Endocrine disrupting chemicals and ovotoxicity

描述（由申请人提供）：妇女每天都暴露于内分泌干扰化学品（EDCs）。这是令人担忧的，因为已知许多EDCs会导致不孕症和/或卵巢早衰（早期绝经）。一些内分泌干扰物还可能导致雌二醇（E2）水平降低或氧化应激。低E2水平和氧化应激是令人担忧的，因为它们可能导致不孕症，过早绝经，或许多不良健康结果，如过早衰老，心血管疾病，情绪障碍，炎症和骨质疏松症。迄今为止，对内分泌干扰物引起低E2水平、氧化应激、不孕和/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（甲氧滴滴涕; MXC），模型邻苯二甲酸酯（邻苯二甲酸二乙基己酯; DEHP和单（2-乙基-5-羟己基）邻苯二甲酸酯; MEHP）和双酚A（BPA）降低E2水平，破坏小鼠的窦状卵泡。我们的初步数据还表明，MXC、DEHP、MEHP和BPA通过抑制卵泡生长和加速小鼠的自流而破坏窦状卵泡。鉴于这些内分泌干扰物对E2水平和有腔卵泡产生类似的影响，目前研究的目标是确定它们是否通过共同途径减少E2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测试以下假设：所选模型内分泌干扰物减少E2合成和/或增加E2代谢，导致E2水平降低;并且E2水平降低导致氧化应激，这导致卵泡生长缓慢和自流，随后是不孕和/或卵巢早衰。为了检验这一假设，将完成以下具体目标：1）确定选定的内分泌干扰物是否通过抑制E2合成和/或通过增加E2代谢来减少E2，2）比较选定的内分泌干扰物在窦卵泡中引起氧化应激的能力，以及3）比较选定的内分泌干扰物引起不孕症和卵巢早衰的能力。拟议的工作将增加我们对选定的内分泌干扰物引起卵毒性的机制的理解。重要的是要了解这些内分泌干扰物损害卵巢的机制，因为这可能导致开发新的靶点，用于治疗低E2水平，不孕症和内分泌干扰物诱导的过早绝经。通过确定所选的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集中在窦卵泡中的共同靶点上，或者是否应该集中在单独的干预策略上。 公共卫生相关性：这项工作将大大提高我们对内分泌干扰物引起卵巢毒性的机制的理解。这种理解的提高可能会导致开发新的目标，用于治疗环境化学物质引起的不孕症和过早绝经。

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.