PHYTOESTROGEN ACTION THROUGH ESTROGEN RECEPTORS a & B

存在于大豆制品中的植物雌激素正在被人类越来越多地消耗；特别是女性使用大豆异黄酮浓缩液来缓解更年期症状。这种接触对健康的长期影响尚不清楚，但由于植物雌激素可能具有内源性和合成雌激素的许多生物效应，因此它们可能既有有益的影响，也有有害的影响。然而，雌激素的药理学是复杂的，并不是所有的雌激素都有与雌二醇（内源性雌激素）相同的有益和有害活性。雌激素的作用也由两种雌激素受体介导，erα和erβ，这两种蛋白质具有不同的组织分布并调节不同的基因集。erα和erβ对亚型选择性配体的反应也不同，这是一个重要的问题，因为植物雌激素比雌二醇对erβ有更明显的偏好。

Phytoestrogens, present in soy-based products, are being consumed by humans in increasing quantities; particularly by women tasking soy isoflavones concentrates for relief of menopausal symptoms. The long-term health effects of this exposure are not known, but because phytoestrogens likely share many of the biological effects of endogenous and synthetic estrogens, they might share their detrimental as well as beneficial effects. The pharmacology of estrogens is complex, however, and not all estrogens have the same profile of beneficial vs. detrimental activities as does estradiol, the endogenous estrogen. Estrogen action is also mediated by two estrogen receptors, ERalpha and ERbeta, proteins that have different tissue distributions and regulated somewhat different sets of genes. ERalpha and ERbeta also respond differently to subtype-selective ligands, an issue of importance because phytoestrogens have a more distinct preference for ERbeta than estradiol. This Project is part of a Research Program Project whose overall goal is to evaluate the long-term health effects that phytoestrogen exposure might have in aging women, using appropriate animal models for breast cancer, lipid metabolism, and cognition. The aims of this Project are: (1) to characterize on a genome-wide basis the pattern of genes that are regulated by the various phytoestrogens through ERalpha and ERbeta in target cells and tissues, and how this pattern compares with regulation by estradiol and other estrogens, (2) to define how the phytoestrogens (as opposed to estradiol and other estrogens) bind to and regulate the conformation and coregulator interaction of the two estrogen receptors, ERalpha and ERbeta, including identifying the specific co-regulator proteins through which these phytoestrogen-receptor complexes than act at specific promoter sites, using novel fluorescence methods developed in our laboratories, and (3) to use novel pharmacological tools, namely specific agonists and antagonists of ERalpha and ERbeta developed in our laboratories, as defined hormonal probes to assess the balance of phytoestrogen action through the two ER subtypes. The results of this project should provide important information on the manner in which phytoestrogens regulate gene expression through ERalpha and ERbeta, in comparison with that of other natural and synthetic estrogens. This information will be useful in evaluating the long-term health effects of phytoestrogen exposure in aging women.