Time-varying associations of gestational and childhood triclosan with pubertal and adrenarchal outcomes in early adolescence.

Background: Triclosan is an endocrine-disrupting chemical, but associations with pubertal outcomes remain unclear. We examined associations of gestational and childhood triclosan with adolescent hormone concentrations and pubertal stage. Methods: We quantified urinary triclosan concentrations twice during pregnancy and seven times between birth and 12 years in participants recruited from Cincinnati, OH (2003-2006). We averaged concentrations across pregnancy and childhood and separately considered individual exposure periods in multiple informant models. At 12 years, we measured serum hormone concentrations (males [n = 72] and females [n = 84]-dehydroepiandrosterone-sulfate, luteinizing hormone, follicle-stimulating hormone; males-testosterone; females-estradiol). Also at age 12 years, participants self-reported physical development and menarchal timing. We estimated associations (95% confidence interval) of triclosan with hormone concentrations, more advanced physical development, and age at menarche. Results: For females, each doubling of childhood triclosan was associated with 16% lower estradiol concentrations (-29%, 0%), with stronger associations for measures closer to adolescence. We found suggestive evidence that higher triclosan at any age was associated with ~10% (for gestational triclosan: -18%, -2%) lower follicle-stimulating hormone concentrations among males and early postnatal (1-3 years) triclosan was associated with 63% (5%, 96%) lower odds of advanced pubic hair development in females. In multiple informant models, each doubling of gestational triclosan concentrations was associated with 5% (0%, 9%) earlier age at menarche, equivalent to 5.5 months. Conclusion: Gestational and childhood triclosan concentrations were related to some pubertal outcomes including hormone concentrations and age at menarche. Our findings highlight the relevance of elucidating potential sex-specific and time-dependent actions of triclosan.

Associations of Prenatal Per- and Polyfluoroalkyl Substance (PFAS) Exposures with Offspring Adiposity and Body Composition at 16-20 Years of Age: Project Viva.

BACKGROUND: Findings on the associations between prenatal PFAS exposures and offspring adiposity are inconsistent. Whether such associations may extend to adolescence is especially understudied. OBJECTIVES: We investigated associations of prenatal PFAS exposures with offspring adiposity and body composition at 16-20 years of age. METHODS: We studied 545 mother-child pairs in the prospective prebirth cohort Project Viva (Boston, Massachusetts). We measured six PFAS (PFOA, PFOS, PFNA, PFHxS, EtFOSAA, and MeFOSAA) in maternal early pregnancy (median age=9.6wk, range: 5.7-19.6 wk) plasma samples. At the late adolescence visit (median age=17.4 y, range: 15.9-20.0 y), we obtained anthropometric measures and assessed body composition using bioelectrical impedance analysis and dual-energy X-ray absorptiometry. We examined associations of individual PFAS with obesity [i.e., age- and sex-specific body mass index (BMI) ≥95th percentile] and adiposity and body composition using multivariable Poisson and linear regression models, respectively. We assessed PFAS mixture effects using Bayesian kernel machine regression (BKMR) and quantile g-computation. We used fractional-polynomial models to assess BMI trajectories (at 3-20 years of age) by prenatal PFAS levels. RESULTS: Thirteen percent (n=73) of the children had obesity in late adolescence. After multivariable adjustment, higher prenatal PFAS concentrations were associated with higher obesity risk [e.g., 1.59 (95% CI: 1.19, 2.12), 1.24 (95% CI: 0.98, 1.57), and 1.49 (95% CI: 1.11, 1.99) times the obesity risk per doubling of PFOS, PFOA, and PFNA, respectively]. BKMR showed an interaction between PFOA and PFOS, where the positive association between PFOS and obesity was stronger when PFOA levels were lower. Each quartile increment of the PFAS mixture was associated with 1.52 (95% CI: 1.03, 2.25) times the obesity risk and 0.52 (95% CI: -0.02, 1.06) kg/m2 higher BMI. Children with higher prenatal PFOS, EtFOSAA, and MeFOSAA concentrations had higher rates of BMI increase starting from 9-11 years of age. DISCUSSION: Prenatal PFAS exposures may have obesogenic effects into late adolescence. https://doi.org/10.1289/EHP12597.

Associations of Gestational Perfluoroalkyl Substances Exposure with Early Childhood BMI z-Scores and Risk of Overweight/Obesity: Results from the ECHO Cohorts.

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 z-scores; 19.6% children had more than one BMI measurement. We estimated covariate-adjusted associations of individual PFAS and their mixture with child BMI z-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 z-scores and risk of overweight/obesity. For instance, each doubling in perfluorohexane sulfonic acid concentrations was associated with higher BMI z-scores (ß=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 N-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 z-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. https://doi.org/10.1289/EHP11545.

