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Context Per- and polyfluoroalkyl substances (PFAS) and phthalates are 2 families of environmental endocrine disruptors that may be associated with areal lower bone mineral density (aBMD). Objective To examine associations between serum PFAS and urinary phthalate biomarker concentrations and their mixtures with aBMD Z-scores in adolescents. Design, Patients, and Measures We examined serial cross-sectional data from male (n = 453) and female (n = 395) 12- to 19-year-old participants in the 2011 through 2016 National Health and Nutrition Examination Survey with measures of serum PFAS, urinary phthalate metabolites, and dual-energy X-ray absorptiometry aBMD Z-scores (total body less head). In sex-specific models, we used linear regression to examine associations of individual PFAS and phthalate biomarkers with aBMD Z-scores, and Bayesian kernel machine regression to examine the association of the overall PFAS/phthalate biomarker mixture with aBMD Z-scores. We replicated the analysis, stratifying by race/ethnicity. Results Participants were (mean ± SD) 15 ± 2.1 years of age. In males, each doubling of serum perfluorooctanoate (PFOA), perfluorooctane sulfonate, urinary mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate, and the overall PFAS/phthalate mixture was associated with a lower aBMD Z-score (eg, for PFOA: -0.24; 95% CI, -0.41 to -0.06). Serum PFOA and urinary MiBP were associated with higher aBMD Z-scores in females (eg, for PFOA: 0.09; 95% CI, -0.07 to 0.25). Findings did not differ by race/ethnicity. Conclusions Certain PFAS and phthalates may be associated with reduced bone mineral density in adolescent males. Bone mineral density tracks across the life course, so if replicated in longitudinal cohorts, this finding may have implications for lifelong skeletal health.

Background Diet is thought to account for most adult human exposure to per- and polyfluoroalkyl substances (PFAS). Children are particularly vulnerable to adverse health effects of PFAS and may have different eating habits than adults. However, studies of dietary patterns and PFAS in children are limited. Methods We studied 548 Boston-area children with food frequency questionnaire data (89 food items) in early childhood (median age 3.3 years) and plasma concentrations of 6 PFAS quantified in mid-childhood (median age 7.7 years). We used univariate linear regression to examine associations between each food item and PFAS, accounting for multiple comparisons. We next used reduced rank regression (RRR) to estimate overall percent variation in PFAS explained by diet and identify dietary patterns most correlated with PFAS. All models were adjusted for race/ethnicity, maternal education, and household income. Results In univariate analyses, 2-(N-methyl-perfluorooctane sulfonamide) acetate (MeFOSAA) plasma concentrations were 17.8% (95% CI: 7.2, 29.5) and 17.0% (95% CI: 6.4, 28.7) higher per SD increment in intake of ice cream and soda, respectively. RRR identified 6 dietary patterns that together explained 18% variation in the plasma concentrations of the 6 PFAS, of which 50% was explained by a dietary pattern consisting of primarily packaged foods (including ice cream and soda) and fish. Children with higher intake of the packaged foods and fish dietary pattern had higher plasma concentrations of all PFAS, particularly MeFOSAA and PFOS. Conclusions Our analysis examined food intake in association with several PFAS in children and identified dietary determinants that may be sources of PFAS exposure or reflect correlated lifestyle or toxicokinetic factors. Further investigation may help inform measures to modify childhood PFAS exposure.

BackgroundPer- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals that have been associated with cardiovascular risk factors including elevated body weight and hypercholesterolemia. Therefore, PFAS may contribute to the development of atherosclerosis and cardiovascular disease (CVD). However, no previous study has evaluated associations between PFAS exposure and arterial calcification.Methods and resultsThis study used data from 666 prediabetic adults enrolled in the Diabetes Prevention Program trial who had six PFAS quantified in plasma at baseline and two years after randomization, as well as measurements of coronary artery calcium (CAC) and ascending (AsAC) and descending (DAC) thoracic aortic calcification 13-14years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (400)]. We used logistic regression to assess associations between PFAS and presence of AsAC and DAC. We adjusted models for baseline sex, age, BMI, race/ethnicity, cigarette smoking, education, treatment assignment (placebo or lifestyle intervention), and statin use. PFAS concentrations were similar to national means; 53.9% of participants had CAC>11, 7.7% had AsAC, and 42.6% had DAC. Each doubling of the mean sum of plasma concentrations of linear and branched isomers of perfluorooctane sulfonic acid (PFOS) was associated with 1.49-fold greater odds (95% CI: 1.01, 2.21) of severe versus low CAC. This association was driven mainly by the linear (n-PFOS) isomer [1.54 (95% CI: 1.05, 2.25) greater odds of severe versus low CAC]. Each doubling of mean plasma N-ethyl-perfluorooctane sulfonamido acetic acid concentration was associated with greater odds of CAC in a dose-dependent manner [OR=1.26 (95% CI:1.08, 1.47) for moderate CAC and OR=1.37 (95% CI:1.07, 1.74) for severe CAC, compared to low CAC)]. Mean plasma PFOS and n-PFOS were also associated with greater odds of AsAC [OR=1.67 (95% CI:1.10, 2.54) and OR=1.70 (95% CI:1.13, 2.56), respectively], but not DAC. Other PFAS were not associated with outcomes.ConclusionsPrediabetic adults with higher plasma concentrations of select PFAS had higher risk of coronary and thoracic aorta calcification. PFAS exposure may be a risk factor for adverse cardiovascular health among high-risk populations.

Objective: The aim of this study was to investigate the relationship of BMI with subsequent statural growth among children born in the era of the obesity epidemic.Methods: Among 18,271 children from Belarus (n = 16,781, born 1996 to 1997) and the United States (n = 1,490, born 1999 to 2002), multivariable linear and ordinal logistic regression was used to analyze associations of BMI z score from infancy to adolescence with subsequent standardized length and height velocity, standing height and its components (trunk and leg lengths), and pubertal timing.Results: The prevalence of early adolescent obesity was 6.2% in Belarus and 12.8% in the United States. In both Belarusian and US children, higher BMI z scores in infancy and childhood were associated with faster length and height velocity in early life, while higher BMI z scores during middle childhood were associated with slower length and height velocity during adolescence. Associations with greater standing height and trunk length and earlier pubertal development in adolescence were stronger for BMI z scores at middle childhood than BMI z scores at birth or infancy.Conclusions: These findings in both Belarus and the United States support the role of higher BMI in accelerating linear growth in early life (taller stature and longer trunk length) but earlier pubertal development and slower linear growth during adolescence.

