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BACKGROUND: Gestational phthalate and phenol exposure disrupts adipogenesis, contributing to obesity in mice. Whether gestational phthalate or phenol exposure is associated with infant body composition has not been investigated in humans. OBJECTIVE: We examined associations between biomarkers of phthalate and phenol exposure in midpregnancy and infant size and body composition at birth and at 5 months of age. METHODS: Analyses were conducted among 438 infants from the Healthy Start prospective pregnancy cohort. Sixteen phthalate and phenol biomarkers were quantified in spot urine samples collected at 24–28 wk of gestation. Infant outcomes measured at birth and at 5 months of age included size [weight (in grams)] and body composition [fat and lean masses (in grams); percentage fat mass]. Single- (linear) and multipollutant (quantile g-computation) models were used to estimate associations of phthalate and phenol biomarkers with infant outcomes at birth and at 5 months of age. Models were adjusted for sociodemographics, sample collection timing, and lifestyle factors and used to examine for effect modification by infant sex. RESULTS: In single-pollutant models, mono-benzyl phthalate and di-n-butyl phthalate were inversely associated with percentage fat mass [ß: -0.49 (95% CI: -0:91, -0:08) and -0:51 (95% CI: -1.02, 0.01), respectively] in male but not female infants at birth. Similar, but less precise, associations were observed at 5 months of age. In multipollutant models, a 1-quartile increase in the phthalate and phenol biomarker mixture was inversely associated with percentage fat mass at birth [-1.06 (95% CI: -2.21, 0.1)] and at 5 months of age [-2.14 (95% CI: -3.88, -0.39)] among males, but associations were null among females [0.48 (95% CI: -0.78, 1.75) and -0.64 (95% CI: -2.68, 1.41), respectively]. Similar associations were observed with infant weight. CONCLUSION: In this U.S.-based prospective cohort, gestational phthalate and phenol biomarkers were inversely associated with infant weight and fat mass, particularly in males. [ABSTRACT FROM AUTHOR]

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

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype. OBJECTIVES: We estimated associations of prenatal PFAS with DNA methylation in umbilical cord blood. We evaluated associations of methylation at selected sites with neonatal cardio-metabolic indicators. METHODS: Among 583 mother–infant pairs in a prospective cohort, five PFAS were quantified in maternal serum (median 27 wk of gestation). Umbilical cord blood DNA methylation was evaluated using the Illumina HumanMethylation450 array. Differentially methylated positions (DMPs) were evaluated at a false discovery rate (FDR)< 0.05 and differentially methylated regions (DMRs) were identified using comb-p (Å idák-adjusted 푝< 0.05). We estimated associations between methylation at candidate DMPs and DMR sites and the following outcomes: newborn weight, adiposity, and cord blood glucose, insulin, lipids, and leptin. RESULTS: Maternal serum PFAS concentrations were below the median for females in the U.S. general population. Moderate to high pairwise correlations were observed between PFAS concentrations (?= 0.28-0.76). Methylation at one DMP (cg18587484), annotated to the gene TJAP1, was associated with perfluorooctanoate (PFOA) at FDR < 0.05. Comb-p detected between 4 and 15 DMRs for each PFAS. Associated genes, some common across multiple PFAS, were implicated in growth (RPTOR), lipid homeostasis (PON1, PON3, CIDEB, NR1H2), inflammation and immune activity (RASL11B, RNF39), among other functions. There was suggestive evidence that two PFAS-associated loci (cg09093485, cg09637273) were associated with cord blood triglycerides and birth weight, respectively (FDR < 0.1). DISCUSSION: DNA methylation in umbilical cord blood was associated with maternal serum PFAS concentrations during pregnancy, suggesting potential associations with offspring growth, metabolism, and immune function. Future research should explore whether DNA methylation changes mediate associations between prenatal PFAS exposures and child health outcomes. [ABSTRACT FROM AUTHOR]

Background: Per- and polyfluoroalkyl substances (PFAS) are a chemical class widely used in industrial and commercial applications because of their unique physical and chemical properties. Between 2013 and 2016 PFAS were detected in public water systems and private wells in El Paso County, Colorado. The contamination was likely due to aqueous film forming foams used at a nearby Air Force base.Objective: To cross-sectionally describe the serum concentrations of PFAS in a highly exposed community, estimate associations with drinking water source, and explore potential demographic and behavioral predictors.Methods: In June 2018, serum PFAS concentrations were quantified and questionnaires administered in 213 non-smoking adult (ages 19-93) participants residing in three affected water districts. Twenty PFAS were quantified and those detected in >50% of participants were analyzed: perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA) and perfluoroheptane sulfonate (PFHpS). Unadjusted associations were estimated between serum PFAS concentrations and several predictors, including water consumption, demographics, personal behaviors and employment. A multiple linear regression model estimated adjusted associations with smoking history.Results: Study participants' median PFHxS serum concentration (14.8 ng/mL) was approximately 12 times as high as the U.S. national average. Median serum concentrations for PFOS, PFOA, PFNA and PFHpS were 9.7 ng/mL, 3.0 ng/mL, 0.4 ng/mL and 0.2 ng/mL, respectively. Determinants of PFHxS serum concentrations were water district of residence, frequency of bottled water consumption, age, race/ethnicity, and smoking history. Determinants of serum concentrations for the other four PFAS evaluated included: water district of residence, bottled water consumption, age, sex, race/ethnicity, smoking history, and firefighter or military employment.Conclusions: Determinants of serum concentrations for multiple PFAS, including PFHxS, included water district of residence and frequency of bottled water consumption. Participants' dominant PFAS exposure route was likely consumption of PFAS-contaminated water, but certain demographic and behavioral characteristics also predicted serum concentrations. [ABSTRACT FROM AUTHOR]

The article comments on a study which investigated the associations between serum per- and polyfluoroalkyl (PFAS) concentrations and antibody response to vaccination against SARS-CoV-2 in adults in Ronneby, Sweden. It points out the failure of the study to indicate the adverse effects of PFAS exposure on antibody response to vaccination against SARS-CoV-2 in adults, as well to identify the role of underlying vulnerability and resilience factors in diverse populations.

