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Environmental Exposures and Autism

Environmental Exposures and Autism. Claudia S. Miller, M.D., M.S. Professor, Family & Community Medicine The University of Texas Health Science Center at San Antonio millercs@uthscsa.edu. Synthetic Organic Chemical Production United States, 1945 - 1985.

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Environmental Exposures and Autism

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  1. Environmental Exposures and Autism Claudia S. Miller, M.D., M.S. Professor, Family & Community Medicine The University of Texas Health Science Center at San Antonio millercs@uthscsa.edu

  2. Synthetic Organic Chemical ProductionUnited States, 1945 - 1985 Source: U.S. Intern. Trade Commission

  3. U.S. Pesticide Production,All types, 1927-1988 Source: EPA Market Estimates, 1986, 1988; Pimentel & Andow, 1984; Metcalf, 1980.

  4. 90% of Americans Spend 90% of the Day Indoors • Our Boxes: • Home • Workplace • School • Vehicles

  5. Historical Development of Ventilation Standards in the U.S. Mage and Gammage 1985, Evaluation of Changes in Outdoor Air Quality Occurring over the Past Several Decades, In Indoor Air and Human Health.Gammage and Kaye Eds., Chelsea, MI, Lewis Publishers, p. 13)

  6. Evidence for TILT • Similar reports in different regions/countries • Complaints of new intolerances for foods, alcohol, caffeine, and medications, not only chemicals • Resemblance to addiction • Plausible anatomic locus • Recent animal models

  7. Diagnosing Chemical and Food Triggers for Autism Using an EMU

  8. Chemical Intolerance – Genotypes • Canadian case control study to determine whether chemically intolerant individuals differ from controls for genetic polymorphisms in drug-metabolizing enzymes • Caucasian female cases (203) and controls (162) • CYP2D6, NAT1, NAT2, PON1, PON2, MTHFR were genotyped • Significant difference found in cases vs. controls for CYP2D6 (p=0.02) • OR CYP2D6 homozygous active=3.36 (p=0.01) • OR NAT2 rapid metabolizer=4.14 (p=0.01) Source: McKeown-Essen et al, Int J Epidemiol 2004; 33:1-8

  9. Chemical Intolerance – Genotypes • CPY2D6 metabolizes centrally acting drugs and toxins such as tricyclic antidepressants, selective serotonin re-uptake inhibitors, monoamine oxidase inhibitors, amphetamines, codeine, neuroleptics, neurotoxins, and endogenous neurotransmitters • Latter finding may be relevant to observations that poor metabolizers score higher on anxiety scales and lower on socialization scales • NAT2 expresses arylamine transferase which determines susceptibility to aromatic amines Source: McKeown-Essen et al, Int J Epidemiol 2004; 33:1-8

  10. Chemical Intolerance – Genotypes • Cases were more likely to be heterozygous for PON1-55 (OR=2.05, p=0.04) and PON1-192 (OR=1.57, p=0.04) • PON genes have been linked to Gulf War veterans’ illnesses (Haley et al., 1999) • Post hoc analysis showed significant effect of being a rapid metabolizer for both NAT2 and CYP2D6: • OR for rapid/rapid vs. slow/slow combination of CYP2D6 and NAT2 was 18.7 • Other studies: Binkley et al., 2001 showed higher prevalence of cholecystokinin B receptor allele 7 compared with controls • Conclusion: chemically intolerant individuals differ from controls for genetic polymorphisms in enzymes that metabolize drugs/toxins/endogenous neurotransmitters Source: McKeown-Essen et al, Int J Epidemiol 2004; 33:1-8

  11. Phase II Detoxification Phase I Detoxification Parent Compound Reactive Intermediate CI CI S O O O P P Elimination O O [S] + H3C H3C O O N N CI CI CYP 3A4 CYP 2B6(polymorphic) CH3 CH3 CI CI PON1 (polymorphic) Chlorpyrifos Chlorpyrifos-oxon 1 2 3 • Neurodevelopmental toxicity • Free sulfur atoms • inactivate CYP3A4 • CYP3A4 cannot • metabolize testosterone • Endocrine disruption— hypermasculinity • Acetylcholinesterase inhibition • Oxidative stress • Neurodevelopmental toxicity Chlorpyrifos Detoxification

  12. Impact of Xenobiotic Exposures on Neurodevelopment

  13. Relationship between TILT, Addiction and Abdiction TILT (Loss of Tolerance) Avoid Withdrawal (2 strategies) Avoid substance altogether Take substance regularly Abdiction Addiction

  14. High validity, reliability Sensitivity 92%, specificity 95% Symptom scale derived by factor analysis “Symptom star” (Miller and Prihoda, ToxIndustrHealth 15:370-385, 1999) http://familymed.uthscsa.edu/queesi.pdf

  15. Online Autism Surveyhttp://familymed.uthscsa.edu/autismsurvey/ • Currently over 400 participants • Family histories • Environmental exposures • Chemical intolerances

  16. P < .05 Environmental Exposures During PregnancyAutism cases (n = 210 children) and Controls (n = 369 children) P < .04 P < .003 ns Pesticide exposure Chemical exposure Vaccinated while pregnant Received Rhogam for Rh incompatibilty Did you use pesticides, herbicides or have pest control services during your pregnancy? Were you exposed to fumes/chemicals (such as paint and refinishing products or new carpet, etc.) on the job or at home during your pregnancy?

  17. Reaction to vaccination Received no childhood vaccinations Antibiotic use P < .05 Medical/Health Care DifferencesBetween Autism Cases and Controls P < .04 ns Multiple infections requiring prolonged use of antibiotics Reactions to vaccinations that prompted a call to the doctor

  18. P=.001 P=.002 P=.030 Maternal QEESI Score Comparisons Between ASD (n=280), ADHD (n=147) and Controls (n=149) Symptoms Chemical intolerances Other exposures

  19. Comparison of Food Allergies/Intolerancesand Food Preferences/Cravings BetweenASD (n=280), ADHD (n=147) and Controls (n=149) Food allergies/ sensitivities Food preferences/ cravings

  20. P=.001 P=.004 P=.033 QEESI Score Comparisons Between Autism (n=187), ADHD (n=147) and Controls (n=149) Symptoms Chemical intolerances Other exposures

  21. Comparison of Food Allergies/Intolerancesand Food Preferences/Cravings BetweenAutism (n=187), ADHD (n=147) and Controls (n=149) Food Allergies/ sensitivities Food Preferences/ cravings Autism differs significantly from Control and ADHD (P<.001), Autism and ADHD differ significantly (P<.001) from Control but not from each other.

  22. http://steer.uthscsa.edu/

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