Plasma concentrations of per- and polyfluoroalkyl substances in pregnancy and breastfeeding duration in Project Viva.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) may disrupt mammary gland development and function; thereby inhibiting milk supply and breastfeeding duration. However, conclusions on the potential effects of PFAS and breastfeeding duration are limited by prior epidemiologic studies that inconsistently adjusted for past cumulative breastfeeding duration and by a lack of examination of the joint effects of PFAS mixtures. METHODS: In Project Viva, a longitudinal cohort that enrolled pregnant participants from 1999 to 2002 in the greater Boston, MA area, we studied 1079 women who ever attempted to lactate. We investigated associations of plasma concentrations of select PFAS in early pregnancy (mean: 10.1 weeks gestation) with breastfeeding termination by 9 months, after which women typically cite self-weaning as the reason for terminating breastfeeding. We used Cox regression for single-PFAS models and quantile g-computation for mixture models, adjusting for sociodemographics, prior breastfeeding duration, and weeks of gestation at the time of blood draw. RESULTS: We detected 6 PFAS [perfluorooctane sulfonate; perfluorooctanoate (PFOA); perfluorohexane sulfonate; perfluorononanoate; 2-(N-ethyl-perfluorooctane sulfonamido) acetate (EtFOSAA); 2-(N-methyl-perfluorooctane sulfonamide) acetate (MeFOSAA)] in >98 % of samples. Sixty percent of lactating women terminated breastfeeding by 9 months postpartum. Women with higher plasma concentrations of PFOA, EtFOSAA, and MeFOSAA had a greater hazard of terminating breastfeeding in the first 9 months postpartum [HR (95 % CI) per doubling concentration: 1.20 (1.04, 1.38) for PFOA; 1.10 (1.01, 1.20) for EtFOSAA; 1.18 (1.08, 1.30) for MeFOSAA]. In the quantile g-computation model, simultaneously increasing all PFAS in the mixture by one quartile was associated with 1.17 (95 % CI: 1.05, 1.31) greater hazard of terminating breastfeeding in the first 9 months. CONCLUSION: Our findings suggest that exposure to PFAS may be associated with reduced breastfeeding duration and draw further attention to environmental chemicals that may dysregulate human lactation.

Birth Outcomes in Relation to Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Stress in the Environmental Influences on Child Health Outcomes (ECHO) Program.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress. OBJECTIVES: We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships. METHODS: We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS. RESULTS: We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of ß=-0.15 [95% confidence interval (CI): -0.27, -0.03], ß=-0.14 (95% CI: -0.28, -0.002), ß=-0.22 (95% CI: -0.23, -0.10), ß=-0.06 (95% CI: -0.18, 0.06), and ß=-0.25 (95% CI: -0.37, -0.14), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: ORPFNA=0.56 (95% CI: 0.38, 0.83), ORPFDA=0.52 (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [-0.28; 95% highest posterior density (HPD): -0.44, -0.14] and decreased odds of large-for-gestational-age (OR=0.49; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress. DISCUSSION: Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.

Associations of urinary metabolite concentrations of phthalates and phthalate replacements with body composition from mid-childhood to early adolescence.

BACKGROUND: Phthalates may adversely influence body composition by lowering anabolic hormones and activating peroxisome-proliferator activated receptor gamma. However, data are limited in adolescence when body mass distributions rapidly change and bone accrual peaks. Also, potential health effects of certain phthalate/replacements [e.g., di-2-ethylhexyl terephthalate (DEHTP)] have not been well studied. METHODS: Among 579 children in the Project Viva cohort, we used linear regression to evaluate associations of urinary concentrations of 19 phthalate/replacement metabolites from mid-childhood (median: 7.6 years; 2007-2010) with annualized change in areal bone mineral density (aBMD) and lean, total fat, and truncal fat mass as measured by dual-energy X-ray absorptiometry between mid-childhood and early adolescence (median: 12.8 years). We used quantile g-computation to assess associations of the overall chemical mixture with body composition. We adjusted for sociodemographics and tested for sex-specific associations. RESULTS: Urinary concentrations were highest for mono-2-ethyl-5-carboxypentyl phthalate [median (IQR): 46.7 (69.1) ng/mL]. We detected metabolites of most replacement phthalates in a relatively small number of participants [e.g., 28% for mono-2-ethyl-5-hydrohexyl terephthalate (MEHHTP; metabolite of DEHTP)]. Detectable (vs. non-detectable) MEHHTP was associated with less bone and greater fat accrual in males and greater bone and lean mass accrual in females [e.g., change in aBMD Z-score/year (95% CI): -0.049 (-0.085, -0.013) in males versus 0.042 (0.007, 0.076) in females; pinteraction<0.01]. Children with higher concentrations of mono-oxo-isononyl phthalate and mono-3-carboxypropyl phthalate (MCPP) had greater bone accrual. Males with higher concentrations of MCPP and mono-carboxynonyl phthalate had greater accrual of lean mass. Other phthalate/replacement biomarkers, and their mixtures, were not associated with longitudinal changes in body composition. CONCLUSIONS: Concentrations of select phthalate/replacement metabolites in mid-childhood were associated with changes in body composition through early adolescence. As use of phthalate replacements such as DEHTP may be increasing, further investigation can help better understand the potential effects of early-life exposures.

