Prenatal Phenol and Paraben Exposures and Adverse Birth Outcomes: A Prospective Analysis of U.S. Births.

BACKGROUND: Synthetic chemicals are increasingly being recognized for potential independent contributions to preterm birth (PTB) and low birth weight (LBW). Bisphenols, parabens, and triclosan are consumer product chemicals that act via similar mechanisms including estrogen, androgen, and thyroid disruption and oxidative stress. Multiple cohort studies have endeavored to examine effects on birth outcomes, and systematic reviews have been limited due to measurement of 1-2 spot samples during pregnancy and limited diversity of populations. OBJECTIVE: To study the effects of prenatal phenols and parabens on birth size and gestational age (GA) in 3,619 mother-infant pairs from 11 cohorts in the NIH Environmental influences on Child Health Outcomes program. RESULTS: While many associations were modest and statistically imprecise, a 1-unit increase in log10 pregnancy averaged concentration of benzophenone-3 and methylparaben were associated with decreases in birthweight, birthweight adjusted for gestational age and SGA. Increases in the odds of being SGA were 29% (95% CI: 5%, 58%) and 32% (95% CI: 3%, 70%), respectively. Bisphenol S in third trimester was also associated with SGA (OR 1.52, 95% CI 1.08, 2.13). Associations of benzophenone-3 and methylparaben with PTB and LBW were null. In addition, a 1-unit increase in log10 pregnancy averaged concentration of 2,4-dichlorophenol was associated with 43% lower (95% CI: -67%, -2%) odds of low birthweight; the direction of effect was the same for the highly correlated 2,5-dichlorophenol, but with a smaller magnitude (-29%, 95% CI: -53%, 8%). DISCUSSION: In a large and diverse sample generally representative of the United States, benzophenone-3 and methylparaben were associated with lower birthweight as well as birthweight adjusted for gestational age and higher odds of SGA, while 2,4-dichlorophenol. These associations with smaller size at birth are concerning in light of the known consequences of intrauterine growth restriction for multiple important health outcomes emerging later in life.

Associations of early life phthalate exposures with adolescent lipid levels and insulin resistance: The HOME Study.

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

Gestational and childhood phthalate exposures and adolescent body composition: The HOME study.

BACKGROUND: Early life phthalate exposures may disrupt metabolism but results from human studies are inconsistent and few have examined body composition during adolescence. We investigated associations of gestational and childhood urinary phthalate biomarker concentrations with body composition at age 12 years. METHODS: We used data from 206 mother-child pairs in a prospective pregnancy and birth cohort enrolled in Cincinnati, OH from 2003 to 2006. We measured nine phthalate metabolites in spot urine samples collected twice from mothers during pregnancy and up to seven times from children at 1, 2, 3, 4, 5, 8, and 12 years. At age 12 years, we assessed fat and lean mass of the whole body and android and gynoid subregions, and visceral fat area with dual x-ray absorptiometry, and calculated android to gynoid %fat ratio and age- and sex-standardized fat and lean mass index z-scores. Using a multiple informant model, we estimated covariate-adjusted associations between urinary phthalate biomarker concentrations at each time period and outcomes at age 12 years. We assessed effect measure modification by child sex using stratified models. RESULTS: Generally, urinary mono-benzyl phthalate (MBzP) concentrations were modestly associated with lower fat and lean mass. Each 10-fold increase in urinary MBzP concentrations during gestation and at ages 5 and 8 years was associated with a -0.34 (95%CI: -0.72, 0.05), -0.44 (95% CI: -0.83, -0.05), and -0.35 (95% CI: -0.71, 0.00) z-score difference in lean body mass index, respectively. Urinary monoethyl phthalate, mono-(3-carboxypropyl) phthalate, and summed di(2-ethylhexyl) phthalate metabolites were associated with greater lean mass at some exposure periods. Slightly weaker but similar patterns of association were found with other body composition measures; associations did not differ by child sex. CONCLUSION: While most associations were weak, exposure to certain phthalates during gestation and childhood may be associated with adolescent body composition, particularly lean mass.

Prenatal maternal organophosphorus pesticide exposures, paraoxonase 1, and childhood adiposity in the Mount Sinai Children's Environmental Health Study.

