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Background Trimethylamine N-oxide (TMAO) and its precursors choline, betaine, and carnitine have been associated with cardiometabolic disease in nonpregnant adults. However, studies examining TMAO and its precursors in relation to cardiometabolic conditions during pregnancy are lacking. Objectives The primary objective was to estimate the association of TMAO and its precursors in maternal and cord plasma with gestational diabetes mellitus (GDM) and pre-eclampsia (PE) among women in the Boston Birth Cohort. A secondary objective was to determine whether associations vary by race/ethnicity. Methods ORs for each outcome according to tertiles and to an SD increment of TMAO, choline, betaine, and carnitine were estimated using logistic regression. Final models were adjusted for covariates. Results Among 1496 women, 115 women had GDM and 159 had PE during the index pregnancy. Intermetabolite correlations of TMAO and its precursors were stronger within cord plasma (r = 0.38–0.87) than within maternal plasma (r = 0.08–0.62). Maternal TMAO was associated with higher odds of GDM (third compared with first tertile OR: 1.75; 95% CI: 1.04, 2.94), whereas maternal choline, betaine, and carnitine were not associated with GDM. Maternal TMAO and choline were not associated with PE, whereas carnitine was associated with higher (OR: 1.86; 95% CI: 1.18, 2.94) and betaine with lower odds of PE (OR: 0.37; 95% CI: 0.23, 0.59). In cord plasma, TMAO was not associated with GDM or PE, but choline, betaine, and carnitine were associated with higher odds of PE (OR: 3.11; 95% CI: 1.62, 5.96; OR: 2.65; 95% CI: 1.42, 4.93; OR: 2.56; 95% CI: 1.39, 4.69, respectively). Cord choline was associated with lower odds of GDM (OR: 0.52; 95% CI: 0.27, 0.99), whereas other cord metabolites were not significantly associated with GDM. Associations did not vary by race/ethnicity. Conclusions TMAO and its precursors were associated with GDM and PE, but the associations differed based on the metabolite medium (maternal compared with cord plasma). This trial was registered at clinicaltrials.gov as NCT03228875. [ABSTRACT FROM AUTHOR]

Background Prenatal environmental phenol and phthalate exposures may alter immune or inflammatory responses leading to respiratory and allergic disease. Objectives We estimated associations of prenatal environmental phenol and phthalate biomarkers with respiratory and allergic outcomes among children in the Mount Sinai Children's Environmental Health Study. Methods We quantified urinary biomarkers of benzophenone-3, bisphenol A, paradichlorobenzene (as 2,5-dichlorophenol), triclosan, and 10 phthalate metabolites in third trimester maternal samples and assessed asthma, wheeze, and atopic skin conditions via parent questionnaires at ages 6 and 7 years ( n  = 164 children with 240 observations). We used logistic regression to estimate covariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) per standard deviation difference in natural log biomarker concentrations and examined effect measure modification by child's sex. Results Associations of prenatal 2,5-dichlorophenol (all outcomes) and bisphenol A (asthma outcomes) were modified by child's sex, with increased odds of outcomes among boys but not girls. Among boys, ORs for asthma diagnosis per standard deviation difference in biomarker concentration were 3.00 (95% CI: 1.36, 6.59) for 2,5-dichlorophenol and 3.04 (95% CI: 1.38, 6.68) for bisphenol A. Wheeze in the past 12 months was inversely associated with low molecular weight phthalate metabolites among girls only (OR: 0.27, 95% CI: 0.13, 0.59) and with benzophenone-3 among all children (OR: 0.65, 95% CI: 0.44, 0.96). Conclusions Prenatal bisphenol A and paradichlorobenzene exposures were associated with pediatric respiratory outcomes among boys. Future studies may shed light on biological mechanisms and potential sexually-dimorphic effects of select phenols and phthalates on respiratory disease development. [ABSTRACT FROM AUTHOR]

Background: Emerging experimental studies suggest that parabens could affect metabolism by altering the microbiome or signaling pathways involved in adipocyte differentiation. While human exposure to parabens is widespread, epidemiologic studies assessing the role of these chemicals on adiposity measures are scarce.Objective: We examined associations of parabens with adiposity measures among adults and children in the U.S. general population.Methods: We conducted covariate-adjusted linear and logistic regression models to examine associations between urinary biomarker concentrations of four parabens (butyl-BP, ethyl-EP, methyl-MP, and propyl paraben-PP) and measures of adiposity (obesity; body mass index, BMI or BMI z-score; and waist circumference) among 4730 adults (2007-2014) and 1324 children (2007-2012), participating in the National Health and Nutrition Examination Survey. We also assessed heterogeneity of associations by gender.Results: We generally observed significant inverse associations between adiposity measures and paraben biomarker concentrations among adults (BP, EP, MP, PP) and children (MP). For example, adjusted prevalence odds ratios (95% confidence intervals, CI) for obesity per a ten-fold increase in MP concentrations were 0.64 (95% CI: 0.55, 0.73) for adults and 0.71(95% CI: 0.52, 0.95) for children. Strength of inverse associations typically increased monotonically with increasing paraben exposure quartiles; and, in general, inverse associations were more pronounced among females. Associations remained when controlling for other phenolic compounds previously linked with adiposity measures.Conclusions: In this cross-sectional study of adiposity measures and parabens, we observed consistent inverse associations in a representative sample of U.S adults and children. Further studies are warranted to confirm our findings, examine the potential role of paraben sequestration in adipose tissue, and elucidate mechanisms by which parabens could alter metabolism. [ABSTRACT FROM AUTHOR]

Early life exposure to endocrine disrupting chemicals may alter adipogenesis and energy balance leading to changes in obesity risk. Several studies have evaluated the association of prenatal bisphenol A exposure with childhood body size but only one study of male infants has examined other environmental phenols. Therefore, we assessed associations between prenatal exposure to environmental phenols and fat mass in a prospective birth cohort. We quantified four phenol biomarkers in third trimester maternal spot urine samples in a cohort of women enrolled in New York City between 1998 and 2002 and evaluated fat mass in their children using a Tanita scale between ages 4 and 9 years (173 children with 351 total observations). We estimated associations of standard deviation differences in natural log creatinine-standardized phenol biomarker concentrations with percent fat mass using linear mixed effects regression models. We did not observe associations of bisphenol A or triclosan with childhood percent fat mass. In unadjusted models, maternal urinary concentrations of 2,5-dichlorophenol were associated with greater percent fat mass and benzophenone-3 was associated with lower percent fat mass among children. After adjustment, phenol biomarkers were not associated with percent fat mass. However, the association between benzophenone-3 and percent fat mass was modified by child's sex: benzophenone-3 concentrations were inversely associated with percent fat mass in girls (beta = − 1.51, 95% CI = − 3.06, 0.01) but not boys (beta = − 0.20, 95% CI = − 1.69, 1.26). Although we did not observe strong evidence that prenatal environmental phenols exposures influence the development of childhood adiposity, the potential antiadipogenic effect of benzophenone-3 in girls may warrant further investigation. [ABSTRACT FROM AUTHOR]

[Display omitted] • We conducted a metabolome-wide association study to understand how in utero exposure to Pb, Hg, Cd, Se, and Mn may affect the metabolic programming of fetuses. • We used data from the Boston Birth Cohort, an ongoing prospective birth cohort that comprises a predominantly urban, low-income, minority population in the United States. • After Bonferroni correction, there were 25 cord metabolites associated with at least one of the metals or trace elements. • Whether these metals- and trace elements-associated changes in cord metabolites can influence a child's risk of cardiometabolic diseases remains to be determined. Exposure to metals lead (Pb), mercury (Hg), and cadmium (Cd) and trace elements selenium (Se) and manganese (Mn) has been linked to the developmental origins of cardiometabolic diseases, but the mechanisms are not well-understood. Conduct a metabolome-wide association study to understand how in utero exposure to Pb, Hg, Cd, Se, and Mn affects the metabolic programming of fetuses. We used data from the Boston Birth Cohort, which enrolled mother-child pairs from Boston, MA. We measured metals and trace elements in maternal red blood cells (RBCs) collected 24–72 h after delivery, and metabolites in cord blood collected at birth. We used multivariable linear regression to examine associations of metals and trace elements with metabolites and Bonferroni correction to account for multiple comparisons. We assessed non-linear associations of metals and trace elements with metabolites using restricted cubic spline plots. This analysis included 670 mother-child pairs (57% non-Hispanic Black and 24% Hispanic). After Bonferroni correction, there were 25 cord metabolites associated with at least one of the metals or trace elements. Pb was negatively associated with the xenobiotic piperine, Cd was positively associated with xenobiotics cotinine and hydroxycotinine, and Hg was associated with 8 lipid metabolites (in both directions). Se and Mn shared associations with 6 metabolites (in both directions), which mostly included nucleotides and amino acids; Se was additionally associated with 7 metabolites (mostly amino acids, nucleotides, and carnitines) and Mn was additionally associated with C36:4 hydroxy phosphatidylcholine. Restricted cubic spline plots showed that most associations were linear. Maternal RBC metal and trace element concentrations were associated in a dose-dependent fashion with cord blood metabolites. What remains to be determined is whether these metals- and trace elements-associated changes in cord metabolites can influence a child's risk of cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Early-life exposure to phthalates alters behaviors in animals. However, epidemiological evidence on childhood phthalate exposure and attention-deficit/hyperactivity disorder (ADHD) behaviors is limited. This study included 243 children from the ReCHARGE (Revisiting Childhood Autism Risks from Genetics and Environment) study, who were previously classified as having autism spectrum disorder (ASD), developmental delay, other early concerns, and typical development in the CHARGE case-control study. Twenty phthalate metabolites were measured in spot urine samples collected from children aged 2–5 years. Parents reported on children's ADHD symptoms at ages 8–18 years using Conners-3 Parent Rating Scale. Covariate-adjusted negative binomial generalized linear models were used to investigate associations between individual phthalate metabolite concentrations and raw scores. Weighted quantile sum (WQS) regression with repeated holdout validation was used to examine mixture effects of phthalate metabolites on behavioral scores. Effect modification by child sex was evaluated. Among 12 phthalate metabolites detected in >75% of the samples, higher mono-2-heptyl phthalate (MHPP) was associated with higher scores on Inattentive (β per doubling = 0.05, 95% confidence interval [CI]: 0.02, 0.08) and Hyperactive/Impulsive scales (β = 0.04, 95% CI: 0.00, 0.07), especially among children with ASD. Higher mono-carboxy isooctyl phthalate (MCiOP) was associated with higher Hyperactivity/Impulsivity scores (β = 0.07, 95% CI: −0.01, 0.15), especially among typically developing children. The associations of the molar sum of high molecular weight (HMW) phthalate metabolites and a phthalate metabolite mixture with Hyperactivity/Impulsivity scores were modified by sex, showing more pronounced adverse associations among females. Exposure to phthalates during early childhood may impact ADHD behaviors in middle childhood and adolescence, particularly among females. Although our findings may not be broadly generalizable due to the diverse diagnostic profiles within our study population, our robust findings on sex-specific associations warrant further investigations. • Phthalate metabolites at 2–5 years and ADHD behaviors at 8–18 years were studied. • MHPP was associated with more ADHD behaviors, especially among children with ASD. • Associations of a phthalate mixture with ADHD behaviors were modified by child sex. • Among females, HMW phthalates were associated with more hyperactivity/impulsivity. [ABSTRACT FROM AUTHOR]

Ultra-processed food has low nutritional quality, is associated with development of chronic diseases, and may increase exposure to chemicals used in food packaging and production. To assess associations of ultra-processed food consumption with exposure to phthalates and bisphenols, including newer replacements, in the general U.S. population. Among 2212 National Health and Nutrition Examination Survey (NHANES) 2013–2014 participants (≥6 years), we classified items reported in a 24-h dietary recall according to the NOVA food processing classification system and calculated energy intake from ultra-processed food. Urinary concentrations of mono-benzyl (MBzP), mono-(3-carboxypropyl) (MCPP), mono-(carboxyisononyl) (MCNP), mono-(carboxyisoctyl) (MCOP), and four metabolites of di(2-ethylhexyl) (∑DEHP) phthalates and bisphenols A, F, and S were measured in spot urine samples. We estimated percent changes in natural log creatinine-standardized concentrations per 10% higher energy from ultra-processed food in covariate-adjusted multivariable linear regression models. We examined effect measure modification by age group, race/ethnicity, and poverty:income ratio and assessed associations with minimally processed food intake. In adjusted models, higher energy from ultra-processed food was associated with higher urinary concentrations of MCPP, MCNP, and MCOP but not MBzP, ∑DEHP, or bisphenols. Each 10% higher energy from ultra-processed food was associated with 8.0% (95% CI: 5.6%, 10.3%) higher urinary MCOP concentrations, with a stronger association among children than adolescents or adults. Ultra-processed sandwiches/hamburgers, French fries/other potato products, and ice cream/pops were associated with higher concentrations of multiple chemicals. Higher energy from minimally processed food was associated with lower concentrations of MCPP, MCNP, MCOP, and bisphenols A and F. Ultra-processed food consumption may increase exposure to currently used phthalates. Additional research is needed to determine whether minimally processed food diets or changes in food production practices can reduce phthalate and bisphenol exposures and related health effects, particularly among children who are more vulnerable to toxicants and tend to consume more ultra-processed food than adults. • Ultra-processed food is related to higher levels of phthalates but not bisphenols. • Minimally processed food is related to lower levels of phthalates and bisphenols A and F. • Magnitudes of some associations are stronger among children. • Chemical exposures may contribute to adverse health effects of ultra-processed food. [ABSTRACT FROM AUTHOR]

Background: Growing literature linking unconventional natural gas development (UNGD) to adverse health has implicated air pollution and stress pathways. Persons with heart failure (HF) are susceptible to these stressors.Objectives: This study sought to evaluate associations between UNGD activity and hospitalization among HF patients, stratified by both ejection fraction (EF) status (reduced [HFrEF], preserved [HFpEF], not classifiable) and HF severity.Methods: We evaluated the odds of hospitalization among patients with HF seen at Geisinger from 2008 to 2015 using electronic health records. We assigned metrics of UNGD activity by phase (pad preparation, drilling, stimulation, and production) 30 days before hospitalization or a frequency-matched control selection date. We assigned phenotype status using a validated algorithm.Results: We identified 9,054 patients with HF with 5,839 hospitalizations (mean age 71.1 ± 12.7 years; 47.7% female). Comparing 4th to 1st quartiles, adjusted odds ratios (95% confidence interval) for hospitalization were 1.70 (1.35 to 2.13), 0.97 (0.75 to 1.27), 1.80 (1.35 to 2.40), and 1.62 (1.07 to 2.45) for pad preparation, drilling, stimulation, and production metrics, respectively. We did not find effect modification by HFrEF or HFpEF status. Associations of most UNGD metrics with hospitalization were stronger among those with more severe HF at baseline.Conclusions: Three of 4 phases of UNGD activity were associated with hospitalization for HF in a large sample of patients with HF in an area of active UNGD, with similar findings by HFrEF versus HFpEF status. Older patients with HF seem particularly vulnerable to adverse health impacts from UNGD activity. [ABSTRACT FROM AUTHOR]

Perfluoroalkyl substances (PFAS) are persistent endocrine disrupting chemicals found in industrial and commercial products. Previous research has shown that other endocrine disrupting chemicals such as phthalates and bisphenol A may alter circulating levels of vitamin D; however, no research has examined associations between PFAS and vitamin D biomarkers. We conducted a cross-sectional analysis of 7040 individuals aged 12 years and older participating in the 2003-2010 cycles of the United States National Health and Nutrition Examination Survey (NHANES). Concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and total 25-hydroxyvitamin D [25(OH)D] were measured in serum samples. We used multivariable linear regression to estimate covariate-adjusted differences in total 25(OH)D or prevalence odds of vitamin D deficiency per log2 change in PFAS concentrations. We also assessed potential effect measure modification by gender, age, and race/ethnicity. PFAS were detected in over 98% of the samples. In adjusted models, each 2-fold increase in PFOS was associated with 0.9 nmol/L (95% CI: 0.2, 1.5) lower total 25(OH)D concentrations, with associations significantly stronger among whites (β: -1.7; 95% CI: -2.6, -0.7) and individuals older than 60 years of age (β: -1.7; 95% CI: -2.9, -0.5). Each 2-fold increase in PFHxS was associated with 0.8 nmol/L (95% CI: 0.3, 1.3) higher total 25(OH)D, and this association was not modified by age, gender, and race/ethnicity. PFOA and PFNA were not associated with total 25(OH)D. When assessing prevalence odds of vitamin D deficiency, we observed similar patterns of association with PFAS concentrations. Our results suggest that some PFAS may be associated with altered vitamin D levels in the United States population, and associations may vary by chemical, age, and race/ethnicity. Prospective epidemiological studies are needed to confirm our findings and determine their implications for vitamin D-associated health outcomes in children and adults. [ABSTRACT FROM AUTHOR]

