ENDOCRINE DISRUPTING CHEMICALS AND AROMATASE

描述：（改编自申请人的描述）许多工业和 环境化学物质模拟、拮抗或间接改变活性 尤其是类固醇激素 在女性中，这些化学物质 主要影响雌激素的活性。 人们普遍认为， 化学物质与雌激素受体结合，要么模仿雌激素受体的作用， 激素或阻断其活性。 然而，也有可能， 这些化合物可以通过抑制 芳香酶活性或诱导芳香酶表达，导致改变 女性体内雌激素的水平。 芳香化酶是细胞色素P450酶 合成雌激素的细胞 初步结果表明，植物雌激素和 有机氯化合物可作为女性内分泌干扰物， 通过改变雌激素的活性来改变雌激素的水平 芳香酶或该酶的表达。 将进行实验 提供了一个分子和机制的基础，植物雌激素和 有机氯化合物影响雌激素生物合成（即，芳香酶 功能）在女性。 对化合物的结构要求， 芳香化酶的催化性能将由计算机测定 建模和评价它们与芳香酶突变体的相互作用。 在 此外，植物雌激素和有机氯化合物对 芳香酶在整个关键暴露期的表达（新生儿， 绝经前、妊娠和绝经后）将使用细胞 用利用不同启动子的细胞系进行培养研究， 芳香化酶表达。

DESCRIPTION: (adapted from the applicant's description) Many industrial and environmental chemicals mimic, antagonize, or indirectly alter the activity of hormones, particularly steroid hormones. In women, these chemicals mainly affect the activity of estrogens. It is commonly thought that these chemicals bind to the estrogen receptor, either imitating the action of the hormone or blocking its 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 synthesizes estrogen. Preliminary results have been obtained to indicate that phytoestrogens and organochlorine compounds can act as endocrine disrupters in women by modifying the level of estrogen through altering either the activity of aromatase or the expression of the enzyme. Experiments will be carried out to provide a molecular and mechanistic basis as to how phytoestrogens and organochlorine compounds affect estrogen biosynthesis (i.e., aromatase function) in women. The structural requirement for the compounds to modify the catalytic properties of aromatase will be determined by computer modeling and by evaluation of their interactions with aromatase mutants. In addition, the effects of phytoestrogens and organochlorine compounds on aromatase expression throughout critical periods of exposure (neonatal, premenopausal, pregnant, and postmenopausal) will be investigated using cell culture studies with cell lines that utilize different promoters for aromatase expression.