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Background: Prenatal exposure to endocrine-disrupting chemicals (EDCs) may disrupt normal fetal and postnatal growth. Studies have mainly focused on individual aspects of growth at specific time points using single chemical exposure models. However, humans are exposed to multiple EDCs simultaneously, and growth is a dynamic process., Objective: The objective of this study was to evaluate the associations between prenatal exposure to EDCs and children's body mass index (BMI) growth trajectories using single exposure and mixture modeling approaches., Methods: Using data from the INfancia y Medio Ambiente (INMA) Spanish birth cohort ( n = 1,911 ), prenatal exposure to persistent chemicals [hexachlorobenzene (HCB), 4-4'-dichlorodiphenyldichloroethylene (DDE), polychlorinated biphenyls (PCB-138, -150, and -180), 4 perfluoroalkyl substances (PFAS)] and nonpersistent chemicals (8 phthalate metabolites, 7 phenols) was assessed using blood and spot urine concentrations. BMI growth trajectories were calculated from birth to 9 years of age using latent class growth analysis. Multinomial regression was used to assess associations for single exposures, and Bayesian weighted quantile sum (BWQS) regression was used to evaluate the EDC mixture's association with child growth trajectories., Results: In single exposure models exposure to HCB, DDE, PCBs, and perfluorononanoic acid (PFNA) were associated with increased risk of belonging to a trajectory of lower birth size followed by accelerated BMI gain by 19%-32%, compared with a trajectory of average birth size and subsequent slower BMI gain [e.g., relative risk ratio (RRR) per doubling in DDE concentration = 1.19 (95% CI: 1.05, 1.35); RRR for PFNA = 1.32 (95% CI: 1.05, 1.66)]. HCB and DDE exposure were also associated with higher probability of belonging to a trajectory of higher birth size and accelerated BMI gain. Results from the BWQS regression showed the mixture was positively associated with increased odds of belonging to a BMI trajectory of lower birth size and accelerated BMI gain (odds ratio per 1-quantile increase of the mixture = 1.70 ; credible interval: 1.03, 2.61), with HCB, DDE, and PCBs contributing the most., Discussion: This study provides evidence that prenatal EDC exposure, particularly persistent EDCs, may lead to BMI trajectories in childhood characterized by accelerated BMI gain. Given that accelerated growth is linked to a higher disease risk in later life, continued research is important. https://doi.org/10.1289/EHP11103.

Background: Prenatal exposure to persistent organic pollutants (POPs) may contribute to the development of childhood obesity and metabolic disorders. However, little is known about whether the maternal nutritional status during pregnancy can modulate these associations., Objectives: The main objective was to characterize the joint associations and interactions between prenatal levels of POPs and nutrients on childhood obesity., Methods: We used data from to the Spanish INfancia y Medio Ambiente-Environment and Childhood (INMA) birth cohort, on POPs and nutritional biomarkers measured in maternal blood collected at the first trimester of pregnancy and child anthropometric measurements at 7 years of age. Six organochlorine compounds (OCs) [dichlorodiphenyldichloroethylene, hexachlorobenzene (HCB), β - hexachlorocyclohexane ( β - HCH ) and polychlorinated biphenyls 138, 153, 180] and four per- and polyfluoroalkyl substances (PFAS) were measured. Nutrients included vitamins (D, B12, and folate), polyunsaturated fatty acids (PUFAs), and dietary carotenoids. Two POPs-nutrients mixtures data sets were established: a ) OCs, PFAS, vitamins, and carotenoids ( n = 660 ), and b ) OCs, PUFAs, and vitamins ( n = 558 ). Joint associations of mixtures on obesity were characterized using Bayesian kernel machine regression (BKMR). Relative importance of biomarkers and two-way interactions were identified using gradient boosting machine, hierarchical group lasso regularization, and BKMR. Interactions were further characterized using multivariate regression models in the multiplicative and additive scale., Results: Forty percent of children had overweight or obesity. We observed a positive overall joint association of both POPs-nutrients mixtures on overweight/obesity risk, with HCB and vitamin B12 the biomarkers contributing the most. Recurrent interactions were found between HCB and vitamin B12 across screening models. Relative risk for a natural log increase of HCB was 1.31 (95% CI: 1.11, 1.54, p Interaction = 0.02 ) in the tertile 2 of vitamin B12 and in the additive scale a relative excess risk due to interaction of 0.11 (95% CI: 0.02, 0.20) was found. Interaction between perfluorooctane sulfonate and β - cryptoxanthin suggested a protective effect of the antioxidant on overweight/obesity risk., Conclusion: These results support that maternal nutritional status may modulate the effect of prenatal exposure to POPs on childhood overweight/obesity. These findings may help to develop a biological hypothesis for future toxicological studies and to better interpret inconsistent findings in epidemiological studies. https://doi.org/10.1289/EHP11258.

