SIGNALING PATHWAYS IN CHEMICAL INDUCED OVOTOXICITY

描述：（改编自研究者摘要）。环境 4-乙烯基环己烯（VCH）是一种化学品，在橡胶制造过程中产生 轮胎、阻燃剂、杀虫剂、增塑剂和抗氧化剂。给药 (30 d）与二环氧化物代谢物，4-乙烯基环己烯二环氧化物（VCD） 破坏卵巢中的大多数小腔前（原始）卵泡 老鼠和老鼠的实验。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包含在 这些卵泡会导致卵巢早衰。因此， 妇女对环境中的卵毒素的敏感性令人关切。除了VCH和 VCD、其他可形成二环氧化物的工业化学品、丁二烯和 异戊二烯也会破坏小鼠原始卵泡。这些卵毒素 都是通过类似的细胞机制起作用的，这是未知的。既往VCD研究 (80 mg/kg）的大鼠试验表明，破坏小卵泡需要每天 给药（10天），是通过生理性细胞死亡（细胞凋亡）， 伴随着与凋亡相关的基因（Bax）表达的改变。的 这里提出的研究将调查受体介导的信号传导的作用， 调节VCD诱导的细胞凋亡的途径。使用标识为 还将在大鼠中测试VCD和其他具有卵毒性的职业性二环氧化物， 确定这些事件是否代表了卵泡发育的普遍机制， 杀伤性待检验的假设是VCD和其他卵毒性物质 二环氧化物可破坏小的窦前（原始）卵泡 通过常见的细胞内信号传导途径。具体目标是：1） 确定生长因子受体是否在卵泡凋亡中受到影响 2）鉴定参与VCD信号传导的蛋白激酶通路 对于卵毒性，3）表征VCD对稳态基因的影响 表达，以及4）确定是否由 其他化学物质也是通过类似的机制。这些研究将使用一个综合的 形态学，生物化学和分子方法，以提供更大的 了解环境化学品引起的卵毒性，因此，将 更深入地了解这些具体因素对 妇女生殖健康。

DESCRIPTION: (Adapted from the Investigator's Abstract). 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. As a result, exposure of women to ovotoxicants in the environment is of concern. In addition to VCH and VCD, other industrial chemicals that can form diepoxides, butadiene and isoprene, also destroy primordial follicles in mice. Whether these ovotoxicants all act by similar cellular mechanisms is unknown. Previous studies with VCD (80 mg/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). The studies proposed here will investigate the role of receptor-mediated signaling pathways that regulate VCD-induced apoptosis. Using end-points identified with VCD, other ovotoxic occupational diepoxides will also be tested in rats to determine whether these events represent a universal mechanism of follicular destruction. The hypothesis to be tested is that VCD and other ovotoxic diepoxides cause destruction of small pre-antral (primordial) ovarian follicles via common intracellular signaling pathways. The Specific Aims are to: 1) determine whether growth factor receptors are affected in follicular apoptosis induced by VCD, 2) identify protein kinase pathways involved in VCD signaling for ovotoxicity, 3) characterize the effect of VCD on steady state gene expression in ovotoxicity, and 4) determine whether ovotoxicity induced by other chemicals is via similar mechanisms. The studies will use an integrated morphological, biochemical, and molecular approach to provide a greater understanding of ovotoxicity caused by environmental chemicals, and thus, will provide greater insight as to the impact of these specific factors on reproductive health in women.