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Out of the Past: Old Exposures, Heritable Effects, and Emerging Concepts for Autism Research


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Slides from "Out of the Past: Old Exposures, Heritable Effects, and Emerging Concepts for Autism Research." Given by Jill Escher April 8, 2016 at Florida State University's Symposium on the Developing Brain. The presentation highlights a significant gap in autism research: what factors might be driving the heterogenous de novo genomic errors seen in autism?

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Out of the Past: Old Exposures, Heritable Effects, and Emerging Concepts for Autism Research

  1. 1. Old Exposures, Heritable Effects, and Emerging Concepts for Autism Research Jill Escher, MA, JD @JillEscher for AutismEscher Fund Humans start as molecules G e r m l i n e E x p o s u r e s . o r g OUT OF THE PAST:
  2. 2. “WHAT EPIDEMIC? IT’S JUST NATURAL NEURODIVERSITY AND SHIFTING DIAGNOSTICS” Autism is just a “strange gift” handed down through millions of years of evolution. Wrong!
  3. 3. DRAMATIC SURGE IN SERIOUSLY DISABLING AUTISM CASES Calif. Department of Developmental Services Autism Cases by BirthYear 1943-2010
  4. 4. WHAT’S CAUSING AUTISM? GENES 100s of genes contribute—about 10% of cases can be attributed to known genomic errors, 10% more forecast ENVIRONMENT Exogenous factors—ie, prematurity, certain drugs, maybe 20% UNKNOWN Probably at least 60% of cases, but strong evidence of heritability 60% 20% 10% 10%
  5. 5. ARE WE ASKING THE RIGHT QUESTIONS? Genes or environment? How about genes and environment?
  6. 6. MUTAGENESIS: HETEROGENOUS DE NOVO MUTATIONS FOUND IN AUTISM Yuen et al 2015: 69% of the affected siblings carried different ASD- relevant mutations. Brandler et al 2016: “We propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs.” Iossifov et al 2015: Supports theory that 'ultra-rare' mutations of vulnerable genes may play causal role in roughly half of ASD cases.
  7. 7. EPIMUTAGENESIS: EXPOSURES CAN ALTER HOW GENES WORK Hormone mimics/ endocrine disruptors Industrial chemicals Nutrition (eg, vitamins, folate, famine) Acute stress Drugs and pharmaceuticals Cigarette smoke Plasticizers Epigenetics: “Heritable changes in gene expression caused by mechanisms other than alterations to underlying DNA sequence.” Pesticides Radiation Exercise
  8. 8. Methylation Chemical tags on DNA. Histone modification Chemical tags on DNA structural proteins. Lab of Moshe Szyf “Don’t bother transcribing this gene.” “This gene is open for business!” EPIGENETIC FACTORS CAN UP-REGULATE OR DOWN-REGULATE GENE EXPRESSION ncRNAs Can regulate gene output May carry environmental info via gametes For example:
  9. 9. EXPOSURES CAN ALTER SOMATIC GENE EXPRESSION Thalidomide DES (Diethylstilbestrol) Fetal Alcohol Syndrome
  10. 10. IN UTERO EXPOSURES CAN ALTER GERMLINE, TOO, THROUGH MUTAGENESIS OR EPIMUTAGENESIS F0 = Mother F1 = Fetus F2 = Germ cells / grandchildren A highly vulnerable phase for the F2s.
  11. 11. “CRITICAL WINDOW” OF FETAL GERMLINE DEVELOPMENT Primordial germ cells DNA de-methylation and re-methylation: Period of dynamic and vulnerable epigenetic reprogramming
  12. 12. GENES ARE JUST A PART OF “HERITABILITY” • Protein-coding genes (exome) represent only 1.5% of genome. • Most of the genome is about transcription and regulation. • And on top of that, a wide variety of epigenetic processes, including imprinting. • Brain development depends on subtle control of gene expression, dosage and timing, not just Mendellian “genetics.”
  13. 13. DO GERMLINE EXPOSURES MATTER? MY STORY WOULD SUGGEST YES Son, 17 Daughter, 10 I was born in 1965 in Los Angeles. I have three beautiful, genetically normal children from three low-risk, normal pregnancies. Yet two of my children are severely neurodevelopmentally disabled, nonverbal autistic, will need lifelong 24/7 1:1 care.
