Toxicology of environmental estrogens

It has been hypothesized that environmental contaminants that modulate endo crine signaling pathways may be causally linked to adverse health effects i n humans. There has been particular concern regarding synthetic estrogens a nd their role in disrupting normal development of the male reproductive tra ct. Most estrogenic industrial compounds, such as bisphenol A (BPA) and non ylphenol, typically bind estrogen receptors alpha (ER alpha) and beta (ER b eta) and induce transactivation of estrogen-responsive genes/reporter genes , but their potencies are usually greater than or equal to 1000-fold lower than observed for 17 beta -estradiol (E2). Selective estrogen receptor modu lators (SERMs) represent another class of synthetic estrogens that are bein g developed for treatment of hormone-dependent problems. The SERMs differen tially activate wild-type ER alpha and variant forms expressing activation function 1 (ER-AF1) and AF2 (ER-AF2) in human HepG2 hepatoma cells transfec ted with a pC3-luciferase construct, and these in vitro differences reflect their unique in 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; BP A; 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 synth etic and phytoestrogens induce distinct patterns of gene activation in HepG 2 and U2 osteogenic sarcoma cells, suggesting that these compounds will ind uce tissue-specific in vivo ER agonist or antagonist activities. The predic ted differences between these compounds, based on results of the in vitro b ioassay, have been confirmed. For example, BPA inhibits E2-induced response s in the rodent uterus, and HPTE and structurally related compounds are ERa agonists and ERP antagonists in assays carried out in HepG2 and other canc er cell lines.