Arsenic, benzene, trichloroethene (TCE), formaldehyde, and polycyclic aromatic hydrocarbons (PAHs) may have endocrine-disrupting effects at lower doses than those required for hematotoxicity or cancer induction. There is some evidence that they can modulate steroid hormone levels in both the corticosteroid and sex steroid pathways, potentially causing multiple adverse health effects. Here we propose to examine the disrupting effects of these common Superfund contaminants on glucocorticoid and sex steroid hormones and their tissue-specific effects in cell lines in vitro, mice in vivo, and perhaps most importantly in humans with well- characterized exposures. Endogenous cortisol is produced in response to stress and acts on the glucocorticoid receptor (GR) triggering metabolic and other disruptions. Environmental chemicals can also impact the GR pathway and are defined as ?stressogens.? An example is arsenic, which alters GR signaling, but the mechanisms by which this impacts different cell types expressing GR are unclear. Cumulative risk assessment of non-genetic environmental stressors is a priority of EPA and we have developed novel approaches to do so under the exposome paradigm. Our first central hypothesis is that arsenic is a stressogen that alters GR activity, alone and in conjunction with other chemicals, with tissue-specific biological consequences. We propose to use an exposomic approach to understand the dose-dependent effects of arsenic, alone and in conjunction with other Superfund contaminants, on the glucocorticoid pathway in liver, adipocyte and blood cells in vitro; in mice in vivo; and in exposed humans (Aims 1-3). We will use a sensitive GR activity bioassay to screen Superfund contaminants that alter GR activity and will measure total glucocorticogenic (G) activity in media from exposed cells and in small volumes of human plasma from subjects exposed to arsenic. Use of the GR bioassay directly with plasma is novel. Our preliminary screening data show that arsenic is a GR antagonist and the PAH benzo(a)pyrene, an agonist. Arsenic, as well as TCE, benzene, formaldehyde and PAHs also cause adverse reproductive effects potentially by modulating natural estrogen and androgen sex hormones. Thus, our second central hypothesis is that these contaminants modulate estrogen receptor (ER) and androgen receptor (AR) activity by altering natural sex hormone levels. We will screen chemical effects on the production of these hormones (steroidogenesis) in validated mammalian cell models, and total estrogenic (E) and androgenic (A) activity and endogenous hormone levels in plasma from exposed populations (Aims 4- 5). Our preliminary data show that TCE increases E but not A activity in exposed males probably through aromatase induction. Our overall goal is to understand the dose-dependent effects of key Superfund chemicals on steroid hormone pathways, to support comprehensive and cumulative risk assessment.

Public Health Relevance

PROJECT 2: NARRATIVE We propose a comprehensive exposomic approach to characterize the dose-dependent effects of arsenic, benzene, trichloroethene, formaldehyde and polycyclic aromatic hydrocarbons on the endocrine system, specifically on the glucocorticoid and sex steroid pathways, in cellular and animal models, and most importantly in exposed human subjects from well-designed epidemiological studies. Findings will fill gaps in the published data regarding the potential endocrine disrupting and stress inducing effects of these chemicals and could have broad implications for risk assessment and policy.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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Special Emphasis Panel (ZES1)
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University of California Berkeley
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Rothman, Nathaniel; Zhang, Luoping; Smith, Martyn T et al. (2018) Formaldehyde, Hematotoxicity, and Chromosomal Changes-Response. Cancer Epidemiol Biomarkers Prev 27:120-121
Yik-Sham Chung, Clive; Timblin, Greg A; Saijo, Kaoru et al. (2018) Versatile Histochemical Approach to Detection of Hydrogen Peroxide in Cells and Tissues Based on Puromycin Staining. J Am Chem Soc 140:6109-6121
Rappaport, Stephen M (2018) Redefining environmental exposure for disease etiology. NPJ Syst Biol Appl 4:30
Tachachartvanich, Phum; Sangsuwan, Rapeepat; Ruiz, Heather S et al. (2018) Assessment of the Endocrine-Disrupting Effects of Trichloroethylene and Its Metabolites Using in Vitro and in Silico Approaches. Environ Sci Technol 52:1542-1550
Guyton, Kathryn Z; Rieswijk, Linda; Wang, Amy et al. (2018) Key Characteristics Approach to Carcinogenic Hazard Identification. Chem Res Toxicol :
Roh, Taehyun; Steinmaus, Craig; Marshall, Guillermo et al. (2018) Age at Exposure to Arsenic in Water and Mortality 30-40 Years After Exposure Cessation. Am J Epidemiol 187:2297-2305
Daniels, Sarah I; Chambers, John C; Sanchez, Sylvia S et al. (2018) Elevated Levels of Organochlorine Pesticides in South Asian Immigrants Are Associated With an Increased Risk of Diabetes. J Endocr Soc 2:832-841
Guyton, Kathryn Z; Rusyn, Ivan; Chiu, Weihsueh A et al. (2018) Application of the key characteristics of carcinogens in cancer hazard identification. Carcinogenesis 39:614-622
Grigoryan, Hasmik; Edmands, William M B; Lan, Qing et al. (2018) Adductomic signatures of benzene exposure provide insights into cancer induction. Carcinogenesis 39:661-668
Barazesh, James M; Prasse, Carsten; Wenk, Jannis et al. (2018) Trace Element Removal in Distributed Drinking Water Treatment Systems by Cathodic H2O2 Production and UV Photolysis. Environ Sci Technol 52:195-204

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