Exposure to per- and polyfluoroalkyl substances (PFASs) may interfere with lipid regulation. However, most previous studies were cross-sectional with the risk of reverse causation, suggesting a need for long-term prospective studies. We examined the relationship of baseline plasma PFAS concentrations with repeated measures of blood lipids. We included 888 prediabetic adults from the Diabetes Prevention Program (DPP) and DPP Outcomes Study, who had measurements of 6 plasma PFAS concentrations at baseline (1996–1999) and repeated measures of blood lipids over 15 years of follow-up, and were initially randomized to placebo or a lifestyle intervention. We used linear regression to examine cross-sectional associations of PFAS concentrations and lipid levels at baseline, and evaluated prospective risks of hypercholesterolemia and hypertriglyceridemia using Cox proportional hazard models, and tested for effect modification by study arm. Participants (65.9% female, 57.0% White, 65.9% aged 40–59 years) had comparable PFAS concentrations [e.g., median (IQR) perfluorooctanoic acid (PFOA) 4.9 ng/mL (3.2)] with the general U.S. population in 1999–2000. We observed higher total cholesterol at baseline per doubling of PFOA (β: 6.1 mg/dL, 95% CI: 3.1, 9.04), perfluorohexane sulfonic acid (PFHxS, β: 2.2 mg/dL, 95% CI: 0.2, 4.3), and perfluorononanoic acid (PFNA, β: 2.9 mg/dL, 95% CI: 0.7, 5.0). Prospectively, baseline concentrations of several PFASs, including PFOA, PFOS, PFHxS and PFNA, predicted higher risks of incident hypercholesterolemia and hypertriglyceridemia, but only in the placebo group and not the lifestyle intervention group. For example, participants in the placebo group with PFOA concentration > median (4.9 ng/mL) were almost twice as likely (HR: 1.90, 95% CI: 1.25, 2.88) to develop hypertriglyceridemia compared to those ≤median. Findings suggest adverse effects of some PFASs on lipid profiles in prediabetic adults. However, the detrimental effect was attenuated with a lifestyle intervention. Keywords: Lipid and cholesterol, Hyperlipidemia, Per- and polyfluoroalkyl substances, Environmental epidemiology, Lifestyle intervention, Prospective assessment

OBJECTIVE Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are suspected endocrine disruptors widely detected across populations. We examine the extent to which PFASs are associated with diabetes incidence and microvascular disease. Secondarily, we tested whether a lifestyle intervention modifies associations and decreases concentrations. RESEARCH DESIGN AND METHODS We analyzed data from a prospective cohort of 957 participants from the Diabetes Prevention Program (DPP) trial and Diabetes Prevention Program Outcomes Study (DPPOS). At baseline, participants were randomized to an intensive lifestyle intervention of diet, physical activity, and behavior modification or a placebo medication. We quantified plasma concentrations of six PFASs at baseline and 2 years after randomization. Participants were monitored for ∼15 years, repeatedly tested for diabetes, and evaluated for microvascular disease at the end of the follow-up. RESULTS A doubling in baseline branched perfluorooctanoic acid concentration was associated with a 14% increase in diabetes risk for the placebo (hazard ratio [HR] 1.14, 95% CI 1.04, 1.25) but not in the lifestyle intervention group (HR 1.01, 95% CI 0.92, 1.11, Pinteraction = 0.11). Mean change in plasma baseline branched perfluorooctanoic acid concentration was greater for the placebo (0.96 ng/mL; 95% CI 0.71, 1.22) compared with the lifestyle intervention group (0.31 ng/mL; 95% CI 0.14, 0.48) 2 years after randomization. Each doubling in N-ethyl-perfluorooctane sulfonamido acetic acid was associated with 17% greater odds of prevalent microvascular disease (OR 1.17, 95% CI 1.05, 1.31), and a similar association was observed for perfluorodimethylhexane sulfonic acid (OR 1.18, 95% CI 1.04, 1.35), regardless of treatment. CONCLUSIONS Some plasma PFASs were associated with diabetes and microvascular disease. Our results suggest that exercise and diet may attenuate the diabetogenic association of PFASs.

Background Residential wood stove use has become more prevalent in high-income countries, but only limited data exist on indoor exposure to PM2.5 and its components. Methods From 2014 to 2016, we collected 7-day indoor air samples in 137 homes of pregnant women in Northern New England, using a micro-environmental monitor. We examined associations of wood stove use with PM2.5 mass and its components [black carbon (BC), organic and elemental carbon and their fractions, and trace elements], adjusted for sampling season, community wood stove use, and indoor activities. We examined impact of stove age, EPA-certification, and wood moisture on indoor pollutants. Results Median (IQR) household PM2.5 was 6.65 (5.02) µg/m3 and BC was 0.23 (0.20) µg/m3. Thirty percent of homes used a wood stove during monitoring. In homes with versus without a stove, PM2.5 was 20.6% higher [although 95% confidence intervals (-10.6, 62.6) included the null] and BC was 61.5% higher (95% CI: 11.6, 133.6). Elemental carbon (total and fractions 3 and 4), potassium, calcium, and chloride were also higher in homes with a stove. Older stoves, non-EPA-certified stoves, and wet or mixed (versus dry) wood were associated with higher pollutant concentrations, especially BC. Conclusions Homes with wood stoves, particularly those that were older and non-EPA-certified or burning wet wood had higher concentrations of indoor air combustion-related pollutants.

Objective: To determine whether prenatal sex hormones from maternal saliva are associated with birth weight-for-gestational age. Study Design: We measured salivary progesterone, testosterone, estradiol, dehydroepiandrosterone (DHEA) and cortisone in 504 pregnant women in a Mexico City cohort in the. We performed linear and modified Poisson regression to examine associations of log-transformed hormones with birth weight-for-gestational age z-scores and the risk of small-for-gestational age (SGA) and large-for-gestational age (LGA) adjusting for maternal age, sex, BMI, parity, smoking, education and socioeconomic status. Results: 15% of infants were SGA and 2% were LGA. Each interquartile range increment in testosterone/estradiol ratio was associated with a 0.12 decrement in birth weight-for-gestational age z-score (95% CI: −0.27, −0.02) and a 50% higher risk of SGA versus appropriate-for-gestational age (AGA) (95% CI: 1.13, 1.99). Conclusion: Higher salivary testosterone/estradiol ratios may affect fetal growth, and identifying the predictors of hormone levels may be important to optimizing fetal growth.