Background: Maternal dietary intake during pregnancy may influence offspring growth and adiposity. Specific dietary patterns associated with newborn adiposity have not been identified.Objective: We aimed to identify patterns of maternal dietary intake associated with gestational weight gain (GWG) and fasting glucose during pregnancy and to evaluate whether adherence to these patterns is associated with newborn adiposity.Methods: In the Healthy Start prospective cohort, dietary intake during pregnancy was assessed via 24-h recalls. Reduced-rank regression identified dietary patterns predictive of GWG and fasting glucose. Associations between dietary patterns and newborn fat mass, fat-free mass, and adiposity were estimated by using linear regression models among 764 ethnically diverse mother-infant pairs.Results: Two dietary patterns were identified. Pattern 1, correlated with greater GWG (r = 0.22, P < 0.01), was characterized by a higher consumption of poultry, nuts, cheese, fruits, whole grains, added sugars, and solid fats. Greater adherence to pattern 1 (upper compared with lower tertile) predicted a greater newborn fat-free mass (61 g; 95% CI: 12, 110 g) but no difference in fat mass or adiposity. Pattern 2, correlated with greater maternal fasting glucose (r = 0.16, P < 0.01), was characterized by a higher consumption of eggs, starchy vegetables, solid fats, fruits, and nonwhole grains and a lower consumption of dairy foods, dark-green vegetables, and whole grains. Greater adherence to pattern 2 was associated with a greater newborn birth weight (80 g; 95% CI: 15, 145 g), fat mass (33 g; 95% CI: 8, 59 g), and adiposity (0.9%; 95% CI: 0.3%, 1.6%).Conclusions: Among pregnant women, adherence to a dietary pattern characterized by an intake of poultry, nuts, cheese, and whole grains was associated with greater GWG but not maternal fasting glucose or newborn adiposity. Adherence to a pattern characterized by an intake of eggs, starchy vegetables, and nonwhole grains was associated with higher maternal fasting glucose and greater newborn adiposity. Maternal dietary patterns during pregnancy may influence newborn body composition. [ABSTRACT FROM AUTHOR]

BACKGROUND: Certain perfluoroalkyl and polyfluoroalkyl substances (PFAS) are widespread, persistent environmental contaminants. Prenatal PFAS exposure has been associated with lower birth weight; however, impacts on body composition and factors responsible for this association are unknown. OBJECTIVES: We aimed to estimate associations between maternal PFAS concentrations and offspring weight and adiposity at birth, and secondarily to estimate associations between PFAS concentrations and maternal glucose and lipids, and to evaluate the potential for these nutrients to mediate associations between PFAS and neonatal outcomes. METHODS: Within the Healthy Start prospective cohort, concentrations of 11 PFAS, fasting glucose, and lipids were measured in maternal mid-pregnancy serum (n=628). Infant body composition was measured using air displacement plethysmography. Associations between PFAS and birth weight and adiposity, and between PFAS and maternal glucose and lipids, were estimated via linear regression. Associations were decomposed into direct and indirect effects. RESULTS: Five PFAS were detectable in >50% of participants. Maternal perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) concentrations were inversely associated with birth weight. Adiposity at birth was approximately 10% lower in the highest categories of PFOA, PFNA, and perfluorohexane sulfonate (PFHxS) compared to the lowest categories. PFOA, PFNA, perfluorodecanoate (PFDeA), and PFHxS were inversely associated with maternal glucose. Up to 11.6% of the effect of PFAS on neonatal adiposity was mediated by maternal glucose concentrations. Perfluorooctane sulfonate (PFOS) was not significantly associated with any outcomes studied. CONCLUSIONS: Follow-up of offspring will determine the potential long-term consequences of lower weight and adiposity at birth associated with prenatal PFAS exposure. [ABSTRACT FROM AUTHOR]

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

Perfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants, and human exposure to these substances may be related to preeclampsia, a common pregnancy complication. Previous studies have found serum concentrations of PFAS to be positively associated with pregnancy-induced hypertension and preeclampsia in a population with high levels of exposure to perfluorooctanoate. Whether this association exists among pregnant women with background levels of PFAS exposure is unknown. Using data from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health, we carried out a study of nulliparous pregnant women enrolled in 2003–2007 (466 cases, 510 noncases) to estimate associations between PFAS concentrations and an independently validated diagnosis of preeclampsia. We measured levels of 9 PFAS in maternal plasma extracted midpregnancy; statistical analyses were restricted to 7 PFAS that were quantifiable in more than 50% of samples. In proportional hazards models adjusted for maternal age, prepregnancy body mass index (weight (kg)/height (m)2), educational level, and smoking status, we observed no strongly positive associations between PFAS levels and preeclampsia. We found an inverse association between preeclampsia and the highest quartile of perfluoroundecanoic acid concentration relative to the lowest quartile (hazard ratio = 0.55, 95% confidence interval: 0.38, 0.81). Overall, our findings do not support an increased risk of preeclampsia among nulliparous Norwegian women with background levels of PFAS exposure. [ABSTRACT FROM AUTHOR]