Background & Aims Narcotic analgesics are not recommended for long-term management of pain for patients with inflammatory bowel disease (IBD), particularly pediatric patients. We compared chronic use of narcotics among children with IBD and the general population and investigated factors associated with narcotic use in the pediatric IBD population. Methods This cross-sectional study included children (younger than 18 years old) with continuous enrollment in a large administrative claims database from 2010 through 2011 (n = 4,911,286). Children with IBD were identified through diagnosis codes and dispensation of IBD medication (n = 4344); they were matched for age, sex, and region with 5 children without IBD (n = 21,720). Chronic narcotic use was defined as ≥3 dispensements of narcotics. We estimated prevalence odds ratios (PORs) and 95% confidence intervals (CIs), comparing narcotic use on the basis of IBD status and evaluating variables associated with narcotic use by patients with IBD by using conditional and unconditional logistic regression. Results The prevalence of chronic narcotic use was 5.6% among children with IBD vs 2.3% in the general population (POR, 2.6; 95% CI, 2.2–3.0). Compared with the general population, POR for chronic narcotic use was significantly higher for pediatric IBD patients with psychological impairment (POR, 6.8; 95% CI, 4.3–10.6) than those without (POR, 2.3; 95% CI, 1.9–2.7). Older age, increased healthcare utilization, fracture, and psychological impairment were strongly associated with chronic use of narcotics among children with IBD. Conclusions Chronic narcotic use is common in pediatric IBD patients, particularly among those with anxiety and depression. Increased awareness of psychological comorbidity, screening, and treatment may reduce symptoms that lead to narcotic use and its complications. [ABSTRACT FROM AUTHOR]

The 2017–2018 U.S. PFAS exposure burden calculator was designed to provide a summary exposure score for per - and polyfluoroalkyl substances (PFAS) mixtures using targeted PFAS analyte data. Its aim was to place PFAS burden score estimates onto a common scale based on nationally representative U.S. reference ranges from 2017 to 2018, enabling comparisons of overall PFAS burden scores across studies even if they did not measure the same set of PFAS analytes. To use the U.S. PFAS exposure burden calculator for comparing the same mixture of PFAS compounds in similarly aged adolescents and their associations with cardiometabolic outcomes in the HOME Study and NHANES between 2015 and 2018. We applied the PFAS burden calculator to 8 PFAS analytes measured in the serum of adolescents from the HOME Study (Cincinnati, Ohio; age range 11–14 years; years: 2016–2019; n = 207) and NHANES (US; age range 12–14 years; years 2015–2018; n = 245). We used the non-parametric Mann-Whitney U test and chi-squared test to compare the two study samples. In both studies, we examined associations of PFAS burden scores with the same cardiometabolic outcomes, adjusted for the same core set of covariates using regression analyses. We conducted sensitivity analyses to verify robustness of exposure-outcome associations, by accounting for measurement error of PFAS burden scores. PFAS burden scores were significantly different (p = 0.004) between the HOME Study (median: 0.00, interquartile range − 0.37, 0.34) and the NHANES samples (median: 0.04, IQR -0.11, 0.54), while no significant difference was found for PFAS summed concentrations (p = 0.661). In the HOME Study, an interquartile (IQR) increase in PFAS burden score was associated with higher total cholesterol [7.0 mg/dL, 95% CI: 0.6, 13.4]; HDL [2.8 mg/dL, 95% CI: 0.4, 5.2]; LDL [5.9 mg/dL, 95% CI: 0.5, 11.3], insulin [0.1 log(mIU/L), 95% CI: 0.01, 0.2], and HOMA-IR [0.1, 95% CI: 0.01, 0.2]. In NHANES, an IQR increase in PFAS burden score was associated with higher diastolic blood pressure [2.4 mmHg, 95% CI: 0.4, 4.4] but not with other outcomes. Sensitivity analyses in the HOME Study and NHANES were consistent with the main findings. Performance of the U.S. PFAS exposure burden calculator was similar in a local versus national sample of adolescents, and may be a useful tool for the assessment of PFAS mixtures across studies. • A PFAS exposure burden calculator estimate a person's overall exposure burden to PFASs. • In the NHANES sample, adolescent PFAS exposure burden was associated with higher cholesterol and insulin resistance. • In the HOME Study sample, adolescent PFAS exposure burden was associated with higher diastolic blood pressure. • A standardized PFAS exposure burden metric can be useful for cross-study comparisons. [ABSTRACT FROM AUTHOR]

