Signaling Pathways in Chemical Induced Ovotoxicity

描述(由申请人提供)：女性每天在工作场所以及环境(香烟烟雾、汽车尾气)中暴露于可能损害腔前(原始)卵泡的化学物质。这些卵泡受损会导致早期卵巢衰竭(更年期)。由于更年期与各种健康障碍相关，这代表了一种看似合理的健康风险。给小鼠和大鼠服用职业化学品4-乙烯基环己烯二环氧化物(VCD)会破坏原始卵泡，反复给药可导致啮齿类动物早期卵巢衰竭。正在进行的大鼠机制研究有助于将VCD描述为研究异物诱导的原始卵泡破坏的模型化学物质。然而，引发卵母细胞退化的确切机制仍不清楚。因此，这里建议扩大VCD获得的机制信息库，以进一步识别这些机制。由于已知有多种环境化学物质可以破坏原始毛囊，与VCD相关的信息将被证明适用于在环境中暴露更多的化学物质。因此，还将对VCD的卵毒性与另一种存在于香烟烟雾和汽车尾气中的环境化学物质9，10-二甲基苯并四茂铁(DMBA)的选定参数进行比较。需要检验的假设是，VCD通过上调转录前和转录后的细胞内通路导致原始卵泡的破坏，而DMBA也会引发类似的事件。其具体目的是：1)鉴定和表征VCD剂量直接调节的基因表达；2)剖析参与VCD诱导的卵毒性的信号通路；3)比较DMBA和VCD启动的信号事件；4)表征卵巢隔室对VCH、VCD和DMBA的生物激活和解毒能力。具体地说，研究VCD损害卵巢原始卵泡的机制(S)，并将其与DMBA进行比较，将提供更大的能力来预测妇女暴露在环境中的早期绝经的潜在风险。这种更大的认识将使人们认识到环境对女性更年期年龄的全球影响。

DESCRIPTION (provided by applicant): Women are exposed daily in the workplace, as well as the environment (cigarette smoke, automobile exhaust) to chemicals that can damage small pre-antral (primordial) ovarian follicles. Damage to these follicles can result in early ovarian failure (menopause). Because menopause is associated with a variety of health disorders, this represents a plausible health risk. Dosing of mice and rats with the occupational chemical, 4-vinyl-cyclohexene diepoxide (VCD) destroys primordial follicles and early ovarian failure can be caused in rodents by repeated dosing. On-going mechanistic studies in rats have helped characterize VCD as a model chemical for the study of xenobiotic-induced destruction of primordial follicles. However, the exact mechanism, which initiates oocyte degeneration, remains unknown. Thus, it is proposed here to expand the base of mechanistic information obtained with VCD to further identify those mechanisms. Because a variety of environmental chemicals are known to destroy primordial follicles, VCD-related information will prove applicable to chemicals that are sources of greater exposure in the environment. Therefore, a comparison between selected parameters of VCD-induced ovotoxicity and another environmental chemical, 9,10-dimethylbeznanthracene, DMBA, present in cigarette smoke and automobile exhaust will also be made. The hypothesis to be tested is that VCD causes destruction of primordial follicles by upregulation of pre- and post-transcriptional intracellular pathways and DMBA initiates similar events. The Specific Aims are to: 1) identify and characterize gene expression directly regulated by VCD dosing, 2) dissect signaling pathways involved in VCD-induced ovotoxicity 3) compare selected signaling events initiated by DMBA with those of VCD, and 4) characterize the ability of ovarian compartments to bioactivate and detoxify VCH, VCD, and DMBA. Specifically investigating the mechanism(s) by which VCD damages ovarian primordial follicles and comparing this with DMBA will provide a greater ability to predict potential risks for early menopause from environmental exposures in women. This greater awareness will lead to an appreciation of the global impact of the environment on age of menopause in women