Neurotoxicity of Ortho-Phthalates: Recommendations for Critical Policy Reforms to Protect Brain Development in Children.

Robust data from longitudinal birth cohort studies and experimental studies of perinatally exposed animals indicate that exposure to ortho-phthalates can impair brain development and increase risks for learning, attention, and behavioral disorders in childhood. This growing body of evidence, along with known adverse effects on male reproductive tract development, calls for immediate action.Exposures are ubiquitous; the majority of people are exposed to multiple ortho-phthalates simultaneously. We thus recommend that a class approach be used in assessing health impacts as has been done with other chemical classes. We propose critically needed policy reforms to eliminate ortho-phthalates from products that lead to exposure of pregnant women, women of reproductive age, infants, and children. Specific attention should be focused on reducing exposures among socially vulnerable populations such as communities of color, who frequently experience higher exposures.Ortho-phthalates are used in a vast array of products and elimination will thus necessitate a multipronged regulatory approach at federal and state levels. The fact that manufacturers and retailers have already voluntarily removed ortho-phthalates from a wide range of products indicates that this goal is feasible.

Prenatal and early childhood exposure to phthalates and childhood behavior at age 7 years.

BACKGROUND: Emerging evidence suggests that phthalate exposure may be associated with behavior problems in children and that these associations may be sex specific. METHODS: In a follow up study of 411 inner-city minority mothers and their children, mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monethyl phthalate (MEP) and four di-2-ethylhexyl phthalate metabolites (DEHP) were quantified in maternal urine samples collected during the third trimester and in child urine samples at ages 3 and 5 years. The Conners' Parent Rating Scale-Revised: Long Form (CPRS) and Child Behavior Checklist (CBCL) were administered to the mothers to assess children's behavior problems at 7 years of age. The analysis included children with available measures of CBCL, CPRS and phthalates measured in maternal urine. We performed both Quasi-Poisson regression and a mixture analysis using Weighted Quantile Sum(WQS) regression to assess the risk for CPRS scores and for internalizing and externalizing behaviors (from the CBCL) following intra-uterine exposure to the phthalate metabolites for boys and girls separately. RESULTS: Among boys, increases in in anxious-shy behaviors were associated with prenatal exposure to MBzP (Mean Ratio [MR] = 1.20, 95%CI 1.05-1.36) and MiBP (Mean Ratio (MR) = 1.22, 95%CI 1.02-1.47). Among girls, increases in perfectionism were associated with MBzP (MR = 1.15, 95%CI 1.01-1.30). In both boys and girls, increases in psychosomatic problems were associated with MiBP (MR = 1.28, 95%CI 1.02-1.60), and MnBP (MR = 1.28, 95%CI 1.02-1.59), respectively. Among girls, decreased hyperactivity was associated with two DEHP metabolites, mono(2-ethyl-5-oxohexyl) phthalate (MR = 0.83, 95%CI 0.71-0.98) and mono(2-ethyl-5-hydroxyhexyl) phthalate (MR = 0.85, 95%CI 0.72-0.99). Using weighted Quantile Sum logistic regression, no associations were found between the Weighted Quantile Sum (WQS) of phthalate metabolites and CPRS scores or externalizing and internalizing behaviors. Nonetheless, when the analysis was performed separately for DEHP and non-DEHP metabolites significant associations were found between the WQS of DEHP metabolites and social problems in boys (OR = 2.15, 95%CI 1.13-4.06, p-value = 0.02) anxious-shy problems in girls (OR = 2.19, 95%CI 1.15-4.16, p = 0.02), and emotional lability problems in all children (OR = 0.61, 95%CI 0.38-0.97, p = 0.04). MEHP and MEOHP were the most highly weighted DEHP metabolites in WQS mixture. The analysis performed with CBCL scale corroborated these associations. CONCLUSION: Concentration of non-DEHP metabolites was associated with anxious-shy behaviors among boys. DEHP phthalate metabolites were associated with decreased hyperactivity and impulsivity among girls on CPRS scores. These findings lend further support to the adverse associations between prenatal phthalate exposure and childhood outcomes, and clearly suggest that such associations are sex and mixture specific.

Perinatal phthalates exposure decreases fine-motor functions in 11-year-old girls: Results from weighted Quantile sum regression.