Synthetic chemicals are increasingly being recognized for potential independent contributions to preterm birth (PTB) and low birth weight (LBW). Bisphenols, parabens, and triclosan are consumer product chemicals that act via similar mechanisms including estrogen, androgen, and thyroid disruption and oxidative stress. Multiple cohort studies have endeavored to examine effects on birth outcomes, and systematic reviews have been limited due to measurement of 1–2 spot samples during pregnancy and limited diversity of populations. To study the effects of prenatal phenols and parabens on birth size and gestational age (GA) in 3,619 mother-infant pairs from 11 cohorts in the NIH Environmental influences on Child Health Outcomes program. While many associations were modest and statistically imprecise, a 1-unit increase in log 10 pregnancy averaged concentration of benzophenone-3 and methylparaben were associated with decreases in birthweight, birthweight adjusted for gestational age and SGA. Increases in the odds of being SGA were 29% (95% CI: 5%, 58%) and 32% (95% CI: 3%, 70%), respectively. Bisphenol S in third trimester was also associated with SGA (OR 1.52, 95% CI 1.08, 2.13). Associations of benzophenone-3 and methylparaben with PTB and LBW were null. In addition, a 1-unit increase in log 10 pregnancy averaged concentration of 2,4-dichlorophenol was associated with 43% lower (95% CI: −67%, −2%) odds of low birthweight; the direction of effect was the same for the highly correlated 2,5-dichlorophenol, but with a smaller magnitude (-29%, 95% CI: −53%, 8%). In a large and diverse sample generally representative of the United States, benzophenone-3 and methylparaben were associated with lower birthweight as well as birthweight adjusted for gestational age and higher odds of SGA, while 2,4-dichlorophenol. These associations with smaller size at birth are concerning in light of the known consequences of intrauterine growth restriction for multiple important health outcomes emerging later in life. [ABSTRACT FROM AUTHOR]

Early life environmental exposures may affect bone mass accrual in childhood, but only one study has assessed the role of environmental phenols on child bone health. We used data from 223 mother-child dyads enrolled in the Health Outcomes and Measures of the Environment (HOME) Study (Cincinnati, OH; 2003–2006). We quantified benzophenone-3, bisphenol A (BPA), 2,5-dichlorophenol, and triclosan in maternal urine collected at 16- and 26-weeks gestation and calculated the average of creatinine-adjusted concentrations. We performed dual x-ray absorptiometry at age 12 years and calculated Z-scores for whole body (less head), total hip, femoral neck, and 1/3rd distal radius bone mineral content (BMC) and areal bone mineral density (aBMD) as well as ultra-distal radius aBMD and spine BMC and bone mineral apparent density (BMAD). We estimated covariate-adjusted associations per doubling of maternal urinary environmental phenol concentrations in linear regression models. We also examined effect measure modification by child's sex and estimated associations of the environmental phenol mixture with BMC and aBMD using quantile g-computation. We observed generally null associations for all analytes and bone measures. Yet, in adjusted models, higher urinary 2,5-dichlorophenol concentrations were associated with higher 1/3rd distal radius BMC (β: 0.09; 95% CI: 0.02, 0.17) and aBMD (β: 0.09; 95% CI: 0.02, 0.17) Z-scores in the overall sample. In sex-stratified analyses, the magnitude of the BMC association was positive for females (β: 0.16; 95% CI: 0.06, 0.26) and null for males (β: 0.02; 95% CI: 0.08, 0.13). The environmental phenol mixture was associated with greater 1/3rd distal radius BMC and aBMD Z-scores in both sexes, which was mostly driven by benzophenone-3 in males and 2,5-dichlorophenol in females. In this prospective cohort study, we observed generally null associations for environmental phenols with BMC and aBMD at age 12 years. While there was a positive association of 2,5-dichlorophenol concentrations during fetal development with distal radius BMC and aBMD at age 12 years, future studies utilizing methods capable of differentiating cortical and trabecular bone are needed to elucidate potential mechanisms and implications for bone strength and microarchitecture. • Gestational urinary 2,5-dichlorophenol concentrations were associated with greater distal radius bone mineral density. • Associations for gestational urinary benzophenone-3, bisphenol A, and triclosan were null. • The environmental phenol mixture was associated with greater distal radius bone mineral content and density. [ABSTRACT FROM AUTHOR]

Early-life phthalate exposures may disrupt metabolic processes; however few prospective studies have assessed whether these associations extend to cardiometabolic outcomes during adolescence. Among 183 mother-adolescent pairs in a prospective cohort study that enrolled pregnant women in Cincinnati, OH (2003–2006), we quantified nine phthalate metabolites in spot urine samples collected twice from mothers during pregnancy and up to seven times from children. At age 12 years, we assessed triglycerides, high-density (HDL) and low-density (LDL) lipoprotein cholesterol, insulin, and glucose from fasting serum samples and calculated homeostatic model assessment of insulin resistance (HOMA-IR). Using multiple informant models, we estimated covariate-adjusted associations between urinary phthalate concentrations at each time period and cardiometabolic biomarkers at age 12 years, including modification by child sex. Although most associations were weak or null, monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), and monobenzyl phthalate (MBzP) concentrations were generally associated with lower LDL at age 12 years. A 10-fold increase in 4- and 12-year MEP was associated with −15.3 mg/dL (95% CI: 27.5, −3.13 mg/dL) and −11.8 mg/dL (−22.0, −1.51 mg/dL) lower LDL, respectively. Discrepant associations were observed in females versus males: a 10-fold increase in 3-year MEP concentrations was associated with 12.0 mg/dL (95% CI: 7.11, 31.1 mg/dL) higher LDL levels in males and −30.4 mg/dL (95% CI: 50.9, −9.8 mg/dL) lower LDL levels in females. Some urinary phthalate concentrations were cross-sectionally associated with HOMA-IR. Early-life phthalate biomarker concentrations may be inversely associated with LDL during early adolescence in an exposure-period and sex-dependent manner. • Phthalate exposures are ubiquitous among pregnant women and children. • Phthalates may be metabolic disruptors that affect cardiometabolic health. • Some phthalates were associated with lower lipid levels. • Associations varied by exposure period and child sex. [ABSTRACT FROM AUTHOR]

