Endocrine Disrupting Chemicals and Aromatase

描述（由申请人提供）：芳香酶是将雄激素转化为雌激素的酶。申请人已经假设并证明芳香酶是内分泌干扰化学品的重要靶标。已发现这些化合物抑制芳香酶活性，这导致经处理的细胞中雌激素水平的降低和雄激素水平的增加。已经进行了动物实验，证明了抗芳香酶化学品的体内作用。此外，环境化学物质（植物化学物质和异种化学物质）被发现修改芳香酶在各种组织中的表达，这导致雄激素转化为雌激素的比例的变化。抑制芳香酶或抑制芳香酶表达的化合物在体内表现为抗雌激素或雄激素样化合物。相反地，增加芳香酶表达或增强芳香酶活性（或稳定性）的化合物实际上可以作为抗雄激素或雌激素样化合物起作用。在过去四年中在申请人的实验室中进行的研究表明，雌激素相关受体α（ERR-α）和雌激素受体α（ER-α）可以调节芳香酶的表达。也已经表明，内分泌干扰化学品，通过作为这两种受体的配体，可以改变处理的细胞中芳香酶的表达。 芳香酶、ER-α和ERR-α都是维持我们内分泌功能的重要参与者。为了继续和扩大申请人实验室目前的努力，以确定内分泌干扰化学品，这是建议在这个竞争性的更新申请，他们利用他们新建立的高通量计算机辅助虚拟筛选方法来搜索内分泌干扰化学品，作为这些蛋白质的配体/抑制剂。还进一步提出，它们通过评价它们的构效关系来确定这些化学品的结构特征。这种结构信息对于识别意外的内分泌干扰化学品将是有价值的。拟议的研究将侧重于1014种植物化学物质（包括查耳酮、色酮、香豆素、黄烷酮、黄酮和异黄酮），这些化学物质将从Indofine Co（萨默维尔，新泽西）购买。此外，建议通过体外和体内实验证实化合物（已通过高通量筛选方法鉴定）的内分泌干扰作用。

DESCRIPTION (provided by applicant): Aromatase is the enzyme that converts androgen to estrogen. The applicant has hypothesized and demonstrated that aromatase is an important target of endocrine disrupting chemicals. These compounds have been found to inhibit aromatase activity, which results in both a decrease in the level of estrogen and an increase in the level of androgen in treated cells. Animal experiments have been performed that demonstrated the in vivo action of anti-aromatase chemicals. Additionally, environmental chemicals (both phytochemicals and xenochemicals) were found to modify the expression of aromatase in various tissues, which results in a change in the conversion ratio of androgen to estrogen. The compounds that inhibit aromatase or suppress aromatase expression behave as antiestrogens or androgen-like compounds in vivo. Conversely, compounds that either increase aromatase expression or enhance aromatase activity (or stability) may actually function as anti-androgens or estrogen-like compounds. Research conducted in the applicant's laboratory during the last four years demonstrated that estrogen-related receptor alpha (ERR-alpha) and estrogen receptor alpha (ER-alpha) can regulate the expression of aromatase. It has also been shown that endocrine disrupting chemicals, by acting as the ligands of these two receptors, can modify the expression of aromatase in treated cells. Aromatase, ER-alpha, and ERR-alpha are all important players in maintaining our endocrine function. To continue with and expand on the current efforts in the applicant's laboratory to identify endocrine disrupting chemicals, it is proposed in this competitive renewal application that they utilize their newly established high throughput computer-assisted virtual screening approach to search endocrine disrupting chemicals which serve as ligands/inhibitors of these proteins. It is also further proposed that they determine the structural characteristics of these chemicals by evaluating their structure activity relationship. Such structural information will be valuable for the identification of unanticipated endocrine disrupting chemicals. The proposed studies will focus on 1014 phytochemicals (including chalcones, chromones, coumarins, flavanones, flavones and isoflavones) that would be purchased from Indofine Co (Somerville, New Jersey). In addition, it is proposed that the endocrine disrupting actions of compounds (which have been identified by the high throughput screening method) be confirmed through both in vitro and in vivo experiments.