Faculty Bibliography

BACKGROUND:A large body of evidence has documented the effects of ortho-phthalates, additives to soft plastic used in food packaging, on premature birth. Ortho-phthalates are increasingly replaced with alternatives including tere-phthalates and di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH). A limited toxicological literature suggests that DINCH metabolites disrupt sex hormones and promote oxidant stress known to contribute to adverse birth outcomes, and epidemiologic studies have also been limited in sample size, inclusivity of different populations and measurements at different time points in pregnancy. METHODS:We leveraged a large American cohort comprised of mother-child dyads from twenty-two cohorts to assess associations of trimester-specific and pregnancy-wide DINCH metabolites with birth weight (BW) and gestational age (GA). FINDINGS/RESULTS:Average prenatal urinary DINCH was inversely associated with birth length, birthweight, and birthweight for gestational age z-scores, but not GA. A tenfold increase in the pregnancy-averaged DINCH metabolite cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (MCOCH) was associated with a decrease of 27.43 g (95%CI: -54.81, -0.04) in birthweight. Trimester-specific analyses revealed stronger associations for third trimester DINCH exposure with birth outcomes. INTERPRETATION/CONCLUSIONS:In a large American cohort representing a broad range of backgrounds, we identified an inverse association of DINCH with standardized measures of birth size, but not gestational age. Further studies should examine joint exposures to DINCH, tere- and orthophthalates, and repeated measures across pregnancy.

Hypomineralized second primary molars (HSPM) affect approximately 6.8% of children. Molars affected by HSPM mineralize between 20 wk of gestation and 15 to 17 mo of age. Experimental studies suggest that exposure to endocrine-disrupting chemicals, including di-2-ethylhexyl phthalate (DEHP) and bisphenol A (BPA), may disrupt enamel formation, but evidence in humans remains limited. This study investigates the association between prenatal exposure to individual phthalates, BPA, and their mixtures and the odds of HSPM in children. It was embedded in the Generation R study, a population-based prospective birth cohort in the Netherlands. Maternal urinary concentrations of BPA and 11 phthalate metabolites were measured each trimester. HSPM was diagnosed at age 6 y based on European Academy of Paediatric Dentistry criteria. Multivariate logistic regression models and Bayesian weighted quantile sum regression were used to assess individual and mixture associations, respectively. Among 1,160 mother-child pairs, 10.2% of children were diagnosed with HSPM. In single-exposure models, higher prenatal concentrations of monobenzyl phthalate (mBzBP) were associated with lower odds of HSPM (odds ratio [OR] = 0.76; 95% confidence interval [CI]: 0.59 to 0.97). Second-trimester exposure to DEHP metabolites showed a nonsignificant trend toward increased HSPM odds (eg, mEOHP OR = 1.15; 95% confidence interval [CI]: 0.91 to 1.45). Sex-specific associations were observed: higher BPA and phthalate concentrations were associated with lower likelihood of HSPM in girls (eg, BPA OR = 0.70; 95% CI: 0.50 to 0.98) and higher odds in boys (p-interaction < 0.10). Mixture analyses showed a nonsignificant inverse association for overall prenatal exposure (OR = 0.84; 95% CI: 0.63 to 1.15), with mBzBP contributing most to the mixture. No overall association was observed for DEHP mixture, although sex-specific trends were consistent with single-exposure results. Prenatal exposure to phthalates and BPA may influence HSPM development. These findings highlight the need to consider early-life endocrine-disrupting chemical mixture exposure in HSPM etiology.

BACKGROUND:Perinatal exposure to phthalates, parabens, and phenols-common endocrine disrupting chemicals (EDCs)-has been associated with adverse health outcomes, but the underlying biological mechanisms remain unclear. This study aims to explore the associations between perinatal EDC exposure--individually and as a mixture--and the neonatal metabolome, which provides a readout of metabolic processes and the factors that impact them. METHODS:EDCs and the metabolome were characterized in umbilical cord blood plasma from 175 pregnant participants recruited through the Columbia Center for Children's Environmental Health. Nontargeted screening revealed 15 EDCs using gas chromatography coupled to high resolution mass spectrometry (HRMS) and 5835 metabolic features using liquid chromatography HRMS. Correlated features were grouped into 21 modules using weighted gene co-expression network analysis and into integrative networks using xMWAS. Linear regression and quantile g-computation were used to assess associations between EDC exposures and individual metabolic feature abundance and the modules. RESULTS:We observed 2208 metabolome-wide associations between individual metabolic features and EDCs modeled individually and one association with the EDC mixture. Eight EDCs were individually associated with 7 modules, and the EDC mixture was associated with 1 module. Pathway enrichment analyses revealed phenol and phthalate exposures were associated with fatty acid and energy metabolism. xMWAS networks demonstrated similar EDC-module and EDC-metabolic feature relationships. CONCLUSION/CONCLUSIONS:Perinatal EDC exposure, individually and as a mixture, is associated with individual metabolic features and metabolic networks measured in cord plasma. These results could offer insight into the biological processes underpinning relationships between perinatal EDC exposure and adverse health outcomes.

BACKGROUND:Studies of prenatal exposure to non-persistent chemicals often assume biomarker measurements from a single urine sample can represent exposure pregnancy. The validity of this assumption depends on biomarker concentration variability across gestation, which is not well-characterized for many chemicals. OBJECTIVE:To assess the intra-individual variability of non-persistent chemical concentrations measured in 3 pregnancy urine samples. METHODS:We measured 154 analytes from 12 classes in 3 urine samples collected across gestation from 90 participants in 3 Environmental influences on Child Health Outcomes Cohort sites. For each cohort site, we estimated intraclass correlation coefficients (ICCs) of 58 analytes with >60% detection using log2-transformed concentrations of specific gravity (SG)-standardized values. We classified analyte ICCs by the site-specific median relative to the limits of detection (LODs) to evaluate the influence of exposure levels on reliability estimates. As secondary analyses, we calculated kappa statistics for 56 analytes with 20-60% detection to assess agreement of detection frequencies across the 3 timepoints. RESULTS:ICCs (range: -0.12 to 0.91) varied by cohort site, except for benzophenone-1 and propyl paraben (consistently >0.5) and bisphenol F (consistently <0.1). We observed site-specific trends for parabens, benzophenones, antimicrobials, phthalates, polycyclic aromatic hydrocarbons, and aromatic amines. Analytes with median:LOD ratios >50 were more stable throughout pregnancy (e.g., benzophenones, propyl paraben, antimicrobials, and naphthalenes), except for some phthalate metabolites, which may indicate high sporadic exposures. Analytes with median:LOD ratios <10 had lower ICCs, except for benzophenone-8, which may indicate low-level chronic exposure. Kappa statistics of the 56 analytes with 20-60% detection ranged from -0.22 to 0.53. SIGNIFICANCE/CONCLUSIONS:ICCs varied by cohort site. Lower ICCs were generally observed for analytes with lower concentrations. For the majority of non-persistent chemicals, a single pregnancy measure may better represent exposure near the time of sample collection rather than for the entire pregnancy. IMPACT/CONCLUSIONS:Understanding the intra-individual variability of urinary non-persistent chemical biomarkers across multiple pregnancy timepoints is important to inform study design, statistical analysis, and interpretation in future studies.

OBJECTIVE:To examine the association between prenatal exposure to a mixture of EDCs and attention-deficit/hyperactivity disorder (ADHD) symptoms in children. METHODS:Participating were mother-child pairs from the Environmental influences on Child Health Outcomes (ECHO) Cohort (n = 3,962, 18 Sites, 2001-2021). Maternal spot urine samples collected during pregnancy were sent to the Wadsworth Center Human Health Exposure Analysis Resource laboratory and analyzed using a single assay workflow. From those samples, 24 urinary metabolites of EDCs with detection frequency > 70%, were grouped as molar sum of high- and low-molecular-weight phthalates, polycyclic aromatic hydrocarbons, bisphenol S, organophosphate esters, and organophosphate and pyrethroid pesticides. Child ADHD symptoms were assessed using raw scores from the Child Behavior Checklist for preschool-aged (CBCL/1½-5) and school-aged (CBCL/6-18) Attention-Deficit/Hyperactivity Problems subscale. Scores ≥ the 85th and 95th percentiles were respectively classified as borderline and clinical thresholds. Quantile g-computation estimated the expected change in ADHD outcome associated with a one-quartile increase in all prenatal EDC mixture concentrations, using negative binomial models for raw scores and binomial models for percentile thresholds. RESULTS:Prenatal exposure to the EDC mixture was not associated with child ADHD symptoms in preschool-aged or school-aged children in adjusted models for either continuous raw scores or percentile thresholds. CONCLUSION/CONCLUSIONS:Overall our findings on prenatal EDC mixture exposure and ADHD symptoms were not robust to full adjustment. Future research that can delineate factors such as windows of vulnerability and trajectories of ADHD-related symptoms may help clarify mixed findings in the literature.

Aside from specific occupational exposures, ingestion is believed to be the primary route of exposure to PFAS, a class of forever chemicals known for their ability to repel oil and water, reduce friction, and resist high temperatures. The goal was to explore the geographic distribution of PFAS water contamination versus human exposure and identify dietary factors that may explain high PFAS levels among rural residents. We performed PFAS analyses among 160 rural participants, who provided blood samples and survey responses in our chemical exposure cross-sectional study. We mapped the geographic distribution of PFAS contamination based on water testing versus human samples results. We also used health surveys and food frequency questionnaire data to identify factors associated with high PFAS levels. The geographic mismatch between the distribution of PFAS water contamination and human exposure highlights the need to assess other potential sources, which identified potential dietary sources of these chemical hazards.