CONTEXT There are limited data on the nature of environmental lead hazards identified during residential inspections for child blood lead levels (BLLs) of less than 10 μg/dL. We compare inspection findings for child BLLs of 5 to 9 μg/dL versus 10 μg/dL or more. DESIGN We reviewed inspection reports in Maine from September 2016 to March 2018. We used continuity-adjusted or Fisher's exact test for categorical variables and Wilcoxon rank-sum tests for continuous variables to compare differences in child, family, household, and lead hazard characteristics between BLL categories (5-9 μg/dL vs ≥10 μg/dL). We used Spearman correlation coefficients to assess relationships between home surface lead dust measurements and BLLs. RESULTS Of 351 residential inspections, 272 (77%) were for children with BLLs of 5 to 9 μg/dL. Children with BLLs of 5 to 9 μg/dL as compared with children with BLLs of 10 μg/dL or more were less likely to chew window sills and door frames (8% vs 21%; P = .01), but otherwise were similar with respect to other established risk factors for lead poisoning. Children with BLLs of 5 to 9 μg/dL tended to have fewer paint hazards inside their homes (64% vs 78%; P = .03), and they were more likely to have dust-only hazards (8% vs 3%) or no identified lead paint hazards (23% vs 15%), though these differences were not statistically significant. For children with BLLs of 5 to 9 μg/dL, BLL was weakly correlated with average window sill dust level (Spearman r = 0.16; P = .01) and average floor dust level (r = 0.13; P = .03), but these correlations were not observed for children with BLLs of 10 μg/dL and higher. CONCLUSIONS We have found that inspections of homes of children with BLLs of 5 to 9 μg/dL are nearly as likely to identify lead hazards that require abatement as inspections of homes of children with BLLs of 10 μg/dL.

Despite increasing concerns about neurotoxicity of fluoride in children, sources of fluoride exposure apart from municipal water fluoridation are poorly understood. We aimed to describe the associations of demographics, drinking water characteristics, diet, and oral health behaviors with plasma fluoride concentrations in U.S. children. We used data from 3928 6&ndash, 19-year-olds from the 2013&ndash, 2016 National Health and Nutrition Examination Survey. We used a 24-h dietary recall to estimate recent consumption of fluoridated tap water and select foods. We estimated the associations of fluoridated tap water, time of last dental visit, use of toothpaste, and frequency of daily tooth brushing with plasma fluoride concentrations. The participants who consumed fluoridated (&ge, 0.7 mg/L) tap water (n = 560, 16%) versus those who did not had 36% (95% CI: 22, 51) higher plasma fluoride. Children who drank black or green tea (n = 503, 13%) had 42% higher plasma fluoride concentrations (95% CI: 27, 58) than non-tea drinkers. The intake of other foods and oral health behaviors were not associated with plasma fluoride concentrations. The consumption of fluoridated tap water and tea substantially increases plasma fluoride concentrations in children. Quantifying the contribution of diet and other sources of fluoride is critical to establishing safe target levels for municipal water fluoridation.

Background Children are vulnerable to adverse health effects associated with phthalates, and food is one source of exposure. A comprehensive analysis investigating urinary phthalate metabolite concentrations in relation to food type and source has yet to be undertaken. Objectives We use reduced rank regression, a dimension reduction method, to identify dietary patterns associated with urinary phthalate metabolites in children in a large US study. Methods We used data from 2369 participants 6–19 years old from the 2011–2016 National Health and Nutrition Examination Survey who recalled their diet over the 24 h prior to urine collection. We used dietary data to estimate intake and source (i.e., prepared at a restaurant vs. purchased from a grocery store) of 136 food groups. We used reduced rank regression to identify dietary patterns explaining variation in overall urinary concentrations of ∑di-2-ethylhexyl phthalate and seven phthalate metabolites. We also examined pairwise associations between food groups and urinary phthalate metabolites. Results We identified eight dietary patterns that cumulatively explained 12.1% of variation in urinary phthalate metabolites, including a dietary pattern characterized by certain starchy vegetables (e.g., plantains and lima beans), quick breads, and citrus juice prepared at a restaurant. A one SD increase in this food pattern score was associated with a 37.2% higher monocarboxyoctyl phthalate (MCOP) concentration (95% CI: 30.3, 44.4). We also observed weak associations between certain food groups and urinary phthalate metabolites (e.g., a one SD increase in intake of certain starchy vegetables prepared at a restaurant was associated with a 1.8% [95% CI: 0.7, 2.8] higher MCOP). Conclusions Children whose diets were characterized by higher consumption of certain starchy vegetables, quick breads, and citrus juices prepared at a restaurant had higher urinary phthalate metabolites. More detailed information on the specific methods of food processing and details on packaging materials is needed.

Context Per- and polyfluoroalkyl substances (PFAS) may alter body composition by lowering anabolic hormones and increasing inflammation, but data are limited, particularly in adolescence when body composition is rapidly changing. Objective To evaluate associations of PFAS plasma concentrations in childhood with change in body composition through early adolescence. Methods A total of 537 children in the Boston-area Project Viva cohort participated in this study. We used multivariable linear regression and Bayesian kernel machine regression (BKMR) to examine associations of plasma concentrations of 6 PFAS, quantified by mass spectrometry, in mid-childhood (mean age, 7.9 years; 2007-2010) with change in body composition measured by dual-energy x-ray absorptiometry from mid-childhood to early adolescence (mean age, 13.1 years). Results In single-PFAS linear regression models, children with higher concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoate (PFDA), and perfluorohexane sulfonate (PFHxS) had less accrual of lean mass (eg, −0.33 [95% CI: −0.52, −0.13] kg/m2 per doubling of PFOA). Children with higher PFOS and PFHxS had less accrual of total and truncal fat mass (eg, −0.32 [95% CI: −0.54, −0.11] kg/m2 total fat mass per doubling of PFOS), particularly subcutaneous fat mass (eg, −17.26 [95% CI −32.25, −2.27] g/m2 per doubling of PFOS). Children with higher PFDA and perfluorononanoate (PFNA) had greater accrual of visceral fat mass (eg, 0.44 [95% CI: 0.13, 0.75] g/m2 per doubling of PFDA). Results from BKMR mixture models were consistent with linear regression analyses. Conclusion Early life exposure to some but not all PFAS may be associated with adverse changes in body composition.

