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Abstract Background Cardiometabolic risk factors among youth are rising. Epigenetic age acceleration, a biomarker for aging and disease-risk, has been associated with adiposity in children, but its association with other cardiometabolic risk markers remains understudied. We employed data from the Health Outcomes and Measures of the Environment (HOME) study, a prospective pregnancy and birth cohort in the greater Cincinnati metropolitan area, to examine whether accelerated epigenetic age at birth as well as accelerated epigenetic age and faster pace of biological aging at age 12 years were associated with higher cardiometabolic risk in adolescents. Results After adjusting for potential confounders, including estimated cell type proportions, epigenetic gestational age acceleration at birth, derived from the Bohlin, Knight, and Haftorn clocks using cord blood DNA methylation data, was not associated with cardiometabolic risk z-scores or individual cardiometabolic risk score components (visceral fat, leptin to adiponectin ratio, HOMA-IR, triglycerides to HDL-C ratio, HbA1c, or systolic blood pressure) at age 12 years. We also did not observe any associations of epigenetic age acceleration, calculated with Horvath’s skin and blood, Hannum’s, and Wu’s epigenetic clocks using peripheral blood at age 12 years, with these same cardiometabolic risk markers. In contrast, faster pace of biological aging was associated with higher cardiometabolic risk [βs (95% CIs)] cardiometabolic risk score 0.25 (0.07, 0.42); visceral fat 0.21 (0.05, 0.38); and hemoglobin A1c 0.23 (0.05, 0.41) per standard deviation increase in pace of biological aging. Faster pace of biological aging was also positively associated with systolic blood pressure, triglycerides to HDL-C ratio, HOMA-IR, and leptin to adiponectin ratio, although these associations were not statistically significant. Conclusions Our findings provide evidence that faster pace of biological aging was associated with higher cardiometabolic risk score, visceral fat, and HbA1c at age 12 years. Further research is needed to determine whether these associations persist from adolescence through adulthood.

Abstract Background A major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations. Methods Data from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight

Abstract Background Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships. Methods We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes – six organochlorine compounds (OCs) and five metals – that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. Results Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (β = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (β = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (β = 23 g; 95% CI: -25, 71) compared to those with higher educational status (β = -9 g; 95% CI: -24, 6). Conclusions Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

Abstract Background Exposure to environmental chemicals such as phthalates, phenols, and polycyclic aromatic hydrocarbons (PAHs) during pregnancy can increase the risk of adverse newborn outcomes. We explored the associations between maternal exposure to select environmental chemicals and DNA methylation in cord blood mononuclear cells (CBMC) and placental tissue (maternal and fetal sides) to identify potential mechanisms underlying these associations. Method This study included 75 pregnant individuals who planned to give birth at the University of Cincinnati Hospital between 2014 and 2017. Maternal urine samples during the delivery visit were collected and analyzed for 37 biomarkers of phenols (12), phthalates (13), phthalate replacements (4), and PAHs (8). Cord blood and placenta tissue (maternal and fetal sides) were also collected to measure the DNA methylation intensities using the Infinium HumanMethylation450K BeadChip. We used linear regression, adjusting for potential confounders, to assess CpG-specific methylation changes in CBMC (n = 54) and placenta [fetal (n = 67) and maternal (n = 68) sides] associated with gestational chemical exposures (29 of 37 biomarkers measured in this study). To account for multiple testing, we used a false discovery rate q-values

Abstract 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 (β: 0.23; 95% CI: 0.08, 0.38) and lower satiety responsiveness (β: -0.14; 95% CI: -0.26, -0.02); in males, prenatal and postnatal cotinine was related to lower food responsiveness (prenatal: β: -0.25; 95% CI: -0.04, -0.06; postnatal: β: -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.

Few studies have considered household interventions for reducing endocrine disrupting chemical (EDC) exposures. We conducted a secondary analysis of a randomized controlled trial, originally designed to reduce lead exposure, to evaluate if the intervention lowered EDC exposures in young children. Study participants were children from the Cincinnati, Ohio area (n = 250, HOME Study). Prenatally, families received a housing intervention that included paint stabilization and dust mitigation, or as a control, injury prevention measures. At 24-months, we measured organophosphate esters (OPEs) and phthalates or their metabolites in dust and urine. We measured perfluoroalkyl substances (PFAS) in dust and serum at 24- and 36-months, respectively. We assessed associations between dust and biomarker EDCs using Spearman correlations, characterized EDC mixtures via principal components analysis, and investigated treatment effects using linear regression. To mitigate selection bias, we fit statistical models using inverse probability of retention weights. Correlations between dust EDCs and analogous biomarkers were weak-to-moderate (ρ’s ≤ 0.3). The intervention was associated with 23 % (95 % CI: −38, −3) lower urinary DEHP metabolites and, in a per-protocol analysis, 34 % lower (95 % CI: −55, −2) urinary MBZP. Additionally, among Black or African American children, the intervention was associated with lower serum concentrations of several PFAS (e.g., −42 %; 95 % CI: −63, −8 for PFNA). Household interventions that include paint stabilization and dust mitigation may reduce childhood exposures to some phthalates and PFAS in Blacks/African Americans. These findings highlight the need for larger studies with tailored and sustained housing interventions.

Introduction: The factors and patterns associated with antibiotic consumption in infants are unclear. Our aim was to assess the cumulative incidence of antibiotic consumption from birth to 16 months and identify factors associated with antibiotic consumption among infants aged 4–16 months. Material and methods: We conducted a cross-sectional study in 2016 in a sample of 18 882 women from Galicia, Spain, who had given birth to a live child between September 1, 2015 and August 31, 2016. We calculated the cumulative incidence of antibiotic consumption based on maternal reports regarding the infant’s consumption from birth to 14 months obtained through interviews; we did not estimate consumption at ages 15 and 16 months due to the small sample size. To assess which factors were associated with antibiotic consumption, we carried out a nested case-control study matching cases and controls for birth month on a 1:1 ratio. Results: The cumulative incidence of antibiotic consumption among infants aged 0–14 months increased from 7.5% to 66.0%. The case-control study included data for 1852 cases and 1852 controls. Daycare attendance (OR: 3.8 [95% CI: 3.2–4.6]), having older siblings (OR: 1.8 [95% CI: 1.6–2.1]), health care visits to private clinics (OR: 1.6 [95% CI: 1.4–2.0]), and passive smoking (OR: 1.3 [95% CI: 1.1–1.6]) were associated with an increased probability of antibiotic consumption. Maternal age between 30–39 years or 40 years and over at the time of birth was associated with a decreased probability of antibiotic consumption (OR: 0.8 [95% CI, 0.7–1.0] and OR: 0.6 [95% CI: 0.5–0.8], respectively). Conclusions: Some of the factors associated with antibiotic consumption in infants are modifiable and should be considered in the development of public health measures aimed at reducing antibiotic consumption. Resumen: Introducción: Los factores y patrones asociados al consumo de antibióticos en los lactantes no están claros. Nuestro objetivo fue evaluar la incidencia acumulada de consumo de antibióticos desde el nacimiento hasta los 16 meses e identificar los factores asociados al consumo de antibióticos entre lactantes de 4 a 16 meses. Material y métodos: Se realizó un estudio transversal en 2016 que incluyó una muestra de la población de 18.882 mujeres españolas de Galicia que habían dado a luz a un niño vivo entre el 1 de septiembre de 2015 y el 31 de agosto de 2016. Se calculó la incidencia acumulada de consumo de antibióticos a partir de los resultados de la entrevista a la madre sobre el consumo del lactante desde el nacimiento hasta los 14 meses; no se estimó a los 15 y 16 meses debido al reducido tamaño muestral. Para valorar las características asociadas al consumo de antibióticos se anidó en el estudio transversal un estudio de casos y controles emparejando por mes de nacimiento, un control por caso. Resultados: La incidencia acumulada de consumo de antibióticos entre los lactantes de 0 a 14 meses de edad aumentó del 7,5% al 66,0%. Para el estudio de casos y controles, se obtuvo información de 1.852 casos y de 1.852 controles. La asistencia a la guardería (OR: 3,8 [IC 95%: 3,2–4,6]), tener hermanos/as mayores (OR: 1,8 [IC 95%: 1,6–2,1]), las consultas sanitarias en la clínica privada (OR: 1,6 [IC 95%:1,4–2,0]) o haber estado expuesto al humo ambiental de tabaco (OR: 1,3 [IC 95%: 1,1–1,6]) se asociaron con un mayor riesgo de consumo de antibióticos. Tener madres de entre 30 y 39 años o de 40 años y más en el momento del parto se asoció con un menor riesgo de consumo de antibióticos (OR: 0,8 [IC 95%: 0,7–1,0] y OR: 0,6 [IC 95%: 0,5–0,8], respectivamente). Conclusiones: Algunos de los factores asociados al consumo de antibióticos en los lactantes pueden ser modificables y deben ser considerados en el desarrollo de medidas de salud pública dirigidas a reducir el consumo de antibióticos.

Resumen: Introducción: Los factores y patrones asociados al consumo de antibióticos en los lactantes no están claros. Nuestro objetivo fue evaluar la incidencia acumulada de consumo de antibióticos desde el nacimiento hasta los 16 meses e identificar los factores asociados al consumo de antibióticos entre lactantes de 4 a 16 meses. Material y métodos: Se realizó un estudio transversal en 2016 que incluyó una muestra de la población de 18.882 mujeres españolas de Galicia que habían dado a luz a un niño vivo entre el 1 de septiembre de 2015 y el 31 de agosto de 2016. Se calculó la incidencia acumulada de consumo de antibióticos a partir de los resultados de la entrevista a la madre sobre el consumo del lactante desde el nacimiento hasta los 14 meses; no se estimó a los 15 y 16 meses debido al reducido tamaño muestral. Para valorar las características asociadas al consumo de antibióticos se anidó en el estudio transversal un estudio de casos y controles emparejando por mes de nacimiento, un control por caso. Resultados: La incidencia acumulada de consumo de antibióticos entre los lactantes de 0 a 14 meses de edad aumentó del 7,5% al 66,0%. Para el estudio de casos y controles, se obtuvo información de 1.852 casos y de 1.852 controles. La asistencia a la guardería (OR: 3,8 [IC 95%: 3,2-4,6]), tener hermanos/as mayores (OR: 1,8 [IC 95%: 1,6-2,1]), las consultas sanitarias en la clínica privada (OR: 1,6 [IC 95%:1,4-2,0]) o haber estado expuesto al humo ambiental de tabaco (OR: 1,3 [IC 95%: 1,1-1,6]) se asociaron con un mayor riesgo de consumo de antibióticos. Tener madres de entre 30 y 39 años o de 40 años y más en el momento del parto se asoció con un menor riesgo de consumo de antibióticos (OR: 0,8 [IC 95%: 0,7-1,0] y OR: 0,6 [IC 95%: 0,5-0,8], respectivamente). Conclusiones: Algunos de los factores asociados al consumo de antibióticos en los lactantes pueden ser modificables y deben ser considerados en el desarrollo de medidas de salud pública dirigidas a reducir el consumo de antibióticos. Abstract: Introduction: The factors and patterns associated with antibiotic consumption in infants are unclear. Our aim was to assess the cumulative incidence of antibiotic consumption from birth to 16 months and identify factors associated with antibiotic consumption among infants aged 4 to 16 months. Material and methods: We conducted a cross-sectional study in 2016 in a sample of 18,882 women from Galicia, Spain, who had given birth to a live child between September 1, 2015 and August 31, 2016. We calculated the cumulative incidence of antibiotic consumption based on maternal reports regarding the infant's consumption from birth to 14 months obtained through interviews; we did not estimate consumption at ages 15 and 16 months due to the small sample size. To assess which factors were associated with antibiotic consumption, we carried out a nested case-control study matching cases and controls for birth month on a 1:1 ratio. Results: The cumulative incidence of antibiotic consumption among infants aged 0 to 14 months increased from 7.5% to 66.0%. The case-control study included data for 1,852 cases and 1,852 controls. Daycare attendance (OR: 3.8 [95% CI: 3.2-4.6]), having older siblings (OR: 1.8 [95% CI: 1.6-2.1]), health care visits to private clinics (OR: 1.6 [95% CI: 1.4-2.0]), and passive smoking (OR: 1.3 [95% CI: 1.1-1.6]) were associated with an increased probability of antibiotic consumption. Maternal age between 30-39 years or 40 years and over at the time of birth was associated with a decreased probability of antibiotic consumption (OR: 0.8 [95% CI, 0.7-1.0] and OR: 0.6 [95% CI: 0.5-0.8], respectively). Conclusions: Some of the factors associated with antibiotic consumption in infants are modifiable and should be considered in the development of public health measures aimed at reducing antibiotic consumption.

Background/Objectives: Pregnant women are exposed to numerous endocrine disrupting chemicals (EDCs) that can affect hormonal pathways regulating pregnancy outcomes and fetal development. Thus, we evaluated overall and fetal sex-specific associations of phthalate/replacement, paraben, and phenol biomarkers with sex-steroid and thyroid hormones. Methods: Illinois women (n = 302) provided plasma for progesterone, estradiol, testosterone, free T4 (FT4), total T4 (TT4), and thyroid stimulating hormone (TSH) at median 17 weeks gestation. Women also provided up-to-five first-morning urine samples monthly across pregnancy (8–40 weeks), which we pooled to measure 19 phthalate/replacement metabolites (reflecting ten parent compounds), three parabens, and six phenols. We used linear regression to evaluate overall and fetal sex-specific associations of biomarkers with hormones, as well as weighted quantile sum and Bayesian kernel machine regression (BKMR) to assess cumulative associations, non-linearities, and chemical interactions. Results: In women of relatively high socioeconomic status, several EDC biomarkers were associated with select hormones, without cumulative or non-linear associations with progesterone, FT4, or TT4. The biomarker mixture was negatively associated with estradiol (only at higher biomarker concentrations using BKMR), testosterone, and TSH, where each 10% mixture increase was associated with −5.65% (95% CI: −9.79, −1.28) lower testosterone and −0.09 μIU/mL (95% CI: −0.20, 0.00) lower TSH. Associations with progesterone, testosterone, and FT4 did not differ by fetal sex. However, in women carrying females, we identified an inverted u-shaped relationship of the mixture with estradiol. Additionally, in women carrying females, each 10% increase in the mixture was associated with 1.50% (95% CI: −0.15, 3.18) higher TT4, whereas in women carrying males, the mixture was associated with −1.77% (95% CI: −4.08, 0.58) lower TT4 and −0.18 μIU/mL (95% CI: −0.33, −0.03) lower TSH. We also identified select chemical interactions. Conclusion: Some biomarkers were associated with early-to-mid pregnancy hormones. There were some sex-specific and non-linear associations. Future studies could consider how these findings relate to pregnancy/birth outcomes.

Background: Epidemiologic studies on health effects of parental preconception exposures are limited despite emerging evidence from toxicological studies suggesting that such exposures, including to environmental chemicals, may affect offspring health. Objective: We investigated whether maternal and paternal preconception and maternal pregnancy urinary phthalate metabolite and bisphenol A (BPA) concentrations were associated with child behavior. Methods: We analyzed data from the Preconception Environmental exposure And Childhood health Effects (PEACE) Study, an ongoing prospective cohort study of children aged 6–11 years whose parent(s) previously enrolled in the prospective preconception Environment and Reproductive Health (EARTH) study. Using linear mixed models, we estimated covariate-adjusted associations of 11 urinary phthalate metabolite and BPA concentrations collected prior to conception and during pregnancy with Behavioral Assessment System for Children-3 (BASC-3) T-scores (higher scores indicate more problem behaviors). Results: This analysis included 134 mothers, 87 fathers and 157 children (24 sets of twins); parents were predominantly non-Hispanic white (mothers and fathers86%). Higher maternal preconception or pregnancy monobenzyl phthalate (MBzP) concentrations were related to higher mean externalizing problems T-scores in their children (β = 1.3 per 1-loge unit increase; 95 % CI: −0.2, 2.4 and β = 2.1, 95 % CI: 0.7, 3.6, respectively). Higher maternal preconception monocarboxyoctyl phthalate (MCOP) was suggested to be related to lower mean externalizing problems T-scores (β = -0.9; 95 % CI: −1.8, 0.0). Higher paternal preconception MCOP was suggestively associated with lower internalizing problems (β = -0.9; 95 %CI:-1.9, 0.1) and lower Behavioral Symptoms Index (BSI) T-scores (β = -1.3; 95 % CI: −2.1, −0.4). Conclusion: In this cohort, higher maternal preconception and pregnancy MBzP were associated with worse parent-reported child behavior, while higher maternal and paternal preconception MCOP concentrations were related to lower BASC-3 scores.

