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Background/objectives: Prenatal exposure to ambient air pollution is associated with adverse cardiometabolic outcomes in childhood. We previously observed that prenatal black carbon (BC) was inversely associated with adiponectin, a hormone secreted by adipocytes, in early childhood. Changes to DNA methylation have been proposed as a potential mediator linking in utero exposures to lasting health impacts., Methods: Among 532 mother-child pairs enrolled in the Colorado-based Healthy Start study, we performed an epigenome-wide association study of the relationship between prenatal exposure to a component of air pollution, BC, and DNA methylation in cord blood. Average pregnancy ambient BC was estimated at the mother's residence using a spatiotemporal prediction model. DNA methylation was measured using the Illumina 450K array. We used multiple linear regression to estimate associations between prenatal ambient BC and 429,246 cysteine-phosphate-guanine sites (CpGs), adjusting for potential confounders. We identified differentially methylated regions (DMRs) using DMRff and ENmix-combp. In a subset of participants (n = 243), we investigated DNA methylation as a potential mediator of the association between prenatal ambient BC and lower adiponectin in childhood., Results: We identified 44 CpGs associated with average prenatal ambient BC after correcting for multiple testing. Several genes annotated to the top CpGs had reported functions in the immune system. There were 24 DMRs identified by both DMRff and ENmix-combp. One CpG (cg01123250), located on chromosome 2 and annotated to the UNC80 gene, was found to mediate approximately 20% of the effect of prenatal BC on childhood adiponectin, though the confidence interval was wide (95% CI: 3, 84)., Conclusions: Prenatal BC was associated with DNA methylation in cord blood at several sites and regions in the genome. DNA methylation may partially mediate associations between prenatal BC and childhood cardiometabolic outcomes., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Certain endocrine-disrupting chemicals (EDCs) are widespread in consumer products and may alter glucose metabolism. However, the impact of EDC exposures on glucose and insulin regulation during pregnancy is incompletely understood, despite potential adverse consequences for maternal and infant health. We estimated associations between 37 urinary biomarkers of EDCs and glucose-insulin traits among pregnant women., Methods: Seventeen phthalate or phthalate substitute metabolites, six environmental phenols, four parabens, and ten organophosphate ester metabolites were quantified in mid-pregnancy urine from 298 participants in the Healthy Start Study. Fasting blood glucose, insulin, and hemoglobin A1c were assessed concurrently, and Homeostasis Model Assessment 2-Insulin Resistance (HOMA2-IR) was calculated. Gestational diabetes diagnoses and screening results were obtained from medical records for a subset of participants. We estimated associations between each EDC and outcome separately using linear and robust Poisson regression models and analyzed EDC mixture effects., Results: The EDC mixture was positively associated with glucose, insulin, and HOMA2-IR, although overall associations were attenuated after adjustment for maternal BMI. Two mixture approaches identified di(2-ethylhexyl) phthalate (DEHP) metabolites as top contributors to the mixture's positive associations. In single-pollutant models, DEHP metabolites were positively associated with fasting glucose, fasting insulin, and HOMA2-IR even after adjustment for maternal BMI. For example, each interquartile range increase in log 2 -transformed mono(2-ethyl-5-oxohexyl) phthalate was associated with 2.4 mg/dL (95% confidence interval (CI): 1.1, 3.6) higher fasting glucose, 11.8% (95%CI: 3.6, 20.5) higher fasting insulin, and 12.3% (95%CI: 4.2, 21.1) higher HOMA2-IR. Few EDCs were associated with hemoglobin A1c or with a combined outcome of impaired glucose tolerance or gestational diabetes., Discussion: Exposures to phthalates and particularly DEHP during pregnancy are associated with altered glucose-insulin regulation. Disruptions in maternal glucose metabolism during pregnancy may contribute to adverse pregnancy outcomes including gestational diabetes and fetal macrosomia, and associated long-term consequences for maternal and child health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Organophosphate esters (OPEs) are increasing in use as flame retardants and plasticizers and concerns have been raised given their endocrine-disrupting activities and possible obesogenic consequences. However, longitudinal studies on gestational OPE exposure and childhood obesity are scarce. This study examined whether OPE levels in maternal urine during pregnancy were associated with the risk of childhood obesity., Methods: OPEs were analyzed in pregnancy urine samples of 5,087 individuals from 14 studies contributing to the Environmental influences on Child Health Outcomes (ECHO) Cohort. BDCPP, DBUP/DIBP, and DPHP, detected in > 80 % of the samples, were modeled continuously and by tertiles; whereas BCPP, BBOEP, and BCETP, detected in 50-80 % of samples, were modeled categorically (not-detected, low, and high). Childhood obesity was defined by BMI z-score ≥ 95th percentile according to WHO (<2 years) and the CDC (≥2 years) metrics. Adjusted modified Poisson regression models assessed childhood obesity risk and the mixture effect was assessed using Bayesian kernel machine regression (BKMR)., Results: BMI measurements were available for 3,827 children in infancy (0.5-1.9 years), 3,921 children in early childhood (2.0-4.9 years), and 2,541 children in mid-childhood (5.0-10.0 years). Obesity was present in 16-21 % of children across age groups. In mid-childhood DBUP/DIBP second and third versus first tertiles were associated with increased obesity risk (RR 1.14; 95 % CI: 1.02, 1.28; and RR 1.11; 95 % CI: 0.97, 1.27; respectively); whereas BDCPP second and third versus first tertiles reflected an inverse association with obesity risk (RR 0.85; 95 % CI: 0.80, 0.91 and RR 0.91; 95 % CI: 0.77, 1.07; respectively). No association with obesity risk was observed for DPHP, BCPP, BBOEP, and BCETP. Directions observed were consistent with those seen in BKMR models., Conclusions: This study identified mixed associations between gestational OPE exposure and childhood obesity. Further investigation across a comprehensive range of OPE exposures is warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Existing evidence suggests that exposure to phthalates is higher among younger age groups. However, limited knowledge exists on how phthalate exposure, as well as exposure to replacement plasticizers, di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) and di-2-ethylhexyl terephthalate (DEHTP), change from infancy through early childhood., Methods: Urine samples were collected across the first 5 years of life from typically developing infants and young children enrolled between 2017 and 2020 in the longitudinal UNC Baby Connectome Project. From 438 urine samples among 187 participants, we quantified concentrations of monobutyl phthalate (MnBP), mono-3-carboxypropyl phthalate (MCPP), monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), and metabolites of di(2-ethylhexyl) phthalate (DEHP), diisonoyl phthalate (DiNP), DINCH and DEHTP. Specific gravity (SG) adjusted metabolite and molar sum concentrations were compared across age groups. Intraclass correlation coefficients (ICCs) were calculated among 122 participants with multiple urine specimens (373 samples)., Results: Most phthalate metabolites showed high detection frequencies (>80% of samples). Replacement plasticizers DINCH (58-60%) and DEHTP (>97%) were also commonly found. DiNP metabolites were less frequently detected (<10%). For some metabolites, SG-adjusted concentrations were inversely associated with age, with the highest concentrations found in the first year of life. ICCs revealed low to moderate reliability in metabolite measurements (ρ = 0.10-0.48) suggesting a high degree of within-individual variation in exposure among this age group. The first 6 months (compared to remaining age groups) showed an increased ratio of carboxylated metabolites of DEHP and DEHTP, compared to other common metabolites, but no clear age trends for DINCH metabolite ratios were observed., Conclusion: Metabolites of phthalates and replacements plasticizers were widely detected in infancy and early childhood, with the highest concentrations observed in the first year of life for several metabolites. Higher proportions of carboxylated metabolites of DEHP and DEHTP in younger age groups indicate potential differences in metabolism during infancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose of Review: Environmental chemical exposures may disrupt child development, with long-lasting health impacts. To date, U.S. studies of early environmental exposures have been limited in size and diversity, hindering power and generalizability. With harmonized data from over 60,000 participants representing 69 pregnancy cohorts, the National Institutes of Health's Environmental influences on Child Health Outcomes (ECHO) Program is the largest study of U.S. children's health. Here, we: (1) review ECHO-wide studies of chemical exposures and maternal-child health; and (2) outline opportunities for future research using ECHO data., Recent Findings: As of early 2024, in addition to over 200 single-cohort (or award) papers on chemical exposures supported by ECHO, ten collaborative multi-cohort papers have been made possible by ECHO data harmonization and new data collection. Multi-cohort papers have examined prenatal exposure to per- and polyfluoroalkyl substances (PFAS), phthalates, phenols and parabens, organophosphate esters (OPEs), metals, melamine and aromatic amines, and emerging contaminants. They have primarily focused on describing patterns of maternal exposure or examining associations with maternal and infant outcomes; fewer studies have examined later child outcomes (e.g., autism) although follow up of enrolled ECHO children continues. The NICHD's Data and Specimen Hub (DASH) database houses extensive ECHO data including over 470,000 chemical assay results and complementary data on priority outcome areas (pre, peri-, and postnatal, airway, obesity, neurodevelopment, and positive health), making it a rich resource for future analyses. ECHO's extensive data repository, including biomarkers of chemical exposures, can be used to advance our understanding of environmental influences on children's health. Although few published studies have capitalized on these unique harmonized data to date, many analyses are underway with data now widely available., (© 2024. The Author(s).)

Background: Per and polyfluoroalkyl substances (PFAS), a class of environmentally and biologically persistent chemicals, have been used across many industries since the middle of the 20 th century. Some PFAS have been linked to adverse health effects., Objective: Our objective was to incorporate known and potential PFAS sources, physical characteristics of the environment, and existing PFAS water sampling results into a PFAS risk prediction map that may be used to develop a PFAS water sampling prioritization plan for the Colorado Department of Public Health and Environment (CDPHE)., Methods: We used random forest classification to develop a predictive surface of potential groundwater contamination from two PFAS, perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). The model predicted PFAS risk at locations without sampling data into one of three risk categories after being "trained" with existing PFAS water sampling data. We used prediction results, variable importance ranking, and population characteristics to develop recommendations for sampling prioritization., Results: Sensitivity and precision ranged from 58% to 90% in the final models, depending on the risk category. The model and prioritization approach identified private wells in specific census blocks, as well as schools, mobile home parks, and public water systems that rely on groundwater as priority sampling locations. We also identified data gaps including areas of the state with limited sampling and potential source types that need further investigation., Impact Statement: This work uses random forest classification to predict the risk of groundwater contamination from two per- and polyfluoroalkyl substances (PFAS) across the state of Colorado, United States. We developed the prediction model using data on known and potential PFAS sources and physical characteristics of the environment, and "trained" the model using existing PFAS water sampling results. This data-driven approach identifies opportunities for PFAS water sampling prioritization as well as information gaps that, if filled, could improve model predictions. This work provides decision-makers information to effectively use limited resources towards protection of populations most susceptible to the impacts of PFAS exposure., (© 2024. The Author(s).)

Background: The 2017-2018 U.S. PFAS exposure burden calculator was designed to provide a summary exposure score for per- and polyfluoroalkyl substances (PFAS) mixtures using targeted PFAS analyte data. Its aim was to place PFAS burden score estimates onto a common scale based on nationally representative U.S. reference ranges from 2017 to 2018, enabling comparisons of overall PFAS burden scores across studies even if they did not measure the same set of PFAS analytes., Objective: To use the U.S. PFAS exposure burden calculator for comparing the same mixture of PFAS compounds in similarly aged adolescents and their associations with cardiometabolic outcomes in the HOME Study and NHANES between 2015 and 2018., Methods: We applied the PFAS burden calculator to 8 PFAS analytes measured in the serum of adolescents from the HOME Study (Cincinnati, Ohio; age range 11-14 years; years: 2016-2019; n = 207) and NHANES (US; age range 12-14 years; years 2015-2018; n = 245). We used the non-parametric Mann-Whitney U test and chi-squared test to compare the two study samples. In both studies, we examined associations of PFAS burden scores with the same cardiometabolic outcomes, adjusted for the same core set of covariates using regression analyses. We conducted sensitivity analyses to verify robustness of exposure-outcome associations, by accounting for measurement error of PFAS burden scores., Results: PFAS burden scores were significantly different (p = 0.004) between the HOME Study (median: 0.00, interquartile range - 0.37, 0.34) and the NHANES samples (median: 0.04, IQR -0.11, 0.54), while no significant difference was found for PFAS summed concentrations (p = 0.661). In the HOME Study, an interquartile (IQR) increase in PFAS burden score was associated with higher total cholesterol [7.0 mg/dL, 95% CI: 0.6, 13.4]; HDL [2.8 mg/dL, 95% CI: 0.4, 5.2]; LDL [5.9 mg/dL, 95% CI: 0.5, 11.3], insulin [0.1 log(mIU/L), 95% CI: 0.01, 0.2], and HOMA-IR [0.1, 95% CI: 0.01, 0.2]. In NHANES, an IQR increase in PFAS burden score was associated with higher diastolic blood pressure [2.4 mmHg, 95% CI: 0.4, 4.4] but not with other outcomes. Sensitivity analyses in the HOME Study and NHANES were consistent with the main findings., Conclusions: Performance of the U.S. PFAS exposure burden calculator was similar in a local versus national sample of adolescents, and may be a useful tool for the assessment of PFAS mixtures across studies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shelley H. Liu reports financial support was provided by National Institute of Child Health and Human Development. Shelley H. Liu reports financial support was provided by National Institute of Environmental Health Sciences. Jessie Buckley reports financial support was provided by National Institute of Environmental Health Sciences. Joseph Braun reports financial support was provided by National Institute of Environmental Health Sciences. J.M.B. has been compensated for serving as an expert witness for plaintiffs in litigation over PFAS contaminated drinking water., (Copyright © 2023. Published by Elsevier Inc.)

Background: Phthalates are synthetic chemicals widely used in consumer products and have been identified to contribute to preterm birth. Existing studies have methodological limitations and potential effects of di-2-ethylhexyl phthalate (DEHP) replacements are poorly characterised. Attributable fractions and costs have not been quantified, limiting the ability to weigh trade-offs involved in ongoing use. We aimed to leverage a large, diverse US cohort to study associations of phthalate metabolites with birthweight and gestational age, and estimate attributable adverse birth outcomes and associated costs., Methods: In this prospective analysis we used extant data in the US National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program from 1998 to 2022 to study associations of 20 phthalate metabolites with gestational age at birth, birthweight, birth length, and birthweight for gestational age z-scores. We also estimated attributable adverse birth outcomes and associated costs. Mother-child dyads were included in the study if there were one or more urinary phthalate measurements during the index pregnancy; data on child's gestational age and birthweight; and singleton delivery., Findings: We identified 5006 mother-child dyads from 13 cohorts in the ECHO Program. Phthalic acid, diisodecyl phthalate (DiDP), di-n-octyl phthalate (DnOP), and diisononyl phthalate (DiNP) were most strongly associated with gestational age, birth length, and birthweight, especially compared with DEHP or other metabolite groupings. Although DEHP was associated with preterm birth (odds ratio 1·45 [95% CI 1·05-2·01]), the risks per log 10 increase were higher for phthalic acid (2·71 [1·91-3·83]), DiNP (2·25 [1·67-3·00]), DiDP (1·69 [1·25-2·28]), and DnOP (2·90 [1·96-4·23]). We estimated 56 595 (sensitivity analyses 24 003-120 116) phthalate-attributable preterm birth cases in 2018 with associated costs of US$3·84 billion (sensitivity analysis 1·63- 8·14 billion)., Interpretation: In a large, diverse sample of US births, exposure to DEHP, DiDP, DiNP, and DnOP were associated with decreased gestational age and increased risk of preterm birth, suggesting substantial opportunities for prevention. This finding suggests the adverse consequences of substitution of DEHP with chemically similar phthalates and need to regulate chemicals with similar properties as a class., Funding: National Institutes of Health., Competing Interests: Declaration of interests LT acknowledges honoraria from Houghton Mifflin Harcourt, Audible, Paidos, and Kobunsha; travel support from the Endocrine Society, WHO, United Nations Environment Programme, Japan Environment and Health Ministries, and the American Academy of Pediatrics; and scientific advisory board activities for Beautycounter, IS-Global, and Footprint. MER acknowledges funding from the National Institute of General Medical Sciences, the National Institute of Environmental Health Sciences (NIEHS), and the New Hampshire Department of Environmental Services, as well as honoraria from the National Institutes of Health and UMass-Amherst, and advisory board relationships to the New England Graduate Women in Science and Engineering and Mill Run III Condo. AA acknowledges grant support from NIEHS. CN acknowledges the National Institute of Neurological Disorders and Stroke support. ESB acknowledges honoraria from the University of Rochester and SUNY-Downstate. All the authors have received funding from the NIH ECHO programme., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B 12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health., (© 2023. The Author(s).)

Background/objectives: Observational and experimental studies have suggested that prenatal exposure to per- and polyfluoroalkyl substances (PFAS) can increase childhood adiposity and cardiometabolic disruption. However, most previous studies have used weight-based measures that cannot distinguish between fat mass and lean mass. We evaluated associations of prenatal PFAS exposure with precisely measured body composition and cardiometabolic biomarkers in early childhood., Subjects: 373 eligible mother-infant pairs in the Healthy Start longitudinal cohort., Methods: We used multiple linear regression and Bayesian kernel machine regression models to estimate associations between five PFAS in maternal mid-pregnancy serum, and early childhood adiposity via air displacement plethysmography. Secondary outcomes included body mass index, waist circumference, and fasting serum lipids, glucose, insulin and adipokines. Models were adjusted for potential confounders and effect modification by child sex was evaluated., Results: The median age of children at assessment was 4.6 years. Prenatal concentration of perfluorooctanoate (PFOA) was positively associated with percent fat mass (0.89% per log 2 -unit increase, 95% CI: 0.15, 1.64), while perfluorononanoate (PFNA) was positively associated with fat mass index and body mass index. Cardiometabolic markers in blood were generally not associated with prenatal PFAS in this population. Mixture models confirmed the importance of PFNA and PFOA in predicting percent fat mass, while PFNA was most important for fat mass index, body mass index, and waist circumference. There were no significant effects of the five PFAS as a mixture, potentially due to opposing effects of different PFAS., Conclusions: Our results agree with previous studies showing that prenatal serum concentrations of certain PFAS are positively associated with early childhood adiposity. Notably, associations were stronger for measures incorporating precisely measured fat mass compared to measures of body size or weight. Early life increases in adiposity may precede the development of adverse cardiometabolic health outcomes in children exposed to PFAS during gestation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Importance: Postpartum depression (PPD) affects up to 20% of childbearing individuals, and a significant limitation in reducing its morbidity is the difficulty in modifying established risk factors. Exposure to synthetic environmental chemicals found in plastics and personal care products, such as phenols, phthalates, and parabens, are potentially modifiable and plausibly linked to PPD and have yet to be explored., Objective: To evaluate associations of prenatal exposure to phenols, phthalates, parabens, and triclocarban with PPD symptoms., Design, Setting, and Participants: This was a prospective cohort study from 5 US sites, conducted from 2006 to 2020, and included pooled data from 5 US birth cohorts from the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) consortium. Participants were pregnant individuals with data on urinary chemical concentrations (phenols, phthalate metabolites, parabens, or triclocarban) from at least 1 time point in pregnancy and self-reported postnatal depression screening assessment collected between 2 weeks and 12 months after delivery. Data were analyzed from February to May 2022., Exposures: Phenols (bisphenols and triclosan), phthalate metabolites, parabens, and triclocarban measured in prenatal urine samples., Main Outcomes and Measures: Depression symptom scores were assessed using the Edinburgh Postnatal Depression Scale (EPDS) or the Center for Epidemiologic Studies Depression Scale (CES-D), harmonized to the Patient-Reported Measurement Information System (PROMIS) Depression scale. Measures of dichotomous PPD were created using both sensitive (EPDS scores ≥10 and CES-D scores ≥16) and specific (EPDS scores ≥13 and CES-D scores ≥20) definitions., Results: Among the 2174 pregnant individuals eligible for analysis, nearly all (>99%) had detectable levels of several phthalate metabolites and parabens. PPD was assessed a mean (SD) of 3 (2.5) months after delivery, with 349 individuals (16.1%) and 170 individuals (7.8%) screening positive for PPD using the sensitive and specific definitions, respectively. Linear regression results of continuous PROMIS depression T scores showed no statistically significant associations with any chemical exposures. Models examining LMW and HMW phthalates and di (2-ethylhexyl) phthalate had estimates in the positive direction whereas all others were negative. A 1-unit increase in log-transformed LMW phthalates was associated with a 0.26-unit increase in the PROMIS depression T score (95% CI, -0.01 to 0.53; P = .06). This corresponded to an odds ratio (OR) of 1.08 (95% CI, 0.98-1.19) when modeling PPD as a dichotomous outcome and using the sensitive PPD definition. HMW phthalates were associated with increased odds of PPD (OR, 1.11; 95% CI, 1.00-1.23 and OR, 1.10; 95% CI, 0.96-1.27) for the sensitive and specific PPD definitions, respectively. Sensitivity analyses produced stronger results., Conclusions and Relevance: Phthalates, ubiquitous chemicals in the environment, may be associated with PPD and could serve as important modifiable targets for preventive interventions. Future studies are needed to confirm these observations.

Background: Synthetic chemicals are increasingly being recognized for potential independent contributions to preterm birth (PTB) and low birth weight (LBW). Bisphenols, parabens, and triclosan are consumer product chemicals that act via similar mechanisms including estrogen, androgen, and thyroid disruption and oxidative stress. Multiple cohort studies have endeavored to examine effects on birth outcomes, and systematic reviews have been limited due to measurement of 1-2 spot samples during pregnancy and limited diversity of populations., Objective: To study the effects of prenatal phenols and parabens on birth size and gestational age (GA) in 3,619 mother-infant pairs from 11 cohorts in the NIH Environmental influences on Child Health Outcomes program., Results: While many associations were modest and statistically imprecise, a 1-unit increase in log 10 pregnancy averaged concentration of benzophenone-3 and methylparaben were associated with decreases in birthweight, birthweight adjusted for gestational age and SGA. Increases in the odds of being SGA were 29% (95% CI: 5%, 58%) and 32% (95% CI: 3%, 70%), respectively. Bisphenol S in third trimester was also associated with SGA (OR 1.52, 95% CI 1.08, 2.13). Associations of benzophenone-3 and methylparaben with PTB and LBW were null. In addition, a 1-unit increase in log 10 pregnancy averaged concentration of 2,4-dichlorophenol was associated with 43% lower (95% CI: -67%, -2%) odds of low birthweight; the direction of effect was the same for the highly correlated 2,5-dichlorophenol, but with a smaller magnitude (-29%, 95% CI: -53%, 8%)., Discussion: In a large and diverse sample generally representative of the United States, benzophenone-3 and methylparaben were associated with lower birthweight as well as birthweight adjusted for gestational age and higher odds of SGA, while 2,4-dichlorophenol. These associations with smaller size at birth are concerning in light of the known consequences of intrauterine growth restriction for multiple important health outcomes emerging later in life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: Assess if cord blood differentially methylated regions (DMRs) representing human metastable epialleles (MEs) associate with offspring adiposity in 588 maternal-infant dyads from the Colorado Health Start Study. Materials & methods: DNA methylation was assessed via the Illumina 450K array (~439,500 CpG sites). Offspring adiposity was obtained via air displacement plethysmography. Linear regression modeled the association of DMRs potentially representing MEs with adiposity. Results & conclusion: We identified two potential MEs, ZFP57 , which associated with infant adiposity change and B4GALNT4 , which associated with infancy and childhood adiposity change. Nine DMRs annotating to genes that annotated to MEs associated with change in offspring adiposity (false discovery rate <0.05). Methylation of approximately 80% of DMRs identified associated with decreased change in adiposity.

Background: Widespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results., Objectives: We conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex., Methods: We included 6,646 pregnant participants from 16 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program. Nine OPE biomarkers were quantified in maternal urine samples collected primarily during the second and third trimester and modeled as log 2 -transformed continuous, categorized (high/low/nondetect), or dichotomous (detect/nondetect) variables depending on detection frequency. We used covariate-adjusted linear, logistic, and multinomial regression with generalized estimating equations, accounting for cohort-level clustering, to estimate associations of OPE biomarkers with gestational length and birth weight outcomes. Secondarily, we assessed effect modification by sex., Results: Three OPE biomarkers [diphenyl phosphate (DPHP), a composite of dibutyl phosphate and di-isobutyl phosphate (DBUP/DIBP), and bis(1,3-dichloro-2-propyl) phosphate] were detected in > 85 % of participants. In adjusted models, DBUP/DIBP [odds ratio (OR) per doubling = 1.07 ; 95% confidence interval (CI): 1.02, 1.12] and bis(butoxyethyl) phosphate (OR for high vs. nondetect = 1.25 ; 95% CI: 1.06, 1.46), but not other OPE biomarkers, were associated with higher odds of preterm birth. We observed effect modification by sex for associations of DPHP and high bis(2-chloroethyl) phosphate with completed gestational weeks and odds of preterm birth, with adverse associations among females. In addition, newborns of mothers with detectable bis(1-chloro-2-propyl) phosphate, bis(2-methylphenyl) phosphate, and dipropyl phosphate had higher birth weight-for-gestational-age z -scores ( β for detect vs. nondetect = 0.04 - 0.07 ); other chemicals showed null associations., Discussion: In the largest study to date, we find gestational exposures to several OPEs are associated with earlier timing of birth, especially among female neonates, or with greater fetal growth. https://doi.org/10.1289/EHP13182.