Background: Per- and polyfluoroalkyl substances (PFAS) are widely used chemicals, some of which have been linked to type 2 diabetes. We tested whether PFAS concentrations were cross-sectionally associated with metabolites previously shown to predict incident type 2 diabetes using the Diabetes Prevention Program (DPP), a trial of individuals at high risk of type 2 diabetes. Methods: We evaluated 691 participants enrolled in the DPP with baseline measures of 10 PFAS (including total perfluorooctanesulfonic acid (PFOS), total perfluorooctanoic acid (PFOA), and Sb-PFOA [branched isomers of PFOA]) and 77 metabolites. We used log2-transformed PFAS concentrations as exposures and standardized metabolite concentrations as outcomes in linear regression models adjusted for age, sex, race/ethnicity, use of anti-hyperlipidemic or triglyceride-lowering medication, income, years of education, marital status, smoking, and family history of diabetes, with Benjamini-Hochberg linear step-up false discovery rate correction. Results: Sb-PFOA was associated with the largest number of tested metabolites (29 of 77). Each doubling in Sb-PFOA was associated with higher leucine (β=0.07 [95%CI: 0.02, 0.11] SD) and lower glycine (-0.08 [95%CI: -0.03, -0.13] SD). Each doubling of either total PFOA or n-PFOA was associated with -0.13 [95%CI: -0.04, -0.22] SD lower glycine. PFOA and Sb-PFOA were positively associated with multiple triacylglycerols and diacylglycerols, and total PFOS, total PFOA, and Sb-PFOA were positively associated with phosphatidylethanolamines.Conclusions: PFAS concentrations are associated with metabolites linked to type 2 diabetes (particularly amino acid, glycerolipid and glycerophospholipid pathways). Further prospective research is needed to test whether these metabolites mediate associations of PFAS and type 2 diabetes.

Context Per- and polyfluoroalkyl substances (PFAS) are environmental chemicals linked to weight gain and type 2 diabetes. Objective We examined the extent to which PFAS plasma concentrations during pregnancy were associated with postpartum anthropometry and biomarkers. Design, Patients, and Measures We studied women recruited between 1999 and 2002 in the Project Viva prospective cohort with pregnancy plasma concentrations of PFAS, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid (EtFOSAA). Three-year postpartum anthropometry measurements were available from 786 to 801 women, blood pressure from 761 women, and blood biomarkers from 450 to 454 women. We used multivariable regression to evaluate the association of log2-transformed PFAS with postpartum anthropometry, blood pressure, and blood biomarkers (leptin, adiponectin, sex hormone binding globulin [SHBG], hemoglobin A1c, interleukin-6 [IL-6], C-reactive protein), adjusting for age, prepregnancy body mass index, marital status, race/ethnicity, education, income, smoking, parity, and breastfeeding history. Results Pregnancy concentrations of certain PFAS were associated with greater adiposity (eg, 0.4 cm [95% confidence interval [95%CI]: −0.1, 0.9] greater waist circumference per doubling in EtFOSAA; 0.2 cm [95%CI: −0.1, 0.5] greater mid-upper arm circumference per doubling in PFOA; 1.2 mm [95%CI: 0.1, 2.2] thicker sum of subscapular and triceps skinfolds per doubling in PFOS) and higher systolic blood pressure (eg, 1.2 mm Hg [95%CI: 0.3, 2.2] per doubling in PFOS) at 3 years postpartum. Higher EtFOSAA concentrations were also associated with 10.8% higher IL-6 (95%CI: 3.3, 18.9) and 6.1% lower SHBG (95%CI: 0.7, 11.2) per doubling. Conclusions Pregnancy concentrations of EtFOSAA, PFOS, and PFOA were associated with adverse postpartum cardiometabolic markers.

This cohort study uses data from the New Hampshire Birth Cohort Study to assess maternal glycemia and newborn size among pregnant women who use wood-burning stoves in their New England homes.

Background Maternal and neonatal thyroid function is critical for growth and neurodevelopment. Exposure to individual per- and polyfluoroalkyl substances (PFAS) can alter circulating thyroid hormone levels, but few studies have investigated effects of combined exposure to multiple PFAS. Objectives Estimate associations of exposure to multiple PFAS during early pregnancy with maternal and neonatal thyroid function. Methods The study population consisted of 726 mothers and 465 neonates from Project Viva, a Boston, Massachusetts area longitudinal pre-birth cohort. We measured six PFAS [perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), 2-(N-ethyl-perfluorooctane sulfonamido)acetate (EtFOSAA), and 2-(N-methyl-perfluorooctane sulfonamido)acetate (MeFOSAA)] and thyroxine (T4), Free T4 Index (FT4I), and thyroid stimulating hormone (TSH) in maternal plasma samples collected during early pregnancy, and neonatal T4 in postpartum heel sticks. We estimated individual and joint effects of PFAS exposure with thyroid hormone levels using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR), and evaluated potential non-linearity and interactions among PFAS using BKMR. Results Higher concentrations of the PFAS mixture were associated with significantly lower maternal FT4I, with MeFOSAA, EtFOSAA, PFOA, and PFHxS contributing most to the overall mixture effect in BKMR and WQS regression. In infants, higher concentrations of the PFAS mixture were associated with lower T4 levels, primarily in males, with PFHxS and MeFOSAA contributing most in WQS, and PFHxS contributing most in BKMR. The PFAS mixture was not associated with maternal T4 or TSH levels. However, in maternal BKMR analyses, ln-PFOS was positively associated with T4 levels (Δ25th to 75th percentile: 0.21 µg/dL; 95% credible interval: −0.03, 0.47) and ln-PFHxS was associated with a non-linear effect on TSH levels. Conclusions These findings support the hypothesis that there may be combined effects of prenatal exposure to multiple PFAS on maternal and neonatal thyroid function, but the direction and magnitude of these effects may vary across individual PFAS.