The understanding of the impact of prenatal exposure to metal mixtures on birth weight is limited. We aimed to identify metal mixture components associated with birth weight and to determine additional pairwise interactions between metals showing such associations. Concentrations of 18 metals were measured using inductively coupled plasma mass spectrometry in urine samples collected in the 3rd trimester from a prenatal cohort (discovery; n = 1849) and the Healthy Baby Cohort (replication; n = 7255) in Wuhan, China. In the discovery set, we used two penalized regression models, i.e., elastic net regression for main effects and a lasso for hierarchical interactions, to identify important mixture components associated with birth weight, which were then replicated. We observed that 8 of the 18 measured metals were retained by elastic net regression, with five metals (vanadium, manganese, iron, cesium, and barium) showing negative associations with Z-scores for birth weight and three metals (cobalt, zinc, and strontium) showing positive associations. In replication set, associations remained significant for vanadium (β = −0.035; 95% confidence interval [CI], −0.059 to −0.010), cobalt (β = 0.073; 95% CI, 0.049 to 0.097), and zinc (β = 0.040; 95% CI, 0.016 to 0.065) after Bonferroni correction. We additionally identified and replicated a single pairwise interaction between iron and copper exposure on birth weight (P

Abstract Background Between 1962 and 1971, the US Air Force sprayed Agent Orange across Vietnam, exposing many soldiers to this dioxin-containing herbicide. Several negative health outcomes have been linked to Agent Orange exposure, but data is lacking on the effects this chemical has on the genome. Therefore, we sought to characterize the impact of Agent Orange exposure on DNA methylation in the whole blood and adipose tissue of veterans enrolled in the Air Force Health Study (AFHS). Methods We received adipose tissue (n = 37) and whole blood (n = 42) from veterans in the AFHS. Study participants were grouped as having low, moderate, or high TCDD body burden based on their previously measured serum levels of dioxin. DNA methylation was assessed using the Illumina 450 K platform. Results Epigenome-wide analysis indicated that there were no FDR-significantly methylated CpGs in either tissue with TCDD burden. However, 3 CpGs in the adipose tissue (contained within SLC9A3, LYNX1, and TNRC18) were marginally significantly (q

The associations between urinary phenol concentrations and markers of thyroid function and autoimmunity among potentially susceptible subgroups, such as subfertile women, have been understudied, especially when considering chemical mixtures. We evaluated cross-sectional associations of urinary phenol concentrations, individually and as a mixture, with serum markers of thyroid function and autoimmunity. We included 339 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2009–2015). We quantified four phenols in urine using isotope dilution high-performance liquid chromatography–tandem mass spectrometry, and biomarkers of thyroid function (thyroid-stimulating hormone (TSH), free and total thyroxine (fT4, TT4), and triiodothyronine (fT3, TT3)), and autoimmunity (thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies (Ab)) in serum using electrochemoluminescence assays. We fit linear and additive models to investigate the association between urinary phenols—both individually and as a mixture—and serum thyroid function and autoimmunity, adjusted for confounders. As a sensitivity analysis, we also applied Bayesian Kernel Machine Regression (BKMR) to investigate non-linear and non-additive interactions. Urinary bisphenol A was associated with thyroid function, in particular, fT3 (mean difference for a 1 log unit increase in concentration: −0.088; 95% CI [−0.151, −0.025]) and TT3 (−0.066; 95% CI [−0.112, −0.020]). Urinary methylparaben and triclosan were also associated with several thyroid hormones. The overall mixture was negatively associated with serum fT3 concentrations (mean difference comparing all four mixture components at their 75th vs. 25th percentiles: −0.19, 95% CI [−0.35, −0.03]). We found no evidence of non-linearity or interactions. These results add to the current literature on phenol exposures and thyroid function in women, suggesting that some phenols may alter the thyroid system.

Background/objectives: Pregnant women are exposed to multiple phthalates and their replacements, which are endocrine disrupting chemicals associated with adverse maternal and child health outcomes. Identifying maternal characteristics associated with phthalate/replacement exposure during pregnancy is important. Methods: We evaluated 13 maternal sociodemographic and lifestyle factors, enrollment year, and conception season as determinants of exposure biomarkers of phthalates and their replacements in 482 pregnant women from the Illinois Kids Development Study (I-KIDS, enrolled 2013–2018). We quantified 19 phthalate/replacement metabolites in pools of five first-morning urines collected across pregnancy. K-means clustering identified women with distinct patterns of biomarker concentrations and principal component analysis (PCA) identified principal component (PC) profiles of biomarkers that exist together. We used multivariable regression models to evaluate associations of predictors with identified k-means clusters and PCs. Results: K-means clustering identified two clusters of women: 1) low phthalate/di(2-ethylhexyl) terephthalate (∑DEHTP) and 2) high phthalate/∑DEHTP biomarker concentrations. PCA identified four PCs with loadings heaviest for biomarkers of plasticizer phthalates [di-isononyl, di-isodecyl, di-n-octyl phthalates] (PC1), of other phthalates [dibenzyl, di-n-butyl, di-iso-butyl phthalates] (PC2), of phthalate replacements [∑DEHTP, di(isononyl) cyclohexane-1,2-dicarboxylate (∑DiNCH)] (PC3), and of monoethyl phthalate [MEP] (PC4). Overall, age, marital status, income, parity, pre-pregnancy BMI, caffeine intake, enrollment year, and conception season were independently associated with k-means cluster membership and at least one PC. Additionally, race/ethnicity, education, employment, pregnancy intention, smoking status, alcohol intake, and diet were associated with at least one PC. For instance, women who conceived in the spring, summer, and/or fall months had lower odds of high phthalate/∑DEHTP cluster membership and had lower plasticizer phthalate, phthalate replacement, and MEP PC scores. Conclusions: Conception season, enrollment year, and several sociodemographic/lifestyle factors were predictive of phthalate/replacement biomarker profiles. Future studies should corroborate these findings, with a special focus on replacements to which pregnant women are becoming increasingly exposed.

Abstract Background Organophosphate esters (OPEs)—used as flame retardants and plasticizers—are associated with adverse pregnancy outcomes such as reduced fecundity and live births and increased preterm delivery. OPEs may interfere with growth and metabolism via endocrine-disruption, but few studies have investigated endocrine-related outcomes. The objective of this pilot study (n = 56 mother-infant pairs) was to evaluate associations of OPEs with gestational weight gain (GWG), gestational age at delivery, infant anthropometry, and infant feeding behaviors. Methods We quantified OPE metabolites (bis-2-chloroethyl phosphate [BCEP], bis (1,3-dichloro-2-propyl) phosphate [BDCPP], diphenyl phosphate [DPHP]) in pooled maternal spot urine collected throughout pregnancy (~ 12, 28, and 35 weeks’ gestation). We obtained maternal sociodemographic characteristics from questionnaires administered at enrollment and perinatal characteristics from medical record abstraction. Trained research assistants measured infant weight, length, head and abdominal circumferences, and skinfold thicknesses at birth and 6 weeks postpartum. Mothers reported infant feeding behavior via the Baby Eating Behavior Questionnaire (BEBQ). Using multiple linear regression, we assessed associations of log2-transformed maternal urinary OPE metabolites with GWG, gestational age at delivery, infant anthropometry at birth, weekly growth rate, and BEBQ scores at 6 weeks postpartum. We used linear mixed effects (LME) models to analyze overall infant anthropometry during the first 6 weeks of life. Additionally, we considered effect modification by infant sex. Results We observed weak positive associations between all OPE metabolites and GWG. In LME models, BDCPP was associated with increased infant length (β = 0.44 cm, 95%CI = 0.01, 0.87) and weight in males (β = 0.14 kg, 95%CI = 0.03, 0.24). BDCPP was also associated with increased food responsiveness (β = 0.23, 95%CI = 0.06, 0.40). DPHP was inversely associated with infant abdominal circumference (β = − 0.50 cm, 95%CI = − 0.86, − 0.14) and female weight (β = − 0.19 kg, 95%CI = − 0.36, − 0.02), but positively associated with weekly growth in iliac skinfold thickness (β = 0.10 mm/wk., 95%CI = 0.02, 0.19). Further, DPHP was weakly associated with increased feeding speed. BCEP was associated with greater infant thigh skinfold thickness (β = 0.34 mm, 95%CI = 0.16, 0.52) and subscapular skinfold thickness in males (β = 0.14 mm, 95%CI = 0.002, 0.28). Conclusions Collectively, these findings suggest that select OPEs may affect infant anthropometry and feeding behavior, with the most compelling evidence for BDCPP and DPHP.

Background: Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants used as flame retardants. Gestational PBDE exposure has been associated with a variety of behavior problems in children, but little is known about its impact into adolescence, particularly on social skills, which are important for achieving social competence, establishing identity, and forming lasting relationships. Objective: We investigated associations between gestational exposure to PBDEs and social skills and problem behaviors in early adolescence in a longitudinal pregnancy and birth cohort in Cincinnati, Ohio (recruited 2003–2006). Methods: We measured maternal serum concentrations of five PBDE congeners during gestation. At age 12, we measured social skills and problem behaviors scores for 243 adolescents using self- and caregiver-report on the Social Skills Improvement System (SSiS). We used multivariable linear regression models to estimate associations between maternal PBDE concentrations and SSiS scores, controlling for potential covariates. We report associations for the five congeners and a summary exposure variable (∑5BDE: the sum of BDE- 28, 47, 99, 100, and 153, n = 197). Results: We found sex-specific associations of ∑5BDE concentrations with adolescent-reported Problem Behaviors (∑5BDE × sex pint = 0.02) and caregiver-reported Social Skills (∑5BDE × sex pint = 0.02). In sex-stratified models, log10 transformed data revealed increased maternal ∑5BDE concentration among males was associated with decreased caregiver-reported Social Skills composite score (β = -10.2, 95% CI: −19.5, −1.0), increased adolescent-reported Problem Behaviors composite score (β = 12.1, 95% CI: 5.4, 18.8), and increased caregiver-reported Problem Behaviors composite score (β = 6.2, 95% CI: 0.7, 11.7). Further analysis on SSiS subscales revealed similar patterns in significant associations among males. There were no statistically significant associations in stratified models among females despite higher ∑5BDE exposure (Female GM=40.15 ng/g lipid, GSE=1.10; Male GM=35.30 ng/g lipid, GSE=1.09). Discussion: We found gestational PBDE exposure in males was associated with poorer behavioral outcomes, extending previous findings among this cohort into early adolescence.

Milk formation in the breast during breastfeeding is a complex hormonally regulated process, potentially sensitive to the effects of endocrine-disrupting chemical exposures. The environmental chemicals, per- and polyfluoroalkyl substances (PFAS) are known endocrine disruptors. PFAS exposure have been associated with insufficient mammary gland development in mice and reduced breastfeeding duration in humans. The aim of this review was to gather the epidemiological evidence on the association between PFAS exposure and breastfeeding duration. Using PubMed and Embase, we performed a systematic literature search (on 23 January 2023) to identify epidemiological studies examining the association between maternal PFAS exposure and breastfeeding duration. Animal studies, reviews, and non-English studies were excluded. The risk of bias was assessed using the risk of bias in non-randomized studies of exposures tool. Estimates describing the association between PFAS exposure and the duration of breastfeeding were identified, and the data were synthesized separately for each type of PFAS and for the duration of exclusive and total breastfeeding. Six studies with between 336 and 2374 participants each were identified. PFAS exposure was assessed in serum samples (five studies) or based on residential address (one study). Five out of six studies found shorter total duration of breastfeeding with higher PFAS exposure. The most consistent associations were seen for perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA). The finding of a potential causal association between PFAS exposure and breastfeeding duration is in agreement with findings from experimental studies.

Background: Exposure to triclosan, an antimicrobial chemical used in some personal care and cleaning products, has been associated with reduced birth weight in some, but not all epidemiological studies. Objectives: We conducted a systematic review and meta-analysis to characterize the relation of gestational triclosan exposure with infant birth weight and identify sources of heterogeneity between studies. Methods: We identified original studies measuring urinary triclosan concentrations during pregnancy and reporting their association with infant birth weight, gestational age (GA) adjusted birth weight (g), or GA-standardized birth weight z-scores. Using a random effects model, we estimated differences in these outcomes per 10-fold increase in triclosan concentrations and considered triclosan levels and infant sex as sources of heterogeneity. Using Navigation Guide Methods, we evaluated risk of bias within individual studies and across the body of evidence. Results: Among thirteen studies, median triclosan concentrations varied by almost 2-orders of magnitude (0.6–29 ng/mL), with higher concentrations in North American and some European studies compared to Asian ones. Associations between triclosan and birth weight (β:-20 g; 95% CI:-65, 26; n = 6) were stronger than those for GA-adjusted birth weight (β:-12 g; 95% CI:-29, 5; n = 9). Triclosan was not associated with GA-standardized birth weight z-scores (β:-0.04; 95% CI:-0.16, 0.07; n = 5). The association between triclosan and GA-adjusted birth weight was stronger in studies with median triclosan values ≥10 ng/mL compared to studies with median values

Background: Toxicology studies have identified pregnancy as a window of susceptibility for endocrine disrupting chemicals (EDCs) and cardiometabolic indices in women. No study in humans, however, has examined EDC mixtures and cardiometabolic indices during pregnancy. Methods: We used the Health Outcomes and Measures of the Environment (HOME) Study to examine whether bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), per- and polyfluoroalkyl substances (PFAS), and phthalates are associated with blood pressure, glucose, and lipids in 388 pregnant women. We measured PBDEs and PFAS in serum at 16 weeks gestation, while BPA and phthalate metabolites were quantified in urine at 16 and 26 weeks gestation. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to estimate covariate-adjusted associations of individual EDCs and their mixtures with cardiometabolic indices during pregnancy. Results: A 10-fold increase in BDE-28 was associated with a 13.1 mg/dL increase in glucose (95% Confidence Interval [CI] 2.9, 23.2) in linear regression. The BKMR model also identified BDE-28 as having a positive association with glucose. BDE-28, BDE-47, and BDE-99 were positively associated with total cholesterol in both single- and multi-pollutant models, whereas a suggestive negative association was noted with BDE-153. Mono-n-butyl phthalate (MBP) (β = -7.9 mg/dL, 95% CI −12.9, −3.0) and monobenzyl phthalate (MBzP) (β = −6.3 mg/dL, 95% CI −10.6, −2.0) were both associated with significant decreases in cholesterol in linear regression, but only MBzP was identified as an important contributor in the BKMR model. Conclusion: Overall, we observed positive associations between PBDEs with glucose and cholesterol levels during pregnancy, while negative associations were found between some phthalate biomarkers and cholesterol. No relationship was noted for BPA or PFAS with cardiometabolic indices during pregnancy across both models.

Background: Pregnancy induces numerous cardiovascular and metabolic changes. Alterations in these sensitive processes may precipitate long-term post-delivery health consequences. Studies have reported associations between phthalates and metabolic complications of pregnancy, but no study has investigated metabolic outcomes beyond pregnancy. Objectives: To examine associations of exposure to phthalates during pregnancy with post-delivery metabolic health. Design: We quantified 15 urinary phthalate biomarker concentrations during the second and third trimesters among 618 pregnant women from Mexico City. Maternal metabolic health biomarkers included fasting blood measures of glycemia [glucose, insulin, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR], % hemoglobin A1c (HbA1c%)] and lipids (total, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, triglycerides), at 4–5 and 6–8 years post-delivery. To estimate the influence of the phthalates mixture, we used Bayesian weighted quantile sum regression and Bayesian kernel machine regression; for individual biomarkers, we used linear mixed models. Results: As a mixture, higher urinary phthalate biomarker concentrations during pregnancy were associated with post-delivery concentrations of plasma glucose (interquartile range [IQR] difference: 0.13 SD, 95%CrI: 0.05, 0.20), plasma insulin (IQR difference: 0.06 SD, 95%CrI: −0.02, 0.14), HOMA-IR (IQR difference: 0.08 SD, 95% CrI: 0.01, 0.16), and HbA1c% (IQR difference: 0.15 SD, 95%CrI: 0.05, 0.24). Associations were primarily driven by mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and the sum of dibutyl phthalate biomarkers (∑DBP). The phthalates mixture was associated with lower HDL (IQR difference: −0.08 SD, 95%CrI: −0.16, −0.01), driven by ∑DBP and monoethyl phthalate (MEP), and higher triglyceride levels (IQR difference: 0.15 SD, 95%CrI: 0.08, 0.22), driven by MECPTP and MEP. The overall mixture was not associated with total cholesterol and LDL. However, ∑DBP and MEP were associated with lower and higher total cholesterol, respectively, and MECPTP and ∑DBP were associated with lower LDL. Conclusions: Phthalate exposure during pregnancy is associated with adverse long-term changes in maternal metabolic health. A better understanding of timing of the exact biological changes and their implications on metabolic disease risk is needed.

Background: Triclosan exposure may decrease circulating thyroxine levels or cause neuron apoptosis, which in turn may adversely affect neurodevelopment. However, few studies have examined the association of early life triclosan exposure with child behavior. Objective: To quantify the association between early-life triclosan exposure and child behavior at age 8-years in 202 mother-child pairs from the HOME study (Cincinnati, OH; enrolled: 2003–2006). Methods: We quantified urinary triclosan concentrations up to 3 times in mothers (16-weeks, 26-weeks, and delivery) and up to 6 times in children (1, 2, 3, 4, 5, and 8 years). Parents rated children's problem behaviors at age 8-years using the Behavioral Assessment System for Children-2 (BASC-2). Adjusting for covariates and accounting for exposure measurement error, we estimated changes in behavior problem scores per 10-fold increase in mean gestational and childhood triclosan concentrations. In addition, we estimated sex-specific associations. Results: Child sex modified the association of gestational and childhood triclosan with several BASC-2 scales (sex × triclosan p-values

Background: Days of extreme temperature may be associated with transiently higher risk of preterm birth, but prior studies have been limited and results have been heterogeneous. Objectives: To evaluate the association between days of extreme heat and cold and risk of preterm birth among ~32 million live singleton births between 1989 and 2002 across 403 counties in the contiguous United States (US). Methods: We used a distributed lag nonlinear model to estimate the association between population-weighted daily mean temperature and risk of preterm birth in each county and then pooled results across geographic regions and climate zones. We defined extreme heat and cold as the 95th and 5th percentile of the county-specific temperatures, respectively. Results: Preterm birth accounted for 9.3% of deliveries. There was a monotonic association between ambient temperature and risk of preterm birth. Days of extreme heat and cold were associated with a relative risk of preterm birth of 1.025 (95% CI: 1.015, 1.036) and 0.985 (95% CI: 0.976, 0.993) over the subsequent four days, respectively, relative to the county-specific median temperature. If causal, the fraction of preterm births attributable to extreme heat was 0.17% (empirical 95% CI: 0.14%, 0.19%), corresponding to 154 (empirical 95% CI: 127, 173) preterm births per million births. Extreme heat was more strongly associated with preterm birth in regions with colder and drier climates, and among younger women. Days of extreme cold temperature were associated with lower rather than higher risk of preterm birth. Conclusions: Days of extreme heat, but not extreme cold, are associated with higher risk of preterm birth in the contiguous US. If causal, these results may have important implications for the management of pregnant women during forecasted periods of extreme heat. Keywords: Heat, Cold, Preterm birth, Birth cohort, United States

Background: Animal studies suggest polybrominated diphenyl ethers (PBDEs) may be obesogens. However, epidemiologic studies investigating childhood exposure to PBDEs and adiposity are limited, with several reporting an inverse association. Objectives: To investigate associations between repeated childhood PBDE concentrations and adiposity measures at age 8 years. Methods: We examined 206 children from the Health Outcomes and Measures of the Environment Study, a birth cohort in Cincinnati, OH (2003–2006). Serum PBDEs were measured at ages 1, 2, 3, 5, and 8 years. We used multiple imputation to estimate missing PBDE concentrations. At 8 years, we measured weight, height, waist circumference, and body fat percentage. We used multiple informant models to estimate age-specific associations between PBDEs and adiposity measures. Results: We observed significant inverse associations between BDE-153 with all adiposity measures that became increasingly stronger with later childhood measurements. A 10-fold increase in BDE-153 at ages 1 and 8 years was associated with 2% (95% CI −3.9, −0.1) and 7% (95% CI −9.1, −4.7) lower body fat, respectively. No statistically significant associations were found with BDE-28, -47, -99, or -100. Child sex modified some associations; inverse associations between BDE-153 and body fat were stronger among boys, while positive and null associations were noted among girls. Conclusions: Childhood BDE-153 concentrations were inversely associated with adiposity measures and these associations became stronger as BDE-153 measurements were more proximal to adiposity measures. Inverse associations could be attributed to reverse causality arising from greater storage of PBDEs in adipose tissue of children with higher adiposity. Keywords: Polybrominated diphenyl ethers (PBDEs), Flame retardants, Endocrine disruptors, Postnatal, Childhood, Weight, Adiposity, Body mass index, Children, Epidemiology

Background: Exposure to some environmental chemicals is ubiquitous and linked to a variety of adverse outcomes, including children's health. While few studies have assessed the contribution of both male and female exposures to children's health, understanding the patterns of couple's exposure is needed to understand their joint effects. Objective: We assessed the correlation patterns between male and female partners' concentrations of 37 environmental chemical biomarkers. We also assessed the temporal reliability of the biomarkers within couples. Methods: We calculated Spearman pairwise correlations between specific gravity adjusted urinary biomarker concentrations and hair mercury concentrations among 380 couples enrolled in the Environment and Reproductive Health (EARTH) study at the Massachusetts General Hospital Fertility Center (2004–2017). We calculated intra-class correlation coefficients (ICCs) for couple's biomarkers to assess the temporal variability of these exposures within a couple using multiple paired-samples from couples. Results: All biomarkers were positively correlated within couples (range: 0.05 for tert-butylphenyl phenyl phosphate to 0.66 for triclosan). In general, the biomarkers with the highest within couple correlation were those of chemicals for which diet (e.g., di(2-ethylhexyl) phthalate), personal care products use (e.g., triclosan, benzophenone-3), and the indoor environment (e.g., 2,5-dichlorophenol) are considered primary exposure sources. Most other biomarkers were moderately correlated (0.3–

Introduction: Exposure to the antimicrobial agent triclosan is ubiquitous. Research in animals shows that triclosan can cause decreases in thyroxine concentrations. However, the potential effects of triclosan on thyroid function in humans are unclear. Objective: To estimate the association between urinary triclosan concentrations and serum thyroid function biomarkers in women seeking assisted reproduction treatment in the Environment and Reproductive Health (EARTH) Study. Methods: We conducted a cross-sectional study of 317 women enrolled in the EARTH Study, a prospective preconception cohort that recruits Boston area couples. Using samples collected at study entry, we quantified urinary triclosan and serum thyroid function biomarker concentrations, specifically free and total thyroxine and triiodothyronine, thyroid-stimulating hormone (TSH), and thyroid antibodies. We estimated covariate-adjusted differences in thyroid function biomarkers per 10-fold increase in triclosan using linear regression models. We examined effect modification by body mass index (BMI) and infertility diagnosis. Results: The median urinary triclosan concentration was 7.8 μg/L (IQR: 3.0–59 μg/L). Each 10-fold increase in triclosan was inversely associated with free triidothyronine (T3) (β: −0.06 pg/mL; 95% CI: −0.1, −0.01), thyroperoxidase antibody (TPOAb) (−10%; 95% CI: −19, −0.4), and thyroglobulin antibody (TgAb) (−12%; 95% CI: −23,0.9) concentrations. BMI and infertility diagnosis modified the association of triclosan with free T3 and TPOAb, respectively. Conclusion: Urinary triclosan concentrations were inversely associated with specific serum thyroid function biomarkers in this cohort, suggesting that triclosan may affect thyroid homeostasis and autoimmunity. Keywords: Endocrine disrupting chemicals, Triclosan, Thyroid hormones, Women, Epidemiology

Background: Polybrominated diphenyl ethers (PBDEs) exist extensively in the environment and human beings. PBDE concentrations are higher in children than adults. A previous study found that prenatal PBDE exposure was associated with decreased reading skills in children; however, evidence is limited on the potential impact of childhood exposure to PBDEs. The study examined the association between childhood PBDE exposures and reading ability in children at ages 5 and 8 years. Methods: The study included 230 children from an ongoing prospective pregnancy and birth cohort study, the Health Outcomes and Measures of Environment (HOME) Study, conducted in Cincinnati, Ohio. Children's serum concentrations of eleven PBDE congeners were measured at 1, 2, 3, 5, and 8 years. The Woodcock-Johnson Tests of Achievement - III and the Wide Range Achievement Test - 4 were administered to assess children's reading skills at ages 5 and 8 years, respectively. We used multiple informant models to examine the associations between repeated measures of PBDEs and reading scores at ages 5 and 8 years. We also estimated the βs and 95% CIs of the association of PBDE measure at each age by including interaction terms between PBDE concentrations and child age in the models. Results: All childhood BDE-153 concentrations were inversely associated with reading scores at 5 and 8 years, but associations were not statistically significant after covariate adjustment. For example, a 10-fold increase in BDE-153 concentrations at ages 3 and 5 years was associated with a −5.0 (95% confidence interval (CI): −11.0, 1.0) and −5.5 (95% CI: −12.5, 1.4) point change in Basic Reading score at age 5 years, respectively. Similarly, the estimates for Brief Reading score at age 5 years were −4.5 (95% CI: −10.5, 1.5) and −5.2 (95% CI: −12.2, 1.7) point changes, respectively. Serum concentration of BDE-47, -99, -100, and Sum4PBDEs (sum of BDE-47, 99, 100, and 153) at every age were inversely associated with reading scores at ages 5 and 8 years in unadjusted analyses. While the adjusted estimates were much attenuated and became non-significant, the direction of most of the associations was not altered. Conclusion: Our study has shown a suggestive but non-significant trend of inverse associations between childhood PBDE serum concentrations, particularly BDE-153, and children's reading skills. Future studies with a larger sample size are needed to examine these associations. Keywords: Polybrominated diphenyl ethers, Childhood, Serum concentration, Reading ability

Background: Per- and polyfluoroalkyl substances (PFAS) may adversely influence cardiometabolic risk. However, few studies have examined if the timing of early life PFAS exposure modifies their relation to cardiometabolic risk. We examined the influence of gestational and childhood PFAS exposure on adolescents’ cardiometabolic risk. Methods: We quantified concentrations of four PFAS (perfluorooctanoate [PFOA], perfluorooctane sulfonate [PFOS], perfluorononanoate [PFNA], and perfluorohexane sulfonate [PFHxS]) in sera collected during pregnancy, at birth, and at ages 3, 8, and 12 years from 221 mother–child pairs in the HOME Study (enrolled 2003–06, Cincinnati, Ohio). We measured cardiometabolic risk factors using physical examinations, fasting serum biomarkers, and dual-energy X-ray absorptiometry scans at age 12 years. Cardiometabolic risk summary scores were calculated by summing age- and sex-standardized z-scores for individual cardiometabolic risk factors. We used multiple informant models to estimate covariate-adjusted associations of serum PFAS concentrations (log2-transformed) at each visit with cardiometabolic risk scores and their individual components, and tested for differences in associations across visits. Results: The associations of serum PFOA concentrations with cardiometabolic risk scores differed across visits (P for heterogeneity = 0.03). Gestational and cord serum PFOA concentrations were positively associated with cardiometabolic risk scores (βs and 95% confidence intervals [95% CIs]: gestational 0.8 [0.0, 1.6]; cord 0.9 [-0.1, 1.9] per interquartile range increase). These positive associations were primarily driven by homeostatic model assessment for insulin resistance index (β = 0.3 [0.1, 0.5]) and adiponectin to leptin ratio (β = -0.5 [-1.0, 0.0]). Other individual cardiometabolic risk factors associated with gestational PFOA included insulin and waist circumference. Gestational and cord PFHxS were also associated with higher cardiometabolic risk scores (βs: gestational 0.9 [0.2, 1.6]; cord 0.9 [0.1, 1.7]). Conclusion: In this cohort of children with higher gestational PFOA exposure, fetal exposure to PFOA and PFHxS was associated with unfavorable cardiometabolic risk in adolescence.

Background: Early-life phthalate exposures may adversely influence neurodevelopment by disrupting thyroid hormone homeostasis, altering brain lipid metabolism, or reducing gonadal hormone concentrations. Previous literature examining gestational phthalate exposure and child behavior were inconclusive and few prospective studies have examined childhood phthalate exposure, particularly phthalate mixtures. We investigated whether gestational and childhood phthalate exposures were associated with child behavior. Methods: We used data from 314 mother–child pairs in the HOME Study, a longitudinal pregnancy and birth cohort that enrolled pregnant women from Cincinnati, Ohio. We quantified urinary concentrations of 11 phthalate metabolites in samples collected twice during gestation from women and six times from their children when they were ages 1, 2, 3, 4, 5, and 8 years. We assessed children’s behavior at ages 2, 3, 4, 5, and 8 years using the Behavioral Assessment System for Children-2. Using linear mixed models, we estimated covariate-adjusted associations of measurement-error-corrected gestational and childhood phthalate metabolite concentrations (per interquartile range increase) with repeated child behavior assessments. We used Weighted Quantile Sum (WQS) regression to estimate the association of phthalate mixtures with child behavior. Results: Gestational mono(3-carboxypropyl) phthalate (MCPP) concentrations were associated with more problem behaviors (internalizing: β = 0.9, 95% confidence interval [CI] = -0.1, 1.9; externalizing: β = 1.0, 95%CI = -0.1, 2.0; behavioral symptoms index [BSI]: β = 1.1, 95%CI = 0.1, 2.1). Higher childhood monobenzyl phthalate (MBzP) (β = 1.4; 95%CI = 0.0, 2.7), monocarboxynonyl phthalate (MCNP) (β = 3.2; 95%CI = 1.6, 4.8), monocarboxyoctyl phthalate (MCOP) (β = 0.9; 95%CI = 0.0, 1.7), MCPP (β = 1.8; 95%CI = 0.2, 3.5), and monoethyl phthalate (MEP) (β = 1.6; 95%CI = 0.1, 3.1) concentrations were associated with higher BSI composite scores. Consistent with this, the weighted childhood phthalate index was associated with more problem behaviors (internalizing: β = 1.5, 95%CI = −0.2, 3.1; externalizing: β = 1.7, 95%CI = 0.1, 3.5; BSI: β = 1.7, 95%CI = 0.2, 3.2); MBzP, MCNP, and MEP largely contributed to these associations. Conclusion: Our findings suggest that childhood exposure to phthalate mixtures may be associated with children’s problem behaviors.

Background: Experimental studies in rodents suggest that polybrominated diphenyl ethers (PBDEs) and poly- and perfluoroalkyl substances (PFAS) may contribute to depressive symptoms. Few studies have examined the impact of these chemicals on depression in adults.Objective:To examine the associations between serum PBDE and PFAS concentrations during pregnancy and repeated measures of depressive symptoms in women assessed from pregnancy to 8 years postpartum.Methods:This study was based on 377 women from the Health Outcomes and Measures of the Environment Study, a birth cohort in Cincinnati, OH (USA). PBDEs (BDE-28, -47, -99, -100, -153, and ∑PBDEs) and PFAS (perfluorooctanoate [PFOA], perfluorooctane sulfonate [PFOS], perfluorohexane sulfonate [PFHxS], perfluorononanoate [PFNA]) were quantified in maternal serum at 16 ± 3 weeks gestation. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II) at ~20 weeks gestation and up to seven times during postpartum visits (4 weeks, 1, 2, 3, 4, 5, and 8 years). We used linear mixed models to estimate covariate-adjusted associations between chemical concentrations and repeated measures of BDI-II. Multinomial logistic regression models were used to estimate the relative risk ratios of having a medium or high depression trajectory.Results:We found that a 10-fold increase in BDE-28 at 16 ± 3 weeks gestation was associated with significantly increased BDI-II scores (β = 2.5 points, 95% confidence interval [CI] 0.8, 4.2) from pregnancy to 8 years postpartum. Significant positive associations were also observed with BDE-47, -100, -153, and ∑PBDEs. A 10-fold increase in ∑PBDEs was associated with a 4.6-fold increased risk (95% CI 1.8, 11.8) of a high trajectory for BDI-II compared to a low trajectory. We observed no significant associations between PFAS and BDI-II scores.Conclusion:PBDEs during pregnancy were associated with more depressive symptoms among women in this cohort.

Background: Phenol exposure during pregnancy has been associated with preterm birth, but the potential effect of preconception exposure in either parent is unknown. There is a growing body of evidence to suggest that the preconception period is a critical window of vulnerability for adverse pregnancy outcomes. Objective: We examined whether maternal and paternal preconception urinary concentrations of select phenols were associated with the risk of preterm birth among couples attending fertility care. Methods: The analysis included 417 female and 229 male participants of the Environment and Reproductive Health (EARTH) Study who gave birth to 418 singleton infants between 2005 and 2018 and for whom we had phenol biomarkers quantified in at least one urine sample collected before conception. Mothers and fathers provided an average of 4 and 3 urine samples during the preconception period, respectively. We calculated the geometric mean of bisphenol A (BPA), bisphenol S (BPS), benzophenone-3, triclosan, and the molar sum of parabens (ΣParabens) urinary concentrations to estimate each participant’s preconception exposure. Risk ratios (RRs) of preterm birth (live birth before 37 completed weeks’ gestation) were estimated using modified Poisson regression models adjusted for covariates. Results: The mean (SD) gestational age among singletons was 39.3 (1.7) weeks with 8% born preterm. A natural log-unit increase in maternal preconception BPA (RR 1.94; 95% CI: 1.20, 3.14) and BPS (RR 2.42; 95% CI: 1.01, 5.77) concentration was associated with an increased risk of preterm birth. These associations remained after further adjustment for maternal prenatal and paternal preconception biomarker concentrations. Paternal preconception ΣParabens concentrations showed a possible elevated risk of preterm birth (RR 1.36; 95% CI: 0.94, 1.96). No consistent pattern of association was observed for benzophenone-3 or triclosan biomarkers in either parent. Discussion: Maternal preconception urinary BPA and BPS concentrations, as well as paternal preconception urinary parabens concentrations were prospectively associated with a higher risk of preterm birth. Subfertile couples’ exposure to select phenols during the preconception period may be an unrecognized risk factor for adverse pregnancy outcomes. Keywords: Bisphenol, Paraben, Triclosan, Benzophenone, Preconception, Preterm birth

Objective: We performed a systematic review of the epidemiology literature to identify the neurodevelopmental effects associated with phthalate exposure. Data sources and study eligibility criteria: Six phthalates were included in the review: di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and diethyl phthalate (DEP). The initial literature search (of PubMed, Web of Science, and Toxline) included all studies of neurodevelopmental effects in humans, and outcomes were selected for full systematic review based on data availability. Study evaluation and synthesis methods: Studies of neurodevelopmental effects were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework. For studies of cognition and motor effects in children ≤4 years old, a random effects meta-analysis was performed. Results: The primary outcomes reviewed here are (number of studies in parentheses): cognition (14), motor effects (9), behavior, including attention deficit hyperactivity disorder (20), infant behavior (3), and social behavior, including autism spectrum disorder (7). For each phthalate/outcome combination, there was slight or indeterminate evidence of an association, with the exception of motor effects for BBP, which had moderate evidence. Conclusions and implications of key findings: Overall, there is not a clear pattern of association between prenatal phthalate exposures and neurodevelopment. There are several possible reasons for the observed null associations related to exposure misclassification, periods of heightened susceptibility, sex-specific effects, and the effects of phthalate mixtures. Until these limitations are adequately addressed in the epidemiology literature, these findings should not be interpreted as evidence that there are no neurodevelopmental effects of phthalate exposure.The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.

Introduction: Exposure to mixtures of environmental chemicals are prevalent among pregnant women and may be associated with altered fetal growth and gestational age. To date, most research regarding environmental chemicals and neonatal outcomes has focused on the effect of individual agents. Methods: In a prospective cohort of 380 pregnant women from Cincinnati, OH (enrolled 2003–2006), we used biomarkers to estimate exposure to 43 phenols, phthalates, metals, organophosphate/pyrethroid/organochlorine pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, perfluoroalkyl substances (PFAS), and environmental tobacco smoke. Using three approaches, we estimated covariate-adjusted associations of chemical mixtures or individual chemicals with gestational-age-specific birth weight z-scores, birth length, head circumference, and gestational age: k-means clustering, principal components (PC), and one-chemical-at-a-time regression. Results: We identified three chemical mixture profiles using k-means clustering. Women in cluster 1 had higher concentrations of most phenols, three phthalate metabolites, several metals, organophosphate/organochlorine pesticides, polychlorinated biphenyls, and several PFAS than women in clusters 2 and 3. On average, infants born to women in clusters 1 (−1.2 cm; 95% CI: −1.9, −0.5) and 2 (−0.5 cm; 95% CI: −1.1, 0.1) had lower birth length than infants in cluster 3. Six PCs explained 50% of the variance in biomarker concentrations and biomarkers with similar chemical structures or from shared commercial/industrial settings loaded onto commons PCs. Each standard deviation increase in PC 1 (organochlorine pesticides, some phenols) and PC 6 (cadmium, bisphenol A) was associated with 0.2 cm (95% CI: −0.4, 0.0) and 0.1 cm (95% CI: −0.4, 0.1) lower birth length, respectively. Organochlorine compounds, parabens, and cadmium were inversely associated with birth length in the one-chemical-at-a-time analysis. Cluster membership, PC scores, and individual chemicals were not associated with other birth outcomes. Conclusion: All three methods of characterizing multiple chemical exposures in this cohort identified inverse associations of select organochlorine compounds, phenols, and cadmium with birth length, but not other neonatal outcomes.

Objective: We performed a systematic review of the epidemiology literature to identify the male reproductive effects associated with phthalate exposure. Data sources and study eligibility criteria: Six phthalates were included in the review: di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and diethyl phthalate (DEP). The initial literature search (of PubMed, Web of Science, and Toxline) included all studies of male reproductive effects in humans, and outcomes were selected for full systematic review based on data availability. Study evaluation and synthesis methods: For each outcome, studies were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework. Results: The primary outcomes reviewed here are (number of included/excluded studies in parentheses): anogenital distance (6/1), semen parameters (15/9), time to pregnancy (3/5), testosterone (13/8), timing of pubertal development (5/15), and hypospadias/cryptorchidism (4/10). Looking at the overall hazard, there was robust evidence of an association between DEHP and DBP exposure and male reproductive outcomes; this was based primarily on studies of anogenital distance, semen parameters, and testosterone for DEHP and semen parameters and time to pregnancy for DBP. There was moderate evidence of an association between DINP and BBP exposure and male reproductive outcomes based on testosterone and semen parameters for DINP and semen parameters and time to pregnancy for BBP. DIBP and DEP were considered to have slight evidence of an association. For DIBP, the less conclusive evidence was attributed to a more limited literature base (i.e., fewer studies) and lower exposure levels in the population, decreasing the ability to observe an effect. For DEP, the findings were consistent with experimental animal data that suggest DEP does not haves as strong an anti-androgenic effect as other phthalates. Conclusions and implications of key findings: Overall, despite some inconsistencies across phthalates in the specific outcomes associated with exposure, these results support that phthalate exposure at levels seen in human populations may have male reproductive effects, particularly DEHP and DBP. The relative strength of the evidence reflects differing levels of toxicity as well as differences in the range of exposures studied and the number of available studies.The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.

Traffic-related air and noise pollution may increase the risk for cardiovascular disorders, especially among susceptible populations like pregnant women. The objective of this study was to evaluate the association of exposure to traffic-related air pollution and traffic noise with blood pressure in pregnant women. We extracted systolic blood pressure (SBP) and diastolic blood pressure (DBP) at ≥20 weeks gestation, as well as hypertensive disorders of pregnancy from medical records in the HOME Study, a prospective pregnancy and birth cohort from Cincinnati, OH (n = 370). We estimated exposure to elemental carbon attributable to traffic (ECAT),11 ECAT = elemental carbon attributable to traffic. a marker of traffic-related air pollution, at women's residences at ~20 weeks gestation using a validated land use regression model and traffic noise using a publicly available transportation noise model. We used linear mixed models and modified Poisson regression adjusted for covariates to examine associations of ECAT and traffic noise with blood pressure and hypertensive disorders of pregnancy risk, respectively. In adjusted models, we found a 1.6 (95% CI = 0.02, 3.3; p = 0.048) mm Hg increase in SBP associated with an interquartile range increase in ECAT concentration; the association was stronger after adjusting for traffic noise (1.9 mm Hg, 95% = 0.1, 3.7; p = 0.035). ECAT concentrations were not significantly associated with DBP or hypertensive disorders of pregnancy, and traffic noise was not associated with SBP, DBP, or hypertensive disorders of pregnancy. There was no evidence of a joint effect of traffic noise and ECAT on any outcome. In this cohort, higher residential traffic-related air pollution exposure at ~20 weeks gestation was associated with higher SBP in late pregnancy. It is important for future studies of traffic-related air or noise pollution to jointly consider both exposures and neighborhood characteristics given their correlation and potential cumulative impact on cardiovascular health. Keywords: Traffic, Air pollution, Noise, Maternal blood pressure, Hypertension

Abstract Background Excess weight gain in infancy and childhood is associated with increased risk of subsequent obesity. Identifying patterns of infancy and childhood weight gain associated with subsequent obesity or overweight status could help identify children at highest risk. Thus, we examined patterns of infancy and early childhood BMI in relation to mid-childhood overweight and obesity status. Methods In a prospective cohort of 215 children from Cincinnati, OH (born: 2003–2006), we measured weight and length or height at ages 4 weeks and 1, 2, 3, 4, 5, and 8 years. We calculated BMI z-scores using World Health Organization references. Using linear fixed effect models, we estimated mean BMI at each age and rates of change in BMI between ages 4 weeks and 5 years by children’s overweight and obesity status at age 8 years, assessed with BMI z-scores or bioelectric impedance analysis (BIA). Results Children who became overweight (BMI, n = 51 and BIA, n = 37) or obese (BMI, n = 22 and BIA, n = 29) at age 8 years had greater BMI at all ages compared to normal weightchildren. Children who were overweight had similar rates of change in BMI as children who were lean. Children who were obese had greater gains in BMI between age 4 weeks and 5 years, with the most rapid gains in the first 2 years. Conclusions Results from this study of modest sample size, suggest that adiposity patterns in the first 5 years of life are related to subsequent childhood overweight and obesity risk.

