ENVIRONMENTAL EPOXIDES--MECHANISMS OF OVOTOXICITY

环境化学品4-乙烯基环己烯（VCH）是在 橡胶轮胎、阻燃剂、杀虫剂、 增塑剂和抗氧化剂。 二环氧化物给药（30天） 代谢产物4-乙烯基环己烯二环氧化物（VCD）破坏了大部分 小鼠卵巢中的小腔前（原始）卵泡， 大鼠 女性出生时有有限数量的原始卵泡 不能再生;因此，破坏卵母细胞的化学物质 这些卵泡中含有的蛋白质会导致卵巢早衰。 妇女暴露于已知的卵子毒性物质，如香烟烟雾和 化疗剂与绝经早期有关，因此， 在工业环境中可能接触其他卵毒性化学品 令人担忧 先前在大鼠中使用VCD（80 mg/kg）的研究表明， 破坏小卵泡需要每天给药（10天）， 生理性细胞死亡（凋亡），并伴随着改变 凋亡相关基因（bax）、氧化应激 （超氧化物歧化酶）和解毒（环氧化物水解酶）。 的 研究，这里提出将表征氧化应激的作用， 和卵泡代谢在VCD诱导的凋亡中的作用。 实验 一种方法将涉及利用对VCD的响应性的转变 我们已经观察到小卵泡给药的保护作用（1 剂量），对细胞凋亡的影响（10和15日剂量）。此外，本发明的目的是， 这些研究将使用我们现有的分离的小卵泡系统， 与共聚焦显微镜一起发展， 在特定的细胞中。 待检验的假设为：VCD 启动小腔前卵泡的氧化应激反应 在重复给药后发生改变以触发bax的发作， 介导的凋亡。 具体目标是：1）表征 bax介导的细胞凋亡中的氧化应激反应，2）与VCD相关 代谢与小卵泡中的氧化应激，以及3）评估 压力激活的凋亡途径。 这些研究将使用 综合形态学、生物化学和分子学方法， 更深入地了解由以下因素引起的卵毒性机制： 职业性的，环氧化物。 这些研究的结果将提供 更深入地了解暴露于卵毒性环境的影响， 化学品对妇女生殖健康的影响。

The environmental chemical, 4-Vinylcyclohexene (VCH) is produced in the manufacture of rubber tires, flame retardants, insecticides, plasticizers, and antioxidants. Dosing (30 d) with the diepoxide metabolite, 4- vinylcyclohexene diepoxide (VCD) destroys the majority of small pre-antral (primordial) follicles in the ovaries of mice and rats. Females are born with a finite number of primordial follicles that cannot be regenerated; thus, chemicals that destroy oocytes contained in these follicles can produce premature ovarian failure. Exposure of women to known ovotoxicants such as cigarette smoke and chemotherapeutic agents has been associated with early menopause, thus, potential exposure to other ovotoxic chemicals in the industrial setting is of concern. Previous studies with VCD (80mg/kg) in rats showed that destruction of small follicles requires daily dosing (10 days), is via physiological cell death (apoptosis), and is accompanied by altered expression of genes associated with apoptosis (bax), oxidative stress (superoxide dismutase, and detoxification (epoxide hydrolase). The studies, proposed here will characterize the role of oxidative stress and follicular metabolism in VCD-induced apoptosis. The experimental approach will involve exploiting the shift in responsiveness to VCD dosing we have observed in small follicles from a protective effect (1 dose), to an apoptotic effect (10 and 15 daily doses). Additionally, these studies will use the isolated small follicle system we have developed in conjunction with confocal microscopy to localize events within specific cells. The hypothesis to be tested is that: VCD initiates an oxidative stress response in small pre-antral follicles that is altered after repeated dosing to trigger the onset of bax- mediated apoptosis. The Specific Aims are 1) to characterize the oxidative stress response in bax-mediated apoptosis, 2) to relate VCD metabolism with oxidative stress in small follicles, and 3) to evaluate the stress-activated pathway to apoptosis. The studies will use an integrated morphological, biochemical and molecular approach to provide a greater understanding of the mechanisms of ovotoxicity caused by occupational, epoxides. The results of these studies will provide greater insight as to the impact of exposure to ovotoxic environmental chemicals on reproductive health in women.