethionine (SAM) to S- REGULATION OF CNS PROGENITORS BY REDOX STATE:adenosylhomocysteine (SAM/SAH ratio), an index of IMPLICATIONS FOR AUTISM AND UNDERSTANDING THEmethylation capacity, was significantly reduced and the mean INTERPLAY BETWEEN GENES AND ENVIRONMENT. Marklevel of glutathione (GSH), the major intracellular antioxidant, Noble, Dept. of Biomedical Genetics, University of Rochesterwas also significantly decreased. The oxidized disulfide form Medical Center, Rochester, NY 14642of glutathione (GSSG) was significantly increased resulting in a Several autism-related topics will be considered in this2-fold reduction in the GSH/GSSG redox ratio. Several presentation. First, we have discovered a novel regulatorymetabolic precursors for glutathione synthesis were also lower pathway (the redox/Fyn/c-Cbl pathway; PLoS Biology Vol. 5, No. 2, e35 doi:10.1371/journal.pbio.0050035) that is activatedNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 22by chemically diverse toxicants that share only the property of Changes in localized and global intracellular Ca2+exhibiting pro-oxidant activity. Activation of this pathway by concentration represent one of the most common ways inexposure to environmentally relevant levels of multiple which cells regulate cell cycle, terminal differentiation,toxicants, or to clinically relevant levels of thimerosal, leads to migration, and death. Moreover intracellular Ca2+ signalssuppression of division of the progenitor cells that form the orchestrate hundreds, if not thousands, of biochemicalmyelin-forming oligodendrocytes of the CNS. Such processes essential for metabolism, transport, secretion, andmechanistic convergence forces a recognition of the difficulties regulation of gene transcription and translation in mostinherent in epidemiological studies of diseases in which mammalian cell types. Several of the candidate genes forputative environmental contributions may each be sufficient, autism encode proteins whose primary role is to generatebut none of which has the property of being necessary (a intracellular Ca2+ signals (e.g., CaV1.2) or are themselvessituation analogous to our current understanding of the tightly regulated by local fluctuations in Ca2+ concentrationscontributions of various oncogenes to neoplastic (e.g., neuroligin). Some Ca2+ channels are tightly regulated bytransformation). Moreover, the relationship of our findings to cellular redox and metabolic states. One prominent example ischanges in the CNS of individuals with autism will be the family of ryanodine-sensitive Ca2+ channels (i.e.,considered, as well as the importance of understanding the ryanodine receptors; RyRs), macromolecular proteincontributions of differences in individual susceptibility to complexes anchored within specialized region of theenvironmental insults – a problem of particular interest in the microsomal (ER) membrane where they coordinate localizedcontext of multiple reports indicating that children with autism Ca2+ signals (Ca2+ microdomains). RyRs have been shown tomay be more oxidized than appropriately matched controls. be exquisitely sensitive to changes in redox potentials across the ER membrane produced by GSH/GSSG and NAD+/NADH51 ratios and by redox cycling and/or arlyating xenobioticTHE RELATIONSHIP BETWEEN OXIDATIVE STRESS, electrophiles. Chemical, biochemical, and biophysical studiesIMMUNE CELLS AND INFLAMMATION IN AUTISM. P have identified hyper-reactive cysteines within RyR complexesAshwood. Department of Medical Microbiology and that are essential for redox sensing, glutathionylation, andImmunology and the M.I.N.D. Institute, University of California nitrosylation. Several chemicals of concern to environmentalat Davis, CA, USA. health (e.g., reactive metabolites of PCBs, benzo[a]pyrene, Autism spectrum disorders (ASD) are part of a broad and naphthoquinones) dysregulate the spatial and temporalspectrum of neurodevelopmental disorders that occur in fidelity of Ca2+ microdomains via RyR-mediated mechanisms.childhood. They are characterized by impairments in social We have addressed if mutations within RyRs and theirinteraction, verbal and non-verbal communication and the associated proteins such as CaV1.2 amplify susceptibility topresence of restricted and repetitive stereotyped behaviors. At chemicals known to target Ca2+-dependent processes.the present time, the etiology of ASD are largely unknown but Inherent abnormalities in Ca2+ signaling pathways maygenetic, environmental, immunological and neurological factors represent a major point of convergence for gene x environmentare all thought to play a role in the development of ASD. interactions contributing to autism risk and severity, as well asRecently, increasing research has focused on the connections other developmental disorders. Supported by funding frombetween the immune system and the nervous system including NIEHS and US EPA.their possible role in the development of ASD. Neuro-immuneinteractions begin early during embryogenesis and persist Panel Discussion and Q&Athroughout an individual’s lifetime, with successfulneurodevelopment contingent upon a normal balanced • How do nutritional factors influence autism? Does dietimmune response. There is potential that aberrant immune (supplements) mitigate autistic phenotypes and/or co-activity during vulnerable and critical periods of morbidities?neurodevelopment could participate in the generation of • What are the sources of heavy metal exposure (mercury,neurological dysfunction characteristic of ASD. Moreover, there lead, cadmium, arsenic)?is increasing evidence of an immunological dysfunction inchildren with autism, supported by genetic studies indicating a • What are the sources of organic quinones and epoxideslink between autism and genes that have immune functions. • Household chemicals as pro-oxidants; what are they?Systemic immune aberrations in autism have been linked both • What are the new pesticides of particular concern toto the generation of autoimmunity and with dysfunctional autistic children?immunity including abnormalities or deficits of function inimmune cell subsets, leading to an inappropriate or ineffectiveimmune response to pathogen challenge. In support of this, wehave recently identified alterations in the numbers and function Platformof specific immune cells in the blood of children with autism SESSION XIII: AUTISM SPECTRUM DISORDERSthat may contribute to a dysregulated or aberrant immuneresponse. This presentation will examine the current status of Session Chair: George Perryour research linking the immune response with ASD and the Co-Chair: Cindy Lawlerrelationship between oxidative stress and inflammation. 5352 THE AUTISTIC PHENOTYPE EXHIBITS A REMARKABLEREDOX SENSING OF CALCIUM CHANNELS – A LOCALIZED MODIFICATION OF BRAIN PROTEINS BYCONVERGENCE OF GENES AND ENVIRONMENT. I.N. PRODUCTS OF FREE RADICAL-INDUCED LIPID 1 1 2 3 3Pessah. Department of Veterinary Molecular Biosciences and OXIDATION. TA Evans , SL Siedlak , L Lu , X Fu , Z Wang , 4 5 6 3The Center for Children’s Environmental Health, University of WR McGinnis , E Fakhoury , RJ Castellani , SL Hazen , WJCalifornia, Davis, California, USA Walsh5, AT Lewis5, RG Salomon2, MA Smith1, X Zhu1, GNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 23Perry1,7. Departments of 1Pathology and 2Chemistry, Case taking into account both the magnitude of the response, andWestern Reserve University, Cleveland, OH 44106; how many responses went up or down within a subjectDepartments of 3Molecular Cardiology and of 3Cardiovascular population. There was a significant increase in the proliferativeMedicine, Cleveland Clinic Foundation, Cleveland, Ohio response following PHA stimulation in the presence of 100 nM 4 544195; Ashland, OR 97520; Pfeiffer Treatment Center, PBDE-47 for the ASD group compared to a reduction in the TD 6Health Research Institute, Warrenville, IL 60555; Department controls. When the cells were preincubated with PBDE-47 atof Pathology, University of Maryland, Baltimore, MD 21201; 500 nM, the proliferative response was not affected in the TD7 College of Sciences, University of Texas at San Antonio, San controls but was significantly elevated in the ASD subjects (p<Antonio, TX 78249 0.05). Regarding cytokine production, exposure to 100 nM Oxidative damage has been documented in the peripheral PBDE-47 resulted in significantly lower values for IL-6, MIP-tissues of autism patients. In this study, we sought evidence of 1alpha and MIP-1beta in both the TD and ASD groups. Theoxidative injury in autistic brain. Carboxyethyl pyrrole (CEP) relative responses of the ASD and TD subjects diverged in theand iso[4]levuglandin (iso[4]LG)E2-protein adducts, that are presence of 100 nM PBDE, with TD showing greateruniquely generated through peroxidation of docosahexaenoate reductions in levels of the cytokine IL-12, and the chemokinesand arachidonate-containing lipids respectively, and heme- MIP-1alpha and MIP-1beta. This data suggests that in vitrooxygenase-1 were detected immunocytochemically in cortical exposure of PBMC to PBDE-47 affects cell proliferation andbrain tissues and by ELISA in blood plasma. Significant cytokine production in a pediatric population. Moreover, PBMCimmunoreactivity toward all three of these markers of oxidative from the ASD subjects was differentially affected whendamage in the white matter and often extending well into the compared to the TD controls suggesting evidence of agrey matter of axons was found in every case of autism differential sensitivity to the environmental contaminant PBDE-examined. This striking threadlike pattern appears to be a 47. Keywords: autism, T cell, PBDE-47.hallmark of the autistic brain as it was not seen in any controlbrain, young or aged, used as controls for the oxidative 55assays. Western blot and immunoprecipitation analysis BRAIN LEVELS OF OXIDATIVE STRESS MARKERS,confirmed neurofilament heavy chain to be a major target of MERCURY AND SELENIUM IN AUTISM. Elizabeth M.CEP-modification. In contrast, in plasma from 27 autism Sajdel-Sulkowska1, Boguslaw Lipinski2, Herb Windom3, Tapanspectrum disorder patients and 11 age-matched healthy Audhya4, Woody McGinnis5. 1 Dept. Psychiatry Harvardcontrols we found similar levels of plasma CEP (124.5 ± 57.9 Medical School and BWH, Boston MA; 2. Dept, Psychiatryversus 110.4 ± 30.3 pmol/mL), iso[4]LGE2 protein adducts BWH, Boston, MA; 3. Skidaway Institute of Oceanography,(16.7 ± 5.8 versus 13.4 ± 3.4 nmol/mL), anti-CEP (1.2 ± 0.7 Savannah, GA; 4.Vitamin Diagnostics, Cliffwood Beach, NJ; 5.versus 1.2 ± 0.3) and anti-iso[4]LGE2 autoantibody titre (1.3 ± Ashland, OR, USA1.6 versus 1.0 ± 0.9), and no differences between the ratio of This study examined oxidative stress hypothesis in autismNO2Tyr/Tyr (7.81 E-06 ± 3.29 E-06 versus 7.87 E-06 ± 1.62 E- and compared for the first time the cerebellar levels of the06). These findings provide the first direct evidence of oxidative stress markers 3-nitrotyrosine (3-NT; an index ofincreased oxidative stress in the autistic brain. It seems likely oxidative protein modifucation), 8-hydroxy-2’-deoxyguanosinethat oxidative injury of proteins in the brain would be (8-OH-dG; an index of oxidative DNA damage), mercury (Hg),associated with neurological abnormalities and provide a and the antioxidant selenium (Se) levels between control andcellular basis at the root of autism spectrum disorders. autistic subjects. Homogenates were prepared from the frozenKeywords: oxidative, autism, neurological. cerebellar tissue of control (n=10; mean age, 15.5 years; mean PMI, 15.5 hours) and autistic (n=9; mean age 12.1 years;54 mean PMI, 19.3 hours) subjects. The levels of 3-NT and 8-OH-DIVERGENT EFFECTS OF PBDE-47 ON T CELL IMMUNE dG were determined by specific ELISAs. The level ofRESPONSES IN AUTISTIC AND TYPICALLY DEVELOPING cerebellar 3-NT was increased from 20.25±2.64 pmol/g inCHILDREN. Ashwood, P.1,4,5 Schauer2,4,5, J., Pessah, I.N. 3,4,5 cerebellar tissue from control cases to 34.19±6.75 pmol/g inand J. Van de Water2,4,5 1Department of Medical Microbiology cerebellar tissue from autistic cases (p=0.045), whichand Immunology. 2Division of Rheumatology, Allergy and represents 68.8% increase in autism. Cerebellar 8-OH-dGClinical Immunology, University of California at Davis. was increased from 0.71±0.08 pmol/ug DNA in controls to3 Department of Veterinary Molecular Biosciences, 4The 0.96±0.33 pmol/ug DNA in tissue from autistic cases, but the 5M.I.N.D. Institute, NIEHS Center for Children’s Environmental 35.2% increase was not statistically significant. Cerebellar Hg,Health, University of California, Davis. Davis, CA 95616 USA measured by atomic absorption spectrometry, was increased Autism spectrum disorders (ASD) are a complex from 14.93±3.26 pmol/g tissue in controls (n=10) to fromneurodevelopmental disorder that manifest in childhood. 25.11±8.25 pmol/ tissue in autistic cases (n=9); the 68.2%Current models suggest a role for both genes and the increase in Hg was not statistically significant. However, thereenvironment in the etiology of autism. There is evidence that was a positive correlation between cerebellar 3-NT and Hgimmune dysregulation and autoimmune reactivity may levels (r=0.7961, p=0.0001). A small decrease in cerebellar Secontribute to the etiology of ASD. The potential differential levels in autism, measured by atomic absorption spectroscopy,effect of a common environmental polybrominated was not statistically significant but it was accompanied by adiphenylether, PBDE-47 on the immune response in children 42.9% reduction in the molar ratio of Se to Hg in the autisticwith ASD (n=19) and age-matched typically developing cerebellum. While preliminary, the results support thecontrols (TD, n=18) were compared. Peripheral blood hypothesis of oxidative stress in autism. Supported by ARI.;mononuclear cells (PBMC) were exposed for 4 hrs ex vivo to brain samples were obtained from the NICHD Brain and Tissueeither 100 nM or 500 nM PBDE47 for 4 hrs. PBMC were then Bank for Developmental Disorders at the University ofchallenged with the T cell mitogen, PHA. We measured both Maryland. Keywords: autistic brain, oxidative stress, metals.the proliferative response and cytokine production followingstimulation. The data was analyzed by Wilcoxon rank testsNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 2456 57AN EMERGING GENE-ENVIRONMENT INTERACTION AUTISM: MATERNALLY DERIVED ANTIBODIES SPECIFICMODEL: AUTISM SPECTRUM DISORDER RESULTING FOR FETAL BRAIN PROTEINS. D. Braunschweig,1,7,8 P.FROM EXPOSURE TO ENVIRONMENTAL CONTAMINANTS Ashwood,2,7,8 P.Krakowiak,3,7,8 I. Hertz-Picciotto,3,7,8 R.DURING GESTATION. Lanissa A Brown1, Letha Woods2, Hansen,4,7,8 L. Croen,5,7,8 I.N. Pessah,6,7.8 and J. Van deMonique McCallister1, Sheng Liu1, Mark Maguire2, Ford F. Water 1,7,8 1 Division of Rheumatology, Allergy and ClinicalEbner2, Michael Aschner3, Pat Levitt4 and Darryl B. Hood1. 2 Immunology, University of California at Davis. Dept of Medical1 Dept of Neurobiology and Neurotoxicology, Center for Microbiology and Immunology, University of California at Davis. 3Molecular and Behavioral Neuroscience, Meharry Medical Dept of Public Health Sciences, Division of Epidemiology,College, Nashville, TN 37208; 2Dept of Psychology, Center for 4 University of California at Davis, Dept of Pediatrics, University of 5Cognitive and Integrative Neuroscience, Vanderbilt University, California at Davis. Division of Research, Kaiser Permanente 3 6Nashville, TN 37203; Dept of Pediatrics and Center in Northern California, Oakland, CA. Dept of Veterinary MolecularMolecular Toxicology, Vanderbilt University, Nashville, TN Biosciences, University of California at Davis 7The M.I.N.D.37203; 4Vanderbilt Kennedy Center for Research in Child and 8 Institute, University of California at Davis. NIEHS Center forHuman Development, Nashville, TN 37203 Children’s Environmental Health, University of California, Davis. Residing, working, or playing in close proximity to Davis, CA 95616 USAindustrial environmental polluters can lead to gestational Autism is a profound disorder of neurodevelopment withexposure to environmental contaminants at levels that may poorly understood biological origins. A potential role forimpair learning and memory. Environmental contaminants maternal autoantibodies in the etiology of some cases ofsuch as Benzo(a)pyrene [B(a)P] and 2,3,7,8, autism has been proposed in previous studies. To investigatetetrachlorodibenzo-p-dioxin (TCDD) have been shown to cross this hypothesis, maternal plasma antibodies against humanthe placenta exposing the fetus to the contaminant body fetal and adult brain proteins were analyzed by western blot inburden of the mother. Consequently, a gestational exposure to 61 mothers of children with autistic disorder and 102 controlsenvironmental contaminants may result in increased adverse matched for maternal age and birth year (62 mothers ofhealth outcomes, possibly affecting cognitive performance as typically developing children (TD) and 40 mothers of childrenis seen in autism spectrum disorder. Previous studies have with non-ASD developmental delays (DD)). We observeddemonstrated that hippocampal and/or cortical synaptic reactivity to two protein bands at approximately 73kDa andplasticity (as measured by long-term potentiation and S1- 37kDa in plasma from 7 of 61 (11.5%) mothers of children withcortex spontaneous/evoked neuronal activity) and learning autism (AU) against fetal but not adult brain, which was notbehavior (as measured by fixed-ratio performance operant noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40testing) is significantly impaired in B(a)P and/or TCDD- p=0.0401). Further, the presence of reactivity to these twoexposed offspring. These previous studies have also revealed bands was associated with a diagnosis of behavioralthat brain to body weight ratios are greater in exposed regression in the child when compared to the TD (p=0.0019)offspring relative to controls indicative of intrauterine growth and DD (0.0089) groups. Individual reactivity to the 37kDaretardation which has been shown to manifest as low birth band was observed significantly more often in the AUweight in offspring. Recent epidemiological studies have population compared with TD (p=0.0086) and DD (p=0.002)identified an effect of prenatal exposure to airborne polycyclic mothers, yielding a 5.69-fold odds ratio (95% confidencearomatic hydrocarbons on neurodevelopment within the first interval 2.09 - 15.51) associated with this band. The presencethree years of life among a minority, inner-city cohort of of these antibodies in the plasma of some mothers of childrenchildren (Perera et al., 2006). This talk will present data with autism, as well as the differential findings betweenobtained from the utilization of a susceptibility-exposure mothers of children with early onset and regressive autism mayparadigm that provides a point of reference for suggest an association between the transfer of IgGneurotoxicological studies of environmental contaminant autoantibodies during early neurodevelopment and the risk ofeffects on indices of development in general, and on developing of autism in some children.neurodevelopment in particular. Environmental contaminantinduced effects on 1) metabolite bioavailability and dispositionto critical CNS structures are presented to be causative to Roundtable Discussiondecrements in (2) glutamatergic receptor subunit mRNA and SESSION XIV: WHAT IS THE WEIGHT OF EVIDENCEprotein expression, (3) hippocampal and sensory cortex THAT ENVIRONMENTAL CONTAMINANTS AND/ORcellular responses, and (4) fixed-ratio performance learning GENETIC FACTORS INFLUENCE THE ETIOLOGY OFbehavior. These studies collectively support associations NEUROLOGICAL DISORDERS?between neurobehavioral deficits and gestational exposure to Focus on Cross-Cutting Issues of Environmentalenvironmental levels of these contaminants. A molecular-level Exposures related to Autism, Alzheimer’s and PDmechanism will be presented suggesting markers of exposurethat should be studied further. The identified markers serve as Discussion Leaders: Richard Seegal, Isaac Pessah, Tedtemplates for learning and memory in model systems and from Schettlera vulnerability perspective, serve as targets for dysregulationduring development in susceptible populations that have been Theme and Rationale: The etiologic factors responsible fordisproportionately exposed to these environmental the neurological diseases and disorders discussed this weekcontaminants. Supported by NIH grants S11ES014156, (i.e., Alzheimer’s disease, Attention Deficit Disorder, AutismU54NS014071, T32MH065782, and RRO3032. Keywords: Spectrum Disorders, and Parkinson’s disease) are complex,autism spectrum disorder, environmental contaminants,learning and memory. multi-factorial and thought to involve interactions between environmental factors and genetic predispositions. However, the relative importance of these major risk factors and theNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 25mechanisms by which they may interact are poorly the cognitive deficits seen following developmental exposureunderstood. Hence, progress in identifying susceptible to lead, mercury and PCBs?individuals or developing therapeutic interventions has not yetresulted in a reduction in the incidence or consequences of Roundtable Discussants and Disease Focus:these diseases. Autism Participants from each plenary session will discuss, S. Jill Jamesusing criteria set forth by the Institute of Medicine for the M. Christopher Newlandstrength of association(s), the evidence that environmentalcontaminants, lifestyle and genetic factors play in each Alzheimer’sdisease/disorder. Are there certain disorders that are more Don Schmechel,likely to be induced by environmental contaminants; are there Nasser Zawia,some disorders that are primarily genetic in nature? Finally, Parkinson’sdespite the emphasis on the role(s) of environmental Anumantha Kanthasamycontaminants in the etiology of cognitive dysfunctions, is it Syed Imamuseful to ask whether genetic susceptibilities also contribute to IOM Criteria. USING THE CRITERIA DEVELOPED BY THE IOM, WHAT DEGREE OF CERTAINTY/ASSOCIATION CAN BE ASSIGNED TO THE ROLE OF ENVIRONMENTAL CONTAMINANTS IN THE ETIOLOGY OF AUTISM, ALZHEIMER’S DISEASE, PARKINSON’S DISEASE? Sufficient Evidence of a Causal Relationship Evidence from available studies is sufficient to conclude that a causal relationship exists between exposure to a specific agent and a specific health outcome in humans, and the evidence is supported by experimental data. The evidence fulfills the guidelines for sufficient evidence of an association (below) and satisfies several of the guidelines used to assess causality: strength of association, dose-response relationship, consistency of association, and a temporal relationship. Sufficient Evidence of an Association Evidence from available studies is sufficient to conclude that there is a positive association. A consistent positive association has been observed between exposure to a specific agent and a specific health outcome in human studies in which chance and bias, including confounding, could be ruled out with reasonable confidence. For example, several high-quality studies report consistent positive associations, and the studies are sufficiently free of bias, including adequate control for confounding. Limited/Suggestive Evidence of an Association Evidence from available studies suggests an association between exposure to a specific agent and a specific health outcome in human studies, but the body of evidence is limited by the inability to rule out chance and bias, including confounding, with confidence. For example, at least one high-quality study reports a positive association that is sufficiently free of bias, including adequate control for confounding. Other corroborating studies provide support for the association, but they were not sufficiently free of bias, including confounding. Alternatively, several studies of less quality show consistent positive associations, and the results are probably not due to bias, including confounding. Inadequate/Insufficient Evidence to Determine Whether an Association Exists Evidence from available studies is of insufficient quantity, quality, or consistency to permit a conclusion regarding the existence of an association between exposure to a specific agent and a specific health outcome in humans. Limited/Suggestive Evidence of No Association Evidence from available studies is consistent in not showing a positive association between exposure to a specific agent and a specific health outcome after exposure of any magnitude. A conclusion of no association is inevitably limited to the conditions, magnitudes of exposure, and length of observation in the available studies. The possibility of a very small increase in risk after exposure studied cannot be excluded. Consensus Not Reached on Category of Association If the entire committee did not agree on a conclusion, then the association was not assigned a category.NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 26SESSION VIII: POSTER SESSION pairs of mothers and their babies were recruited between April 2004 and January 2005. We interviewed them by a structuredThe poster session is a highlight of this conference series and questionnaire before delivery and collected umbilical cordprovides an ideal opportunity for one-on-one personal blood at birth. Lead levels in umbilical cord blood (PbCB) wereexchange of research information and ideas in an informal analyzed by Agilent 7500C ICP-MS. The Comprehensivesetting with a unique consortium of participants expert in Developmental Inventory for Infants and Toddlers (CDIIT) wasvarious aspects of the theme and neurotoxicology in general. used for assessing the neurodevelopment in cognition,The General Poster Session has proven to be a wonderful language, gross and fine motor, social, and self-help at 6 andvenue for informal, in-depth discussion, collaboration 24 months of age accompanying with Home Observation andbuilding, and mentoring of young scientists. It is an Measurement of the Environment (HOME) scale. We used real-time PCR to detect VDR-FokI polymorphism. We usedimportant networking opportunity for students. Judging and multiple linear regression and GEE models to estimate theselection of Pre – and Post-Doctoral Student Awardees will gene-environment interaction effect. After controlling forbe made during the session. maternal education, breastfeeding and smoking, infant sex and gestational age, and HOME score, social scores in childrenP-58 with Ft(CT) or FF(CC) allele and PbCB >=1.64 μg/dl wereTHE COMBINED EFFECT OF TRANSCULTURAL significantly lower than those with ff(TT) allele and PbCB <1.64MARRIAGE AND BREAST FEEDING ON CHILDREN’SNEUROBEHAVIORAL DEVELOPMENT AT 6 AND 18 μg/dl. However, language scores were significantly lower inMONTHS OF AGE. Li-Ching Chu, Pau-Chung Chen. Institute children with Ft(CT) or FF(CC) allele regardless of PbCBof Occupational Medicine and Industrial Hygiene, National levels. We can conclude that VDR-FokI may modify theTaiwan University College of Public Health, Taipei, Taiwan relationship of prenatal exposure to environmental lead and The purpose of this study was to explore the combined neurodevelopment during the first two years of life, especiallyeffect of transcultural marriage and breastfeeding duration and for social entity. Key words: lead, genetic polymorphisms,on children’s neurobehavioral development. This study was neurodevelopmentbased on the pilot databases of the Taiwan Birth Cohort Study. P-60 Pre-Doc Award CompetitionQuestionnaire interviews were used to collect the information COTININE IN UMBILICAL CORD BLOOD, GENETICon the duration of breastfeeding, neurobehavioral development POLYMORPHISMS, AND NEURODEVELOPMENT AT THEscale including gross motor, fine motor, language, and self- 1 AGE OF TWO YEARS. Chia-Jung Hsieh, Hua-Fang Liao, 2help and social competence, and its covariates at the age 6 (n 3 4 Kuen-Yuh Wu, Wu-Shiun Hsieh, Yi-Ning Su, Suh-Fang 5= 1574) and 18 months (n = 1423). Mother’s ethnicity was Jeng,2 Shih-Ni Yu,1 Pau-Chung Chen1. 1 Institute ofgrouped into two groups: Taiwanese and foreign-born and the Occupational Medicine and Industrial Hygiene, Nationalduration of breastfeeding into three groups: never breastfed, Taiwan University College of Public Health, Taipei, 2Schoolless than four months, and four months and more. The and Graduate Institute of Physical Therapy, National Taiwanreference group was never breastfed children born to University College of Medicine, Taipei, 3Division ofTaiwanese mothers. Multiple linear regression models were Environmental Health and Occupational Medicine, Nationalused to estimate the effects and controlled for potential 4 Health Research Institutes, Miaoli, Department of Pediatrics,confounders including maternal age, education, marital status, 5 and Department of Medical Genetics, National Taiwansmoking during pregnancy, and parity, and infant sex and University Hospital and National Taiwan University College ofgestational age. We found that neurobehavioral development Medicine, Taipei, Taiwanscales at the age of 18 months increased consistently with The aim of the study was to explore the interaction effectincreasing duration of breastfeeding either in children born to of gene and cotinine on child neurodevelopment at 2 years ofTaiwanese or foreign-born mothers. Although foreign-born age. This study was one investigation of the Taiwan Birthmothers were in lower education level, lower family income, Panel Study and a total of 145 pregnant women and theirand more living in rural area than Taiwanese mothers, longer neonates were recruited between April 2004 and Januarybreastfeeding duration could still benefit to their children’s 2005. We interviewed them by a structured questionnaireneurobehavioral development. Key words: breast feeding, before delivery and collected umbilical cord blood at birth. Theethnicity, neurodevelopment cord blood cotinine level was analyzed by using HPLC-MS/MS and the detection limited of this method was 0.05 ng/ml. TheP-59 Comprehensive Developmental Inventory for Infants andLEAD IN UMBILICAL CORD BLOOD, VDR-FokI Toddlers (CDIIT) was used for assessing thePOLYMORPHISM AND CHILDREN’S neurodevelopment in cognition, language, gross and fineNEURODEVELOPMENT AT THE AGE OF TWO YEARS. motor, social, and self-help at 2 years of age accompanyingChen-Chung Ko,1 Yaw-Huei Hwang,1 Hua-Fang Liao,2 Wu- with Home Observation and Measurement of the EnvironmentShiun Hsieh,3 Suh-Fang Jeng,2 Yi-Ning Su,4 Hui-Chen Wu,1 (HOME) scale. Four metabolic genes, GSTM1, GSTT1, 1 1Pau-Chung Chen . Institute of Occupational Medicine and CYP1A1 MspI and CYP1A1 Ile462Val, were detected by real-Industrial Hygiene, National Taiwan University College of time PCR. We used multiple linear regression and ANCOVA 2Public Health, Taipei, School and Graduate Institute of models to estimate the gene-environment interaction effect.Physical Therapy, National Taiwan University College of Cotinine levels were negatively associated with cognition,Medicine, Taipei, 3Department of Pediatrics, and 4Department language and fine motor scores. In addition, there wereof Medical Genetics, National Taiwan University Hospital and interaction effects between genotypes (GSTT1 and CYP1A1National Taiwan University College of Medicine, Taipei, Taiwan Ile462Val) and cotinine levels on language and total scores. It The aim of this study was to explore the risk of prenatal can be concluded that GSTT1 and CYP1A1 Ile462Val canexposure to low-level lead and gene-environment interaction modify the effect of prenatal exposure to cotinine on early childon early children’s neurodevelopment. This study was one neurodevelopment. Key words: prenatal exposure, cotinine,investigation of the Taiwan Birth Panel Study and a total of 200 neurodevelopment, genetic polymorphisms.NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 27P-61 (β = -4.8, SE = 2.5, P value = 0.0542). However, prenatal MnPRENATAL AND POSTNATAL EXPOSURE TO levels were negatively associated with the whole DQs,ENVIRONMENTAL TOBACCO SMOKE AND CHILDREN’S cognitive DQs, and language DQs at 24 months of age (β = -NEUROBEHAVIORAL DEVELOPMENT AT 6 TO 18 3.8, SE = 1.9, P value = 0.0476; β = -8.4, SE = 3.2, P value =MONTHS OF AGE. Shan-An Chou, Pau-Chung Chen. 0.0098; β = -4.5, SE = 2.0, P value = 0.0254). In the GEEInstitute of Occupational Medicine and Industrial Hygiene, analyses, negative associations were still kept in the wholeNational Taiwan University College of Public Health, Taipei, DQs, cognitive DQs, and fine-motor DQs (β = -3.9, SE = 1.6, PTaiwan value = 0.0134). We can conclude that fetuses may be The purpose of this study was to evaluate the associations vulnerable to environmental Mn exposure. However, ourbetween prenatal and postnatal exposure to environmental findings still need further research to be verified. Keywords:tobacco smoke (ETS) and early children’s neurobehavioral prenatal exposure, manganese, psychomotor development,development. This study was based on the pilot databases of children.the Taiwan Birth Cohort Study. A total of 1,496 infant-parentpairs completed interviews on the information of ETS P-63 Pre-Doc Award Competitionexposure, neurobehavioral development scale including gross- AUTISM: MATERNALLY DERIVED ANTIBODIES SPECIFIC 1,7,8motor, fine-motor, language, self-help and social competence, FOR FETAL BRAIN PROTEINS. D. Braunschweig, P.and its covariates at the age of 6 and 18 months. We used Ashwood,2,7,8 P.Krakowiak,3,7,8 I. Hertz-Picciotto,3,7,8multiple linear regression and mixed models to estimate the R.Hansen,4,7,8 L. Croen,5,7,8 I.N. Pessah,6,7.8 and J. Van de 1,7,8 1effects of ETS in the four groups: non-exposed, exposed Water Division of Rheumatology, Allergy and Clinical 2during the periods of prenatal to 6 months only, 7 to 18 months Immunology, University of California at Davis. Department ofonly, and prenatal to 18 months. After controlling for maternal Medical Microbiology and Immunology, University of California 3nationality, education, marital status, breastfeeding duration, at Davis. Department of Public Health Sciences, Division of 4and infant’s sex and gestational age, there were no significant Epidemiology, University of California at Davis, Department ofeffects on the scale at the age of 6 months. However, there Pediatrics, University of California at Davis. 5Division ofwere significantly negative associations between exposure to Research, Kaiser Permanente Northern California, Oakland,ETS and the scale of fine-motor at the age of 18 months in CA. 6Department of Veterinary Molecular Biosciences, 7each exposed group compared to non-exposed group. In the University of California at Davis The M.I.N.D. Institute, 8analyses of mixed models, there still was a significantly University of California at Davis. NIEHS Center for Children’snegative association in the exposed group during the period of Environmental Health, University of California, Davis. Davis,prenatal to 18 months. Additional evidence of the effect of CA 95616 USAexposure to ETS on early children’s neurobehavioral Autism is a profound disorder of neurodevelopment withdevelopment especially for fine motor performance is reported poorly understood biological origins. A potential role foreither in prenatal or postnatal periods. Key words: maternal autoantibodies in the etiology of some cases ofenvironmental tobacco smoke, children, neurobehavioral autism has been proposed in previous studies. To investigatedevelopment this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot inP-62 61 mothers of children with autistic disorder and 102 controlsPRENATAL EXPOSURE TO MANGANESE AND matched for maternal age and birth year (62 mothers ofPSYCHOMOTOR DEVELOPMENT AT 6 AND 24 MONTHS typically developing children (TD) and 40 mothers of children 1 2OF AGE. Feng-Chiao Su , Hua-Fang Liao , Yaw-Huei with non-ASD developmental delays (DD)). We observedHwang1, Wu-Shiun Hsich3, Hui-Chen Wu1, Suh-Fang Jeng2, reactivity to two protein bands at approximately 73kDa andYi-Ning Su4, Pau-Chung Chen1. 1Institute of Occupational 37kDa in plasma from 7 of 61 (11.5%) mothers of children withMedicine and Industrial Hygiene, National Taiwan University autism (AU) against fetal but not adult brain, which was notCollege of Public Health, Taipei, Taiwan, 2School and noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40Graduate Institute of Physical Therapy, National Taiwan p=0.0401). Further, the presence of reactivity to these two 3University College of Medicine, Taipei, Taiwan, Department of bands was associated with a diagnosis of behavioral 4Pediatrics, and Department of Medical Genetics National regression in the child when compared to the TD (p=0.0019)Taiwan University Hospital and National Taiwan University and DD (0.0089) groups. Individual reactivity to the 37kDacollege of Medicine, Taipei, Taiwan. band was observed significantly more often in the AU Due to limited information about the potential effect of population compared with TD (p=0.0086) and DD (p=0.002)prenatal manganese exposure on children’s mothers, yielding a 5.69-fold odds ratio (95% confidenceneurodevelopment, we conducted this study to evaluate the interval 2.09 - 15.51) associated with this band. The presenceassociations between prenatal exposure to Mn and of these antibodies in the plasma of some mothers of childrenpsychomotor development in children at 6 and 24 months of with autism, as well as the differential findings betweenage. It is one of the investigations of the Taiwan Birth Panel mothers of children with early onset and regressive autism mayStudy. We measured children’s development by the suggest an association between the transfer of IgGComprehensive Developmental Inventory for Infants and autoantibodies during early neurodevelopment and the risk ofToddlers (CDIIT) at 6 (n=131) and 24 months of age (n=198) developing of autism in some children.accompanying with Home Observation and Measurement ofthe Environment (HOME) scale. Samples of cord blood wereanalyzed by Agilent 7500C ICP-MS and the arithmetic mean ofMn level was 51.92µg/L. There were no negativelyassociations between prenatal Mn levels and developmentalquotients (DQs) of the CDIIT at 6 months of age with theexception of the fine-motor DQs in the borderline significanceNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 28P-64 questionnaires; and medical and neurological screeningADDRESSING NEUROINFLAMMATION IN AUTISM AND exams. Blood samples were collected to measure AcetylPDD WITH IV LIPID THERAPY. Kane PC, Braccia D, Cartaxo, Cholinesterase. Children not working in agriculture, matchedA, Kane E. Haverford Wellness Center Havertown, PA and on age and education, also participated in the study. MultipleKinnelon, NJ USA regression, controlling for age and years of education, found Aberrant lipid metabolism in the formation of very long the applicator groups, both young and older, performedchain fatty acids forming ceramides or lipid rafts may follow significantly worse than the controls on the majority ofexposure to neurotoxins and serve as biomarkers of neurobehavioral tests. The applicators reported significantlyneuroinflammation in patients presenting with ASD (Autistic more neurological symptoms identified than the controls. ASpectrum Disorder) and Pervasive Developmental Delay significant decrease in Acetyl Cholinesterase level was found(PDD). Detailed history of exposure of neurotoxins as heavy in the applicator group compared to the controls. Working moremetals (such as maternal fish consumption), xenobiotics days in the current season is associated with worse(pesticides), and microbial exposure (fumonisin from corn) neurobehavioral performance and more reported symptoms.were carefully evaluated in our 50 subjects along with This study replicated the findings of research on adult cottonappropriate laboratory testing. A two day intravenous protocol works.was introduced to stabilize brain architecture and to addressneurotoxic exposure and neuroinflammation. Day one P-66consisted of bolus IV dosing of phosphatidylcholine (PC) NEUROANTIBODIES IN POPULATIONS EXPOSED TO 1 2followed by Leucovorin and rGlutathione (rGSH) fast push. On PESTICIDES. HAN EL-Fawal , NAN El-Fawal , NMB El- 3 4 1the second day of therapy IV Sodium Phenylbutyrate (PB) was Fawal and MY Shamy . Neurotoxicology Laboratory, Mercyadministered to address aberrant lipid metabolism along with College, Dobbs Ferry, NY, 2Faculty of Dentistry, University of 3PC by lipid exchange, Leucovorin and rGSH fast push on Alexandria, Alexandria, Egypt, Purchase College, SUNY, 4either side of the phenylbutyrate drip. IV therapy was continued Purchase, NY, High Institute of Public Health, University oftwice monthly or Day 1 and Day 2 IV protocol was rotated on a Alexandria, Alexandria, Egypt.weekly basis. Our targeted IV therapy is an attempt to clear In recent years, a growing body of epidemiological andneurotoxins, support hepatic function., address cell membrane experimental evidence has accumulated suggesting that risk ofphospholipid integrity, and stabilize the state of developing neurodegenerative diseases, particularly sporadicneuroinflammation that may accompany ASD and PDD. Oral Parkinson’s Disease (PD), may be associated with exposurestherapy included highly unsaturated fatty acids (HUFA), 4:1 to environmental toxicants, particularly pesticides. There haveratio of omega-6 to omega-3 polyunsaturated fatty acids been several reports of neuroantibodies in sera and cerebral(PUFA), fatty alcohols, butyrate or Phenylbutyrate, PC and spinal fluid of individuals with neurodegenerative diseases,methylation support. Oral targeted treatment regimes were including Alzheimer’s, PD and Amyotrophic Lateral Sclerosis.utilized after red cell lipid analysis had been completed at Targeted antigens have included neurofilaments (NF), glialKennedy Krieger Institute’s Peroxisomal laboratory. We noted fibrillary acidic protein (GFAP) and myelin basic protein (MBP),marked improvement in cognition, behavior, eye contact and among others. To investigate whether a similar humoralspeech with the first round of our two day IV protocol in our 50 response occurs with pesticide exposure, residents of El-ASD and PDD subjects. No side effects have been noted in Behayrah Province of Egypt (aged 35-55) were recruited. Theyour nutritional IV lipid therapy. Continued IV and oral lipid included 48 year-round farmers (F; 11 females; 37 males) andtherapy has yielded sustained clinical improvement in all 27 part-time farm workers (P; 10 females; 17 males). Asubjects. Ten subjects lost the diagnosis of autism with one demographically- and socieconomically-matched group of 50patient losing the ASD diagnosis after five infusions of IV lipid (R; 11 females and 39 males) workers at a frozen food planttherapy. acted as a reference population. All farmers were occupationally exposed to orgnaophosphates (e.g.,P-65 Pre-Doc Award Competition metamidophos), carbamate (e.g., zineb) and paraquat. TheNEUROBEHAVIORAL EFFECTS AMONG ADOLESCENT order of neuroantibody, IgG isotype, prevalence against NFPESTICIDES APPLICATORS IN EGYPT. AA Ismail1,2, DS triplet, GFAP and MBP was F>P>R. In addition, after adjustingRohlman2, ME Abou Salem1, AA Mechael1, OM Hendy3, GM for gender and age, there were significant differences based 1 1Abdel Rasoul . Community, Environmental and Occupational on duration and exposure (p<0.05). When data was adjustedMedicine Department, Faculty of Medicine, Menoufiya for gender and exposure, there was also a significant (p<0.05) 2University, Shebin Elkom, Egypt; Center for Research on trend based on age. No significant differences were observedOccupational and Environmental Toxicology, Oregon Health & based on gender. The number of detectable antibodiesScience University, Portland, OR, USA; 3Clinical Pathology correlated with scores of the neurological exam. Interestingly, aDepartment, National Liver Institute, Menoufiya University, subset of F had antibodies against acetylcholinesterase. ThisShebin Elkom, Egypt. study indicates that long-term exposure to pesticides with Nearly 40% of the Egyptian work force is employed in known neurotoxic potential and suspected of being risk factorsagriculture. The cotton industry relies on children and for PD result in detectable levels of serum neuroantibodiesadolescents, who work seasonally, to apply pesticides to the reported in patients with neurodegenerative diseases. Potentialcotton crops. Although previous research has examined adult mechanisms underlying production and functional significancepesticide exposure in Egypt, no research has examined the is discussed. Keywords: neuroantibodies, pesticides,health effects in adolescents. The aim of this study was to biomarkers.examine the impact of pesticide exposure on children andadolescents spraying cotton fields. Male children currentlyapplying pesticides between the ages of 9 and 19 (N=50) wererecruited for the study. They completed a neurobehavioral testbattery; personality inventory; work, health, and exposureNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 29P-67 Pre-Doc Award Competition ST co-cultures according to the following treatment scheme:MODERATE PERINATAL ARSENIC PERTURBS THE HPA SAL-SN/SAL-ST; SAL-SN/LPS-ST; LPS-SN/SAL-ST; LPS-AXIS AND HAS LONG-TERM AFFECTS ON LEARNING SN/LPS-ST. The co-cultures were incubated for 7 days atAND MEMORY BEHAVIOR. Ebany J. Martinez, University of 37˚C undisturbed, followed by fixation and analysis of cells forNew Mexico Health Sciences Center Department of anti-tyrosine hydroxylase immunoreactivity (THir). SupernatantNeurosciences and College of Pharmacy Department of was also collected from each co-culture condition to assessToxicology and Andrea Allan, PhD, University of New Mexico trophic activity on SN primary cultures. The resultsHealth Sciences Center Department of Neurosciences, demonstrated two overt effects. First, co-cultures establishedAlbuquerque, New Mexico, USA from fetuses prenatally exposed to LPS had less process Arsenic is one of the most common naturally occurring extension morphologically. Second, there were fewer DA cellscontaminants found in the environment, particularly in water. in the LPS-SN/LPS-ST condition compared to the SAL-While most studies on arsenic have focused on its SN/SAL-ST and SAL-SN/LPS-ST conditions (F3,26=19.5,carcinogenic potential, a few studies suggest that arsenic can p<0.001). In addition, SN monocultures established from LPSadversely affect human cognitive development in both rodents prenatally exposed fetuses exhibited drastic reductions in THirand humans. The mechanism through which it produces this cell counts when compared to controls (F5,32=31.69, P<0.001).damage is yet to be elucidated; however, arsenic has been In conclusion, given the reduced process extension andshown to perturb the hypothalamic-pituitary-adrenal (HPA) reduced cell counts observed in the LPS-SN/SAL-ST, LPS-axis. Perturbation of this axis has been implicated in both SN/LPS-ST and SN monoculture conditions, LPS may mediatecognitive damage and the promotion of carcinogenesis. One its effect by altering striatal derived trophic interactions with DAparameter of this axis, the glucocorticoid receptor, has been neurons. With an alteration in DA neuron process extension,shown to be altered by arsenic. These receptors are found access to target derived trophic factors would also be altered,throughout the central nervous system but are particularly leading to increased apoptotic culling of DA neurons. The dataconcentrated in the hippocampus, an area of the brain of presented here are consistent with our previous observationscentral importance for learning and memory. We examined the in vivo. Further studies will access whether factors associatedimpact of perinatal exposure to 50 parts per billion (ppb) with the SN or ST are responsible for the prenatal LPS effectsarsenic on HPA axis parameters and learning/memory on developing DA neurons. Supported by DOD and thebehavioral tests in the C57BL6/J mouse. Novel object task was Richard Nopar Foundation.used as a measure of visual and spatial learning and memory.One parameter scored was latency to reach the novel object in P-69which arsenic-exposed animals showed longer latency to PERINATAL EXPOSURE TO 2,2’3,5’6-PENTACHLORO-reach novel object than did controls. Paired-pulse inhibition BIPHENYL (PCB95) ALTERS SEIZURE SENSITIVITY ANDwas also decreased in arsenic-exposed animals. The Elevated PERSISENTLY CHANGES HIPPOCAMPAL CA1Plus Maze, used as a measure of anxiety, revealed higher EXCITABILITY. Kyung Ho Kim1, Salim Yalcin Inan2, Robertanxiety in arsenic-exposed offspring compared to controls. F. Berman2, and Isaac N. Pessah1. 