Faculty Bibliography

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.

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:Maternal vitamin D level is an important determinant of pregnancy and child health outcomes. Exposure to air pollution is suspected to increase the risk of vitamin D deficiency, but the evidence is scarce. We investigated the association between air pollution during pregnancy and maternal vitamin D levels. METHODS:A total of 15,935 pregnant women from 5 birth cohorts in Europe and U.S were included. Averaged concentrations of nitrogen oxides, fine and coarse particles, and composition of fine particles from conception until vitamin D measurement were estimated at participants' residential addresses using land-use regression or other spatiotemporal models. Cohorts measured vitamin D as 25(OH)D or 25(OH)D3 levels in serum or plasma at early or mid-pregnancy. We defined suboptimal vitamin D levels as levels below 20 ng/mL. We performed logistic regression models for each cohort to estimate the association between air pollution exposure and suboptimal vitamin D levels and pooled cohort-specific estimates in a random-effect meta-analysis. Models were adjusted for sociodemographic and lifestyle characteristics and month of conception. RESULTS:We found an association between PM2.5 and higher odds of suboptimal vitamin D levels (i.e., below 20 ng/mL) (odds ratio per 5 μg/m3 increase in PM2.5, 1.43 95%CI: 1.02, 1.99). There was no association between other air pollutant exposure and vitamin D levels. CONCLUSIONS:PM2.5 exposure might contribute to suboptimal levels of vitamin D in pregnancy. Reducing air pollution exposure should be a priority because vitamin D deficiency may adversely influence offspring development.

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.

Prenatal organophosphate (OP) pesticide exposure may be associated with reduced fetal growth, although studies are limited and have mixed results. We investigated associations between prenatal OP pesticide exposure and fetal size and modification by fetal sex. Maternal urinary concentrations of dialkyl phosphate (DAP) metabolites were measured at three time points. Fetal biometrics were obtained from ultrasounds in the second (n=773) and third (n=535) trimesters. Associations between pregnancy-averaged ΣDAP and fetal biometry z-scores were determined through multiple linear regression. Modification by sex was investigated through stratification and interaction. In the second trimester, one ln-unit increase in ΣDAP was associated with lower estimated fetal weight (-0.15 SD; 95% CI: -0.29, -0.01), head circumference (-0.11 SD; CI: -0.22, 0.01), biparietal diameter (-0.14 SD; CI: -0.27, -0.01), and abdominal circumference (-0.12 SD; CI: -0.26, 0.01) in females. In the third trimester, one ln-unit increase in ΣDAP was associated with lower head circumference (-0.14 SD; CI: -0.28, 0.00) and biparietal diameter (-0.12 SD; CI: -0.26, 0.03) in males. Our results suggest that prenatal OP pesticide exposure is negatively associated with fetal growth in a sex-specific manner, with associations present for females in mid-gestation and males in late gestation.

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.

There is growing concern that exposure to per/polyfluoroalkyl substances (PFAS), persistent chemicals used widely to make consumer products water- or grease-proof, may alter immune function, leading to reduced vaccine response or greater susceptibility to infections. We investigated associations between two legacy PFAS (PFOA and PFOS) and infant cytokine levels measured in newborn dried bloodspots (NDBS) from a large population-based birth cohort in Upstate New York, to determine whether exposure to legacy PFAS is associated with variability in cytokine profiles in newborns. We performed adjusted mixed effects regressions for each cytokine against PFOS and PFOA followed by exploratory factor analysis (EFA) on specific cytokine subsets selected via the prior regressions. Among 3448 neonates (2280 singletons and 1168 twins), significant cytokines were dominated by cytokines negatively associated with the given PFAS. Adjusted single-pollutant models with continuous log-transformed PFOA showed significant negative associations with IL-16 (-0.07, 95% CI: -0.3, -0.1), IL-5 (-0.05, 95%CI: -0.09, -0.02), IL-6 (-0.06, 95%CI: -0.1, -0.02), 6-Ckine (0.06, 95% CI: -0.10, -0.02) and significant positive associations with IL-1α (0.066, 95%CI: 0.03, 0.11), MCP-1 (0.06, 95%CI: 0.03, 0.10). Estimates for PFOS were slightly larger than estimates for PFOA but only significant for 6-Ckine (-0.21, 95%CI: -0.09, -0.33) after correction for multiplicity. Our data consistently suggest that legacy PFAS exposures are associated with disrupted, typically reduced, cytokine levels in neonates, with PFOA exposure resulting in more significant differences in individual cytokines and cytokine groupings than PFOS. Regression by PFAS quartile shows evidence of nonlinear dose-response relationships for most cytokines and cytokine groupings.

This is an invitation letter for the principal investigators and cohort studies to join the Consortium on Thyroid and Pregnancy. The inclusion criteria are population-based cohorts with data on maternal thyroid function during pregnancy and any measurement of known groups of endocrine disrupting chemicals.