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It has been hypothesized that environmental contaminants that modulateendocrine signaling pathways may be causally linked to adverse health effectsin humans. There has been particular concern regarding synthetic estrogens andtheir role in disrupting normal development of the male reproductive tract.Most estrogenic industrial compounds, such as bisphenol A (BPA) andnonylphenol, typically bind estrogen receptors α (ERα) andβ (ERβ) and induce transactivation of estrogen-responsivegenes/reporter genes, but their potencies are usually ≥1000-foldlower than observed for 17β-estradiol (E2). Selective estrogenreceptor modulators (SERMs) represent another class of synthetic estrogensthat are being developed for treatment of hormone-dependent problems. TheSERMs differentially activate wild-type ERα and variant formsexpressing activation function 1 (ER-AF1) and AF2 (ER-AF2) in human HepG2hepatoma cells transfected with a pC3-luciferase construct, and thesein vitro differences reflect theiruniquein vivo biologies. The HepG2 cell assay has alsobeen used in our laboratories to investigate the estrogenic activities of thefollowing structurally diverse synthetic and phytoestrogens:4′-hydroxytamoxifen; BPA;2′,4′,6′-trichloro-4-biphenylol;2′,3′,4′,5′-tetrachloro-4-biphenylol;p-t-octylphenol;p-nonylphenol; naringenin; kepone; resveratrol; and2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE).The results show that synthetic and phytoestrogens induce distinct patterns ofgene activation in HepG2 and U2 osteogenic sarcoma cells, suggesting thatthese compounds will induce tissue-specific in vivo ERagonist or antagonist activities. The predicted differences between thesecompounds, based on results of the in vitrobioassay,have been confirmed. For example, BPA inhibits E2-induced responses in therodent uterus, and HPTE and structurally related compounds are ERαagonists and ERβ antagonists in assays carried out in HepG2 and othercancer cell lines. |
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