Background: Early life exposure to air pollution, such as particulate matter ≤2.5 μm (PM 2.5 ), may be associated with obesity and adverse cardiometabolic health outcomes in childhood. However, the toxicity of PM 2.5 varies according to its chemical composition. Black carbon (BC) is a constituent of PM 2.5 , but few studies have examined its impact on childhood cardiometabolic health. Therefore, we examined relationships between prenatal and early childhood exposure to BC and markers of adiposity and cardiometabolic health in early childhood., Methods: This study included 578 mother-child pairs enrolled in the Healthy Start study (2009-2014) living in the Denver-metro area. Using a spatiotemporal prediction model, we assessed average residential black carbon levels during pregnancy and in the year prior to the early childhood follow-up visit at approximately 5 years old. We estimated associations between prenatal and early childhood BC and indicators of adiposity and cardiometabolic biomarkers in early childhood (mean 4.8 years; range, 4.0, 8.3), using linear regression., Results: We found higher early childhood BC was associated with higher percent fat mass, fat mass index, insulin, and homeostatic model assessment for insulin resistance (HOMA-IR), and lower leptin and waist circumference at approximately 5 years old, after adjusting for covariates. For example, per interquartile range (IQR) increase in early childhood BC (IQR, 0.49 μg/m 3 ) there was 3.32% higher fat mass (95% CI; 2.05, 4.49). Generally, we did not find consistent evidence of associations between prenatal BC and cardiometabolic health outcomes in early childhood, except for an inverse association between prenatal BC and adiponectin, an adipocyte-secreted hormone typically inversely associated with adiposity., Conclusions: Higher early childhood, but not in utero, ambient concentrations of black carbon, a component of air pollution, were associated with greater adiposity and altered insulin homeostasis at approximately 5 years old. Future studies should examine whether these changes persist later in life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

EXPOSURE TO POLY: and perfluoroalkyl substances (PFAS) in early life may increase the risk of childhood asthma, but evidence has been inconsistent. We estimated associations between maternal serum concentrations of PFAS during pregnancy and clinician-diagnosed asthma incidence in offspring through age eight. We included 597 mother-child pairs with PFAS quantified in mid-pregnancy serum and childhood medical records reviewed for asthma diagnoses. We used separate Cox proportional hazards models to assess the relationship between log-transformed concentrations of five PFAS and the incidence of asthma. We estimated associations between the PFAS mixture and clinician-diagnosed asthma incidence using quantile-based g-computation. PFAS concentrations were similar to those among females in the US general population. Seventeen percent of children (N = 104) were diagnosed with asthma during follow-up. Median (interquartile range) duration of follow-up was 4.7 (4.0, 6.2) years, and median age at asthma diagnosis was 1.7 (0.9, 2.8) years. All adjusted hazard ratios (HRs) were elevated, but all 95% confidence intervals (CI) included the null. The HR (95% CI) of asthma for a one-quartile increase in the PFAS mixture was 1.17 (0.86, 1.61). In this cohort of children followed to eight years of age, prenatal PFAS concentrations were not significantly associated with incidence of clinician-diagnosed asthma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The etiology of childhood appetitive traits is poorly understood. Early-life epigenetic processes may be involved in the developmental programming of appetite regulation in childhood. One such process is DNA methylation (DNAm), whereby a methyl group is added to a specific part of DNA, where a cytosine base is next to a guanine base, a CpG site. We meta-analyzed epigenome-wide association studies (EWASs) of cord blood DNAm and early-childhood appetitive traits. Data were from two independent cohorts: the Generation R Study (n = 1,086, Rotterdam, the Netherlands) and the Healthy Start study (n = 236, Colorado, USA). DNAm at autosomal methylation sites in cord blood was measured using the Illumina Infinium HumanMethylation450 BeadChip. Parents reported on their child's food responsiveness, emotional undereating, satiety responsiveness and food fussiness using the Children's Eating Behaviour Questionnaire at age 4-5 years. Multiple regression models were used to examine the association of DNAm (predictor) at the individual site- and regional-level (using DMRff) with each appetitive trait (outcome), adjusting for covariates. Bonferroni-correction was applied to adjust for multiple testing. There were no associations of DNAm and any appetitive trait when examining individual CpG-sites. However, when examining multiple CpGs jointly in so-called differentially methylated regions, we identified 45 associations of DNAm with food responsiveness, 7 associations of DNAm with emotional undereating, 13 associations of DNAm with satiety responsiveness, and 9 associations of DNAm with food fussiness. This study shows that DNAm in the newborn may partially explain variation in appetitive traits expressed in early childhood and provides preliminary support for early programming of child appetitive traits through DNAm. Investigating differential DNAm associated with appetitive traits could be an important first step in identifying biological pathways underlying the development of these behaviors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Prenatal exposures to certain poly- and perfluoroalkyl substances (PFAS) are associated with reduced humoral responses to some childhood immunizations., Objective: We estimated associations between prenatal PFAS exposure and child antibody titers for measles, mumps, rubella (MMR), and varicella after immunization., Methods: We measured serum antibody titers of 145 children (4-8 y old) enrolled in the Healthy Start cohort in Colorado, whose mothers had PFAS quantified mid-pregnancy (2009-2014). We used linear and logistic regression models to assess the relationship between five PFAS detected in > 65 % of mothers and continuous or non-high-censored ("low") antibody titers and quantile g-computation to evaluate the overall effect of the PFAS mixture., Results: Median concentrations of individual PFAS were at or below the median reported among females in the United States. After receiving two vaccine doses, seropositive levels of antibodies were detected among most (93%-100%) children. Each log-unit increase in perfluorononanoate was associated with 2.09 [95% confidence interval (CI): 1.13, 3.87] times higher odds of a low measles titer, and each log-unit increase in perfluorooctanoate was associated with 2.46 (95% CI: 1.28, 4.75) times higher odds of a low mumps titer. Odds ratios for all other PFAS were elevated, but CIs included the null. Each quartile increase in the PFAS mixture was associated with 1.35 (95% CI: 0.80, 2.26) times higher odds of a low measles titer and 1.44 (95% CI: 0.78, 2.64) times higher odds of a low mumps titer. No significant associations were observed between PFAS and varicella or rubella antibodies. In stratified analyses, associations were negative among female children, except for perfluorohexane sulfonate and varicella, whereas they were positive among males., Discussion: Some prenatal PFAS were associated with lower antibody titers among fully immunized children. The potential for immunotoxic effects of PFAS requires further investigation in a larger study, because exposure is ubiquitous globally. https://doi.org/10.1289/EHP12863.

