Faculty Bibliography

OBJECTIVES/OBJECTIVE:Fetal exposure to phthalates and bisphenols might have long-lasting effects on growth and fat development. Not much is known about the effects on general and organ fat development in childhood. We assessed the associations of fetal exposure to phthalates and bisphenols with general and organ fat measures in school-aged children. METHODS:In a population-based, prospective cohort study among 1128 mother-child pairs, we measured maternal urinary phthalate metabolites and bisphenol concentrations in first, second, and third trimester. Offspring body mass index, fat mass index by dual-energy X-ray absorptiometry, and visceral and pericardial fat indices and liver fat fraction were measured by magnetic resonance imaging at 10 years. RESULTS:After adjustment for confounders and correction for multiple testing, an interquartile range increase in first trimester phthalic acid concentrations remained associated with a 0.14 (95% confidence interval: 0.05, 0.22) standard deviation score increase in pericardial fat index. We also observed tendencies for associations of higher maternal low molecular weight phthalate urinary concentrations in second trimester with childhood pericardial fat index, but these were not significant after adjustment for multiple testing. High molecular weight phthalate, di-2-ethylhexyl phthalate, and di-n-octyl phthalate concentrations were not associated with childhood outcomes. Maternal urinary bisphenol concentrations were not associated with childhood adiposity. CONCLUSIONS:Maternal first trimester phthalic acid concentrations are associated with increased childhood pericardial fat index at 10 years of age, whereas maternal bisphenol concentrations are not associated with childhood adiposity. We did not find significant sex-specific effects. These findings should be considered as hypothesis generating and need further replication and identification of underlying mechanisms.

BACKGROUND:Most pregnant women are exposed to bisphenols, a group of chemicals that can interfere with various components of the thyroid system. OBJECTIVES/OBJECTIVE:To investigate the association of maternal urinary bisphenol concentrations during pregnancy with maternal, newborn and early childhood thyroid function. METHODS:This study was embedded in Generation R, a prospective, population-based birth cohort (Rotterdam, the Netherlands). Maternal urine samples were analyzed for eight bisphenols at early (<18), mid (18-25) and late (>25 weeks) pregnancy. Maternal serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and total thyroxine (TT4) were measured in early pregnancy and child TSH and FT4 were measured in cord blood and childhood. RESULTS: = 0.08). DISCUSSION/CONCLUSIONS:Our findings show that exposure to bisphenols may interfere with the thyroid system during pregnancy. Furthermore, the potential developmental toxicity of exposure to bisphenols during pregnancy could affect the thyroid system in the offspring in a sex-specific manner.

Per- and polyfluoroalkyl substances (PFAS), polybrominated diphenyl ethers (PBDEs), and organophosphate esters (OPEs) are found in building materials and associated with thyroid disease, infertility, and impaired development. This study's objectives were to (1) compare levels of PFAS, PBDEs, and OPEs in dust from spaces with conventional versus "healthier" furniture and carpet, and (2) identify other product sources of flame retardants in situ. We measured 15 PFAS, 8 PBDEs, and 19 OPEs in dust from offices, common areas, and classrooms having undergone either no intervention (conventional rooms in older buildings meeting strict fire codes; n = 12), full "healthier" materials interventions (rooms with "healthier" materials in buildings constructed more recently or gut-renovated; n = 7), or partial interventions (other rooms with at least "healthier" foam furniture but more potential building contamination; n = 28). We also scanned all materials for bromine and phosphorus as surrogates of PBDEs and OPEs respectively, using x-ray fluorescence. In multilevel regression models, rooms with full "healthier" materials interventions had 78% lower dust levels of PFAS than rooms with no intervention (p < 0.01). Rooms with full "healthier" interventions also had 65% lower OPE levels in dust than rooms with no intervention (p < 0.01) and 45% lower PBDEs than rooms with only partial interventions (p < 0.10), adjusted for covariates related to insulation, electronics, and furniture. Bromine loadings from electronics in rooms were associated with PBDE concentrations in dust (p < 0.05), and the presence of exposed insulation was associated with OPE dust concentrations (p < 0.001). Full "healthier" materials renovations successfully reduced chemical classes in dust. Future interventions should address electronics, insulation, and building cross-contamination.

