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Stephen H. Safe,¹ Lea Pallaroni,¹ Kyungsil Yoon,¹ Kevin Gaido,² Susan Ross,² and Donald McDonnell³

¹Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA; ²CIIT Centers for Health Research, Research Triangle Park, North Carolina, USA; ³Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA

Abstract

Estrogenic industrial compounds such as bisphenol A (BPA) and nonylphenol typically bind estrogen receptor (ER) and ERß and induce transactivation of estrogen-responsive genes/reporter genes, but their potencies are usually 1000-fold lower than observed for 17ß-estradiol. Risk assessment of estrogenic compounds on the basis of their potencies in simple reporter gene or binding assays may be inappropriate. For example, selective ER modulators (SERMs) represent another class of synthetic estrogens being developed for treatment of hormone-dependent problems. SERMs differentially activate wild-type ER and variant forms expressing activation function 1 (ER-AF1) and AF2 (ER-AF2) in human HepG2 hepatoma cells transfected with an estrogen-responsive complement C3 promoter-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 ; 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. The results show that synthetic and phytoestrogens are weakly estrogenic but induce distinct patterns of ER agonist/antagonist activities that are cell context- and promoter-dependent, suggesting that these compounds will induce tissue-specific in vivo ER agonist or antagonist activities. These results suggest that other receptors, such as the aryl hydrocarbon receptor, that also bind structurally diverse ligands may exhibit unique responses in vivo that are not predicted by standard in vitro bioassays. Key words: agonists, antagonists, estrogen receptor, estrogens, structure-activity. Environ Health Perspect 110(suppl 6) :925-929 (2002) .

http://ehpnet1.niehs.nih.gov/docs/2002/suppl-6/925-929safe/abstract.html