MECHANISTIC STUDIES OF OVARIAN TOXICITY

1995年，我们定义了阿司匹林的体内和体外卵巢毒性。 乙二醇单甲醚(EGME)，一种在 化工和食品工业。直到我们的研究，生殖的地点 对女性的毒性还不清楚。我们发现埃格姆(300) Mg/kg)可特异性刺激黄体细胞孕酮的产生 在体循环训练导致SD大鼠黄体形成 肥大和生理性假孕。同样，活跃的 鸡蛋的代谢物在一定剂量下刺激孕酮的产生--和 培养的大鼠黄体细胞呈时间依赖性。我们目前正在 检验孕酮刺激是通过中介的假说 通过增加受体介导的cAMP，并探索相关的 体外cAMP刺激的大鼠黄体细胞和黄体细胞信号转导通路 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诱导减少 颗粒细胞凋亡，与Egme的结果支持这一结论 CAMP水平似乎在决定颗粒是否 细胞分化或发生凋亡。其他正在进行的工作涉及 芳香酶和BRCA1原位杂交方法的建立 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 呋喃西林的利用正在进行中。组织学，内分泌学的结果， 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肿瘤的发展 卵巢癌的模特。

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.