Faculty Bibliography

BACKGROUND:Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous chemicals with mechanisms of toxicity that include endocrine disruption. We examined associations of prenatal urinary PAH with spontaneous preterm birth (PTB) and gestational age (GA) at birth. We also assessed whether infant sex modifies the association of PAH exposure with spontaneous PTB and GA at birth. METHODS:-transformed OH-PAH concentrations as the exposure, adjusted for specific gravity and suspected confounders. Effect modification by infant sex was assessed using interaction terms and marginal estimates. RESULTS:Percent detection was highest for 2-OH-NAP (99.8%) and lowest for 1-OH-PYR (65.2%). Prevalence of spontaneous PTB was 5.5% (N = 92). Ten-fold higher 2-OH-NAP exposure was associated with 1.60-day (95% CI: -2.92, -0.28) earlier GA at birth. Remaining associations in the pooled population were null. Among females, we observed significant inverse associations between 1-OH-PYR and PTB (OR: 2.65 [95% CI: 1.39, 5.05]); and 2-OH-NAP with GA: -2.46 days [95% CI: -4.15, -0.77]). Among males, we observed an inverse association between 2/3/9-OH-FLUO and PTB (OR = 0.40 [95% CI: 0.17,0.98]). ORs for PTB were higher among females than males for 2-OH-PHEN (p = 0.02) and 1-OH-PYR (p = 0.02). DISCUSSION/CONCLUSIONS:We observed inverse associations of 2-OH-NAP exposure with GA and null associations of remaining OH-PAHs with GA and PTB. Females may be more susceptible to spontaneous PTB or shorter GA following prenatal exposure to some OH-PAHs. This study is the first to assess sex-specific OH-PAH toxicity in relation to spontaneous PTB and GA.

BACKGROUND:Prenatal phthalate exposure has been associated with lower birth weight but also higher weight in childhood. Few studies have examined weight or adiposity from birth to childhood and thus cannot assess growth trajectories associated with exposure. OBJECTIVE:We assessed associations between maternal phthalate exposures in pregnancy and child weight and adiposity measured prenatally through childhood (3-6 years of age). METHODS: RESULTS: DISCUSSION:We observed associations between prenatal exposure to phthalates and lower weight at birth but not at childhood follow-up visits. However, for adiposity, we observed an interesting pattern of association with low adiposity at delivery as well as high adiposity at 3-4 years of age. Although it is not clear from our results whether these associations occur within the same children, such a pattern of adiposity in early life has been linked to cardiometabolic disease in adulthood and deserves special attention as an outcome in the study of prenatal exposures in the developmental origins of health and disease. https://doi.org/10.1289/EHP10077.

BACKGROUND:In utero exposure to bisphenols, widely used in consumer products, may alter lung development and increase the risk of respiratory morbidity in the offspring. However, evidence is scarce and mostly focused on bisphenol A (BPA) only. OBJECTIVE:To examine the associations of in utero exposure to BPA, bisphenol F (BPF), and bisphenol S (BPS) with asthma, wheeze, and lung function in school-age children, and whether these associations differ by sex. METHODS:We included 3,007 mother-child pairs from eight European birth cohorts. Bisphenol concentrations were determined in maternal urine samples collected during pregnancy (1999-2010). Between 7 and 11 years of age, current asthma and wheeze were assessed from questionnaires and lung function by spirometry. Wheezing patterns were constructed from questionnaires from early to mid-childhood. We performed adjusted random-effects meta-analysis on individual participant data. RESULTS:Exposure to BPA was prevalent with 90% of maternal samples containing concentrations above detection limits. BPF and BPS were found in 27% and 49% of samples. In utero exposure to BPA was associated with higher odds of current asthma (OR = 1.13, 95% CI = 1.01, 1.27) and wheeze (OR = 1.14, 95% CI = 1.01, 1.30) (p-interaction sex = 0.01) among girls, but not with wheezing patterns nor lung function neither in overall nor among boys. We observed inconsistent associations of BPF and BPS with the respiratory outcomes assessed in overall and sex-stratified analyses. CONCLUSION:This study suggests that in utero BPA exposure may be associated with higher odds of asthma and wheeze among school-age girls.

BACKGROUND:Fetal exposure to endocrine-disrupting chemicals such as phthalates and bisphenols might lead to fetal cardiovascular developmental adaptations and predispose individuals to cardiovascular disease in later life. OBJECTIVES/OBJECTIVE:We examined the associations of maternal urinary bisphenol and phthalate concentrations in pregnancy with offspring carotid intima-media thickness and distensibility at the age of 10 y. METHODS:In a population-based, prospective cohort study of 935 mother-child pairs, we measured maternal urinary phthalate and bisphenol concentrations at each trimester. Later, we measured child carotid intima-media thickness and distensibility in the children at age 10 y using ultrasound. RESULTS: DISCUSSION/CONCLUSIONS:In this large prospective cohort, higher maternal urinary bisphenols concentrations were associated with smaller childhood carotid intima-media thickness. Further studies are needed to replicate this association and to identify potential underlying mechanisms. https://doi.org/10.1289/EHP10293.

Previous studies have provided data on determinants of phthalates in pregnant women, but results were disparate across regions. We aimed to identify the food groups and demographic factors that predict phthalate exposure in an urban contemporary pregnancy cohort in the US. The study included 450 pregnant women from the New York University Children's Health and Environment Study in New York City. Urinary concentrations of 22 phthalate metabolites, including metabolites of di-2-ethylhexylphthalate (DEHP), were determined at three time points across pregnancy by liquid chromatography coupled with tandem mass spectrometry. The Diet History Questionnaire II was completed by pregnant women at mid-pregnancy to assess dietary information. Linear mixed models were fitted to examine determinants of urinary phthalate metabolite concentrations. Using partial-linear single-index (PLSI) models, we assessed the major contributors, among ten food groups, to phthalate exposure. Metabolites of DEHP and its ortho-phthalate replacement, diisononyl phthalate (DiNP), were found in >90% of the samples. The sum of creatinine-adjusted DiNP metabolite concentrations was higher in older and single women and in samples collected in summer. Hispanic and non-Hispanic Black women had lower urinary concentrations of summed metabolites of di-n-octyl phthalate (DnOP), but higher concentrations of low molecular weight phthalates compared with non-Hispanic White women. Each doubling of grain products consumed was associated with a 20.9% increase in ∑DiNP concentrations (95%CI: 4.5, 39.9). PLSI models revealed that intake of dried beans and peas was the main dietary factor contributing to urinary ∑DEHP, ∑DiNP, and ∑DnOP levels, with contribution proportions of 76.3%, 35.8%, and 27.4%, respectively. Urinary metabolite levels of phthalates in pregnant women in NYC varied by age, marital status, seasonality, race/ethnicity, and diet. These results lend insight into the major determinants of phthalates levels, and may be used to identify exposure sources and guide interventions to reduce exposures in susceptible populations.

Exposure to endocrine-disrupting chemicals (EDCs) contributes to substantial disease burden worldwide. We aim to quantify the disease burden and costs of EDC exposure in Canada and to compare these results with previously published findings in the European Union (EU) and United States (US). EDC biomonitoring data from the Canadian Health Measures Survey (2007-2011) was applied to 15 exposure-response relationships, and population and cost estimates were based on the 2010 general Canadian population. EDC exposure in Canada (CAD 24.6 billion) resulted in substantially lower costs than the US (USD 340 billion) and EU (USD 217 billion). Nonetheless, our findings suggest that EDC exposure contributes to substantial and costly disease burden in Canada, amounting to 1.25% of the annual Canadian gross domestic product. As in the US, exposure to polybrominated diphenyl ethers was the greatest contributor of costs (8.8 billion for 374,395 lost IQ points and 2.6 billion for 1610 cases of intellectual disability). In the EU, organophosphate pesticides were the largest contributor to costs (USD 121 billion). While the burden of EDC exposure is greater in the US and EU, there remains a similar need for stronger EDC regulatory action in Canada beyond the current framework of the Canadian Environmental Protection Act of 1999.

