Evaluating Mixtures of Urinary Phthalate Metabolites and Serum Per-/Polyfluoroalkyl Substances in Relation to Adolescent Hair Cortisol: The HOME Study.

Results of toxicological studies indicate that phthalates and per-/polyfluoroalkyl substances (PFAS), 2 classes of endocrine-disrupting chemicals, may alter the functioning of the hypothalamic-pituitary-adrenocortical (HPA) axis. We evaluated the associations of urinary phthalate metabolites and serum PFAS during gestation and childhood with adolescent hair cortisol concentrations (pg/mg hair) at age 12 years, an integrative marker of HPA axis activity (n = 205 mother-child pairs; Cincinnati, Ohio; enrolled 2003-2006). We used quantile-based g-computation to estimate associations between mixtures of urinary phthalate metabolites or serum PFAS and hair cortisol. We also examined whether associations of individual phthalate metabolites or PFAS with cortisol varied by the timing of exposure. We found that a 1-quartile increase in all childhood phthalate metabolites was associated with 35% higher adolescent hair cortisol (phthalate mixture ψ = 0.13; 95% confidence interval: 0.03, 0.22); these associations were driven by monoethyl phthalate, monoisobutyl phthalate, and monobenzyl phthalate. We did not find evidence that phthalate metabolites during gestation or serum PFAS mixtures were related to adolescent hair cortisol concentrations. We found suggestive evidence that higher childhood concentrations of individual PFAS were related to higher and lower adolescent hair cortisol concentrations. Our results suggest that phthalate exposure during childhood may contribute to higher levels of chronic HPA axis activity.

Estimating effects of longitudinal and cumulative exposure to PFAS mixtures on early adolescent body composition.

Few methods have been used to characterize repeatedly measured biomarkers of chemical mixtures. We applied latent profile analysis (LPA) to serum concentrations of 4 perfluoroalkyl and polyfluoroalkyl substances (PFAS) measured at 4 time points from gestation to age 12 years. We evaluated the relationships between profiles and z scores of height, body mass index, fat mass index, and lean body mass index at age 12 years (n = 218). We compared LPA findings with an alternative approach for cumulative PFAS mixtures using g-computation to estimate the effect of simultaneously increasing the area under the receiver operating characteristic curve (AUC) for all PFAS. We identified 2 profiles: a higher PFAS profile (35% of sample) and a lower PFAS profile (relative to each other), based on their average PFAS concentrations at all time points. The higher PFAS profile had generally lower z scores for all outcomes, with somewhat larger effects for males, though all 95% CIs crossed the null. For example, the higher PFAS profile was associated with a 0.50-unit lower (ß = -0.50; 95% CI, -1.07 to 0.08) BMI z score among males but not among females (ß = 0.04; 95% CI, -0.45 to 0.54). We observed similar patterns with AUCs. We found that a higher childhood PFAS profile and higher cumulative PFAS mixtures may be associated with altered growth in early adolescence. This article is part of a Special Collection on Environmental Epidemiology.

Per- and polyfluoroalkyl substances and bone mineral content in early adolescence: Modification by diet and physical activity.

BACKGROUND: Per- and polyfluoroalkyl substance (PFAS) exposures may negatively impact bone mineral accrual, but little is known about potential mitigators of this relation. We assessed whether associations of PFAS and their mixture with bone mineral content (BMC) in adolescence were modified by diet and physical activity. METHODS: We included 197 adolescents enrolled in a prospective pregnancy and birth cohort in Cincinnati, Ohio (2003-2006). At age 12 years, we collected serum for PFAS measurements and used dual-energy x-ray absorptiometry to measure BMC. We calculated dietary calcium intake and Health Eating Index (HEI) scores from repeated 24-h dietary recalls, physical activity scores using the Physical Activity Questionnaire for Older Children (PAQ-C), and average moderate to vigorous physical activity (MVPA) based on accelerometry. We estimated covariate-adjusted differences in BMC z-scores per interquartile range (IQR) increase of individual PFAS concentrations using linear regression and per simultaneous IQR increase in all four PFAS using g-computation. We evaluated effect measure modification (EMM) using interaction terms between each modifier and PFAS. RESULTS: Higher serum perfluorooctanoic acid, perfluorooctanesulfonic acid, and perfluorononanoic acid concentrations and the PFAS mixture were associated with lower BMC z-scores. An IQR increase in all PFAS was associated with a 0.27 (-0.54, 0.01) lower distal radius BMC z-score. Associations with lower BMC were generally stronger among adolescents classified as < median for calcium intake, HEI scores, or MVPA compared to those ≥ median. The difference in distal radius BMC z-score per IQR increase in all PFAS was -0.38 (-0.72, -0.04) for those with

Early life exposure to secondhand tobacco smoke and eating behaviors at age 12 years.

