ENDOCRINE DISRUPTING CHEMICALS AND AROMATASE

许多工业和环境化学品模仿、拮抗或间接改变激素的活性，特别是类固醇激素。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，也有可能其中一些化合物通过抑制芳香酶活性或诱导芳香酶表达而间接发挥作用，导致女性雌激素水平的变化。芳香酶是一种细胞色素P450酶，可将雄激素转化为雌激素。在之前的赠款期间，该实验室在三个方面取得了重要成就。已经证明，计算机模拟、芳香酶定点突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抑制芳香族酶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，该系统可用于高通量筛选具有抗芳香酶活性的内分泌干扰物。此外，孤儿受体ERRpha-1被确定为内分泌干扰物的目标。这一授权期的具体目标是：(1)完善酵母筛选系统，作为一种高通量方法，以确定芳香酶抑制剂的内分泌干扰物和雄激素受体的配体；(2)确定具有抗芳香酶活性的内分泌干扰物的结合性质；以及(3)研究内分泌干扰物与ERRpha-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.