Ulrike Luderer, M.D., Ph.D.
100 Theory Drive (Suite 100)
University of California Irvine
Irvine, CA 92697
Lab Tel: (949) 824-3389
Office Tel: (949) 824-8081
ANTIOXIDANT PROTECTIVE MECHANISMS IN OVARIAN FOLLICLES
Our research is aimed at elucidating the mechanisms by which toxicants disrupt reproductive function and the protective mechanisms that prevent toxicant-induced reproductive dysfunction. Reactive oxygen species are produced during normal ovarian function, and they may also be produced as a result of toxicant metabolism. Our earlier work demonstrated a role for reactive oxygen species in mediating spontaneous apoptosis in follicles deprived of hormonal support and apoptosis caused by exposure to ovarian toxicants. We discovered that reactive oxygen species increased in ovarian follicles cultured without gonadotropin support prior to any increase in endpoints of apoptosis and that follicle stimulating hormone stimulated synthesis of the antioxidant glutathione (GSH) and suppressed the rise in reactive oxygen species (Tsai-Turton and Luderer, 2006). We further showed that GSH depletion in cultured follicles reversed the protective, suppressive effect of follicle stimulating hormone on reactive oxygen species and on apoptosis (Tsai-Turton and Luderer, 2006). This work provides evidence that the protective effects of follicle stimulating hormone are mediated in part via upregulation of GSH synthesis. We also showed that increased generation of reactive oxygen species was an early event in the induction of apoptosis in cultured follicles by dimethylbenzanthracene, a polycyclic aromatic hydrocarbon pollutant (Tsai-Turton et al, 2007a) and in the induction of apoptosis in cultured granulosa cells by the anticancer drug cyclophosphamide (Tsai-Turton et al, 2007b) and by ionizing radiation (Cortes-Wanstreet et al, 2008). Furthermore, depletion of GSH potentiated and supplementation of GSH prevented dimethylbenzanthracene, cyclophosphamide, and radiation-induced apoptosis in follicles and granulosa cells. Together these results demonstrate a critical role for GSH in preventing reactive oxygen species initiated apoptosis in ovarian follicles.
More recently, we have utilized a mouse model that is genetically deficient in GSH synthesis due to deletion of the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis. We discovered that Gclm null female mice have poor oocyte quality with very low oocyte GSH concentrations and that this leads to early preimplantation embryonic mortality and small litter sizes. Prenatal exposure to the environmental pollutant benzo[a]pyrene destroyed ovarian germ cells, accelerated reproductive senescence, and caused epithelial ovarian cancer in the female offspring, and Gclm null females were more sensitive than Gclm wild type littermates (Lim et al, 2013). We are continuing to investigate the interactions between genetic deficiencies in antioxidant capacity and toxicant exposure in ovarian toxicity, reproductive aging and ovarian cancer.
- Barcellos-Hoff MH, Blakely E, Burma S, Fornace AJ, Gerson S, Hlatky L, Kirsch D, Luderer U, Shay J, Wang Y, Weil M. Concepts and Challenges in Cancer Risk Prediction for the Space Radiation Environment. Life Sciences in Space Research. In press.
- Lim J, Nakamura BN, Mohar I, Kavanagh TJ, Luderer U. 2015 Glutamate Cysteine Ligase Modifier Subunit (Gclm) Null Mice Have Increased Ovarian Oxidative Stress and Accelerated Age-Related Ovarian Failure. Endocrinology. Epub June 17, 2015. DOI: 10.1210/en.2015-1206
- Luderer U. 2104. Ovarian Toxicity from Reactive Oxygen Species. In: G. Litwack (Ed in Chief), Vitamins and Hormones, Volume 94: 99-127, Endocrine Disrupters. Academic Press/Elsevier.
- Ortiz L, Nakamura BN, Li X, Blumberg B, Luderer U. 2013 In Utero Exposure to Benzo[a]pyrene Increases Adiposity and Causes Hepatic Steatosis in Female Mice, and Glutathione Deficiency Is Protective. Toxicology Letters. 223(2): 260-267. doi:10.1016/j.toxlet.2013.09.017 Reprinted in Toxicology Letters 230(2): 314-321, special issue “Environmental Contaminants and Target Organ Toxicities.”
- Glutathione-Deficient Mice have Increased Sensitivity to Transplacental Benzo[a]pyrene-Induced Premature Ovarian Failure and Ovarian Tumorigenesis.Lim J, Lawson GW, Nakamura BN, Ortiz L, Hur JA, Kavanagh TJ, Luderer U. Cancer Research. 2013; 73(2):1-10. DOI: 10.1158/0008-5472.CAN-12-3636
- Effects of Gestational and Lactational Exposure to Heptachlor Epoxide on Age at Puberty and Reproductive Function in Men and Women.Luderer U, Kesner JS, Fuller JM, Krieg EF Jr, Meadows JW, Tramma SL, Yang H, Baker D. Environmental Research. 2013; Accepted for publication.DOI: 10.1016/j.envres.2012.11.001
- Oxidative Damage Increases and Antioxidant Gene Expression Decreases with Aging in the Mouse Ovary. Lim J, Luderer U. Biology of Reproduction. 2011; 84: 775-782
- Increased sensitivity to testicular toxicity of transplacental benzo[a]pyrene exposure in male glutamate cysteine ligase modifier subunit knockout (Gclm-/-) mice. Nakamura BN, Mohar I, Lawson GW, Hoang YD, Cortés MM, Ortiz L, Patel R, Rau BA, McConnachie L, Kavanagh TJ, Luderer U. Toxicological Sciences. 2012; 126(1): 227-241. DOI: 10.1093/toxsci/kfs017.