Predictors of urinary biomarker concentrations of phthalates and some of their replacements in children in the Project Viva cohort.

BACKGROUND: Some phthalates are still widely used in food packaging, toys, and personal care products, and links to adverse health have motivated substitution with replacement chemicals. Few studies have examined patterns and predictors of phthalate replacement biomarkers in children. OBJECTIVE: To examine associations of sociodemographic, dietary, and urine collection characteristics with urinary concentrations of biomarkers of select phthalates and their replacements in mid-childhood. METHODS: We studied 830 children ages 6-10 years in 2007-2010 in a Boston-area cohort. We quantified urinary metabolites and summed their concentrations to calculate biomarkers of the concentrations of ten parent phthalates/replacements. We used linear regression to examine mutually adjusted associations of each predictor with each phthalate biomarker. We used logistic regression to examine predictors of 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) biomarker detectability. RESULTS: Predictor characteristics explained 25-48% of urinary biomarker variability. Di-2-ethylhexyl terephthalate (DEHTP) biomarker was higher in females (18.7% [95% CI: 0.7, 39.9]), children who consumed more meat and dairy, and samples collected from later years. DINCH biomarker was more detectable in females (odds ratio [OR] 2.1 [95% CI: 1.5, 3.0]) and samples from later years. SIGNIFICANCE: Populations of children with increased urinary concentrations of phthalate and replacement biomarkers can be targeted for future study of sources of exposure, and identifying dietary predictors of biomarkers will directly guide future interventions. IMPACT: Our study uses data from a large cohort that is one of the first to measure DINCH, DEHTP, and metabolites of di-isononyl phthalate and di-isodecyl phthalate. Additionally, we evaluate predictors during mid-childhood when biomarkers might be highest. As the use of replacement phthalates increases, our study is one of the first to examine biomarker patterns and predictors among children.

Associations Between Prenatal Blood Metals and Vitamins and Cord Blood Peptide Hormone Concentrations.

Background: Nonessential metals have endocrine disrupting properties, interfere with cellular processes, generate reactive oxygen and deplete antioxidants, while essential metals and vitamins act as antioxidants. The extent to which prenatal metals and vitamins are associated with cord blood hormones involved in maternal and fetal metabolic and growth processes is unknown. Methods: We measured six nonessential (arsenic, barium, cadmium, cesium, lead, mercury) and four essential (magnesium, manganese, selenium, zinc) metals and trace elements, and two vitamins (B12 and folate) in first trimester blood from participants in the longitudinal pre-birth Project Viva cohort, who were recruited between 1999-2002 in eastern Massachusetts. We measured adiponectin, C-peptide, IGF-1, IGF-2, IGFBP-3, insulin, and leptin concentrations in cord blood (~n=695). We used covariate-adjusted quantile g-computation for mixtures and linear regression for individual exposures to estimate associations with cord blood peptide hormones. Results: The essential metal mixture (magnesium, manganese, selenium, zinc) was associated with higher IGF-1 (ß=3.20 ng/ml per quartile, 95% CI: 0.39, 6.01), IGF-2 (ß=10.93 ng/ml, 95% CI: 0.08, 21.79), and leptin (ß=1.03 ng/ml, 95% CI: 0.25, 1.80). Magnesium was associated with higher leptin (ß=2.90 ng/ml, 95% CI: 0.89, 4.91), while B12 was associated with lower adiponectin, IGF-2, and leptin, but higher C-peptide. Other individual nonessential metals were associated with cord blood hormones. Conclusions: Our findings suggest that some prenatal metals and vitamins are associated with cord blood hormones, which may influence growth and development.

Early-pregnancy plasma per- and polyfluoroalkyl substance (PFAS) concentrations and hypertensive disorders of pregnancy in the Project Viva cohort.

