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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：
10725953
负责人：
Aileen Frances Keating
金额：
$ 6.53万
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/10725953
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&apos 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

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.

项目摘要：肥胖是一个全球性的公共卫生问题。一些化学物质会导致闭经，