Background Exposure to ionizing radiation increases the risk of chronic metabolic disorders such as insulin resistance and type 2 diabetes. Internal ionizing radiation from inhaled radioactive aerosol may contribute to the associations between fine particulate matter (PM2.5) and gestational diabetes mellitus (GDM). Methods We used the Massachusetts Registry of Vital Records to study 1,061,937 pregnant women from 2001 to 2015 with a singleton pregnancy without pre-existing diabetes. Gross β activity measured by seven monitors of the U.S. Environmental Protection Agency's RadNet monitoring network was utilized to represent ambient particle radioactivity (PR). We obtained GDM status from birth certificates and used logistic regression analyses adjusted for socio-demographics, maternal comorbidities, PM2.5, temperature and relative humidity. We also examined effect modification by smoking habits. Results Ambient particle radioactivity exposure during first and second trimester of pregnancy was associated with higher odds of GDM (OR: 1.18 (95% CI 1.10 to 1.22). Controlling for PM2.5 did not substantially change the effects of PR on GDM. In women that reported being former or current smokers, the association between PR and GDM was null. In the full cohort, the overall effect of PM2.5 on GDM without adjusting for PR was not significant. Conclusion This is the first population-based study to examine the association between particle radioactivity and gestational diabetes mellitus - one of the most common pregnancy-related diseases with lifelong effects for the mother and the fetus. This finding has important public health policy implications because it enhances our understanding about the toxicity of PR, a modifiable risk factor, which to date, has been considered only as an indoor and occupational air quality risk.

BackgroundHair cortisol concentration (HCC) is an increasingly used measure of systemic cortisol concentration. However, determinants of HCC in children and adolescents are unclear because few prospective studies have been conducted to date.Study designWe followed 725 children in Project Viva, a pre-birth cohort study of mothers and children, who provided hair samples at mid-childhood (median age: 7.7 years) or early adolescence (median age: 12.9 years). We examined associations of various factors measured from pregnancy to mid-childhood with HCC in mid-childhood and early adolescence, as well as change in HCC between these time points (ΔHCC).ResultsThere were 426 children with HCC measurements in both mid-childhood and early adolescence, 173 children with measures only in mid-childhood, and 126 with measures only in early adolescence. HCC was lower in mid-childhood (median 1.0pg/mg [interquartile range, IQR: 0.5, 2.4]) than early adolescence (2.2pg/mg [1.1, 4.4]). In multivariable-adjusted regression models, female sex (β = -0.41, 95% CI: -0.67, -0.15) and birth weight-for-gestational age z-score (β = -0.19, 95% CI: -0.33, -0.04) were associated with lower mid-childhood HCC, while prenatal smoking was associated with higher mid-childhood HCC (β = 0.53, 95% CI: 0.04, 1.01). In early adolescence, child age (β = 0.34 per year, 95% CI: 0.21, 0.46) female sex (β = 0.33, 95% CI: 0.10, 0.57), and maternal pre-pregnancy body mass index (β = 0.15 per 5-kg/m2, 95% CI: 0.01, 0.29) were positively associated with HCC. Child anthropometric measures and biomarker concentrations were not associated with HCC.ConclusionMaternal pre-pregnancy BMI, maternal prenatal smoking, and low birth weight were associated with higher mid-childhood and adolescent HCC. However, few postnatal characteristics were associated with HCC.

Background: Growing evidence suggests that exposure to per- and polyfluoroalkyl substances (PFASs) may disrupt lipid homeostasis and liver function, but data in children are limited. Objective: We examined the association of prenatal and mid-childhood PFAS exposure with lipids and alanine aminotransferase (ALT) levels in children. Methods: We studied 682 mother-child pairs from a Boston-area pre-birth cohort. We quantified PFASs in maternal plasma collected in pregnancy (median 9.7weeks gestation, 1999–2002) and in child plasma collected in mid-childhood (median age 7.7years, 2007–2010). In mid-childhood we also measured fasting total (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and ALT. We then derived low-density lipoprotein cholesterol (LDL-C) from TC, HDL-C, and TG using the Friedewald formula. Results: Median (interquartile range, IQR) perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorodecanoate (PFDeA) concentrations in child plasma were 6.2 (5.5), 4.3 (3.0), and 0.3 (0.3) ng/mL, respectively. Among girls, higher child PFOS, PFOA, and PFDeA concentrations were associated with detrimental changes in the lipid profile, including higher TC and/or LDL-C [e.g., β per IQR increment in PFOS=4.0mg/dL (95% CI: 0.3, 7.8) for TC and 2.6mg/dL (−0.5, 5.8) for LDL-C]. However, among both boys and girls, higher plasma concentrations of these child PFASs were also associated with higher HDL-C, which predicts better cardiovascular health, and slightly lower ALT, which may indicate better liver function. Prenatal PFAS concentrations were also modestly associated with improved childhood lipid and ALT levels. Conclusions: Our data suggest that prenatal and mid-childhood PFAS exposure may be associated with modest, but somewhat conflicting changes in the lipid profile and ALT levels in children. Keywords: Per- and polyfluoroalkyl substances, Lipids, Liver function, Pregnancy, Childhood

Background Exposure to per- and polyfluoroalkyl substances (PFAS) may disrupt pubertal timing. Higher PFAS plasma concentrations have been associated with later pubertal timing in girls, but cross-sectional findings may be explained by reverse causation. Objectives To assess prospective associations between PFAS plasma concentrations in mid-childhood and markers of pubertal timing in male and female adolescents. Methods We studied 640 children in Project Viva, a Boston-area prospective cohort. We examined associations of plasma concentrations of 6 PFAS measured at mean 7.9 (SD 0.8) years (2007–2010) with markers of pubertal timing. Parents reported a 5-item pubertal development score at early adolescence (mean 13.1 (SD 0.8) years) and reported age at menarche annually. We calculated age at peak height velocity using research and clinical measures of height. We used sex-specific linear and Cox proportional hazards regression to estimate associations of single PFAS with outcomes, and we used Bayesian Kernel Machine Regression (BKMR) to estimate associations of the PFAS mixture with outcomes. Results Plasma concentrations were highest for perfluorooctane sulfonate (PFOS) [median (IQR) 6.4(5.6) ng/mL], followed by perfluorooctanoate (PFOA) [4.4(3.0) ng/mL]. In early adolescence, girls were further along in puberty than boys [pubertal development score mean (SD) 2.9 (0.7) for girls and 2.2(0.7) for boys; age at peak height velocity mean (SD) 11.2y (1.0) for girls and 13.1y (1.0) for boys]. PFAS was associated with later markers of pubertal timing in girls only. For example, each doubling of PFOA was associated with lower pubertal development score (−0.18 units; 95% CI: −0.30, −0.06) and older age at peak height velocity (0.23 years; 95% CI: 0.06, 0.40)]. We observed similar associations for PFOS, perfluorodecanoate (PFDA), and the PFAS mixture. PFAS plasma concentrations were not associated with age at menarche or markers of pubertal timing in boys. Discussion Higher PFAS plasma concentrations in mid-childhood were associated with later onset of puberty in girls.