1 Departments ofResults from the behavioral studies suggest that moderate Molecular Biosciences, School of Veterinary Medicine andperinatal arsenic can have long-lasting adverse effects on 2 Department of Neurological Surgery, School of Medicine,learning and memory and anxiety-like behavior. In addition to University of California, Davis, California, USAthe behavioral studies, several measurements of the HPA axis Several epidemiological studies indicated that exposure towill be taken, including glucocorticoid receptor levels, PCBs during development can cause neurotoxicity to childrencorticosterone levels and ACTH levels. The results are not but the underlying mechanisms remain unclear. The presentavailable at time of abstract submission. study examined how PCB95 (2,2’3,5’6-pentachlorobiphenyl) influences synaptic transmission in rats exposed during theP-68 Pre-Doc Award Competition perinatal period (GD5~PND21). Field excitatory postsynapticPRENATAL LPS EXPOSURE ALTERS THE FATE OF potentials (fEPSP) were evoked by single pulse stimulation ofDEVELOPING DOPAMINE PROJECTIONS. Angela Schaffer Collateral/Commissural fibers in striatum radiatum ofJ.Monahan, Zaodung Ling, and Paul M. Carvey. Rush the CA1 region using a multi-electrode array. Picrotoxin (PTX,Univerisity Chicago, IL 60605 100 M) applied to hippocampal slices from the test group (6 Numerous neurotoxiology studies have approached non- mg/kg/day) enhanced synaptic efficacy (218±22% of baseline;familial Parkinson’s disease from the standpoint of adult p<0.01) with prominent after-discharges (epileptic wave form)exposure. Data from our lab, however, implicates prenatal compared to the relatively smaller enhancement (109±8% ofexposure as being as important to consider as adult exposure. baseline; p<0.05) observed in slices from corn oil (vehicle)When gravid female rats were exposed to bacterotoxin exposed rats. We further investigated whether PCB95lipopolysaccaharide (LPS) offspring exhibited reduced influenced sensitivity to seizures induced by bis-2,2,2-numbers of dopamine (DA) neurons, less striatal DA, an triflurothyl ether (flurothyl) and pentylenetetrazole (PTZ).increase in DA activity and an increase in pro-inflammatory Latency of the first flurothyl-induced myoclonic jerk wascytokine release. The mechanism through which LPS significantly faster (p<0.05) and recovered slowly in animalsproduces this effect is unknown to date. Using in vitro exposed to 1 mg/kg/day compared to rats in the 6 mg/kg/daytechniques, we hypothesize that prenatal LPS exposure alters PCB95 and vehicle treatment groups on PND35. The 1the early stages of DA process development, leading to mg/kg/day PCB95 exposed animals kindled significantly fasterunderdevelopment and loss of DA neurons in striato-nigral co- (P<0.05 on days 10, 12 and 13) compared to either the vehiclecultures. Female rats at E9.5 were injected with 100,000 or the 6 mg/kg/day PCB95 treatment groups at PTZ kindlingendotoxin units of LPS or 0.9% saline (SAL). At E14.5, the (30 mg/kg, i.p. every 48 hrs) beginning on PND60. Different 3mesencephalic region (substantia nigra, (SN)) and lateral patterns of [ H]ryanodine binding were identified inganglionic eminence (striatum (ST)) were dissected from each hippocampal membranes isolated from the three treatmentfetus and pooled per animal. Single cells were plated as SN- groups, indicating alterations in ryanodine receptor (RyR)NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 30activity and/or expression, a known target of non-coplanar 14) hippocampus by real-time quantitative PCR. The effects ofPCBs. These results indicate that perinatal PCB95 exposure NCM on hippocampus gene expression were weaker thansensitizes seizure susceptibility, especially in the presence of those resulting from MeHg, PCBs and OCs administeredGABAA block, through RyR dysfunction. Keywords: PCB95, separately. For instance, the genes Csad, Sparc11, Nnat,Ryanodine receptor, Seizure Basp1, Hspa8, Rab22a and Tuba1 were significantly affected in male hippocampus either by methylmercury, polychlorinatedP-70 Post-Doc Award Competition biphenyls or organochlorines pesticides exposure, but only onePERINATAL EXPOSURE TO 2,2’,4,4’-TETRABROMO- of these genes, Sparcl1, was perturbed by NCM treatment.DIPHENYL ETHER (PBDE-47) RETARDS GROWTH AND These observations are consistent with our previous resultsDELAYS NEURODEVELOPMENT OF C57BL/6J MICE. that revealed a masking effect of contaminant co-exposure onTramAnh N. Ta, Pavel Aronov, Mari S. Golub, Jozsef Lango, cerebellum gene transcription. Further, these neurotoxicantsIsaac N. Pessah, Robert F. Berman. Center for Children’s were found to have region-specific effects on gene expression.Environmental Health, University of California Davis, Davis, For example, Sparc1l, which facilitates neural cells migration,California 95618, USA. was perturbed by OCs, PCBs and NCM in hippocampus but Polybrominated diphenyl ethers (PBDEs) are widely used was not affected in cerebellum. Implications of these findingsas flame retardants and have become pervasive environmental for risk assessment will be discussed.contaminants. Chemical stability and lipophilicity have resultedin bioaccumulation of PBDEs with increasing levels detected in P-72 Pre-Doc Award Competitionhumans and in wildlife that may represent a major health risk. ALUMINUM INDUCED ELECTROPHYSIOLOGICAL,We evaluated the potential developmental neurotoxicity of BIOCHEMICAL AND COGNITIVE MODIFICATIONS IN THEPBDE-47, one of the most abundant PBDE congeners HIPPOCAMPUS OF AGING RATS. Pallavi Sethi1, 2, Amar 1 1 2identified in human tissues. Female C57BL6/J mice were Jyoti , Rameshwar Singh , Ejaz Hussain and Deepak 1 1exposed to a daily oral dose of 0, 0.03, 0.1 or 1 mg/kg Sharma . Neurobiology Laboratory, School of Life Sciences, 2beginning 4 weeks prior to conception, continuing through Jawaharlal Nehru University, New Delhi, 1110067.gestation and lactation, and ending at weaning on PND 21. Department of Biosciences, Jamia Millia Islamia, New Delhi,The levels of PBDE-47 in blood, brain, liver and adipose India.tissues of dams were markedly increased after 4 weeks of Aluminum is the most abundant metal which gets an easyexposure, around the time of mating, and continued to access to the body through the use of cooking utensils,increase after 8 weeks of exposure, approximately the time of antiperspirants; medicines etc. It gains easy access to theparturition. The levels of PBDE-47 between parturition and the central nervous system under normal physiological conditionsend of lactation, however, appeared to decrease significantly, and accumulates in different brain regions. It has beenpossibly reflecting to mobilization of PBDE-47 from fat stores reported to be involved in the etiology of severalinto milk during lactation. Brain PBDE-47 levels in the neurodegenerative diseases. In this study, we haveoffspring at PND 1 approached those of the dams after 8 investigated the effects of long-term intake of aluminumweeks of exposure. Perinatal exposure to PBDE-47 resulted in chloride (AlCl3) on the cognitive functions and the hippocampala significant dose-dependent growth retardation and delay of electrical activity. Wistar rats were fed with aluminum chloridemotor development in exposed offspring. These results (500ppm) for 6 months in the drinking water. Effect of longindicate that developmental exposure to low-levels of PBDE-47 term intake of AlCl3 was studied on the CA1 and CA3resulted in significant bioaccumulation in target organs, hippocampal neural activity and biochemical parameters.including brain, and is associated with early deficits in exposed Morris water maze and open field tests were performed toneonates. This study is supported by NIEHS 1 P01 ES11269. investigate the cognitive status of rats intoxicated with aluminum. Ultrastructural alterations were also observed. OurP-71 studies indicate that aluminum intake leads to increasedCOMPARATIVE GENE EXPRESSION ANALYSIS IN multiple unit activity and adversely affects the spatial learningDEVELOPING RAT BRAIN EXPOSED TO MIXTURES OF and memory abilities of rats. Aluminum intake increases lipidMETHYL MERCURY, POLYCHLORINATED BIPHENYLS peroxidation and protein kinase C Activity while decreases theAND ORGANOCHLORINE PESTICIDES. B.K. Padhi1, G. Na-K ATPase and antioxidant enzyme activity. ThePelletier1, A. Williams2, C. Yauk1, W.J. Bowers1. 1Environment compromised antioxidant system might be playing a crucial 2and Occupational Toxicology Division, Biostatistics and role in the observed aluminium-induced alterations. InEpidemiology Division, HECSB, Health Canada, Ottawa, summary the results of the present study implicates thatCanada, K1A 0K9. aluminum intake exerts its neurotoxic effects by altering the Although human populations are continuously exposed to neuronal firing of CA1 and CA3 fields of the hippocampuscomplex mixtures of contaminants, the effects of such which positively correlates with the cognitive deficits andexposure on the developing brain transcriptome are poorly biochemical changes. Keywords: Aluminum chloride, multiplecharacterized. The Northern Contaminant Mixture (NCM) was, unit activity, behavioral tests.therefore, formulated to reflect the blood contaminant profile ofCanadian Arctic populations. Sprague-Dawley rat dams weredosed daily from the first day of gestation to post-natal day 14with 5 mg NCM /kg b.w., or with the main components of thismixture, namely methylmercury (2 mg MeHg/kg b.w.),polychlorinated biphenyls (1.1 mg PCBs/kg b.w.) andorganochlorine pesticides (1.9 mg OCs/kg b.w.), administeredseparately at the same concentration found in the NCM. Wecompared the transcriptional perturbations induced by NCM tothe effects of its main components in post-natal day 14 (PNDNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 31P-73 the caudate putamen induced by methylmercury may beMOLECULAR AND GENETIC ANALYSIS IN NOVEL related to the hyperactivity in mice. Keywords: Methylmercury,MODELS OF METHYLMERCURY NEUROTOXICITY Grimes, caudate putamen, hyperactivity.KA.1, Henry, TB.2, Braun, K.3, Nass, R.1. Depts. of Pediatrics 1and Pharmacology , Vanderbilt University Medical Center, P-75 2Nashville, TN, USA; Center for Environmental Biotechnology , SELENIUM PREVENTION & TREATMENT OF MERCURYThe University of Tennessee, Knoxville, TN, USA; Dept. of TOXICITY NVC Ralston and LJ Raymond. Energy & 3Zoology/Developmental Neurobiology , Otto von Guericke Environmental Research Center, University of North Dakota,University Magdeburg, Germany Grand Forks, ND, U.S.A. Methylmercury (MeHg) exposure from occupational, Since dietary selenium (Se) status influences sensitivity toenvironmental, and contaminated foods is a significant threat mercury (Hg) toxicity, this study examined the protective andto public health. The toxin easily passes the blood brain barrier therapeutic effects of dietary Se intakes at levels that reflectand can cause severe psychological and neurological the dietary range. Torula yeast based diets that wereproblems. Although MeHg poisonings have been studied for nutritionally complete other than low Se (0.1 μmole/kg; ~0.01decades, the molecular determinants involved in the cellular ppm), were supplemented with sodium selenite to eitherpathology are largely unknown. A significant hindrance in normal (1.0 μmole/kg), or rich (10 μmole/kg) levels, andidentifying the molecular basis of the toxicity is the high prepared with or without methylmercury (MeHg) at 50 μmole/kgcomplexity of the vertebrate brain and lack of facile in vivo (10 ppm). Weanling male Long Evans rats fed these diets weregenetic models to determine and explore the mechanisms monitored for effects on growth and motor function in a 3 x 2involved in the cellular dysfunction. The genetically tractable feeding study. In the absence of MeHg, all rats grew normally.nematode C. elegans and the zebrafish D. rerio are powerful MeHg treated rats fed low Se diets showed depressed weightmodels to identify and characterize the cellular, developmental, gains relative to untreated control groups after two weeks,and molecular components involved in MeHg toxicity. The started to lose weight and showed hind limb crossing after 11genes and regulatory pathways in these organisms are highly weeks, and were terminal after 18 weeks on the diets. MeHgconserved with humans, and homologues of proteins involved treated rats fed normal Se diets showed depressed weightin metal and oxidative stress responses in vertebrates have gains, but did not show hind limb crossing or weight loss duringbeen identified in both models. Our initial studies indicate that the study. MeHg-treated rats fed Se-rich diets grew andC. elegans are highly sensitive to MeHg exposure, and that behaved normally. The Se-Treatment study started on week 11very low concentrations confer cell death. We have instituted of the Se-Protection study. Rats that were rescued bygenome-wide microarray analyses of gene expression switching them to Se-rich diets on week 11 started gainingfollowing exposure to MeHg, and our results indicate that weight after a week and grew rapidly regardless of whethergenes involved in protein folding, cell growth, and oxidative their diets still contained 10 ppm MeHg or not. Motor functionstress play significant roles in the neurotoxicity. We are defects in these rats stabilized shortly after beginning on Se-currently exploring the role these genes and others play in the rich diets, but defects did not reverse. Untreated rats fed hightoxicity in vertebrate cell and primary neuron cultures. We will MeHg diets with low Se continued to lose weight until motoralso describe our plans to build on our in vivo studies that disabilities and deaths necessitated termination of the group oninclude a novel genome-wide screen to identify mediators and week 18 as described above. In summary, dietary Se protectssuppressors of MeHg neurotoxicity. Keywords: neurotoxicity, against MeHg toxicity, and Se treatment of intoxicated animalsmodel organisms, mercury. prevented lethality and stabilized neurological consequences. Keywords: Mercury, selenium, brain.P-74METHYLMERCURY EXPOSURE INDUCES P-76HYPERACTIVITY AND NEURONAL LOSS IN THE METHYLMERCURY, DIETARY FISH OILS, AND BRAIN 1 1CAUDATE PUTAMEN IN MICE. Masumi Sawada, Masatake FATTY ACIDS MC Craig-Schmidt , CA Teodorescu , EE 1 1 2Fujimura and Akira Yasutake. National Institute for Minamata Eckley , A Inniss , and MC Newland Departments of NutritionDisease, 4058-18 Hama, Minamata, Kumamoto 867-0008, and Food Science1 and Psychology2, Auburn University,JAPAN Auburn, AL USA Methylmercury is highly toxic, and can result in adverse Marine fish are a major source of the neurotoxicanteffects in central nervous system of humans and animals. methylmercury (MeHg) as well as n-3 polyunsaturated fattySeveral studies have reported neurological effects of acids (PUFAs), which are beneficial to the developing brain.methylmercury, such as paralysis and hyperactivity in adult We examined MeHgs influence over PUFA content in themice. However, pathological examinations are not well developing brain. Pregnant rats consumed a diet rich orunderstood in mice. In this study, to examine pathological and marginal in n-3 PUFAs and drinking water containing MeHg inbehavioral changes induced by methylmercury exposure in a 2 (diet) X 3 (MeHg) factorial design. Because they share amice, female mice received exposure to 20 or 30 ppm synthetic pathway, we examined both n-6 and n-3 PUFAs inmethylmercury via drinking water. The methylmercury treated the neonatal brain. Prior to mating, female Long Evans ratsmice displayed locomotor hyperactivity but showed decreases drank water containing 0, 0.5, or 5 ppm of Hg as MeHg andin the number of rearing. Histopathological examination consumed either a Fish Oil (FO) or a Coconut oil (CO) diet.showed significant decrease in the number of neurons in the Both diets were based on the AIN-93 formulation. The fatbilateral caudate putamen in the methylmercury treated mice. mixture for the CO diet consisted of 42.8% palm oil, 9.2%In case of using NeuN, there was a significant decrease in the safflower oil, 15.0% soybean oil and 33% coconut oil, whereasnumber of mature neurons. In the TUNEL reaction, a lot of the FO diet contained 33% fish oil instead of coconut oil.nuclei of small neurons were labeled and GFAP positive cells Docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoicwere detected in the caudate putamen in the methylmercury acid (EPA, 20:5n-3) were provided in the FO diet each at 5% oftreated mice. These results suggest that the neuronal loss in total fatty acids. The diets were similar in n-6 PUFA content.NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 32 2 2 3The ratio of n-3 to n-6 PUFAs was 1:2 and 1:16 in the FO and Parameswarann ; Jerome Cohen ; Jagdeep Sandhu ;HenrykCO diets, respectively. DHA (as wt % total fatty acids) in brain 3 3 1phosphophatidylcholine (PC) and phosphatidylethanolamine Borowy-Borowski ; Marianna Sikorska and Siyaram Pandey .