Introduction: To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive., Objective: We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs., Methods: Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis., Results: A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education., Conclusion: We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444.

Background: Exposure to perfluoroalkyl substances (PFASs) may increase risk for metabolic diseases; however, epidemiologic evidence is lacking at the present time. Pregnancy is a period of enhanced tissue plasticity for the fetus and the mother and may be a critical window of PFAS exposure susceptibility., Objective: We evaluated the associations between PFAS exposures and metabolic outcomes in pregnant women., Methods: We analyzed 1,240 pregnant women from the Spanish INMA [Environment and Childhood Project (INfancia y Medio Ambiente)] birth cohort study (recruitment period: 2003-2008) with measured first pregnancy trimester plasma concentrations of four PFASs (in nanograms/milliliter). We used logistic regression models to estimate associations of PFASs (log 10 -transformed and categorized into quartiles) with impaired glucose tolerance (IGT) and gestational diabetes mellitus (GDM), and we used linear regression models to estimate associations with first-trimester serum levels of triglycerides, total cholesterol, and C-reactive protein (CRP)., Results: Perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were positively associated with IGT (137 cases) [OR per log 10 -unit increase=1.99 (95% CI: 1.06, 3.78) and OR=1.65 ( 95% CI: 0.99, 2.76), respectively]. PFOS and PFHxS associations with GDM (53 cases) were in a similar direction, but less precise. PFOS and perfluorononanoate (PFNA) were negatively associated with triglyceride levels [percent median change per log 10 -unit increase=-5.86% (95% CI: -9.91%, -1.63%) and percent median change per log 10 -unit increase=-4.75% (95% CI: -8.16%, -0.61%, respectively], whereas perfluorooctanoate (PFOA) was positively associated with total cholesterol [percent median change per log 10 -unit increase=1.26% (95% CI: 0.01%, 2.54%)]. PFASs were not associated with CRP in the subset of the population with available data ( n =640)., Conclusions: Although further confirmation is required, the findings from this study suggest that PFAS exposures during pregnancy may influence lipid metabolism and glucose tolerance and thus may impact the health of the mother and her child. https://doi.org/10.1289/EHP1062.

Background: Perfluoroalkyl substances (PFAS) may affect body mass index (BMI) and other components of cardiometabolic (CM) risk during childhood, but evidence is scarce and inconsistent., Objectives: We estimated associations between prenatal PFAS exposures and outcomes relevant to cardiometabolic risk, including a composite CM-risk score., Methods: We measured perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in maternal plasma (first trimester). We assessed weight gain from birth until 6 mo. At 4 and 7 y, we calculated the age- and sex-specific z -scores for BMI, waist circumference (WC), and blood pressure (BP) (n≈1,000). At age 4, we calculated the age-, sex-, and region-specific z -scores for cholesterol, triglycerides (TGs), high-density (HDL-C), and low-density lipoprotein cholesterol (LDL-C) (n=627). At age 4, we calculated a CM-risk score (n=386) as the sum of the individual age-, sex-, and region-specific z -scores for WC, BP, HDL-C, and TGs. We used the average between the negative of HDL-C z -score and TGs z -score to give similar weight to lipids and the other components in the score. A higher score indicates a higher cardiometabolic risk at age 4., Results: PFOS and PFOA were the most abundant PFAS (geometric mean: 5.80 and 2.32 ng/mL, respectively). In general, prenatal PFAS concentrations were not associated with individual outcomes or the combined CM-risk score. Exceptions were positive associations between prenatal PFHxS and TGs z -score [for a doubling of exposure, β=0.11; 95% confidence interval (CI): 0.01, 0.21], and between PFNA and the CM-risk score (β=0.60; 95% CI: 0.04, 1.16). There was not clear or consistent evidence of modification by sex., Conclusions: We observed little or no evidence of associations between low prenatal PFAS exposures and outcomes related to cardiometabolic risk in a cohort of Spanish children followed from birth until 7 y. https://doi.org/10.1289/EHP1330.