Maternal smoking during pregnancy is associated with low fetal growth and adverse cardiometabolic health in offspring. However, hormonal pathways underlying these associations are unclear. Therefore, we examined maternal smoking habits and umbilical cord blood hormone profiles in a large, prospective cohort.We studied 978 mother/infant pairs in Project Viva, a Boston-area cohort recruited 1999-2002. We categorized mothers as early pregnancy smokers, former smokers, or never smokers. Outcomes were cord blood concentrations of IGF-1, IGF-2, IGFBP-3, leptin, adiponectin, insulin, and C-peptide. We used linear regression models adjusted for maternal pre-pregnancy body mass index (BMI), race/ethnicity, parity, education, and infant sex. We conducted analyses in the full cohort and stratified by infant sex.Thirteen percent of women were early pregnancy smokers, 20% former smokers, and 68% never smokers. Infants of early pregnancy smokers had lower IGF-1 adjusted for IGFBP-3 [-5.2ng/mL (95% CI: -8.6, -1.7)], with more pronounced associations in girls [-10.7ng/mL (95% CI: -18.5, -2.9) vs. -4.0ng/mL (95% CI: -8.4, 0.4) for boys]. Early pregnancy smoking was not associated with cord blood hormones other than IGF-1. Infants of former smokers had a cord blood hormone profile similar to infants of never smokers.As compared to mothers who never smoked, early pregnancy smokers had infants with lower cord blood IGF-1 which could prime adverse metabolic outcomes. This provides further reason to support smoking cessation programs in women of reproductive age.

Background: Perfluoroalkyl substances (PFASs) are synthetic chemicals that may persist in the environment and in humans. There is a possible association between early-life PFAS exposure and metabolic dysfunction in later life, but data are limited. Methods: We studied 665 mother–child pairs in Project Viva, a Boston, Massachusetts-area cohort recruited 1999–2002. We quantified concentrations of PFASs [perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorodecanoate (PFDeA)] in maternal plasma collected at the first prenatal visit (median, 9.6 weeks gestation) and in child plasma from the mid-childhood research visit (median, 7.7 years). We assessed leptin, adiponectin, and homeostatic model assessment of insulin resistance (HOMA-IR) in mid-childhood. We fit covariate-adjusted linear regression models and conducted stratified analyses by child sex. Results: Children with higher PFAS concentrations had lower HOMA-IR [e.g., –10.1% (95% CI: –17.3, –2.3) per interquartile range increment in PFOA]. This inverse association between child PFAS and HOMA-IR was more pronounced in females [e.g., PFOA: –15.6% (95% CI: –25.4, –4.6) vs. –6.1% (95% CI: –16.2, 5.2) for males]. Child PFAS plasma concentrations were not associated with leptin or adiponectin. Prenatal PFAS plasma concentrations were not associated with leptin, adiponectin, or HOMA-IR in offspring. Conclusions: We found no evidence for an adverse effect of early-life PFAS exposure on metabolic function in mid-childhood. In fact, children with higher PFAS concentrations had lower insulin resistance. Antecedentes: las sustancias perfluoroalquilo (PFAS) son sustancias químicas sintéticas que pueden persistir en el medio ambiente y en los seres humanos. Existe una posible asociación entre la exposición temprana al PFAS y la disfunción metabólica en la edad adulta, pero los datos son limitados. Métodos: Estudiamos 665 parejas de madre e hijo en el Proyecto Viva, una cohorte del área de Boston, Massachusetts, reclutada en 1999-2002. Se cuantificaron las concentraciones de PFAS [perfluorooctanoato (PFOA), sulfonato de perfluorooctano (PFOS), perfluorononanoato (PFNA), sulfonato de perfluorohexano (PFHxS) y perfluorodecanoato (PFDeA)] en el plasma materno recolectado en la primera visita prenatal (mediana de 9,6 semanas), y en el plasma infantil de la visita de investigación de la niñez media (mediana, 7,7 años). Evaluamos la leptina, la adiponectina y la evaluación del modelo homeostático de la resistencia a la insulina (HOMA-IR) en la infancia media. Ajustamos modelos de regresión lineal ajustados por covariables y realizamos análisis estratificados por sexo del niño. Resultados: Los niños con concentraciones más altas de PFAS tenían HOMA-IR más bajo [por ejemplo, –10,1% (IC del 95%: –17,3, –2,3) por incremento de rango intercuartílico en PFOA]. Esta asociación inversa entre PFAS infantil y HOMA-IR fue más pronunciada en las mujeres [p. Ej., PFOA: –15,6% (IC del 95%: –25,4, –4,6) frente a –6,1% (IC del 95%: –16,2, 5,2) para machos]. Las concentraciones plasmáticas de PFAS en niños no se asociaron con leptina o adiponectina. Las concentraciones plasmáticas prenatales de PFAS no se asociaron con leptina, adiponectina o HOMA-IR en la descendencia. Conclusiones: No encontramos evidencia de un efecto adverso de la exposición temprana al PFAS sobre la función metabólica en la niñez media. De hecho, los niños con concentraciones más altas de PFAS tenían menor resistencia a la insulina. Antecedentes: As substâncias perfluoroalquílicas (PFASs) são produtos químicos sintéticos que podem persistir no meio ambiente e nos seres humanos. Há uma possível associação entre a exposição precoce ao PFAS e disfunção metabólica na vida adulta, mas os dados são limitados. Métodos: Estudamos 665 pares de mãe e filho no Projeto Viva, uma coorte da área de Boston, Massachusetts, recrutada em 1999–2002. Quantificamos as concentrações de PFASs [perfluorooctanoato (PFOA), perfluorooctano sulfonato (PFOS), perfluorononanoato (PFNA), sulfonato de perfluorohexano (PFHxS) e perfluorodecanoato (PFDeA)] no plasma materno coletado na primeira visita pré-natal (mediana). e no plasma infantil da visita de pesquisa do meio da infância (mediana, 7,7 anos). Avaliamos a leptina, a adiponectina e a avaliação do modelo homeostático de resistência à insulina (HOMA-IR) no meio da infância. Ajustamos modelos de regressão linear ajustados por covariável e conduzimos análises estratificadas por sexo da criança. Resultados: Crianças com concentrações mais altas de PFAS tiveram menor HOMA-IR [por exemplo, –10,1% (IC 95%: –17,3, –2,3) por incremento do intervalo interquartil no PFOA]. Esta associação inversa entre crianças PFAS e HOMA-IR foi mais pronunciada em mulheres [por exemplo, PFOA: –15,6% (IC 95%: –25,4, –4,6) vs. –6,1% (IC 95%: –16,2, 5,2) para machos]. As concentrações plasmáticas de crianças PFAS não foram associadas à leptina ou adiponectina. As concentrações plasmáticas de PFAS pré-natal não foram associadas à leptina, adiponectina ou HOMA-IR na prole. Conclusões: Não encontramos evidências de um efeito adverso da exposição precoce ao PFAS sobre a função metabólica na metade da infância. Na verdade, crianças com concentrações mais altas de PFAS apresentaram menor resistência à insulina. Boston Children’s Hospital, United States Harvard Medical School, United States Harvard Pilgrim Health Care Institute, United States Boston University School of Public Health, United States Universidad Nacional, Costa Rica National Center for Environmental Health, United States Harvard School of Public Health, United States University of California, United States Instituto Regional de Estudios en Sustancias Tóxicas

