Signaling Pathways in Chemical Induced Ovotoxicity

描述(申请人提供)：女性出生时有一个有限的原始卵泡池，一旦耗尽，就无法更换。暴露在环境化学物质中可能会导致这一池的耗尽，导致卵巢早衰或早绝经期。各种健康障碍都与更年期有关，因此，早期绝经是真正的健康风险。4-乙烯基环己烯(VCH)及其二环氧代谢物VCD可选择性破坏大鼠和小鼠卵巢的原始卵泡和小初级卵泡，是研究环境化学暴露引起卵子毒性的模型化学品。初步研究表明，c-Kit/Kit配体/PI3激酶信号通路的改变参与了VCD诱导的卵毒性。此外，抑制PI3激酶信号转导可防止VCD诱导的原始卵泡丢失，而雌二醇处理可保护小初级卵泡免受VCD诱导的破坏。需要检验的假设是，VCD通过与PI3K信号通路的相互作用，刺激原始到小的初级募集，导致卵巢小腔前卵泡的选择性丧失。该提案将研究四个具体目标：1)鉴定VCD诱导的卵子毒性的细胞事件，2)检测VCD诱导的卵泡毒性过程中原始卵泡向初级卵泡募集的增加，3)表征保护VCD引起的卵泡丢失的途径，以及4)确认VCD诱导的卵泡破坏所涉及的下游事件。这些结果将提供对基本卵巢生理过程的迫切需要的洞察，以及阐明环境化学暴露对这些过程的扰动。最终目标是充分了解和确定解决方案，以防止因女性暴露于异种生物而导致的卵巢早衰。这种更大的认识将使人们认识到环境对妇女更年期年龄的全球影响。公共卫生相关性：这项研究的主要目标是更准确地确定4-乙烯基环己烯二环氧化物损害卵巢卵泡的细胞机制。这一结果将有助于理解环境化学物质可能导致女性提前绝经的机制。这将使人们认识到环境对妇女生殖寿命的全球影响。

DESCRIPTION (provided by applicant): Females are born with a finite pool of primordial follicle which, once depleted, cannot be replaced. Exposure to environmental chemicals can cause depletion of this pool, leading to premature ovarian failure, or early menopause. A variety of health disorders are associated with menopause, thus early menopause represents a genuine health risk. 4-vinylcyclohexene (VCH) and its diepoxide metabolite, VCD, cause selective destruction of primordial and small primary follicles in the ovaries of rats and mice, and serve as model chemicals to study the mechanisms by which environmental chemical exposures cause ovotoxicity. Preliminary studies have supported that alterations in the c-Kit/Kit ligand/PI3 kinase signaling pathway are involved in VCD-induced ovotoxicity. Additionally, inhibition of PI3 kinase signaling protected against VCD-induced primordial follicle loss, while estradiol treatment protected small primary follicles from VCD-induced destruction. The hypothesis to be tested is that VCD causes selective loss of ovarian small pre-antral follicles by stimulation of primordial to small primary recruitment via interactions with the PI3K signaling pathway. Four Specific Aims will be investigated in this proposal: 1) identification of the cellular event that initiates VCD-induced ovotoxicity, 2) examination of increased primordial to primary follicle recruitment during VCD-induced ovotoxicity, 3) characterization of the pathways that protect against follicle loss caused by VCD, and 4) confirmation of downstream events involved in VCD-induced follicle destruction. The results will provide much needed insight into basic ovarian physiological processes as well as elucidating perturbations to these processes that are a result of environmental chemical exposures. The ultimate aim is to fully understand and identify solutions to prevent premature ovarian failure occurring due to xenobiotic exposures in females. This greater awareness will lead to an appreciation of the global impact of the environment on age of menopause in women. PUBLIC HEALTH RELEVANCE: The major objective of the studies is to identify more precisely cellular mechanisms by which 4- vinylcyclohexene diepoxide damages ovarian follicles. The results will provide an understanding of mechanisms by which environmental chemicals may cause early menopause in women. This will lead to an appreciation of the global impact of the environment on the reproductive life span in women.