- Roles of Reactive Oxygen Species and Antioxidants in Ovarian Toxicity. Devine PJ, Perreault SD, Luderer U. Biology of Reproduction. 2012; 86(2): 27, 1-10. DOI: 10.1095/biolreprod.111.095224
- Lack of Maternal Glutamate Cysteine Ligase Modifier Subunit (Gclm) Decreases Oocyte Glutathione Concentrations and Disrupts Preimplantation Development in Mice. Nakamura BN, Fielder TJ, Hoang YD, Lim J, McConnachie LA, Kavanagh TJ, Luderer U. Endocrinology. 2011; 152: 2806-2815
- Knockout of the Transcription Factor Nrf2 Disrupts Spermatogenesis in an Age-Dependent Manner. Nakamura BN, Lawson G, Chan JY, Banuelos J, Cortés MM, Hoang YD, Ortiz L, Rau BA, Luderer U. 2010, Free Radical Biology and Medicine. 49:1368-1379.
- Follicle-Stimulating Hormone and Estradiol Interact to Stimulate Glutathione Synthesis in Rat Ovarian Follicles and Granulosa Cells. Hoang YD, Nakamura BN, Luderer U. 2009 Biology of Reproduction. 81:636-646.
- Overexpression of Glutamate Cysteine Ligase Protects Human COV434 Granulosa Tumor Cells against Oxidative and Gamma-Radiation Induced Cell Death. Cortes-Wanstreet MM, Giedzinski E, Limoli CL, Luderer U. 2009 Mutagenesis 24:211-224
- Induction of Apoptosis by 9,10-Dimethyl-1,2-benzanthracene (DMBA) in Cultured Preovulatory Rat Follicles Is Preceded by a Rise in Reactive Oxygen Species and Is Prevented by Glutathione.Tsai-Turton M, Nakamura BN, Luderer U. Biology of Reproduction. 2007, 77: 442-451.
- Cyclophosphamide-Induced Apoptosis in COV434 Human Granulosa Cells Involves Oxidative Stress and Glutathione Depletion. Tsai-Turton M, Luong BT, Tan Y, Luderer U. Toxicological Sciences. 2007 98: 216-230.
- Opposing Effects of Glutathione Depletion and FSH on Reactive Oxygen Species and Apoptosis in Cultured Preovulatory Rat Follicles. Tsai-Turton M, Luderer U. Endocrinology. 2006, 147: 1224-1236.
- Minimal Ovarian Upregulation of Glutamate Cysteine Ligase Expression in Response to Suppression of Glutathione by Buthionine Sulfoximine. Hoang YD, Avakian AP, Luderer U. Reproductive Toxicology. 2006, 21:186-196.
- Gonadotropin Regulation of Glutamate Cysteine Ligase Catalytic and Modifier Subunit Expression in the Rat Ovary is Subunit and Follicle Stage-Specific. Tsai-Turton M, Luderer U. American Journal of Physiology Endocrinology and Metabolism. 2005, 289: E391-E402.
- Effects of Occupational Solvent Exposure on Reproductive Hormone Concentrations and Fecundability in Men. Luderer U, Bushley, A, Stover, BD, Bremner WJ, Faustman EM, Takaro TK, Checkoway H, Brodkin CA. American Journal of Industrial Medicine. 2004, 46:614-626
- Gestational and Lactational Exposure to Heptachlor Does Not Alter Reproductive System Development in Rats. Lawson G, Luderer U. Veterinary and Human Toxicology. 2004, 46:113-118.
- Effects of cyclophosphamide and buthionine sulfoximine on ovarian glutathione and apoptosis. Lopez SG, Luderer U. Free Radical Biology and Medicine. 2004, 36:1366-1377.
- Temporal Association between Serum Prolactin Concentration and Exposure to Styrene. Luderer U, Tornero-Velez R, Shay T, Rappaport SM, Heyer N, Echeverria D. Occupational and Environmental Medicine. 2004, 61:325-333.
- Localization of Glutamate Cysteine Ligase Subunit mRNA within the Rat Ovary and Relationship to Follicular Atresia, Luderer U, Diaz D, Faustman EM, Kavanagh TJ. Molecular Reproduction and Development. 2003, 65:254-261
- Gonadotropin Regulation of Glutathione Synthesis in the Rat Ovary, Luderer U, Kavanagh TJ, White CC, Faustman EM, Reproductive Toxicology., 2001, 15:495-504
- Reproductive endocrine effects of acute toluene exposure in men and women., Luderer U, Morgan MS, Brodkin, CA, Kalman DA, Faustman EM, Occupational and Environmental Medicine, 1999, 56: 657-666
- Differential gonadotropin responses to N-methyl-D,L-aspartate in metestrous, proestrous and ovariectomized rats, Luderer U, Strobl FJ, Levine JE, Schwartz NB, Biology of Reproduction, 1993, 48: 857-866
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