Long-term behavioural effects of
  developmental exposure to
      organophosphates




                   Ora Kofman
    ...
Why is pesticide exposure in children
different from exposure in adults?

Neurotransmitters and related enzymes
have neuro...
Formation of synapses continues after birth and is influenced
by sensory stimulation and learning, drugs and toxins.


   ...
Neonatal rats injected unilaterally with basal forebrain
ACh neuronal toxin on day of birth and postnatal day 2
show reduc...
Control        Lesioned     Control         Lesioned




Neonatal rats injected with ACh neuronal toxin on
P0 and P2 show ...
Prenatal exposure to OP pesticide alters cortical thickness and gene expression
Exposure


Accidental   Chronic
poisoning    low dose
             exposure
% cases recorded
                        Plants       Rat      Cleaning   Medicine    Pesticide   Kerosene
               ...
Who is at risk?
•In urban and rural areas high levels of
pesticides have been found in blood
of pregnant women and cord bl...
Exposure during pregnancy

   Young et al. Neurotoxicology 2005 :

Total metabolite levels of OP pesticides associated
wit...
Exposure during pregnancy

 Eskenazi et al. Env Health Perspect 2007

Followup of children exposed in utero to OPs at
6, 1...
Exposure during pregnancy
Grandjean et al., Pediatrics 2006
Impaired visual memory (Stanford Binet
drawings) and copying
d...
Exposure during childhood

 Grandjean et al., Pediatrics 2006

 Participants: Children in Ecuador
 whose mother work in fl...
Exposure during childhood
Rohlman et al., Neurotoxicology
2005

Slower motor performance (tapping)
Summary: Exposure to OPs during early development:
             from birth to childhood

        Foetus -Infant           ...
Motor Inhibition and Learning Impairments in School-Aged
      Children Following Exposure to Organophosphate Pesticides i...
Hospitalizations under age 3 with acute
   poisoning at Soroka University Medical
    Center. More than 90% of poisonings
...
Statue and Knock-Tap tests from
NEPSY battery.


Inhibition and ability to ignore distraction
Stand like a statue with eye...
Statue


Number of points (Mean + SEM)
                                                                         Knock Tap
...
12                                                                              Control OP
                               ...
Future Directions
    Exploring Gene x exposure interactions in rodents


AChE I inhibitors or stress induce alternate spl...
Forced swim test- prolonged immobility is
regarded as enhanced depression (helplessness)
Stages of brain development dependent on induction of genes
   240

at different stages. Development is influenced by subs...
Elevated plus maze: Rodent
                                       test for anxiety
                                       ...
Future Directions
 Exploring Gene x Exposure Interactions in rodents

Injection of DFP in mice at age 4-10 or 14-20 days

...
THANKS
                                                    Ali Massarwa
    Andrea Berger, PhD
                           ...
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Env Hlth Coalition June 10 09 Haifa

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Env Hlth Coalition June 10 09 Haifa