INTRODUCTION: Phthalates are a group of high production chemicals, generally used as plasticizers and odor enhancers. Phthalates cross the blood-placenta barrier and are associated with deficits in cognitive functions and behavior problems in offspring. We previously reported sex-specific associations with motor function when phthalates are considered singly. Because exposure to phthalates usually occurs as mixtures, here we assess these associations between a mixture of phthalates and motor function at age 11 years. METHODS: Data come from the prospective cohort study of mothers and offspring who participated in the Columbia Center for Children's Environmental Health birth cohort (CCCEH). Seven phthalate metabolites were measured in maternal spot urine obtained during the third trimester and motor function was evaluated using the short form of the Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition (BOT-2) at the age of 11 years. We used Weighted Quartile Sum (WQS) regression models to examine the effect of phthalate metabolites in males and females separately. The models were adjusted for child age in months, child BMI, maternal race (African-American vs. Dominican), prenatal alcohol consumption, maternal demoralization score, HOME score, and urine specific gravity. In a secondary analysis we used linear regression models to examine the association between the sum of molar concentrations of both DEHP and non-DEHP metabolites, and outcomes of gross and fine motor functions. RESULTS: 209 mother-child pairs were eligible for this analysis. A significant decrease in fine-motor functions was observed among females, but not among males, following exposure to high levels of weighted quartile sum of seven phthalate metabolites (Covariates-adjusted coefficient estimate B = -2.7, 95% Confidence Interval [CI] -4.64 to -0.75, p = 0.01 for females [n = 116] and B = -1.63, 95%CI -3.94 to 0.69, p = 0.16 for males [n = 93]). The most highly weighted phthalate metabolites, associated with fine-motor functions among females, were MBP, MBZP, and MIBP, all non-DEHP phthalates. No significant associations were found between the weighted quartile sum of seven phthalate metabolites and gross-motor functions at the age of 11 years for males (B = -0.81, 95%CI -1.17 to 1.96, p = 0.23). With the molar sum of four non-DEHP phthalates as main predictor of linear regression models, we found significant decrease in gross and fine motor functions among females prenatally exposed to non-DEHP phthalates B = -0.98, 95%CI -1.98 to 0.03, p = 0.05 and B = -0.85, 95%CI -1.49 to -0.20, p = 0.01, respectively). CONCLUSIONS: Phthalate exposure during pregnancy was associated with decreased motor functions among 11-year-old girls.

A preliminary study on prenatal polybrominated diphenyl ether serum concentrations and intrinsic functional network organization and executive functioning in childhood.

BACKGROUND: The prenatal period is a period of vulnerability during which neurotoxic exposures exert persistent changes in brain development and behavior. Polybrominated diphenyl ethers (PBDEs), used as flame retardants in commercial products, are known to be developmental neurotoxicants. PBDEs were phased out of use in the United States a decade ago, but exposure remains widespread due to their release from existing products and biopersistence. Despite consistent animal and epidemiological evidence of developmental neurotoxicity, the neural substrates linking prenatal PBDE serum concentrations to impaired neurodevelopment are poorly understood. METHODS: In the present study, we used resting state functional magnetic resonance imaging (fMRI) to examine associations between prenatal PBDE concentrations measured in maternal serum and intrinsic functional network organization (i.e., global and local efficiency; estimated using a graph-theoretical approach) in 5-year-old children (n = 34). We explored whether PBDE serum concentrations were associated with executive functioning (EF) assessed using a parent-report questionnaire (BRIEF-P) (n = 106) and whether changes in intrinsic functional network organization linked the association between prenatal PBDE serum concentrations and EF problems. RESULTS: Children with higher prenatal PBDE serum concentrations showed: (a) increased global efficiency of brain areas involved in visual attention (e.g., inferior occipital gyrus) (ß's = .01, FDR-corrected p's ≤ .05); (b) more reported EF problems (ß's = .001, FDR-corrected p's ≤ .05). Higher global efficiency of brain areas involved in visual attention was associated with more EF problems (ß's = .01, FDR-corrected p's < .05). CONCLUSIONS: Intrinsic functional network organization of visual attention brain areas linked prenatal PBDE concentrations to EF problems in childhood. Visual attention may contribute to the development of higher-order cognitive functions, such as EF, which could be explored in future studies.

Pre- and Postnatal Polybrominated Diphenyl Ether Concentrations in Relation to Thyroid Parameters Measured During Early Childhood.

Background: Penta-brominated diphenyl ethers (PentaBDEs) are endocrine-disrupting chemicals that structurally resemble thyroid hormones and were widely used as flame retardants in household consumer products from 1975 to 2004. Polybrominated diphenyl ethers (PBDEs) cross the placenta, and evidence suggests that for many children, body burdens may peak during the toddler years. This study aimed to understand the impact of exposure timing by examining both pre- and postnatal exposure to BDE-47, the predominant penta-brominated diphenyl ether congener detected in humans, in relation to thyroid hormone parameters measured during early childhood. Methods: The Columbia Center for Children's Environmental Health Mothers and Newborns Study is a prospective birth cohort of African American and Dominican maternal-child pairs. Pregnant women were recruited from two prenatal clinics in Northern Manhattan and the South Bronx between 1998 and 2006. Participants included 158 children with (i) plasma PBDE concentrations measured at birth and in the toddler years (age 2-3 years), and (ii) serum thyroid parameters measured at three and/or five years of age. Outcomes included concentrations of serum thyrotropin, free thyroxine, and total thyroxine. Results: Children with high exposure to BDE-47 during the prenatal period (-17% [confidence interval -29 to -2]) or toddler age (-19% [confidence interval -31 to -5]) had significantly lower geometric mean thyrotropin levels compared to children with low BDE-47 exposure throughout early life. Associations with thyroxine were also inverse; however, they did not reach statistical significance at the p = 0.05 level. Sex-stratified models suggest associations with postnatal exposure may be stronger among boys compared to girls. Conclusions: The thyroid regulatory system may be sensitive to BDE-47 during pre- and postnatal periods.