BACKGROUND: Animal studies suggest that organophosphorus pesticides (OPs) may be environmental obesogens. While prenatal OP exposures have been associated with altered infant glucose metabolism, associations with pediatric adiposity remain unknown. METHODS: We summed concentrations of three dimethylphosphate (∑DMP) and three diethylphosphate (∑DEP) metabolites of OPs measured in third trimester spot urine samples collected from pregnant women enrolled in New York City, 1998-2002. We measured percent fat mass using bio-electrical impedance analysis and calculated age- and sex-standardized body mass index (BMI) z-scores from anthropometric measurements collected at approximately 4, 6, and 7-9 years of age (166 children, 333 observations). We assessed covariate-adjusted associations of OPs with repeated adiposity measures using linear mixed models and evaluated effect measure modification (EMM) by sex and paroxonase (PON) 1 -108C/T and Q192R polymorphisms measured in maternal peripheral blood samples. RESULTS: The geometric mean urinary concentration of ∑DMP metabolites (29.9 nmol/L, IQR: 105.2 nmol/L) was higher than ∑DEP metabolites (8.8 nmol/L, IQR: 31.2 nmol/L). Adjusted associations were null, with differences in fat mass per 10-fold increase in prenatal ∑DMP and ∑DEP concentrations of 0.7% (95% CI: -0.6, 2.0) and 0.8% (95% CI: -0.4, 2.0), respectively. Maternal PON1-108C/T polymorphisms modified relationships of prenatal ∑DMP with percent fat mass (EMM p-value = 0.18) and ∑DEP with BMI z-scores (EMM p-value = 0.12). For example, ∑DMP was modestly associated with increased percent fat mass among children of mothers with the at-risk CT or TT genotype (ß = 1.2%, 95% CI: -0.6, 3.0) but not among those whose mothers had the CC genotype (ß = -0.4%, 95% CI: -2.4, 1.5). Associations were not modified by sex or maternal PON1 Q192R polymorphisms. CONCLUSIONS: We observed little evidence of a relationship between prenatal OP exposures and child adiposity, although there was some suggestion of increased risk among offspring of mothers who were slow OP metabolizers. Larger studies are warranted to further evaluate possible associations of prenatal OP exposures with child adiposity and differences by maternal PON1 genotype, which regulates OP metabolism and may increase susceptibility to exposure.

Gestational Exposures to Phthalates and Folic Acid, and Autistic Traits in Canadian Children.

BACKGROUND: The etiology of autism spectrum disorder is poorly understood. Few studies have investigated the link between endocrine-disrupting chemicals and autistic traits. We examined the relationship between gestational phthalates and autistic traits in 3- to 4-y-old Canadian children. We also investigated potential effect modification by sex and folic acid supplementation. METHODS: We enrolled 2,001 women>18 years of age during the first trimester of pregnancy between 2008 and 2011 from 10 cities in Canada. At 3-4 years of age, 610 children underwent neuropsychological assessments including the Social Responsiveness Scale-II (SRS-2) as a measure of autistic traits and social impairment. We measured 11 phthalate metabolites in maternal first trimester urine samples and assessed folic acid supplementation from reported intakes. We estimated covariate-adjusted differences in SRS-2 T-scores with a doubling in phthalate concentrations in 510 children with complete data. RESULTS: Mean total SRS T-score was 45.3 (SD=6.1). Children with higher gestational exposure to mono-n-butyl (MBP) and mono-3-carboxypropyl (MCPP) concentrations exhibited significantly higher total SRS T-scores, indicating greater overall social impairment, as well as higher scores on subdomains, indicating deficits in social cognition, social communication, social motivation, and restricted interests/repetitive behaviors. A doubling in MBP or MCPP concentrations was associated with 0.6 (95% CI: 0.1, 1.0) and 0.5 (95% CI: 0.1, 0.8) higher total SRS T-scores. Associations were consistently and significantly stronger in boys (ßMBP=1.0; 95% CI: 0.4, 1.6; n=252) compared with girls (ßMBP=0.1; 95% CI: -0.6, 0.7; n=258) and among children who had lower prenatal folic acid supplementation (<400µg/d) (ßMBP=1.3; 95% CI: 0.4, 2.3; n=59) compared with those who had adequate folic acid supplementation (≥400µg/d) (ßMBP=0.4; 95% CI: -0.1, 0.8; n=451). CONCLUSIONS: Higher gestational concentrations of some phthalate metabolites were associated with higher scores of autistic traits as measured by the SRS-2 in boys, but not girls; these small size effects were mitigated by first trimester-of-pregnancy folic acid supplementation. https://doi.org/10.1289/EHP5621.

Associations of serum perfluoroalkyl substance and vitamin D biomarker concentrations in NHANES, 2003-2010.

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

Prenatal urinary triclosan concentrations and child neurobehavior.