(PE) was greater in FO pups than in the CO pups (3.60 1. Chemistry & Biochemistry, University of Windsor, Windsor,vs.1.89; 28.75 vs.16.06, respectively). Conversely, n-6 PUFAs ON, Canada. 2. Psychology, University of Windsor, Windsor,were lower in the FO pups than the CO pups. MeHg exposure ON, Canada. 3. Institute for Biological Sciences, Nationaldid not affect neonatal DHA content, total n-3 content, or n-6 Research Council of Canada, Ottawa, ON, Canada. *Currentcontent in the PE fraction. However, in the PC fraction, there address: St John’s Medical College, Bangaluru. India.was a small effect of MeHg on n-3 fatty acids, but the biological Parkinson’s disease (PD) is a progressive neurologicalsignificance of this is uncertain. Thus, DHA in the brain of disorder caused by the loss of dopaminergic (DA) neurons inneonatal rats was influenced by diet but little to no effect of the substantia nigra pars compacta and consequently theirMeHg on the n-3 or n-6 fatty acids in brain was observed. projections to other brain areas. Present studies correlate(Funded by NIEHS ES10865 and AAES 13-014) exposure to herbicide paraquat (PQ) to an increased incidence of PD. Increased oxidative stress resulting from mitochondrialP-77 dysfunction has been implicated upon exposure to paraquat.AIR POLLUTION, OXIDATIVE STRESS AND This assertion is derived from previous findings from ourNEUROTOXICITY. Arezoo Campbell , Sheba M. J. 1 laboratory that PQ causes oxidative stress and apoptosis inMohanKumar2 and Bellina Veronesi3 1Department: of differentiated human neuroblastoma cells. ParticularlyPharmaceutical Sciences, Western University of Health important is the fact that pre-treatment with water soluble 2Sciences, Pomona, CA., Department of Pharmacology and Coenzyme Q10 (WS-CoQ10) protects cells against PQ toxicity.Toxicology, Michigan State University, E. Lansing, MI and The present study was designed to investigate the in vivo3 Neurotoxicology Division, NHEERL, US. EPA, RTP, NC. effects of PQ and the neuroprotective properties of WS-CoQ10. Increased incidents of classic and variant forms of We have successfully established a model of PD in Longneurodegenerative diseases suggest that environmental Evans hooded male rats by injecting them with PQ. Bothchemicals and susceptibility factors (e.g., genetics, diseased behavioral and biochemical parameters were studied to assessstates, obesity, etc.) may be contributory. Particulate matter the toxicity caused by PQ as well as the neuroprotective(PM) is a type of air pollution that is associated with sudden effects of WS-CoQ10. Results indicated the evidence of motordeaths in the elderly and respiratory distress in susceptible balance dysfunction as observed by a drastically reducedpopulations (e.g., asthmatics). PM particles contain numerous tendency to turn around and walk backwards on the rotorodbiological (e.g., bacterial) and chemical (e.g., pesticides, following PQ injections. Lipid peroxidation and GSHtransition metals) contaminants on their surface that convey measurements revealed that PQ induced oxidative stress,free radical activity and damage target cells and tissues while lowered ATP production corresponded to mitochondrialthrough oxidative stress (OS) pathways. Although toxicity dysfunction. Immunohistochemistry illustrated the loss of DAstudies have largely focused on PM’s cardiopulmonary targets, neurons and PD-like symptoms in the injected rats.recent reports indicate that nanosize PM particles exit the Considerably, neuroprotection and amelioration of these PD-lungs shortly after inhalation, enter the systemic circulation and like symptoms were observed in rats fed with WS-CoQ10.distribute to numerous organ systems, including the brain. Altogether, we present a novel model of sporadic PD causedSince the brain is highly vulnerable to OS-damage, its by PQ and present an encouraging possibility for the inhibitionneurotoxic susceptibility to PM exposure was examined. This of progressive neuronal loss by the unique formulation of WS-poster will highlight the results of three independent studies CoQ10.that link PM, OS and neurotoxicity (neurochemical,neuropathological) using normal (C57) and transgenic mice P-79(ApoE -/-) mice exposed by inhalation to concentrated ambient EXACERBATION OF PARKINSON’S DISEASE WITHPM (CAPs). Data generated from these studies confirm that EXPOSURE TO NEUROTOXINS MAY BE RESPONSIVEPM stimulates inflammatory changes in the brain along innate TO LIPID THERAPY. Kane PC, Braccia D, Kane E. Haverfordimmunity pathways, alters neurotransmitter levels that are key Wellness Center, Havertown, PA USAto the neurodocrine stress response, and produces Patients presenting with Parkinson’s Disease may haveneurodegeneration in the OS-sensitive neurons of the exacerbation of their symptoms with exposure to neurotoxinssubstantia nigra of exposed mice. In vitro studies of as pesticides, heavy metals, xenobiotics, and microbialimmortalized microglia exposed to CAPs indicate that they infections (viral as polio, fungal as fumonisin, bacterial asrespond with cellular and genomic endpoints indicating an up- borrelia burgdorferi). Aberrant lipid metabolism in the formationregulation of OS pathways and Toll-like receptors. Together of very long chain fatty acids forming ceramides or lipid raftsthese data-sets confirm that the brain is targeted by PM air may follow exposure to neurotoxins and serve as biomarkerspollution and that OS is an important predisposing factor to this of neuroinflammation in patients presenting with Parkinson’ssusceptibility. (This abstract has been reviewed by the USEPA, Disease. We have developed an IV protocol to addressNHEERL and does not necessarily reflect Agency policy). neurotoxic exposure with bolus IV dosing ofKeywords: Particulate matter, oxidative stress, phosphatidylcholine (PC) followed by Leucovorin andneurodegeneration. rGlutathione (rGSH) fast push. On the second day of therapy IV Sodium Phenylbutyrate (PB) is administered to addressP-78 Pre-Doc Award Competition aberrant lipid metabolism along with PC by lipid exchange,PARAQUAT INDUCES OXIDATIVE STRESS, NEURONAL Leucovorin and rGSH fast push on either side of theLOSS AND PARKINSONISM IN RATS: phenylbutyrate drip . Our targeted IV therapy is an attempt toNEUROPROTECTION BY WATER-SOLUBLE COQ10. Mallika clear neurotoxins, support hepatic function., address cell 1 1* 2 membrane phospholipid integrity, and stabilize the state ofSomayajulu-Nitu ; T. S. Sridhar , Anca Matei, ; Vera neuroinflammation that can accompany Parkinson’s Disease.NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 33Oral therapy includes highly unsaturated fatty acids (HUFA), in the sod1 gene are linked to an inherited form of amyotrophic4:1 ratio of omega-6 to omega-3 polyunsaturated fatty acids lateral sclerosis (ALS), a disease that manifests in progressive(PUFA), fatty alcohols, butyrate or Phenylbutyrate, and PC. degeneration of motor neurons. In nearly all eukaryotic cells,Targeted treatment protocols are utilized after red cell lipid copper insertion into SOD1 is controlled by a copperanalysis has been completed at Kennedy Krieger Institute’s chaperone for SOD1 (CCS) that is also known to catalyze thePeroxisomal laboratory. We have noted sustained clinical oxidation of an unusual intra-subunit disulfide bond found inimprovement within the first few weeks after initiation of the holoenzyme. The nematode Caenorhabditis elegans is thetreatment in our 20 subjects with 20 to 40% reduction in only known eukaryotic organism that doesn’t have a genetremor. Continued IV and oral lipid therapy yields further coding for CCS, and its SOD1 apparently utilizes an alternativeimprovement as 50 to 60% reduction in tremor where pathway for activation. This CCS-independent activation isneurotoxic exposure is a complicating factor. also detected in mammalian cells where it is estimated to operate on approximately 20% of the SOD1 pool. Here weP-80 Pre-Doc Award Competition present the X-ray structures of apo and holo forms of SOD1PROTECTIVE EFFICACY OF BACOPA MONNIERI from C. elegans determined at 1.1 Å and 1.3 Å resolutionEXTRACT AGAINST ROTENONE INDUCED NEUROTOXIC respectively, and compare them to the known structures ofEFFECTS IN DROSOPHILA. Ravikumar Hosamani, K.N human and yeast SOD1. Unlike human SOD1, yeast SOD1 isChandrashekar and Muralidhara. Biochemistry & Nutrition, strictly CCS-dependent for copper activation. This comparisonCentral Food Technological Research Institute, Mysore, India established that although all three metal-bound enzymes have Bacopa monnieri (BM), referred to as Brahmi and used for only minor deviations in the canonical SOD1 fold, the structurecenturies in Ayurvedic system of medicine as a brain tonic/ of apo worm-SOD1 reveals remarkable differences in thememory enhancer possesses multi-pharmacological conformations of the electrostatic and zinc loop elements. Theneuroprotective properties. The Drosophila system provides a importance of the "opened" loop conformations in the contextsuitable model for understanding the mechanisms of of metal loading is discussed. This work was supported bydopaminergic neuronal dysfunction. The current study aimed to NIH-NINDS grant NS39112 (P.J.H), and NIH-NIGMS granttest the hypothesis that exposure of Drosophila to an ethanolic GM50016 (V.C.C.). Keywords: superoxide dismutase, ALS, C.extract of BM can protect against Rotenone (ROT) induced elegans.locomotor deficits, oxidative stress and mortality. Chronicexposure of Drosophila to ROT (a complex I inhibitor) is P-82demonstrated to recapitulate the main symptomatic feature of UTILIZATION OF DROSOPHILA SYSTEM TOParkinson’s disease (eg. selective loss of dopaminergic UNDERSTAND THE EMERGING ROLE OFneurons and locomotor deficits). Exposure of adult male flies PHYTOCHEMCIALS AS NEUROMODULATORS. Dr.(Oregon K) to an ethanolic extract of BM (0.05, 0.1 %, 7 d) Muralidhara. Biochemistry & Nutrition, Central Foodresulted in a significant (25%) diminution in the endogenous Technological Research Institute, Mysore, Karnataka ,Indialevels of lipid peroxidation (cytosol and mitochondria) with A large body of evidence indicates that oxidative stress isconcomitant elevation in the activity of Catalase, SOD and involved in the pathophysiology of neurodegeneration inGST. While ROT treatment (250,500 and 1000 μM, 7 d) Parkinson’s, Alzheimer’s and other neurodegenerativecaused significant mortality (20, 50 and 75 %) among flies, co- diseases. Oxidative stress can induce neuronal damage andtreatment with BM (0.1%) markedly reduced the lethality. BM modulate intracellular signaling ultimately leading to neuronalafforded robust protection against ROT induced locomotor death either by apoptosis or necrosis. Accordingly variousdeficits (measured in a negative geotaxis assay) as it markedly antioxidant polyphenolic compounds which can effectively(>75%) improved the locomotor performance of ROT flies. reduce or block neuronal death occurring in theFurther, ROT induced inhibition of complex I activity was pathophysiology of these neurodisorders can serve ascompletely restored to normalcy by BM treatment. Abrogation potential neuroprotective candidates. Chronic exposure ofof ROT induced oxidative stress by BM clearly suggests that its Drosophila to sublethal doses of rotenone (a complex Ineuroprotective effects are probably mediated through inhibitor) is demonstrated to recapitulate the main symptomaticmodulation of such mechanisms. These findings are consistent feature of Parkinsons disease. Since the Drosophila systemwith the hypothesis that BM ethanolic extract has propensity to provides a suitable model for understanding the mechanismsprotect against neurodegenerative processes and Drosophila of dopaminergic neuronal dysfunction, we have utilized thiscan serve as an effective screen prior to testing of model to understand the neuroprotective efficacy ofneuroprotective efficacy of phytochemicals in mammalian Phytochemicals. In this regard, we have tested the hypothesismodels. Keywords: neuromodulation, oxidative stress, whether exposure of Drosophila to ferulic acid (FA), quercetinneurotoxicity. (Q) can protect against ROT- induced locomotor deficits, oxidative stress, and lethality. Exposure of adult male fliesP-81 Post-Doc Award Competition (Oregon K) to ROT (500 and 1000 μM, 7 d) resulted in aSTRUCTURAL STUDIES OF WORM CU/ZN SUPEROXIDE significant lethality (50 and 75 %). Interestingly, co-exposureDISMUTASE. O. N. Pakhomova1,, J. P. Schuermann1,, L. T. with FA (0.1%) afforded total protection against ROT toxicity.Jensen2, V. Cizewski Culotta2, P. J. Hart1. 1Department of Only FA afforded robust protection against ROT inducedBiochemistry, University of Texas Health Science Center, San locomotor deficits (measured in a negative geotaxis assay). 2Antonio, USA, Department of Environmental Health Sciences, While FA alone had no effect on fly behavior, it markedlyJohn Hopkins University Bloomberg School of Public Health, (>50%) improved the performance of ROT flies. However, Q atBaltimore, USA. similar concentrations failed to protect against ROT induced Copper-zinc superoxide dismutase (SOD1) is a neurotoxicity. Significant amelioration of ROT inducedhomodimeric metallo-enzyme that converts toxic superoxide oxidative stress by FA indicates that the protective effects areradical anions into water and hydrogen peroxide, thereby most probably mediated through attenuation of oxidativeproviding defense against reactive oxygen species. Mutations stress. Our further studies are directed towards a betterNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 34understanding of the underlying biochemical mechanism/s by quantify the mRNA levels of serotonin, dopamine and GABAwhich FA protects the flies from ROT induced neurotoxicity receptors. The hippocampus showed dose-dependentand examine if similar protective effects can be reproduced in decrease in 5HTr2a, D2R and GABAa1. The cortex showeda ROT mouse model. Keywords: neuromodulator, oxidative significant decrease in 5HTr1a, 5HTr2a, D1R and GABAa1 atstress, neurotoxicity. 