Faculty Bibliography

BACKGROUND:Evidence suggests prenatal phthalate exposure adversely affects children's behavior. However, epidemiological studies on alternative plasticizers remain scarce. This study investigated associations of gestational exposure to phthalates and alternative plasticizers with internalizing and externalizing behaviors in children aged 1.5-5 years. METHODS:The study included 2617 mother-child dyads from 13 Environmental influences on Child Health Outcomes (ECHO) cohorts. Maternal urine samples, primarily collected mid- to late-pregnancy, were analyzed for 27 phthalate metabolites and 6 alternative plasticizer metabolites. Based on detection frequency, metabolite concentrations were modeled either continuously or categorically (Group 1: non-detectable, 2: lower detectable, 3: higher detectable). Covariate-adjusted associations between individual metabolite concentrations and internalizing and externalizing T-scores on the Child Behavior Checklist for Ages 1½-5 were estimated using linear mixed-effects models. Effect modification by child sex was also examined. RESULTS:for MHxP Group 3 = 1.23, 95% CI: 0.35, 2.12). We observed no robust associations between phthalate metabolites and internalizing T-scores, nor between cyclohexane-1,2-dicarboxylic acid mono carboxyisooctyl ester (DINCH) metabolites and any behavioral outcomes. Child sex modified associations between several metabolites and externalizing T-scores, although the direction of effect varied by metabolite. CONCLUSION/CONCLUSIONS:This large-scale study suggests that prenatal exposure to several phthalates, but not to the alternative plasticizer DINCH, may be associated with a small-to-modest increase in externalizing behaviors in young children.

BACKGROUND/UNASSIGNED:The relationship between prenatal exposure to low-level air pollution and child autism spectrum disorder (ASD) is unclear. OBJECTIVE/UNASSIGNED:To examine associations of prenatal air pollution exposure with autism. METHODS/UNASSIGNED:quantiles) using quantile regression and with ASD diagnosis using logistic regression. Models were run within census divisions, and coefficients were pooled in a meta-analysis. RESULTS/UNASSIGNED:also was associated with ASD. DISCUSSION/UNASSIGNED:Associations with ASD outcomes were present even at low levels of air pollutants. https://doi.org/10.1289/EHP16675.

BACKGROUND/UNASSIGNED:Organophosphate ester flame retardants and plasticizers (OPEs) have myriad uses in industry and consumer products. Increasing human exposure to OPEs has raised concerns about their potential effects on child neurodevelopment during pregnancy. OBJECTIVE/UNASSIGNED:We investigated whether OPE urinary concentrations during pregnancy were associated with child autism-related outcomes. METHODS/UNASSIGNED:We included 4159 mother-child pairs from 15 cohorts in the NIH Environmental influences on Child Health Outcomes (ECHO) Consortium, with children born from 2006-2020 (median age [interquartile range]: 6 [4,10] years). Nine OPE biomarkers were measured in urine samples collected mid- to late pregnancy. Dilution-adjusted biomarkers were modeled continuously, categorically (high [> median], moderate [≤ median], non-detect), or as detect/non-detect depending on their detection frequency. We assessed child autism-related traits via a) parent report on the Social Responsiveness Scale (SRS) and b) clinical autism diagnosis. We examined associations of OPEs with child outcomes, including modification by child sex, using generalized estimating equations to account for clustering by ECHO cohort. RESULTS/UNASSIGNED:Compared with non-detectable concentrations, high exposure to bis(butoxyethyl) phosphate (BBOEP) was associated with higher autistic trait scores (adj-β 0.97, 95% confidence interval [CI]: 0.42, 1.52) and greater odds of autism diagnosis (adjusted odds ratio [adj-OR]: 1.27, 95% CI: 1.07, 1.50). Bis(1-chloro-2-propyl) phosphate (BCPP) showed associations with autistic trait scores (BCPP adj-β for high exposure vs. non-detect: 0.34, 95% CI: -0.46, 1.13; BCPP adj-β for moderate exposure vs. non-detect: 0.72, 95% CI: 0.24, 1.20). High exposure to bis(2-chloroethyl) phosphate (BCETP) was associated with lower odds of autism diagnosis (adj-OR: 0.76, 95% CI: 0.60, 0.95). Other OPEs showed no associations in adjusted models. Associations between BBOEP and higher autistic trait scores were stronger in males than females. DISCUSSION/UNASSIGNED:Prenatal exposure to OPEs, specifically BCPP and BBOEP, may be associated with higher risk of autism diagnosis and related traits in childhood. https://doi.org/10.1289/EHP16177.