Phthalate esters are man-made chemicals commonly used as plasticizers and solvents, and humans may be exposed through ingestion, inhalation, and dermal absorption. Little is known about predictors of phthalate exposure, particularly in Asian countries. Because phthalates are rapidly metabolized and excreted from the body following exposure, it is important to evaluate whether phthalate metabolites measured at a single point in time can reliably rank exposures to phthalates over a period of time. We examined the concentrations and predictors of phthalate metabolite concentrations among 50 middle-aged women and 50 men from two Shanghai cohorts, enrolled in 1997–2000 and 2002–2006, respectively. We assessed the reproducibility of urinary concentrations of phthalate metabolites in three spot samples per participant taken several years apart (mean interval between first and third sample was 7.5 years [women] or 2.9 years [men]), using Spearman's rank correlation coefficients and intra-class correlation coefficients. We detected ten phthalate metabolites in at least 50% of individuals for two or more samples. Participant sex, age, menopausal status, education, income, body mass index, consumption of bottled water, recent intake of medication, and time of day of collection of the urine sample were associated with concentrations of certain phthalate metabolites. The reproducibility of an individual's urinary concentration of phthalate metabolites across several years was low, with all intra-class correlation coefficients and most Spearman rank correlation coefficients ≤ 0.3. Only mono(2-ethylhexyl) phthalate, a metabolite of di(2-ethylhexyl) phthalate, had a Spearman rank correlation coefficient ≥ 0.4 among men, suggesting moderate reproducibility. These findings suggest that a single spot urine sample is not sufficient to rank exposures to phthalates over several years in an adult urban Chinese population. [ABSTRACT FROM AUTHOR]

The developing fetus may be particularly susceptibility to environmental osteotoxicants, but studies of pregnancy phthalate exposures and childhood bone health are scarce. To examine relations of pregnancy phthalate exposure biomarkers with early adolescent bone mineral density (BMD) and bone mineral content (BMC) in a prospective birth cohort. We used data from 223 pregnant mothers and their children enrolled in a Cincinnati, OH area cohort from 2003 to 2006. We quantified monoethyl phthalate (MEP), monoisobutyl phthalate, monobutyl phthalate, monobenzyl phthalate, mono-(3-carboxypropyl) phthalate (MCPP), and four metabolites of di-2-ethylhexyl phthalate in maternal urine collected at 16 and 26 weeks gestation, and calculated the average of creatinine-standardized concentrations. Using dual x-ray absorptiometry measures at age 12 years, we calculated BMD and BMC Z -scores for six skeletal sites. In overall and sex-stratified models, we estimated covariate-adjusted associations per 2-fold increase in phthalate biomarker concentrations using linear regression, and estimated joint effects of the phthalate biomarkers mixture using Bayesian kernel machine regression (BKMR) and quantile g-computation. In single phthalate models, several biomarkers were positively associated with BMC and BMD. For example, each doubling of MEP and MCPP, 1/3rd distal radius BMD Z -score increased by 0.09 (95% CI: 0.01, 0.17) and 0.16 (95% CI: 0.01, 0.31), respectively. For phthalate mixtures, associations were generally U-shaped among males and positive-linear among females, using both statistical methods. Mixture associations were strongest with forearm sites: in BKMR models, increasing all biomarkers from the 50th to 90th percentile was associated with a 0.64 (95% CI: 0.01, 1.28) greater 1/3rd distal radius BMD Z -score in males, and a 0.49 (95% CI: −0.13, 1.10) greater ultradistal radius BMD Z -score in females. In this study, phthalate exposures during gestation were associated with increased BMD Z-scores in early adolescence, though further research is needed to determine implications for long-term skeletal health. • Gestation may be a particularly susceptible period for osteotoxicant exposure. • Phthalates are ubiquitous chemicals used in plastics and consumer products. • Studies of pregnancy phthalate exposure and offspring bone health are scarce. • Phthalate levels associated with greater adolescent bone mineral density and content. [ABSTRACT FROM AUTHOR]