Background: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth., Objectives: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a ) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b ) exposure-response models stratified by race and ethnicity., Methods: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth., Results: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): - 34 % , 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: - 19 % , 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono- n -butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants., Conclusions: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Background: Drinking water is a common source of exposure to inorganic arsenic. In the US, the Safe Drinking Water Act (SDWA) was enacted to protect consumers from exposure to contaminants, including arsenic, in public water systems (PWS). The reproductive effects of preconception and prenatal arsenic exposure in regions with low to moderate arsenic concentrations are not well understood., Objectives: This study examined associations between preconception and prenatal exposure to arsenic violations in water, measured via residence in a county with an arsenic violation in a regulated PWS during pregnancy, and five birth outcomes: birth weight, gestational age at birth, preterm birth, small for gestational age (SGA), and large for gestational age (LGA)., Methods: Data for arsenic violations in PWS, defined as concentrations exceeding 10 parts per billion, were obtained from the Safe Drinking Water Information System. Participants of the Environmental influences on Child Health Outcomes Cohort Study were matched to arsenic violations by time and location based on residential history data. Multivariable, mixed effects regression models were used to assess the relationship between preconception and prenatal exposure to arsenic violations in drinking water and birth outcomes., Results: Compared to unexposed infants, continuous exposure to arsenic from three months prior to conception through birth was associated with 88.8 g higher mean birth weight (95% CI: 8.2, 169.5), after adjusting for individual-level confounders. No statistically significant associations were observed between any preconception or prenatal violations exposure and gestational age at birth, preterm birth, SGA, or LGA., Conclusions: Our study did not identify associations between preconception and prenatal arsenic exposure, defined by drinking water exceedances, and adverse birth outcomes. Exposure to arsenic violations in drinking water was associated with higher birth weight. Future studies would benefit from more precise geodata of water system service areas, direct household drinking water measurements, and exposure biomarkers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear., Methods: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points., Results: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N)., Conclusions: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous, environmentally persistent chemicals, and prenatal exposures have been associated with adverse child health outcomes. Prenatal PFAS exposure may lead to epigenetic age acceleration (EAA), defined as the discrepancy between an individual's chronologic and epigenetic or biological age., Objectives: We estimated associations of maternal serum PFAS concentrations with EAA in umbilical cord blood DNA methylation using linear regression, and a multivariable exposure-response function of the PFAS mixture using Bayesian kernel machine regression., Methods: Five PFAS were quantified in maternal serum (median: 27 weeks of gestation) among 577 mother-infant dyads from a prospective cohort. Cord blood DNA methylation data were assessed with the Illumina HumanMethylation450 array. EAA was calculated as the residuals from regressing gestational age on epigenetic age, calculated using a cord-blood specific epigenetic clock. Linear regression tested for associations between each maternal PFAS concentration with EAA. Bayesian kernel machine regression with hierarchical selection estimated an exposure-response function for the PFAS mixture., Results: In single pollutant models we observed an inverse relationship between perfluorodecanoate (PFDA) and EAA (-0.148 weeks per log-unit increase, 95% CI: -0.283, -0.013). Mixture analysis with hierarchical selection between perfluoroalkyl carboxylates and sulfonates indicated the carboxylates had the highest group posterior inclusion probability (PIP), or relative importance. Within this group, PFDA had the highest conditional PIP. Univariate predictor-response functions indicated PFDA and perfluorononanoate were inversely associated with EAA, while perfluorohexane sulfonate had a positive association with EAA., Conclusions: Maternal mid-pregnancy serum concentrations of PFDA were negatively associated with EAA in cord blood, suggesting a pathway by which prenatal PFAS exposures may affect infant development. No significant associations were observed with other PFAS. Mixture models suggested opposite directions of association between perfluoroalkyl sulfonates and carboxylates. Future studies are needed to determine the importance of neonatal EAA for later child health outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Gestational phthalate and phenol exposure disrupts adipogenesis, contributing to obesity in mice. Whether gestational phthalate or phenol exposure is associated with infant body composition has not been investigated in humans., Objective: We examined associations between biomarkers of phthalate and phenol exposure in midpregnancy and infant size and body composition at birth and at 5 months of age., Methods: Analyses were conducted among 438 infants from the Healthy Start prospective pregnancy cohort. Sixteen phthalate and phenol biomarkers were quantified in spot urine samples collected at 24-28 wk of gestation. Infant outcomes measured at birth and at 5 months of age included size [weight (in grams)] and body composition [fat and lean masses (in grams); percentage fat mass]. Single- (linear) and multipollutant (quantile g-computation) models were used to estimate associations of phthalate and phenol biomarkers with infant outcomes at birth and at 5 months of age. Models were adjusted for sociodemographics, sample collection timing, and lifestyle factors and used to examine for effect modification by infant sex., Results: In single-pollutant models, mono-benzyl phthalate and di- n -butyl phthalate were inversely associated with percentage fat mass [ β : - 0.49 (95% CI: - 0.91 , - 0.08 ) and - 0.51 (95% CI: - 1.02 , 0.01), respectively] in male but not female infants at birth. Similar, but less precise, associations were observed at 5 months of age. In multipollutant models, a 1-quartile increase in the phthalate and phenol biomarker mixture was inversely associated with percentage fat mass at birth [ - 1.06 (95% CI: - 2.21 , 0.1)] and at 5 months of age [ - 2.14 (95% CI: - 3.88 , - 0.39 )] among males, but associations were null among females [0.48 (95% CI: - 0.78 , 1.75) and - 0.64 (95% CI: - 2.68 , 1.41), respectively]. Similar associations were observed with infant weight., Conclusion: In this U.S.-based prospective cohort, gestational phthalate and phenol biomarkers were inversely associated with infant weight and fat mass, particularly in males. https://doi.org/10.1289/EHP12500.

Childhood appetitive traits are consistently associated with obesity risk, and yet their etiology is poorly understood. Appetitive traits are complex phenotypes which are hypothesized to be influenced by both genetic and environmental factors, as well as their interactions. Early-life epigenetic processes, such as DNA methylation (DNAm), may be involved in the developmental programming of appetite regulation in childhood. In the current study, we meta-analyzed epigenome-wide association studies (EWASs) of cord blood DNAm and early-childhood appetitive traits. Data were from two independent cohorts: the Generation R Study ( n =1,086, Rotterdam, the Netherlands) and the Healthy Start study ( n =236, Colorado, USA). DNAm at autosomal methylation sites in cord blood was measured using the Illumina Infinium HumanMethylation450 BeadChip. Parents reported on their child's food responsiveness, emotional undereating, satiety responsiveness and food fussiness using the Children's Eating Behaviour Questionnaire at age 4-5 years. Multiple regression models were used to examine the association of DNAm (predictor) at the individual site- and regional-level (using DMRff) with each appetitive trait (outcome), adjusting for covariates. Bonferroni-correction was applied to adjust for multiple testing. There were no associations of DNAm and any appetitive trait at the individual site-level. However, at the regional level, we identified 45 associations of DNAm with food responsiveness, 7 associations of DNAm with emotional undereating, 13 associations of DNAm with satiety responsiveness, and 9 associations of DNAm with food fussiness. This study shows that DNAm in the newborn may partially explain variation in appetitive traits expressed in early childhood and provides preliminary support for early programming of child appetitive traits through DNAm. Investigating differential DNAm associated with appetitive traits could be an important first step in identifying biological pathways underlying the development of these behaviors., Competing Interests: Declarations of interest: none

Per- and polyfluoroalkyl substances (PFAS) are endocrine-disrupting chemicals that may affect breastfeeding duration. We examined associations between maternal PFAS concentrations during pregnancy and breastfeeding cessation. We investigated potential effect modification by parity status., Methods: Among 555 women enrolled in the Healthy Start study (2009-2014), we quantified maternal serum concentrations of 5 PFAS during mid- to late-pregnancy (mean 27 weeks of gestation). Participants self-reported their breastfeeding practices through 18-24 months postnatally. Among all participants and stratified by parity, we estimated associations between maternal PFAS concentrations and breastfeeding discontinuation by 3 and 6 months, using Poisson regression, and breastfeeding duration, using Cox regression., Results: Median PFAS concentrations were similar to those in the general US population. Associations between PFAS and breastfeeding duration differed by parity status. After adjusting for covariates, among primiparous women, associations between PFAS and breastfeeding cessation by 3 and 6 months were generally null, with some inverse associations. Among multiparous women, there were positive associations between perfluorohexane sulfonate, perfluorooctane sulfonate, perfluorooctanoate (PFOA), and perfluorononanoate and breastfeeding cessation by 3 and 6 months. For example, per ln-ng/mL increase in PFOA, the risk ratio for breastfeeding discontinuation by 6 months was 1.45 (95% confidence interval, 1.18, 1.78). Hazard ratios reflected similar patterns between PFAS and breastfeeding duration., Conclusions: Among primiparous women, we did not find evidence for associations between PFAS concentrations and breastfeeding duration. In contrast, among multiparous women, PFAS serum concentrations were generally inversely associated with breastfeeding duration, though estimates may be biased due to confounding by unmeasured previous breastfeeding., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Background: Gestational per- and polyfluoroalkyl substances (PFAS) exposure may be associated with adiposity and increased risk of obesity among children and adolescents. However, results from epidemiological studies evaluating these associations are inconsistent., Objectives: We estimated the associations of pregnancy PFAS concentrations with child body mass index (BMI) z -scores and risk of overweight/obesity in eight U.S. cohorts., Methods: We used data from 1,391 mother-child pairs who enrolled in eight Environmental influences on Child Health Outcomes (ECHO) cohorts (enrolled: 1999-2019). We quantified concentrations of seven PFAS in maternal plasma or serum in pregnancy. We measured child weight and height between the ages of 2 and 5 y and calculated age- and sex-specific BMI z -scores; 19.6% children had more than one BMI measurement. We estimated covariate-adjusted associations of individual PFAS and their mixture with child BMI z -scores and risk of overweight/obesity using linear mixed models, modified Poisson regression models, and Bayesian approaches for mixtures. We explored whether child sex modified these associations., Results: We observed a pattern of subtle positive associations of PFAS concentrations in pregnancy with BMI z -scores and risk of overweight/obesity. For instance, each doubling in perfluorohexane sulfonic acid concentrations was associated with higher BMI z -scores ( β = 0.07 ; 95% CI: 0.01, 0.12). Each doubling in perfluroundecanoic acid [ relative risk  ( RR ) = 1.10 ; 95% CI: 1.04, 1.16] and N -methyl perfluorooctane sulfonamido acetic acid ( RR = 1.06 ; 95% CI: 1.00, 1.12) was associated with increased risk of overweight/obesity, with some evidence of a monotonic dose-response relation. We observed weaker and more imprecise associations of the PFAS mixture with BMI or risk of overweight/obesity. Associations did not differ by child sex., Discussion: In eight U.S.-based prospective cohorts, gestational exposure to higher levels of PFAS were associated with slightly higher childhood BMI z -score and risk of overweight or obesity. Future studies should examine associations of gestational exposure to PFAS with adiposity and related cardiometabolic consequences in older children. https://doi.org/10.1289/EHP11545.

