Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder

Abstract

Background: Maternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals.

Objective: We examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD).

Methods: Participants were California children born from 2000-2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case-control study at age 2-5 y, were clinically confirmed to have ASD (n=296) or typical development (n=220), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003-2011. High vs. low daily FA intake was dichotomized at 800μg (median). Mothers' addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure.

Results: High FA intake (≥800μg) during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with <800μg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models.

Conclusions: In this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed. https://doi.org/10.1289/EHP604.

Figure 1.

Autism spectrum disorder odds ratios for pesticide and folic acid exposure combinations. Odds ratios and 95% confidence intervals (bars) for the association between Autism spectrum disorder (ASD) and combinations of exposures to pesticides and average maternal folic acid (FA) intake ($<800\mathrm{\mu }\mathrm{g}/\mathrm{d}$, $\ge 800\mathrm{\mu }\mathrm{g}/\mathrm{d}$) during the first month of pregnancy were adjusted for home ownership, child’s year of birth, maternal intake of vitamins B₆ and D (natural log) in the first month of pregnancy. In all comparisons, the reference group was those with above-median FA intake ($\ge 800\mathrm{\mu }\mathrm{g}$) during the first pregnancy month and no pesticide exposure.

Figure 2.

Pathways connecting folic acid to potential mechanisms of environmental contaminants. Folic acid inputs into the folate cycle through conversion to tetrahydrofolate (THF), which augments folate’s essential role as a donor and acceptor of one-carbon units, important for the biosynthesis of nucleic acids, proteins, and methyl groups (Crider et al. 2012). During development, biosynthesis of nucleic acids is necessary for DNA synthesis, repair, and cell division, and methyl groups are important for regulation of gene expression (Crider et al. 2012). Environmental contaminants such as pesticides can trigger immune responses and inflammation (Voccia et al. 1999) that induce cellular proliferation and DNA synthesis; similarly, pesticides can induce DNA damage (Corsini et al. 2008; Undeğer and Başaran 2005) that requires repair; both of these folate-dependent processes necessitate biosynthesis of nucleic acids, which could deplete folate at a time during early pregnancy when demand is high but could potentially be countered with high folate quantities. Environmental contaminants can also induce oxidative stress (Abdollahi et al. 2004); in response, homocysteine is permanently removed from the methionine cycle through degradation into cysteine in the transsulfuration cycle, where it is converted to cysteine and then to glutathione, a universal antioxidant (Schmidt and LaSalle 2011). This diversion of the methionine cycle towards glutathione antioxidant reactions and away from DNA synthesis, repair, and methylation may be countered by high folate supply, driving conversion of homocysteine to methionine and the biosynthesis of methionine to S-adenosylmethionine (SAM), which serves as a methyl donor for methylation reactions that are particularly critical during key periods of growth and remethylation at the start of development. Note: CNV, copy number variation.