Environment and Autism: Current State of the Science

Abstract

Research into environmental risk factors for autism has grown dramatically over the past 10 years, providing evidence that non-genetic factors acting during the prenatal period may influence the underlying neurodevelopmental processes. This paper reviews the evidence on modifiable preconception and/or prenatal factors that have been associated with autism spectrum disorder (ASD), including only human studies with at least 50 cases of ASD, having a valid comparison group, conducted within the past decade, and focusing on maternal lifestyle or environmental chemicals. Consistent results have been reported for an association of higher maternal intake of certain nutrients and supplements with reduction in ASD risk, with the strongest evidence for folic acid supplements. A number of studies have demonstrated significant increases in ASD risk with estimated exposure to air pollution during the prenatal period, particularly for heavy metals and particulate matter. A few studies suggest a link with organophosphate pesticides. More rigorous ascertainment of exposure is needed for studies of substance use; most investigations adjusting for potential confounders, but relying on self-reported use, have shown no links between maternal smoking or alcohol consumption and ASD. Little research has assessed other persistent and non-persistent organic chemical pollutants, such as are found in common household or personal care products, in association with ASD specifically. More work is needed to examine fats, vitamins, and other maternal nutrients, as well as endocrine-disrupting chemicals and pesticides, in association with ASD, given sound biological plausibility and evidence regarding other neurodevelopmental outcomes. In addition, the field could be advanced by the use of large-scale epidemiologic studies, attention to critical etiologic windows and how these vary by exposure, interactions with genetic susceptibility, and a focus on underlying mechanisms.

Keywords: air pollution; autism; endocrine disruptors; environment; lifestyle; nutrition; pesticides; tobacco smoke.

Figure 1. Critical periods of Susceptibility indicated from Studies of Autism Spectrum Disorder

Neuropathology (autopsy and imaging) studies of brains of individuals with autism spectrum disorder found evidence of dysregulated neurogenesis, neuronal migration, and neuronal maturation compared to brains of typically developed individuals, processes that generally occur in the first half of pregnancy. Figure 1 shows windows of critical periods indicated by evidence from epidemiological studies of environmental factors demonstrating an association with autism spectrum disorder. Not all exposures shown in the figure are covered in this review, but they are included as exemplary of critical time windows. Time periods of higher risk within pregnancy have variable results, but tend to congregate in the first half of pregnancy. Days=Fetal days after conception. For exposures with more than one study, dark blue indicates overlapping period and light blue indicates timing suggested by one but not all studies. Images adapted from those in The Developing Human: Clinically Oriented Embryology, 6th Edition (1998). This material is reproduced with permission of John Wiley and Sons, Inc. a The study by Suren et al.¹⁴ indicated that up to 6 weeks prior to (and 6 weeks after) conception (4 weeks before LMP to 8 weeks after) was important. b The study by Rai et al.²³ collected information on use since becoming pregnant at the first antenatal visit which usually takes place before the end of the first trimester (median 10 weeks gestation). 1. Wegiel J, Kuchna I, Nowicki K, et al. The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol. Jun 2010;119(6):755–770. 2. Samuelsen GB, Larsen KB, Bogdanovic N, et al. The changing number of cells in the human fetal forebrain and its subdivisions: a stereological analysis. Cereb Cortex. Feb 2003;13(2):115–122. 3. de Graaf-Peters VB, Hadders-Algra M. Ontogeny of the human central nervous system: what is happening when? Early Hum Dev. Apr 2006;82(4):257–266. 4. Sidman RL, Rakic P. Neuronal migration, with special reference to developing human brain: a review. Brain Res. Nov 9 1973;62(1):1–35. 5. Sarnat HB, Nochlin D, Born DE. Neuronal nuclear antigen (NeuN): a marker of neuronal maturation in early human fetal nervous system. Brain Dev. Mar 1998;20(2):88–94. 6. Stoner R, Chow ML, Boyle MP, et al. Patches of Disorganization in the Neocortex of Children with Autism. New England Journal of Medicine. 2014;370(13):1209–1219. 7. Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect. Jun 2011;119(6):873–877. 8. Volk HE, Lurmann F, Penfold B, Hertz-Picciotto I, McConnell R. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry. Jan 2013;70(1):71–77. 9. Eskenazi B, Marks AR, Bradman A, et al. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ Health Perspect. May 2007;115(5):792–798. 10. Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect. Oct 2007;115(10):1482–1489. 11. Shelton JF, Geraghty EM, Tancredi DJ, et al. Prenatal Residential Proximity to Agricultural Pesticides and Neurodevelopmental 1 Disorders in the CHARGE Study. Environ Health Perspect. In Press. 12. Schmidt RJ, Hansen RL, Hartiala J, et al. Prenatal Vitamins, One-carbon Metabolism Gene Variants, and Risk for Autism. Epidemiology. Jul 2011;22(4):476–485. 13. Schmidt RJ, Tancredi DJ, Ozonoff S, et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. Jul 2012;96(1):80–89. 14. Suren P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. Feb 13 2013;309(6):570–577. 15. Chess S. Autism in children with congenital rubella. J Autism Child Schizophr. Jan-Mar 1971;1(1): 33–47. 16. Arndt TL, Stodgell CJ, Rodier PM. The teratology of autism. Int J Dev Neurosci. Apr–May 2005;23(2–3):189–199. 17. Zerbo O, Iosif AM, Walker C, Ozonoff S, Hansen RL, Hertz-Picciotto I. Is Maternal Influenza or Fever During Pregnancy Associated with Autism or Developmental Delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study. J Autism Dev Disord. May 5 2013;43(1):25–33. 18. Atladottir HO, Henriksen TB, Schendel DE, Parner ET. Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study. Pediatrics. Dec 2012;130(6):e1447–1454. 19. Stromland K, Nordin V, Miller M, Akerstrom B, Gillberg C. Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol. Apr 1994;36(4):351–356. 20. Moore SJ, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. Jul 2000;37(7):489–497. 21. Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J. Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol. Jun 24 1996;370(2):247–261. 22. Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry. Nov 2011;68(11):1104–1112. 23. Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ. 2013;346:f2059. 24. Beversdorf DQ, Manning SE, Hillier A, et al. Timing of prenatal stressors and autism. J Autism Dev Disord. Aug 2005;35(4):471–478.