Drinking water can be a major source of poly- and perfluoroalkyl substance (PFAS) exposure for humans. The lack of historic data on PFAS drinking-water concentrations and consumption patterns are a limiting factor for developing estimates of past exposure. Here, in contribution to a community-scale PFAS health effects study near fire training facilities that contaminated a local aquifer with PFASs, we present a novel water-infrastructure, mass-balance mixing model coupled to a non-steady state, single-compartment toxicokinetic model that used Monte Carlo simulations to estimate the start of PFAS exposure in drinking water for individuals within three PFAS-impacted communities in El Paso County, Colorado. Our modeling focused on perfluorohexane sulfonic acid (PFHxS) because median serum PFHxS concentrations in a sample of local residents ( n = 213) were twelve times the median observed in the U.S. National Health and Nutrition Examination Survey (2015-2016). Modeling results for study participants were grouped according to their community of residence, revealing a median start of exposure for the town of Fountain of 1998 (25-75% interquartile range [IQR], 1992 to 2010), 2006 (IQR 1995 to 2012) for Security, and 2009 (IQR 1996-2012) for Widefield. Based on the towns' locations relative to an identified hydraulically upgradient PFAS source, the modeled exposure sequencing does not completely align with this conceptual flow model, implying the presence of an additional PFAS source for the groundwater between Widefield and Fountain.

Purpose: Assess family-level factors associated with childhood immunization schedule adherence., Design: Prospective cohort; Setting; The Healthy Start study enrolled 1,410 pregnant women in Denver, Colorado 2009-2014., Subjects: Children with available vaccination data in medical records (0-6 years old)., Measures: Vaccine schedule completion and compliance., Analysis: Logistic regression comparing family-level factors that differ based on vaccine schedule adherence., Results: Most immunizations required in Colorado for school entry were below national completion goals with 61.8% of participants (n = 532/861) completing the full vaccination series. Most participants received the first dose of individual vaccines on time (73.5% - 90.7%), but fewer received all doses on time (21.0% - 39.5%). Factors associated with not completing the vaccination series (OR [95% CI]) included: in-utero exposure to cigarette smoke (1.97 [1.41, 2.75]), single parent household (1.70 [1.21, 2.38]), children identified as non-White (Hispanic 1.40 [1.01, 1.94]; Black 1.88 [1.24, 2.85]; Other 2.17 [1.34, 3.49]), mothers not working outside the home (1.98 [1.46, 2.67]), and household income <$70,000 per year (<$40,000 1.93 [1.35, 2.75]; $40,000-$70,000 1.64 [1.09, 2.46]). Conversely, families with more educated mothers (0.47 [0.29, 0.76]) and older parents (0.97 [0.94, 0.99]) were significantly more likely to complete the series., Conclusions: These findings may help identify groups at risk of immunization schedule non-adherence and may be used to target education/advocacy campaigns to reduce hesitancy and increase access in these populations.

Background: Overnutrition in utero may increase offspring risk of nonalcoholic fatty liver disease (NAFLD), but the specific contribution of maternal diet quality during pregnancy to this association remains understudied in humans., Objectives: This study aimed to examine the associations of maternal diet quality during pregnancy with offspring hepatic fat in early childhood (median: 5 y old, range: 4-8 y old)., Methods: Data were from 278 mother-child pairs in the longitudinal, Colorado-based Healthy Start Study. Multiple 24-h recalls were collected from mothers during pregnancy on a monthly basis (median: 3 recalls, range: 1-8 recalls starting after enrollment), and used to estimate maternal usual nutrient intakes and dietary pattern scores [Healthy Eating Index-2010 (HEI-2010), Dietary Inflammatory Index (DII), and Relative Mediterranean Diet Score (rMED)]. Offspring hepatic fat was measured in early childhood by MRI. Associations of maternal dietary predictors during pregnancy with offspring log-transformed hepatic fat were assessed using linear regression models adjusted for offspring demographics, maternal/perinatal confounders, and maternal total energy intake., Results: Higher maternal fiber intake and rMED scores during pregnancy were associated with lower offspring hepatic fat in early childhood in fully adjusted models [Back-transformed β (95% CI): 0.82 (0.72, 0.94) per 5 g/1000 kcal fiber; 0.93 (0.88, 0.99) per 1 SD for rMED]. In contrast, higher maternal total sugar and added sugar intakes, and DII scores were associated with higher offspring hepatic fat [Back-transformed β (95% CI): 1.18 (1.05, 1.32) per 5% kcal/d added sugar; 1.08 (0.99, 1.18) per 1 SD for DII]. Analyses of dietary pattern subcomponents also revealed that lower maternal intakes of green vegetables and legumes and higher intake of "empty calories" were associated with higher offspring hepatic fat in early childhood., Conclusions: Poorer maternal diet quality during pregnancy was associated with greater offspring susceptibility to hepatic fat in early childhood. Our findings provide insights into potential perinatal targets for the primordial prevention of pediatric NAFLD., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress., Objectives: We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships., Methods: We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS., Results: We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of β = - 0.15 [95% confidence interval (CI): - 0.27 , - 0.03 ], β = - 0.14 (95% CI: - 0.28 , - 0.002 ), β = - 0.22 (95% CI: - 0.23 , - 0.10 ), β = - 0.06 (95% CI: - 0.18 , 0.06), and β = - 0.25 (95% CI: - 0.37 , - 0.14 ), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: OR PFNA = 0.56 (95% CI: 0.38, 0.83), OR PFDA = 0.52 (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [ - 0.28 ; 95% highest posterior density (HPD): - 0.44 , - 0.14 ] and decreased odds of large-for-gestational-age ( OR = 0.49 ; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress., Discussion: Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.

Childhood obesity is a precursor to future health complications. In adults, neighborhood walkability is inversely associated with obesity prevalence. Recently, it has been shown that current urban walkability has been influenced by historical discriminatory neighborhood disinvestment. However, the relationship between this systemic racism and obesity has not been extensively studied. The objective of this study was to evaluate the association of neighborhood walkability and redlining, a historical practice of denying home loans to communities of color, with childhood obesity. We evaluated neighborhood walkability and walkable destinations for 250 participants of the Healthy Start cohort, based in the Denver metropolitan region. Eligible participants attended an examination between ages 4 and 8. Walkable destinations and redlining geolocations were determined based on residential addresses, and a weighting system for destination types was developed. Sidewalks and trails in Denver were included in the network analyst tool in ArcMap to calculate the precise walkable environment for each child. We implemented linear regression models to estimate associations between neighborhood characteristics and child body mass index (BMI) z-scores and fat mass percent. There was a significant association between child BMI and redlining (β: 1.36, 95% CI: 0.106, 2.620). We did not find an association between walkability measures and childhood obesity outcomes. We propose that cities such as Denver pursue built environment policies, such as inclusionary zoning and direct investments in neighborhoods that have been historically neglected, to reduce the childhood health impacts of segregated poverty, and suggest further studies on the influences that redlining and urban built environment factors have on childhood obesity., (© 2022. The New York Academy of Medicine.)

Background: When evaluating the impact of environmental exposures on human health, study designs often include a series of repeated measurements. The goal is to determine whether populations have different trajectories of the environmental exposure over time. Power analyses for longitudinal mixed models require multiple inputs, including clinically significant differences, standard deviations, and correlations of measurements. Further, methods for power analyses of longitudinal mixed models are complex and often challenging for the non-statistician. We discuss methods for extracting clinically relevant inputs from literature, and explain how to conduct a power analysis that appropriately accounts for longitudinal repeated measures. Finally, we provide careful recommendations for describing complex power analyses in a concise and clear manner., Methods: For longitudinal studies of health outcomes from environmental exposures, we show how to [1] conduct a power analysis that aligns with the planned mixed model data analysis, [2] gather the inputs required for the power analysis, and [3] conduct repeated measures power analysis with a highly-cited, validated, free, point-and-click, web-based, open source software platform which was developed specifically for scientists., Results: As an example, we describe the power analysis for a proposed study of repeated measures of per- and polyfluoroalkyl substances (PFAS) in human blood. We show how to align data analysis and power analysis plan to account for within-participant correlation across repeated measures. We illustrate how to perform a literature review to find inputs for the power analysis. We emphasize the need to examine the sensitivity of the power values by considering standard deviations and differences in means that are smaller and larger than the speculated, literature-based values. Finally, we provide an example power calculation and a summary checklist for describing power and sample size analysis., Conclusions: This paper provides a detailed roadmap for conducting and describing power analyses for longitudinal studies of environmental exposures. It provides a template and checklist for those seeking to write power analyses for grant applications., (© 2023. The Author(s).)

Background: Early-life exposure to tobacco is associated with obesity, but the most susceptible developmental periods are unknown., Objective: To explore windows of susceptibility in a cohort of 568 mother-child pairs., Methods: We measured seven measures of tobacco exposure (five self-reported and two biomarkers) spanning from pre-conception to age 5 years. Mothers self-reported active smoking (pre-conception, 17 weeks, and delivery) and household smokers (5 and 18 months postnatally). Cotinine was measured in maternal urine (27 weeks) and child urine (5 years). Adiposity (fat mass percentage) was measured at birth and 5 years via air displacement plethysmography. Using a multiple informant approach, we tested whether adiposity (5 years) and changes in adiposity (from birth to 5 years) differed by the seven measures of tobacco exposure., Results: The associations may depend on timing. For example, only pre-conception (β = 3.1%; 95% CI: 1.0-5.1) and late gestation (β = 4.0%; 95% CI: 0.4-7.6) exposures influenced adiposity accretion from birth to 5 years (p for interaction = 0.01). Early infancy exposure was also associated with 1.7% higher adiposity at 5 years (95% CI: 0.1-3.2). Mid-pregnancy and early childhood exposures did not influence adiposity., Conclusions: Pre-conception, late gestation, and early infancy exposures to tobacco may have the greatest impact on childhood adiposity., (© 2022 World Obesity Federation.)

Background: Both environmental and social factors have been linked to birth weight and adiposity at birth, but few studies consider the effects of exposure mixtures. Our objective was to identify which components of a mixture of neighborhood-level environmental and social exposures were driving associations with birth weight and adiposity at birth in the Healthy Start cohort., Methods: Exposures were assessed at the census tract level and included air pollution, built environment characteristics, and socioeconomic status. Prenatal exposures were assigned based on address at enrollment. Birth weight was measured at delivery and adiposity was measured using air displacement plethysmography within three days. We used non-parametric Bayes shrinkage (NPB) to identify exposures that were associated with our outcomes of interest. NPB models were compared to single-predictor linear regression. We also included generalized additive models (GAM) to assess nonlinear relationships. All regression models were adjusted for individual-level covariates, including maternal age, pre-pregnancy BMI, and smoking., Results: Results from NPB models showed most exposures were negatively associated with birth weight, though credible intervals were wide and generally contained zero. However, the NPB model identified an interaction between ozone and temperature on birth weight, and the GAM suggested potential non-linear relationships. For associations between ozone or temperature with birth weight, we observed effect modification by maternal race/ethnicity, where effects were stronger for mothers who identified as a race or ethnicity other than non-Hispanic White. No associations with adiposity at birth were observed., Conclusions: NPB identified prenatal exposures to ozone and temperature as predictors of birth weight, and mothers who identify as a race or ethnicity other than non-Hispanic White might be disproportionately impacted. However, NPB models may have limited applicability when non-linear effects are present. Future work should consider a two-stage approach where NPB is used to reduce dimensionality and alternative approaches examine non-linear effects., (© 2022. The Author(s).)

Background: Prenatal exposure to ambient air pollution has been associated with adverse offspring health outcomes. Childhood health effects of prenatal exposures may be mediated through changes to DNA methylation detectable at birth., Methods: Among 429 non-smoking women in a cohort study of mother-infant pairs in Colorado, USA, we estimated associations between prenatal exposure to ambient fine particulate matter (PM 2.5 ) and ozone (O 3 ), and epigenome-wide DNA methylation of umbilical cord blood cells at delivery (2010-2014). We calculated average PM 2.5 and O 3 in each trimester of pregnancy and the full pregnancy using inverse-distance-weighted interpolation. We fit linear regression models adjusted for potential confounders and cell proportions to estimate associations between air pollutants and methylation at each of 432,943 CpGs. Differentially methylated regions (DMRs) were identified using comb-p. Previously in this cohort, we reported positive associations between 3rd trimester O 3 exposure and infant adiposity at 5 months of age. Here, we quantified the potential for mediation of that association by changes in DNA methylation in cord blood., Results: We identified several DMRs for each pollutant and period of pregnancy. The greatest number of significant DMRs were associated with third trimester PM 2.5 (21 DMRs). No single CpGs were associated with air pollutants at a false discovery rate <0.05. We found that up to 8% of the effect of 3rd trimester O 3 on 5-month adiposity may be mediated by locus-specific methylation changes, but mediation estimates were not statistically significant., Conclusions: Differentially methylated regions in cord blood were identified in association with maternal exposure to PM 2.5 and O 3 . Genes annotated to the significant sites played roles in cardiometabolic disease, immune function and inflammation, and neurologic disorders. We found limited evidence of mediation by DNA methylation of associations between third trimester O 3 exposure and 5-month infant adiposity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Higher adherence to the Mediterranean diet during pregnancy is related to a lower risk of preterm birth and to better offspring cardiometabolic health. DNA methylation may be an underlying biological mechanism. We evaluated whether maternal adherence to the Mediterranean diet was associated with offspring cord blood DNA methylation.We meta-analysed epigenome-wide association studies (EWAS) of maternal adherence to the Mediterranean diet during pregnancy and offspring cord blood DNA methylation in 2802 mother-child pairs from five cohorts. We calculated the relative Mediterranean diet (rMED) score with range 0-18 and an adjusted rMED excluding alcohol (rMEDp, range 0-16). DNA methylation was measured using Illumina 450K arrays. We used robust linear regression modelling adjusted for child sex, maternal education, age, smoking, body mass index, energy intake, batch, and cell types. We performed several functional analyses and examined the persistence of differential DNA methylation into childhood (4.5-7.8 y).rMEDp was associated with cord blood DNA methylation at cg23757341 (0.064% increase in DNA methylation per 1-point increase in the rMEDp score, SE = 0.011, P = 2.41 × 10 -8 ). This cytosine-phosphate-guanine (CpG) site maps to WNT5B , associated with adipogenesis and glycaemic phenotypes. We did not identify associations with childhood gene expression, nor did we find enriched biological pathways. The association did not persist into childhood.In this meta-analysis, maternal adherence to the Mediterranean diet (excluding alcohol) during pregnancy was associated with cord blood DNA methylation level at cg23757341. Potential mediation of DNA methylation in associations with offspring health requires further study.

Importance: Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth., Objective: To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US., Design, Setting, and Participants: Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included., Exposures: Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated., Main Outcomes and Measures: Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n = 539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth., Results: The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively., Conclusions and Relevance: Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery.

Background: Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children., Methods: We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4-13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration., Results: We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10 -8 ). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10 -8 , n = 577) and sleep onset latency (p = 8.8 × 10 -9 , n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716-2539)., Conclusion: DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available., (© 2022. The Author(s).)

Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Prenatal air pollution exposure has been associated with adverse childhood cardiometabolic outcomes. It is unknown whether evidence of metabolic disruption associated with air pollution is identifiable at birth. We examined exposure to prenatal ambient air pollution and cord blood cardiometabolic biomarkers among 812 mother-infant pairs in the Healthy Start study., Methods: Using inverse-distance-weighted interpolation of ambient concentrations obtained from stationary monitors, we estimated daily particulate matter ≤2.5 micrometers (PM 2.5 ) and ozone (O 3 ) concentrations at participant residences. Daily estimates were averaged by trimester, full-pregnancy, and the 7 and 30 days prior to delivery. Associations of air pollution with the following cord blood biomarkers were estimated via multivariable linear regression: glucose, insulin, glucose/insulin ratio (GIR), leptin, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, free fatty acids, and triglycerides., Results: In this Denver-based cohort, PM 2.5 concentrations were lower than in many US urban areas, but O 3 concentrations regularly exceeded federal air quality standards. Higher O 3 concentrations during pregnancy were consistently associated with higher insulin and lower GIR in cord blood. For example, an interquartile range increase in full pregnancy O 3 (6.3 parts per billion [ppb]) was associated with 0.13 log-µIU/ml (95% confidence interval [CI] = 0.04, 0.22) higher cord blood insulin, after adjusting for PM 2.5 and other confounders. We found positive, but generally nonsignificant, associations between PM 2.5 and leptin and isolated associations between pollutants during certain exposure periods and lipids., Conclusions: In this cohort with moderately high O 3 exposure, prenatal concentrations of O 3 were positively associated with cord blood insulin. Future studies should examine the implications for offspring long-term health., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report. This work was supported in part by grants from the National Institute of Environmental Health Sciences (R00ES025817), the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076648), and the National Institutes of Health Office of the Director (UH3OD023248). The University of Colorado Cancer Center laboratory received support from the National Cancer Institute (UL1 TR001082). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. C.F., D.D., D.S.K.T., J.L.P., and A.P.S. contributed to the conception and design of this study. All authors contributed to the acquisition, analysis, and interpretation of data. C.F. and A.P.S. participated in drafting the article. D.D., L.D.B., D.S.K.T., J.L.P., J.L.A., S.M., S.E.M., and W.B.A. participated in revising the article critically for important intellectual content. All authors gave approval of the final article. Sponsorships or competing interests that may be relevant to content are disclosed at the end of the article., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Objective: Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations., Research Design and Methods: To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression., Results: Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] -0.013 [2.1 × 10-3], P value corrected for false discovery rate [PFDR] = 5.1 × 10-3) and cg02988288 (β [SE]-0.013 [2.3 × 10-3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm., Conclusions: Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses., (© 2022 by the American Diabetes Association.)

Background: Per- and polyfluoroalkyl substances (PFASs) are widespread and persistent environmental contaminants. Exposure to several PFASs has been associated with altered immune function in humans, including autoimmune disease and impaired response to vaccination. However, changes to the profile of inflammatory biomarkers in adults exposed to PFASs has not been extensively described., Objective: To estimate cross-sectional associations between serum PFASs and markers of inflammation among adults in a population exposed to aqueous film forming foam (AFFF)-contaminated drinking water., Methods: We quantified concentrations of 48 PFASs in non-fasting serum samples from 212 non-smoking adults. In the same serum samples, we measured concentrations of ten pro- and anti-inflammatory cytokines. We restricted analysis to seven PFASs detected in >85% of participants and the following four cytokines detected in ≥30% of participants: interleukin [IL]-1β, IL-6, IL-10, and tumor necrosis factor [TNF]-α. We fit multiple linear regression or logistic regression models, adjusted for potential confounders, to estimate associations between concentrations of each PFAS and either continuous or categorical (above vs below limit of detection) concentrations of each cytokine. We additionally applied Bayesian kernel machine regression to describe the combined effect of the PFAS mixture on each cytokine outcome., Results: Certain PFAS concentrations in this sample were elevated compared to a US nationally representative sample; median levels of PFHxS, ΣPFOS and ΣPFOA in this sample were 13.8, 2.1 and 1.7 times higher, respectively, than medians observed in the U.S., Sample: Higher concentrations of multiple PFASs were significantly associated with lower odds of detectable IL-1β. Weaker associations were observed with other cytokines. In general, perfluoroalkyl carboxylic acids had inverse associations with TNF-α, whereas the perfluoroalkyl sulfonic acids showed positive associations., Conclusions: We observed preliminary evidence of altered inflammatory profiles among adults with elevated serum concentrations of PFASs due to contaminated drinking water. Modifications to inflammatory pathways may be one mechanism by which PFAS exposures produce adverse health effects in humans, but this finding requires verification in longitudinal studies as well as phenotypic anchoring to immune function outcomes., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Background: Prenatal exposure to ambient air pollution and traffic have been related to a lower birth weight and may be associated with greater adiposity in childhood. We aimed to examine associations of maternal exposure to ambient air pollution and traffic during pregnancy with indicators of adiposity in early childhood., Methods: We included 738 participants of the Colorado-based Healthy Start study whose height, weight, waist circumference and/or fat mass were measured at age 4-6 years. We estimated residential exposure to ambient concentrations of fine particulate matter (PM 2.5 ) and ozone (O 3 ) averaged by trimester and throughout pregnancy via inverse distance-weighted interpolation of central site monitoring data. We assessed the distance to the nearest major roadway and traffic density in multiple buffers surrounding the participants' homes. Associations of prenatal exposure to air pollution and traffic with overweight, waist circumference, percent fat mass and fat mass index (FMI) were assessed by logistic and linear regression., Results: Associations of exposure to PM 2.5 and O 3 at the residential address during pregnancy with percent fat mass and FMI at age 4-6 years were inconsistent across trimesters. For example, second trimester PM 2.5 was associated with a higher percent fat mass (adjusted difference 0.70% [95% CI 0.05, 1.35%] per interquartile range (IQR; 1.3 µg/m 3 ) increase), while third trimester PM 2.5 was associated with a lower percent fat mass (adjusted difference -1.17% [95% CI -1.84, -0.50%] per IQR (1.3 µg/m 3 ) increase). Residential proximity to a highway during pregnancy was associated with higher odds of being overweight at age 4-6 years. We observed no associations of prenatal exposure to PM 2.5 and O 3 with overweight and waist circumference., Conclusions: We found limited evidence of associations of prenatal exposure to ambient PM 2.5 and O 3 with indicators of adiposity at age 4-6 years. Suggestive relationships between residential proximity to a highway during pregnancy and greater adiposity merit further investigation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: A growing number of studies have identified both toxic and essential metals which influence fetal growth. However, most studies have conducted single-cohort analyses, which are often limited by narrow exposure ranges, and evaluated metals individually. The objective of the current study was to conduct an environmental mixture analysis of metal impacts on fetal growth, pooling data from three geographically and demographically diverse cohorts in the United States participating in the Environmental Influences on Child Health Outcomes program., Methods: The pooled sample (N = 1,002) included participants from the MADRES, NHBCS, and PROTECT cohorts. Associations between seven metals (antimony, cadmium, cobalt, mercury, molybdenum, nickel, tin) measured in maternal urine samples collected during pregnancy (median: 16.0 weeks gestation) and birth weight for gestational age z-scores (BW for GA) were investigated using Bayesian Kernel Machine Regression (BKMR). Models were also stratified by cohort and infant sex to investigate possible heterogeneity. Chromium and uranium concentrations fell below the limits of detection for most participants and were evaluated separately as binary variables using pooled linear regression models., Results: In the pooled BKMR analysis, antimony, mercury, and tin were inversely and linearly associated with BW for GA, while a positive linear association was identified for nickel. The inverse association between antimony and BW for GA was observed in both males and females and for all three cohorts but was strongest for MADRES, a predominantly low-income Hispanic cohort in Los Angeles. A reverse j-shaped association was identified between cobalt and BW for GA, which was driven by female infants. Pooled associations were null for cadmium, chromium, molybdenum, and uranium, and BKMR did not identify potential interactions between metal pairs., Conclusions: Findings suggest that antimony, an understudied metalloid, may adversely impact fetal growth. Cohort- and/or sex-dependent associations were identified for many of the metals, which merit additional investigation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Associations have been shown between concurrent assessment of dietary intake of advanced glycation end products (AGEs) and childhood allergic outcomes. We examined the association between maternal AGEs intake and development of offspring asthma, wheeze, atopic dermatitis, allergic rhinitis and food allergies, and sought to determine whether the intake of AGEs was associated with cord sera cytokines/chemokines., Methods: Pregnant women ≥16 years were recruited in the Healthy Start study, a prospective pre-birth cohort from Colorado (N = 1410). The analysis included 962 dyads with adequate diet (≥2 recalls) and allergy outcome details. AGEs intake was estimated for each mother by matching intakes reported using 24-h dietary recalls during pregnancy to a reference database of commonly consumed foods' AGEs values. Child diagnoses of asthma and allergies up to 8 years were obtained from electronic medical records. Cord sera cytokines and chemokines were analysed in a subset (N = 462) of children., Results: The median [IQR] AGEs intake for the overall sample was 11,919 kU/day [8293, 16,573]. Unadjusted analysis showed a positive association between maternal AGEs intake in pregnancy and rhinitis up to 8 years of age (HR = 1.03; 95% CI: 1.01, 1.06), but the association was attenuated and no longer significant in adjusted models (HR = 1.01; 95% CI: 0.98, 1.04). Both adjusted and unadjusted models showed no associations between AGEs intake in pregnancy and any of the other outcomes (p > .05). There were no significant associations between any cytokine or chemokine measured and AGEs intake or any of the outcomes studied (p > .05)., Conclusion: The study showed that maternal AGEs intake was not associated with offspring asthma and allergy outcomes. AGEs exposure during pregnancy may not have the same impact on child development as postnatal exposure., (© 2021 John Wiley & Sons Ltd.)