Abstract: Background: Perfluoroalkyl substances (PFASs) are widespread and persistent environmental pollutants. Previous studies, primarily among non-pregnant individuals, suggest positive associations between PFAS levels and certain blood lipids. If there is a causal link between PFAS concentrations and elevated lipids during pregnancy, this may suggest a mechanism by which PFAS exposure leads to certain adverse pregnancy outcomes, including preeclampsia. Methods: This cross-sectional analysis included 891 pregnant women enrolled in the Norwegian Mother and Child (MoBa) Cohort Study in 2003–2004. Non-fasting plasma samples were obtained at mid-pregnancy and analyzed for nineteen PFASs. Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured in plasma. Linear regression was used to quantify associations between each PFAS exposure and each lipid outcome. A multiple PFAS model was also fitted. Results: Seven PFASs were quantifiable in >50% of samples. Perfluorooctane sulfonate (PFOS) concentration was associated with total cholesterol, which increased 4.2mg/dL per inter-quartile shift (95% CI=0.8, 7.7) in adjusted models. Five of the seven PFASs studied were positively associated with HDL cholesterol, and all seven had elevated HDL associated with the highest quartile of exposure. Perfluoroundecanoic acid showed the strongest association with HDL: HDL increased 3.7mg/dL per inter-quartile shift (95% CI=2.5, 4.9). Conclusion: Plasma concentrations of PFASs were positively associated with HDL cholesterol, and PFOS was positively associated with total cholesterol in this sample of pregnant Norwegian women. While elevated HDL is not an adverse outcome per se, elevated total cholesterol associated with PFASs during pregnancy could be of concern if causal. [Copyright &y& Elsevier]

Background: Perfluoroalkyl substances (PFASs) are a group of highly persistent chemicals that are widespread contaminants in wildlife and humans. Exposure to PFAS affects thyroid homeostasis in experimental animals and possibly in humans. The objective of this study was to examine the association between plasma concentrations of PFASs and thyroid stimulating hormone (TSH) among pregnant women. Methods: A total of 903 pregnant women who enrolled in the Norwegian Mother and Child Cohort Study from 2003 to 2004 were studied. Concentrations of thirteen PFASs and TSH were measured in plasma samples collected around the 18th week of gestation. Linear regression models were used to evaluate associations between PFASs and TSH. Results: Among the thirteen PFASs, seven were detected in more than 60% of samples and perfluorooctane sulfonate (PFOS) had the highest concentrations (median, 12.8 ng/mL; inter-quartile range [IQR], 10.1 -16.5 ng/mL). The median TSH concentration was 3.5 (IQR, 2.4 - 4.8) μIU/mL. Pregnant women with higher PFOS had higher TSH levels. After adjustment, with each 1 ng/mL increase in PFOS concentration, there was a 0.8% (95% confidence interval: 0.1%, 1.6%) rise in TSH. The odds ratio of having an abnormally high TSH, however, was not increased, and other PFASs were unrelated to TSH. Conclusions: Our results suggest an association between PFOS and TSH in pregnant women that is small and may be of no clinical significance. [ABSTRACT FROM AUTHOR]

Abstract: Fecal glucocorticoid (fGC) concentrations are reliable, non-invasive indices of physiological stress that provide insight into an animal''s energetic and social demands. To better characterize the long-term stressors in adult members of a female-dominant, seasonally breeding species – the ring-tailed lemur (Lemur catta) – we first validated fecal samples against serum samples and then examined the relationship between fGC concentrations and seasonal, social, demographic, genetic, and reproductive variables. Between 1999 and 2006, we collected 1386 fecal samples from 32 adult, semi-free-ranging animals of both sexes. In males and non-pregnant, non-lactating females, fGC concentrations were significantly elevated during the breeding season, specifically during periods surrounding known conceptions. Moreover, group composition (e.g., multi-male versus one-male) significantly predicted the fGC concentrations of males and females in all reproductive states. In particular, the social instability introduced by intra-male competition likely created a stressor for all animals. We found no relationship, however, between fGC and the sex, age, or heterozygosity of animals. In reproducing females, fGC concentrations were significantly greater during lactation than during the pre-breeding period. During pregnancy, fGC concentrations were elevated in mid-ranking dams, relative to dominant or subordinate dams, and significantly greater during the third trimester than during the first or second trimesters. Thus, in the absence of nutritional stressors, social dominance was a relatively poor predictor of fGC in this female-dominant species. Instead, the animals were maximally challenged by their social circumstances and reproductive events—males by competition for mating opportunities and females by late-term gestation and lactation. [Copyright &y& Elsevier]

The article presents a study that examines the skeletal remains of Egyptian and Nubian agriculturists to assess the health and physiological stress of the population. Under the study, the remains were scored for the presence of linear enamel hypoplasia (LEH) of the dentition. Result shows a high prevalence of LEH and suggests poor health and high stress among Nile valley agriculturists. It also indicates that agricultural innovation occurred as a response to ecological or demographic pressure.

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

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

Prenatal exposures to ambient air pollution and traffic have been associated with adverse birth outcomes, and may also lead to an increased risk of obesity. Obesity risk may be reflected in changes in body composition in infancy. To estimate associations between prenatal ambient air pollution and traffic exposure, and infant weight and adiposity in a Colorado-based prospective cohort study. Participants were 1125 mother-infant pairs with term births. Birth weight was recorded from medical records and body composition measures (fat mass, fat-free mass, and adiposity [percent fat mass]) were evaluated via air displacement plethysmography at birth (n = 951) and at ~5 months (n = 574). Maternal residential address was used to calculate distance to nearest roadway, traffic density, and ambient concentrations of fine particulate matter (PM 2.5) and ozone (O 3) via inverse-distance weighted interpolation of stationary monitoring data, averaged by trimester and throughout pregnancy. Adjusted linear regression models estimated associations between exposures and infant weight and body composition. Participants were urban residents and diverse in race/ethnicity and socioeconomic status. Average ambient air pollutant concentrations were generally low; the median, interquartile range (IQR), and range of third trimester concentrations were 7.3 μg/m3 (IQR: 1.3, range: 3.3–12.7) for PM 2.5 and 46.3 ppb (IQR: 18.4, range: 21.7–63.2) for 8-h maximum O 3. Overall there were few associations between traffic and air pollution exposures and infant outcomes. Third trimester O 3 was associated with greater adiposity at follow-up (2.2% per IQR, 95% CI 0.1, 4.3), and with greater rates of change in fat mass (1.8 g/day, 95% CI 0.5, 3.2) and adiposity (2.1%/100 days, 95% CI 0.4, 3.7) from birth to follow-up. We found limited evidence of an association between prenatal traffic and ambient air pollution exposure and infant body composition. Suggestive associations between prenatal ozone exposure and early postnatal changes in body composition merit further investigation. • Exposure to traffic and air pollution was estimated for 1125 pregnant women. • Offspring body composition was assessed at birth and at ~5 months old. • We found limited evidence of associations with prenatal traffic and air pollution. • Third trimester 8-h maximum ozone was associated with greater 5-month adiposity. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is the leading cause of death among individuals with diabetes, but little is known about the role of exposures to environmental chemicals such as pesticides in the early development of CVD risk in this population. To describe changes over time in concentrations of pesticide biomarkers among youth with diabetes in the United States and to estimate the longitudinal association between these concentrations and established risk factors for CVD. Pesticide biomarkers were quantified in urine and serum samples from 87 youth with diabetes participating in the multi-center SEARCH cohort study. Samples were obtained around the time of diagnosis (baseline visit, between 2006 and 2010) and, on average, 5.4 years later (follow-up visit, between 2012 and 2015). We calculated geometric mean (95% CI) pesticide biomarker concentrations. Eight CVD risk factors were measured at these two time points: body mass index (BMI) z-score, HbA1c, insulin sensitivity, fasting C-peptide (FCP), LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. Linear regression models were used to estimate the associations between each pesticide biomarker at baseline and each CVD risk factor at follow-up, adjusting for baseline health outcome, elapsed time between baseline and follow up, sex, age, race/ethnicity, and diabetes type. Participants were, on average, 14.2 years old at their baseline visit, and most were diagnosed with type 1 diabetes (57.5%). 4-nitrophenol, 3-phenoxybenzoic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), 3,5,6-trichloro-2-pyridinol, 2,2-bis(4-chlorophenyl)-1,1-dichloroethene, and hexachlorobenzene were detected in a majority of participants at both time points. Participants in the highest quartile of 2,4-D and 4-nitrophenol at baseline had HbA1c levels at follow-up that were 1.05 percentage points (95% CI: −0.40, 2.51) and 1.27 percentage points (0.22, 2.75) higher, respectively, than participants in the lowest quartile of these pesticide biomarkers at baseline. These participants also had lower log FCP levels (indicating reduced beta-cell function) compared to participants in the lowest quartile at baseline: beta (95% CI) for log FCP of −0.64 (−1.17, −0.11) for 2,4-D and −0.39 (−0.96, 0.18) for 4-nitrophenol. In other words, participants in the highest quartile of 2,4-D had a 47.3% lower FCP level compared to participants in the lowest quartile, and those in the highest quartile of 4-nitrophenol had a 32.3% lower FCP level than those in the lowest quartile. Participants with trans-nonachlor concentrations in the highest quartile at baseline had HbA1c levels that were 1.45 percentage points (−0.11, 3.01) higher and log FCP levels that were −0.28 (−0.84, 0.28) lower than participants in the lowest quartile at baseline, that is to say, participants in the highest quartile of trans-nonachlor had a 24.4% lower FCP level than those in the lowest quartile. While not all of these results were statistically significant, potentially due to the small same size, clinically, there appears to be quantitative differences. No associations were observed between any pesticide biomarker at baseline with BMI z-score or insulin sensitivity at follow-up. Exposure to select pesticides may be associated with impaired beta-cell function and poorer glycemic control among youth with diabetes. • Prospective associations of pesticides with clinical outcomes in youth with diabetes. • 2,4-D and 4-nitrophenol were associated with poorer glycemic control. • 2,4-D and 4-nitrophenol were associated with impaired beta-cell function. • Trans-nonachlor was associated with poorer glycemic control. • Trans-nonachlor was associated with impaired beta-cell function. [ABSTRACT FROM AUTHOR]