BACKGROUND: Hypertensive disorders of pregnancy (HDP), defined here as hypertensive disorders with onset in pregnancy (i.e., gestational hypertension, preeclampsia, and preeclampsia superimposed on chronic hypertension), affect up to 10% of pregnancies in the United States and are associated with substantial maternal and neonatal morbidity and mortality. Per- and polyfluoroalkyl substances (PFAS) are associated with adverse cardiometabolic outcomes during pregnancy, but associations between PFAS and HDP are inconsistent and joint effects of PFAS mixtures have not been evaluated. METHODS: We studied 1,558 pregnant individuals from the Project Viva cohort, recruited during 1999-2002. We quantified concentrations of eight PFAS in plasma samples (median 9.7 weeks of gestation). Using clinical records, we calculated trimester-specific mean systolic (SBP) and diastolic (DBP) blood pressure and categorized HDP status [no HDP (normotensive & chronic hypertension), gestational hypertension, preeclampsia]. We estimated associations of individual PFAS with HDP using multinomial logistic regression and estimated associations with blood pressure using linear regression. We used Bayesian kernel machine regression (BKMR) and quantile g-computation to assess joint effects of the PFAS mixture on HDP and blood pressure measures. RESULTS: Four percent of participants developed preeclampsia and 7% developed gestational hypertension. We observed higher odds of gestational hypertension, but not preeclampsia, per doubling of perfluorooctanoate (PFOA) [OR = 1.51 (95% confidence interval: 1.12, 2.03)], perfluorooctane sulfonate (PFOS) [OR = 1.38 (1.04, 1.82)], and perfluorohexane sulfonate [OR = 1.28 (1.06, 1.54)] concentrations. We observed higher mean DBP per doubling of PFOA [2nd trimester (T2): 0.39 mmHg (-0.01, 0.78); 3rd trimester (T3): 0.56 mmHg (0.14, 0.98)] and PFOS [T2: 0.46 mmHg (0.11, 0.82); T3: 0.43 mmHg (0.05, 0.80)]. The PFAS mixture was positively associated with odds of gestational hypertension [75th vs. 50th percentile: OR = 1.14 (95% credible interval:1.03, 1.25), BKMR] and mean DBP [T2 = 0.17 mmHg (-0.06, 0.40); T3 = 0.22 mmHg (-0.03, 0.48), BKMR]. CONCLUSIONS: These findings suggest that exposure to certain PFAS may increase the odds of gestational hypertension during pregnancy, with potential implications for subsequent maternal and child health outcomes.

Serum PFAS and Urinary Phthalate Biomarker Concentrations and Bone Mineral Density in 12-19 Year Olds: 2011-2016 NHANES.

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 ±â€…SD) 15 ±â€…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.

Arsenic exposure during pregnancy and postpartum maternal glucose tolerance: evidence from Bangladesh.

BACKGROUND: Arsenic exposure has been associated with gestational diabetes mellitus. However, the extent to which arsenic exposure during pregnancy is associated with postpartum glucose intolerance is unknown. METHODS: We studied 323 women in Bangladesh. We assessed arsenic exposure in early pregnancy via toenail and water samples. We measured fasting glucose and insulin in serum at a mean (SD) of 4.0 (3.5) weeks post-delivery. We ran covariate-adjusted, linear regression models to examine associations of arsenic concentrations with HOMA-IR, a marker of insulin resistance, and HOMA-ß, a marker of beta cell function. RESULTS: Median (IQR) arsenic concentration was 0.45 (0.67) µg/g in toenails and 2.0 (6.5) µg/L in drinking water. Arsenic concentrations during pregnancy were not associated with insulin resistance or beta cell function postpartum. HOMA-IR was 0.07% (- 3.13, 3.37) higher and HOMA-ß was 0.96% (- 3.83, 1.99) lower per IQR increment in toenail arsenic, but effect estimates were small and confidence intervals crossed the null. CONCLUSIONS: Although arsenic exposure during pregnancy has been consistently associated with gestational diabetes mellitus, we found no clear evidence for an adverse effect on postpartum insulin resistance or beta cell function.

Dietary correlates of urinary phthalate metabolite concentrations in 6-19 Year old children and adolescents.

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.

Prospective associations of mid-childhood plasma per- and polyfluoroalkyl substances and pubertal timing.

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.

Dietary patterns and PFAS plasma concentrations in childhood: Project Viva, USA.

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.

Plasma Concentrations of Per- and Polyfluoroalkyl Substances and Body Composition From Mid-Childhood to Early Adolescence.

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.

Per- and polyfluoroalkyl substances and calcifications of the coronary and aortic arteries in adults with prediabetes: Results from the diabetes prevention program outcomes study.

BACKGROUND: Per- 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 RESULTS: This 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 13-14 years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (<10), moderate (11-400) and severe (>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. CONCLUSIONS: Prediabetic 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.

Per- and polyfluoroalkyl substance plasma concentrations and metabolomic markers of type 2 diabetes in the Diabetes Prevention Program trial.

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 (ß = 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.

Predictors of Plasma Fluoride Concentrations in Children and Adolescents.

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 6-19-year-olds from the 2013-2016 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 (≥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.

Per- and Polyfluoroalkyl Substance Exposure, Gestational Weight Gain, and Postpartum Weight Changes in Project Viva.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Pregnancy PFAS were associated with greater gestational weight gain, weight retention, and weight gain years after pregnancy.