Gestational Exposures to Phthalates and Folic Acid, and Autistic Traits in Canadian Children

Youssef Oulhote, Bruce Lanphear, Joseph M Braun, Glenys M Webster, Tye E Arbuckle, Taylor Etzel, Nadine Forget-Dubois, Jean R Seguin, Maryse F Bouchard, Amanda MacFarlane, Emmanuel Ouellet, William Fraser, Gina Muckle, Youssef Oulhote, Bruce Lanphear, Joseph M Braun, Glenys M Webster, Tye E Arbuckle, Taylor Etzel, Nadine Forget-Dubois, Jean R Seguin, Maryse F Bouchard, Amanda MacFarlane, Emmanuel Ouellet, William Fraser, Gina Muckle

Abstract

Background: The etiology of autism spectrum disorder is poorly understood. Few studies have investigated the link between endocrine-disrupting chemicals and autistic traits. We examined the relationship between gestational phthalates and autistic traits in 3- to 4-y-old Canadian children. We also investigated potential effect modification by sex and folic acid supplementation.

Methods: We enrolled 2,001 women>18 years of age during the first trimester of pregnancy between 2008 and 2011 from 10 cities in Canada. At 3-4 years of age, 610 children underwent neuropsychological assessments including the Social Responsiveness Scale-II (SRS-2) as a measure of autistic traits and social impairment. We measured 11 phthalate metabolites in maternal first trimester urine samples and assessed folic acid supplementation from reported intakes. We estimated covariate-adjusted differences in SRS-2 T-scores with a doubling in phthalate concentrations in 510 children with complete data.

Results: Mean total SRS T-score was 45.3 (SD=6.1). Children with higher gestational exposure to mono-n-butyl (MBP) and mono-3-carboxypropyl (MCPP) concentrations exhibited significantly higher total SRS T-scores, indicating greater overall social impairment, as well as higher scores on subdomains, indicating deficits in social cognition, social communication, social motivation, and restricted interests/repetitive behaviors. A doubling in MBP or MCPP concentrations was associated with 0.6 (95% CI: 0.1, 1.0) and 0.5 (95% CI: 0.1, 0.8) higher total SRS T-scores. Associations were consistently and significantly stronger in boys (βMBP=1.0; 95% CI: 0.4, 1.6; n=252) compared with girls (βMBP=0.1; 95% CI: -0.6, 0.7; n=258) and among children who had lower prenatal folic acid supplementation (<400μg/d) (βMBP=1.3; 95% CI: 0.4, 2.3; n=59) compared with those who had adequate folic acid supplementation (≥400μg/d) (βMBP=0.4; 95% CI: -0.1, 0.8; n=451).

Conclusions: Higher gestational concentrations of some phthalate metabolites were associated with higher scores of autistic traits as measured by the SRS-2 in boys, but not girls; these small size effects were mitigated by first trimester-of-pregnancy folic acid supplementation. https://doi.org/10.1289/EHP5621.

Figures

Figure 1.
Figure 1.
Exposure–response relationship and 95% confidence intervals for the associations between maternal SG-standardized urinary MBP concentrations (in micrograms per liter) and child SRS-2 T-scores at 3–4 years of age (n=510). (A) Social Awareness; (B) Social Cognition; (C) Social Communication; (D) Social Motivation; (E) Restricted Interest/Repetitive Behavior; and (F) Total SRS score. p-Values for significance (p) were derived with Wald tests using the Bayesian covariance matrix for the coefficients and departure from linearity (p-departure) were derived by comparing the models with urinary phthalate concentrations introduced as a spline function and as a linear term. Note: DF, degrees of freedom for the smooth term; MBP, mono-n-butyl; SG, specific gravity; SRS-2, Social Responsiveness Scale–II.
Figure 2.
Figure 2.
Difference (95% CI) in children’s SRS-2 T-scores for a doubling in gestational SG-standardized urinary phthalate concentrations, by child sex (n=510). Significant effect modification by sex at p<0.1 is indicated by red asterisks. Corresponding estimates and p-values for effect modification are provided in Table 2. Note: BP, mono-n-butyl phthalate; CI, confidence interval; DEHP, di-(2-ethylhexyl) phthalate; DSM-5, Diagnostic and Statistical Manual of Mental Disorders–5th edition; MBzP, mono-benzyl phthalate; MCPP, mono-3-carboxypropyl phthalate; MEP mono-ethyl phthalate; SG, specific gravity; SRS-2, Social Responsiveness Scale–II.
Figure 3.
Figure 3.
Difference (95% CI) in children’s SRS-2 T-scores for a doubling in gestational SG-standardized urinary phthalate concentrations, by folic acid supplementation during pregnancy (<400μg/d/≥400μg/d) (n=510). Significant effect modification by folic acid supplementation at p<0.1 is indicated by red asterisks. Corresponding estimates and p-values for effect modification are provided in supplementary material, Table S3. Note: CI, confidence interval; DEHP, di-(2-ethylhexyl) phthalate; DSM-5, Diagnostic and Statistical Manual of Mental Disorders–5th edition; MBP, mono-n-butyl phthalate; MBzP, mono-benzyl phthalate; MCPP, mono-3-carboxypropyl phthalate; MEP mono-ethyl phthalate; SG, specific gravity; SRS-2, Social Responsiveness Scale–II.

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