Analysis of the molecular mechanisms of human estrogen receptors alpha and beta reveals differential specificity in target promoter regulation by xenoestrogens.

Most of the currently available information on the transcriptional activities of endocrine-disrupting chemicals (xenoestrogens) through estrogen receptors alpha (ERalpha) and beta (ERbeta) has been derived from transactivation studies on synthetic estrogen-responsive reporters. Thus, the ability of the xenoestrogen-liganded ERs to regulate endogenous estrogen-responsive gene expression has not been well characterized. Here, we have evaluated the activities of xenoestrogens through ERalpha and ERbeta on the vitellogenin A2 estrogen-response element (ERE) and the human pS2, lactoferrin, and complement 3 physiological target gene promoters. Using mammalian cell transient transfection assays, we found that the activities of xenoestrogens were mediated in a promoter-specific manner. For example, when bound to all ligands examined, ERalpha displayed high levels of transcription on the vitellogenin ERE and the lactoferrin promoter, but substantially lower activity on the complement 3 and pS2 promoters. However, one of the most important observations was that there were significant differences in the relative transcriptional activities of xenoestrogen-bound ERalpha and ERbeta on different promoters, suggesting that ERalpha and ERbeta make unique contributions to xenoestrogen action in target cells. When probing the molecular mechanism of the promoter-specific activities observed, we found that the transcriptional activity of the ERs correlated with the ability of each receptor to assume an active conformation on specific promoters. Taken together, the results indicate that the transcriptional activities of xenoestrogens are mediated in a promoter-specific manner and that estrogen-responsive promoters communicate differently with ERalpha and ERbeta by influencing their structures in a distinct manner that leads to diversity in their transcriptional responses.