Faculty Bibliography

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.

Prenatal exposure to phthalates might influence the development of childhood obesity. Most previous studies used body mass index (BMI) at a specific age instead of BMI development, which might be a better indicator of later health. We aimed to assess the association of prenatal phthalate exposure with longitudinal BMI development from infancy to adolescence. Among 1,379 mother-child pairs from a population-based cohort study, phthalate concentrations were measured in maternal spot urine samples, collected during first, second and third trimester. We estimated age- and sex-adjusted BMI standard deviation scores (SDS) at 6 months and 1, 2, 3, 4, 6, 10 and 13 years. We examined the associations of maternal phthalate urine concentrations during pregnancy with repeated measures of BMI using linear mixed effects models. An interquartile range higher natural log-transformed maternal first trimester high-molecular weight phthalate and di-2-ethylhexylphthalate (DEHP) urine concentrations were associated with a -0.10 (95% confidence interval (CI) -0.15 to -0.04), and -0.09 (95% CI -0.15 to -0.04) lower age- and sex-adjusted BMI at 6 months. An interquartile range higher natural log-transformed maternal first trimester phthalic acid and low-molecular weight phthalate urine concentrations were associated with a 0.11 (95% CI 0.03 to 0.18) and 0.13 (95% CI 0.04 to 0.21) higher age- and sex-adjusted BMI at 13 years old. No significant associations were observed for maternal second and third trimester phthalate urine concentrations with BMI. Thus, higher maternal phthalate metabolites urine concentrations appear to be related to lower BMI at early ages but with higher BMI at later ages.

Many phthalates have been identified as endocrine-disrupting chemicals because they alter hormone functions throughout the lifespan. Nationally representative biomonitoring data are available from the United States, Canada, and Europe, but data elsewhere are sparse, making extrapolations of related disease and disability burdens difficult. We therefore examined trends in urinary phthalate metabolite concentrations in non-occupationally exposed populations in countries other than the United States, Canada, and Europe, where representative data are already available at the country level. We systematically reviewed studies published between 2000 and 2023 and analyzed changes in urinary phthalate metabolite concentrations across time using mixed-effects meta-regression models with and without a quadratic term for time. We controlled for region, age, and pregnancy status, and identified heterogeneity using Cochran's Q-statistic and I² index. Our final analysis consisted of 216 studies. Non-pregnant and youth populations exhibited nearly 2.0-fold or greater difference in concentration compared to pregnant and adult populations. Phthalates with significant regional differences had 10-fold higher concentrations in the Middle East and South Asia than in other regions. Our meta-regressions identified an exponential increase in DBP exposure through MnBP concentration internationally (beta: 0.65 ng/mL/year²) and in Eastern and Pacific Asia (EPA) (beta: 0.78 ng/mL/year²). Most DEHP and DnOP metabolites significantly declined internationally and in EPA, while MEP concentration declined by 10.62 ng/mL in Latin America and 8.98 ng/mL in Africa over time. Our findings fill gaps in phthalate exposure data and set the stage for further analysis of the attributable disease burden and cost at regional and international levels, especially in low- and middle-income countries.

Concerns persist about the potential impact of prenatal exposure to bisphenols (BP) and their replacement analogues on childhood asthma and allergies. Previous studies on single and small cohorts had limited statistical power, few investigated analogues BPF and BPS, and even fewer examined atopic outcomes. Our objective was to assess whether prenatal exposures to individual environmental bisphenols (BPA, BPF, BPS) influence risk of childhood asthma, allergic rhinitis, and atopic dermatitis. Data from the U.S. Environmental Influences on Child Health Outcomes (ECHO) consortium were harmonized on measures of prenatal urinary BPA, BPF and BPS and asthma and allergic rhinitis (ages 5-9 years) and atopic dermatitis (up to age 3 years) from 1905 mother-child pairs that were collected between 1998 and 2017. Across the 2012 federal ban of BPA from certain infant products, median BPA levels decreased from 1.11 ng/ml to 0.86 ng/ml; median BPF levels decreased from 0.51 ng/ml to 0.39 ng/ml; and median BPS levels increased from 0.23 ng/ml to 0.31 ng/ml (dilution adjusted; p < 0.001 for all three median comparisons). Prenatal measures of BPA, BPF, and BPS were unrelated to the risk of childhood asthma, allergic rhinitis, or atopic dermatitis in the total population. Modest sex-dependent effects were observed: only among girls, second tertile levels of BPF was associated with a reduced odds of asthma (odds ratio (OR) 0.27, 95% confidence interval (CI) 0.08, 0.93); a continuous index of prenatal BPS was associated with reduced odds of atopic dermatitis (OR 0.64, 95% CI 0.44, 0.93). The ongoing and changing patterns of exposure to bisphenols in the U.S. population require further study with additional attention to time windows of exposure and co-occurring social determinants of health, to continue to inform current policies and evaluate the importance of limiting exposure to BPA and its analogues on childhood asthma, allergic rhinitis, and atopic dermatitis.

BACKGROUND:PAH exposure is associated with adverse health outcomes, but exposure sources in pregnancy are not well-understood. OBJECTIVES/OBJECTIVE:We examined associations between urinary OH-PAHs during pregnancy and environmental tobacco smoke (ETS) and short-term ambient air pollution exposure. Participants included 1603 pregnant non-smokers in three cohorts from 7 sites across the USA. We also examined associations with intake of foods typically high in PAHs in one cohort with dietary assessment data (n = 801). METHODS:quartile adjusted for specific gravity, site, batch, household income, education, employment status, neighborhood deprivation index, season, and year. For the food model, PAH dietary intakes were estimated using food frequency questionnaire data and standard portion weights from a national database. RESULTS:was not associated with any OH-PAH, nor was self-reported dietary intake. CONCLUSIONS:and diet measured via usual intakes appear less influential. Our findings underscore the importance of policies/actions to reduce environmental tobacco smoke exposure among pregnant people.

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.