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

• 批准号: 9887875
• 负责人: Aileen Frances Keating
• 金额: $ 45.97万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 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/9887875
• 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; 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; Population; 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' 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

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.

项目摘要：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不育。受影响的女性会受到慢性、永久性的健康影响 因为她们绝经后的寿命比例延长了，从而增加了患上 相关健康并发症发展(包括冠心病、肥胖症、II型糖尿病、 骨质疏松症和抑郁症)。生殖功能障碍也是由肥胖引起的，我们发表了一篇 多项研究表明，肥胖女性的卵巢对化学物质高度敏感 暴露会导致卵巢损伤和不孕。这种敏感度的提高源于丰度的变化。 卵巢内的化学代谢蛋白的增加，并引起了人们对肥胖女性患 以卵巢为目标的环境化学物质暴露。 我们已发表的初步数据有力地支持肥胖女性的卵巢发生了化学变化。 当暴露在导致DNA损伤的化学物质中时，除了新陈代谢外，还会出现迟钝的DNA修复反应。 这是令人担忧的，因为DNA损伤可能导致雌性失去生育能力或对后代构成风险 如果这一损害修复不当，将对健康产生不利影响。事实上，肥胖女性的后代增加了 先天缺陷。然而，我们已经在成年青春期后小鼠身上展示了我们的发现，无论这些影响 在怀孕期间经历肥胖环境或青春期前遗体的女性也会出现这种情况 不清楚，但代表着对女性公共健康的主要担忧。根据我们强有力的令人担忧的证据 对于肥胖女性卵巢对化学物质引起的损伤的高度敏感性，我们将机械地 调查我们的中心假设，肥胖通过减少DNA修复来增强卵子毒性 损伤，改变卵巢的化学生物转化，并诱导氧化应激。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；在妊娠、青春期前和青春期后。我们将调查我们的 通过完成三个特定目标的假设：目标1将调查肥胖对DNA修复的影响 对DMBA暴露的反应；AIM 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诱导的影响。这部作品 适用于一般女性健康、卵巢毒性、不孕不育，甚至延伸至致癌。数据 具有基本的和翻译的重要性，并与NIEHS的任务相关。这个提议是开创性的， 创新性的，并结合了改变的生理和代谢状态对卵巢毒性的相加效应 由于环境中的化学物质暴露而发生。