Associations of prenatal exposure to a mixture of persistent organic pollutants with social traits and cognitive and adaptive function in early childhood: Findings from the EARLI study.

BACKGROUND: Literature suggests that maternal exposure to persistent organic pollutants (POPs) may influence child neurodevelopment. Evidence linking prenatal POPs and autism spectrum disorder has been inconclusive and few studies have examined the mixture effect of the POPs on autism-related traits. OBJECTIVE: To evaluate the associations between prenatal exposure to a mixture of POPs and autism-related traits in children from the Early Autism Risk Longitudinal Investigation study. METHODS: Maternal serum concentrations of 17 POPs (11 polychlorinated biphenyls [PCBs], 4 polybrominated diphenyls [PBDEs], and 2 persistent pesticides) in 154 samples collected during pregnancy were included in this analysis. We examined the independent associations of the natural log-transformed POPs with social, cognitive, and behavioral traits at 36 months of age, including Social Responsiveness Scale (SRS), Mullen Scales of Early Learning-Early Learning Composite (MSEL-ELC), and Vineland Adaptive Behavior Scales (VABS) scores, using linear regression models. We applied Bayesian kernel machine regression and quantile g-computation to examine the joint effect and interactions of the POPs. RESULTS: Higher ln-PBDE47 was associated with greater deficits in social reciprocity (higher SRS score) (ß = 6.39, 95% CI: 1.12, 11.65) whereas higher ln-p,p'-DDE was associated with lower social deficits (ß = -8.34, 95% CI: -15.32, -1.37). Positive associations were observed between PCB180 and PCB187 and cognitive (MSEL-ELC) scores (ß = 5.68, 95% CI: 0.18, 11.17; ß = 4.65, 95% CI: 0.14, 9.17, respectively). Adaptive functioning (VABS) scores were positively associated with PCB170, PCB180, PCB187, PCB196/203, and p,p'-DDE. In the mixture analyses, we did not observe an overall mixture effect of POPs on the quantitative traits. Potential interactions between PBDE99 and other PBDEs were identified in association with MSEL-ELC scores. CONCLUSIONS: We observed independent effects of PCB180, PCB187, PBDE47, and p,p' DDE with ASD-related quantitative traits and potential interactions between PBDEs. Our findings highlight the importance of assessing the effect of POPs as a mixture.

Bayesian Weighted Sums: A Flexible Approach to Estimate Summed Mixture Effects.

OBJECTIVES: Methods exist to study exposure mixtures, but each is distinct in the research question it aims to address. We propose a new approach focused on estimating both the summed effect and individual weights of one or multiple exposure mixtures: Bayesian Weighted Sums (BWS). METHODS: We applied BWS to simulated and real datasets with correlated exposures. The analytic context in our real-world example is an estimation of the association between polybrominated diphenyl ether (PBDE) congeners (28, 47, 99, 100, and 153) and Autism Spectrum Disorder (ASD) diagnosis and Social Responsiveness Scores (SRS). RESULTS: Simulations demonstrate that BWS performs reliably. In adjusted models using Early Autism Risk Longitudinal Investigation (EARLI) data, the odds of ASD for a 1-unit increase in the weighted sum of PBDEs were 1.41 (95% highest posterior density 0.82, 2.50) times the odds of ASD for the unexposed and the change in z-score standardized SRS per 1 unit increase in the weighted sum of PBDEs is 0.15 (95% highest posterior density -0.08, 0.38). CONCLUSIONS: BWS provides a means of estimating the summed effect and weights for individual components of a mixture. This approach is distinct from other exposure mixture tools. BWS may be more flexible than existing approaches and can be specified to allow multiple exposure groups based on a priori knowledge from epidemiology or toxicology.

The Association Between Maternal Prenatal Fish Intake and Child Autism-Related Traits in the EARLI and HOME Studies.

We examined the association between prenatal fish intake and child autism-related traits according to Social Responsiveness Scale (SRS) and cognitive development scores in two US prospective pregnancy cohorts. In adjusted linear regression analyses, higher maternal fish intake in the second half of pregnancy was associated with increased child autism traits (higher raw SRS scores; ß = 5.60, 95%CI 1.76, 12.97). Differences by fish type were suggested; shellfish and large fish species were associated with increases, and salmon with decreases, in child SRS scores. Clear patterns with cognitive scores in the two cohorts were not observed. Future work should further evaluate potential critical windows of prenatal fish intake, and the role of different fish types in association with child autism-related outcomes.

Meconium androgens are correlated with ASD-related phenotypic traits in early childhood in a familial enriched risk cohort.

BACKGROUND: Prenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD). This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results. METHODS: To provide an orthogonal measure of fetal exposure, this study used meconium, the first stool of a newborn, to measure prenatal androgen exposure from infants in the Early Autism Risk Longitudinal Investigation (EARLI). EARLI is a familial-enriched risk cohort that enrolled pregnant mothers who already had a child with an ASD diagnosis. In the younger child, we investigated the association between meconium unconjugated (u) and total (t) concentrations of major androgens testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4), and ASD-related traits at 12 and 36 months of age. Traits were measured at 12 months with Autism Observation Scale for Infants (AOSI) and at 36 months with total score on the Social Responsiveness Scale (SRS). One hundred and seventy children had meconium and AOSI, 140 had meconium and SRS, and 137 had meconium and both AOSI and SRS. RESULTS: Separate robust linear regressions between each of the log-transformed androgens and log-transformed SRS scores revealed three-way interaction between sex of the child, sex of the proband, and testosterone concentration. In the adjusted analyses, t-T, u-A4, and u-DHEA (P ≤ 0.01) were positively associated with AOSI scores, while u-T (P = 0.004) and u-DHEA (P = 0.007) were positively associated with SRS total score among females with female probands (n = 10). Additionally, higher concentrations of u-T (P = 0.01) and t-T (P = 0.01) predicted higher SRS total score in males with male probands (n = 63). Limitations Since we explored three-way interactions, this resulted in a limited sample size for some analyses. This study was from an enriched-risk cohort which may limit generalizability, and this study used ASD-assessment scales as outcomes instead of diagnostic categories. Additionally, the novel use of meconium in this study limits the ability to compare the results in this cohort to others due to the paucity of research on meconium. CONCLUSIONS: This study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies.