ENDOCRINE DISRUPTING CHEMICALS AND AROMATASE

许多工业和环境化学物质模拟、拮抗或间接改变激素，特别是类固醇激素的活性。人们普遍认为，这些化学物质与雌激素受体或雄激素受体结合，要么模仿激素的作用，要么阻断它们的活性。然而，也有可能这些化合物中的一些通过抑制芳香化酶活性或诱导芳香化酶表达以间接方式起作用，从而导致女性雌激素水平的变化。芳香化酶是一种细胞色素P450酶，可将雄激素转化为雌激素。在之前的资助期内，该实验室在三个领域取得了重要成果。研究表明，计算机建模、芳香化酶位点定向诱变和抑制谱分析是评估内分泌干扰物（如黄酮类和异黄酮类植物雌激素）对芳香化酶抑制的分子基础的有用工具。此外，该实验室还开发了一种酵母筛选系统，可用于筛选具有抗芳香酶活性的内分泌干扰物的高通量方法。此外，孤儿受体ERRalpha-1被确定为内分泌干扰物的靶标。该资助期的具体目标是：(1)完善酵母筛选系统，作为一种高通量方法来识别芳香化酶抑制剂的内分泌干扰物和雄激素受体的配体；(2)确定具有抗芳香化酶活性的内分泌干扰物的结合性质；(3)研究内分泌干扰物与ERRalpha-1相互作用的分子基础。

Many industrial and environmental chemicals mimic, antagonize, or indirectly alter the activity of hormones, particularly steroid hormones. It is commonly thought that these chemicals bind to the estrogen receptor or androgen receptor, either imitating the action of the hormones or blocking their activity. However, it is also possible that some of these compounds may act in an indirect fashion by either inhibiting aromatase activity or inducing aromatase expression, resulting in a change in the level of estrogen in women. Aromatase is a cytochrome P450 enzyme that converts androgen to estrogen. During the previous grant period, this laboratory has made important accomplishments in three areas. It has been demonstrated that computer modeling, aromatase site-directed mutagenesis, and inhibition profile analyses are useful tools for evaluating the molecular basis of the inhibition of aromatase by endocrine disrupters such as flavone and isoflavone phytoestrogens. Furthermore, the laboratory has developed a yeast screen system that can be adapted for use as a high throughput method to screen endocrine disrupters with anti- aromatase activity. In addition, the orphan receptor ERRalpha-1 was identified as a target of endocrine disrupters. The specific aims for this grant period are: (1) to refine the yeast screening system as a high throughput approach to identify endocrine disrupters for aromatase inhibitors and ligands for androgen receptors; (2) determine the binding nature of endocrine disrupters that have anti-aromatase activity; and (3) to investigate the molecular basis of the interaction of endocrine disrupters with ERRalpha-1.