Background: Exposure to some perfluoroalkyl substances (PFAS), such as perfluorohexane sulfonate (PFHxS), perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA), may alter levels of sex hormones and insulin-like growth factor-1 (IGF-1) in animals. Human studies on this topic are scarce, and none have been conducted in young children., Objectives: We investigated the relationship between levels of PFAS and estradiol, total testosterone, and IGF-1 in 2,292 children (6-9 years of age) from the C8 Health Project who lived near a chemical plant in the Mid-Ohio Valley (USA) with local contamination from PFOA., Methods: Serum samples were collected in 2005-2006 and analyzed for PFAS, sex hormones, and IGF-1. Results from regression models were expressed as the adjusted percentage difference (95% CI) per sex-specific interquartile range (IQR) increment of each PFAS serum concentration. Analyses by PFAS quartiles were also conducted., Results: Median concentrations of PFHxS, PFOA, PFOS, and PFNA were 8, 35, 22, and 1.7 ng/mL in boys and 7, 30, 21, and 1.7 ng/mL in girls. In boys, PFOA concentrations were significantly associated with testosterone levels (-4.9%; 95% CI: -8.7, -0.8%); PFOS with estradiol (-4.0%; 95% CI: -7.7, -0.1%), testosterone (-5.8%; 95% CI: -9.4, -2.0%), and IGF-1 (-5.9%; 95% CI: -8.3, -3.3%); and PFNA with IGF-1 (-3.5%; 95% CI: -6.0, -1.0%). In girls, significant associations were found between PFOS and testosterone (-6.6%; 95% CI: -10.1, -2.8%) and IGF-1 (-5.6%; -8.2, -2.9%); and PFNA and IGF-1 (-3.8%; 95% CI: -6.4, -1.2%). In both sexes, the magnitudes of the associations decreased monotonically across quartiles for both testosterone and IGF-1 in relation to PFOS, and for IGF-1 and PFNA in girls., Conclusions: To our knowledge, this is the first study suggesting that PFAS are associated with lower levels of IGF-1 and sex hormones in young children., Citation: Lopez-Espinosa MJ, Mondal D, Armstrong BG, Eskenazi B, Fletcher T. 2016. Perfluoroalkyl substances, sex hormones, and insulin-like growth factor-1 at 6-9 years of age: a cross-sectional analysis within the C8 Health Project. Environ Health Perspect 124:1269-1275; http://dx.doi.org/10.1289/ehp.1509869.

Background: Air pollution exposure during pregnancy has been associated with impaired fetal growth. However, few studies have measured fetal biometry longitudinally, remaining unclear as to whether there are windows of special vulnerability., Objective: The aim was to investigate the impact of nitrogen dioxide (NO2) exposure on fetal and neonatal biometry in the Spanish INMA study., Methods: Biparietal diameter (BPD), femur length (FL), abdominal circumference (AC), and estimated fetal weight (EFW) were evaluated for up to 2,478 fetuses in each trimester of pregnancy. Size at 12, 20, and 34 weeks of gestation and growth between these points, as well as anthropometry at birth, were assessed by SD scores derived using cohort-specific growth curves. Temporally adjusted land-use regression was used to estimate exposure to NO2 at home addresses for up to 2,415 fetuses. Associations were investigated by linear regression in each cohort and subsequent meta-analysis., Results: A 10-μg/m(3) increase in average exposure to NO2 during weeks 0-12 was associated with reduced growth at weeks 0-12 in AC (-2.1%; 95% CI: -3.7, -0.6) and EFW (-1.6%; 95% CI: -3.0, -0.3). The same exposure was inversely associated with reduced growth at weeks 20-34 in BPD (-2.6%; 95% CI: -3.9, -1.2), AC (-1.8%; 95% CI: -3.3, -0.2), and EFW (-2.1%; 95% CI: -3.7, -0.2). A less consistent pattern of association was observed for FL. The negative association of this exposure with BPD and EFW was significantly stronger in smoking versus nonsmoking mothers., Conclusions: Maternal exposure to NO2 in early pregnancy was associated with reduced fetal growth based on ultrasound measures of growth during pregnancy and measures of size at birth.

