Faculty Bibliography

While definitions vary, endocrine-disrupting chemicals (EDCs) have two fundamental features: their disruption of hormone function and their contribution to disease and disability. The unique vulnerability of children to low-level EDC exposures has eroded the notion that only the dose makes the thing a poison, requiring a paradigm shift in scientific and policy practice. In this review, we discuss the unique vulnerability of children as early as fetal life and provide an overview of epidemiological studies on programming effects of EDCs on neuronal, metabolic, and immune pathways as well as on endocrine, reproductive, and renal systems. Building on this accumulating evidence, we dispel and address existing myths about the health effects of EDCs with examples from child health research. Finally, we provide a list of effective actions to reduce exposure, and subsequent harm that are applicable to individuals, communities, and policy-makers. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Fetal exposure to phthalates and bisphenols could be associated with kidney function. We aim to assess the association between maternal urine concentrations of phthalates and bisphenols during pregnancy and kidney function and size during childhood. In 1366 pregnant women from a prospective population-based cohort, we measured urine concentrations of phthalates, more specifically phthalic acid and metabolites of low molecular weight phthalates (LMWP) and high molecular weight phthalates (HMWP), with its subgroups of di-2-ethylhexylphthalate (DEHP) and di-n-octylphthalate (DNOP) metabolites, and bisphenol A, S and F during first, second and third trimester. We explored three methods of adjustment for maternal hydration status: creatinine standardization, covariate adjustment for creatinine and covariate-adjusted creatinine standardization plus covariate adjustment. We measured kidney size, calculated estimated glomerular filtration rate (eGFR) and the albumin/creatinine ratio in urine and assessed microalbuminuria at 6 years old. When applying creatinine standardization, we found some associations of higher maternal second trimester urine phthalic acid and overall mean phthalic acid and LMWP concentrations with higher eGFR. These associations were lessened when applying other methods of creatinine adjustment. The associations found when we applied the covariate adjustment for creatinine method were also lessened when applying other methods of creatinine adjustment. Only the association of higher second trimester phthalic acid maternal urine concentrations with higher eGFR at 6 years old remained significant irrespective of the method of creatinine adjustment. There were no consistent associations of maternal bisphenol A, S and F urine concentrations with childhood kidney function. There were no associations of maternal phthalate or bisphenol urine concentrations with kidney volume in children at 6 years old. Concluding, no consistent associations of maternal phthalate or bisphenol urine concentrations with childhood kidney function or volume could be found. Furthermore, the method of adjusting maternal urine phthalate and bisphenol concentrations for urinary dilution had a substantial effect on the associations with childhood kidney function, as it changed the conclusions about the directionality of the associations. Future studies including maternal kidney function are needed to further elucidate these association in humans.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous endocrine-disrupting combustion by-products that have been linked to preterm birth. One possible mechanism is through disruption of placental corticotropin releasing hormone (pCRH), a key hormone implicated in parturition. As an extension of recent research identifying pCRH as a potential target of endocrine disruption, we examined maternal PAH exposure in relation to pCRH in a large, diverse sample. Participants, drawn from the CANDLE cohort, part of the ECHO-PATHWAYS Consortium, completed study visits at 16-29 weeks (V1) and 22-39 weeks (V2) gestation (n=812). Seven urinary mono-hydroxylated PAH metabolites (OH-PAHs) were measured at V1 and serum pCRH at V1 and V2. Associations between individual log-transformed OH-PAHs (as well as two summed PAH measures) and log(pCRH) concentrations across visits were estimated using mixed effects models. Minimally-adjusted models included gestational age and urinary specific gravity, while fully-adjusted models also included sociodemographic characteristics. We additionally evaluated effect modification by pregnancy complications, fetal sex, and maternal childhood trauma history. We observed associations between 2-OH-Phenanthrene (2-OH-PHEN) and rate of pCRH change that persisted in fully adjusted models (β=0.0009, 0.00006, 0.0017), however, positive associations with other metabolites (most notably 3-OH-Phenanthrene and 1-Hydroxypyrene) were attenuated after adjustment for sociodemographic characteristics. Associations tended to be stronger at V1 compared to V2 and we observed no evidence of effect modification by pregnancy complications, fetal sex, or maternal childhood trauma history. In conclusion, we observed modest evidence of association between OH-PAHs, most notably 2-OH-PHEN, and pCRH in this sample. Additional research using serial measures of PAH exposure is warranted, as is investigation of alternative mechanisms that may link PAHs and timing of birth, such as inflammatory, epigenetic, or oxidative stress pathways.