BACKGROUND/UNASSIGNED:Maternal sustained smoking during pregnancy is associated with thousands of differentially methylated CpGs in newborns, but impacts of other prenatal tobacco smoking exposures remain unclear. OBJECTIVE/UNASSIGNED:To identify differential DNA methylation in newborns from maternal sustained smoking and less studied prenatal smoking exposures (i.e., maternal exposure to secondhand smoke [SHS] exposure during pregnancy, maternal quitting before pregnancy, paternal smoking around conception, paternal quitting before pregnancy). METHODS/UNASSIGNED:We conducted a large meta-analysis of prenatal tobacco smoking exposures and epigenome-wide newborn blood DNA methylation through the Pregnancy And Childhood Epigenetics Consortium (PACE). Across 19 cohorts, 11,175 parent-newborn pairs contributed information on at least one prenatal smoking exposure, mostly from questionnaires. Maternal blood or urine cotinine measurements, available in a few studies, provided objective data on maternal SHS and smoking during pregnancy. Primary analyses used Illumina450K methylation data; secondary analyses in 5 cohorts examined CpGs unique to the EPIC array. RESULTS/UNASSIGNED:) was associated with paternal former smoking. Forty-one novel genes were identified using maternal cotinine measurements compared to questionnaire. In EPIC unique analyses (n=3,415), differential methylation was observed with maternal sustained smoking (211 CpGs), maternal SHS (5 CpGs), and paternal former smoking (4 CpGs). Smoking-associated CpGs in blood were strongly enriched for functional elements across multiple tissues. CONCLUSIONS/UNASSIGNED:Maternal sustained smoking has the largest impact on newborn DNA methylation, suggesting a strong influence of the intrauterine environment. We observed minimal impacts for less studied exposures including SHS, maternal former smoking and paternal smoking. https://doi.org/10.1289/EHP16303.

Polycystic ovarian syndrome (PCOS) is a common female endocrinologic condition that affects both the metabolic and reproductive systems and is the most frequent cause of anovulatory infertility. It is also associated with a range of psychiatric outcomes in individuals, including bulimia nervosa, schizophrenia, bipolar disorder, depression, anxiety, and personality disorders. At the same time, evidence suggests that hyperandrogenism, the characteristic trait of PCOS, may impair fetal neurodevelopment. Epidemiological studies have linked maternal PCOS with a variety of behavioral and psychiatric conditions in offspring including autism spectrum disorder and attention deficit hyperactivity disorder. In this review, we explore evidence for potential underlying biological mechanisms that might explain these observed associations, discuss the complex interplay between genetics and various environmental factors across generations, and highlight avenues for future research.

UNLABELLED:Exposures to phthalates and synthetic phenols are common among expectant mothers in the US. Previous studies on the neurotoxicity of these compounds have primarily assessed the effects of individual compounds on child behavior, but have not assessed potential combined effects of these substances. We assessed associations between prenatal exposure to a mixture of phthalates and phenols with behavioral problems among preschool-age children participating in the Environmental influences on Child Health Outcome (ECHO) Program. The study sample included 878 mother-child pairs from three cohorts with data on urinary concentrations of 10 phenols and 11 phthalate metabolites during pregnancy, along with caregiver reported Child Behavioral Checklist Ages 1½ to 5 (CBCL) data. Using covariate-adjusted weighted quantile sum (WQS) regression, we estimated associations between the phenol - phthalate mixture and CBCL behavioral scales T-scores. We fitted additional models stratified by sex due to previous reports of sex-specific associations. No statistically significant associations were observed in the overall sample when both male and female children were combined. However, in males, a quintile increase in the WQS index was associated with a 0.04 (95% CI: 0.00; 0.08) higher T-score of externalizing problems. The major contributors to this mixture effect were butylparaben (with a weight of 21%), benzophenone-3 (15%) and MCNP (11%). Conversely, in females, significant negative associations were observed between the WQS index with the total behavioral problems scale (beta = −0.05, 95% CI: −0.09; −0.01), externalizing problems (beta = −0.06, 95% CI = −0.10; −0.02) and internalizing problems (beta = −0.04, 95% CI: −0.08; −0.00). CONCLUSION::Our findings suggest that exposure to synthetic phenols and phthalate metabolite mixtures during pregnancy may impact childhood externalizing behavior with distinct associations in males and females. These findings contribute to the existing evidence on the combined effects of these compounds during development, emphasizing the need for further research on the combined effects of these mixtures.

Environmental exposures often exhibit temporal variability, prompting extensive research to understand their dynamic impacts on human health. There has been a growing interest in studying time-dependent exposure mixtures beyond a single exposure. However, current analytic methods typically assess each exposure individually or assume an additive relationship. This paper aims to fill the gap in method development for evaluating the joint effects of multiple time-dependent exposures on a scalar outcome. We introduce a dynamic single-index scalar-on-function model to characterize the exposure mixture's time-varying effect through a non-parametric bivariate exposure-time-outcome surface function. Utilizing B-spline tensor product bases to approximate the surface function, we propose a profiling algorithm for model estimation and establish large-sample properties for the resulting single-index estimators. In addition, we introduce a non-parametric hypothesis testing procedure to determine whether the surface function varies over time at each fixed mixture level and a model averaging solution to circumvent the issue of knot selection for spline approximations. The performance of our proposed methods is examined through extensive simulations and further illustrated using real-world applications.

