Phthalates and Ovarian Toxicity

女性生育力取决于足够数量的健康原始卵泡的发育以及原始卵泡持续生长为初级卵泡，然后为窦前卵泡，最终为窦卵泡，这是唯一能够释放卵子用于受精和合成性类固醇激素的卵泡。由于有限的卵巢储备在出生时就建立起来，卵泡生长（卵泡发生）是一个不可逆的过程，卵泡发生的异常调节可能会对生殖产生不利影响。特别是，原始卵泡的加速消耗，特别是通过原始卵泡向初级卵泡的不规则激活，可导致不孕和卵巢早衰。尽管卵泡发生对生育和健康的重要性，但我们对控制卵泡从原始到初级阶段生长的环境因素知之甚少。我们的初步数据表明，内分泌干扰化学品邻苯二甲酸二（2-乙基己基）酯（DEHP）及其主要代谢产物邻苯二甲酸单（2-乙基己基）酯（MEHP）可加速小鼠卵泡生成。此外，我们的初步数据表明，DEHP会使调节卵泡发生的途径（磷酸肌醇3-激酶（PI 3 K）信号通路）的关键组分水平失调。这些数据令人担忧，因为邻苯二甲酸酯是人体组织中存在的主要污染物之一，并且它们存在于无数消费品、个人护理产品、杀虫剂、木材饰面、粘合剂、溶剂、润滑剂、防腐剂和医疗器械中。鉴于我们的初步数据，正常生育力对生殖和非生殖健康的重要性，以及人类普遍暴露于邻苯二甲酸酯，我们建议使用小鼠来测试以下假设：暴露于邻苯二甲酸酯及其代谢物通过PI 3 K途径和相关途径加速卵泡发生，导致不孕症和卵巢早衰。为了验证这一假设，我们提出了以下三个具体目标：1）确定邻苯二甲酸酯的环境相关剂量（DEHP、MEHP和邻苯二甲酸酯混合物）通过PI 3 K途径和相关途径加速卵巢卵泡生成，2）确定卵巢是否有能力对邻苯二甲酸酯代谢物做出反应，并将DEHP和邻苯二甲酸酯混合物代谢为毒性代谢物，和3）确定邻苯二甲酸酯诱导的卵泡生成加速是否导致不孕和卵巢早衰。总的来说，拟议的工作将确定邻苯二甲酸酯引起雌性哺乳动物卵巢毒性和生殖功能障碍的机制。反过来，这可能导致开发用于治疗邻苯二甲酸酯诱导疾病的新靶点。

Female fertility depends on the development of an adequate number of healthy primordial ovarian follicles as well the constant growth of primordial follicles to primary follicles then to pre-antral follicles and eventually to antral follicles, which are the only follicles capable of releasing an egg for fertilization and synthesizing sex steroid hormones. Because a finite ovarian reserve is established at birth and follicular growth (folliculogenesis) is an irreversible process, aberrant regulation of folliculogenesis can have adverse reproductive implications. In particular, accelerated depletion of primordial follicles, particularly through irregular activation of primordial follicles to primary follicles, can result in infertility and premature ovarian failure. Despite the importance of folliculogenesis for fertility and health, we know very little about the environmental factors that control the growth of follicles from the primordial to primary stage. Our preliminary data indicate that the endocrine disrupting chemical di(2-ethylhexyl) phthalate (DEHP) and its primary metabolite mono(2-ethylhexyl) phthalate (MEHP) accelerate folliculogenesis in mice. Further, our preliminary data indicate that DEHP dysregulates the levels of key components of a pathway that regulates folliculogenesis, the phosphoinositide 3-kinase (PI3K) signaling pathway. These data are of concern because phthalates are one of the top contaminants present in human tissues and they are present in a myriad of consumer products, personal care products, pesticides, wood finishes, adhesives, solvents, lubricants, defoaming agents, and medical devices. Given our preliminary data, the importance of normal fertility for reproductive and non-reproductive health, and the ubiquitous exposure of humans to phthalates, we propose to use mice to test the hypothesis that exposure to phthalates and their metabolites accelerates ovarian folliculogenesis through the PI3K pathway and related pathways, leading to infertility and premature ovarian failure. To test this hypothesis, we propose the following three specific aims: 1) determine if environmentally relevant doses of phthalates (DEHP, MEHP, and a phthalate mixture) accelerate ovarian folliculogenesis via the PI3K pathway and related pathways, 2) determine if the ovary has the capacity to respond to phthalate metabolites and to metabolize DEHP and the phthalate mixture into toxic metabolites, and 3) determine if phthalate-induced acceleration of folliculogenesis leads to infertility and premature ovarian failure. Collectively, the proposed work will determine the mechanisms by which phthalates cause ovarian toxicity and reproductive dysfunction in female mammals. In turn, this may lead to the development of novel targets for the treatment of phthalate-induced diseases.