BACKGROUND:Fish and other seafood are an important dietary source of per- and polyfluoroalkyl substances (PFAS) exposure in many areas of the world, and PFAS were found to be pervasive in fish from the Great Lakes area. Few studies, however, have examined the associations between Great Lakes Basin fish consumption and PFAS exposure. Many licensed anglers and Burmese refugees and immigrants residing in western New York State consume fish caught from the Great Lakes and surrounding waters, raising their risk of exposure to environmental contaminants including PFAS. The aims of this study were to: 1) present the PFAS exposure profile of the licensed anglers and Burmese refugees and 2) examine the associations between serum PFAS levels and local fish consumption. METHODS:Licensed anglers (n = 397) and Burmese participants (n = 199) provided blood samples and completed a detailed questionnaire in 2013. We measured 12 PFAS in serum. Multiple linear regression was used to assess associations between serum PFAS concentrations and self-reported consumption of fish from Great Lakes waters. RESULTS:Licensed anglers and Burmese participants reported consuming a median of 16 (IQR: 6-36) and 88 (IQR: 44-132) meals of locally caught fish in the year before sample collection, respectively (data for Burmese group restricted to 10 months of the year). Five PFAS were detected in almost all study participants (PFOS, PFOA, PFHxS, PFNA and PFDA; 97.5-100%). PFOS had the highest median serum concentration in licensed anglers (11.6 ng/mL) and the Burmese (35.6 ng/mL), approximately two and six times that of the U.S. general population, respectively. Serum levels of other PFAS in both groups were generally low and comparable to those in the general U.S. POPULATION/METHODS:Among licensed anglers, Great Lakes Basin fish meals over the past year were positively associated with serum PFOS (P < 0.0001), PFDA (P < 0.0001), PFHxS (P = 0.01), and PFNA (P = 0.02) and the number of years consuming locally caught fish was positively associated with serum PFOS (P = 0.01) and PFDA (P = 0.01) levels. In the Burmese group, consuming Great Lakes Basin fish more than three times a week in the past summer was positively associated with serum PFOS (P = 0.004) and PFDA (P = 0.02) among the Burmese of non-Karen ethnicity, but not among those of Karen ethnicity, suggesting potential ethnic differences in PFAS exposure. CONCLUSIONS:Great Lakes Basin fish consumption was associated with an increase in blood concentrations of some PFAS, and especially of PFOS, among licensed anglers and Burmese refugees and immigrants in western New York State. In the Burmese population, there may be other important PFAS exposure routes related to residential history and ethnicity. Continued outreach efforts to increase fish advisory awareness and reduce exposure to contaminants are needed among these populations.

BACKGROUND:Animal and epidemiological studies suggest that prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) may negatively impact toddler neurodevelopment. METHODS:We investigated this association in 835 mother-child pairs from CANDLE, a diverse pregnancy cohort in the mid-South region of the U.S. PAH metabolite concentrations were measured in mid-pregnancy maternal urine. Cognitive and Language composite scores at ages 2 and 3 years were derived from the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-3). Behavior Problem and Competence scores at age 2 were derived from the Brief Infant and Toddler Social Emotional Assessment (BITSEA). We used multivariate linear or Poisson regression to estimate associations with continuous scores and relative risks (RR) of neurodevelopment delay or behavior problems per 2-fold increase in PAH, adjusted for maternal health, nutrition, and socioeconomic status. Secondary analyses investigated associations with PAH mixture using Weighted Quantile Sum Regression (WQS) with a permutation test extension. RESULTS: = 0.05). All other estimates were consistent with null associations. CONCLUSION/CONCLUSIONS:In this large southern U.S. population we observed some support for adverse associations between PAHs and neurodevelopment.

Volatile organic compounds (VOCs) are ubiquitous environmental pollutants that are associated with birth defects, leukemia, neurocognitive deficits, reproductive impairment and cancer in humans exposed to these compounds. Exposure to VOCs can be assessed by measuring their metabolites in urine. Little is known, however, about the temporal variability in urinary VOC metabolite (VOCM) concentrations within and between individuals. In this study, we determined the variability in the concentrations of 38 VOCMs in urine samples collected from 19 healthy individuals across a period of 44 days. We also measured seven biomarkers of oxidative stress (lipid, protein and DNA damage) in urine to assess the relationship of VOC exposure to oxidative stress. Seventeen VOCMs had detection frequencies (DFs) of >60% in urine, and we limited further data analysis to those compounds. The creatinine-adjusted geometric mean concentrations of VOCMs ranged from 2.70 μg/g to 327 μg/g in spot and 2.60 μg/g to 551 μg/g in first morning void (FMV) urine samples. Calculation of the intra-class correlation coefficients (ICCs) for 17 VOCM concentrations to assess their predictability and repeatability in urinary measurements showed ranges of 0.080-0.425 in spot and 0.050-0.749 in FMV urine samples, revealing notable within-individual variability. Our results suggest that taking only single measurements of VOCM concentrations in urine in epidemiological investigations may lead to exposure misclassification. In addition, VOCM concentrations were significantly and positively correlated with oxidative stress biomarkers. This study thus provides important information for formulating sampling strategies in the biomonitoring of VOC exposure in human populations.

