Phthalates and Ovarian Toxicity

女性的生育力取决于足够数量的健康原始卵泡的发育，以及原始卵泡不断生长到初级卵泡，然后是腔前卵泡，最后是有腔卵泡，这是唯一能够释放卵子进行受精和合成性类固醇激素的卵泡。由于有限的卵巢储备是在出生时建立的，而卵泡的生长(卵泡发生)是一个不可逆转的过程，对卵泡发生的异常调节可能会产生不利的生殖影响。特别是，原始卵泡的加速枯竭，特别是通过原始卵泡到初级卵泡的不规则激活，可能导致不孕和卵巢早衰。尽管卵泡发生对生育和健康很重要，但我们对控制卵泡从原始阶段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，内分泌干扰物邻苯二甲酸二(2-乙基己基)酯(DEHP)及其主要代谢物邻苯二甲酸单(2-乙基己基)酯(MEHP)可促进小鼠卵泡的发生。此外，我们的初步数据表明，DEHP扰乱了调控卵泡发生的关键成分的水平，即磷脂酰肌醇3-激酶(PI3K)信号通路。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最大污染物之一，它们存在于各种消费品、个人护理产品、杀虫剂、木材饰面、粘合剂、溶剂、润滑剂、消泡剂和医疗设备中。鉴于我们的初步数据，正常生育对生殖和非生殖健康的重要性，以及人类无处不在的邻苯二甲酸盐暴露，我们建议使用小鼠来验证这样的假设，即暴露于邻苯二甲酸盐及其代谢产物通过PI3K途径和相关途径加速卵巢卵泡形成，导致不孕不育和卵巢早衰。为了验证这一假设，我们提出了以下三个具体目标：1)确定环境相关剂量的邻苯二甲酸酯(DEHP、MEHP和邻苯二甲酸盐混合物)是否通过PI3K途径和相关途径促进卵巢卵泡发生；2)确定卵巢是否有能力对邻苯二甲酸盐代谢物做出反应，并将DEHP和邻苯二甲酸盐混合物代谢成有毒代谢物；以及3)确定邻苯二甲酸盐诱导的卵泡形成加速是否会导致不孕和卵巢早衰。总的来说，这项拟议的工作将确定邻苯二甲酸盐导致雌性哺乳动物卵巢毒性和生殖功能障碍的机制。反过来，这可能会导致开发治疗邻苯二甲酸酯引起的疾病的新靶点。

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.