MECHANISTIC STUDIES OF OVARIAN TOXICITY

在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。在我们的研究之前， 雌性动物的毒性未知。 我们发现EGME（300 mg/kg）特异性刺激黄体细胞孕酮的产生， 体内循环Sprague-Dawley大鼠，导致黄体 肥大和生理性假性萎缩。 同样，积极的 EGME的代谢物以一定剂量刺激孕酮产生， 时间依赖性的方式在培养的大鼠黄体细胞。 我们目前正在 检验孕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刺激的细胞信号传导通路， 然后是人类黄体细胞。 我们以前的工作表明， 化学介导的受体刺激的cAMP减少诱导 颗粒细胞凋亡，EGME的结果支持以下结论 cAMP水平似乎是决定颗粒细胞 细胞分化或经历凋亡。 其他正在进行的工作涉及 芳香化酶和BRCA 1原位杂交技术的发展 组织切片中的信息。 这些技术应该有助于梳理出 卵巢癌的发病机制 此外，一项卵巢癌研究 利用呋喃西林正在进行中。组织学，内分泌学， 从呋喃唑酮的分子分析中 建立肿瘤发生的机制，并导致肿瘤的发展。 卵巢癌的模型。

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.