Prenatal exposures to certain per - and polyfluoroalkyl substances (PFAS) have been linked to lower weight and adiposity at birth but greater weight and adiposity in childhood. We hypothesized that faster growth in early infancy may be associated with maternal PFAS concentrations. Among 415 mother-infant pairs in a longitudinal cohort study, we estimated associations between maternal pregnancy serum concentrations of six PFAS and offspring weight and adiposity at ~5 months of age, and growth in early infancy. Linear and logistic regression models were adjusted for potential confounders including maternal pre-pregnancy body mass index. Effect modification by infant sex was evaluated. We evaluated potential confounding by correlated exposures via multipollutant linear regression and elastic net penalized regression. Associations between maternal PFAS concentrations and infant weight and adiposity differed by offspring sex. In male infants, maternal perfluorooctanoate and perfluorononanoate were positively associated with adiposity, with percent fat mass increases of 1.5–1.7% per ln-ng/mL increase in PFAS (median adiposity at ~5 months: 24.6%). Maternal perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were associated with lower weight-for-age z-score among female infants only (−0.26 SD per ln-ng/mL PFOS, 95% CI −0.43, −0.10; −0.17 SD per ln-ng/mL PFHxS, 95% CI −0.33, −0.01). In analyses pooled by sex, 2-(N -methyl-perfluorooctane sulfonamido) acetate above vs. below the limit of detection was associated with greater odds of rapid growth in weight-for-age (odds ratio [OR] 2.2, 95% CI 1.1, 4.3) and weight-for-length (OR 3.3, 95% CI 1.8, 6.2). Multipollutant models generally confirmed the results and strengthened some associations. We observed sex- and chemical-specific associations between maternal serum PFAS concentrations and infant weight and adiposity. Multipollutant models suggested confounding by correlated PFAS with opposing effects. Although maternal PFAS concentrations are inversely associated with infant weight and adiposity at birth, rapid gain may occur in infancy, particularly in fat mass. • Associations between maternal PFAS and infant weight and adiposity differed by sex. • Prenatal PFOA and PFNA were associated with greater 5-month adiposity in males. • Prenatal PFOS and PFHxS were associated with lower weight-for-age in females. • MeFOSAA was associated with greater odds of rapid growth from 0 to 5 months of age. [ABSTRACT FROM AUTHOR]

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

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

Background: Perfluoroalkyl substances (PFASs) are a group of highly persistent chemicals that are widespread contaminants in wildlife and humans. Exposure to PFAS affects thyroid homeostasis in experimental animals and possibly in humans. The objective of this study was to examine the association between plasma concentrations of PFASs and thyroid stimulating hormone (TSH) among pregnant women.Methods: A total of 903 pregnant women who enrolled in the Norwegian Mother and Child Cohort Study from 2003 to 2004 were studied. Concentrations of thirteen PFASs and TSH were measured in plasma samples collected around the 18th week of gestation. Linear regression models were used to evaluate associations between PFASs and TSH.Results: Among the thirteen PFASs, seven were detected in more than 60% of samples and perfluorooctane sulfonate (PFOS) had the highest concentrations (median, 12.8 ng/mL; inter-quartile range [IQR], 10.1 -16.5 ng/mL). The median TSH concentration was 3.5 (IQR, 2.4 - 4.8) μIU/mL. Pregnant women with higher PFOS had higher TSH levels. After adjustment, with each 1 ng/mL increase in PFOS concentration, there was a 0.8% (95% confidence interval: 0.1%, 1.6%) rise in TSH. The odds ratio of having an abnormally high TSH, however, was not increased, and other PFASs were unrelated to TSH.Conclusions: Our results suggest an association between PFOS and TSH in pregnant women that is small and may be of no clinical significance. [ABSTRACT FROM AUTHOR]

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

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

Certain endocrine-disrupting chemicals (EDCs) are widespread in consumer products and may alter glucose metabolism. However, the impact of EDC exposures on glucose and insulin regulation during pregnancy is incompletely understood, despite potential adverse consequences for maternal and infant health. We estimated associations between 37 urinary biomarkers of EDCs and glucose-insulin traits among pregnant women. Seventeen phthalate or phthalate substitute metabolites, six environmental phenols, four parabens, and ten organophosphate ester metabolites were quantified in mid-pregnancy urine from 298 participants in the Healthy Start Study. Fasting blood glucose, insulin, and hemoglobin A1c were assessed concurrently, and Homeostasis Model Assessment 2-Insulin Resistance (HOMA2-IR) was calculated. Gestational diabetes diagnoses and screening results were obtained from medical records for a subset of participants. We estimated associations between each EDC and outcome separately using linear and robust Poisson regression models and analyzed EDC mixture effects. The EDC mixture was positively associated with glucose, insulin, and HOMA2-IR, although overall associations were attenuated after adjustment for maternal BMI. Two mixture approaches identified di(2-ethylhexyl) phthalate (DEHP) metabolites as top contributors to the mixture's positive associations. In single-pollutant models, DEHP metabolites were positively associated with fasting glucose, fasting insulin, and HOMA2-IR even after adjustment for maternal BMI. For example, each interquartile range increase in log 2 -transformed mono(2-ethyl-5-oxohexyl) phthalate was associated with 2.4 mg/dL (95% confidence interval (CI): 1.1, 3.6) higher fasting glucose, 11.8% (95%CI: 3.6, 20.5) higher fasting insulin, and 12.3% (95%CI: 4.2, 21.1) higher HOMA2-IR. Few EDCs were associated with hemoglobin A1c or with a combined outcome of impaired glucose tolerance or gestational diabetes. Exposures to phthalates and particularly DEHP during pregnancy are associated with altered glucose-insulin regulation. Disruptions in maternal glucose metabolism during pregnancy may contribute to adverse pregnancy outcomes including gestational diabetes and fetal macrosomia, and associated long-term consequences for maternal and child health. • DEHP metabolites were positively associated with fasting glucose at mid-pregnancy. • DEHP metabolites were positively associated with HOMA2-IR at mid-pregnancy. • Results were generally consistent between single- and multi-pollutant models. • Few other endocrine disruptors were associated with glucose-insulin traits. [ABSTRACT FROM AUTHOR]

Existing evidence suggests that exposure to phthalates is higher among younger age groups. However, limited knowledge exists on how phthalate exposure, as well as exposure to replacement plasticizers, di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) and di-2-ethylhexyl terephthalate (DEHTP), change from infancy through early childhood. Urine samples were collected across the first 5 years of life from typically developing infants and young children enrolled between 2017 and 2020 in the longitudinal UNC Baby Connectome Project. From 438 urine samples among 187 participants, we quantified concentrations of monobutyl phthalate (MnBP), mono-3-carboxypropyl phthalate (MCPP), monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), and metabolites of di(2-ethylhexyl) phthalate (DEHP), diisonoyl phthalate (DiNP), DINCH and DEHTP. Specific gravity (SG) adjusted metabolite and molar sum concentrations were compared across age groups. Intraclass correlation coefficients (ICCs) were calculated among 122 participants with multiple urine specimens (373 samples). Most phthalate metabolites showed high detection frequencies (>80% of samples). Replacement plasticizers DINCH (58–60%) and DEHTP (>97%) were also commonly found. DiNP metabolites were less frequently detected (<10%). For some metabolites, SG-adjusted concentrations were inversely associated with age, with the highest concentrations found in the first year of life. ICCs revealed low to moderate reliability in metabolite measurements (ρ = 0.10–0.48) suggesting a high degree of within-individual variation in exposure among this age group. The first 6 months (compared to remaining age groups) showed an increased ratio of carboxylated metabolites of DEHP and DEHTP, compared to other common metabolites, but no clear age trends for DINCH metabolite ratios were observed. Metabolites of phthalates and replacements plasticizers were widely detected in infancy and early childhood, with the highest concentrations observed in the first year of life for several metabolites. Higher proportions of carboxylated metabolites of DEHP and DEHTP in younger age groups indicate potential differences in metabolism during infancy. • We quantified metabolites of phthalates and replacement plasticizers from urine samples collected in infancy/early childhood. • We found widespread exposure to a range of phthalates and replacement plasticizers among this age group. • We found highest concentrations of several phthalates, including MnBP, MCPP, MiBP, MEP, and MBzP, in the first year of life. • Proportions of carboxylated metabolites of DEHP and DEHTP were higher in the first six months compared to remaining ages. [ABSTRACT FROM AUTHOR]

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

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

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

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

OBJECTIVE Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345–248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870–135342620) was located in the gene body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate–adjusted P value threshold of 0.05. CONCLUSIONS Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences. [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 exposure to air pollution, such as particulate matter ≤2.5 μm (PM 2.5), may be associated with obesity and adverse cardiometabolic health outcomes in childhood. However, the toxicity of PM 2.5 varies according to its chemical composition. Black carbon (BC) is a constituent of PM 2.5 , but few studies have examined its impact on childhood cardiometabolic health. Therefore, we examined relationships between prenatal and early childhood exposure to BC and markers of adiposity and cardiometabolic health in early childhood. This study included 578 mother-child pairs enrolled in the Healthy Start study (2009–2014) living in the Denver-metro area. Using a spatiotemporal prediction model, we assessed average residential black carbon levels during pregnancy and in the year prior to the early childhood follow-up visit at approximately 5 years old. We estimated associations between prenatal and early childhood BC and indicators of adiposity and cardiometabolic biomarkers in early childhood (mean 4.8 years; range, 4.0, 8.3), using linear regression. We found higher early childhood BC was associated with higher percent fat mass, fat mass index, insulin, and homeostatic model assessment for insulin resistance (HOMA-IR), and lower leptin and waist circumference at approximately 5 years old, after adjusting for covariates. For example, per interquartile range (IQR) increase in early childhood BC (IQR, 0.49 μg/m3) there was 3.32% higher fat mass (95% CI; 2.05, 4.49). Generally, we did not find consistent evidence of associations between prenatal BC and cardiometabolic health outcomes in early childhood, except for an inverse association between prenatal BC and adiponectin, an adipocyte-secreted hormone typically inversely associated with adiposity. Higher early childhood, but not in utero , ambient concentrations of black carbon, a component of air pollution, were associated with greater adiposity and altered insulin homeostasis at approximately 5 years old. Future studies should examine whether these changes persist later in life. • Black carbon concentrations during pregnancy and in early childhood for the offspring were estimated.. • Body composition and biomarkers of cardiometabolic health were measured in children at approximately 5 years of age. • Higher early childhood black carbon concentrations were associated with greater adiposity and altered insulin homeostasis. • Overall, prenatal black carbon was not associated with cardiometabolic outcomes in early childhood. [ABSTRACT FROM AUTHOR]

