SIGNALING PATHWAYS IN CHEMICAL INDUCED OVOTOXICITY

描述：(改编自《调查者摘要》)。环境问题 化工产品4-乙烯基环己烯(VCH)是橡胶生产过程中产生的 轮胎、阻燃剂、杀虫剂、增塑剂和抗氧化剂。给药 (30d)与二环氧化物的代谢物4-乙烯基环己烯二环氧化物(VCD) 破坏卵巢中大多数小的腔前(原始)卵泡 老鼠和大鼠。女性出生时只有有限数量的原始卵泡 不能再生的；因此，破坏包含在 这些卵泡会导致卵巢早衰。因此，暴露于 女性对环境中的卵毒物是令人关注的。除了VCH和 VCD、可形成二环氧化物的其他工业化学品、丁二烯和 异戊二烯，也破坏小鼠的原始毛囊。这些卵毒剂是否 所有这些都是通过类似的细胞机制发挥作用的，目前尚不清楚。以前对VCD的研究 大鼠口服(80 mg/kg)表明，每天需要破坏小卵泡 剂量(10天)，是通过生理性细胞死亡(细胞凋亡)，并且是 伴随着凋亡相关基因表达的改变(Bax)。这个 这里提出的研究将调查受体介导的信号传递的作用。 调控VCD诱导的细胞凋亡的途径。使用标识为的端点 VCD、其他卵毒职业性二环氧化物也将在大鼠身上进行测试，以 确定这些事件是否代表卵泡的普遍机制 毁灭。需要检验的假设是VCD和其他卵毒性 双环氧化物破坏小的腔前(原始)卵泡 通过共同的细胞内信号通路。具体目标是：1) 确定生长因子受体在卵泡凋亡中是否受到影响 VCD诱导，2)确定VCD信号转导途径 在卵子毒性方面，3)VCD对稳态基因的影响 在卵毒性中的表达，以及4)决定是否有卵毒性 其他化学物质也是通过类似的机制。研究将使用一种综合的 形态、生化和分子方法提供了更大的 了解环境化学品造成的卵子毒性，从而将 更深入地了解这些特定因素对 妇女的生殖健康。

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.