Background: Several studies have reported decreases in birth size associated with exposure to organochlorine compounds (OCs), but uncertainties remain regarding the critical windows of prenatal exposure and the effects on fetal body segments., Objective: We examined the relationship between prenatal OC concentrations and fetal anthropometry., Methods: We measured 4,4´-dichlorodiphenyldichloroethylene (4,4´-DDE), hexachlorobenzene (HCB), and polychlorinated biphenyl (PCB) congeners (138, 153, and 180) in 2,369 maternal and 1,140 cord serum samples in four Spanish cohorts (2003-2008). We used linear mixed models to obtain longitudinal growth curves for estimated fetal weight (EFW), abdominal circumference (AC), biparietal diameter (BPD), and femur length (FL) adjusted by parental and fetal characteristics. We calculated standard deviation (SD) scores of growth at 0-12, 12-20, and 20-34 weeks of gestation as well as size at gestational week 34 for the four parameters. We studied the association between OCs and the fetal outcomes by cohort-specific linear models and subsequent meta-analyses., Results: PCBs were associated with a reduction in AC up to mid-pregnancy, and BPD and FL from gestational week 20 onward. An inverse association was also found between HCB and AC growth in early pregnancy. The reduction of these parameters ranged from -4% to -2% for a doubling in the OC concentrations. No association between 4,4´-DDE and fetal growth was observed., Conclusions: To our knowledge, this is the first study to report an association between prenatal exposure to some PCBs and HCB and fetal growth: AC during the first two trimesters of pregnancy, and BPD and FL later in pregnancy., Citation: Lopez-Espinosa MJ, Murcia M, Iñiguez C, Vizcaino E, Costa O, Fernández-Somoano A, Basterrechea M, Lertxundi A, Guxens M, Gascon M, Goñi-Irigoyen F, Grimalt JO, Tardón A, Ballester F. 2016. Organochlorine compounds and ultrasound measurements of fetal growth in the INMA cohort (Spain). Environ Health Perspect 124:157-163; http://dx.doi.org/10.1289/ehp.1408907.

Background: The presence of perfluoroalkyl acids (PFAAs) in breast milk has been documented, but their lactational transfer has been rarely studied. Determination of the elimination rates of these chemicals during breastfeeding is important and critical for assessing exposure in mothers and infants., Objectives: We aimed to investigate the association between breastfeeding and maternal serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS). For a subset of the population, for whom we also have their infants' measurements, we investigated associations of breastfeeding with infant serum PFAA concentrations., Methods: The present analysis included 633 women from the C8 Science Panel Study who had a child < 3.5 years of age and who provided blood samples and reported detailed information on breastfeeding at the time of survey. PFAA serum concentrations were available for all mothers and 8% (n = 49) of the infants. Maternal and infant serum concentrations were regressed on duration of breastfeeding., Results: Each month of breastfeeding was associated with lower maternal serum concentrations of PFOA (-3%; 95% CI: -5, -2%), PFOS (-3%; 95% CI: -3, -2%), PFNA (-2%; 95% CI: -2, -1%), and PFHxS (-1%; 95% CI: -2, 0%). The infant PFOA and PFOS serum concentrations were 6% (95% CI: 1, 10%) and 4% (95% CI: 1, 7%) higher per month of breastfeeding., Conclusions: Breast milk is the optimal food for infants, but is also a PFAA excretion route for lactating mothers and exposure route for nursing infants.

