Toxicology of environmental estrogens

Abstract

It has been hypothesized that environmental contaminants that modulate endocrine signaling pathways may be causally linked to adverse health effects in humans. There has been particular concern regarding synthetic estrogens and their role in disrupting normal development of the male reproductive tract. Most estrogenic industrial compounds, such as bisphenol A (BPA) and nonylphenol, typically bind estrogen receptors α (ERα) and β (ERβ) and induce transactivation of estrogen-responsive genes/reporter genes, but their potencies are usually ≥1000-fold lower than observed for 17β-estradiol (E2). Selective estrogen receptor modulators (SERMs) represent another class of synthetic estrogens that are being developed for treatment of hormone-dependent problems. The SERMs differentially activate wild-type ERα and variant forms expressing activation function 1 (ER-AF1) and AF2 (ER-AF2) in human HepG2 hepatoma cells transfected with a pC3-luciferase construct, and these in vitro differences reflect their uniquein vivo biologies. The HepG2 cell assay has also been used in our laboratories to investigate the estrogenic activities of the following 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; and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). The results show that synthetic and phytoestrogens induce distinct patterns of gene activation in HepG2 and U2 osteogenic sarcoma cells, suggesting that these compounds will induce tissue-specific in vivo ER agonist or antagonist activities. The predicted differences between these compounds, based on results of the in vitrobioassay, have been confirmed. For example, BPA inhibits E2-induced responses in the rodent uterus, and HPTE and structurally related compounds are ERα agonists and ERβ antagonists in assays carried out in HepG2 and other cancer cell lines.