OBJECTIVE:Anogenital distance (AGD) is a postnatal marker of in utero exposure to androgens and anti-androgens, and a predictor of reproductive health. We examined the association between gestational exposure to phthalates and AGD in male and female infants. METHODS:In 506 mother-infant pairs (276 males, 230 females), we measured urinary concentrations of phthalate metabolites at < 18 and 18-25 weeks of gestation and AGD at child age 12.9 months (95 % range 11.4-21.1). Phthalate metabolite concentrations were adjusted for urinary dilution, averaged, and natural log-transformed. We measured anus-clitoris distance (AGDac) and anus-fourchette distance (AGDaf) in females, and anus-scrotum distance, anus-penis distance, and penile width in males. We used linear regression and partial-linear single-index (PLSI) models to examine associations between phthalates and AGD as single pollutants and in mixture. RESULTS:Fifty-eight percent of mothers were Hispanic, followed by 27 % non-Hispanic White. Higher exposures to ∑di-isononyl(phthalate) (∑DiNP) was associated with longer AGDaf [1.28 mm (95 % confidence interval [CI]: 0.52, 2.03) and 0.97 mm (95 %CI: 0.25, 1.69), respectively]. Higher exposures to ∑di(2-ethylhexyl)phthalate (∑DEHP) was associated with longer AGDac [2.80 mm (95 %CI: 1.17, 4.44), and 1.90 mm (95 %CI: 0.76, 3.04), respectively]. No association was observed between phthalate metabolites and AGD in males after multiple testing correction. In mixture analyses, ∑DiNP and ∑DEHP were the main contributors to longer AGD in females. We also detected an interaction between ∑DiNP and ∑DEHP in association with AGD in females. CONCLUSION/CONCLUSIONS:Early pregnancy phthalate exposure was associated with longer AGD in female infants. Biological mechanisms underlying these associations should be further investigated.

BACKGROUND:Maternal thyroid dysfunction and maternal depression during pregnancy may increase the risk of child behavioral and emotional problems. We sought to investigate the independent and interactive associations of these two risk factors with child behavior problems. METHODS:We combined data from four cohorts in the Environmental influences on Child Health Outcomes (ECHO) program (N = 949). Maternal thyroid function (thyroid-stimulating hormone [TSH], free thyroxine [fT4], thyroid peroxidase autoantibodies [TPO-Ab], fT4/TSH ratio) was measured predominantly during the first half of pregnancy. We harmonized maternal depression into a continuous measure of antepartum depressive symptomatology and a dichotomous measure reflecting (history of) clinical depression. Child internalizing and externalizing problems were harmonized to the T-score metric of the Child Behavior Checklist. We used multiple linear regression and random effects meta-analysis to assess the average relationship between each predictor and outcome, and the variability in these relationships across cohorts. RESULTS:Across cohorts, antepartum depressive symptomatology was positively associated with both internalizing (meta B = 2.879, 95 % CI 1.87-3.89, p < .001) and externalizing problems (meta B = 1.683, 95 % CI 0.67-2.69, p = .001). None of the indicators of maternal thyroid function was associated with child behavior problems across cohorts. TPO-Ab concentrations were positively associated with child externalizing problems only in offspring of depressed mothers (meta B = 3.063, 95 % CI 0.73-5.40, p = .010). CONCLUSIONS:This study supports the importance of maternal antepartum mental health for child behavior across diverse populations. However, we found little empirical evidence for an association between maternal thyroid function within the normal range during pregnancy and child behavioral problems.

OBJECTIVE:Poverty and systemic racism within rare intertwined. Children of marginalized racial and ethnic identities experience higher levels of poverty and adverse psychiatric outcomes. Thus, in models of poverty and neurodevelopment, race and ethnicity-as proxies for exposure to systemic disadvantage-are regularly considered confounders. Recently, however, some researchers claimed that using race and ethnicity as confounders is statistically dubious, and potentially socially damaging. Instead, they argue for the use of variables measuring other social determinants of health (SDoH). We explore this approach. METHOD/METHODS:Data are from 7,836 10-year-olds in the Adolescent Brain and Cognitive Development study. We fit mixed regression models for the association of household poverty measures with psychiatric symptoms, magnetic resonance imaging-derived (MRI) cortical measures, and cognition with and without (1) race and ethnicity adjustment; (2); poverty-by-race and ethnicity interaction terms and (3) alternative SDoH variables. Propensity-based weights were used to calibrate the sample to key US demographics. RESULTS:For psychiatric and cognitive outcomes, poverty-outcome relationships differed across racial and ethnic groups (poverty-by-race-and-ethnicity interaction p<0.05). For MRI outcomes, adjusting for race and ethnicity changed the estimate of poverty's impact. Alternative SDoH adjustment could not fully account for the impact of race and ethnicity on the associations explored. CONCLUSION/CONCLUSIONS:Poverty and race and ethnicity combine to influence neurodevelopment. Results suggest effects of poverty are generally inconsistent across race and ethnicity, which supports prior research demonstrating the non-equivalence of SDoH indicators by race and ethnicity. Studies exploring these relationships should assess interaction between poverty and race and ethnicity and/or stratify when appropriate. Replacing race and ethnicity with alternative SDoH may induce bias.