and perfluoroalkyl substances (PFAS) in early life may increase the risk of childhood asthma, but evidence has been inconsistent. We estimated associations between maternal serum concentrations of PFAS during pregnancy and clinician-diagnosed asthma incidence in offspring through age eight. We included 597 mother-child pairs with PFAS quantified in mid-pregnancy serum and childhood medical records reviewed for asthma diagnoses. We used separate Cox proportional hazards models to assess the relationship between log-transformed concentrations of five PFAS and the incidence of asthma. We estimated associations between the PFAS mixture and clinician-diagnosed asthma incidence using quantile-based g-computation. PFAS concentrations were similar to those among females in the US general population. Seventeen percent of children (N = 104) were diagnosed with asthma during follow-up. Median (interquartile range) duration of follow-up was 4.7 (4.0, 6.2) years, and median age at asthma diagnosis was 1.7 (0.9, 2.8) years. All adjusted hazard ratios (HRs) were elevated, but all 95% confidence intervals (CI) included the null. The HR (95% CI) of asthma for a one-quartile increase in the PFAS mixture was 1.17 (0.86, 1.61). In this cohort of children followed to eight years of age, prenatal PFAS concentrations were not significantly associated with incidence of clinician-diagnosed asthma. • Prenatal exposures to five PFAS were quantified among 597 mother-child pairs. • Asthma diagnoses were obtained from childhood medical records through age 8 years. • Individual PFAS and the PFAS mixture were not associated with childhood asthma risk. • We did not observe effect modification by the sex of the child. [ABSTRACT FROM AUTHOR]

Background Phthalates and phenols are suspected endocrine disrupting chemicals that may adversely impact fetal outcomes following in utero exposure. Understanding predictors of exposure to phthalates and phenols during the prenatal period is important. Methods We measured urinary concentrations of 15 phthalate metabolites and 11 phenols in 446 pregnant women enrolled in the Healthy Start pre-birth cohort. Creatinine-adjusted geometric means (GM) for each urinary biomarker were compared across categories of potential sociodemographic and dietary predictors. To assess the independent relationship between each significant food group predictor and biomarker we used multivariable models, adjusted for sociodemographic predictors. Results The phthalate metabolites with the highest concentrations were monoethyl phthalate (GM: 41.1 µg/g creatinine) and monocarboxyisooctyl phthalate (GM: 20.5 µg/g creatinine). Benzophenone-3 (GM: 124.6 µg/g creatinine) and methyl paraben (GM: 119.9 µg/g creatinine) were the phenols with the highest concentrations. Concentrations of the metabolites of di-n-butyl phthalate and di(2-ethylhexyl) phthalate were significantly higher in younger, unmarried or unemployed mothers, those who were overweight or obese, those with lower educational attainment, or those of minority race/ethnicity (p-values < 0.05). Metabolites of di-n-butyl phthalate concentrations were 18% lower in those who consumed milk ≥ 7 times per week (95% CI: 30–4%). Benzophenone-3 and triclosan concentrations were significantly higher in older, married, or employed mothers, those with normal body mass index, higher educational attainment, higher household income, or who were non-Hispanic white (p-values < 0.05). Benzophenone-3 concentrations were 62% higher in those who consumed seafood ≥ 5 times per month (95% CI: 16–127%). Conclusions We observed differences in urinary concentrations of phthalates and phenol biomarkers by sociodemographic predictors in an ethnically diverse cohort of pregnant women. These results and future analyses from this prospective cohort will help inform targeted interventions to reduce exposure to these potential endocrine disrupting chemicals during pregnancy. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous, environmentally persistent chemicals, and prenatal exposures have been associated with adverse child health outcomes. Prenatal PFAS exposure may lead to epigenetic age acceleration (EAA), defined as the discrepancy between an individual's chronologic and epigenetic or biological age. We estimated associations of maternal serum PFAS concentrations with EAA in umbilical cord blood DNA methylation using linear regression, and a multivariable exposure-response function of the PFAS mixture using Bayesian kernel machine regression. Five PFAS were quantified in maternal serum (median: 27 weeks of gestation) among 577 mother-infant dyads from a prospective cohort. Cord blood DNA methylation data were assessed with the Illumina HumanMethylation450 array. EAA was calculated as the residuals from regressing gestational age on epigenetic age, calculated using a cord-blood specific epigenetic clock. Linear regression tested for associations between each maternal PFAS concentration with EAA. Bayesian kernel machine regression with hierarchical selection estimated an exposure-response function for the PFAS mixture. In single pollutant models we observed an inverse relationship between perfluorodecanoate (PFDA) and EAA (−0.148 weeks per log-unit increase, 95% CI: −0.283, −0.013). Mixture analysis with hierarchical selection between perfluoroalkyl carboxylates and sulfonates indicated the carboxylates had the highest group posterior inclusion probability (PIP), or relative importance. Within this group, PFDA had the highest conditional PIP. Univariate predictor-response functions indicated PFDA and perfluorononanoate were inversely associated with EAA, while perfluorohexane sulfonate had a positive association with EAA. Maternal mid-pregnancy serum concentrations of PFDA were negatively associated with EAA in cord blood, suggesting a pathway by which prenatal PFAS exposures may affect infant development. No significant associations were observed with other PFAS. Mixture models suggested opposite directions of association between perfluoroalkyl sulfonates and carboxylates. Future studies are needed to determine the importance of neonatal EAA for later child health outcomes. • Maternal perfluorodecanoate levels linked to decelerated epigenetic aging of child. • Perfluoroalkyl carboxylates, sulfonates had opposing effects on epigenetic aging. • Decelerated epigenetic aging associated with carboxylate exposures. • Mixtures analysis reflects effects of complex PFAS exposure profiles. • Epigenetic aging may suggest mechanism for PFAS exposure on later health outcomes. [ABSTRACT FROM AUTHOR]

