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

ABSTRACT: BACKGROUND:Endocrine-disrupting chemicals (EDCs) 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 examined the agonistic activity of EDCs through ER? and ER?. We also investigated the effects of EDCs on ER-mediated target genes. METHODS:HepG2 and HeLa cells were used to determine the agonistic activity of EDCs on ER? and ER? via the luciferase reporter assay. Ishikawa cells stably expressing ER? were used to determine changes in endogenous ER target gene expression by EDCs. RESULTS:Twelve EDCs were categorized into three groups on the basis of product class and similarity of chemical structure. As shown by luciferase reporter analysis, the EDCs act as ER agonists in a cell type- and promoter-specific manner. Bisphenol A, bisphenol AF, and 2-2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (group 1) strongly activated ER? estrogen responsive element (ERE)-mediated responses. Daidzein, genistein, kaempferol, and coumestrol (group 2) activated both ER? and ER? ERE-mediated activities. Endosulfan and kepone (group 3) weakly activated ER?. Only a few EDCs significantly activated the "tethered" mechanism via ER? or ER?. Results of real-time polymerase chain reaction indicated that bisphenol A and bisphenol AF consistently activated endogenous ER target genes, but the activities of other EDCs on changes of ER target gene expression were compound specific. CONCLUSION:Although EDCs with similar chemical structures (in the same group) tended to have comparable ER? and ER? ERE-mediated activities, similar chemical structure did not correlate with previously reported ligand binding affinities of the EDCs. Using ER?-stable cells, we observed that EDCs differentially induced activity of endogenous ER target genes.

SUBMITTER: Li Y 

PROVIDER: S-EPMC3620735 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature