Faculty Bibliography

CONTEXT/BACKGROUND:Postpartum depression (PPD) is a serious psychiatric disorder. While causes remain poorly understood, perinatal sex hormone fluctuations are an important factor, and allopregnanolone in particular has emerged as a key determinant. While synthetic environmental chemicals such as bisphenols and phthalates are known to affect sex hormones, no studies have measured allopregnanolone and the consequences of these hormonal changes on PPD have not been interrogated. OBJECTIVE:To investigate associations of repeated measures of urinary bisphenols and phthalates in early- and mid-pregnancy with serum pregnenolone, progesterone, allopregnanolone, and pregnanolone concentrations in mid-pregnancy and PPD symptoms at four months postpartum. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION/UNASSIGNED:Prospective cohort study of 139 pregnant women recruited between 2016-18. Bisphenols and phthalates were measured in early- and mid-pregnancy urine samples. Serum sex steroid hormone concentrations were measured in mid-pregnancy. PPD was assessed at 4 months postpartum using the Edinburgh Postnatal Depression Scale (EPDS). Multiple informant models were fit using generalized estimating equations. MAIN OUTCOME MEASURES/METHODS:Serum levels of allopregnanolone, progesterone, pregnanolone, and pregnenolone were examined as log-transformed continuous variables. PPD symptoms were examined as continuous EPDS scores and dichotomously with scores ≥10 defined as PPD. RESULTS:Di-n-octyl phthalate (DnOP) and diisononyl phthalate (DiNP) metabolites were associated with reduced progesterone concentrations. Log-unit increases in ∑DnOP and ∑DiNP predicted 8.1% (95% Confidence Interval (CI): -15.2%, -0.4%) and 7.7% (95% CI: -13.3%, -1.7%) lower progesterone, respectively. ∑DnOP was associated with increased odds of PPD (odds ratio=1.48 (95% CI: 1.04, 2.11)). CONCLUSIONS:Endocrine disrupting chemicals may influence hormonal shifts during pregnancy as well as contribute to PPD.

BACKGROUND:Exposure to bisphenols may affect fetal growth and development. The trimester-specific effects of bisphenols on repeated measures of fetal growth remain unknown. Our objective was to assess the associations of maternal bisphenol urine concentrations with fetal growth measures and birth outcomes and identify potential critical exposure periods. METHODS:In a population-based prospective cohort study among 1379 pregnant women, we measured maternal bisphenol A, S and F urine concentrations in the first, second and third trimester. Fetal head circumference, length and weight were measured in the second and third trimester by ultrasound and at birth. RESULTS:An interquartile range increase in maternal pregnancy-averaged bisphenol S concentrations was associated with larger fetal head circumference (difference 0.18 (95% confidence interval (CI) 0.01 to 0.34) standard deviation scores (SDS), p-value< 0.05) across pregnancy. When focusing on specific critical exposure periods, any detection of first trimester bisphenol S was associated with larger second and third trimester fetal head circumference (difference 0.15 (95% CI 0.05 to 0.26) and 0.12 (95% CI 0.02 to 0.23) SDS, respectively) and fetal weight (difference 0.12 (95% CI 0.02 to 0.22) and 0.16 (95% CI 0.06 to 0.26) SDS, respectively). The other bisphenols were not consistently associated with fetal growth outcomes. Any detection of bisphenol S and bisphenol F in first trimester was also associated with a lower risk of being born small size for gestational age (Odds Ratio 0.56 (95% CI 0.38 to 0.74) and 0.55 (95% CI 0.36 to 0.85), respectively). Bisphenols were not associated with risk of preterm birth. CONCLUSIONS:Higher maternal bisphenol S urine concentrations, especially in the first trimester, seem to be related with larger fetal head circumference, higher weight and a lower risk of being small size for gestational age at birth.

BACKGROUND:Growing evidence suggests that exposure to environmental chemicals, such as pesticides, impacts renal function and chronic kidney disease (CKD). However, it is not clear if pesticides may affect CKD progression and no studies exist in children. OBJECTIVES/OBJECTIVE:The objective of this study was to examine associations between serially measured urinary OP pesticide metabolites and clinical and laboratory measures of kidney function over time among children with CKD. METHODS:-isoprostane) were determined in the same specimens. Estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure were assessed annually. RESULTS:DAPs were associated with increased KIM-1 and 8-OHdG throughout follow-up. A standard deviation increase in ∑diethyl metabolites was associated with increases of 11.9% (95% Confidence Interval (CI): 4.8%, 19.4%) and 13.2% (95% CI: 9.3%, 17.2%) in KIM-1 and 8-OHdG over time, respectively. DAPs were associated with lower eGFR at baseline and higher eGFR over subsequent years. CONCLUSIONS:These findings provide preliminary evidence suggesting that urinary DAP metabolites are associated with subclinical kidney injury among children with CKD, which may signal the potential for clinical events to manifest in the future. The results from this study are significant from both a clinical and public health perspective, given that OP pesticide exposure is a modifiable risk factor.

Pregnant women are widely exposed to organophosphate (OP) pesticides, which are potentially neurotoxicant for the developing fetus. We aimed to identify principal demographic and dietary predictors of OP pesticide exposure among 450 pregnant women participating in the New York University Children's Health and Environment Study (enrolled 2016-19). Urinary concentrations of six dialkyl phosphate (DAP) metabolites (3 dimethyl (DM) metabolites and 3 diethyl (DE) metabolites) of OP pesticides were determined at three time points across pregnancy. At mid-gestation, the Diet History Questionnaire II was used to assess women's dietary intake over the past year. Demographic characteristics were obtained using questionnaires and/or electronic health records. We used linear mixed models to evaluate the associations of demographic and food groups with DAP metabolite levels, and partial-linear single-index (PLSI) models to analyze the contribution proportions of food groups to DAP metabolite concentrations and the dose-response relationships between them. We observed that pregnant women in NYC had lower levels of OP pesticide metabolites than pregnant populations in Europe, Asia, and other regions in the U.S. Having lower pre-pregnancy body mass index and being Asian, employed, and single were associated with higher DAP metabolite concentrations. Fruit and grain intakes were associated with higher ∑DM, ∑DE, and ∑DAP levels. ∑DE concentrations increased 9.0% (95% confidence interval (CI) = 1.2%, 17.4%) per two-fold increase in dairy consumption, whereas ∑DE concentrations decreased 1.8% (95%CI = -3.1%, -0.4%) per two-fold increase in seafood consumption. The PLSI model indicated that among the food mixture, fruit and grains were the main food groups contributed to higher levels of ∑DAP, while meat contributed to lower levels of ∑DAP. The contribution proportions of fruit, grains, and meat were 18.7%, 17.9%, and 39.3%, respectively. Our results suggest that fruit, grains, and meat are major dietary components associated with OP pesticide exposure in urban pregnant women.

OBJECTIVE:We previously found that antibiotic use at <24 months of age was associated with slightly higher body weight at 5 years of age. In this study, we examine associations of early life antibiotic prescriptions with weight outcomes at 108 to 132 months of age ("10 years"). METHODS:We used electronic health record data from 2009 through 2016 from 10 health systems in PCORnet, a national distributed clinical research network. We examined associations of any (vs no) antibiotics at <24 months of age with body mass index z-score (BMI-z) at 10 years adjusted for confounders selected a priori. We further examined dose response (number of antibiotic episodes) and antibiotic spectrum (narrow and broad). RESULTS:Among 56,727 included children, 57% received any antibiotics at <24 months; at 10 years, mean (standard deviation) BMI-z was 0.54 (1.14), and 36% had overweight or obesity. Any versus no antibiotic use at <24 months was associated with a slightly higher BMI-z at 10 years among children without a complex chronic condition (β 0.03; 95% confidence interval [CI] 0.01, 0.05) or with a complex chronic condition (β 0.09; 95% CI 0.03, 0.15). Any versus no antibiotic use was not associated with odds of overweight or obesity at 10 years among children without (odds ratio 1.02; 95% CI 0.97, 1.07) or with a complex chronic condition (odds ratio 1.07; 95% CI 0.96, 1.19). CONCLUSIONS:The small and likely clinically insignificant associations in this study are consistent with our previous 5-year follow-up results, suggesting that, if this relationship is indeed causal, early increases in weight are small but maintained over time.

IMPORTANCE/OBJECTIVE:Exposure to phthalates may affect fetal growth, but previous studies are inconsistent and have not explored the trimester-specific effects of phthalates on repeated measures of fetal growth. OBJECTIVE:To assess the associations of maternal phthalate metabolites urine concentrations with fetal growth measures and birth outcomes and identify potential windows of vulnerability to exposure. DESIGN/METHODS:Population-based prospective cohort study, the Generation R Study (2002-2006). Data analysis was performed from November 2019 to June 2020. SETTING/METHODS:Rotterdam, the Netherlands. PARTICIPANTS/METHODS:1379 pregnant women. EXPOSURES/UNASSIGNED:Maternal phthalate metabolites urine concentrations in first, second and third trimester. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Fetal head circumference, length and weight measured in the second and third trimester by ultrasound and at birth and preterm birth and small size for gestational age at birth. RESULTS:Higher pregnancy-averaged phthalic acid, low molecular weight phthalate (LMWP), high molecular weight phthalate (HMWP) and di-2-ethylhexylphthalate (DEHP) concentrations tended to be associated with lower fetal weight SDS across gestation. The associations of phthalic acid and LMWP with fetal weight became stronger as pregnancy progressed (differences -0.08 (95% CI -0.14 to -0.02) SDS and -0.09 (95% CI -0.16 to -0.02) SDS at 40 weeks per interquartile range increase in phthalic acid and LMWP, respectively). Higher concentrations of specific LMWP, HMWP and DEHP metabolites were also associated with smaller head circumference and lower length SDS at birth and an increased risk of preterm birth and small size for gestational age at birth (p-values < 0.05). We observed differences by timing of exposure in these associations. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Higher maternal phthalate metabolites urine concentrations seem to be related with fetal growth restriction and preterm birth. Phthalates may have trimester specific effects on fetal growth and birth outcomes. Further studies are needed to explore the underlying mechanisms and long-term consequences.

