PATHOGENESIS OF OVARIAN TOXICANTS

卵巢毒素的发病机制

• 批准号: 2152914
• 负责人: BARBARA J DAVIS
• 金额: $ 6.85万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2152914
• 关键词: androstenedione; chemical structure function; cyclic AMP; cyclophosphamide; electron microscopy; estradiol; ethylene glycols; follicle stimulating hormone; granulosa cell; histopathology; laboratory rat; light microscopy; luteinizing hormone; menstrual cycle; ovary disorder; pathologic process; phthalates; progesterone; toxin

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.

许多环境、工业和治疗性化学物质使女性感到不安 繁殖。卵巢显然是其中许多化学物质的靶子， 但卵巢毒物的作用机制尚不清楚。因此，这 该提案将阐明主要卵巢毒物 破坏生殖所必需的细胞。 卵巢对化学侮辱的反应是用三种特殊的 卵巢毒物作为探针。环磷酰胺被用来迅速杀死 正在增殖的细胞。邻苯二甲酸二(2-乙基己基)酯用于扰动 颗粒细胞的生长和分化。乙二醇单甲基 乙醚被用来定位卵母细胞。卵巢形态的微扰 (光学和电子显微镜定量研究)和卵巢功能 (雌二醇、孕酮、雄烯二酮)和垂体功能(FSH、Lb) 根据发情周期和化学物质的时间进行评估 曝光。 颗粒细胞是卵巢内和卵巢细胞间交换的中心环节。 卵巢外沟通；因此，对颗粒细胞的毒性侮辱可能 导致卵巢功能障碍。这个实验室的工作已经确定 女性生殖毒物邻苯二甲酸单(2-乙基己基)酯 减少FSH介导的cAMP在培养的大鼠颗粒细胞中的积聚。 CAMP和雌二醇，一种cAMP依赖的颗粒细胞产物和 关键调节激素，将在培养的卵泡刺激素刺激下被测量 颗粒细胞检验单抗原发毒性的假说 邻苯二甲酸(2-乙基己基)酯对颗粒细胞的调节作用 在FSH刺激下cAMP积聚。结构-活性关系将 然后进行检验，以检验FSH刺激的变化 CAMP蓄积是女性生殖毒性的主要机制 属于邻苯二甲酸酯类。