800 ppm, but did not extend this tendency at 1000 ppm. The pons-medulla showed decrease in 5HTr1a and 5HTr3a at 400P-83 Pre-Doc Award Competition ppm or over. The mRNA expressions of D2R in theSPLICE VARIANT SPECIFIC UPREGULATION OF hippocampus and 5HTR1a and 5HTR3a in the pons-medullaCA+2/CALMODULIN DEPENDENT PROTEIN KINASE 1G oblongata were the most sensitive indicators. The result 1BY PYRETHROID INSECTICIDES IN VIVO. J A Harrill , K M suggests that mRNA expression analysis is useful in 2 1Crofton . Curriculum in Toxicology, UNC-CH, Chapel Hill, NC, identification of the susceptible brain regions to 1BP exposure,2 Neurotoxicology Division, NHEERL, ORD, USEPA, RTP, NC. as well as providing potential biomarkers for the central Pyrethroid insecticides induce neurotoxicity in mammals nervous system toxicity.by interfering with ion channel function in excitable neuronalmembranes. Previous work demonstrated dose-dependent P-85 Pre-Doc Award Competitionincreases in expression of Ca+2/calmodulin dependent protein EXPRESSIONS CHANGES OF CYTOSKELETAL PROTEINkinase (Camk1g) mRNA following acute deltamethrin (DLT) AND RELATED PROTEIN KINASES IN CEREBRUMand permethrin (PERM) exposure. Camk1g exists in two CORTEX OF 2,5-HEXANEDIONE SUBCHRONIC TREATED +2 +2splice variants, Camk1g1 (Ca -sensitive) and Camk1g2 (Ca - RATS. Wang QingShan Student and Xie KeQin Advisor.insensitive). This study determines if changes in Camk1g Institute of Toxicology, Shandong University, Jinan, ShanDong,mRNA expression are due to changes in both splice variants or China.up-regulation of a single splice variant. Adult Long-Evans rats Occupational exposure to n-hexane produces a(n = 8 / group) were acutely exposed (p.o) with: PERM (1, 10, neuropathy characterized as a central-peripheral distal40, 100 mg/kg), DLT (0.3, 1, 3 mg/kg) or corn oil vehicle. axonopathy, which is mediated by 2,5-hexanedione (HD). ToCerebrocortical tissue was collected at 6 h post-dosing. In investigate the mechanisms of the neuropathy induced by HD,addition, rats were exposed to PERM (100 mg/kg) or DLT (3 the relative levels of cytoskeletal protein (NF-L, NF-M, phos-mg/kg) and cerebrocortical tissue collected at 1, 3, 6 or 9 hours NF-H, phos- & non-phos-NF-H, α-tubulin, β-tubulin and β-actin)with time matched vehicle controls. Expression of Camk1g1 and protein kinases or activator (PKA, PKC, CDK-5,and Camk1g2 mRNA was measured via quantitative RT-PCR. P35precursor, P35 and P25) in rats cerebral cortex wereDose-dependent increases in Camk1g1 mRNA expression determined. HD was administrated to Wistar rats bywere observed for DLT and PERM at 6 h (~2-fold). In addition, intraperitoneal injection at dosage of 200 or 400 mg/kg for 8a small increase in Camk1g2 was also observed at 6 h with weeks. The results showed that the levels of NFs sununitsDLT (<1.2-fold). The increases in Camk1g1 expression for (NF-L, NF-M, phos-NF-H, phos- & non-phos-NF-H) in both theDLT and PERM peak between 3 & 6 h post-exposure and supernatant and the pellet fractions significantly decreased inreturn to control levels by 9 h. Correlations demonstrated that the 200 and 400 mg/kg HD group rats, respectively. Significantdose- and time- dependent increases in Camk1g mRNA (P < 0.01) negative correlations between NFs levels and gaitexpression are due primarily to increases in the Camk1g1 abnormality were also observed. The contents of α-tubulin andsplice variant. Camk1g1 is a mediator of activity-dependent β-actin in the pellet fraction also decreased, while β-tubulin andneuronal morphogenesis and suggests that Camk1g1 β-actin contents in the supernatant increased significantly.upregulation may disrupt of this cellular process in the Expressions of PKC, CDK-5, P35precursor, P35 and P25developing nervous system. This abstract does not showed the same pattern with the NFs. They decreased innecessarily reflect the policy of the US EPA. Keywords: both the cytosolic and membrane fractions of rats treated withpyrethroid, dose-response, Ca+2/CaM-kinase 200 or 400 mg/kg HD. Thus, HD intoxication was associated with decline of NFs contents, and the disruption of NFsP-84 homeostasis between the phosphorylation andEFFECT OF 1-BROMOPROPANE EXPOSURE ON GENE dephosphorylation and followed by proteolysis might beEXPRESSION OF NEUROTRANSMITTER RECEPTORS ascribed to NFs proteins alteration. The reductions of NFs andAND EXPLORATION OF BIOMARKERS FOR THE decline of NFs phosphorylation status might be one of theCENTRAL NERVOUS SYSTEM TOXICITY. S Sahabudeen molecular mechanisms of HD-induced peripheral neuropathy.and G Ichihara. Department of Occupational & Environmental Keywords: neuropathy, cytoskeletal protein, phosphorylationHealth, Nagoya University Graduate School of Medicine,Nagoya, Japan P-86 1-Bromopropane (1BP), an alternative to ozone-depleting INVOLVEMENT OF CALPAINS IN THE PERIPHERALsolvents, is known to exhibit neurotoxicity and reproductive AXONOPATHY INDUCED BY 2,5-HEXANEDIONE. Songtoxicity in animals and humans. The present study investigated Fuyong and Xie KeQin. Institute of Toxicology, Shandongeffects of exposure to 1BP on gene expression of University, Jinan, ShanDong, China.neurotransmitters in the rat brain to explore possible Occupational exposure to n-hexane, or its neurotoxicbiomarkers for the central nervous system toxicity. Thirty six metabolite 2,5-hexanedione (2,5-HD) may produce a central-F344 rats were randomly divided into 4 groups of nine and peripheral axonopathy, the longest and largest distal axons areexposed to 1BP at 0, 400, 800 and 1000 ppm for 8 hrs/day; / preferentially targeted. To investigate the role of calpains ondays/week for 4 weeks. At the end of the experiment, rats the axonopathy induced by 2,5-HD, adult male rats werewere decapitated and the brain was dissected into the cortex, administered at a dosage of 400 mg/kg/day 2,5-HD for 8caudate putamen, midbrain hippocampus, amygdale, pons- weeks. The relative levels and total activity of m-calpain and μ-medulla oblongata and cerebellum. Total RNA from brain calpain in sciatic nerves at four time-points of HD neuropathyparts was extracted and real time PCR was conducted to were determined by immunoblotting and fluorescence assay.NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 35The levels of u-calpain in rat sciatic nerve were increased through parturition. Only pups were gavaged (same doses)significantly following HD. In the supernatant fraction, the from PND 1 through PND 22. Post-weaning dosing continuedcontents of u-calpain increased by 30% and 63% (P<0.01) at via drinking water. One male and one female per litter (7-9time point of week 4 and 8 respectively when compared to the litters/treatment group/sex) were tested under a PR schedulecontrols. Correspondingly, u-calpain increased by 31% and of food pellet reinforcement. Between 8 to approximately 1259% (P<0.01) respectively in the pellet fraction. As far as m- months of age rats were observed to have significantlycalpain is concerned, a similar elevation was observed only in reduced motivation as measured by number of reinforcersthe late stage of experiment. The levels of m-calpain in the earned (repeated measures ANOVA, P < 0.05), with Tukey’ssupernatant and pellet fractions increased by 46% and 61% post-hoc test showing significantly reduced motivation in the(P<0.01) respectively at time-point of week 8. Furthermore, the 0.3 mg/kg/day group when compared to the control group.total activity of m-calpain and μ-calpain increased by 14%, Reductions in motivation continued to be most prominent in the20% (p<0.05), and 34% (p<0.01) respectively on week 2 4 three highest dose groups as measured by both reinforcersand 8. These findings suggest that HD intoxication is earned and response rate. The control group alsoassociated with the progressive upregulation and activation of demonstrated the highest overall post-reinforcement pausecalpains, which might involve in the development of HD duration. No significant effect of ACR was observed on bodyneurotoxicity. Keywords: 2,5-hexanedione, calpain, toxic weight during this time period. These results suggest thataxonopathy. chronic ACR exposure produces reduced appetitive motivation in rats throughout their first year of life. Supported by ORISEP-87 Post-Doc Award Competition (JG) and NTP 224-93-0001. Keywords: acrylamide,THE REVERSIBILITY OF NEUROFILAMENTS DECLINE motivation, operant testing.INDUCED BY 2,5-HEXANEDIONE IN RAT SCIATICNERVES. Song Fuyong and Xie KeQin. Institute of P-89Toxicology, Shandong University, Jinan, ShanDong, China. EFFECTS OF CHRONIC ORAL ACRYLAMIDE EXPOSURE Exposure of humans and experimental rats to n-hexane ON INCREMENTAL REPEATED ACQUISITION (LEARNING)produces a central-peripheral axonopathy, the longest and PERFORMANCE IN ADULT FISCHER 344 RATS . M.G.largest distal axons are preferentially targeted. Metabolism Paule and J. Garey. Division of Neurotoxicology, Nationalstudies have suggested that the neuropathy induced by n- Center for Toxicological Research/FDA, Jefferson, AR, USAhexane is mediated by its metabolite, 2,5-hexanedione (2,5- Humans are exposed to the neurotoxicant acrylamideHD). To investigate the reversibility of the axonopathy induced (ACR) via the diet in starchy foods that have been exposed toby 2,5-HD, adult male rats were administered at a dosage of high cooking temperatures. The effects of relatively low levels400 mg/kg/day 2,5-HD (five times per week) for 2, 4 and 8 of ACR on learning were assessed in Fischer 344 rats using anweeks respectively. After stopping HD exposure, half of 8- incremental repeated acquisition (IRA) task. ACR-exposedweek treated animals were allowed to naturally recover for 16 Fischer 344 rats have been shown by our laboratory to haveweeks. The relative levels of NF-H, NF-M, and NF-L in sciatic altered IRA task performance by 4 months of age: rats treatednerves of rats were determined by immunoblotting during the with 5.0 mg/kg/day completed significantly less of the task thanHD neuropathy. The results showed that NFs content in nerve controls, and this observation continued through 8 months oftissues demonstrated a progressive decline as the intoxication age. The current study extends our assessment tocontinued. Furthermore, after a recovery of 16 weeks, the approximately 12 months of age. Subjects were treated sincelevels of three NF subunits in sciatic nerves displayed an implantation (gestational day 6): dams were gavaged with 0,inconsistent recovery. Among them, the level of NF-H in sciatic 0.1, 0.3, 1.0 or 5.0 mg/kg/day ACR through parturition.nerves returned to normal completely, and NF-L also showed a Gavaging continued at the same doses to pups only throughsignificant recovery, whereas NF-M in sciatic nerves did not postnatal day 22, after which dosing continued via theirdemonstrate an obvious recovery. These findings suggest that drinking water. One male and one female per litter (8-10 perHD-induced NFs decline is at least partially irreversible within treatment group) were tested. Rats learned new sequences ofthe time frame of this study, which might be associated with lever presses daily for food reinforcers. From approximately 8-the incomplete recovery of neurological dysfunctions of HD- 12 months of age, the previously noted effect of ACR ontreated rats. Keywords: 2,5-hexanedione, neurofilament, toxic percent task completed persisted. No significant effect of ACRaxonopathy. on task accuracy was observed. Response rate was highest in the control group and lowest in the 5.0 mg/kg/day treatmentP-88 Post-Doc Award Competition group; however, a comparison of the 5.0 mg/kg/day doseCHRONIC LOW-DOSE ACRYLAMIDE EXPOSURE group rate to that of controls was not statistically significant asREDUCES APPETITIVE MOTIVATION IN FISHER 344 RATS it was between 4-8 months of age. The results show that withBETWEEN 8 TO 12 MONTHS OF AGE. J. Garey and M.G. continued daily exposure, the effects of ACR on learningPaule. Division of Neurotoxicology, National Center for measures observed at 4 months of age have persisted throughToxicological Research/FDA, Jefferson, AR, USA one year of age. Supported by ORISE (JG) and NTP 224-93- Acrylamide (ACR) is a neurotoxicant found in minute 001.quantities in a wide range of human food items. While ACR isknown to produce peripheral neuropathy in rats and humans, P-90little is known of its ability to affect cognitive function. Our THE ROLE OF NMDA RECEPTOR REGULATION IN PCP- 1*previous work has shown that rats treated with ACR from INDUCED CORTICAL APOPTOSIS. Cheng Wang , Natalyagestation day 6 through 8 months of age demonstrated Sadovova , Xiaoju Zou , Sherry Ferguson , Merle Paule1 and 2 1 1reduced motivation in a food-reinforced Progressive Ratio (PR) William Slikker1. 1Division of Neurotoxicology, NCTR, FDA and 2task. The current study extends our work through Toxicologic Pathology Associates, Jefferson, Arkansas.approximately 12 months of age. Pregnant Fischer 344 dams Phencyclidine (PCP) is an N-methyl-D-aspartate (NMDA)were gavaged with 0, 0.1, 0.3, 1.0 or 5.0 mg/kg/day ACR receptor antagonist known to cause selective neurotoxicity inNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 36the cortex, although the exact mechanism by which it does so P-92 Pre-Doc Award Competitionremains unknown. The purpose of this study was to determine DEVELOPMENTAL PHENCYCLIDINE (PCP) OR KETAMINEwhether up-regulation of NMDA receptor subunits NR1, NR2A, TREATMENT INCREASES THE FREQUENCY OFand NR2B promote PCP-induced apoptotic cell death. A ABNORMAL ACTIVITY IN SPRAGUE-DAWLEY RAT PUPS.corticostriatal organotypic slice culture preparation was used to SY Boctor1,2, N Sadovova3, X Zou2, C Wang2, SA Ferguson2; 1determine the effects of antisense oligonucleotides on PCP- Dept. of Interdisciplinary Biomedical Science, UAMS, Littleinduced apoptosis and NR subunit upregulation. NR1, NR2A, Rock, AR, USA; 2Div. of Neurotoxicology, National Center for 3or NR2B (2 µM) antisense strands were added alone or with Toxicological Research/FDA, Jefferson, AR, USA; ToxicologicPCP (3 µM) for a 48 hrs incubation period. Cortical apoptosis, Pathology Associates, Jefferson, AR, USAmeasured using an ELISA assay for apoptotic cell death, was Developmental treatment with the N-methyl-D-aspartateseen in the PCP alone samples, as well as the NR2B (NMDA) antagonists, PCP or ketamine, can trigger apoptoticantisense plus PCP samples. Co-incubation of PCP with either neurodegeneration in nonhuman primates and rodents. SuchNR1 or NR2A antisense significantly reduced PCP-induced ketamine-induced apoptotic neurodegeneration may beapoptosis. Western analysis of treated cortex measured levels clinically relevant since ketamine is commonly administered toof the pro-apoptotic protein Bax, and showed that NR1 and pediatric patients. In this study, male and female Sprague-NR2A antisense plus PCP samples prevented the increase in Dawley rats were subcutaneously treated with: saline; 10Bax caused by PCP treatment. No significant effect was seen mg/kg PCP (1x/day) on postnatal days (PNDs) 7, 9 and 11; 20among treated striatum samples. These data suggest that NR1 mg/kg ketamine (6 injections every 2 hrs on PND 7 only); or aand NR2A antisense offers neuroprotection from apoptosis, similar regimen of ketamine and 250 mg/kg L-carnitine on PNDand that upregulation of the NR1 and NR2A subunits, following 7 with a single daily injection of 250 mg/kg L-carnitine on PNDsPCP administration, is at least partly responsible for the 8-11. Each litter (n=48) was culled to 8 pups (4/sex). Pupsobserved apoptotic DNA fragmentation. We will also present were randomly assigned to the 4 treatment groups (saline,Western blot data from the striatum that will determine whether PCP, ketamine, ketamine + L-carnitine) with 1the PCP-induced upregulation of NR subunits is selective for pup/sex/treatment/litter. Post-injection, the pups were returnedthe cortex. Supported by NTP and NCTR E-2155. Keywords: to the home cage with their dam and observed 4 times for thePhencyclidine, NMDA receptors, apoptosis. next 32 minutes. Observations were conducted by testers blind to experimental treatment. At each observation, the behavioralP-91 state of each pup was categorized as normal activity (active,PROTECTIVE EFFECTS OF 7-NITROINDAZOLE ON grooming), abnormal activity (paddling, paresis, wall climbing),KETAMINE-INDUCED NEUROTOXICITY IN RAT or normal inactivity (quiet, nursing). On PND 7, ketamine-FOREBRAIN CULTURE. N. Sadovova1, C. Wang2, T.A. treated pups exhibited significantly higher levels of abnormalPatterson2, X. Zou2, X. Fu3, J.P. Hanig4, M.G. Paule2, S.F. Ali2 activity than the control or ketamine + L-carnitine-treated rats.and W. Slikker, Jr.2 1Toxicologic Pathology Associates, The ketamine- and ketamine + L-carnitine-treated pups wereJefferson, AR; 2Division of Neurotoxicology and 3Division of not significantly different from the control pups or from eachBiochemical Toxicology, National Center for Toxicological other on PNDs 8-11. PCP-treated pups displayed significantlyResearch/U.S. Food & Drug Administration, Jefferson, higher levels of abnormal activity on PNDs 7, 9 and 11 4AR:, and Center for Drug Evaluation and Research/U.S. Food compared to the other treatment groups. Thus, levels of& Drug Administration, Silver Spring, MD abnormal activity were elevated only on treatment days and Ketamine, a noncompetitive N-methyl-D- only for ketamine or PCP treatment groups. There were no sexaspartate (NMDA) receptor antagonist, is used as a general differences. Thus, developmental PCP or ketamine treatmentanesthetic in infants. Recent data suggest that anesthetic caused an acute increase in abnormal activity in Sprague-drugs may cause neurodegeneration during development. The Dawley rat pups. (This work was supported through anpurpose of this study was to determine the dose and temporal interagency agreement (IAG no. 244-93-001) between theresponse of Ketamine-induced toxicity using newborn rat National Institute of Environmental Health Sciences/NIH, andforebrain cultures and also to determine if co-administration of the National Center for Toxicological Research/FDA, in support7-nitroindazole, a neuronal nitric oxide synthase (nNOS) of the activities of the National Toxicology Program.)inhibitor, could protect or reverse ketamine-induced cell death. Keywords: development, ketamine, behavior.Neural cells collected from the rat forebrain were incubated for24 hrs with 1, 10 or 20 µM ketamine alone or with Ketamine P-93(10µM) plus 1, 5, 10 or 20 µM 7-nitroindazole. Ketamine CO-EXPOSURE OF HEAVY METALS AND PSYCHO-caused an increase in DNA fragmentation and elevated STIMULANTS ALTER DOPAMINE TRANSPORTER (DAT)immunoreactivity to nitrotyrosine, a marked reduction in the DENSITY WITHOUT CHANGES IN DAT FUNCTION. ANexpression of the neuronal marker polysialic acid neural cell Hood and DR Wallace. Department of Forensic Science,adhesion molecule (PSA-NCAM) and a reduction in Oklahoma State University Center for Health Sciences, Tulsa,mitochondrial metabolism, as well as a decreased BCL-XL/Bax Oklahoma, USAratio. No significant effect was observed in the release of Scope and Method of Study: Heavy metals may alter thelactate dehydrogenase (LDH). Ketamine-induced neurotoxic abuse liability of drugs due to actions on the dopamineeffects were effectively blocked by 7-nitroindazole (10µM). transporter (DAT). This study examined the effects ofThese data indicate a role for nitric oxide in the enhanced extended, low-level heavy metal and psychostimulant co-degeneration induced by ketamine in vitro and also suggest exposure on DAT function. SK-N-SH cells, incubated in thethat blocking nNOS may help reduce the risk of using ketamine presence of multiple concentrations of lead (Pb), mercury (Hg),in pediatric anesthesia. (Supported by Interagency Agreement cocaine (COC) and methamphetamine (MA), to determine#224-93-0001 between the NCTR/FDA and the NIEHS/NTP). optimum time/concentration for non-lethal exposure assays.Keywords: Ketamine, Apoptosis, 7-Nitroindazol. DAT studies were conducted in N2A cells expressing hDAT. [3H]GBR12935 binding assays were performed to determineNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 37DAT expression at the plasma membrane. [3H]Dopamine (DA) neurotransmitter function. Keywords: membrane estrogenuptake assays were conducted to establish effects on DAT receptors, dopamine efflux, xenoestrogens.functionality. Findings and Conclusions: Following LDH assayoptimization, non-lethal concentrations of drugs and metals P-95 Post-Doc Award Competitionwere chosen (10 μM for HgCl2 and PbCl2; 100 nM for COC THE EFFECTS OF METHYLPHENIDATE ON RHESUSand MA) and a 72 h exposure was selective for subsequent MONKEY PERFORMANCE IN AN OPERANT TESTstudies. DAT density increased when exposed to Hg (146%), BATTERY. JS Rodrigueza, SM Morrisb, CE Hotchkissc, DRPb (175%), COC (115%), or MA (131%) compared to vehicle Mattisond and MG Paulea. aDivision of Neurotoxicology, bvalues. When treatments were combined, DAT density Division of Genetic and Reproductive Toxicology, and cTheincreased in Hg+MA (161%), Hg+Pb+Coc+MA (227%), and Bionetics Corporation; National Center for ToxicologicalHg+Pb (288%). Studies showed the largest increase in DA Research, FDA, Jefferson, AR, and dObstetric and Pediatricuptake when exposed to treatment groups containing MA (35- Pharmacology Branch, National Institute of Child Health and81%), whereas COC groups inhibited uptake (17-20%). Human Development, NIH, Bethesda, MDOverall, a trend was observed where DAT density was This study investigated the effects of chronicincreased, but functional decreases in DA clearance were methylphenidate (MPH) treatment on juvenile rhesus monkeyobserved. Collectively, exposure to low-levels of heavy metals operant behavior. MPH is an amphetamine derivative whichmay increase the risk for altered DA neurotransmission/ has been shown to enhance human performance in someturnover following psychostimulant use, resulting in an operant tasks. MPH, widely prescribed for the treatment ofelevated addictive, or toxic, potential of these already addictive attention deficit-hyperactivity disorder, was administered todrugs. (Work supported by NIH DA13137 to DRW). juvenile non-human primates to determine its effects on the performance of tasks in the NCTR Operant Test Battery (OTB).P-94 Pre-Doc Award Competition The OTB tasks included Progressive Ratio (PR), ConditionedEFFECTS OF ESTRADIOL AND XENOESTROGENS Position Responding (CPR), Delayed Matching-to-SampleON DOPAMINE TRANSPORT. Rebecca A. Alyea1, Kathryn (DMTS) and Incremental Repeated Acquisition (IRA), whichA. Cunningham2, and Cheryl S. Watson1. Department of assess aspects of motivation, color discrimination, short-termBiochemistry & Molecular Biology, Univ. of Texas Medical memory and learning, respectively. Here, juvenile male 2Branch, Galveston TX 77555-0645; Department of monkeys (n=10/group) pressed levers and press-plates forPharmacology & Toxicology, Univ. of Texas Medical Branch, banana-flavored food pellets. Subjects were treated orally,Galveston TX 77555-1031 twice a day, five days per week (M-F) for 66 weeks with The effects of 17β-estradiol (E2) and xenoestrogens (XEs) escalating doses (0.15 mg/kg gradually increased to 2.5 mg/kgon dopamine (DA) transport may have important implications from weeks 23 to 31 for the low dose group, and 1.5 mg/kgfor gender and life stage differences in the incidence of increased to 12.5 mg/kg from weeks 23 to 27 for the high doseneurological disorders. We tested the activities of E2 compared group) and tested in OTB tasks on Mon-Fri for 30 to 60to XEs, such as organochlorine pesticides [dieldrin, minutes after the morning dose. The findings indicate thatendosulfan, o’,p’-dichlorodiphenylethylene (DDE)] and plastics MPH treatment significantly inhibited performance in the high-manufacturing by-products/ detergents [nonylphenol, bisphenol dose (12.5 mg/kg) group as compared to the vehicle control,A] cause DA efflux patterning different from that of E2-mediated and low-dose groups from weeks 43-66. The percent taskDA efflux in a continuous cell line (PC12) used as an in vitro completed and response rates were reduced in the high-dosemodel for neuronal cell function. The activity of the DA group in all tasks during that time. There was a generaltransporter (DAT) was determined by measuring the specific decrease in performance in the high-dose group at the 3.0 (6.0efflux of 3H-DA from preloaded cells. Low concentrations (10-14 daily), 6.0 (12.0 daily) and 12.5 (25.0 daily) mg/kg doses, asto 10-8 M) of E2 administered for 9 minutes caused DA efflux compared to the low-dose and vehicle groups. These effectsvia the DAT. Such rapid estrogenic action suggests a non- of methylphenidate seem primarily due to decreases ingenomic, membrane-initiated response mechanism. Using motivation to perform for food, although response accuracyreceptor specific agonist/antagonists and siRNA knockdown for (ability to solve problems) is also affected. Funding:ERα, ERβ, and GPR30 we determined that DA efflux at 9 InterAgency Agreement between the NICHD and the NCTR.minutes is regulated by E2 via the ERα. Specific inhibitorblockade of protein kinase C prevented E2-mediated DA efflux, P-96suggesting involvement of an altered phosphorylation state of USING OPERANT RESPONSE ACQUISITION TO ASSESSDAT, which may also cause a change in subcellular location, MOUSE MODELS OF ALZHEIMER’S PATHOLOGY. TJas shown for other regulated DAT activity changes. DES, a Zarcone3, A Sagare1, R Deane1, RD Bell1, N Paquette1, D 3 2 2 1 1 1synthetic estrogen, nonylphenol, DDE, and BPA at 1nM Carbonari , R Pendu , PJ Lenting , Z Wu ,& BV Zlokovic .caused rapid DA efflux, with all XEs displaying distinct Frank P. Smith Laboratory for Neuroscience and Neurosurgicaloscillatory patterning. For example, at 5 minutes BPA caused Research, Department of Neurosurgery, University ofsignificant DA efflux while E2 did not; the peak of E2-induced Rochester Medical School, Rochester, New York 14642, USA. 2efflux occurred at 15 min. We chose the optimal DA efflux time Laboratory for Thrombosis and Haemostasis, Department ofpoint for each XE and then determined the dose response for Hematology, University Medical Center Utrecht, 3584 CX -14 -8XE concentrations ranging from 10 to 10 M; XEs caused Utrecht, The Netherlands. 3 Neurobehavioral Facilitydose-response patterns distinct from that of E2. For example, Laboratory, Department of Environmental Medicine, University -14 -11DDE at 10 to 10 M caused significant inhibition of DA efflux of Rochester Medical School, Rochester, New York, USA.when compared to the efflux-promoting effects of E2 at these Mouse models of neurological disorders are created toconcentrations. These data demonstrate that low levels of probe their underlying mechanisms and to test potentialenvironmental contaminants can act as endocrine disruptors treatments. Those models that include behavioral endpointsby altering DA efflux patterns. Thus physiological and often require extensive training or habituation and rely onnonphysiological estrogens can differentially affect labor-intensive human observation or scoring. Such limitations,NTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 38together with experimental designs requiring group sizes able developing nonhuman primate. It is essential that moreto meet statistical requirements, excludes many behavioral information be gathered concerning the neurotoxic potential, ormodels as too complicated and costly. Automated learning lack thereof, of compounds from this very important class oftasks can solve such dilemmas. The present experiment therapeutic agents that are designed to affect central nervousdevised an automated operant acquisition task to assess the system function. Funding: CRADA 119-06 with Boehringerfunctional effects of human brain amyloid-beta over expression Ingelheim Pharmaceuticalsin genetically-engineered mice (APP+/sw) and treatment withlow-density lipoprotein receptor–related protein-1 (LRP-1). P-98During this task, mice were required to poke response holes to RACE-GENE-ENVIRONMENT INTERACTIONS AND +/swearn a liquid reinforcement. Untreated APP mice emitted NEUROTOXICOLOGY: MULTIPLE ENVIRONMENTAL ANDfewer operant responses than control mice. The performance GENETIC VULNERABILITIES TO TOXINS. Roger D. +/swof APP mice treated with LRP-1 more closely resembled Masters. Department of Government, Dartmouth College,that of control mice. Amyloid-beta levels in mouse brain were Hanover, NH 03755, USAalso reduced by LRP-1 treatment. These findings suggest that The importance of multiple genetic and environmentalamyloid-beta levels play a role in the performance of learned factors (including race, social status, and location of residence)behaviors. Moreover, an additional benefit of such operant is likely to be greatly increased by recent findings in behavioraltasks is that by further training and modification of the genetics and environmental toxicology. Such a multi-factorialenvironmental contingencies, operant procedures can be used approach is reinforced by findings of gene-environmentto examine specific motor, sensory, learning, and memory interaction in the etiology of Autism, ADHD, Alzheimers anddeficits symptomatic of many neurological disorders. Asthma. Racial differences are evident in the different rates ofSupported by R37 AG023084, R37 NS34467, & P30 ES01247 lactose intolerance among Blacks and Whites, which affects calcium intake and apparently contributes to the higherP-97 absorption of lead among Blacks we’ve found in three largeASSESSING THE EFFECTS OF CHRONIC DOPAMINERGIC geographic surveys of children’s blood lead levels. Since(D3) AGONIST ADMINISTRATION ON COMPLEX BRAIN social status in males can also influence neurotransmitterFUNCTIONS IN JUVENILE RHESUS MONKEYS USING THE functions, there are many other indications of gene- 1 1NCTR OPERANT TEST BATTERY. T.A. Patterson , M. Li , environment interaction that replace the traditional “one germ, 2 3 3 1C.E. Hotchkiss , A. Mauz , M. Eddie and M.G. Paule . one disease” model of causation in medicine. In1 Division of Neurotoxicology, National Center for Toxicological neurotoxicology, single causes will increasingly be thrown into 2Research/U.S. FDA, Jefferson, AR, The Bionetics new light by findings of multiple environmental risk co-factors 3Corporation, Jefferson, AR and Boehringer Ingelheim Pharma and interactions like those just cited. Instead of focusing onGmbH & Co. KG, Biberach/Riss, Germany the "Maximum Contaminant Limit" ("MCL" -- 50% of lethal The effects of long-term dopaminergic stimulation on the dose) of a toxin, targeted enzymes and functions willability of juvenile rhesus monkeys to learn how to perform increasingly be considered in the light of genetic as well asseveral of the complex behavioral tasks contained in the social class vulnerability and geographic measures ofNational Center for Toxicological Research (NCTR) Operant environmental risk factors. Empirical data will be presentedTest Battery (OTB) were examined using a relatively selective to illustrate this multivariate interactive paradigm in my studiesagonist at dopamine (DA) D3 receptors. Previous studies in of the neurotoxic effects of lead and manganese.our laboratory have demonstrated that several OTB tasks inmonkeys are sensitive to the acute effects of drugs that affect P-99the DA system (e.g., methylphenidate, amphetamine), but the TOXICOLOGY IN THE KITCHEN: POLYHEDRAL GRAPHICconsequences of long-term or chronic exposure to such agents MODELING IN FOOD TOXICOLOGY, ENVIRONMENTALremain unknown. The nonhuman primate has proven to be an NEUROSCIENCE AND NUTRITION. BW Whitman, Mentalexcellent surrogate for studying drug effects on complex brain Health and Behavioral Sciences Services, Carl T. Hayden VAfunction in humans, and our laboratory has a long history with Medical Center, Phoenix, Arizonathis animal model. The OTB tasks included Progressive Ratio While the literature is replete with studies in the realm of(PR), Conditioned Position Responding (CPR), Delayed food toxicology and nutrition, there is a relative paucity ofMatching-to-Sample (DMTS) and Incremental Repeated research regarding the integrated juxtaposition of the diverseAcquisition (IRA), which assess aspects of motivation, color- elements pertaining to food toxicology parameters, and theposition discrimination, short-term memory and learning, manner in which they might dynamically interact. Organizingrespectively. Juvenile rhesus monkeys (n=7-8/group; 22-24 these factors within an organized taxonomy and integratedmonths of age) were treated daily for 180 days with vehicle or model might strategically assist in identifying key insights toa low (0.1), medium (0.5) or high (2.0 mg/kg) dose of a D3 create protective measures and anticipatory guidanceagonist. Subjects were assessed daily for 50 minutes using protocols to minimize public health risk and mitigate disease.the OTB, in which they were required to press levers and Polyhedral modeling has been used in other scientificpress-plates to receive banana-flavored food pellets. Testing disciplines. The application and demonstration of polyhedralwas performed prior to the subjects receiving their daily dose graphic modeling for exploratory problem-solving in foodto decrease the possibility of examining acute rather than neurotoxicology and environmental neuroscience is proposedchronic drug effects. Peak plasma levels of all three doses of here as an approach to clarify these important issues. Thesethe compound occurred within the first two hours after dosing. models will demonstrate visually through spatially juxtaposedThe behavioral findings indicate that treatment did not alter multiplanar geometric surfaces how risks, causal forces andperformance in the OTB compared to the vehicle control modulators would relate to one another and the resultantgroups. This experiment represents the first known attempt to dynamic nexi which occur as the multidimensional character ofdetermine the effects of chronic treatment with a dopamine D3 the model slightly changes. The innovative application of thisreceptor agonist on emerging behavioral capabilities of the interdisciplinary modeling technique in this setting may haveNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 39profound impact in helping to unravel the web of complex specialists and public health professionals to share theirrelationships between toxicants, environmental milieu, human knowledge of agents that affect human and environmentalbehavior and risk modifiers. In this graphic model, the fixed health. The goal of Toxipedia is to be a definitive, yetfocal point is determined to be the milieu of the kitchen and accessible, information resource on the hazards and history ofeating area of the home, where foods and ingredients are chemical and physical agents, regulatory requirements, andorganized, prepared, cooked and eaten. This is the sentinel risk management. As an inter-related web, Toxipedia is a newzone intrinsic in this exploration since it is where the primary tool for scientific information exchange and communication tooccurrence of putative exposure occurs. The toxicologic and with the public, the media, students, NGOs, legislators,aspects of food science and nutrition, with focus on the and practicing professionals. This unique platform provides ankitchen, continues to warrant significant research exploration. interrelated web of information that grows as the toxicologicalGraphic modeling techniques will facilitate this through a better sciences advance and reshapes how we communicateunderstanding of many food toxicology complexities including scientific information. The accuracy and credibility of Toxipediapotentially deleterious food constituents, maladaptive food will be supported by subject-specific associate editors using achoices/eating behaviors, accidental plant based toxicological four-tiered review system. The highest level of review willexposures, suboptimal preparation techniques, ingestion of require peer review, not unlike peer-reviewed professionalmicrobially-derived toxicologically contaminated food products, publications, that can be periodically updated through aand food spoilage/storage paradigms Related risk modifiers rigorous review process. There will be an extensive referenceincluding age, toxicant dose and genetic heterogeneity are also list that will encourage users to explore the primary literature.addressed in the model. Lower levels of review will have progressively less oversight coupled with review-level disclaimers. Providing information onP-100 Toxipedia is a way to satisfy our ethical responsibility to shareFROM SCIENCE TO POLICY: THE LEARNING AND knowledge and advance the science of toxicology to enhanceDEVELOPMENTAL DISABILITIES INITIATIVE. Elise Miller, human, animal and environmental health. Keywords:MEd, Executive Director, Institute for Children’s Environmental Education, information, internet.Health, Freeland, Washington, USA. According to recent studies, the incidence of learning and P-102developmental disabilities appears to be rising, affecting ALTERNATIVE COMMUNITY BASED APPROACH –between 5-15% of children in the U.S. under the age of 18. PRECAUTIONARY ASSESSMENT. SG Gilbert. Institute ofMany factors – heredity, gene expression, social environment, Neurotoxicology & Neurological Disorders, Seattle, WA, USAnutrition and chemical contaminants – contribute to brain Precautionary assessment is a tool that allows the user todevelopment in complex ways. Chemical contaminants, go beyond the principles of risk assessment to include anhowever, have historically been the least research and are the explicit recognition of our values and ethics. Quantitative riskmost preventable. Emerging science suggests that exposures assessment was defined in a 1983 report by the Nationalto certain neurotoxicants such as lead, mercury, pesticides, Research Council as including four basic elements: hazardpolychlorinated biphenyls (PCBs), brominated flame identification, dose-response assessment, exposureretardants, solvents and other known and suspected assessment, and finally risk characterization. Initial efforts wereneurotoxicants can contribute to neurological problems focused on defining a numeric probability for developingincluding learning and developmental disabilities (LDDs). In cancer, which evolved into quantitative risk assessment. Thethis context, the Learning and Developmental Disabilities goal of precautionary assessment (PA) is to move beyond riskInitiative (LDDI), as one of the major working groups of the assessment and allow communities and individual toCollaborative on Health and the Environment (CHE), incorporate their knowledge, values and ethics into a morecoalesced in 2002 to encourage the LDD sector to look comprehensive evaluation of a hazardous condition. The PAcollectively upstream, and in addition to their other efforts, help combines the philosophy and ethics of the precautionaryprevent toxic threats to child development. LDDI has engaged principle with the standard scientific evaluation of the hazards.four major national LDD organizations to leverage educational PA contains three basic area of assessment: a) communityand policy efforts on national and state levels and has over 300 and social issues, b) exposure, and c) hazard and toxicity.institutional members collectively representing over 500,000 Each element is broken down into a series of questions thatconstituencies across the United States. In addition, LDDI are scored numerically to produce a summary score for eachrecently published a scientific consensus statement on the element. The PA is designed to help place the knowledgestate of the science regarding environmental contributors and available within the context of the community. In contrast to theis also working with CHE’s Parkinson’s Disease and the traditional risk assessment, the PA is a more comprehensiveEnvironment Working Group to highlight both the approach to evaluating the human and environmental healthneurodevelopmental and neurodegenerative properties of risks. The vision is that community members can use to PAsome environmental factors. approach to define a more comprehensive evaluation of a situation. Keywords: Precautionary principle, risk assessment,P-101 community.TOXIPEDIA: CONNECTING SCIENCE AND PEOPLE. SGGilbert. Institute of Neurotoxicology and Neurological P-103Disorders, Seattle, Washington, USA NEUROTOXICITY OF ARSENIC ON EXPOSED WORKERS 1 2 1 One of the great challenges facing the toxicological L. Fat and M. Ghita . Occupational Health Department,sciences is communicating scientific information in a manner Institute of Public Health, Cluj-Napoca, Romania, 2Neurologicalthat creates an informed public. Currently there’s no easy way Department, County Hospital, Baia Mare, Romaniafor a specialist to share their knowledge with the public or even Introduction. The scientific literature shows that theother scientists. Toxipedia (www.toxipedia.org) is a new wiki- exposure to arsenic can determine changes in the organismsite concept that is designed to encourage toxicology reactivity, increase the sensibility to pathogen agents, stressNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
  • November 11-14, 2007 ABSTRACTS Page 40and toxics, generating a variety of pathology with long Centers for Diseases Control and Prevention. 172 Jiangsu brecovery. In the acute and chronic exposure to arsenic the Road, Nanjing, Jiangsu Province, 210009, P.R. China.most common neurological manifestation that occur is the Department of Occupational Health, School of Public Health,peripheral neuropathy initial with symmetrical stocking-and- Fudan University, P.R. China. c Center for Disease Control andglove paresthesias and pain accompanied by distal weakness Prevention, Sihong County, Jiangsu Province, Nanjing,P.R.and then with proximally progression of sensory and motor China. 210009 P.R. Chinadeficits. The objective of the study was to analyse the SUMMARY: Blood samples were collected from 512presence of the neurotoxic effects on workers chronically children, aged 8-13 years, living in two villages with differentexposed to arsenic (either arsenic trioxide As2O3 or arsenic levels of fluoride concentrations in drinking water. Serumpentoxide As2O5) and to assess the occupational exposure to fluoride was measured use minitype fluoride ion selectivearsenic. electrode, and children’s intelligence quotient (IQ) was Methods. We investigated biotoxicological and measured with the Combined Raven’s Test for Rural Chinaneurological a group of workers from a non-ferrous (CRT-RC). In the high fluoride village of Wamiao (Mean ofmetallurgical plant, with many occupational diseases, fluoride in drinking water: 2.47±0.79 mg/L, with a range ofespecially chronic intoxication with arsenic. The workers’ mean 0.57~4.50 mg/L), the mean concentration of fluoride in serumage was 35.7±5 years and their mean time of exposure was was 0.081±0.019 mg/L while average IQ was 92.02±13.00, in13.4±7 years. We made clinical and complete neurological the low fluoride village of Xinhuai (mean: 0.36±0.11 mg/L,exams and biotoxicological investigations: urine, hair and nail range: 0.18~0.76 mg/L), the level of fluoride in serum andarsenic. In the same investigation program we also used children’s IQ were 0.041±0.009 mg/L and 100.41±13.21. Thestandard questionnaire on specific symptoms for long term and regression coefficient between serum fluoride levels andhigh level exposure to arsenic. A group with minor signs of children’s IQs was –0.163 (p=0.015) in Wiamiao village, andclinical neuropathy was selected for electromyography (EMG) 0.054 (p=0.362) in Xinhuai village. When the data from 512and nerve conduction velocity registering. The concentration children in both village were considered as a whole, theof arsenic at the workplaces exceeded the admissible children were divided into five subgroups according the level ofconcentrations. serum fluoride, higher serum fluoride concentrations were Results. High values of urine and hair-nail arsenic, over significantly associated with higher rates of IQ score <80. Thethe physiological values were found in 69.8% workers; 13.2% BenchMark Dose (BMD) and the lower-bound confidence limithad polyneuropathy with symmetrical distribution (pains, on BMD (BMDL) of serum fluoride concentration were 0.077paresthesias, hypestesias); 50% were alcohol drinkers. The mg/L and 0.064 mg/L. The reference value dose (RfD) ofspecific clinical syndromes in long term arsenic exposure were serum fluoride among children aged 8-13 years was set topresented in 15-75% of the investigated people: 0.064 mg/L. The IQ was not related to family income, age, andastenovegetative syndrome 75%, pseudoreumatic syndrome parent’s education level. There was significant positive42.5%, dyspeptic syndrome 15%. Family history of high blood relationship between serum fluoride and drinking water fluoridepressure: 27,5% cases. EMG on ulnar and sciatic popliteal (Pearson correlation coefficient = 0.860, p < 0.001). Theextern nerves showed a delayed motor conduction velocity in results indicated that fluoride in drinking water was the main3 cases and values at the lower normal level for the rest. The source of fluoride intake in Wamiao and Xinhuai village, anddetection exam on the ulnar nerve and for SPE nerve there were possibly more than 90% of children would have IQsuggests a pathological troncular neurological compensated higher than 80 when the serum fluoride below 0.064 mg/L.registration. Keywords: Fluoride in serum, Fluoride in drinking water, Conclusion. We found a concordance between the Intelligence quotient.neurological parameters, clinical examinations andbiotoxicological investigations. All the selected cases withneurological complaints proved to be real sensitive toxic ∼ Notes ∼polyneuropathy, more or less severe, in connections either withthe length of the toxic exposure or the alcohol consumption.The workers with greatest and long term arsenic exposure hadthe most frequently neurological signs and symptoms. Thenerve conduction study showed a delayed motor conductionvelocity. Electromyography being able to detect subclinicalpolyneuropathy, we could extend this examination to exposedpersons without clinical manifestations. Taking into account thegreat number of people with high arsenic values the factoryneed to take preventive measures for decreasing the arsenicconcentrations in the environment, the obligativity to use theprotective equipment and objectives for prevention thediseases. Keywords: Arsenic exposure, neurotoxicpolyneuropathy, electromyopraphy.P-104SERUM FLUORIDE LEVEL AND CHILDREN’SINTELLIGENCE QUOTIENT IN TWO VILLAGES IN CHINA. a b bXiang Quanyong , Liang Youxin , Chen Bingheng , Chen a a aLiansheng , Wang Caisheng , Chen Xiaodong , ZhouMingsheng c. a For correspondence: Xiang Quanyong,Department of Environmental Health, Jiangsu ProvinceNTX XXIV: Environmental Etiologies of Neurological Disorders San Antonio, Texas
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