Prenatal and childhood exposure to phthalates and motor skills at age 11 years.

BACKGROUND: Previous reports suggest that prenatal phthalate exposure is associated with lower scores on measures of motor skills in infants and toddlers. Whether these associations persist into later childhood or preadolescence has not been studied. METHODS: In a follow up study of 209 inner-city mothers and their children the concentrations of mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monomethyl phthalate (MEP), mono-carboxy-isooctyl phthalate (MCOP), and four di-2-ethylhexyl phthalate metabolites (ΣDEHP) were measured in spot urine sample collected from the women in late pregnancy and from their children at ages 3, 5, and 7 years. The Bruininks-Oseretsky Test of Motor Proficiency short form (BOT-2) was administered at child age 11 to assess gross and fine motor skills. RESULTS: The total number of children included in the study was 209. Of the 209 children, 116(55.5%) were girls and 93 were (45%) boys. Among girls, prenatal MnBP(b=-2.09; 95%CI: [-3.43, -0.75]), MBzP (b=-1.14; [95%CI: -2.13, -0.14]), and MiBP(b=-1.36; 95%CI: [-2.51, -0.21] and MEP(b=-1.23 [95%CI: -2.36, -0.11]) were associated with lower total BOT-2 composite score. MnBP (b= -1.43; 95% CI: [-2.44, -0.42]) was associated with lower fine motor scores and MiBP(b = -0.56; 95% CI: [-1.12, -0.01]) and MEP (b = -0.60; 95% CI: [-1.14, -0.06])was associated with lower gross motor scores. Among boys, prenatal MBzP (b = -0.79; 95% CI: [-1.40, -0.19]) was associated with lower fine motor composite score. The associations between MEP measured at age 3 and the BOT-2 gross motor, fine motor and total motor score differed by sex. In boys, there was an inverse association between ΣDEHP metabolites measured in childhood at ages 3 (b = -1.30; 95% CI: [-2.34, -0.26]) and 7 years (b = -0.96; 95% CI: [-1.79, -0.13]), and BOT-2 fine motor composite scores. CONCLUSIONS: Higher prenatal exposure to specific phthalates was associated with lower motor function among 11- year old girls while higher postnatal exposure to ΣDEHP metabolites was associated with lower scores among boys. As lower scores on measures of motor development have been associated with more problems in cognitive, socioemotional functioning and behavior, the findings of this study have implications related to overall child development.

Current respiratory symptoms and risk factors in pregnant women cooking with biomass fuels in rural Ghana.

BACKGROUND: More than 75% of the population in Ghana relies on biomass fuels for cooking and heating. Household air pollution (HAP) emitted from the incomplete combustion of these fuels has been associated with adverse health effects including respiratory effects in women that can lead to chronic obstructive pulmonary disease (COPD), a major contributor to global HAP-related mortality. HAP is a modifiable risk factor in the global burden of disease, exposure to which can be reduced. OBJECTIVE: This study assessed the prevalence of respiratory symptoms, as well as associations between respiratory symptoms and HAP exposure, as measured using continuous personal carbon monoxide (CO), in nonsmoking pregnant women in rural Ghana. METHODS: We analyzed current respiratory health symptoms and CO exposures upon enrollment in a subset (n = 840) of the population of pregnant women cooking with biomass fuels and enrolled in the GRAPHS randomized clinical control trial. Personal CO was measured using Lascar continuous monitors. Associations between CO concentrations as well as other sources of pollution exposures and respiratory health symptoms were estimated using logistic regression models. CONCLUSION: There was a positive association between CO exposure per 1 ppm increase and a composite respiratory symptom score of current cough (lasting >5 days), wheeze and/or dyspnea (OR: 1.2, p = 0.03). CO was also positively associated with wheeze (OR: 1.3, p = 0.05), phlegm (OR: 1.2, p = 0.08) and reported clinic visit for respiratory infection in past 4 weeks (OR: 1.2, p = 0.09). Multivariate models showed significant associations between second-hand tobacco smoke and a composite outcome (OR: 2.1, p < 0.01) as well as individual outcomes of cough >5 days (OR: 3.1, p = 0.01), wheeze (OR: 2.7, p < 0.01) and dyspnea (OR: 2.2, p = 0.01). Other covariates found to be significantly associated with respiratory outcomes include involvement in charcoal production business and dyspnea, and involvement in burning grass/field and wheeze. Results suggest that exposure to HAP increases the risk of adverse respiratory symptoms among pregnant women using biomass fuels for cooking in rural Ghana.

