Investigating obesity-induced altered ovarian intracellular signaling

研究肥胖引起的卵巢细胞内信号传导改变

基本信息

批准号：
10531681
负责人：
Aileen Frances Keating
金额：
$ 5.32万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531681
关键词：
AHR gene ATM activation Address Adult Affect Alkylating Agents Amenorrhea Antioxidants Area Aromatic Polycyclic Hydrocarbons Birth Birth Rate ChIP-seq Chemical Exposure Chemicals Chronic Complication Conceptions Congenital Abnormality Coronary heart disease Couples DNA DNA Adducts DNA Damage DNA Repair DNA Repair Gene Data Development Diet Environment Enzymes Estrus Exposure to Fatty acid glycerol esters Female Fertility Foundations Functional disorder Generations Goals Health Hyperphagia Impairment Infertility Investigation Lead Life Light Maintenance Mental Depression Metabolic Metabolic Biotransformation Metabolism Methylation Minority Groups Minority Women Mission Modeling Mus National Institute of Environmental Health Sciences Neonatal Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Oocytes Osteoporosis Ovarian Ovarian Follicle Ovary Oxidative Stress Oxidative Stress Induction Phenotype Physiological Postmenopause Pregnancy Premature Menopause Proteins Puberty Public Health Publishing Reactive Oxygen Species Reproductive Health Research Risk Role Signal Transduction Societies Solid Specific qualifier value Thinness Woman Women&apos s Health Work ataxia telangiectasia mutated protein base carcinogenesis dimethylbenzanthracene environmental chemical exposure experience feeding female fertility girls histone modification improved in utero innovation interest novel offspring ovarian damage ovotoxicant ovotoxicity prepuberty promoter protein metabolism repaired reproductive reproductive success response risk minimization socioeconomics sugar tool transcriptome sequencing

项目摘要

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.

项目概要：肥胖是一个全球性的公共卫生问题。许多化学物质会导致闭经，女性过早绝经和不孕。受影响的女性会经历慢性、永久性的健康影响因为绝经后的生命时间延长了，从而增加了绝经后的可能性相关健康并发症的发生（包括冠心病、肥胖、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，我们发表了一份大量研究表明，肥胖女性的卵巢对化学物质的敏感性更高导致卵巢损伤和不孕的暴露。这种敏感性的增加是由于丰度的改变卵巢内化学代谢蛋白质的变化，引起人们对肥胖女性风险增加的担忧针对卵巢的环境化学物质暴露。我们已发表的强有力的初步数据支持肥胖女性的卵巢已经改变了化学物质当暴露于导致 DNA 损伤的化学物质时，除了 DNA 修复反应减弱之外，新陈代谢也会受到影响。这是令人担忧的，因为 DNA 损伤可能导致女性丧失生育能力或对后代构成风险如果这种损害没有得到适当的修复，就会影响健康。事实上，肥胖女性的后代的患病率有所增加出生缺陷。我们已经在成年青春期后小鼠中证明了我们的发现，然而，这些是否会影响在妊娠期间或青春期前经历肥胖环境的女性中也注意到尚不清楚，但代表了女性公共卫生的一个主要问题。鉴于我们强有力且令人担忧的证据为了提高肥胖女性卵巢对化学损伤的敏感性，我们将机械地研究我们的中心假设：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以及诱导氧化应激。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 损伤对卵巢发育的重要性；妊娠期间、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 将研究肥胖对 DNA 修复的影响对 DMBA 暴露的反应；目标 2 将研究肥胖对 DMBA 化学代谢的影响；和目标 3 将确定 DMBA 暴露和肥胖对诱导卵巢氧化应激的影响。这部作品适用于一般女性健康、卵巢毒性、不孕甚至延伸至致癌。数据具有基础和转化重要性，并且与 NIEHS 的使命相关。这个提议具有开创性，具有创新性，并且将生理和代谢状态改变对卵巢毒性的叠加效应结合起来由于环境化学暴露而发生。