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.

Public Health Relevance

More than 1.5 million of the American women alive today have been or will be diagnosed with premature ovarian failure, sometimes called premature menopause, during their lifetimes. Women with premature ovarian failure have increased risks of cardiovascular disease, osteoporosis, and Alzheimer's disease. Successful completion of the aims will point to new opportunities for prevention of premature ovarian failure, such as public health interventions to decrease exposure to polycyclic aromatic hydrocarbons and antioxidant therapy for women at high risk due to genetics and/or exposures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES020454-03S1
Application #
8792641
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Schug, Thaddeus
Project Start
2014-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2014-10-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Irvine
State
CA
Country
United States
Zip Code
92697
Lim, Jinhwan; Luderer, Ulrike (2018) Glutathione deficiency sensitizes cultured embryonic mouse ovaries to benzo[a]pyrene-induced germ cell apoptosis. Toxicol Appl Pharmacol 352:38-45
Mishra, Birendra; Lawson, Gregory W; Ripperdan, Ryan et al. (2018) Charged-Iron-Particles Found in Galactic Cosmic Rays are Potent Inducers of Epithelial Ovarian Tumors. Radiat Res 190:142-150
Luderer, Ulrike; Christensen, Fletcher; Johnson, Wesley O et al. (2017) Associations between urinary biomarkers of polycyclic aromatic hydrocarbon exposure and reproductive function during menstrual cycles in women. Environ Int 100:110-120
Luderer, Ulrike; Myers, Meagan B; Banda, Malathi et al. (2017) Ovarian effects of prenatal exposure to benzo[a]pyrene: Roles of embryonic and maternal glutathione status. Reprod Toxicol 69:187-195
Lim, Jinhwan; Kong, Weixi; Lu, Muzi et al. (2016) The Mouse Fetal Ovary Has Greater Sensitivity Than the Fetal Testis to Benzo[a]pyrene-Induced Germ Cell Death. Toxicol Sci 152:372-81
Cinco, Rachel; Digman, Michelle A; Gratton, Enrico et al. (2016) Spatial Characterization of Bioenergetics and Metabolism of Primordial to Preovulatory Follicles in Whole Ex Vivo Murine Ovary. Biol Reprod 95:129
Lim, Jinhwan; Ortiz, Laura; Nakamura, Brooke N et al. (2015) Effects of deletion of the transcription factor Nrf2 and benzo [a]pyrene treatment on ovarian follicles and ovarian surface epithelial cells in mice. Reprod Toxicol 58:24-32
Lim, Jinhwan; Nakamura, Brooke N; Mohar, Isaac et al. (2015) Glutamate Cysteine Ligase Modifier Subunit (Gclm) Null Mice Have Increased Ovarian Oxidative Stress and Accelerated Age-Related Ovarian Failure. Endocrinology 156:3329-43
Luderer, Ulrike (2014) Ovarian toxicity from reactive oxygen species. Vitam Horm 94:99-127
Ortiz, Laura; Nakamura, Brooke; Li, Xia et al. (2013) In utero exposure to benzo[a]pyrene increases adiposity and causes hepatic steatosis in female mice, and glutathione deficiency is protective. Toxicol Lett 223:260-7

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