Endocrine-Disrupting Chemicals (EDCs): In Vitro Mechanism of Estrogenic Activation and Differential Effects on ER Target Genes

Yin Li¹, Colin J. Luh¹, Katherine A. Burns¹, Yukitomo Arao¹, Zhongliang Jiang¹, Christina T. Teng², Raymond R. Tice², and Kenneth S. Korach¹

¹Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; ²Biomolecular Screening Branch, Division of National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA

Advance Publication

Abstract

Background: Endocrine-disrupting chemicals (EDCs) are shown to influence the activity of estrogen receptors (ERs) and alter the function of the endocrine system. However, the diversity of EDC effects and mechanisms of action are poorly understood.

Objectives: We identified agonistic activity of EDCs through ERα and ERβ and their effects on ER-mediated target genes.

Methods: HepG2 and HeLa cells were utilized to determine the agonistic activity of EDCs on ERα and ERβ via luciferase reporter assay. Ishikawa cells stably expressing ERα were used to determine changes in endogenous ER target gene expression by EDCs.

Results: Twelve EDCs were categorized into three groups based on their product class and similarity of chemical structure. Luciferase reporter analysis demonstrated that their ER agonistic effects are in a cell type/promoter specific manner. Bisphenol A, Bisphenol AF and 2-2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (Group 1) strongly activated the ERα ERE-mediated responses. Daidzein, Genistein, Kaempferol and Coumestrol (Group 2) activated both the ERα and ERβ ERE-mediated activities. Endosulfan and Kepone (Group 3) weakly activated ERα. Only a few EDCs significantly activated the “tethered” mechanism via ERα or ERβ. Real timePCR results indicated that Bisphenol A and Bisphenol AF consistently activated endogenous ER target genes, but the activities of other EDCs on ER target gene expression changes were compound specific.

Conclusion: EDCs with similar chemical structures tended to have comparable ERα and ERβ ERE-mediated activities, but did not correlate with their previously reported ligand binding affinities. Using ERα stable cells, we show EDCs differentially induce endogenous ER target gene activities.

Citation: Li Y, Luh CJ, Burns KA, Arao Y, Jiang Z, Teng CT, Tice RR, Korach KS. Environ Health Perspect (): .doi:10.1289/ehp.1205951

Received: August 30, 2012; Accepted: January 31, 2013; Published: February 5, 2013

Advance Publication

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