• Urinary biomarkers are subject to measurement error due to urine dilution. • Urine creatinine or specific gravity are often used to correct for dilution. • Urine creatinine and specific gravity vary systematically by several factors. • Methods to correct for dilution should account for these factors to minimize bias. Urinary biomarkers are often corrected for sample dilution using creatinine, which is influenced by sociodemographic factors and certain health conditions. It is unknown whether these factors similarly influence specific gravity. To identify predictors of specific gravity and creatinine and compare methods for correcting estimated chemical concentrations for sample dilution using these measures. We assessed predictors of urinary specific gravity and creatinine among NHANES 2007–2008 participants (n = 7257). We corrected concentrations of mono-n-butyl phthalate (MnBP) for dilution using two methods, each applied to both specific gravity and creatinine: correction using a sample mean of the dilution indicator (i.e., specific gravity or creatinine) and covariate-adjusted standardization. We compared distributions and assessed the agreement of uncorrected or corrected concentrations visually using Bland-Altman plots and statistically by Kendall's τ a. We stratified all analyses by age category (i.e., 6–19 or 20+ years of age). Gender, race/ethnicity, body mass index, and height were associated with urinary specific gravity and creatinine. Distributions of corrected MnBP concentrations were comparable for both methods and dilution indicators, but agreement between methods was greater for specific gravity. Additionally, specific gravity- and creatinine-corrected MnBP concentrations had slightly greater agreement with each other when corrected using a covariate-adjusted standardization method. Specific gravity, like creatinine, is associated with sociodemographic and body composition variables. Accounting for these factors as part of the dilution correction method may be important to minimize bias. [ABSTRACT FROM AUTHOR]

• First study of associations between prenatal OP exposures and child adiposity. • No associations observed between prenatal ∑DMP and ∑DEP and child fat mass or BMI. • Maternal PON1 genotype may modify associations with child adiposity. Animal studies suggest that organophosphorus pesticides (OPs) may be environmental obesogens. While prenatal OP exposures have been associated with altered infant glucose metabolism, associations with pediatric adiposity remain unknown. We summed concentrations of three dimethylphosphate (∑DMP) and three diethylphosphate (∑DEP) metabolites of OPs measured in third trimester spot urine samples collected from pregnant women enrolled in New York City, 1998–2002. We measured percent fat mass using bio-electrical impedance analysis and calculated age- and sex-standardized body mass index (BMI) z-scores from anthropometric measurements collected at approximately 4, 6, and 7–9 years of age (166 children, 333 observations). We assessed covariate-adjusted associations of OPs with repeated adiposity measures using linear mixed models and evaluated effect measure modification (EMM) by sex and paroxonase (PON) 1 –108C/T and Q192R polymorphisms measured in maternal peripheral blood samples. The geometric mean urinary concentration of ∑DMP metabolites (29.9 nmol/L, IQR: 105.2 nmol/L) was higher than ∑DEP metabolites (8.8 nmol/L, IQR: 31.2 nmol/L). Adjusted associations were null, with differences in fat mass per 10-fold increase in prenatal ∑DMP and ∑DEP concentrations of 0.7% (95% CI: −0.6, 2.0) and 0.8% (95% CI: −0.4, 2.0), respectively. Maternal PON1 -108C /T polymorphisms modified relationships of prenatal ∑DMP with percent fat mass (EMM p-value = 0.18) and ∑DEP with BMI z-scores (EMM p-value = 0.12). For example, ∑DMP was modestly associated with increased percent fat mass among children of mothers with the at-risk CT or TT genotype (β = 1.2%, 95% CI: −0.6, 3.0) but not among those whose mothers had the CC genotype (β = −0.4%, 95% CI: −2.4, 1.5). Associations were not modified by sex or maternal PON1 Q192R polymorphisms. We observed little evidence of a relationship between prenatal OP exposures and child adiposity, although there was some suggestion of increased risk among offspring of mothers who were slow OP metabolizers. Larger studies are warranted to further evaluate possible associations of prenatal OP exposures with child adiposity and differences by maternal PON1 genotype, which regulates OP metabolism and may increase susceptibility to exposure. [ABSTRACT FROM AUTHOR]