Phthalates and thyroid function in preschool age children: Sex specific associations.

BACKGROUND: Research relating either prenatal or concurrent measures of phthalate exposure to thyroid function in preschool children is inconclusive. METHODS: In a study of inner-city mothers and their children, metabolites of di-n-butyl phthalate, butylbenzyl phthalate, di-isobutyl phthalate, di(2-ethylhexyl) phthalate, and diethyl phthalate were measured in a spot urine sample collected from women in late pregnancy and from their children at age 3years. We measured children's serum free thyroxine (FT4) and thyroid stimulating hormone (TSH) at age 3. Linear regression models were used to investigate the associations between phthalate metabolites, measured in maternal urine during late pregnancy and measured in child urine at age 3 and thyroid function measured at age 3. RESULTS: Mean concentrations (ranges) were 1.42ng/dL (1.02-2.24) for FT4, and 2.62uIU/mL (0.61-11.67) for TSH. In the children at age 3, among girls, FT4 decreased with increasing loge mono-n-butyl phthalate [estimated b=-0.06; 95% CI: (-0.09, -0.02)], loge mono-isobutyl phthalate [b=-0.05; 95% CI: (-0.09, -0.01)], loge monoethyl phthalate [b=-0.04; 95% CI: (-0.07, -0.01)], and loge mono(2-ethyl-5-hydroxyhexyl) phthalate [b=-0.04; 95% CI: (-0.07, -0.003)] and loge mono(2-ethyl-5-oxy-hexyl) phthalate [b=-0.04; 95% CI: (-0.07, -0.004)]. In contrast, among boys, we observed no associations between FT4 and child phthalate metabolites at age 3. On the other hand, in late gestation, FT4 increased with increasing loge mono-(2-ethylhexyl) phthalate [estimated b=0.04; 95% CI: (0.02, 0.06)] and no sex difference was observed. We found no associations between phthalate biomarkers measured in either the child or prenatal samples and TSH at age 3. CONCLUSIONS: The data show inverse and sex specific associations between specific phthalate metabolites measured in children at age 3 and thyroid function in preschool children. These results may provide evidence for the hypothesis that reductions in thyroid hormones mediate associations between early life phthalate exposure and child cognitive outcomes.

Maternal urinary phthalates and sex-specific placental mRNA levels in an urban birth cohort.

BACKGROUND: Prenatal urinary concentrations of phthalates in women participants in an urban birth cohort were associated with outcomes in their children related to neurodevelopment, autoimmune disease risk, and fat mass at 3,5,7, and 8 years of life. Placental biomarkers and outcomes at birth may offer biologic insight into these associations. This is the first study to address these associations with candidate genes from the phthalate and placenta literature, accounting for sex differences, and using absolute quantitation methods for mRNA levels. METHODS: We measured candidate mRNAs in 180 placentas sampled at birth (HSD17B1, AHR, CGA, CYP19A1, SLC27A4, PTGS2, PPARG, CYP11A1) by quantitative PCR and an absolute standard curve. We estimated associations of loge mRNA with quartiles of urinary phthalate monoesters using linear mixed models. Phthalate metabolites (N = 358) and mRNAs (N = 180) were transformed to a z-score and modeled as independent, correlated vectors in relation to large for gestational age (LGA) and gestational diabetes mellitus (GDM). RESULTS: CGA was associated with 4 out of 6 urinary phthalates. CGA was 2.0 loge units lower at the 3rd vs. 1st quartile of mono-n-butyl phthalate (MnBP) (95% confidence interval (CI): -3.5, -0.5) in male placentas, but 0.6 loge units higher (95% CI: -0.8, 1.9) in female placentas (sex interaction p = 0.01). There was an inverse association of MnBP with PPARG in male placentas (-1.1 loge units at highest vs. lowest quartile, 95% CI: -2.0, -0.1). CY19A1, CYP11A1, CGA were associated with one or more of the following in a sex-specific manner: monobenzyl phthalate (MBzP), MnBP, mono-iso-butyl phthalate (MiBP). These 3 mRNAs were lower by 1.4-fold (95% CI: -2.4, -1.0) in male GDM placentas vs. female and non-GDM placentas (p-value for interaction = 0.04). The metabolites MnBP/MiBP were 16% higher (95% CI: 0, 22) in GDM pregnancies. CONCLUSIONS: Prenatal concentrations of certain phthalates and outcomes at birth were modestly associated with molecular changes in fetal placental tissue during pregnancy. Associations were stronger in male vs. female placentas, and associations with MnBP and MiBP were stronger than other metabolites. Placental mRNAs are being pursued further as potential mediators of exposure-induced risks to the health of the child.

