Endocrine disrupting chemicals and ovotoxicity

描述（由申请人提供）：女性每天都暴露在内分泌干扰化学物质（EDCs）中。这是值得关注的，因为已知许多EDCs会导致不孕和/或卵巢早衰（提前绝经）。一些EDCs也可能导致低雌二醇（E2）水平或氧化应激。E2水平低和氧化应激令人担忧，因为它们可能导致不孕、过早绝经或许多不良健康结果，如早衰、心血管疾病、情绪障碍、炎症和骨质疏松症。迄今为止，关于EDCs导致E2水平低、氧化应激、不孕症和/或卵巢早衰的机制知之甚少。我们的初步研究表明，模型有机氯农药（甲氧基氯；MXC），模型邻苯二甲酸酯(邻苯二甲酸二乙基己酯；DEHP和邻苯二甲酸单（2-乙基-5-羟基己酯）；MEHP)和双酚A （BPA）可降低小鼠体内E2水平并破坏窦泡。我们的初步数据还表明，MXC、DEHP、MEHP和BPA通过抑制小鼠卵泡生长和加速自流来破坏小鼠的窦泡。考虑到这些EDCs对E2水平和窦卵泡有相似的影响，当前研究的目的是确定它们是否通过共同的途径减少E2的产生，诱导卵泡生长缓慢，加速自流，导致不孕和卵巢早衰。具体来说，我们建议使用小鼠来验证所选模型EDCs减少E2合成和/或增加E2代谢，导致E2水平降低的假设；E2水平降低会引起氧化应激，从而导致卵泡生长缓慢和自流，进而导致不孕和/或卵巢早衰。为了验证这一假设，将完成以下具体目标：1)确定选定的内分泌干扰物质是否通过抑制E2合成和/或增加E2代谢来减少E2, 2)比较选定的内分泌干扰物质引起窦卵泡氧化应激的能力，以及3)比较选定的内分泌干扰物质导致不孕和卵巢早衰的能力。所提出的工作将增加我们对选定的EDCs引起卵毒性的机制的理解。了解这些EDCs损害卵巢的机制是很重要的，因为这可能会导致新的靶点的发展，以治疗由EDCs引起的低E2水平、不孕症和过早绝经。通过确定选定的EDCs是否通过共同机制起作用，我们将能够确定治疗不孕症和过早绝经的新靶点的开发是否可以关注于窦卵泡中的共同靶点，或者他们是否应该关注于单独的干预策略。

DESCRIPTION (provided by applicant): Women are exposed to endocrine disrupting chemicals (EDCs) on a daily basis. This is of concern because many EDCs are known to cause infertility and/or premature ovarian failure (early menopause). Some EDCs also may cause low estradiol (E2) levels or oxidative stress. Low E2 levels and oxidative stress are of concern because they may lead to infertility, premature menopause, or a number of adverse health outcomes such as premature aging, cardiovascular disease, mood disorders, inflammation, and osteoporosis. To date, little is known about the mechanisms by which EDCs cause low E2 levels, oxidative stress, infertility, and/or premature ovarian failure. Our preliminary studies indicate that a model organochlorine pesticide (methoxychlor; MXC), model phthalates (diethylhexyl phthalate; DEHP and mono (2-ethyl-5-hydroxyhexyl) phthalate; MEHP), and bisphenol A (BPA) reduce E2 levels and destroy antral follicles in mice. Our preliminary data also indicate that MXC, DEHP, MEHP, and BPA destroy antral follicles by inhibiting follicular growth and accelerating artesian in mice. Given that these EDCs exert similar effects on E2 levels and antral follicles, the goal of the current studies is to determine if they work through common pathways to reduce E2 production, induce slow follicular growth, and accelerate artesian, leading to infertility and premature ovarian failure. Specifically, we propose to use mice to test the hypothesis that selected model EDCs decrease E2 synthesis and/or increase E2 metabolism, leading to decreased E2 levels; and that the decreased E2 levels cause oxidative stress, which leads to slow follicular growth and artesian followed by infertility and/or premature ovarian failure. To test this hypothesis, the following specific aims will be completed: 1) determine if selected endocrine disrupting chemicals reduce E2 by inhibiting E2 synthesis and/or by increasing E2 metabolism, 2) compare the ability of selected endocrine disrupting chemicals to cause oxidative stress in antral follicles, and 3) compare the ability of selected endocrine disrupting chemicals to cause infertility and premature ovarian failure. The proposed work will increase our understanding of the mechanisms by which selected EDCs cause ovotoxicity. It is important to understand the mechanisms by which these EDCs damage the ovary because this may lead to the development of novel targets for the treatment of low E2 levels, infertility, and premature menopause induced by EDCs. By determining whether the selected EDCs work via common mechanisms, we will be able to determine if the development of novel targets for treatment of infertility and premature menopause can focus on common targets in antral follicles or if they should focus on separate intervention strategies. PUBLIC HEALTH RELEVANCE: This work will greatly improve our understanding of the mechanisms by which the endocrine disrupting chemicals cause ovarian toxicity. This improved understanding may lead to the development of novel targets for the treatment of infertility and premature menopause caused by environmental chemicals.