Signaling Pathways in Chemical Induced Ovotoxicity

描述（由申请人提供）：女性出生时有一个有限的原始卵泡池，一旦耗尽，就无法替代。暴露于环境中的化学物质会导致这个池的耗尽，导致卵巢早衰或过早绝经。各种健康障碍与更年期有关，因此过早绝经是一种真正的健康风险。4-乙烯基环己烯（VCH）及其二环氧化物代谢物VCD可选择性破坏大鼠和小鼠卵巢中的原始卵泡和小初级卵泡，并可作为研究环境化学品暴露引起卵巢毒性的机制的模型化学品。初步研究支持c-Kit/Kit配体/PI 3激酶信号通路的改变参与VCD诱导的卵毒性。此外，抑制PI 3激酶信号传导可防止VCD诱导的原始卵泡丢失，而雌二醇治疗可保护小初级卵泡免受VCD诱导的破坏。待检验的假设是VCD通过与PI 3 K信号通路相互作用刺激原始至小初级募集，导致卵巢小腔前卵泡选择性丢失。本提案将研究四个特定目的：1）识别启动VCD诱导的卵毒性的细胞事件，2）检查VCD诱导的卵毒性期间原始卵泡至初级卵泡募集的增加，3）表征保护免受VCD引起的卵泡损失的途径，4）确认VCD诱导的卵泡破坏中涉及的下游事件。这些结果将提供急需的洞察卵巢的基本生理过程，以及阐明扰动这些过程是环境化学品暴露的结果。最终目的是充分了解和确定解决方案，以防止卵巢早衰发生由于外源性暴露在女性。这一更高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：这些研究的主要目的是更精确地确定4-乙烯基环己烯二环氧化物损害卵泡的细胞机制。研究结果将有助于了解环境化学物质可能导致女性更年期提前的机制。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.