Faculty Bibliography

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.

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: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.

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.

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.

Human exposure to poly- and perfluoroalkyl substances (PFASs) is widespread and has received considerable attention in recent years due to their link with adverse health outcomes, including bone health. Nevertheless, no earlier studies have reported serum PFAS concentrations, and their association with incident osteoporosis in populations in Saudi Arabia. In this clinical case-control study, serum samples collected from 208 individuals (n = 100 cases and n = 108 controls) aged 40-89 years from Jeddah, Saudi Arabia, were analyzed for 17 PFASs. Unconditional logistic regression was used to calculate odds ratios (ORs) for association between serum PFAS concentrations and osteoporosis, stratified by gender, age, serum calcium and vitamin D, previous history of fractures and thyroid disorders. Perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorobutanoic acid (PFBA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), perfluoro-n-pentanoic acid (PFPeA) and perfluoroundecanoic acid (PFUnDA) were detected in >80% of serum samples analyzed. PFOS (overall median concentration: 5.08 ng/mL), PFHxS (1.49 ng/mL), PFOA (1.33 ng/mL) and PFNA (0.55 ng/mL) accounted for 94% and 80% of the total serum PFASs concentrations in cases and controls, respectively. Serum PFOA, PFNA and PFUnDA concentrations increased with age in Saudi women. Results from the crude models showed that individuals in the 2nd, 3rd and 4th quartiles of serum PFAS concentrations had 2.3-96-fold increase in odds of diagnosis for osteoporosis compared with those in the 1st quartile (rank order: PFUnDA > PFOA > PFNA > PFOS > PFHxS). Our results suggest that exposure to PFOA, PFOS, PFNA, PFHxS and PFUnDA was associated with osteoporosis in this sample of adult Saudi population.

BACKGROUND:Experimental evidence suggests that exposures to phthalates and bisphenols may interfere with processes related to glucose and lipid metabolism, insulin sensitivity, and body weight. Few studies have considered the possible influence of chemical exposures during pregnancy on maternal weight gain or metabolic health outcomes postpartum. OBJECTIVE:To examine the associations of early and mid-pregnancy bisphenol and phthalate urine concentrations with maternal weight gain 6 years postpartum. METHODS:We analyzed urine samples for bisphenol, phthalate and creatinine concentrations from early and mid-pregnancy in 1192 women in a large, population-based birth cohort in Rotterdam, the Netherlands, and examined postpartum weight gain using maternal anthropometrics before pregnancy and 6 years postpartum. We have used covariate-adjusted linear regressions to evaluate associations of early and mid-pregnancy bisphenols and phthalate metabolites with weight change. Mediator and interaction models have been used to assess the role of gestational weight gain and breastfeeding, respectively. Sensitivity analysis is performed among women without subsequent pregnancies. RESULTS:Among all 1192 mothers included in the analysis, each log unit increase in the average bisphenol A and all assessed phthalate groupings were associated with increased maternal weight gain. As a proxy for phthalate exposure, each log unit increase in averaged phthalic acid was associated with 734 g weight gain (95% CI 273-1196 g) between pre-pregnancy and 6 years postpartum. Mediation by gestational weight gain was not present. Breastfeeding and ethnicity did not modify the effects. Stratification revealed these associations to be strongest among overweight and obese women. Among women without subsequent pregnancies (n = 373) associations of bisphenols, HMW phthalate metabolites and di-2-ethylhexylphthalate metabolites attenuated. For phthalic acid, LMW phthalate metabolites and di-n-octylphthalate metabolites associations increased. Similarly to the whole group, stratification yielded significant results among overweight and obese women. DISCUSSION/CONCLUSIONS:In a large population-based birth cohort, early and mid-pregnancy phthalate exposures are associated with weight gain 6 years postpartum, particularly among overweight and obese women. These data support ongoing action to replace phthalates with safer alternatives.

Parabens are widely used as antimicrobial preservatives in personal care products (PCPs). Stretch mark cream is widely used by pregnant and lactating women for the treatment of striae gravidarum. This can be a potential source of paraben exposure, not only to pregnant/lactating women but also to fetuses/newborns. Little is known, however, with regard to the occurrence of parabens in stretch mark creams. In this study, we analyzed eight parabens and their metabolites in 31 popular stretch mark creams originated from various countries including China. The concentrations of Σparaben (sum of eight parabens/metabolites) ranged from 0.007 to 1630 μg/g, with mean and median values of 453 and 273 μg/g, respectively. Methyl- and propyl-parabens accounted for >95% of Σparaben concentrations. We examined the measured paraben concentrations against ingredients listed on the product labels. Parabens were listed as ingredients in those creams that contained concentrations >100 μg/g except for four samples with such high concentrations. Six cream samples that were labeled 'paraben-free' contained trace levels (0.007-9.92 μg/g) of these preservatives. Mean dermal ∑paraben exposure dose from the use of stretch mark creams (30.6 μg/kg bw/day) was well below the current acceptable daily intake value (5 mg/kg bw/day). In comparison to diet and indoor dust ingestion pathways, paraben-laden stretch mark cream may be a major source of paraben exposure in pregnant and lactating women. This study provides information on parabens and other preservatives in stretch mark creams and measures to reduce exposures during pregnancy and lactation.

BACKGROUND:Prenatal maternal plasma persistent organic pollutant (POP) concentrations have been associated with neonatal outcomes. However, the underlying mechanisms remain unknown. Placental epigenetic mechanisms may be involved, but no prior epigenome-wide studies have investigated the impact of maternal POPs on placental DNA methylation. We studied the association between maternal plasma POP concentration in early pregnancy and epigenome-wide placental DNA methylation among 260 pregnant women from the NICHD Fetal Growth Studies. RESULTS:). Out of the 214 CpG sites, 24 (11%) were significantly correlated with placental expression of 21 genes. Notably, higher PFUnDA was associated with increased methylation at 3 CpG sites (cg13996963, cg12089439, cg18145877) annotated to TUSC3, and increased methylation at those 3 CpG sites was correlated with decreased expression of TUSC3 in the placenta. Increased methylation at cg18145877 (TUSC3) and decreased expression of TUSC3 were correlated with shorter birth length. Out of the 214 CpG sites, methylation at 44 CpG sites was correlated (p value < 0.10) with at least one neonatal anthropometry measure (i.e., birth weight, birth length, and head circumference). Seven CpG sites mediated (p value < 0.05) the association between PBDE 47 and neonatal anthropometry measures. Genes annotating the top differentially methylated CpG sites were enriched in pathways related to differentiation of embryonic cells (PBDE 47) and in pathways related to brain size and brain morphology (PFASs). CONCLUSIONS:DNA methylation changes in the placenta were significantly associated with maternal plasma POPs concentration. The findings suggest that placental DNA methylation and gene expression mechanism may be involved in the prenatal toxicity of POPs and their association with neonatal anthropometry measures.