Prenatal exposure to phthalates and autism spectrum disorder in the MARBLES study

Abstract

BackgroundEvidence from experimental and observational studies suggests that prenatal phthalate exposures may be associated with autism spectrum disorder (ASD). We examined whether prenatal phthalate exposures were associated with an increased risk of ASD.MethodsWe quantified 14 metabolites of eight phthalates in 636 multiple maternal urine samples collected during 2nd and 3rd trimesters of pregnancy from 201 mother-child pairs in MARBLES (Markers of Autism Risk in Babies – Learning Early Signs), a high-risk ASD longitudinal cohort. At 3 years old, children were clinically assessed for ASD and classified into three diagnostic categories: ASD (n = 46), non-typical development (Non-TD, n = 55), and typical development (TD, n = 100). We used multinomial logistic regression to evaluate the association of phthalate metabolite concentrations with ASD and Non-TD.ResultsMost associations of phthalate biomarkers with both ASD and Non-TD were null, with the exception that monoethyl phthalate (MEP) was significantly associated with an increased risk of Non-TD (per 2.72-fold relative increase in concentration: Relative risk ratio (RRR) = 1.38; 95% confidence interval (CI): 1.01, 1.90). When stratified by prenatal vitamin use during the first month of pregnancy, among mothers who took vitamins, ASD risk was inversely associated with mono-isobutyl phthalate (MiBP, RRR = 0.44; 95% CI: 0.21, 0.88), mono(3-carboxypropyl) phthalate (MCPP, RRR = 0.41; 95% CI: 0.20, 0.83) and mono-carboxyisooctyl phthalate (MCOP, RRR = 0.49; 95% CI: 0.27, 0.88), but among mothers who did not take prenatal vitamins, Non-TD risk was positively associated with MCPP (RRR = 5.09; 95% CI: 2.05, 12.6), MCOP (RRR = 1.86; 95% CI: 1.01, 3.39), and mono-carboxyisononyl phthalate (MCNP, RRR = 3.67; 95% CI: 1.80, 7.48). When stratified by sex, among boys, MEP, monobenzyl phthalate, MCPP, MCNP, and sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP) were positively associated with Non-TD risk, but associations with ASD were null. Among girls, associations with both ASD and Non-TD were null.ConclusionsOur study showed that phthalate exposures in mid- to late pregnancy were not associated with ASD in children from this high-risk ASD cohort. Further studies should be conducted in the general population without high-risk genes to confirm our findings.Electronic supplementary materialThe online version of this article (10.1186/s12940-018-0428-4) contains supplementary material, which is available to authorized users.

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

“…To our knowledge, this is the first study to report on these potential protective effects of folate supplementation in regard to the relationship between phthalates exposure and autistic traits. Similar effect modification by prenatal vitamin use has been reported for the associations between MCPP and mono-carboxyisooctyl phthalate (MCOP) and nontypical development (Shin et al 2018). In addition, Shin et al (2018) reported protective effects of mono-isobutyl phthalate, MCPP, and MCOP in relation to child's ASD risk in mothers who reported prenatal vitamins use, and null associations in children of mothers who reported no prenatal vitamins use.…”

“…In contrast, three other studies did not observe associations of phthalates in second and third trimester maternal urine (Braun et al 2014;Shin et al 2018) or house dust collected 2-5 y after birth (Philippat et al 2015) with autistic traits or ASD diagnosis. However, one of those studies reported potential effect modification of the association between some phthalates and ASD by prenatal vitamin use (Shin et al 2018). In addition, two recent studies suggested that folic acid (FA) may mitigate the potential adverse health effects of air pollutants and pesticides in relation to ASD (Goodrich et al 2018;Schmidt et al 2017).…”

“…Because previous studies showed potential sexually dimorphic associations between phthalates and neurodevelopmental outcomes (Kim et al 2011;Shin et al 2018;Zhang et al 2019), we examined sex-specific associations by including a product interaction term between child sex and phthalate concentrations. We also examined whether prenatal FA supplementation modified the association between urinary phthalate concentrations and SRS scores using the same approach.…”

“…Another study reported associations between higher third trimester gestational urinary low-molecular weight phthalate metabolite concentrations and higher Social Responsiveness Scale-II (SRS-2) T-scores in 137 seven-to nineyear-old children (Miodovnik et al 2011). In contrast, three other studies did not observe associations of phthalates in second and third trimester maternal urine (Braun et al 2014;Shin et al 2018) or house dust collected 2-5 y after birth (Philippat et al 2015) with autistic traits or ASD diagnosis. However, one of those studies reported potential effect modification of the association between some phthalates and ASD by prenatal vitamin use (Shin et al 2018).…”

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

“…Much more information is needed to understand which patient populations are most responsive, and whether probiotic treatment would be a valuable alternative. Importantly, there have also been many environmental exposures associated with the development of ASD [180][181][182][183], and more research into the role of the microbiome could help elucidate mechanisms. ASD is just one example of a psychiatric outcome that may sit at the crossroads of microbial dysbiosis and environmental exposure.…”