BACKGROUND:Previous studies of prenatal phthalate exposure and childhood asthma are inconsistent. These studies typically model phthalates as individual, rather than co-occurring, exposures. We investigated whether prenatal phthalates are associated with childhood wheeze and asthma using a mixtures approach. METHODS:We studied dyads from two prenatal cohorts in the ECHO-PATHWAYS consortium: CANDLE, recruited 2006-2011 and TIDES, recruited 2011-2013. Parents reported child respiratory outcomes at age 4-6 years: ever asthma, current wheeze (symptoms in past 12 months) and current asthma (two affirmative responses from ever asthma, recent asthma-specific medication use, and/or current wheeze). We quantified 11 phthalate metabolites in third trimester urine and estimated associations with child respiratory outcomes using weighted quantile sum (WQS) logistic regression, using separate models to estimate protective and adverse associations, adjusting for covariates. We examined effect modification by child sex and maternal asthma. RESULTS:Of 1481 women, most identified as White (46.6%) or Black (44.6%); 17% reported an asthma history. Prevalence of ever asthma, current wheeze and current asthma in children was 12.3%, 15.8% and 12.3%, respectively. Overall, there was no adverse association with respiratory outcomes. In sex-stratified analyses, boys' phthalate index was adversely associated with all outcomes (e.g., boys' ever asthma: adjusted odds ratio per one quintile increase in WQS phthalate index (AOR): 1.42; 95% confidence interval (CI): 1.08, 1.85, with mono-ethyl phthalate (MEP) weighted highest). Adverse associations were also observed in dyads without maternal asthma history, driven by MEP and mono-butyl phthalate (MBP), but not in those with maternal asthma history. We observed protective associations between the phthalate index and respiratory outcomes in analysis of all participants (e.g., ever asthma: AOR; 95% CI: 0.81; 0.68, 0.96), with di(2-ethylhexyl)phthalate (DEHP) metabolites weighted highest. CONCLUSIONS:Results suggest effect modification by child sex and maternal asthma in associations between prenatal phthalate mixtures and child asthma and wheeze.

BACKGROUND:Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. METHODS AND FINDINGS/RESULTS:Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and F2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (β = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 (95% CI: -0.75, -0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. CONCLUSIONS:Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.

The application of neonicotinoid insecticides (neonics) has increased dramatically as a replacement for organophosphate pesticides (OPs) in recent years. Nevertheless, little is known about human exposure to these pesticides in various countries. In this study, concentrations of 14 neonics and six dialkylphosphate metabolites (DAPs) were determined simultaneously in 566 urine samples collected from nine countries during 2010-2014. The highest sum concentration of 14 neonics was found in urine from Vietnam (median: 12.2 ng/mL) whereas that of six DAPs was from China (18.4 ng/mL). The median concentrations of ∑6 DAPs were twice higher than those of ∑14 neonics across the nine countries, which suggested a greater exposure to OPs than neonics. The overall pattern of urinary pesticide concentrations was similar among the nine countries with dimethylphosphate (DMP) and dimethylthiophosphate (DMTP) accounting for 51-89% of the total pesticide concentrations. Differences in urinary pesticide concentrations between genders (female and male), age groups (≤20, 21-49, and ≥50 years), and regions (cities of Shanghai, Guangzhou and Qiqihar) were examined. Total daily exposure doses to OPs were highest in China (515 μg/day) with 15% of the samples exceeding the U.S. Environmental Protection Agency's reference dose for chlorpyrifos (18 μg/day). This is the first study to establish baseline levels of OP and neonics exposure in general populations across nine countries.

BACKGROUND AND AIMS/OBJECTIVE:Fetal exposure to endocrine disruptors such as phthalates and bisphenols may lead to developmental metabolic adaptations. We examined associations of maternal phthalate and bisphenol urine concentrations during pregnancy with lipids, insulin, and glucose concentrations at school age. METHODS:In a population-based, prospective cohort study among 757 mother-child pairs, we measured maternal phthalate and bisphenol urine concentrations in first, second and third trimester of pregnancy. We measured non-fasting lipids, glucose and insulin blood concentrations of their children at a mean age of 9.7 (standard deviation 0.2) years. Analyses were performed for boys and girls separately. RESULTS:An interquartile range (IQR) higher natural log transformed third trimester maternal urine phthalic acid concentration was associated with a 0.20 (95% confidence interval (CI) 0.07-0.34) standard deviation score (SDS) higher triglycerides concentration among boys. Maternal bisphenol urine concentrations were not associated with non-fasting lipid concentrations during childhood. An IQR higher natural log transformed second trimester maternal high molecular weight phthalates (HMWP) and di-2-ethylhexylphthalate (DEHP) urine concentration were associated with a 0.19 (95% CI 0.31-0.07) respectively 0.18 (95% CI 0.31-0.06) SDS lower glucose concentration among boys. An IQR higher natural log transformed third trimester maternal bisphenol F urine concentration was associated with a 0.22 (95% CI 0.35-0.09) SDS lower non-fasting insulin concentration among boys. CONCLUSIONS:Our results suggest potential persisting sex specific effects of fetal exposure to phthalates and bisphenols on childhood lipid concentrations and glucose metabolism. Future studies are needed for replication and exploring underlying mechanisms.