OBJECTIVE To examine associations of hair cortisol concentration (HCC) in mid-childhood and change in HCC from mid-childhood to early adolescence (ΔHCC) with early adolescent adiposity and cardiometabolic biomarker measures. METHODS In Project Viva, a pre-birth cohort of mothers and children, we measured HCC in 599 white children in mid-childhood and in 426 of these participants in early adolescence. We used multivariable linear regression to examine associations of mid-childhood HCC and ΔHCC with BMI-for-age-and-sex z score, waist circumference, waist-height ratio, dual X-ray absorptiometry total and trunk fat mass, a metabolic risk z score, adiponectin, HOMA-IR, high-density lipoprotein, C-reactive protein, interleukin-6, leptin, and systolic blood pressure. RESULTS Over a mean (SD) follow-up of 5.2 (0.8) years, we did not find associations of mid-childhood HCC with BMI-for-age-and-sex z score (β = 0.00 per 1-interquartile range of HCC, 95% confidence interval [CI], -0.08 to 0.07), waist circumference (β = -0.04 cm, 95% CI, -0.83 to 0.74), metabolic risk z score (β = 0.04, 95% CI, -0.03 to 0.11), or other cardiometabolic measures except for an increase in log-transformed HOMA-IR (β = 0.10, 95% CI, 0.04-0.17). ΔHCC was not associated with any outcome measures. CONCLUSIONS We found that mid-childhood HCC was not associated with early adolescent adiposity or cardiometabolic biomarkers except for a slight increase in HOMA-IR.

Objective To investigate the association of preconception parental obesity (body mass index [BMI] ≥30 kg/m2) with offspring pubertal development. Study design Among 1377 children from a prospective prebirth cohort in Boston, we examined markers of puberty (age at peak height velocity [PHV], age at menarche, self-reported pubertal development score), and adrenarche (pictograph Tanner pubic hair staging). We used multivariable regression models to examine associations of maternal and paternal obesity with offspring pubertal indices, and applied marginal structural models to estimate the controlled direct effect not mediated by offspring prepubertal BMI. Results The prevalence of paternal obesity alone, maternal obesity alone, and biparental obesity were 10.5%, 10.1%, and 5%, respectively. After adjusting for demographic and socioeconomic factors, parental heights and maternal age at menarche, maternal obesity alone (vs neither parent with obesity) was associated with earlier age at PHV (β −0.30 years; 95% CI -0.57, −0.03) and higher early adolescent pubertal score (0.29 units; 0.10, 0.48) in boys, but not with pubertal or adrenarchal outcomes in girls. Paternal obesity alone was not associated with any outcomes in either boys or girls. Biparental obesity was associated with earlier age at PHV in boys and earlier menarche in girls. Using marginal structural models with stabilized inverse probability weighting, maternal obesity alone had significant controlled direct effects on age at PHV (−0.31 years; −0.62, 0.00) and on pubertal score (0.22 units; 0.00, 0.44) in boys, independent of prepubertal BMI. Conclusion Maternal, but not paternal, obesity is associated with earlier pubertal development in boys, and such association is independent of prepubertal BMI.

The purpose of this study was to test the extent to which pregnancy per- and polyfluoroalkyl substance (PFAS) concentrations were associated with gestational weight gain and postpartum weight changes.This study was composed of 1,614 women recruited between 1999 and 2002 via the Project Viva cohort with pregnancy plasma concentrations of six PFAS, including perfluorooctanesulfonic acid, perfluorooctanoic acid (PFOA), and 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid. Gestational weight gain was defined as the difference between last pregnancy weight and prepregnancy weight, 1-year postpartum weight retention as the difference between 1-year postpartum weight and prepregnancy weight, and 3-year postpartum weight change as the difference between 3-year postpartum weight and prepregnancy weight.During pregnancy, women gained 0.37 kg (95% CI: 0.11-0.62) more weight per doubling of 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid. At 1 year post partum, women retained 0.55 kg (95% CI: 0.07-1.04) more weight per doubling of PFOA. At 3 years post partum, women gained 0.91 kg (95% CI: 0.25-1.56) more weight per doubling in PFOA. Findings were similar after adjustment for all PFAS. Other PFAS were not associated with weight changes. Postpartum associations were stronger among women with higher prepregnancy BMI. Models were adjusted for demographics.Pregnancy PFAS were associated with greater gestational weight gain, weight retention, and weight gain years after pregnancy.

BACKGROUND: Early protein intake may program later body composition and height growth, perhaps mediated by insulin-like growth factor I (IGF-I). In infancy, higher protein intake is consistently associated with higher IGF-I concentrations and more rapid growth, but associations of protein intake after infancy with later growth and IGF-I are less clear. OBJECTIVES: Our objective was to examine associations of protein intake in early childhood (median 3.2 y) with height, IGF-I, and measures of adiposity and lean mass in mid-childhood (median 7.7 y) and early adolescence (median 13.0 y), and with changes in these outcomes over time. We hypothesized that early childhood protein intake programs later growth. METHODS: We studied 1165 children in the Boston-area Project Viva cohort. Mothers reported children's diet using food-frequency questionnaires. We stratified by child sex and examined associations of early childhood protein intake with mid-childhood and early adolescent BMI z score, skinfold thicknesses, dual-energy X-ray absorptiometry (DXA) fat mass, DXA lean mass, height z score, and IGF-I concentration. We adjusted linear regression models for race/ethnicity, family sociodemographics, parental and birth anthropometrics, breastfeeding status, physical activity, and fast food intake. RESULTS: Mean protein intake in early childhood was 58.3 g/d. There were no associations of protein intake in early childhood with any of the mid-childhood outcomes. Among boys, however, each 10-g increase in early childhood total protein intake was associated with several markers of early adolescent size, namely BMI z score (0.12 higher; 95% CI: 0.01, 0.23), DXA lean mass index (1.34% higher; 95% CI: −0.07%, 2.78%), and circulating IGF-I (5.67% higher; 95% CI: 0.30%, 11.3%). There were no associations with fat mass and no associations with any adolescent outcomes among girls. CONCLUSIONS: Early childhood protein intake may contribute to programming lean mass and IGF-I around the time of puberty in boys, but not to adiposity development. This study was registered at clinicaltrials.gov as NCT02820402.

