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：
8411133
负责人：
Ulrike Luderer
金额：
$ 33.08万
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/8411133
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 In Vitro Intervention Knockout Mice Length Life Measures Meiosis Membrane Potentials Metabolism Mothers Mullerian-inhibiting substance receptor 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（由申请人提供）：当今活着的150万美国妇女在其一生中被诊断为早产卵巢衰竭。早产卵巢衰竭的特征是卵巢卵泡的耗竭加速降低和卵母细胞质量的降低。尽管已经确定了一些过早卵巢衰竭的遗传和环境原因，但在90％的病例中，原因仍然未知。我们先前的工作表明，活性氧是由促性腺激素戒断或化学有毒物质（如多环芳族烃（PAHS））引起的卵巢卵泡凋亡死亡的关键信号，并且补充主要的抗氧化剂（GSH）是保护性的。我们的初步数据表明，缺乏GSH合成的转基因小鼠会导致卵巢过早衰竭，并且卵巢卵泡的耗竭加速且卵母细胞质量差。卵巢发育期间对PAH的暴露会导致啮齿动物的早产卵巢衰竭。 GSH对于PAH代谢产物和PAH代谢过程中产生的活性氧的解毒很重要。该提案旨在检验以下假设：GSH的遗传缺乏通过增加活性氧和卵泡，卵泡和氧化性损伤而导致早产卵巢失败，从而导致程序性细胞死亡，从而导致胚胎GSH不足型在UTERO中导致的卵形曝光，从而导致卵巢的膨胀导致过早的卵巢失效，从而增加卵巢的反应型卵巢溶液。启动Oogonia的细胞死亡的物种。具体目的是：（1）检查活性氧和氧化损伤在早产卵泡耗竭和卵母细胞质量差的遗传GSH缺乏模型中的作用。活性氧在调节细胞死亡和增殖途径中的作用将在体内和体外检查卵巢卵泡和胚胎。（2）描绘了局限于颗粒细胞或卵母细胞的不足GSH合成对卵巢过早衰竭的影响，利用条件敲除小鼠模型具有颗粒细胞和卵母细胞特异性GSH缺乏症的影响。（3）研究GSH缺乏对PAH Benzo [a] pyrene的卵巢程序性细胞死亡和早产卵巢衰竭的影响。拟议的研究将定义单独或与子宫内与苯并[a] pyrene相结合的关键卵巢抗氧化剂GSH中遗传缺乏的机制，导致早产卵巢衰竭。这些研究将具有更广泛的影响，因为由于其他原因，类似的机制可能与卵巢过早失败有关。了解这些机制对于制定预防早产卵巢衰竭的干预措施很重要。