Although human exposure to microplastics (MPs) and the health effects thereof are a global concern, little is known about the magnitude of exposure. In this study, we quantitatively determined the concentrations of polyethylene terephthalate (PET) and polycarbonate (PC) MPs in three meconium and six infant and 10 adult feces samples collected from New York State. PET and PC MPs were found in some meconium samples (at concentration ranges from below the limit of quantification [<LOQ] to 12,000 and <LOQ-110 ng/g dry weight, respectively) and all infant stool specimens (PET: 5700-82,000 ng/g, median, 36,000 ng/g; PC: 49-2100 ng/g, median, 78 ng/g). They were also found in most (PET) or all (PC) adult stool samples but at concentrations an order of magnitude lower than in infants for PET MPs (<LOQ-16,000 ng/g, median, 2600 ng/g). The estimated mean daily exposures from the diet of infants to PET and PC MPs were 83,000 and 860 ng/kg body weight per day, respectively, which were significantly higher than those of adults (PET: 5800 ng/kg-bw/day; PC: 200 ng/kg-bw/d). Our study suggests that infants are exposed to higher levels of MPs than adults.

Despite the widespread use of primary aromatic amines (AAs) in consumer products, little is known about their prevalence in house dust. In this study, we investigated the occurrence of 35 AAs and two tobacco chemical markers (nicotine and its breakdown product cotinine) in 119 samples of house dust collected from five provinces in China. Ten of the 35 AAs and [nicotine and/or cotinine] were found in >80% and 100% of the samples, respectively, at concentration ranges of 29.1-19,200 (median: 700 ng/g) and 23.2-22,400 (4600) ng/g, respectively. Aniline was the predominant AA found in all dust samples (median: 257 ng/g). Dust samples from Henan and Shanxi provinces contained higher summed concentrations of the 10 AAs than those from Sichuan and Shandong, although the concentrations did not vary significantly among the five provinces (p > 0.05). A significant (p = 0.048), positive correlation (r = 0.882) existed between concentrations of nicotine and cotinine in dust samples. Similarly, concentrations of AAs were significantly correlated with those of nicotine in dust samples. Dyestuffs, rubber products, polyurethane foam and tobacco smoke are the major sources of AAs in the indoor environment. The estimated daily intakes (EDI) through dust ingestion ranged from 0.349 (adults) to 6.62 ng/kg-bw/day (toddlers) for AAs and from 1.27 to 51.1 ng/kg-bw/day for nicotine which are below the current tolerable daily intakes.

BACKGROUND:Prenatal exposures to per- and polyfluoroalkyl substances (PFAS) have been linked to reduced fetal growth. However, the detailed molecular mechanisms remain largely unknown. This study aims to investigate biological pathways and intermediate biomarkers underlying the association between serum PFAS and fetal growth using high-resolution metabolomics in a cohort of pregnant African American women in the Atlanta area, Georgia. METHODS:Serum perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) measurements and untargeted serum metabolomics profiling were conducted in 313 pregnant African American women at 8-14 weeks gestation. Multiple linear regression models were applied to assess the associations of PFAS with birth weight and small-for-gestational age (SGA) birth. A high-resolution metabolomics workflow including metabolome-wide association study, pathway enrichment analysis, and chemical annotation and confirmation with a meet-in-the-middle approach was performed to characterize the biological pathways and intermediate biomarkers of the PFAS-fetal growth relationship. RESULTS:-unit increase in serum PFNA concentration was significantly associated with higher odds of SGA birth (OR = 1.32, 95% CI 1.07, 1.63); similar but borderline significant associations were found in PFOA (OR = 1.20, 95% CI 0.94, 1.49) with SGA. Among 25,516 metabolic features extracted from the serum samples, we successfully annotated and confirmed 10 overlapping metabolites associated with both PFAS and fetal growth endpoints, including glycine, taurine, uric acid, ferulic acid, 2-hexyl-3-phenyl-2-propenal, unsaturated fatty acid C18:1, androgenic hormone conjugate, parent bile acid, and bile acid-glycine conjugate. Also, we identified 21 overlapping metabolic pathways from pathway enrichment analyses. These overlapping metabolites and pathways were closely related to amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism perturbations. CONCLUSION/CONCLUSIONS:In this cohort of pregnant African American women, higher serum concentrations of PFOA and PFNA were associated with reduced fetal growth. Perturbations of biological pathways involved in amino acid, lipid and fatty acid, bile acid, and androgenic hormone metabolism were associated with PFAS exposures and reduced fetal growth, and uric acid was shown to be a potential intermediate biomarker. Our results provide opportunities for future studies to develop early detection and intervention for PFAS-induced fetal growth restriction.

BACKGROUND:Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact. OBJECTIVE:We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight. METHODS: RESULTS: DISCUSSION/CONCLUSIONS:Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178.