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）中暴露于可能损害小窦前（原始）卵泡的化学物质。对这些卵泡的损伤可导致早期卵巢衰竭（绝经）。由于更年期与各种健康障碍有关，这代表了一种合理的健康风险。对小鼠和大鼠给予职业化学品4-乙烯基-环己二氧化物（VCD），可破坏原始卵泡，并可通过重复给药在啮齿动物中引起早期卵巢衰竭。在大鼠中进行的机制研究有助于将VCD描述为研究外源性诱导的原始卵泡破坏的模型化学品。然而，启动卵母细胞变性的确切机制仍然未知。因此，建议扩大VCD获得的机械信息的基础，以进一步确定这些机制。由于已知各种环境化学物质会破坏原始卵泡，VCD相关信息将证明适用于环境中暴露量较大的化学物质。因此，VCD诱导的卵毒性和另一种环境化学品，9，10-二甲基苯并蒽，DMBA，存在于香烟烟雾和汽车尾气中的选定参数之间的比较也将进行。待检验的假设是VCD通过上调转录前和转录后细胞内途径导致原始卵泡破坏，DMBA启动类似事件。具体目标是：1）鉴定和表征由VCD剂量直接调节的基因表达，2）剖析VCD诱导的卵毒性中涉及的信号传导途径，3）比较由DMBA引发的选定信号传导事件与VCD引发的信号传导事件，以及4）表征卵巢隔室生物活化和解毒VCH、VCD和DMBA的能力。特别是研究VCD损害卵巢原始卵泡的机制，并将其与DMBA进行比较，将提供更大的能力来预测女性环境暴露导致早期绝经的潜在风险。这一更高的认识将导致对环境对妇女更年期年龄的全球影响的理解

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