Environmentally Relevant Phthalate Exposures and Ovarian Function

项目总结/摘要 大约有670万美国妇女无法怀孕或怀孕。任何 对卵巢造成损害的环境暴露有可能导致妇女不孕。 邻苯二甲酸酯代表了人类生育能力的一个重要问题，因为它们与早期 更年期，激素水平下降，女性早孕丢失。动物模型研究 表明邻苯二甲酸盐可能通过破坏卵巢功能而损害生育能力。卵巢卵泡 卵巢的功能单位，存在于不同的发展阶段，从最不成熟的 原始卵泡到大的排卵前卵泡，在这个阶段，它们能够维持激素 健康卵母细胞的产生和排卵。存活和成功过渡到大排卵前卵泡 阶段取决于各种因素的积极作用，包括促卵泡激素（FSH）、胰岛素- 如生长因子1（IGF 1）和17β-雌二醇（E2），它们形成了一个促生存网络， 保持生育能力。因此，迫切需要确定邻苯二甲酸酯与 这些途径可以提高我们表征邻苯二甲酸酯造成的风险和识别生物标志物的能力， 筛选和治疗由于内分泌失调引起的不孕症的药物靶点。的主要目标 建议，是使用邻苯二甲酸酯的环境相关暴露来测试中心假设， 邻苯二甲酸酯靶向FSH-IGF 1-E2系统，损害卵泡依赖性过程， 通过增加小鼠卵巢卵泡丢失率而导致卵巢衰竭。为了实现我们的目标，我们建议使用 三种邻苯二甲酸盐模型（DBP、DEHP、BBP），以（1）确定环境相关暴露是否 邻苯二甲酸酯改变卵泡动力学并破坏FSH-IGF 1-E2信号传导，（2）确定环境是否 邻苯二甲酸酯的相关暴露通过增加细胞凋亡导致卵泡死亡，以及（3）确定 在依赖于健康的过程中，邻苯二甲酸酯的环境相关暴露导致的表型 卵泡这些研究将使用与环境相关的暴露来确定哪些信号 途径、卵泡类型和单个卵巢细胞隔室对邻苯二甲酸酯最敏感， 这些相关暴露所导致的表型。通过这样做，这项工作将促进 表征邻苯二甲酸酯暴露的风险，并为潜在的生物标志物和治疗提供线索 检测和治疗邻苯二甲酸酯引起的生殖毒性的目标。我们的团队有能力成功地 根据申请中详细说明的经验和机构资源完成拟议的工作。

PROJECT SUMMARY/ABSTRACT Approximately 6.7 million American women are unable to become pregnant or carry a baby to term. Any environmental exposure that causes damage to the ovary has the potential to cause infertility in women. Phthalates represent a significant concern for human fertility because they have been associated with early menopause, decreased hormone levels, and early pregnancy loss in women. Studies in animal models suggest that phthalates may impair fertility through their ability to disrupt ovarian function. Ovarian follicles, the functional units of the ovary, exist in various stages of development that range from the most immature primordial follicles to the large pre-ovulatory follicles, the stage at which they capable of sustaining hormone production and ovulating of health oocyte. Survival and successful transition to the large pre-ovulatory follicle stage depends on the positive actions of various factors including follicle-stimulating hormone (FSH), insulin- like growth factor 1 (IGF1), and 17β-estradiol (E2) which form a pro-survival network critical for the maintenance of fertility. There is, therefore, a critical need to identify the interactions between phthalates and these pathways to improve our ability to characterize the risk posed by phthalates and identify biomarkers and pharmaceutical targets to screen and treat infertility due to endocrine disruption. The main objective of this proposal, is to use environmentally relevant exposures to phthalates to test the central hypothesis that phthalates target the FSH-IGF1-E2 system, compromise follicle-dependent processes, and cause premature ovarian failure by increasing the rate of ovarian follicle loss in mice. To achieve our goal, we propose to use three model phthalates (DBP, DEHP, BBP) to (1) determine whether environmentally relevant exposures to phthalates alter follicular dynamics and disrupt FSH-IGF1-E2 signaling, (2) determine whether environmentally relevant exposures to phthalates cause follicular death by increasing apoptosis, and (3) identify the phenotypes resulting from environmentally relevant exposures to phthalates on processes that rely on healthy ovarian follicles. These studies will use environmentally relevant exposures to identify which signaling pathways, follicle types and individual ovarian cell compartments are most sensitive to phthalates and establish the phenotypes that result from these relevant exposures. By doing so, this work will facilitate the characterization of the risks of phthalate exposure and provide leads for potential biomarkers and therapeutic targets to detect and treat phthalate-induced reproductive toxicity. Our team is well-positioned to successfully complete the proposed work based on experience and institutional resources as detailed in the application.