PATHOGENESIS STUDIES OF OVARIAN TOXICANTS

许多环境，工业和治疗化学品扰乱女性 生殖 卵巢显然是这些化学物质的目标， 但卵巢毒物的机制还不清楚。 因此本 该提案将阐明原发性卵巢毒物 破坏生殖细胞。 卵巢对化学损伤的反应是用三种特异性方法来评估的。 卵巢毒物作为探针。 环磷酰胺是用来快速杀死 增殖细胞。 邻苯二甲酸二（2-乙基己基）酯用于干扰 颗粒细胞的生长和分化。 乙二醇单甲基 乙醚用于靶向卵母细胞。 卵巢形态学紊乱 （定量光学和电子显微镜研究）和卵巢功能 （雌二醇、孕酮、雄烯二酮）和垂体功能（FSH、LB） 的发情周期和化学物质的时间进行评价 exposure. 颗粒细胞是卵巢内和卵巢外基质交换的中心环节。 因此，对颗粒细胞的毒性损伤可能 导致卵巢功能障碍。 这个实验室的工作已经确定 雌性生殖毒物邻苯二甲酸单乙基己酯 降低FSH介导的大鼠颗粒细胞cAMP积累。 环磷酸腺苷和雌二醇，一种环磷酸腺苷依赖的颗粒细胞产物， 关键调节激素，将在培养的FSH刺激的 颗粒细胞，以检验单核苷酸的主要毒性 （2-乙基己基）邻苯二甲酸酯对颗粒细胞的作用是通过改变介导的 在FSH刺激的cAMP积累中。 结构-活性关系将 然后进行检查，以检验这一假设，即FSH刺激的 cAMP积累是雌性生殖毒性的主要机制 邻苯二甲酸盐类物质。

Many environmental, industrial and therapeutic chemicals perturb female reproduction. The ovary is clearly a target for many of these chemicals, but mechanisms of ovarian toxicants are poorly defined. Therefore, this proposal will elucidate mechanisms by which primary ovarian toxicants damage cells essential for reproduction. The ovarian response to chemical insult is evaluated using three specific ovarian toxicants as probes. Cyclophosphamide is used to kill rapidly proliferating cells. Di(2-ethylhexyl) phthalate is used to perturb granulosa cell growth and differentiation. Ethylene glycol monomethyl ether is used to target oocytes. Perturbations in ovarian morphology (quantitative light and electron microscopy studies), and ovarian function (estradiol, progesterone, androstenedione) and pituitary function (FSH, LB) are evaluated with respect to the estrous cycle and time of chemical exposure. The granulosa cell is a central link in the exchange of intraovarian and extraovarian communication; thus, toxic insult to the granulosa cell could result in ovarian dysfunction. Work from this laboratory has determined that the female reproductive toxicant mono(2-ethylhexyl) phthalate decreases FSH mediated cAMP accumulation in cultured rat granulosa cells. Cyclic AMP and estradiol, a cAMP-dependent granulosa cell product and a critical regulatory hormone, will be measured in cultured FSH-stimulated granulosa cells to test the hypothesis that the primary toxicity of mono (2-ethylhexyl) phthalate on granulosa cells is mediated through alterations in FSH-stimulated cAMP accumulation. Structure-activity relationships will then be examined to test the hypothesis that alterations in FSH-stimulated cAMP accumulation is the primary mechanism of female reproductive toxicity of the class of phthalates.