Investigating obesity-induced altered ovarian intracellular signaling

项目概述：肥胖是一个全球性的公共卫生问题。一些化学物质沉淀闭经， 女性过早绝经和不孕。受影响的妇女经历慢性，永久性的健康影响 由于绝经后妇女的寿命延长， 相关的健康并发症发展（包括冠心病、肥胖症、II型糖尿病， 骨质疏松症和抑郁症）。肥胖也会导致生殖功能障碍，我们发表了一份 许多研究表明，肥胖女性的卵巢对化学物质的敏感性增加， 导致卵巢损伤和不孕的暴露。这种增加的敏感性来自于丰度的改变 卵巢内的化学代谢蛋白质，并引起关注的风险增加，肥胖妇女 环境化学品暴露的目标卵巢。 我们强有力的发表和初步数据支持肥胖女性的卵巢改变了化学物质， 当暴露于导致DNA损伤的化学物质时，除了钝化的DNA修复反应外，还可以抑制新陈代谢。 这是令人担忧的，因为DNA损伤可能导致女性生育能力丧失或对后代构成风险 如果这种损害没有得到适当的修复。事实上，肥胖女性的后代患肥胖症的几率增加， 出生缺陷我们已经在成年青春期后小鼠中证明了我们的发现，然而，这些影响是否 在妊娠期或青春期前经历过肥胖环境的女性中也有发现 不清楚，但代表了对女性公共卫生的主要关切。根据我们有力且令人担忧的证据 对于肥胖女性卵巢对化学诱导损伤的高度敏感性，我们将从机制上 研究我们的中心假设，即肥胖通过减少DNA修复而增强卵毒性 损伤、改变卵巢化学生物转化和诱导氧化应激。我们将利用 烷化剂二甲基苯并[a]蒽（DMBA）在三个阶段诱导卵巢DNA损伤， 在卵巢发育中的重要性;在怀孕期间，青春期前和青春期后。我们将调查我们的 通过完成三个具体目标的假设：目标1将调查肥胖对DNA修复的影响 目标2将研究肥胖对DMBA化学代谢的影响;以及 目的3：研究DMBA暴露和肥胖对卵巢氧化应激的影响.这项工作 适用于一般女性健康、卵巢毒性、不孕症甚至致癌。数据 具有基本和转化的重要性，与NIEHS的使命相关。这一提议具有开创性， 创新，并结合改变的生理和代谢状态对卵巢毒性的累加效应， 是由于环境化学品暴露造成的。

Project summary: Obesity is a global public health issue. A number of chemicals precipitate amenorrhea, premature menopause and infertility in females. Affected women experience chronic, permanent health effects since the proportion of their life spent post-menopause is lengthened, thereby increasing the likelihood of associated health complication development (including coronary heart disease, obesity, type II diabetes, osteoporosis and depression). Reproductive dysfunction also results from obesity and we have published a number of studies demonstrating that the ovary of an obese female has heightened sensitivity to chemical exposures that induce ovarian damage and infertility. This increased sensitivity arises from altered abundance of chemical metabolism proteins within the ovary and raises concern about increased risk to obese women of environmental chemical exposures that target the ovary. Our strong published and preliminary data support that the ovary of obese females have altered chemical metabolism in addition to a blunted DNA repair response when exposed to chemicals that cause DNA damage. This is concerning since DNA damage can lead to loss of fertility in females or represent a risk to offspring health should this damage be improperly repaired. Indeed, offspring of obese women have increased rates of birth defects. We have demonstrated our findings in adult post-pubertal mice, however, whether these impacts are also noted in females who experience an obese environment during gestation or pre-pubertally remains unclear but represents a major concern for female public health. In light of our strong and worrying evidence for a heightened sensitivity of the obese female ovary to chemical-induced damage, we will mechanistically investigate our central hypothesis that obesity potentiates ovotoxicity through reduced repair of DNA damage, altered ovarian chemical biotransformation, and induction of oxidative stress. We will utilize the alkylating agent, dimethylbenz[a]anthracene (DMBA) to induce ovarian DNA damage at three stages of importance in ovarian development; during gestation, pre-puberty and post-puberty. We will investigate our hypothesis through completion of three specific aims: Aim 1 will investigate obesity effects on DNA repair response to DMBA exposure; Aim 2 will examine obesity-induced impacts on DMBA chemical metabolism; and Aim 3 will determine effects of DMBA exposure and obesity on induction of ovarian oxidative stress. This work is applicable to general female health, ovarian toxicity, infertility and even extends to carcinogenesis. The data has basic and translational importance and is relevant to the NIEHS mission. This proposal is pioneering, innovative, and couples the additive effect of altered physiological and metabolic status on ovarian toxicity that occurs as a consequence of environmental chemical exposures.