Ulrike Luderer, MD, PhD, MPH
Associate Professor

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telephone:
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University of California, Irvine
Center for Occupational & Environmental Health
100 Theory, Suite 100
Irvine, CA 92617

949-824-8641
949-824-2345

B.S., Brown University
M.D., Ph.D., Northwestern University
M.P.H., University of Washington
Internal Medicine Residency, Evanston Hospital, Northwestern University, Evanston, IL
Occupational and Environmental Medicine Residency, University of Washington, Seattle, WA

Reproductive toxicology, developmental toxicology

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.

Lim J, Lawson GW, Nakamura BN, Ortiz L, Hur JA, Kavanagh TJ, Luderer U. Glutathione-Deficient Mice Have Increased Sensitivity to Transplacental Benzo[a]pyrene-Induced Premature Ovarian Failure and Ovarian Tumorigenesis.Cancer Research. 2013, 73(2):1-10. DOI: 10.1158/0008-5472.CAN-12-3636.

Luderer U, Kesner JS, Fuller JM, Krieg EF Jr, Meadows JW, Tramma SL, Yang H, Baker D. Effects of Gestational and Lactational Exposure to Heptachlor Epoxide on Age at Puberty and Reproductive Function in Men and Women. Environmental Research. 2013, 121:84-94. doi: 10.1016/j.envres.2012.11.001. Epub 2012 Nov 26.

Nakamura BN, Mohar I, Lawson GW, Hoang YD, Cortés MM, Ortiz L, Patel R, Rau BA, McConnachie L, Kavanagh TJ, Luderer U. Increased Sensitivity to Testicular Toxicity of Transplacental Benzo[a]pyrene Exposure in Male Glutamate Cysteine Ligase Modifier Subunit Knockout (Gclm-/-) Mice. Toxicological Sciences. 2012, 126(1):227-41. doi: 10.1093/toxsci/kfs017. Epub 2012 Jan 17.

Devine PJ, Perreault SD, Luderer U. Roles of Reactive Oxygen Species and Antioxidants in Ovarian Toxicity. Biology of Reproduction. 2012, 86(2):27. doi: 10.1095/biolreprod.111.095224. Print 2012 Feb.

Lim J, Luderer U. Oxidative Damage Increases and Antioxidant Gene Expression Decreases with Aging in the Mouse Ovary. Biology of Reproduction. 2011, 84:775-782.

Nakamura BN, Fielder TJ, Hoang YD, Lim J, McConnachie LA, Kavanagh TJ, Luderer U. Lack of Maternal Glutamate Cysteine Ligase Modifier Subunit (Gclm) Decreases Oocyte Glutathione Concentrations and Disrupts Preimplantation Development in Mice. Endocrinology. 2011; 152: 2806-2815.

Nakamura BN, Lawson G, Chan JY, Banuelos J, Cortés MM, Hoang YD, Ortiz L, Rau BA, Luderer U. Knockout of the Transcription Factor Nrf2 Disrupts Spermatogenesis in an Age-Dependent Manner. Free Radical Biology and Medicine. 2010, 49:1368-1379.

Hoang YD, Nakamura BN, Luderer U. Follicle-Stimulating Hormone and Estradiol Interact to Stimulate Glutathione Synthesis in Rat Ovarian Follicles and Granulosa Cells. Biology of Reproduction. 2009, 81:636-646.

Cortes-Wanstreet MM, Giedzinski E, Limoli CL, Luderer U. Overexpression of Glutamate Cysteine Ligase Protects Human COV434 Granulosa Tumor Cells against Oxidative and Gamma-Radiation Induced Cell Death. Mutagenesis. 2009, 24:211-224.

Tsai-Turton M, Nakamura BN, Luderer U. 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. Biology of Reproduction. 2007, 77:442-451.

Tsai-Turton M, Luong BT, Tan Y, Luderer U. Cyclophosphamide-Induced Apoptosis in COV434 Human Granulosa Cells Involves Oxidative Stress and Glutathione Depletion. Toxicological Sciences. 2007, 98: 216-230.

Tsai-Turton M, Luderer U. Opposing Effects of Glutathione Depletion and FSH on Reactive Oxygen Species and Apoptosis in Cultured Preovulatory Rat Follicles. Endocrinology. 2006, 147: 1224-1236.

Hoang YD, Avakian AP, Luderer U. Minimal Ovarian Upregulation of Glutamate Cysteine Ligase Expression in Response to Suppression of Glutathione by Buthionine Sulfoximine. Reproductive Toxicology. 2006, 21:186-196.

Tsai-Turton M, Luderer U. Gonadotropin Regulation of Glutamate Cysteine Ligase Catalytic and Modifier Subunit Expression in the Rat Ovary is Subunit and Follicle Stage-Specific. American Journal of Physiology Endocrinology and Metabolism. 2005, 289: E391-E402.

Luderer U, Bushley, A, Stover, BD, Bremner WJ, Faustman EM, Takaro TK, Checkoway H, Brodkin CA. Effects of Occupational Solvent Exposure on Reproductive Hormone Concentrations and Fecundability in Men. American Journal of Industrial Medicine. 2004, 46:614-626.

Lawson G, Luderer U. Gestational and Lactational Exposure to Heptachlor Does Not Alter Reproductive System Development in Rats. Veterinary and Human Toxicology. 2004, 46:113-118.

Lopez SG, Luderer U. Effects of Cyclophosphamide and Buthionine Sulfoximine on Ovarian Glutathione and Apoptosis. Free Radical Biology and Medicine. 2004, 36:1366-1377.

Luderer U, Tornero-Velez R, Shay T, Rappaport SM, Heyer N, Echeverria D. Temporal Association between Serum Prolactin Concentration and Exposure to Styrene. Occupational and Environmental Medicine. 2004, 61:325-333.

Luderer U, Diaz D, Faustman EM, Kavanagh TJ. Localization of Glutamate Cysteine Ligase Subunit mRNA within the Rat Ovary and Relationship to Follicular Atresia. Molecular Reproduction and Development. 2003, 65:254-261.

Luderer U, Kavanagh TJ, White CC, Faustman EM. Gonadotropin Regulation of Glutathione Synthesis in the Rat Ovary. Reproductive Toxicology. 2001, 15:495-504.

Luderer U, