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Environmental Exposures in Autism Etiology

Environmental Exposures in Autism Etiology. Irva Hertz-Picciotto University of California Davis, M.I.N.D. Institute Center for Children’s Environmental Health & Department of Public Health Sciences. Mechanisms for Environmental Chemicals to Affect Autism Risk.

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Environmental Exposures in Autism Etiology

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  1. Environmental Exposures in Autism Etiology Irva Hertz-Picciotto University of California Davis, M.I.N.D. Institute Center for Children’s Environmental Health& Department of Public Health Sciences

  2. Mechanisms for Environmental Chemicals to Affect Autism Risk • Direct action on neural tissue during: • Differentiation • Migration • Dendritic branching/pruning • Synaptogenesis • Effects on genes that regulate CNS development • Perturbation of immune signaling/inflammation via neurotransmitters &/or cytokines • Endocrine disruption: sex steroids/thyroid hormones

  3. Causes Unknown but Numerous Autism is multifactorial, meaning: multiple causes across the population and within an individual A B B D E F C Most common: 3 or more causes Most rare: one cause Possible: 2 causes

  4. Genes & Environment in Autism? B • Genetics: ~60-90% (twin studies) • Environment: 10-40% = minimum • Sum not 100% • Risk Ratios of 10+: • Congenital rubella • Thalidomide • Risk Ratios ~4 to 5: • Maternal age • Male sex A D C E B F G D H

  5. Center for Children’s Environmental Health (CCEH) • NIEHS call in 2000 • State of the epidemiologic literature on risk factors • Descriptive male:female • Obstetric suboptimality • Twin studies & familial aggregation • Reported trend towards increasing prevalence • Environmental causes: viral, pharmacologic • Need for multi-disciplinary approach • UC Davis CCEH: The CHARGE Study

  6. The CHARGE* Study *CHildhoodAutismRiskfromGeneticsand theEnvironment

  7. Goals of the CHARGE Study To identify causes and contributing risk & protective factors for childhood autism: • Genetic susceptibility • Environmental exposures • Interactions of the two To determine mechanisms of susceptibility and identify subsets of possible distinct etiologies for childhood autism • Immunologic • Genetic/Genomic • Metabolic/metabolomic • Phenotypic

  8. Environmental Exposures • Biospecimens: • Blood (recent exposures) • Child’s hair (recent - depends on length) • Baby lock (first year of life) • Mother’s hair (if long enough, prenatal) • Urine (recent exposure, metabolism) • Newborn blood spot (prenatal) • Interviews: Recall? • Diet • Residential information • Lifestyle • Consumer products • Medical history • Linkage to exposure databases • Air, water, pesticides, haz waste • GIS • Medical records: Completeness? • Pesticides • Metals • Organic pollutants(PCBs, PBDEs, phthalates) • Viruses, bacteria & other infections • Medical procedures & pharmaceuticals • Nutritional factors

  9. DESIGN & METHODS Population-based recruitmentClinical confirmation of dxLinkage to state-of-the-art laboratories

  10. CHARGE Study Design:Case-control - three groups California DDS • Children with autism • Children with developmental delay • Children drawn from general population of births, frequency-matched on age, gender & geography California Birth files All children - Eligibility: 24-60 months, born in Calif, mother English/Spanish speaking, living with biologic parents

  11. The CHARGE Study Clinical Protocol • Confirmation of diagnosis: • ADI and ADOS (autism cases only) • Social Communication Questionnaire (all others) • Cognitive & adaptive development (all children) • Medical Exam • Medical Hx • Parent forms • Medical records obtained • Environmental Exposure Questionnaire

  12. The CHARGE Study Clinical Protocol • Specimens:- blood - urine- hair …from index child, parents & siblings • Newborn blood spots from CDPH GDB

  13. RESULTSImmunologic Deviations

  14. Maternal Antibodies to Fetal Brain Tissue (n=163) Braunschweig et al., Neurotoxicology 2008; 29:226-23

  15. Leptin: a cytokine The CHARGE Study Ashwood et al., J Autism Dev Disorders 2008;38:169-175

  16. RESULTSGenomics, Genetics & Epigenetics

  17. Early Onset Autism (A-E) vs General Population (GP) Gregg et al., Genomics 2008;91:22-29

  18. Differential gene expression in autism compared to typically developing, general population controls Fold-change Gene Affymetrix GeneChip Taqman p-value PAM 1.86 1.51 0.007 SPON2 1.87 1.86 0.005 IL2RB 1.56 1.35 0.046 PRF1 1.79 1.53 0.027 GZMB 2.01 1.72 0.014 CX3CR1 1.60 1.37 0.006 SH2D1B/EAT 2 2.19 1.78 0.011 EDG8 1.99 ND – IGFBP7 1.70 ND – ZNF145 1.99 ND – KIR3DL2 1.58 ND

  19. 227018_at (MSTP141; FLJ14920; FL... 1554638_at (ENDOFIN; KIAA0305; D... 235507_at (FLJ10883) 224429_x_at (MGC10997) 241354_at (FLJ13330) 201883_s_at (GT1; GTB; GGTB2; B4... 233713_at (HSKM-B; ZMYND14; MG... 209128_s_at (TIP110; KIAA0156; p11... 212904_at (KIAA1185; RP1-286D6.3) 201697_s_at (DNMT; MCMT; CXXC9; ... 210164_at (HLP; CCPI; CGL1; CSPB;... 202786_at (DCHT; SPAK) 201080_at (Pip4k2B; PIP5KIIB; PIP5... 230464_at (S1P5; Edg-8; S1PR5; SP... 205291_at (P70-75) 1553681_a_at (P1; PFP; HPLH2; MG... 206118_at (STAT4) 228854_at 1553177_at (EAT2) 233558_s_at (FLJ12716) 217776_at (MDT1; PSDR1; RALR1; S... 209123_at (DHPR; PKU2) 202783_at (MGC126502; MGC12650... 217301_x_at (RBAP48) 200698_at (ELP-1; ERD2.2) 221517_s_at (MED17; CRSP77; DRI... 215743_at (NMT2) 219178_at (FLJ12960) 217761_at (MTCBP-1; SIPL; FLJ1091... 217878_s_at (APC3; HNUC; D0S143... 216153_x_at (ST15; hRECK) Early Onset Autism vs GP: Cell Types Genes – Expression Levels PMN Mono B CD4 CD8 NK Gregg et al., Genomics 2008;91:22-29

  20. Other Related Studies • Candidate genes (Tassone) • MAOA, 5HT-receptor, GSTM1 • SNPs (Gregg) • Copy Number Variants (Selleck) • Epigenetics (Lasalle) - X-Chromosome Inactivation

  21. Dysmorphology • Digital photos are taken of face: frontal and profile views • Blind review by experts in genetics & pediatrics • Identify minor physical anomalies • Disagreements resolved by consensus of all 3 raters. • 242 children were reviewed (121 ASD, 51 DD, and 70 TD) • ASD children more likely to be classified as dysmorphic or partially dysmorphic. • Those with 6 or more dysmorphic features may be a subgroup with a high genetic susceptibility. Angkustsiri et al., in preparation; presented at Ped Acad Soc 2008

  22. RESULTSLipids

  23. Autism and Fatty Acid Profiles (n=250) Wiest et al., in submission

  24. Autism and Fatty Acid Profiles • Docosahexanoic acid (DHA) • abundant in phospholipids of brain and retina • contributes to membrane structure and functioneicosanoid signalinggene expression modulation • Other Functions: • Inhibition of neuronal apoptosis and • Regulating neuronal excitability through GABA receptors • Developing brains obtain DHA from circulation Wiest et al., in submission

  25. RESULTSEnvironmental Chemicals

  26. Hg and Autism • Great interest: known neurotoxin • Most research focused on thimerosal in vaccines • Multiple sources: • Fish • Dental amalgams • Broken thermometers, light bulbs • Nasal sprays, contact lens solution • CHARGE Study approach • Current blood • Baby locks (first haircuts) • Newborn blood spots • Questionnaire about use of products

  27. The CHARGE Study

  28. Prediction of log(Blood Hg)* * Multivariate analysis to adjust for confounding Subjects weighted to adjust for differential participation by SES

  29. Interpretation/Conclusion • No difference in current blood levels of Hg • Does not confirm previous report of higher blood Hg in children with autism • Does not address early life exposures as potential causal factors • Possible sequestering of ethyl as opposed to methyl Hg not addressed in this study • Only 5% of Hg body burden is in circulation

  30. PBDEsPolybrominated diphenyl ethers • Flame retardants • Sweden (1998) and then EU has banned penta and octa-PBDEs • Rodents: lack of ability to habituate to a novel situation. All US women's milk samples were contaminated with PBDEs from 6 to 419 ng/g, lipid, orders of magnitude higher than levels reported in European studies, and are the highest reported worldwide. Mol Nutr Food Res 2008

  31. Pilot Study Results: Autism & PBDEs • Children with ASD do not have higher levels of PBDEs • Contrary to our hypothesis, their levels of PBDEs are lower than in typically developing children • Possibility of reverse causation: behaviors changed? • High SES: more air flow in home? • Association with head growth? • Used a post-dx measurement -- need to measure PBDE exposures during critical windows of development

  32. Televisions･Cell phones･Fax machines･Audio and video equipment･Computers･Printers･Scanners･Photocopiers･Remote controls･Lamp sockets･Hairdryers･Fans･Upholstered sofas･Upholstered chairs･Polyurethane foam･Mattresses･Curtains･Drapes･Carpet padding･Ovens and stoves･Stove hoods･Refrigerators･Dishwashers･Washing machines･Clothes dryer･Microwaves･Toasters･Coffee makers･Water heaters･Wires and cables･Circuit breakers･Electrical outlets Household items that may contain deca-PBDEs

  33. Pesticides & Autism • Roberts et al EHP 2007 • Organochlorines applied commercially within 1/2 mile of mother’s residence at delivery associated with greater risk of autism. • Strongest association in weeks 1-8 of gestation • Eskenazi et al, Basic & Clin Pharm Toxicol 2008 • Organophosphate metabolites (DAPs) in urine collected during pregnancy and 1st year of life associated with autism spectrum disorder symptoms. • These compounds cross the placenta and bioaccumulate.