BACKGROUND:Severe iodine deficiency or excess during pregnancy can cause congenital hypothyroidism (CH). Iodine deficiency is common in pregnant women in the United States. OBJECTIVES:We conducted a nested case-control study in a cohort of ∼2.5 million births in California to determine whether iodine status is related to CH in a US population. METHODS:Dried blood spots from 907 newborns with CH identified by newborn screening and 909 unaffected controls matched by month of birth were obtained from the California Newborn Screening Program to measure whole-blood iodine concentration. Iodine status was compared between cases and controls, and logistic regression was used to assess the association between CH status and blood iodine concentrations. Iodine status was also compared between cases and controls among infants treated in a neonatal intensive care unit (NICU) because CH has been reported in infants exposed to high levels of iodine in the NICU. RESULTS:Blood iodine concentrations did not differ significantly between cases (median: 20.0 ng/mL; IQR: 12.1-29.8 ng/mL) and controls (median: 20.3 ng/mL; IQR: 12.5-30.9 ng/mL; P = 0.59). Neither extremely high nor extremely low blood iodine concentrations (1st, 5th, 95th, and 99th percentiles of the distribution) were more common in cases. Among infants treated in NICUs, however, cases had significantly (P = 0.01) higher iodine (median: 22.7 ng/mL; IQR: 16.4-32.1 ng/mL) compared with controls (median: 17.3 ng/mL; IQR: 8.3-26.6 ng/mL). CONCLUSIONS:CH cases did not have significantly higher or lower iodine in this population, which is reassuring given that maternal iodine deficiency is common in the United States. Among newborns in the NICU, CH cases had higher blood iodine concentrations compared with controls, suggesting that excess iodine exposure in the NICU could be causing CH. It may be beneficial to monitor iodine exposure from surgical procedures, imaging, and iodine-containing disinfectants and to consider non-iodine alternatives.

A pilot study was initiated in 2018 under the Global Atmospheric Passive Sampling (GAPS) Network named GAPS-Megacities. This study included 20 megacities/major cities across the globe with the goal of better understanding and comparing ambient air levels of persistent organic pollutants and other chemicals of emerging concern, to which humans residing in large cities are exposed. The first results from the initial period of sampling are reported for 19 cities for several classes of flame retardants (FRs) including organophosphate esters (OPEs), polybrominated diphenyl ethers (PBDEs), and halogenated flame retardants (HFRs) including new flame retardants (NFRs), tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCDD). The two cities, New York (USA) and London (UK) stood out with ∼3.5 to 30 times higher total FR concentrations as compared to other major cities, with total concentrations of OPEs of 15,100 and 14,100 pg/m³, respectively. Atmospheric concentrations of OPEs significantly dominated the FR profile at all sites, with total concentrations in air that were 2-5 orders of magnitude higher compared to other targeted chemical classes. A moderately strong and significant correlation (r = 0.625, p < 0.001) was observed for Gross Domestic Product index of the cities with total OPEs levels. Although large differences in FR levels were observed between some cities, when averaged across the five United Nations regions, the FR classes were more evenly distributed and varied by less than a factor of five. Results for Toronto, which is a 'reference city' for this study, agreed well with a more in-depth investigation of the level of FRs over different seasons and across eight sites representing different urban source sectors (e.g. traffic, industrial, residential and background). Future sampling periods under this project will investigate trace metals and other contaminant classes, linkages to toxicology, non-targeted analysis, and eventually temporal trends. The study provides a unique urban platform for evaluating global exposome.

Studies on the occurrence of emerging pesticides in surface and drinking water in Vietnam are limited. In this study, lake water (n = 7), river water (n = 1), tap water (n = 46), and bottled water (n = 3) collected from Hanoi and other four provinces in northern Vietnam were analyzed for selected pesticides (including insecticides such as neonicotinoids, fipronil, and chlorpyrifos; fungicide carbendazim; herbicides such as atrazine, terbuthylazine, simazine, 2,4-dichlorophenoxyacetic acid, 2-methyl-4-chlorophenoxyacetic acid, and bentazon) and some of their degradates by liquid chromatography-tandem mass spectrometry. Carbendazim (median: 86.7 ng/L) and triazines (49.3 ng/L) were the major pesticides found in lake water samples, followed by neonicotinoids and their degradation products (15.1 ng/L), chlorpyrifos and its degradate (13.4 ng/L), fipronil and its degradates (3.76 ng/L), chlorophenoxy acid herbicides (2.10 ng/L), and bentazon (0.62 ng/L). Triazines (164 ng/L) were the major pesticides in river water. Higher concentrations (median: 39.3 ng/L; range: 1.20-127) of selected pesticides were found in tap water from Hanoi than those from four other provinces studied (5.49 ng/L; 4.73-66.8 ng/L). Bottled water samples collected from Hanoi contained lower concentrations of pesticide residues (median: 3.54 ng/L, range: 2.18-8.09) than those of tap water samples. The calculated risks from pesticide exposure through ingestion of tap water by the general populations were low. However, fipronil concentrations in lake water exceeded the benchmark value recommended for freshwater in the United States or the Netherlands. Degradation of acetamiprid into desmethyl-acetamiprid was found in lake water.