Environmentally Relevant Phthalate Exposures and Ovarian Function

项目摘要/摘要 大约有670万美国妇女无法怀孕或怀孕到足月。任何 对卵巢造成损害的环境暴露有可能导致女性不孕不育。 邻苯二甲酸酯是人类生育能力的一个重要问题，因为它们与早期的 更年期、荷尔蒙水平下降和妇女早孕丢失。动物模型研究 这表明邻苯二甲酸盐可能通过破坏卵巢功能来损害生育能力。卵巢卵泡， 卵巢的功能单位，存在于发育的不同阶段，从最不成熟的 原始卵泡到大的排卵前卵泡，这是它们能够维持激素的阶段 健康卵母细胞的产生和排卵。存活并成功过渡到大的排卵前卵泡 分期取决于各种因素的积极作用，包括卵泡刺激素(FSH)、胰岛素和 如生长因子1(IGF1)和17β-雌二醇(E2)，它们形成了一个促进生存的网络，对 维持生育能力。因此，迫切需要确定邻苯二甲酸盐和苯二甲酸盐之间的相互作用。 这些途径可以提高我们表征邻苯二甲酸盐构成的风险和识别生物标记物和 筛选和治疗内分泌紊乱所致不孕症的药物靶点。这项工作的主要目标是 建议，是使用与环境相关的邻苯二甲酸盐暴露来测试中心假设 邻苯二甲酸酯以FSH-IGF1-E2系统为靶标，损害卵泡依赖的过程，并导致早产 通过增加小鼠卵巢卵泡的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)到(1)确定是否与环境相关的暴露于 邻苯二甲酸盐改变卵泡动力学并干扰FSH-IGF1-E2信号，(2)决定环境 相关的邻苯二甲酸盐暴露通过增加细胞凋亡而导致卵泡死亡，以及(3)确定 与环境相关的邻苯二甲酸盐暴露导致的表型 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，并建立 由这些相关暴露所导致的表型。通过这样做，这项工作将促进 表征邻苯二甲酸盐暴露的风险，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盐引起的生殖毒性的目标。我们的团队处于有利地位，可以成功地 根据申请书中详述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.