  1. 1. Long-term behavioural effects of developmental exposure to organophosphates Ora Kofman Department of Psychology Zlotowski Centre for Neuroscience Ben-Gurion University of the Negev Beer-Sheva
  2. 2. Why is pesticide exposure in children different from exposure in adults? Neurotransmitters and related enzymes have neurotrophic roles. Cholinergic markers appear at the same time that synaptogenesis, pruning, thalamic and cortical stratification occur in the developing brain. The high level of AChE prior to the development of cholinergic projections, suggests that it has a role in neuronal growth.
  3. 3. Formation of synapses continues after birth and is influenced by sensory stimulation and learning, drugs and toxins. migration
  4. 4. Neonatal rats injected unilaterally with basal forebrain ACh neuronal toxin on day of birth and postnatal day 2 show reduced cortical thickness. Cerebral Cortex 1998 8:142-155
  5. 5. Control Lesioned Control Lesioned Neonatal rats injected with ACh neuronal toxin on P0 and P2 show reduced number of dendrites (A vs B) dendritic spines (C vs D) and axons (E vs F). Robertson et al. Cerebral Cortex 1998 8:142-155
  6. 6. Prenatal exposure to OP pesticide alters cortical thickness and gene expression
  7. 7. Exposure Accidental Chronic poisoning low dose exposure
  8. 8. % cases recorded Plants Rat Cleaning Medicine Pesticide Kerosene poison agents and drugs Mush- rooms Sri Lanka 8 8 51 12 Over age 30 includes suicide attempts Senanayake & Karalliedde, Forensic Sci Int 1988 Trinidad 9.4 21.8 15.9 19.5 Children <16 Pillai, Boland, Jagdeo and Persad, West Indian Med J. 2004 India 9 6.7 20.9 42.5 Children 1-3 Sarker, Ghosh, Barik Indian J Public Health 1990
  9. 9. Who is at risk? •In urban and rural areas high levels of pesticides have been found in blood of pregnant women and cord blood at birth. •Children in agricultural communities: Drift from fields Pesticides on clothes, shoes of parents •Inner city children have higher exposure than children in the suburbs. Dilworth Bart and Moore, Child Development, 2006 Castorina et al. Env Health Perspect 2003 Whyatt et al. Toxicol Appl Pharmacol 2005 Curwin et al. Environmental Health 2007
  10. 10. Exposure during pregnancy Young et al. Neurotoxicology 2005 : Total metabolite levels of OP pesticides associated with abnormal reflexes on the Brazelton assessment. Abnormal reflexes: Rooting Passive Leg Resistance Incurvation Moro
  11. 11. Exposure during pregnancy Eskenazi et al. Env Health Perspect 2007 Followup of children exposed in utero to OPs at 6, 12 and 24 months. •Association between OP metabolites and lower scores on Mental Development Index of Bayley. •Association between OP metabolites and PDD (Pervasive Developmental Disorder) scale of CBCL (Child Behavioral Checklist) at 24 months. •No effects on attention deficit scale of CBCL.
  12. 12. Exposure during pregnancy Grandjean et al., Pediatrics 2006 Impaired visual memory (Stanford Binet drawings) and copying drawings (visuo-constructive, visuo-spatial). Rauh et al. , Pediatrics 2006 Inner city children followed from birth 36 months Psychomotor development index lower in group with high prenatal chlorpyrifos (CPF) exposure: cognitive and psychomotor delays. CBLC: Attention disorder associate with prenatal CPF exposure.
  13. 13. Exposure during childhood Grandjean et al., Pediatrics 2006 Participants: Children in Ecuador whose mother work in floriculture. Simple reaction time is slower in children with higher levels of urinary OP metabolites. Ruckart et al. Env Health Perspect 2004 1-2 years after exposure to methyl parathion: Increased impulsivity and conduct disorders Sanchez Lizardi et al. J. Pediatric Psychol 2008 High OP metabolites associated with more errors in Wisconsin Card Sorting but BETTER concept formation.
  14. 14. Exposure during childhood Rohlman et al., Neurotoxicology 2005 Slower motor performance (tapping)
  15. 15. Summary: Exposure to OPs during early development: from birth to childhood Foetus -Infant Child Lower gestational age Visuospatial impairment Abnormal neonate reflexes Impaired psychomotor Attention deficit development Motor deficit Impaired mental development Social skill deficit (PDD)
  16. 16. Motor Inhibition and Learning Impairments in School-Aged Children Following Exposure to Organophosphate Pesticides in Infancy ORA KOFMAN, ANDREA BERGER, ALI MASSARWA, ALON FRIEDMAN, AND ABED ABU JAFFAR Pediatr Res 60: 88–92, 2006
  17. 17. Hospitalizations under age 3 with acute poisoning at Soroka University Medical Center. More than 90% of poisonings reported were in children from the Bedouin sector.
  18. 18. Statue and Knock-Tap tests from NEPSY battery. Inhibition and ability to ignore distraction Stand like a statue with eyes closed with one hand up as if holding a flag (75 seconds) while experimenter makes different noises. Lose points for movements, eye opening, talking and other rule breaks. Knock – Tap. Experimenter sits opposite child and performs hand movements: strike table with palm down, or fist. Child has to perform the alternate movement and in some cases no movement at all. Inhibition of pre-potent response.
  19. 19. Statue Number of points (Mean + SEM) Knock Tap 29 * 27 25 23 21 19 17 15 P -K e P -O en l O ro l os ro t on er t on C K C Children with OP poisoning had lower scores than age and sex matched controls. No effect on Knock-Tap test.
  20. 20. 12 Control OP 11 OP Verbal list Words recalled (Mean + SEM) learning and 10 9 8 7 recall 6 5 4 Children from 3 both poisoning groups had List A-1 List A-2 List A-3 List A-4 List A-5 List B List A-6 12 11 Control K poorer recall in acquisition Kerosene Words recalled (Mean + SEM) 10 9 8 phase BUT 7 there was no difference in 6 5 4 delayed recall or recognition. 3 List A-1 List A-2 List A-3 List A-4 List A-5 List B List A-6
  21. 21. Future Directions Exploring Gene x exposure interactions in rodents AChE I inhibitors or stress induce alternate splicing of the enzyme AChE to its rare readthrough form AChE –R (Soreq and colleagues). DFP – Kaufer et al. 1998; Meshorer et al. 2002 Soman- Perrier et al. 2005 Diazinon– Jameson et al. 2007 Restraint, but not swim stress – Perrier et al. 2005 Swim stress – Kaufer et al. 1998
  22. 22. Forced swim test- prolonged immobility is regarded as enhanced depression (helplessness)
  23. 23. Stages of brain development dependent on induction of genes 240 at different stages. Development is influenced by substances 220 such as neurotransmitters and enzymes. 200 180 Immobility (sec) swim stress 160 140 120 100 80 60 40 20 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 AChER CTX RQ PCR The greater the AChER levels in cortex, the less immobility depression) is found.
  24. 24. Elevated plus maze: Rodent test for anxiety The less time in the open arms of the maze, the more anxious the mouse is. r=-.21 ,p<.05 2.2 2.0 1.8 1.6 AChE-R cortex 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 -2 0 2 4 6 8 10 12 14 16 18 20 Entries open arms
  25. 25. Future Directions Exploring Gene x Exposure Interactions in rodents Injection of DFP in mice at age 4-10 or 14-20 days •Increased learned anxiety on 2nd exposure to the elevated plus maze. •Females but not males show poor passive avoidance despite evidence of good retention. •Females but not males are impaired in complex discrimination learning involving set shifting. •Male but not females show anhedonia (reduced preference of a sweet solution) and this effect seems to be strain dependent.
  26. 26. THANKS Ali Massarwa Andrea Berger, PhD Amneh Atamneh Alon Friedman, MD PhD Guy Ben Bashat Abd Abu Jaffar, MD Uri Livneh Amir Dori, MD PhD Tamar Lin Israel Science Foundation Or Duek National Institute for Psychobiology in Israel

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