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: 10725958
• 负责人: Aileen Frances Keating
• 金额: $ 6.89万
• 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/10725958
• 关键词: AHR gene; ATM activation; Address; Adult; Affect; Alkylating Agents; Amenorrhea; Anthracenes; Antioxidants; Area; Aromatic Polycyclic Hydrocarbons; Birth Rate; ChIP-seq; Chemical Exposure; Chemicals; Chronic; Complication; Conceptions; Congenital Abnormality; Coronary heart disease; Couples; DNA Adduction; 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; Infertility; Investigation; Learning; Life; Light; Maintenance; Malignant neoplasm of ovary; 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; Osteoporosis; Outcome; Ovarian; Ovarian Follicle; Ovary; Oxidative Stress; Oxidative Stress Induction; PIK3CG gene; Pathway interactions; Periodicity; 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; Spontaneous abortion; Subfecundity; Thinness; Woman; Women' s Health; Work; ataxia telangiectasia mutated protein; carcinogenesis; dimethylbenzanthracene; environmental chemical exposure; experience; feeding; female fertility; girls; histone modification; implantation; improved; in utero; innovation; interest; novel; offspring; oocyte quality; 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：肥胖是一个全球公共卫生问题。许多化学物质会沉淀闭经， 女性的更年期和不育。受影响的妇女经历慢性永久健康影响 由于他们的生命比例延长了，因此增加了 相关的健康并发症发展（包括冠心病，肥胖，II型糖尿病， 骨质疏松和抑郁症）。生殖功能障碍也来自肥胖症，我们发表了 研究的数量表明肥胖女性的卵巢对化学的敏感性提高 诱发卵巢损害和不育的暴露。这种提高的敏感性是由于丰度改变而引起的 卵巢内化学代谢蛋白的 针对卵巢的环境化学暴露。 我们强大的出版和初步数据支持，肥胖女性的卵巢改变了化学药品 当暴露于导致DNA损伤的化学物质时，新陈代谢除了钝化的DNA修复反应。 这是关于DNA损害会导致女性生育能力丧失或代表后代的风险 如果对这种损害进行不当修复，那么健康。确实，肥胖妇女的后代有增加的率 出生缺陷。但是，我们已经证明了我们在成年后小鼠中的发现，但是这些影响是否会影响 在妊娠期间经历肥胖环境的女性中也注意到 不清楚，但代表了女性公共卫生的主要关注点。鉴于我们有力而令人担忧的证据 为了提高肥胖女性卵巢对化学诱导的损伤的敏感性，我们将机械机械地 研究我们的中心假设，即肥胖通过减少DNA的修复来增强卵毒性 损伤，卵巢化学生物转化的改变以及氧化应激的诱导。我们将利用 烷基化剂Dimethylbenz [A]蒽（DMBA）在三个阶段诱导卵巢DNA损伤 卵巢发展的重要性；在妊娠期间，预伯蒂和五角后。我们将调查我们的 通过完成三个特定目的的假设：AIM 1将研究肥胖对DNA修复的影响 对DMBA暴露的反应； AIM 2将检查肥胖引起的对DMBA化学代谢的影响；和 AIM 3将确定DMBA暴露和肥胖对卵巢氧化应激诱导的影响。这项工作 适用于一般女性健康，卵巢毒性，不育症，甚至延伸到致癌作用。数据 具有基本和翻译的重要性，与Niehs任务有关。该建议是开创性的， 创新，并伴侣生理和代谢状况改变对卵巢毒性的添加作用 由于环境化学暴露而发生。