BACKGROUND: Prenatal or early childhood secondhand tobacco smoke (SHS) exposure increases obesity risk. However, the potential mechanisms underlying this association are unclear, but obesogenic eating behaviors are one pathway that components of SHS could perturb. Our aim was to assess associations of prenatal and early childhood SHS exposure with adolescent eating behaviors. METHODS: Data came from a prospective pregnancy and birth cohort (N = 207, Cincinnati, OH). With multiple informant models, we estimated associations of prenatal (mean of 16 and 26 weeks of gestation maternal serum cotinine concentrations) and early childhood cotinine (average concentration across ages 12, 24, 36, and 48 months) with eating behaviors at age 12 years (Child Eating Behaviors Questionnaire). We tested whether associations differed by exposure periods and adolescent's sex. Models adjusted for maternal and child covariates. RESULTS: We found no statistically significant associations between cotinine measures and adolescent's eating behaviors. Yet, in females, prenatal cotinine was associated with greater food responsiveness (ß: 0.23; 95% CI: 0.08, 0.38) and lower satiety responsiveness (ß: -0.14; 95% CI: -0.26, -0.02); in males, prenatal and postnatal cotinine was related to lower food responsiveness (prenatal: ß: -0.25; 95% CI: -0.04, -0.06; postnatal: ß: -0.36; 95% CI: -0.06, -0.11). No significant effect modification by sex or exposure window was found for other eating behaviors. CONCLUSION: Prenatal and early childhood SHS exposures were not related to adolescent's eating behavior in this cohort; however, biological sex may modify these associations.

Contrasting Association of Maternal Plasma Biomarkers of Smoking and 1-Carbon Micronutrients with Offspring DNA Methylation: Evidence of Aryl Hydrocarbon Receptor Repressor Gene-Smoking-Folate Interaction.

BACKGROUND: Maternal prenatal smoking is known to alter offspring DNA methylation (DNAm). However, there are no effective interventions to mitigate smoking-induced DNAm alteration. OBJECTIVES: This study investigated whether 1-carbon nutrients (folate, vitamins B6, and B12) can protect against prenatal smoking-induced offspring DNAm alterations in the aryl hydrocarbon receptor repressor (AHRR) (cg05575921), GFI1 (cg09935388), and CYP1A1 (cg05549655) genes. METHODS: This study included mother-newborn dyads from a racially diverse US birth cohort. The cord blood DNAm at the above 3 sites were derived from a previous study using the Illumina Infinium MethylationEPIC BeadChip. Maternal smoking was assessed by self-report and plasma biomarkers (hydroxycotinine and cotinine). Maternal plasma folate, and vitamins B6 and B12 concentrations were obtained shortly after delivery. Linear regressions, Bayesian kernel machine regression, and quantile g-computation were applied to test the study hypothesis by adjusting for covariables and multiple testing. RESULTS: The study included 834 mother-newborn dyads (16.7% of newborns exposed to maternal smoking). DNAm at cg05575921 (AHRR) and at cg09935388 (GFI1) was inversely associated with maternal smoking biomarkers in a dose-response fashion (all P < 7.01 × 10-13). In contrast, cg05549655 (CYP1A1) was positively associated with maternal smoking biomarkers (P < 2.4 × 10-6). Folate concentrations only affected DNAm levels at cg05575921 (AHRR, P = 0.014). Regression analyses showed that compared with offspring with low hydroxycotinine exposure (<0.494) and adequate maternal folate concentrations (quartiles 2-4), an offspring with high hydroxycotinine exposure (≥0.494) and low folate concentrations (quartile 1) had a significant reduction in DNAm at cg05575921 (M-value, ß ± SE = -0.801 ± 0.117, P = 1.44 × 10-11), whereas adequate folate concentrations could cut smoking-induced hypomethylation by almost half. Exposure mixture models further supported the protective role of adequate folate concentrations against smoking-induced aryl hydrocarbon receptor repressor (AHRR) hypomethylation. CONCLUSIONS: This study found that adequate maternal folate can attenuate maternal smoking-induced offspring AHRR cg05575921 hypomethylation, which has been previously linked to a range of pediatric and adult diseases.

Ultra-processed food consumption and exposure to acrylamide in a nationally representative sample of the US population aged 6 years and older.

Ultra-processed food (UPF) consumption has been associated with cardiovascular disease and cancer. Acrylamide is a probable human carcinogen commonly found in foods that are processed at high temperatures. The aim of this study was to examine the association between dietary energy contribution of UPF and acrylamide exposure, in the US. Among the 4418 participants from cross-sectional 2013-2016 National Health and Nutrition Examination Survey, aged 6+ years, with hemoglobin biomarkers of acrylamide exposure, 3959 that completed the first 24-h dietary recall and had information on all covariates were included in the study. UPF were identified based on the Nova classification system, a four-group food classification based on the extent and purpose of industrial food processing. Linear regression was used to compare average acrylamide and glycidamide hemoglobin (HbAA+HbGA) concentrations across quintiles of daily energy contribution of UPF. Adjusted geometric means of acrylamide and glycidamide hemoglobin concentrations increased monotonically from the lowest to the highest quintile of UPF consumption in the overall population. Compared to the lowest quintile, the highest quintile had 9.1% higher levels of HbAA+HbGA (94.1 vs. 86.3 pmol/g Hb). These positive associations were statistically significant among males and in the young adult population and were largely driven by UPF which are known potential sources of acrylamide. The main effects remained unchanged when excluding current smokers. As both acrylamides and UPF have been previously associated with cardiovascular disease and cancer, our results suggest that acrylamides in UPF may partially explain previously observed links between UPF consumption and these health outcomes.

Toward Advancing Precision Environmental Health: Developing a Customized Exposure Burden Score to PFAS Mixtures to Enable Equitable Comparisons Across Population Subgroups, Using Mixture Item Response Theory.

Quantifying a person's cumulative exposure burden to per- and polyfluoroalkyl substances (PFAS) mixtures is important for risk assessment, biomonitoring, and reporting of results to participants. However, different people may be exposed to different sets of PFASs due to heterogeneity in the exposure sources and patterns. Applying a single measurement model for the entire population (e.g., by summing concentrations of all PFAS analytes) assumes that each PFAS analyte is equally informative to PFAS exposure burden for all individuals. This assumption may not hold if PFAS exposure sources systematically differ within the population. However, the sociodemographic, dietary, and behavioral characteristics that underlie systematic exposure differences may not be known, or may be due to a combination of these factors. Therefore, we used mixture item response theory, an unsupervised psychometrics and data science method, to develop a customized PFAS exposure burden scoring algorithm. This scoring algorithm ensures that PFAS burden scores can be equitably compared across population subgroups. We applied our methods to PFAS biomonitoring data from the United States National Health and Nutrition Examination Survey (2013-2018). Using mixture item response theory, we found that participants with higher household incomes had higher PFAS burden scores. Asian Americans had significantly higher PFAS burden compared with non-Hispanic Whites and other race/ethnicity groups. However, some disparities were masked when using summed PFAS concentrations as the exposure metric. This work demonstrates that our summary PFAS burden metric, accounting for sources of exposure variation, may be a more fair and informative estimate of PFAS exposure.

Exposures to Organophosphate Esters and Respiratory Morbidity among School-Aged Children with Asthma.

Organophosphate esters (OPEs) are an emerging class of chemicals used in a variety of consumer products as flame retardants, plasticizers, and additives. While prior epidemiologic studies suggest that OPEs may impact respiratory health, results remain inconclusive. We examined associations between urinary biomarkers of OPEs and symptoms of respiratory morbidity in a panel study of 147 predominantly Black school-aged children with asthma living in Baltimore City, Maryland. The study consisted of up to four seasonal, week-long, in-home visits where urine samples and self-reported asthma symptoms were collected on days 4 and 7 (nsamples = 438). We quantified concentrations of nine urinary OPE biomarkers: bis(2-chloroethyl) phosphate (BCEtp), bis(1-chloro-2-propyl) phosphate (BCPP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-n-butyl phosphate (DBuP), di-benzyl phosphate (DBzP), di-o-cresylphosphate (DOCP), di-p-cresylphosphate (DPCP), di-(2-propylheptyl) phthalate (DPHP), and 2,3,4,5-tetrabromo benzoic acid (TBBA). We estimated prevalence odds ratios (POR) of respiratory morbidity symptoms using logistic regression with generalized estimating equations to account for our repeated measure design. We assessed BDCIPP and DPHP as continuous (log2) concentrations and dichotomized exposure of BCEtP, DBuP, and DPCP (detect vs non-detect) based on their lower detection frequencies. We adjusted models for season, visit day, age, gender, caregiver education, health insurance type, exposure to household smoking, atopy, and PM2.5. Higher DPHP concentrations were significantly associated with odds of daytime symptoms (POR: 1.26; 95% CI: 1.04-1.53; p = 0.02) where daytime symptoms consisted of trouble breathing due to asthma, reporting bother caused by asthma, and/or limitation in activities due to asthma. DBuP detection was associated with use of rescue medication on the day of sample collection (POR: 2.36; 95% CI: 1.05-5.29; p = 0.04). We also observed several consistent, albeit non-significant (p > 0.05), positive associations for BCEtP and DPCP and respiratory morbidity measures. This is the first study to evaluate the relationship between OPE biomarkers and respiratory morbidity symptoms in children with asthma, and findings suggest that further studies are warranted to confirm whether these associations are causal.

Associations of a Prenatal Serum Per- and Polyfluoroalkyl Substance Mixture with the Cord Serum Metabolome in the HOME Study.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous and persistent chemicals associated with multiple adverse health outcomes; however, the biological pathways affected by these chemicals are unknown. To address this knowledge gap, we used data from 264 mother-infant dyads in the Health Outcomes and Measures of the Environment (HOME) Study and employed quantile-based g-computation to estimate covariate-adjusted associations between a prenatal (∼16 weeks' gestation) serum PFAS mixture [perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] and 14,402 features measured in cord serum. The PFAS mixture was associated with four features: PFOS, PFHxS, a putatively identified metabolite (3-monoiodo-l-thyronine 4-O-sulfate), and an unidentified feature (590.0020 m/z and 441.4 s retention time; false discovery rate <0.20). Using pathway enrichment analysis coupled with quantile-based g-computation, the PFAS mixture was associated with 49 metabolic pathways, most notably amino acid, carbohydrate, lipid and cofactor and vitamin metabolism, as well as glycan biosynthesis and metabolism (P(Gamma) <0.05). Future studies should assess if these pathways mediate associations of prenatal PFAS exposure with infant or child health outcomes, such as birthweight or vaccine response.

Pre- and postnatal exposure to secondhand tobacco smoke and cardiometabolic risk at 12 years: Periods of susceptibility.

BACKGROUND: To identify periods of heightened susceptibility to the association of secondhand tobacco smoke (SHS) exposure with cardiometabolic (CM) risk at age 12 years. METHODS: We used data from 212 adolescents from the HOME Study, a prospective pregnancy and birth cohort in Cincinnati, OH. Using multiple informant models, we estimated associations of maternal serum cotinine (mean of concentrations at 16 and 26 weeks of pregnancy) and children's serum cotinine concentrations (mean of concentrations at ages 1, 2, 3, and 4 years) with a CM risk summary score constructed of five risk components measured at age 12 years. We determined if these associations differed for pre- and postnatal exposure periods, and adolescent's sex. RESULTS: We found some evidence that the cotinine-outcome associations differed by exposure period and sex. Postnatal, but not prenatal, cotinine was associated with higher CM risk scores and individual CM risk component values (interaction p-values = 0.04 to 0.35). Each 10-fold increase in postnatal cotinine was associated with 0.57 (95% CI: 0.32, 1.45), 0.09 (95% CI: 0.13, 0.31), 0.14 (-0.08, 0.35), 0.07 (95% CI: 0.34, 0.48), and 0.11 (95% CI: 0.04, 0.27) higher CM risk, HOMA-IR, TG to HDL-C ratio, leptin to adiponectin ratio, and visceral fat area. Postnatal cotinine was associated with higher visceral fat area among females but not males (sex × period × cotinine interaction p-value = 0.01). CONCLUSIONS: Serum cotinine concentrations during the postnatal period had greater influence on adolescent's CM risk compared to the prenatal period, and these associations may be sex-specific. This study reinforces the need for ongoing public health interventions to minimize children's exposure to SHS.

Dietary per- and polyfluoroalkyl substance (PFAS) exposure in adolescents: The HOME study.

BACKGROUND: Diet is the primary exposure pathway for per- and polyfluoroalkyl substances (PFAS) in non-occupationally exposed populations. Few studies have examined associations of dietary quality and macronutrient intake with PFAS exposure among US adolescents. OBJECTIVE: To assess relationships of self-reported dietary quality and macronutrient intake with serum PFAS concentrations in adolescents. METHODS: We used cross-sectional data from 193 Cincinnati, Ohio area adolescents (median age 12.3 years) collected from 2016 to 2019. Using 24-h food recalls completed by adolescents on three separate days, we derived Healthy Eating Index (HEI) scores, HEI components, and macronutrient intake. We measured perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) concentrations in fasting serum samples. Using linear regression, we estimated covariate-adjusted associations between dietary variables and serum PFAS concentrations. RESULTS: The median HEI score was 44 and median serum PFOA, PFOS, PFHxS, and PFNA concentrations were 1.3, 2.4, 0.7, and 0.3 ng/mL respectively. In adjusted models, higher total HEI scores, whole fruit and total fruit HEI component scores, and total dietary fiber intake were associated with lower concentrations of all four PFAS. For example, serum PFOA concentrations were 7% lower (95% CI: -15, 2) per standard deviation increase in total HEI score and 9% lower (95% CI: -18, 1) per standard deviation increase in dietary fiber. SIGNIFICANCE: Given adverse health effects associated with PFAS exposure, it is crucial to understand modifiable exposure pathways. Findings from this study may inform future policy decisions aiming to limit human exposure to PFAS.

Anthropometric measures and arsenic methylation among pregnant women in rural northern Bangladesh.

INTRODUCTION: Arsenic methylation converts inorganic arsenic (iAs) to monomethyl (MMA) and dimethyl (DMA) arsenic compounds. Body mass index (BMI) has been positively associated with arsenic methylation efficiency (higher DMA%) in adults, but evidence in pregnancy is inconsistent. We estimated associations between anthropometric measures and arsenic methylation among pregnant women in rural northern Bangladesh. METHODS: We enrolled pregnant women (n = 784) (median [IQR] gestational week: 14 [13, 15]) in Gaibandha District, Bangladesh from 2018 to 2019. Anthropometric measures were BMI, subscapular and triceps skinfold thicknesses, and mid-upper arm circumference (MUAC), fat area (MUAFA), and muscle area (MUAMA). Arsenic methylation measures were urinary iAs, MMA, and DMA divided by their sum and multiplied by 100 (iAs%, MMA%, and DMA%), primary methylation index (MMA/iAs; PMI), and secondary methylation index (DMA/MMA; SMI). In complete cases (n = 765 [97.6%]), we fitted linear, beta, and Dirichlet regression models to estimate cross-sectional differences in iAs%, MMA%, DMA%, PMI, and SMI per IQR-unit difference in each anthropometric measure, adjusting for drinking water arsenic, age, gestational age, education, living standards index, and plasma folate, vitamin B12, and homocysteine. RESULTS: Median (IQR) BMI, subscapular skinfold thickness, triceps skinfold thickness, MUAC, MUAFA, and MUAMA were 21.5 (19.4, 23.8) kg/m2, 17.9 (13.2, 24.2) mm, 14.2 (10.2, 18.7) mm, 25.9 (23.8, 28.0) cm, 15.3 (10.5, 20.3) cm2, and 29.9 (25.6, 34.2) cm2, respectively. Median (IQR) iAs%, MMA%, DMA%, PMI, and SMI were 12.0 (9.3, 15.2)%, 6.6 (5.3, 8.3)%, 81.0 (77.1, 84.6)%, 0.6 (0.4, 0.7), and 12.2 (9.3, 15.7), respectively. In both unadjusted and adjusted linear models, all anthropometric measures were negatively associated with iAs%, MMA%, and PMI and positively associated with DMA% and SMI. For example, fully adjusted mean differences (95% CI) in DMA% per IQR-unit difference in BMI, subscapular skinfolds thickness, triceps skinfold thickness, MUAC, MUAFA, and MUAMA were 1.72 (1.16, 2.28), 1.58 (0.95, 2.21), 1.74 (1.11, 2.37), 1.45 (0.85, 2.06), 1.70 (1.08, 2.31), and 0.70 (0.13, 1.27) pp, respectively. CONCLUSIONS: Anthropometric measures were positively associated with arsenic methylation efficiency among pregnant women in the early second trimester.

In-utero co-exposure to toxic metals and micronutrients on childhood risk of overweight or obesity: new insight on micronutrients counteracting toxic metals.

BACKGROUND/OBJECTIVES: Low-level, in-utero exposure to toxic metals such as lead (Pb) and mercury (Hg) is widespread in the US and worldwide; and, individually, was found to be obesogenic in children. To address the literature gaps on the health effects of co-exposure to low-level toxic metals and the lack of intervention strategy, we aimed to investigate the association between in-utero co-exposure to Hg, Pb, cadmium (Cd) and childhood overweight or obesity (OWO) and whether adequate maternal micronutrients (selenium (Se) and folate) can be protective. SUBJECTS/METHODS: This study included 1442 mother-child pairs from the Boston Birth Cohort, a predominantly urban, low-income, Black, and Hispanic population, who were enrolled at birth and followed prospectively up to age 15 years. Bayesian kernel machine regression (BKMR) was applied to estimate individual and joint effects of exposures to metals and micronutrients on childhood OWO while adjusting for pertinent covariables. Stratified analyses by maternal OWO and micronutrient status were performed to identify sensitive subgroups. RESULTS: In this sample of understudied US children, low-level in-utero co-exposure to Hg, Pb, and Cd was widespread. Besides individual positive associations of maternal Hg and Pb exposure with offspring OWO, BKMR clearly indicated a positive dose-response association between in-utero co-exposure to the three toxic metals and childhood OWO. Notably, the metal mixture-OWO association was more pronounced in children born to mothers with OWO; and in such a setting, the association was greatly attenuated if mothers had higher Se and folate levels. CONCLUSIONS: In this prospective cohort of US children at high-risk of toxic metal exposure and OWO, we demonstrated that among children born to mothers with OWO, low-level in-utero co-exposure to Hg, Pb, and Cd increased the risk of childhood OWO; and that adequate maternal Se and folate levels mitigated the risk of childhood OWO. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE WHERE IT WAS OBTAINED: NCT03228875.

Log-transformation of Independent Variables: Must We?

Epidemiologic studies often quantify exposure using biomarkers, which commonly have statistically skewed distributions. Although normality assumption is not required if the biomarker is used as an independent variable in linear regression, it has become common practice to log-transform the biomarker concentrations. This transformation can be motivated by concerns for nonlinear dose-response relationship or outliers; however, such transformation may not always reduce bias. In this study, we evaluated the validity of motivations underlying the decision to log-transform an independent variable using simulations, considering eight scenarios that can give rise to skewed X and normal Y. Our simulation study demonstrates that (1) if the skewness of exposure did not arise from a biasing factor (e.g., measurement error), the analytic approach with the best overall model fit best reflected the underlying outcome generating methods and was least biased, regardless of the skewness of X and (2) all estimates were biased if the skewness of exposure was a consequence of a biasing factor. We additionally illustrate a process to determine whether the transformation of an independent variable is needed using NHANES. Our study and suggestion to divorce the shape of the exposure distribution from the decision to log-transform it may aid researchers in planning for analysis using biomarkers or other skewed independent variables.

Combining Urinary Biomarker Data From Studies With Different Measures of Urinary Dilution.

BACKGROUND: Guidance is lacking for how to combine urinary biomarker data across studies that use different measures of urinary dilution, that is, creatinine or specific gravity. METHODS: Among 741 pregnant participants from four sites of The Infant Development and Environment Study (TIDES) cohort, we assessed the relation of maternal urinary di-2-ethylhexyl phthalate (DEHP) concentrations with preterm birth. We compared scenarios in which all sites measured either urinary creatinine or specific gravity, or where measure of dilution differed by site. In addition to a scenario with no dilution adjustment, we applied and compared three dilution-adjustment approaches: a standard regression-based approach for creatinine, a standard approach for specific gravity (Boeniger method), and a more recently developed approach that has been applied to both (covariate-adjusted standardization method). For each scenario and dilution-adjustment method, we estimated the association between a doubling in the molar sum of DEHP (∑DEHP) and odds of preterm birth using logistic regression. RESULTS: All dilution-adjustment approaches yielded comparable associations (odds ratio [OR]) that were larger in magnitude than when we did not perform dilution adjustment. A doubling of ∑DEHP was associated with 9% greater odds of preterm birth (OR = 1.09, 95% confidence interval [CI] = 0.91, 1.30) when applying no dilution-adjustment method, whereas dilution-adjusted point estimates were higher, and similar across all scenarios and methods: 1.13-1.20 (regression-based), 1.15-1.18 (Boeniger), and 1.14-1.21 (covariate-adjusted standardization). CONCLUSIONS: In our applied example, we demonstrate that it is possible and straightforward to combine urinary biomarker data across studies when measures of dilution differ.

SPR Perspectives: scientific opportunities in the Environmental influences on Child Health Outcomes Program.

Drawing upon extant data from existing pediatric cohorts and new follow-up of a diverse set of pediatric cohorts from across the United States, the Environmental influences on Child Health Outcomes (ECHO) Program creates the opportunity for novel and innovative investigations of many previously inaccessible scientific questions in the area of child health. We describe how the large sample size, diversity of participants, emphasis on team science, and infrastructure for improving research methodology make the ECHO Program a major research resource for improving our understanding of early life determinants of childhood health and well-being. Pediatric researchers leverage the unique features of the ECHO Program to address research questions with the potential to yield far-reaching and long-term impacts on child health. IMPACT: The ECHO Program unites pediatric cohorts from across the United States, allowing for investigations of compelling research questions that were previously infeasible due to limited sample sizes or lack of participant diversity. The focus of the ECHO Program on team science, solution-oriented research, and methodological innovation propels novel scientific investigations that are responsive to the needs of a wide range of stakeholders. Features of the ECHO program's infrastructure poise its investigators to rapidly launch research endeavors that are responsive to time-sensitive and critical needs within the realm of pediatric research.

Exposure to Contemporary and Emerging Chemicals in Commerce among Pregnant Women in the United States: The Environmental influences on Child Health Outcome (ECHO) Program.

Prenatal chemical exposures can influence maternal and child health; however, few industrial chemicals are routinely biomonitored. We assessed an extensive panel of contemporary and emerging chemicals in 171 pregnant women across the United States (U.S.) and Puerto Rico in the Environmental influences on Child Health Outcomes (ECHO) Program. We simultaneously measured urinary concentrations of 89 analytes (103 total chemicals representing 73 parent compounds) in nine chemical groups: bactericides, benzophenones, bisphenols, fungicides and herbicides, insecticides, organophosphate esters (OPEs), parabens, phthalates/alternative plasticizers, and polycyclic aromatic hydrocarbons (PAHs). We estimated associations of creatinine-adjusted concentrations with sociodemographic and specimen characteristics. Among our diverse prenatal population (60% non-Hispanic Black or Hispanic), we detected 73 of 89 analytes in ≥1 participant and 36 in >50% of participants. Five analytes not currently included in the U.S. biomonitoring were detected in ≥90% of samples: benzophenone-1, thiamethoxam, mono-2-(propyl-6-carboxy-hexyl) phthalate, monocarboxy isooctyl phthalate, and monohydroxy-iso-decyl phthalate. Many analyte concentrations were higher among women of Hispanic ethnicity compared to those of non-Hispanic White women. Concentrations of certain chemicals decreased with the calendar year, whereas concentrations of their replacements increased. Our largest study to date identified widespread exposures to prevalent and understudied chemicals in a diverse sample of pregnant women in the U.S.

Variability and predictors of urinary organophosphate ester concentrations among school-aged children.

Organophosphate esters (OPE) are flame retardants and plasticizers used in a wide range of consumer products. Despite their widespread use, few studies have characterized pediatric exposures. We assessed variability and predictors of OPE exposures in a cohort panel study of 179 predominantly Black school-aged children with asthma in Baltimore City, MD. The study design included up to four seasonal week-long in-home study visits with urine sample collection on days 4 and 7 of each visit (nsamples = 618). We quantified concentrations of 9 urinary OPE biomarkers: bis(2-chloroethyl) phosphate (BCEtp), bis(1-chloro-2-propyl) phosphate, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), di-benzyl phosphate (DBuP), di-benzyl phosphate, di-o-cresylphosphate, di-p-cresylphosphate (DPCP), di-(2-propylheptyl) phthalate (DPHP), 2,3,4,5-tetrabromo benzoic acid. We assessed potential predictors of exposure, including demographic factors, household characteristics, and cleaning behaviors. We calculated Spearman/tetrachoric correlations and intraclass correlation coefficients (ICCs) to examine within-week and seasonal intra-individual variability, respectively. We assessed OPE predictors using linear models for continuous log2 concentrations (BDCPP and DPHP) and logistic models for odds of detection (BCEtP, DBuP, DPCP), with generalized estimating equations to account for repeated measures. For all OPEs, we observed moderate within-week correlations (rs: 0.31-0.63) and weak to moderate seasonal reliability (ICC: 0.18-0.38). BDCPP and DPHP concentrations were higher in the summer compared to other seasons. DPHP concentrations were lower among males than females (%diff: -53.5%; 95% CI: -62.7, -42.0) and among participants spending >12 h/day indoors compared to ≤12 h (%diff: -20.7%; 95% CI: -32.2, -7.3). BDCPP concentrations were lower among children aged 8-10 years compared to 5-7 years (%diff: -39.1%; 95% CI: -55.9, -15.9) and higher among children riding in a vehicle on the day of sample collection compared to those who had not (%diff: 28.5%; 95% CI: 3.4, 59.8). This study is the first to characterize within-week and seasonal variability and identify predictors of OPE biomarkers among Black school-aged children, a historically understudied population.