OBJECTIVE:The purpose of this study was to investigate the associations of urinary phthalates and bisphenols at age 6 years old with body fat and cardiovascular risk factors at 6 and 10 years and with the change from 6 to 10 years. METHODS:Among 471 Dutch children, the phthalates and bisphenols urinary concentrations at 6 years and BMI, fat mass index, android fat mass, blood pressure, glucose, insulin, and lipids blood concentrations at 6 and 10 years were measured. RESULTS:An interquartile range increase in di-n-octyl phthalate (DNOP) metabolites concentrations at 6 years was associated with an increased risk of overweight at 6 and 10 years (odds ratio: 1.44; 95% CI: 1.11-1.87, and 1.43; 95% CI: 1.09-1.86, respectively). Also, higher DNOP metabolites concentrations were associated with higher fat mass index at 6 years, higher systolic blood pressure at 10 years, a decrease in high-density lipoprotein cholesterol, and an increase in triglycerides concentrations from 6 to 10 years (P < 0.05). Higher total bisphenols and bisphenol A concentrations were associated with a decrease in BMI from 6 to 10 years (P < 0.01). CONCLUSIONS:DNOP metabolites are associated with overweight and an adverse cardiovascular profile in childhood. Total bisphenols and bisphenol A are associated with a decrease in BMI from 6 to 10 years.

BACKGROUND:Exposure to phthalates is ubiquitous across the United States. While phthalates have anti-androgenic effects in men, there is little research on their potential impacts on sex hormone concentrations in women and that also take into account menopausal status. METHODS:Cross-sectional data on urinary phthalate metabolites, serum sex hormones, and relevant covariates were obtained from the National Health and Nutrition Examination Survey 2013-14 and 2015-16. Women over the age of 20 who were not pregnant or breastfeeding and had not undergone oophorectomy were included (n = 698 premenopausal, n = 557 postmenopausal). Weighted multivariable linear and Tobit regression models stratified by menopausal status were fit with natural log-transformed phthalate concentrations and sex hormone outcomes adjusting for relevant covariates. RESULTS:Phthalate metabolites were associated with differences in sex hormone concentrations among postmenopausal women only. Di-2-ethylhexyl phthalate (DEHP) was associated with lower serum estradiol and bioavailable testosterone concentrations. Specifically, a doubling of DEHP concentrations was associated with 5.9% (95% Confidence Interval (CI): 0.2%, 11.3%) lower estradiol and 6.2% (95% CI: 0.0%, 12.1%) lower bioavailable testosterone concentrations. In contrast, 1,2-cyclohexane dicarboxylic acid di-isononyl ester (DINCH) was associated with higher free testosterone, bioavailable testosterone, and free androgen index. Finally, di-2-ethylhexyl terephthalate (DEHTP) was associated with a higher testosterone-to-estradiol ratio. None of these results retained statistical significance when adjusted for multiple comparisons. CONCLUSIONS:DEHP, DINCH, and DEHTP were associated with differences in serum sex hormone concentrations among postmenopausal women, highlighting the need for further research into the safety of these chemicals.

Preterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate's degree, vocational or technical training [reference category]; bachelor's degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor's degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61-0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00-1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor's degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.

Over the past several decades, scientific consensus has grown around the concept and evidence for human health impacts from exposure to endocrine disrupting chemicals (EDCs). A series of publications have now demonstrated considerable economic costs of EDC exposure-induced adverse health outcomes. This research has suggested economic burdens in the hundreds of billions, even considering only a small subset of EDCs and health. As of yet, regulatory efforts and policies to protect and decrease human exposure to most EDCs have been insufficient and have not kept pace with the science. Given the overwhelming scientific evidence, referenced throughout this collection, as well as the economic costs of inaction, described here, regulations are clearly needed. The EU and some other countries have taken promising steps towards protective regulation of EDCs, though the response of the US and many other countries has been limited or altogether lacking. Regulatory bodies that have and continue to apply risk-based approaches to regulating EDCs have also failed to consider the complete economic impacts of EDC-related health impacts. In this chapter, we will discuss broad strategies taken to regulate EDCs, examine the approaches currently taken to regulate EDCs in a global context (discussing the strengths and weaknesses of these regulations), discuss the economic costs of EDC exposures (detailing where consideration of health and economic costs could improve regulations), and discuss next steps and novel approaches to adapting existing regulatory frameworks to this class of chemicals.