MECHANISTIC STUDIES OF OVARIAN TOXICITY

卵巢毒性的机制研究

• 批准号: 5202135
• 负责人: B DAVIS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5202135
• 关键词: apoptosis; cell cycle; chemical carcinogenesis; cyclic AMP; cytotoxicity; environmental toxicology; fertility; granulosa cell; hormone biosynthesis; human tissue; in situ hybridization; laboratory rat; ovary; ovary neoplasms; progesterone; tissue /cell culture

In 1995, we defined the in-vivo and in-vitro ovarian toxicity of ethylene glycol monomethyl ether (EGME), a commonly used solvent in the chemical and food industries. Until our studies, the site of reproductive toxicity in the female had been unknown. We have found that EGME (300 mg/kg) specifically stimulates luteal cell progesterone production in cycling Sprague-Dawley rats in-vivo resulting in corpora lutea hypertrophy and physiological pseudopregnancy. Similarly, the active metabolite of EGME stimulates progesterone production in a dose- and time-dependent manner in cultured rat luteal cells. We are currently testing the hypothesis that the progesterone-stimulation is mediated through increases in receptor-mediated cAMP, and exploring the related cAMP-stimulated cell-signaling pathways in-vitro in rat luteal cells and then in human luteal cells. Our previous work has shown that chemically-mediated decreases in receptor-stimulated cAMP induce granulosa cell apoptosis, the results with EGME support the conclusion that cAMP levels appear to be critical in determining whether granulosa cells differentiate or undergo apoptosis. Other ongoing work relates to development of in-situ hybridization procedures for aromatase and BRCA1 message in tissue sections. These techniques should help tease out the mechanisms of ovarian cancer. In addition, an ovarian cancer study utilizing nitrofurazone is underway. Results of histology, endocrinology, and molecular analysis from this nitrofurazone study should help establish mechanisms of tumorigenesis and lead to the development of a model for ovarian cancer.

1995年，我们定义了体内和体外卵巢毒性 乙二醇单甲醚（EGME），一种常用的溶剂 化学和食品工业。直到我们的研究为止，生殖部位 对女性的毒性尚不清楚。 我们发现 EGME (300 mg/kg）特异性刺激黄体细胞黄体酮的产生 Sprague-Dawley 大鼠体内循环产生黄体 肥大和生理性假妊娠。 同样，主动 EGME 的代谢物在剂量和剂量下刺激黄体酮的产生 培养的大鼠黄体细胞中的时间依赖性方式。 我们目前 检验黄体酮刺激是介导的假设 通过增加受体介导的 cAMP，并探索相关的 大鼠黄体细胞中 cAMP 刺激的体外细胞信号传导通路 然后在人类黄体细胞中。 我们之前的工作表明 化学介导的受体刺激的 cAMP 减少诱导 颗粒细胞凋亡，EGME结果支持该结论 cAMP 水平似乎对于确定颗粒是否存在至关重要 细胞分化或发生凋亡。 其他正在进行的工作涉及 开发芳香酶和 BRCA1 的原位杂交程序 组织切片中的消息。 这些技术应该有助于梳理出 卵巢癌的机制。 此外，一项卵巢癌研究 呋喃西林的利用正在进行中。组织学、内分泌学结果， 这项呋喃西林研究的分子分析应该会有所帮助 建立肿瘤发生机制并导致开发 卵巢癌模型。