Maternal prenatal urinary phthalate metabolite concentrations and visual recognition memory among infants at 27 weeks.

BACKGROUND: Prior research has demonstrated inverse associations between maternal prenatal urinary phthalate metabolite concentrations and cognitive development assessed in preschool and school-aged children. While there are a limited number of studies that evaluated these associations during infancy, no study has evaluated whether these associations exist when using the Fagan Test of Infant Intelligence (FTII), which captures novelty preference as a function of visual recognition memory. OBJECTIVE: We evaluated associations between phthalate metabolite concentrations in maternal prenatal urine and cognition in infancy using the FTII at 27 weeks and determine if these associations are sex-specific. METHODS: Mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), mono-ethyl phthalate (MEP), mono-3-carboxypropyl phthalate (MCPP) and four di-2-ethylhexyl phthalate metabolites (DEHP) were quantified in urine samples collected from 168 minority women living in urban neighborhoods during their third trimester of pregnancy. The FTII was administered to infants at 27 weeks to measure visual recognition memory and was recorded as the novelty preference score. RESULTS: There were no associations between prenatal phthalate metabolite concentrations and novelty preference score in the full sample. However, there was evidence of effect modification by infant sex. Sex-stratified models demonstrated that compared to girls in the lowest tertile of MBzP concentrations, girls in tertiles 2 and 3 had, on average, 3.98 and 4.65 points lower novelty preference scores (p-value=0.04 and 0.03, respectively). The relationship was similar for ΣDEHP, MiBP, and MEP. Effects among boys were inconsistent and generally not significant. CONCLUSION: Maternal prenatal exposure to some phthalates was negatively associated with visual recognition memory as measured by the FTII among girls at age 27 weeks.

Bisphenol A and Adiposity in an Inner-City Birth Cohort.

BACKGROUND: Early-life exposure to the endocrine disruptor bisphenol A (BPA) may contribute to the development of obesity. Prospective evidence in humans on this topic is limited. OBJECTIVES: We examined prenatal and early-childhood BPA exposures in relation to childhood measures of adiposity in the Columbia Center for Children's Environmental Health (CCCEH) New York City birth cohort. METHODS: BPA concentrations were measured in prenatal (n = 375) and child ages 3 (n = 408) and 5 years (n = 518) spot urine samples. Childhood anthropometric and bioelectrical impedance outcomes included body mass index z-scores (BMIZ) at 5 and 7 years, and fat mass index (FMI), percent body fat (%BF), and waist circumference (WC) at 7 years. Associations were evaluated using multiple linear regression with continuous and tertile BPA concentrations. RESULTS: Prenatal urinary BPA concentrations were positively associated with child age 7 FMI (ß = 0.31 kg/m2; 95% CI: 0.01, 0.60, p = 0.04), %BF (ß = 0.79; 95% CI: 0.03, 1.55, p = 0.04), and WC (ß = 1.29 cm; 95% CI: 0.29, 2.30, p = 0.01), but not BMIZ, or change in BMIZ between ages 5 and 7 years (all p-values > 0.1). FMI results were sex-specific. Child urinary BPA concentrations were not associated with child anthropometric outcomes (all p-values > 0.05). CONCLUSIONS: Analyses of the CCCEH longitudinal birth cohort found associations between prenatal urinary BPA concentrations and FMI, %BF, and WC. Our results suggest that prenatal BPA exposure may contribute to developmental origins of adiposity. These findings are consistent with several prior studies, raising concern about the pervasiveness of BPA. CITATION: Hoepner LA, Whyatt RM, Widen EM, Hassoun A, Oberfield SE, Mueller NT, Diaz D, Calafat AM, Perera FP, Rundle AG. 2016. Bisphenol A and adiposity in an inner-city birth cohort. Environ Health Perspect 124:1644-1650; http://dx.doi.org/10.1289/EHP205.

Prenatal Phthalate Exposures and Body Mass Index Among 4- to 7-Year-old Children: A Pooled Analysis.

BACKGROUND: Phthalates are hypothesized to cause obesity, but few studies have assessed whether prenatal phthalate exposures are related to childhood body mass index (BMI). METHODS: We included 707 children from three prospective cohort studies enrolled in the US between 1998 and 2006 who had maternal urinary phthalate metabolite concentrations measured during pregnancy, and measures of weight and height at ages 4 to 7 years. We calculated age- and sex-standardized BMI z scores and classified children with BMI percentiles ≥85 as overweight/obese. We used mixed effects regression models to estimate associations between a 1 standard deviation increase in natural log phthalate metabolite concentrations and BMI z scores and overweight/obesity. We estimated associations in multiple metabolite models adjusted for confounders, and evaluated heterogeneity of associations by child's sex, race/ethnicity, and cohort. RESULTS: Mono-3-carboxypropyl phthalate concentrations were positively associated with overweight/obese status in children (odds ratio [95% credible interval] = 2.1 [1.2, 4.0]) but not with BMI z scores (ß = -0.02 [-0.15, 0.11]). We did not observe evidence of obesogenic effects for other metabolites. However, monoethyl phthalate and summed di-(2-ethylhexyl) phthalate metabolites (∑DEHP) concentrations were inversely associated with BMI z scores among girls (monoethyl phthalate beta = -0.14 [-0.28, 0.00]; ∑DEHP beta = -0.12 [-0.27, 0.02]). CONCLUSIONS: Maternal urinary mono-3-carboxypropyl phthalate, a nonspecific metabolite of several phthalates, was positively associated with childhood overweight/obesity. Metabolites of diethyl phthalate and DEHP were associated with lower BMI in girls but not in boys, suggesting that prenatal exposures may have sexually dimorphic effects on physical development.

Prenatal Exposure to Organophosphorous Pesticides and Fetal Growth: Pooled Results from Four Longitudinal Birth Cohort Studies.

BACKGROUND: Organophosphorous (OP) pesticides are associated with reduced fetal growth in animals, but human studies are inconsistent. OBJECTIVES: We pooled data from four cohorts to examine associations of prenatal OP exposure with birth weight (n = 1,169), length (n = 1,152), and head circumference (n = 1,143). METHODS: Data were from the CHAMACOS, HOME, Columbia, and Mount Sinai birth cohorts. Concentrations of three diethyl phosphate (ΣDEP) and three dimethyl phosphate (ΣDMP) metabolites of OP pesticides [summed to six dialkyl phosphates (ΣDAPs)] were measured in maternal urine. Linear regression and mixed-effects models were used to examine associations with birth outcomes. RESULTS: We found no significant associations of ΣDEP, ΣDMP, or ΣDAPs with birth weight, length, or head circumference overall. However, among non-Hispanic black women, increasing urinary ΣDAP and ΣDMP concentrations were associated with decreased birth length (ß = -0.4 cm; 95% CI: -0.9, 0.0 and ß = -0.4 cm; 95% CI: -0.8, 0.0, respectively, for each 10-fold increase in metabolite concentration). Among infants with the PON1192RR genotype, ΣDAP and ΣDMP were negatively associated with length (ß = -0.4 cm; 95% CI: -0.9, 0.0 and ß = -0.5 cm; 95% CI: -0.9, -0.1). CONCLUSIONS: This study confirms previously reported associations of prenatal OP exposure among black women with decreased infant size at birth, but finds no evidence of smaller birth weight, length, or head circumference among whites or Hispanics. Contrary to our hypothesis, we found stronger inverse associations of DAPs and birth outcome in infants with the less susceptible PON1192RR genotype. The large pooled data set facilitated exploration of interactions by race/ethnicity and PON1 genotype, but was limited by differences in study populations. CITATION: Harley KG, Engel SM, Vedar MG, Eskenazi B, Whyatt RM, Lanphear BP, Bradman A, Rauh VA, Yolton K, Hornung RW, Wetmur JG, Chen J, Holland NT, Barr DB, Perera FP, Wolff MS. 2016. Prenatal exposure to organophosphorous pesticides and fetal growth: pooled results from four longitudinal birth cohort studies. Environ Health Perspect 124:1084-1092; http://dx.doi.org/10.1289/ehp.1409362.

Prenatal Exposure to Phthalates and Childhood Body Size in an Urban Cohort.

BACKGROUND: Phthalate exposures are hypothesized to increase obesity; however, prior research has been largely cross-sectional. OBJECTIVE: We evaluated associations between prenatal phthalate exposures and body mass index (BMI) at child ages 5 and 7 years. METHODS: Nine metabolites of six phthalates-di(2-ethylhexyl) phthalate (DEHP), di-n-octyl-, di-iso-butyl-, di-n-butyl-, butylbenzyl-, and diethyl phthalates-were measured in spot urine samples collected from pregnant African-American and Dominican women during their third trimester, and from their children at ages 3 and 5 years. To reduce multiple comparison issues, we initially used principal component analysis (PCA) to identify major patterns of natural log (ln)-transformed metabolite concentrations. Height and weight were assessed at ages 5 and 7 years, and fat mass and waist circumference at age 7. Linearized generalized estimating equation analyses related maternal component scores to child anthropometric outcomes at ages 5 (n = 326) and 7 (n = 330) years. RESULTS: PCA identified a DEHP component and a non-DEHP component. In boys, higher maternal non-DEHP, but not DEHP, component scores were associated with lower BMI z-score (ß = -0.30; 95% CI: -0.50, -0.10, n = 156), lower fat percentage (ß = -1.62; 95% CI: -2.91, -0.34, n = 142), and smaller waist circumference (ß = -2.02; 95% CI: -3.71, -0.32, n = 124). No significant associations with anthropometric outcomes were seen in girls (for BMI z-score, ß = 0.07; 95% CI: -0.18, 0.31, n = 181). Interactions between sex and non-DEHP component association with outcomes were statistically significant (p < 0.01). CONCLUSIONS: Contrary to hypotheses, prenatal non-DEHP phthalate exposures were associated with lower BMI z-score, waist circumference, and fat mass in boys during early childhood. CITATION: Maresca MM, Hoepner LA, Hassoun A, Oberfield SE, Mooney SJ, Calafat AM, Ramirez J, Freyer G, Perera FP, Whyatt RM, Rundle AG. 2016. Prenatal exposure to phthalates and childhood body size in an urban cohort. Environ Health Perspect 124:514-520; http://dx.doi.org/10.1289/ehp.1408750.

Prenatal Organophosphorus Pesticide Exposure and Child Neurodevelopment at 24 Months: An Analysis of Four Birth Cohorts.

BACKGROUND: Organophosphorus pesticides (OPs) are used in agriculture worldwide. Residential use was common in the United States before 2001. OBJECTIVES: We conducted a pooled analysis of four birth cohorts (children's centers; n = 936) to evaluate associations of prenatal exposure to OPs with child development at 24 months. METHODS: Using general linear models, we computed site-specific and pooled estimates of the association of total dialkyl (ΣDAP), diethyl (ΣDEP), and dimethylphosphate (ΣDMP) metabolite concentrations in maternal prenatal urine with mental and psychomotor development indices (MDI/PDI) and evaluated heterogeneity by children's center, race/ethnicity, and PON1 genotype. RESULTS: There was significant heterogeneity in the center-specific estimates of association for ΣDAP and ΣDMP and the MDI (p = 0.09, and p = 0.05, respectively), as well as heterogeneity in the race/ethnicity-specific estimates for ΣDAP (p = 0.06) and ΣDMP (p = 0.02) and the MDI. Strong MDI associations in the CHAMACOS population per 10-fold increase in ΣDAP (ß = -4.17; 95% CI: -7.00, -1.33) and ΣDMP (ß = -3.64; 95% CI: -5.97, -1.32) were influential, as were associations among Hispanics (ß per 10-fold increase in ΣDAP = -2.91; 95% CI: -4.71, -1.12). We generally found stronger negative associations of ΣDAP and ΣDEP with the 24-month MDI for carriers of the 192Q PON1 allele, particularly among blacks and Hispanics. CONCLUSIONS: Data pooling was complicated by center-related differences in subject characteristics, eligibility, and changes in regulations governing residential use of OPs during the study periods. Pooled summary estimates of prenatal exposure to OPs and neurodevelopment should be interpreted with caution because of significant heterogeneity in associations by center, race/ethnicity, and PON1 genotype. Subgroups with unique exposure profiles or susceptibilities may be at higher risk for adverse neurodevelopment following prenatal exposure. CITATION: Engel SM, Bradman A, Wolff MS, Rauh VA, Harley KG, Yang JH, Hoepner LA, Barr DB, Yolton K, Vedar MG, Xu Y, Hornung RW, Wetmur JG, Chen J, Holland NT, Perera FP, Whyatt RM, Lanphear BP, Eskenazi B. 2016. Prenatal organophosphorus pesticide exposure and child neurodevelopment at 24 months: an analysis of four birth cohorts. Environ Health Perspect 124:822-830; http://dx.doi.org/10.1289/ehp.1409474.

Gestational weight gain and obesity, adiposity and body size in African-American and Dominican children in the Bronx and Northern Manhattan.

