Developmental Gene-Environment Interactions and Premature Ovarian Failure

点击翻译按钮获取中文摘要

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.