BACKGROUND: Exposure to triclosan, an antimicrobial chemical, is ubiquitous among pregnant women and may reduce thyroid hormone levels that are important for fetal neurodevelopment. Few studies have examined the association between prenatal triclosan exposure and children's neurobehavior. OBJECTIVE: We investigated the relationship of prenatal urinary triclosan concentrations with children's behavior and cognitive abilities at age three years in a prospective pregnancy and birth cohort in Canada. METHODS: We measured triclosan in urine samples collected at ~12 weeks of gestation in 794 Canadian women enrolled in a prospective pregnancy and birth cohort study (MIREC) from 2008 to 2011. Around age 3 years, we assessed children's cognitive abilities using the Wechsler Primary and Preschool Scale of Intelligence-III (WPPSI-III), and two scales of the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). Parents reported children's problem and reciprocal social behaviors using the Behavior Assessment System for Children-2 (BASC-2) and Social Responsiveness Scale-2 (SRS-2), respectively. RESULTS: After adjusting for confounders using multivariable linear regression, triclosan was not associated with most of the 30 examined neurobehavioral scales. Each 10-fold increase in triclosan was associated with better WPPSI-III picture completion scores (ß: 0.2; 95% CI: 0,0.5) and BASC-2 externalizing (ß: -0.5; 95% CI: -1.1, 0) and hyperactivity (ß: -0.6; 95% CI: -1.2, -0.1) scores, suggesting less externalizing and hyperactive behaviors. Child sex did not modify these associations. CONCLUSIONS: In this cohort, urinary triclosan concentrations measured once in early pregnancy were not associated with most assessed aspects of neurobehavior and weakly associated with a few others, but not in the hypothesized direction.

Patterns, Variability, and Predictors of Urinary Triclosan Concentrations during Pregnancy and Childhood.

Exposure to triclosan, an antimicrobial used in many consumer products, is ubiquitous in the United States, yet only limited data are available on the predictors and variability of exposure, particularly in children. We examined the patterns, variability, and predictors of urinary triclosan concentrations in 389 mother-child pairs enrolled in the Health Outcomes and Measures of the Environment Study from 2003 to 2006. We quantified triclosan in 3 urine samples collected from women between 16 weeks of pregnancy and birth and 6 urine samples collected from children between the ages of 1-8 years. For maternal and child samples, we calculated intraclass correlation coefficients (ICCs) to assess triclosan reproducibility and identified sociodemographic predictors of triclosan. Among 8 year old children, we examined associations between triclosan and personal-care product use. We detected triclosan in >70% of urine samples. Median maternal triclosan varied across pregnancy from 17 to 11 ng/mL, while in children, median concentrations increased from 3.6 to 17 ng/mL over the first 4 years of life, declining slightly at later ages. Triclosan reproducibility was fair to good during pregnancy and for child samples taken weeks apart (ICCs = 0.4-0.6) but poor for annual child samples (ICCs = 0.2-0.4). Triclosan was 66% (95% CI: 29-113) higher in 8 year olds using hand soap compared to nonusers and increased monotonically with hand-washing frequency. Toothpaste use in children was also positively associated with triclosan. Our results suggest that urinary triclosan concentrations have modest stability over weeks to months; children are exposed to triclosan through the use of some personal-care products.

Urinary triclosan concentrations during pregnancy and birth outcomes.

BACKGROUND: Triclosan is an antimicrobial chemical used in consumer products, and exposure is ubiquitous among pregnant women in the United States. Triclosan may reduce the levels of thyroid hormones that are important for fetal growth and development. OBJECTIVE: We investigated the relationship of prenatal triclosan exposure with birth anthropometry and gestational duration. METHODS: We used data from 378 mother-child pairs participating in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort from Cincinnati, OH. We measured triclosan concentrations in maternal urine samples collected at 16 and 26 weeks of pregnancy. We abstracted information on neonatal anthropometry and gestational duration from medical records. We used multivariable linear regression to estimate the covariate-adjusted association between the average of the two urinary triclosan concentrations and gestational age standardized weight z-score, length, head circumference, and gestational age at birth. RESULTS: Median urinary triclosan concentrations were 16ng/mL (range: <2.4 to 1501ng/mL). Each 10-fold increase in triclosan was associated with a predicted 0.15 standard deviation decrease (95% CI: -0.30, 0.00) in birth weight z-score, 0.4-cm decrease (95% CI: -0.8, 0.1) in birth length, 0.3-cm decrease (95% CI: -0.5, 0.0) in head circumference, and 0.3-week decrease (95% CI: -0.6, -0.1) in gestational age. Child sex did not modify the associations between triclosan and birth outcomes. CONCLUSIONS: In this cohort, maternal urinary triclosan concentrations during pregnancy were inversely associated with infants' birth weight, length, head circumference, and gestational age.