  14. 14. In 2010, I obtained my mother’s 1965 obstetric records. What did they mean? In 2011, I discovered I had been a subject in a study (Reinisch 1977) examining fetal effects of synthetic steroid hormone drugs. In 2013, I obtained records from the Kinsey Institute detailing my prenatal drug exposures. A TRIO OF UNEXPECTED DISCOVERIES 1. 2. 3.
  15. 15. Progestins, estrogens, corticosteroids. Why? “To prevent miscarriage.” “Mad Men” era of maternal medicine. Such drugging was common. 0 225 450 675 900 Pre 1 2 3 4 5 6 7 8 9 Progestin (Deladroxate) Estrogens (Estradiol) Corticosteroids (Prednisolone) Progestin (Deluteval [Delalutin]) Clomiphene Pergonal Mg of drug My month of gestation in 1965 Roughly equivalent to 20-30,000 birth control pills’ worth of synthetic steroids.} WHAT WERE MY EXPOSURES?
  16. 16. Example: Joan Hutchens was also exposed prenatally to an “anti-miscarriage” hormone regimen in 1965. Three of her five children have idiopathic autism. We started as eggs when our mom was a fetus. I’M NOT ALONE: MANY OTHERS SHARE MY STORY
  17. 17. PREGNANT WOMEN WERE HEAVILY MEDICATED IN THE POST-WAR DECADES Synthetic hormones Sedatives, barbiturates Anti-nausea drugs Amphetamines
  18. 18. LET’S NOT FORGET OTHER EXPOSURES Pesticides (eg, DDT) Agent Orange (dioxin) Flame retardants (eg, PBDEs) PCBs Plasticizers (eg, BPA, phthalates) Air pollution Radiation
  19. 19. PREGNANCY SMOKING WAS COMMON 0 8.5 17 25.5 34 1955 1970 1990 2010 Smoking prevalence among US females Cigarette smoke = mutagenic and epimutagenic components Doctors sometimes recommended it as an appetite suppressant Placenta from a tobacco- exposed pregnancy
  20. 20. Ammonia Arsenic Benzene Benzo(a)pyrene Carbon monoxide DDT/pesticides Formaldehyde Hydrogen cyanide Nicotine Radiation Tar TOXIC COMPONENTS OF CIGARETTES (Short list)
  21. 21. IN ASD, GRANDMATERNAL PREGNANCY SMOKING WAS COMMONLY REPORTED Yes, these are anecdotes but they may raise important questions about potential germline mutagenesis or epimutagenesis. Families had no history of autism. Sampling of the F1 interviewees’ F2’s:
  22. 22. 1. High prevalence, compared to other gestational toxicants 2. Acute levels (eg, 5,400 cigarettes for a pack-a-day pregnant smoker) 3. Ease of ascertainment, compared to other gestational toxicants 4. High toxicity: known mutagenic and epimutagenic compounds 5. F1 somatic DNA damage and pathology: exposure known to raise risks of epimutation, disease and birth defects 6. F1 germline damage demonstrated (molecular, anatomical) 7. F2 pathology demonstrated (eg, Bhide, Rehan) WHY WE SHOULD LOOK FOR F2 EFFECTS OF GRANDMATERNAL SMOKING
  23. 23. AUTISM RESEARCH TODAY 1 2 Toxic Exposures Germline Damage Root Cause Molecular Pathway Brain Differences Phenotypes Interven- tions During critical windows Disruption to germline or early embryo Heritable errors in early cells; or proximal fetal exposures. Impaired molecular pathways Abnormal neurodevel- opment and function Communi- cation, social, behavioral deficits Biological or behavioral treatments “Genetics First”
  24. 24. WHERE I THINK RESEARCH NEEDS TO GO 1 2 3 4 5 6 7 Toxic Exposures Germline Damage Mutation / Epimutation Impaired neurons Brain Differences Phenotypes Interven- tions During critical windows of germline synthesis Disruption to germline or early embryo Heritable errors in early cells Impaired molecular pathways Abnormal neurodevel- opment and function Communica tion, social, behavioral deficits Biological or behavioral treatments Toxicology Genetic Toxicology / Mutagenesis Genetics Neurobiology Neuroscience Psychology/ neurology / psychiatry Therapy / Medicine
  25. 25. FSU, AHEAD OF THE CURVE “We suggest that transgenerational transmission is a plausible mechanism for propagation of environmentally induced ADHD phenotypes in the population.”
  26. 26. “What the public must recognize is that mankind’s most vital asset is not its material wealth but its germ plasm—the very stuff of life. “Since the germinal cells are what determine the health, intellectual capacity, and all the other prime attributes of future generations, everything possible must be done to protect those—humanity’s most precious possessions.” —Geneticist James Neel, 1969 OUR MOST VITAL ASSET