Background: Animal studies suggest that some perfluoroalkyl acids (PFAAs), including perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA) may impair thyroid function. Epidemiological findings, mostly related to adults, are inconsistent., Objectives: We investigated whether concentrations of PFAAs were associated with thyroid function among 10,725 children (1-17 years of age) living near a Teflon manufacturing facility in the Mid-Ohio Valley (USA)., Methods: Serum levels of thyroid-stimulating hormone (TSH), total thyroxine (TT4), and PFAAs were measured during 2005-2006, and information on diagnosed thyroid disease was collected by questionnaire. Modeled in utero PFOA concentrations were based on historical information on PFOA releases, environmental distribution, pharmacokinetic modeling, and residential histories. We performed multivariate regression analyses., Results: Median concentrations of modeled in utero PFOA and measured serum PFOA, PFOS, and PFNA were 12, 29, 20, and 1.5 ng/mL, respectively. The odds ratio for hypothyroidism (n = 39) was 1.54 [95% confidence interval (CI): 1.00, 2.37] for an interquartile range (IQR) contrast of 13 to 68 ng/mL in serum PFOA measured in 2005-2006. However, an IQR shift in serum PFOA was not associated with TSH or TT4 levels in all children combined. IQR shifts in serum PFOS (15 to 28 ng/mL) and serum PFNA (1.2 to 2.0 ng/mL) were both associated with a 1.1% increase in TT4 in children 1-17 years old (95% CIs: 0.6, 1.5 and 0.7, 1.5 respectively)., Conclusions: This is the first large-scale report in children suggesting associations of serum PFOS and PFNA with thyroid hormone levels and of serum PFOA and hypothyroidism.

Background: There are limited data on the associations between maternal or newborn and child exposure to perfluoroalkyl acids (PFAAs), including perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS). This study provides an opportunity to assess the association between PFAA concentrations in mother-child pairs in a population exposed to PFOA via drinking water., Objectives: We aimed to determine the relationship between mother-child PFAA serum concentrations and to examine how the child:mother ratio varies with child's age, child's sex, drinking-water PFOA concentration, reported bottled water use, and mother's breast-feeding intention., Methods: We studied 4,943 mother-child pairs (children, 1-19 years of age). The child:mother PFAA ratio was stratified by possible determinants. Results are summarized as geometric mean ratios and correlation coefficients between mother-child pairs, overall and within strata., Results: Child and mother PFOA and PFOS concentrations were correlated (r = 0.82 and 0.26, respectively). Up to about 12 years of age, children had higher serum PFOA concentrations than did their mothers. The highest child:mother PFOA ratio was found among children ≤ 5 years (44% higher than their mothers), which we attribute to in utero exposure and to exposure via breast milk and drinking water. Higher PFOS concentrations in children persisted until at least 19 years of age (42% higher than their mothers). Boys > 5 years of age had significantly higher PFOA and PFOS child:mother ratios than did girls., Conclusion: Concentrations of both PFOA and PFOS tended to be higher in children than in their mothers. This difference persisted until they were about 12 years of age for PFOA and at least 19 years of age for PFOS.

Background: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) persist in the environment and are found in relatively high concentrations in animal livers. Studies in humans have reported inconsistent associations between PFOA and liver enzymes., Objectives: We examined the cross-sectional association between serum PFOA and PFOS concentrations with markers of liver function in adults., Methods: The C8 Health Project collected data on 69,030 persons; of these, a total of 47,092 adults were included in the present analysis. Linear regression models were fitted for natural log (ln)-transformed values of alanine transaminase (ALT), γ-glutamyltransferase (GGT), and direct bilirubin on PFOA, PFOS, and potential confounders. Logistic regression models were fitted comparing deciles of PFOA or PFOS in relation to high biomarker levels. A multilevel analysis comparing the evidence for association of PFOA with liver function at the individual level within water districts to that at the population level between water districts was also performed., Results: ln-PFOA and ln-PFOS were associated with ln-ALT in linear regression models [PFOA: coefficient, 0.022; 95% confidence interval (CI): 0.018, 0.025; PFOS: coefficient, 0.020; 95% CI: 0.014, 0.026] and with raised ALT in logistic regression models [with a steady increase in the odds ratio (OR) estimates across deciles of PFOA and PFOS; PFOA: OR = 1.10; 95% CI: 1.07, 1.13; PFOS: OR = 1.13; 95% CI: 1.07, 1.18]. There was less consistent evidence of an association of PFOA and GGT or bilirubin. The relationship with bilirubin appears to rise at low levels of PFOA and to fall again at higher levels., Conclusions: These results show a positive association between PFOA and PFOS concentrations and serum ALT level, a marker of hepatocellular damage.