  34. Pesticides & Autism n=531 • CHARGE Study: self-reported use of household products (about 2 dozen) • Use of pet flea or tick soaps/shampoos by mother doubled the risk that the child developed autism. • Associations from 3 months prior to conception through first year of child’s life • These shampoos are formulated primarily with pyrethrins

  35. Pet flea/tick shampoos Mode of Action: Pyrethrins affect the nervous system of insects and result in repeated and extended firings of the nerves. They do this by affecting the flow of sodium out of nerve cells through voltage-sensitive sodium channels. Bio-Groom Flea & Tick Pyrethrin Spray 16 fl oz. EctoKyl CA Pyrethrin Flea Shampoo - 12 oz. Hartz 2 in 1 Rid Flea Dog Shampoo with Pyrethrin - 18 oz.

  36. Toxicities of pyrethroids • Neuronal cell death in hippocampus • Mechanisms may involve not only sodium but also calcium channels • Wide variation in age sensitivity • Piperonyl butoxide enhances toxicity Early life exposure to pyrethrins has been shown to compromise the blood-brain barrier in rodents

  37. Labor Induction &/or Augmentation • Drugs increasingly used to alter the course of labor • Oxytocin receptors throughout the brain • Prostaglandins are potent pro-inflammatory compounds. Walker et al., in preparation (to be presented at IMFAR 2008)

  38. Critical Window(s) for Susceptibility? Conception Delivery 1 year 1st 2nd 3rd LMP Brain Development

  39. Limitations of CHARGE • Numbers large for this type of study (n>1000), but small for studying rare exposures, or rare polymorphisms. • Data on non-medical exposures by retrospective self-report: possible reporting bias • Unclear whether differences (e.g., immune) are: - part of causal pathway - a result of neuropathology - a concommitant parallel effect • Limited specimens that predate the diagnosis => Newest epidemiologic study from the UC Davis Center for Children’s Environmental Health: MARBLES

  40. Markers of Autism Risk in Babies—Learning Early Signs A study of pregnant moms, who already have a child with autism, following their pregnancies and new child

  41. Eligibility Criteria for MARBLES • Be the biological mother or father of a child diagnosed with autism • Be pregnant or planning a pregnancy in the near future • Live within 2-hours drive of the Sacramento/Davis area • Be over the age of 18

  42. Critical Window(s) for Susceptibility? Conception Delivery 1 year 1st 2nd 3rd LMP Brain Development

  43. MARBLES Participants… • Answer questionnaires and telephone interviews about family medical history, illnesses and medications, lifestyle, diet, home product use, and other factors that may influence their baby’s development • Complete weekly symptom diaries during pregnancy and monthly diaries during the first year of child’s life • Donate biological specimens • Permit collection of environmental samples

  44. Investigators • UC Davis Flora Tassone Lihong Qi Janine Lasalle Sally Ozonoff • Univ Minnessota Scott Selleck • Vanderbilt Pat Levitt • USC (Southern Calif) Rob McConnell • Johns Hopkins Li-Ching Lee • UC Davis CCEH Isaac Pessah Robin Hansen Cheryl Walker Judy Van de Water Paul Ashwood Jeffrey Gregg Frank Sharp Bruce German Bruce Hammock Peter Green Robert Berman Danh Nguyen

  45. Be in CHARGE ! http://beincharge.ucdavis.edu/

  46. Grateful thanks to: Paula Krakowiak, Lora Delwiche, Lesley Deprey, Carrie Jones, Beth Goodlin-Jones, Susan Bacalman Nicole Tartaglia, Steve Nowicki, Jean Sakamura, Kathleen Angkuststiri Melissa RoseAmy Harley, Angelica Guzon, Eva Long, Danielle Greenfield, Carola Gutierrez de King, Susana Gonzales, Caroline Grantz, Cynthia Contreras, Devon Baird, Matthew Parro,Alice Baker

  47. Special Thanks to our Funders • NIEHS P01 ES11269 • NIEHS 1R01 ES015359 • NIEHS 1R01 ES 015171 • Environmental Protection Agency (EPA), Science to Achieve Results (STAR) program, R829388 • The M.I.N.D. Institute/UC Davis Matching Funds • Autism Speaks • Cure Autism Now

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