Gestational weight gain (GWG) is potentially modifiable and is associated with infant size and body composition; however, long-term effects on childhood obesity have not been reported among multi-ethnic urban populations. We examined the association between GWG and child anthropometric measures and body composition at 7 years [waist circumference (WC), body mass index z-score (BMIZ), obesity (BMIZ ≥95%ile) and bioelectrical impedance analysis estimates of percentage body fat (%fat)] in African-American and Dominican dyads (n = 323) in the Columbia Center for Children's Environmental Health prospective birth cohort study from 1998 to 2013. Linear and logistic regression evaluated associations between excessive GWG [>Institute of Medicine (IOM) 2009 guidelines] and outcomes, adjusting for pre-pregnancy BMI and covariates. Pre-pregnancy BMI (mean ± standard deviation, all such values) and total GWG were 25.8 ± 6.2 kg m(-2) (45% overweight/obese) and 16.4 ± 7.9 kg (64% > IOM guidelines), respectively. Excessive GWG was associated with higher BMIZ {0.44 [95% confidence interval (CI): 0.2, 0.7], P < 0.001}, WC [ß: 2.9 cm (95% CI: 1.1, 4.6), P = 0.002], %fat at 7 years [ß: 2.2% (95% CI: 1.0, 3.5), P = 0.001)] and obesity [odds ratio: 2.93 (95% CI: 1.5, 5.8), P = 0.002]. Pre-pregnancy BMI was positively associated with child size, adiposity and obesity (all P < 0.05). Excessive GWG was highly prevalent and was associated with child obesity, greater percentage body fat and abdominal adiposity. Strategies to support healthy GWG are warranted to promote healthy growth and prevent childhood obesity.

Excessive gestational weight gain is associated with long-term body fat and weight retention at 7 y postpartum in African American and Dominican mothers with underweight, normal, and overweight prepregnancy BMI.

BACKGROUND: Excessive gestational weight gain (GWG) is associated with postpartum weight retention (PPWR) and abdominal adiposity, but long-term effects are understudied in low-income and minority populations at high risk of obesity and associated sequelae. OBJECTIVE: We examined associations between GWG and long-term PPWR and adiposity in a prospective cohort of African American and Dominican mothers in the Bronx and Northern Manhattan. DESIGN: Women (n = 302) were enrolled during pregnancy and were followed for 7 y postpartum. Linear regression was used to relate excessive GWG [greater than 2009 Institute of Medicine (IOM) guidelines] to outcomes [percentage body fat and long-term PPWR (change in weight from prepregnancy to 7 y postpartum)], adjusting for covariates and included an interaction term between prepregnancy body mass index (BMI; in kg/m(2)) and GWG. RESULTS: Mean ± SD prepregnancy BMI and total GWG were 25.6 ± 5.8 (42% of women had BMI ≥25) and 16.6 ± 7.8 kg (64% of women had total GWG greater than IOM guidelines), respectively. Associations between GWG and long-term PPWR and the percentage body fat varied by prepregnancy BMI (P-interaction ≤ 0.06); excessive GWG was associated with a higher percentage body fat and greater long-term PPWR in mothers with lower prepregnancy BMI. To illustrate the interaction, a predicted covariate-adjusted model, which was used to derive estimates for the percentage body fat and PPWR associated with excessive GWG, was estimated for 2 prepregnancy BMI examples. For a woman with prepregnancy BMI of 22, excessive GWG was associated with 3.0% higher body fat (P < 0.001) and a 5.6-kg higher PPWR (P < 0.001); however, for a woman with a prepregnancy BMI of 30, excessive GWG was associated with 0.58% higher body fat (P = 0.55) and 2.06 kg PPWR (P = 0.24). CONCLUSIONS: Long-term adiposity and PPWR in low-income African American and Dominican mothers were predicted by interacting effects of prepregnancy BMI and excessive GWG. The provision of support for mothers to begin pregnancy at a healthy weight and to gain weight appropriately during pregnancy may have important lasting implications for weight-related health in this population. This study was registered at clinicaltrials.gov as NCT00043498.

Ghana randomized air pollution and health study (GRAPHS): study protocol for a randomized controlled trial.

BACKGROUND: Household air pollution exposure is a major health risk, but validated interventions remain elusive. METHODS/DESIGN: The Ghana Randomized Air Pollution and Health Study (GRAPHS) is a cluster-randomized trial that evaluates the efficacy of clean fuels (liquefied petroleum gas, or LPG) and efficient biomass cookstoves in the Brong-Ahafo region of central Ghana. We recruit pregnant women into LPG, efficient cookstove, and control arms and track birth weight and physician-assessed severe pneumonia incidence in the first year of life. A woman is eligible to participate if she is in the first or second trimester of pregnancy and carrying a live singleton fetus, if she is the primary cook, and if she does not smoke. We hypothesize that babies born to intervention mothers will weigh more and will have fewer cases of physician-assessed severe pneumonia in the first year of life. Additionally, an extensive personal air pollution exposure monitoring effort opens the way for exposure-response analyses, which we will present alongside intention-to-treat analyses. Major funding was provided by the National Institute of Environmental Health Sciences, The Thrasher Research Fund, and the Global Alliance for Clean Cookstoves. DISCUSSION: Household air pollution exposure is a major health risk that requires well-tested interventions. GRAPHS will provide important new evidence on the efficacy of both efficient biomass cookstoves and LPG, and will thus help inform health and energy policies in developing countries. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov on 13 April 2011 with the identifier NCT01335490 .