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Developmental Gene-Environment Interactions and Premature Ovarian Failure

发育基因-环境相互作用和卵巢早衰

基本信息

批准号：
8575335
负责人：
Ulrike Luderer
金额：
$ 33.4万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-10 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8575335
关键词：
Affect Alzheimer&apos s Disease American Antioxidants Apoptosis Apoptotic Aromatic Polycyclic Hydrocarbons Attention Autophagocytosis Benzo(a)pyrene Biochemical Cell Death Cell Proliferation Cessation of life Chemicals Chromosomal Instability Data Development Developmental Gene Diagnosis Drug Metabolic Detoxication Embryo Embryonic Development Enzymes Exposure to Female Fertility Fertilization in Vitro Food Genetic Glutathione Gonadotropins High Risk Woman Hormone Receptor In Vitro Intervention Knockout Mice Length Life Measures Meiosis Membrane Potentials Metabolism Mothers Mus Neonatal Oocytes Oogonia Osteoporosis Ovarian Ovarian Follicle Ovary Oxidative Stress Pathway interactions Perinatal Exposure Phenotype Pregnancy Premature Menopause Premature Ovarian Failure Prevention Preventive Intervention Process Proteins Public Health Reactive Oxygen Species Research Risk Rodent Role Signal Transduction Smoke Staging Supplementation Testing Tobacco Smoke Pollution Weaning Withdrawal Woman Work Zona Pellucida age effect age related antioxidant therapy blastocyst cardiovascular disorder risk cell type cooking fetal gene environment interaction granulosa cell human GCLC protein human GCLM protein in utero in vivo mitochondrial membrane mortality mouse model oxidative damage preimplantation premature promoter protective effect recombinase telomere toxicant

项目摘要

DESCRIPTION (provided by applicant): More than 1.5 million of the American women alive today have been or will be diagnosed with premature ovarian failure during their lifetimes. Premature ovarian failure is characterized by accelerated depletion of ovarian follicles and decreased oocyte quality. Although a few genetic and environmental causes of premature ovarian failure have been identified, the causes remain unknown in 90% of cases. Our previous work showed that reactive oxygen species serve as key signals of apoptotic death of ovarian follicles caused by withdrawal of gonadotropins or by chemical toxicants, like polycyclic aromatic hydrocarbons (PAHs), and that supplementation of the major antioxidant glutathione (GSH) is protective. Our preliminary data show that genetically modified mice deficient in GSH synthesis develop premature ovarian failure, with accelerated depletion of ovarian follicles and poor oocyte quality. Exposure to PAHs during ovarian development causes premature ovarian failure in rodents. GSH is important for detoxification of PAH metabolites and of reactive oxygen species produced during PAH metabolism. This proposal aims to test the hypothesis that a genetic deficiency of GSH causes premature ovarian failure by increasing reactive oxygen species and oxidative damage in follicles, oocytes, and preimplantation embryos, leading to programmed cell death, and that embryonic GSH deficiency sensitizes to premature ovarian failure caused by in utero exposure to PAHs by increasing PAH metabolism-related reactive oxygen species that initiate programmed cell death of oogonia. The specific aims are: (1) To examine the roles of reactive oxygen species and oxidative damage in premature ovarian follicle depletion and poor oocyte quality in a mouse model of genetic GSH deficiency. The roles of reactive oxygen species in modulating cell death and proliferation pathways will be examined in vivo and in vitro in ovarian follicles and embryos. (2) To delineate the effects of deficient GSH synthesis localized to granulosa cells or oocytes on premature ovarian failure utilizing conditional knockout mouse models with granulosa cell- and oocyte-specific GSH deficiency. (3) To investigate the effects of GSH deficiency on transplacental induction of ovarian programmed cell death and premature ovarian failure by the PAH benzo[a]pyrene. The proposed studies will define the mechanisms by which genetic deficiency in the key ovarian antioxidant GSH, alone or in combination with in utero exposure to benzo[a]pyrene, causes premature ovarian failure. These studies will have broader implications because similar mechanisms may be involved in premature ovarian failure due to other causes. Understanding these mechanisms is important to developing interventions for the prevention of premature ovarian failure.

描述(由申请者提供)：今天在世的美国女性中，有超过150万人在有生之年被诊断为或将被诊断为卵巢早衰。卵巢早衰的特征是卵泡加速枯竭和卵母细胞质量下降。虽然已经确定了卵巢早衰的一些遗传和环境原因，但在90%的病例中，原因仍然未知。我们以前的工作表明，活性氧是促性腺激素或多环芳烃(PAHs)等化学毒物引起的卵泡凋亡的关键信号，补充主要抗氧化剂谷胱甘肽(GSH)具有保护作用。我们的初步数据显示，GSH合成不足的转基因小鼠会发生卵巢早衰，卵巢卵泡加速枯竭，卵母细胞质量较差。在卵巢发育期间暴露于多环芳烃会导致啮齿动物卵巢早衰。GSH对多环芳烃代谢产物和多环芳烃代谢过程中产生的活性氧物种的解毒非常重要。这一建议旨在验证这样一种假设，即GSH的遗传缺陷通过增加卵泡、卵母细胞和植入前胚胎中的活性氧物种和氧化损伤，导致程序性细胞死亡而导致卵巢早衰，以及胚胎GSH缺陷通过增加启动卵原细胞程序性细胞死亡的PAH代谢相关的活性氧物种而对宫内暴露于PAHs引起的卵巢早衰敏感。本研究的具体目的是：(1)在遗传性GSH缺乏的小鼠模型中，研究活性氧和氧化损伤在卵泡早衰和卵母细胞质量低下中的作用。在体内和体外，将在卵泡和胚胎中研究活性氧在调节细胞死亡和增殖途径中的作用。(2)利用颗粒细胞和卵母细胞特异性GSH缺乏的条件性基因敲除小鼠模型，探讨颗粒细胞或卵母细胞GSH合成缺陷在卵巢早衰中的作用。(3)探讨GSH缺乏对多环芳烃苯并[a]芘经胎盘诱导卵巢程序性细胞死亡和卵巢早衰的影响。这项拟议的研究将确定关键的卵巢抗氧化剂GSH的遗传缺陷单独或与宫内暴露于苯并[a]芘一起导致卵巢早衰的机制。这些研究将具有更广泛的意义，因为类似的机制可能与其他原因导致的卵巢早衰有关。了解这些机制对于开发预防卵巢早衰的干预措施很重要。