Background: In mediation analysis if unmeasured confounding is present, the estimates for the direct and mediated effects may be over or under estimated. Most methods for the sensitivity analysis of unmeasured confounding in mediation have focused on the mediator-outcome relationship. Results: The Umediation R package enables the user to simulate unmeasured confounding of the exposure-mediator, exposure-outcome, and mediator-outcome relationships in order to see how the results of the mediation analysis would change in the presence of unmeasured confounding. We apply the Umediation package to the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study to examine the role of unmeasured confounding due to population stratification on the effect of a single nucleotide polymorphism (SNP) in the CHRNA5/3/B4 locus on pulmonary function decline as mediated by cigarette smoking. Conclusions: Umediation is a flexible R package that examines the role of unmeasured confounding in mediation analysis allowing for normally distributed or Bernoulli distributed exposures, outcomes, mediators, measured confounders, and unmeasured confounders. Umediation also accommodates multiple measured confounders, multiple unmeasured confounders, and allows for a mediator-exposure interaction on the outcome. Umediation is available as an R package at https://github.com/SharonLutz/Umediation A tutorial on how to install and use the Umediation package is available in the Additional file 1. [ABSTRACT FROM AUTHOR]

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

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

Few studies have demonstrated associations between maternal dietary inflammatory index (DII) during pregnancy and offspring asthma and/or wheeze. The study aimed to assess associations between maternal DII during pregnancy and 1) offspring cord sera pro-inflammatory cytokines (interleukin [IL]-1β, IL-4, IL-6, IL-10, tumor necrosis factor-α) and chemokines (IL-8, monocyte chemoattractant protein-1) at birth and 2) offspring asthma and/or wheeze at age 4 years. The Healthy Start study is a prospective prebirth longitudinal study that recruited pregnant women in Denver, Colorado and tracked their offspring. This study used data from 1228 mother-child dyads enrolled in the Healthy Start study. Pregnant women were recruited in Denver, Colorado, between 2009 and 2014, and offspring tracked until age 4 years. Cord sera cytokines and chemokines were analyzed with multiplex panel immunoassays. Offspring diagnosis of asthma and/or wheeze by age 4 years was extracted from electronic medical records. Unadjusted and adjusted linear and logistic regression models were used to assess associations. Covariates included factors such as nulliparity, race/ethnicity, gestational smoking, and maternal history of asthma. Unadjusted analysis showed that increasing maternal DII scores were associated with increased odds of child asthma and/or wheeze by 4 years (odds ratio = 1.17; 95% CI: 1.07-1.27), but the association was attenuated and no longer statistically significant in the adjusted model (odds ratio = 1.15; 95% CI: 0.99-1.33). There were no significant associations between DII scores and cord sera cytokine or chemokine levels. The study showed that the inflammatory profile of the maternal diet was not associated with cytokines and chemokine levels at birth. The results suggested that a more inflammatory maternal diet was associated with increased odds of offspring asthma and/or wheeze by age 4 years, which could be considered of clinical relevance but the finding was not statistically significant at the.05 level. [ABSTRACT FROM AUTHOR]

Air pollution exposure during pregnancy has been associated with adverse pregnancy and birth outcomes. Inflammation has been proposed as a potential link. We estimated associations between air pollution exposure during pregnancy and inflammatory biomarkers in maternal and cord blood. We evaluated whether maternal inflammation was associated with infant outcomes. Among 515 mother-infant dyads in the Healthy Start study (2009–2014), trimester-long, 7- and 30-day average concentrations of particulate matter ≤2.5 μm (PM 2.5) and ozone (O 3) during pregnancy were estimated, using inverse-distance-weighted interpolation. Inflammatory biomarkers were measured in maternal blood in mid-pregnancy (C-reactive protein [CRP], Interleukin [IL]-6, and tumor necrosis factor-α [TNFα]) and in cord blood at delivery (CRP, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1 [MCP-1], and TNFα). We used linear regression to estimate associations between pollutants and inflammatory biomarkers and maternal inflammatory biomarkers and infant weight and body composition. There were positive associations between PM 2.5 during certain exposure periods and maternal IL-6 and TNFα. There were negative associations between recent O 3 and maternal CRP, IL-6, and TNFα and positive associations between trimester-long O 3 exposure and maternal inflammatory biomarkers, though some 95% confidence intervals included the null. Patterns were inconsistent for associations between PM 2.5 and O 3 and cord blood inflammatory biomarkers. No consistent associations between maternal inflammatory biomarkers and infant outcomes were identified. Air pollution exposure during pregnancy may impact maternal inflammation. Further investigations should examine the health consequences for women and infants of elevated inflammatory biomarkers associated with air pollution exposure during pregnancy. • Exposure to particulate matter ≤2.5 and ozone was estimated for 515 pregnant women. • Inflammatory biomarkers were measured in maternal and cord blood. • Early pregnancy air pollution associated with mid-pregnancy maternal inflammation. • Inconsistent associations between prenatal air pollution and cord blood inflammation. • Maternal inflammatory markers did not predict infant outcomes. [ABSTRACT FROM AUTHOR]