Background: Exposure to triclosan, an antimicrobial chemical, is ubiquitous among pregnant women and may reduce thyroid hormone levels that are important for fetal neurodevelopment. Few studies have examined the association between prenatal triclosan exposure and children's neurobehavior. Objective: We investigated the relationship of prenatal urinary triclosan concentrations with children's behavior and cognitive abilities at age three years in a prospective pregnancy and birth cohort in Canada. Methods: We measured triclosan in urine samples collected at ~12 weeks of gestation in 794 Canadian women enrolled in a prospective pregnancy and birth cohort study (MIREC) from 2008 to 2011. Around age 3 years, we assessed children's cognitive abilities using the Wechsler Primary and Preschool Scale of Intelligence-III (WPPSI-III), and two scales of the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). Parents reported children's problem and reciprocal social behaviors using the Behavior Assessment System for Children-2 (BASC-2) and Social Responsiveness Scale-2 (SRS-2), respectively. Results: After adjusting for confounders using multivariable linear regression, triclosan was not associated with most of the 30 examined neurobehavioral scales. Each 10-fold increase in triclosan was associated with better WPPSI-III picture completion scores (β: 0.2; 95% CI: 0,0.5) and BASC-2 externalizing (β: −0.5; 95% CI: −1.1, 0) and hyperactivity (β: −0.6; 95% CI: −1.2, −0.1) scores, suggesting less externalizing and hyperactive behaviors. Child sex did not modify these associations. Conclusions: In this cohort, urinary triclosan concentrations measured once in early pregnancy were not associated with most assessed aspects of neurobehavior and weakly associated with a few others, but not in the hypothesized direction. Keywords: Triclosan, Prenatal exposure, Child neurobehavior, Children's environmental health

Abstract Background Triclosan is an antimicrobial agent that may affect the gut microbiome and endocrine system to influence adiposity. However, little data from prospective studies examining prenatal and childhood exposures exist. We investigated the relationship between multiple, prospective early life measure of triclosan exposure and child adiposity. Methods In a prospective cohort of 220 mother-child pairs from Cincinnati, OH (enrolled 2003–2006), we quantified triclosan in urine samples collected twice during pregnancy, annually from 1 to 5 years of age, and once at 8 years. We assessed child adiposity at age 8 years using body mass index (BMI), waist circumference, and bioelectric impedance. We estimated covariate-adjusted associations of child adiposity with a 10-fold increase in average prenatal, average early childhood (average of 1–5 years), and 8-year triclosan concentrations. Results Among all children, there was no association between triclosan and child adiposity. While urinary triclosan concentrations at all three time periods were weakly, imprecisely, and inversely associated with all three measures of adiposity among girls, these associations did not differ significantly from those in boys (sex x triclosan p-values> 0.35). Among girls, the strongest associations were generally observed for prenatal triclosan when we adjusted for all three triclosan concentrations and covariates in the same model; BMI z-score (β: -0.13; 95% CI: -0.42, 0.15), waist circumference (β: − 1.7 cm; 95% CI: -4.2, 0.7), and percent body fat (β :-0.6; 95% CI: -2.7, 1.3). In contrast, the associations between triclosan concentrations and adiposity measures were inconsistent among boys. Conclusion We did not observe evidence of an association of repeated urinary triclosan concentrations during pregnancy and childhood with measures of child adiposity at age 8 years in this cohort.

Abstract Background Pregnant women are exposed to a mixture of endocrine disrupting chemicals (EDCs). Gestational EDC exposures may be associated with changes in fetal growth that elevates the risk for poor health later in life, but few studies have examined the health effects of simultaneous exposure to multiple chemicals. This study aimed to examine the association of gestational exposure to five chemical classes of potential EDCs: phthalates and bisphenol A, perfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCPs) with infant birth weight. Methods Using data from the Health Outcomes and Measures of Environment (HOME) Study, we examined 272 pregnant women enrolled between 2003-2006. EDC concentrations were quantified in blood and urine samples collected at 16 and 26 weeks gestation. We used Bayesian Hierarchical Linear Models (BHLM) to examine the associations between newborn birth weight and 53 EDCs, 2 organochlorine pesticides (OPPs) and 2 heavy metals. Results For a 10-fold increase in chemical concentration, the mean differences in birth weights (95% credible intervals (CI)) were 1 g (-20, 23) for phthalates, -11 g (-52, 34) for PFAS, 0.2 g (-9, 10) for PCBs, -4 g (-30, 22) for PBDEs, and 7 g (-25, 40) for OCPs. Conclusion Gestational exposure to phthalates, PFAS, PCBs, PBDEs, OCPs or OPPs had null or small associations with birth weight. Gestational OPP, Pb, and PFAS exposures were most strongly associated with lower birth weight.

Abstract Background Organophospate flame retardants (PFRs) are chemicals of emerging concern due to restrictions on polybrominated diphenyl ether flame retardant formulations. We describe the occurrence, variability, and predictors of urinary metabolites of PFRs among pregnant women. Methods In 2014–2015, 59 women from Providence, RI provided up to 3 spot urine samples during pregnancy (~12, 28, and 35 weeks’ gestation). We created a pooled urine sample per woman and measured nine relevant metabolites in individual and pooled samples. We used linear mixed models to calculate intraclass correlation coefficients (ICCs) across the 3 measurements and to assess sociodemographic and dietary predictors of PFRs. Results The median (IQR) of bis-2-chloroethyl phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), and diphenyl phosphate (DPhP), the metabolites most frequently detected, from pooled samples were: 0.31 μg/L (0.17–0.54), 1.18 μg/L (0.64–2.19), 0.93 μg/L (0.72–1.97), respectively. We observed fair to good reproducibility for BCEP (ICC = 0.50), BDCPP (ICC = 0.60), and DPhP (ICC = 0.43), and excellent agreement between the urinary flame retardant metabolite concentrations averaged across pregnancy versus pooled urine sample concentrations for BCEP (ICC = 0.95), BDCPP (ICC = 0.89), and DPhP (ICC = 0.93). Adjusting for pertinent sociodemographic factors and gestational week of urine collection, each 1 kg increase in pre-pregnancy weight was associated with greater BCEP (1.1%; 95% CI: 0.1, 2.1), BDCPP (1.5%; 95% CI: 0.3, 2.7), and DPhP (0.5%; 95% CI: 0.0, 1.1). Dietary factors were generally not associated with urinary flame retardant metabolites. Conclusions Urinary concentrations of BCEP, BDCPP, and DPhP were frequently detected among women in this pilot study and had fair reproducibility across pregnancy. Body size may be an important predictor of urinary flame retardant metabolite concentrations.

The field of environmental epidemiology has been using “-omics” technologies, including the exposome, metabolome, and methylome, to understand the potential effects and biological pathways of a number of environmental pollutants. However, the majority of studies have focused on a single disease or phenotype, and have not systematically considered patterns of multimorbidity and whether environmental pollutants have pleiotropic effects. These questions could be addressed by examining the relation between environmental exposures and the phenome – the patterns and profiles of human health that individuals experience from birth to death. By conducting Phenome Wide Association Studies (PheWAS), we can generate new hypotheses about new or poorly understood exposures, identify novel associations for established toxicants, and better understand biological pathways affected by environmental pollutants. In this article, we provide a conceptual framework for conducting PheWAS in environmental epidemiology and summarize some of the advantages and challenges to using the PheWAS to study environmental pollutant exposures. Ultimately, by adding the PheWAS to our “-omics” toolbox, we could substantially improve our understanding of the potential health effects of environmental pollutants.

Objective: We performed a systematic review of the epidemiology literature to identify the female reproductive and developmental effects associated with phthalate exposure. Data sources and study eligibility criteria: Six phthalates were included in the review: di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and diethyl phthalate (DEP). The initial literature search (of PubMed, Web of Science, and Toxline) included all studies of female reproductive and developmental effects in humans, and outcomes were selected for full systematic review based on data availability. Study evaluation and synthesis methods: For each outcome, studies were evaluated using criteria defined a priori for risk of bias and sensitivity by two reviewers using a domain-based approach. Evidence was synthesized by outcome and phthalate and strength of evidence was summarized using a structured framework. Results: The primary outcomes reviewed here are (number of included/excluded studies in parentheses): pubertal development (5/13), time to pregnancy (3/4), preterm birth (8/12), and spontaneous abortion (5/0). Among these outcomes, preterm birth had moderate evidence of a positive association with phthalate exposure (specifically DEHP, DBP, and DEP). Exposure levels for BBP, DIBP, and DINP were generally lower than for the phthalates with an observed effect, which may partially explain the difference due to lower sensitivity. Other phthalate/outcome combinations were considered to have slight or indeterminate evidence of an association. Conclusions and implications of key findings: Overall, these results support that some phthalates may be associated with higher odds of preterm birth in humans, though there is some remaining inconsistency. More evidence is needed on the mechanism and relevant exposure window for this association.The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.