Fetal growth is affected by exposure to both prenatal stress and environmental contaminants. The attacks on the World Trade Center (WTC) resulted in exposure to chemicals and psychological stress amongst New York City residents. We measured prenatal maternal stress and exposure to persistent organic pollutants (polybrominated diphenyl ethers, polychlorinated biphenyls, and polychlorinated dibenzo-p-dioxins (PCDDs)) in 108 participants from a Columbia University WTC birth cohort. Principal component (PC) analyses were conducted to characterize the mixture of exposure to the three groups of chemicals. We evaluated the associations between geographical exposures (proximity to the WTC disaster) and both chemical exposures (PCs) and stress (demoralization). We then evaluated the effect these exposures (PCs and stress) had on previously reported associations between geographical WTC exposure and birth outcomes (birth weight and birth length) in this study population to understand their individual roles in the observed associations. Geographical exposure via proximity to the WTC was associated with the PC reflecting higher PCDD exposure (PC3) (β = 0.60, 95% CI: 0.03, 1.18 for living/working within 2 miles of the WTC; and β = 0.73, 95% CI = 0.08, 1.38 for living within 2 miles of WTC). Previously reported reductions in birth weight and length associated with WTC proximity (β = -215.2, 95% CI: -416.2, -14.3 and β = -1.47, 95% CI: -2.6, -0.34, respectively) were attenuated and no longer significant for birth weight (β = -156.4, 95% CI: -358.2, 45.4) after adjusting for PC3, suggesting that PCDDs may act as partial mediators in this previously observed association. The results of this study can help focus future research on the long-term health effects of these prenatally exposed populations.

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.

CONTEXT/BACKGROUND:Accelerating evidence of endocrine-related morbidity has raised alarm about the ubiquitous use of phthalates in the human environment, but studies have not directly evaluated mortality in relation to these exposures. OBJECTIVES/OBJECTIVE:To evaluate associations of phthalate exposure with mortality, and quantify attributable mortality and lost economic productivity in 2013-4 among 55-64 year olds. DESIGN/METHODS:This nationally representative cohort study included 5303 adults aged 20 years or older who participated in the US National Health and Nutrition Examination Survey 2001-2010 and provided urine samples for phthalate metabolite measurements. Participants were linked to mortality data from survey date through December 31, 2015. Data analyses were conducted in July 2020. MAIN OUTCOME MEASURES/METHODS:Mortality from all causes, cardiovascular disease, and cancer. RESULTS:Multivariable models identified increased mortality in relation to high-molecular weight (HMW) phthalate metabolites, especially those of di-2-ethylhexylphthalate (DEHP). Hazard ratios (HR) for continuous HMW and DEHP metabolites were 1.14 (95% CI 1.06-1.23) and 1.10 (95% CI 1.03-1.19), respectively, with consistently higher mortality in the third tertile (1.48, 95% CI 1.19-1.86; and 1.42, 95% CI 1.13-1.78). Cardiovascular mortality was significantly increased in relation to a prominent DEHP metabolite, mono-(2-ethyl-5-oxohexyl)phthalate. Extrapolating to the population of 55-64 year old Americans, we identified 90,761-107,283 attributable deaths and $39.9-47.1 billion in lost economic productivity. CONCLUSIONS:In a nationally representative sample, phthalate exposures were associated with all-cause and cardiovascular mortality, with societal costs approximating $39 billion/year or more. While further studies are needed to corroborate observations and identify mechanisms, regulatory action is urgently needed.