IMPORTANCE/UNASSIGNED:Organophosphate pesticides (OPs) are established neurotoxicants; prenatal OP exposure is widespread in the US population, primarily through diet. Evidence linking prenatal OP exposure to autism spectrum disorder (ASD) and autism-related traits remains inconsistent. OBJECTIVE/UNASSIGNED:To examine the association between prenatal OP exposure and autism-related traits in childhood and to assess potential differences in the association by child sex and maternal diet. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This pooled prospective cohort study used harmonized data from mother-child pairs from 20 study sites in the Environmental influences on Child Health Outcomes (ECHO) cohort. Participants were recruited from January 1997 through December 2019, and autism-related outcomes were assessed in children ages 2 to 19 years. Data analysis was performed from April 2024 and November 2025. EXPOSURE/UNASSIGNED:Prenatal OP exposure using urinary concentrations of 3,5,6-trichloro-2-pyridinol (TCPy) and the sum of 6 dialkyl phosphate (ΣDAP) metabolites. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Parents reported autism-related traits in children using the Social Responsiveness Scale (SRS). Multivariable linear, quantile, and logistic regression models were used to estimate associations between biomarkers and SRS T scores overall and by child sex, adjusting for maternal sociodemographic and behavioral factors. We further adjusted for dietary factors in additional models and tested effect modification by maternal diet quality in exploratory analyses. RESULTS/UNASSIGNED:Among 3339 mother-child pairs examined, mean (SD) maternal age was 31 (6) years, 1665 children (49.9%) were female, and the SRS was administered at a mean (SD) age of 6.4 (3.87) years. Crude or minimally adjusted models suggested inverse associations between prenatal TCPy or ΣDAP levels and SRS scores, but these associations attenuated and lost statistical significance after full adjustment (β per doubling of TCPy concentration [ng/mL] = -0.13; 95% CI, -0.57 to 0.31; β per doubling of ΣDAP [nmol/L] = -0.42; 95% CI, -1.03 to 0.19). Results were consistent across sex-stratified models, secondary analyses using quantile and logistic regressions, various sensitivity analyses, and after adjustments for dietary confounders. There was no evidence of effect modification by diet quality. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this large, prospective cohort study among the ECHO cohort, prenatal OP exposure was not associated with autism-related traits in childhood. Given the known adverse impacts of pesticides in other contexts, further research should consider interactions with other factors, genetic susceptibility, higher exposures, or combined chemical mixtures.

BACKGROUND/UNASSIGNED:Early childhood is a critical window for cardiac development, yet the impact of prenatal factors and early growth patterns on heart structure and function in children with structurally normal hearts remains incompletely described. This study investigates the roles of birth weight (BW), gestational age (GA), birthweight-for-gestational-age (BW/GA) z-score, and weight gain z-score in shaping cardiac dimensions. METHODS/UNASSIGNED:-scores for cardiac dimensions and volumes were used to standardize for body surface area (BSA). BW, BW/GA z-score, GA, and weight gain z-score were analyzed as predictors of these parameters. RESULTS/UNASSIGNED:Higher weight gain z-score was independently associated with smaller cardiac dimension z-scores, particularly in the aortic root, ascending aorta, left atrium diameter, left ventricular internal diameter at end-diastole, left ventricular internal diameter at end-systole, end-systolic volume, end-diastolic volume, and left ventricular mass. While birth characteristics influenced some cardiac parameters, postnatal weight gain emerged as a more significant predictor of cardiac size. Ejection fraction and fractional shortening were not influenced by the predictors in our analysis. CONCLUSIONS/UNASSIGNED:Our findings suggest that postnatal weight gain was more consistently associated with cardiac structure z-scores than anthropometric characteristics at birth. Specifically, contractile myocardial thicknesses were relatively stable across weight gain patterns, whereas vascular structures showed inverse scaling with higher weight gain.

The prenatal period is a critical window for neurodevelopment, during which maternal metabolic processes are increasingly recognized to shape later behavioral and autism-related traits. We examined associations between targeted maternal urinary metabolomic profiles across pregnancy and preschool emotional, behavioral, and autism-related outcomes in the New York University Children's Health and Environment Study (NYU CHES), a large prospective birth cohort. Targeted metabolomics was conducted on maternal urine samples collected in early, mid, and late pregnancy. Child outcomes were assessed at a mean age of 2.3 years using the Child Behavior Checklist (CBCL) total and DSM-5-oriented autism spectrum disorder (ASD) subscale scores. We applied two-stage mixed-effects models to assess overall pregnancy metabolite levels and timepoint-specific negative binomial models to evaluate trimester-specific associations, with covariate adjustment, sex-stratification, and false discovery rate (FDR) correction. Few associations were observed two-stage models. In timepoint-specific analyses, a robust sex- and timing-specific association emerged: among males, higher third-trimester urinary lysoPC a C26:1 was associated with lower CBCL total and ASD subscale scores, surviving stringent FDR correction and remaining robust after adjustment for maternal diet quality. Additional associations involving taurine, inflammatory markers, and acylcarnitines were observed primarily in sex-stratified or diet-adjusted models but were less robust to multiple testing correction. These findings suggest that prenatal metabolic profiles, particularly lipid- and mitochondrial energy-related pathways in late gestation, may contribute to early behavioral and autism-related traits in a sex-specific manner, underscoring the importance of exposure timing and maternal metabolism in the etiology of neurodevelopmental outcomes.