title: 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.
  
  
  OBJECTIVE
  We examined the agonistic activity of EDCs through ERα and ERβ. 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 ERα and ERβ via the 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 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 ERα estrogen responsive element (ERE)-mediated responses. Daidzein, genistein, kaempferol, and coumestrol (group 2) activated both 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. 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.
  
  
  CONCLUSIONS
  Although EDCs with similar chemical structures (in the same group) tended to have comparable ERα and ERβ ERE-mediated activities, similar chemical structure did not correlate with previously reported ligand binding affinities of the EDCs. Using ERα-stable cells, we observed that EDCs differentially induced activity of endogenous ER target genes.
authors: Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, Division of Intramural Research, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina 27709, USA.
authors: Yin
authors: Y
authors: Li
authors: Colin J
authors: CJ
authors: Luh
authors: Katherine A
authors: KA
authors: Burns
authors: Yukitomo
authors: Y
authors: Arao
authors: Zhongliang
authors: Z
authors: Jiang
authors: Christina T
authors: CT
authors: Teng
authors: Raymond R
authors: RR
authors: Tice
authors: Kenneth S
authors: KS
authors: Korach
mesh_terms: D045744:Cell Line, Tumor; D052244:Endocrine Disruptors / Q000494:pharmacology*; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C506487:ESR1 protein, human; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008156:Luciferases
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