Gestational and childhood phthalate exposures and adolescent body composition: The HOME study.

BACKGROUND: Early life phthalate exposures may disrupt metabolism but results from human studies are inconsistent and few have examined body composition during adolescence. We investigated associations of gestational and childhood urinary phthalate biomarker concentrations with body composition at age 12 years. METHODS: We used data from 206 mother-child pairs in a prospective pregnancy and birth cohort enrolled in Cincinnati, OH from 2003 to 2006. We measured nine phthalate metabolites in spot urine samples collected twice from mothers during pregnancy and up to seven times from children at 1, 2, 3, 4, 5, 8, and 12 years. At age 12 years, we assessed fat and lean mass of the whole body and android and gynoid subregions, and visceral fat area with dual x-ray absorptiometry, and calculated android to gynoid %fat ratio and age- and sex-standardized fat and lean mass index z-scores. Using a multiple informant model, we estimated covariate-adjusted associations between urinary phthalate biomarker concentrations at each time period and outcomes at age 12 years. We assessed effect measure modification by child sex using stratified models. RESULTS: Generally, urinary mono-benzyl phthalate (MBzP) concentrations were modestly associated with lower fat and lean mass. Each 10-fold increase in urinary MBzP concentrations during gestation and at ages 5 and 8 years was associated with a -0.34 (95%CI: -0.72, 0.05), -0.44 (95% CI: -0.83, -0.05), and -0.35 (95% CI: -0.71, 0.00) z-score difference in lean body mass index, respectively. Urinary monoethyl phthalate, mono-(3-carboxypropyl) phthalate, and summed di(2-ethylhexyl) phthalate metabolites were associated with greater lean mass at some exposure periods. Slightly weaker but similar patterns of association were found with other body composition measures; associations did not differ by child sex. CONCLUSION: While most associations were weak, exposure to certain phthalates during gestation and childhood may be associated with adolescent body composition, particularly lean mass.

Physical activity modifies the relation between gestational perfluorooctanoic acid exposure and adolescent cardiometabolic risk.

OBJECTIVE: Exposure to per- and polyfluoroalkyl substances (PFAS) - endocrine disrupting chemicals - may increase cardiometabolic risk. We evaluated whether adolescent lifestyle factors modified associations between gestational PFAS exposure and cardiometabolic risk using a prospective cohort study. METHODS: In 166 mother-child pairs (HOME Study), we measured concentrations of four PFAS in maternal serum collected during pregnancy. When children were age 12 years, we calculated cardiometabolic risk scores from visceral adiposity area, blood pressure, and fasting serum biomarkers. We assessed adolescent physical activity and Healthy Eating Index scores using the Physical Activity Questionnaire for Older Children (PAQ-C), actigraphy, and 24-h diet recalls. Using multivariable linear regression and weighted quantile sum regression, we examined whether physical activity or diet modified covariate-adjusted associations of PFAS and their mixture with cardiometabolic risk scores. RESULTS: Physical activity modified associations between perfluorooctanoic acid (PFOA) and cardiometabolic risk scores. Each doubling of PFOA was associated with worse cardiometabolic risk scores among children with PAQ-C scores < median (ß:1.4; 95% CI:0.5, 2.2, n = 82), but not among those with PAQ-C scores ≥ median (ß: 0.2; 95% CI: 1.2, 0.7, n = 84) (interaction p-value = 0.01). Associations were most prominent for insulin resistance, leptin-adiponectin ratio, and visceral fat area. We observed results suggesting that physical activity modified the association of PFAS mixture with cardiometabolic risk scores, insulin resistance, and visceral fat area (interaction p-values = 0.17, 0.07, and 0.10, respectively); however, the 95% CIs of the interaction terms included the null value. We observed similar, but attenuated patterns for PFOA and actigraphy-based measures of physical activity. Diet did not modify any associations. Physical activity or diet did not modify associations for other PFAS. CONCLUSIONS: Childhood physical activity modified associations of prenatal serum PFOA concentrations with children's cardiometabolic risk in this cohort, indicating that lifestyle interventions may ameliorate the adverse effects of PFOA exposure.