Background: Identifying factors that impair bone accrual during childhood is a critical step toward osteoporosis prevention. Exposure to per- and polyfluoroalkyl substances (PFASs) has been associa...

OBJECTIVES: To identify dietary characteristics associated with variation in plasma per- and polyfluoroalkyl substances (PFAS) concentrations among pre-diabetic adults in the US. METHODS: We evaluated cross-sectional associations between diet and plasma PFAS concentrations among pre-diabetic adults in the US enrolled in the Diabetic Prevention Program 1996–1999. Participants reported their diet over the previous year using a 117-item food frequency questionnaire. Plasma concentrations of 6 PFASs were measured using SPE-LC/MS/MS. We calculated daily intake for major food groups and characterized dietary patterns using principal component analysis (PCA). We estimated differences in plasma PFAS concentrations relative to diet using multivariate linear regression models adjusting for age, sex, race, marital status, education, income, smoking, waist circumference and total caloric intake. RESULTS: Participants (N = 941, 65% female , 58% Caucasian, 68% married, 75% with higher education, 95% nonsmoker) had similar plasma PFAS concentrations compared to the general US population measured in 1999–2000. Mean (SD) daily energy intake was 2091 (975) kcal. Using single food group approach, the strongest predictor for plasma PFAS concentrations was fried fish; each SD increase (0.1 serving/day) was associated with 13.6% (95% CI: 7.7, 19.9) and 6.9% (95% CI: 2.2, 11.8) higher median plasma concentration of perfluorononanoic acid (PFNA) and straight-chain perfluorooctanesulfonic acid (n-PFOS), respectively. Some food groups had inverse associations, with the strongest predictor being cruciferous vegetable [11.5% (95% CI: −16.1, −6.6) decrease in median concentration of plasma 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA) per SD (0.3 serving/day) increase in intake]. PCA showed a vegetable diet to be associated with lower plasma PFAS concentrations, and diet patterns of high-fat meat diet and high-fat and low-fiber grains to be associated with higher PFAS concentrations. CONCLUSIONS: Dietary patterns may influence PFAS exposures and/or excretion and absorption pathways. Studies of PFASs with diet-sensitive disease outcomes should account for confounding by diet. FUNDING SOURCES: This work was supported by the US National Institutes of Health grant R01ES024765.

Key Points Question Is exposure to ambient air pollution in the first trimester associated with thyroid function throughout pregnancy? Findings Among 9931 pregnant women in 4 European cohorts and 1 US cohort, an increase of 5 μg/m3 in exposure to particulate matter with an aerodynamic diameter of 2.5 μm or less was associated with 20% higher odds of hypothyroxinemia. Meaning The findings of this study raise the possibility that exposure to particulate matter might disrupt thyroid function in pregnant women., This cohort study evaluates the short-term association of exposure to air pollution in the first trimester with thyroid function throughout pregnancy among European and US cohorts., Importance Air pollutants interact with estrogen nuclear receptors, but their effect on thyroid signaling is less clear. Thyroid function is of particular importance for pregnant women because of the thyroid’s role in fetal brain development. Objective To determine the short-term association of exposure to air pollution in the first trimester with thyroid function throughout pregnancy. Design, Setting, and Participants In this cohort study, 9931 pregnant women from 4 European cohorts (the Amsterdam Born Children and Their Development Study, the Generation R Study, Infancia y Medio Ambiente, and Rhea) and 1 US cohort (Project Viva) with data on air pollution exposure and thyroid function during pregnancy were included. The recruitment period for the Amsterdam Born Children and Their Development Study was January 2003 to March 2004; for Generation R, April 2002 to January 2006; for Infancia y Medio Ambiente, November 2003 to January 2008; for Rhea, February 2007 to February 2008; and for Project Viva, April 1999 to November 2002. Statistical analyses were conducted from January 2018 to April 2019. Main Outcomes and Measures Residential air pollution concentrations (ie, nitrogen oxide and particulate matter [PM]) during the first trimester of pregnancy were estimated using land-use regression and satellite-derived aerosol optical depth models. Free thyroxine, thyrotropin, and thyroid peroxidase antibody levels were measured across gestation. Hypothyroxinemia was defined as free thyroxine below the fifth percentile of the cohort distribution with normal thyrotropin levels, following the American Thyroid Association guidelines. Results Among 9931 participants, the mean (SD) age was 31.2 (4.8) years, 4853 (48.9%) had more than secondary educational levels, 5616 (56.6%) were nulliparous, 404 (4.2%) had hypothyroxinemia, and 506 (6.7%) tested positive for thyroid peroxidase antibodies. Concentrations of nitrogen dioxide and PM with an aerodynamic diameter of 2.5 μm or less (PM2.5) were lower and had less variation in women in the US cohort than those in European cohorts. No associations of nitrogen oxide with thyroid function were found. Higher exposures to PM2.5 were associated with higher odds of hypothyroxinemia in pregnant women (odds ratio per 5-μg/m3 change, 1.21; 95% CI, 1.00-1.47). Although exposure to PM with an aerodynamic diameter of 10 μm or less was not significantly associated with hypothyroxinemia, the coefficient was similar to that for the association of PM2.5 with hypothyroxinemia (odds ratio per 10-μg/m3 change, 1.18; 95% CI, 0.93-1.48). Absorbances of PM2.5 and PM with aerodynamic diameter from 2.5 to 10 μg and were not associated with hypothyroxinemia. There was substantial heterogeneity among cohorts with respect to thyroid peroxidase antibodies (P for heterogeneity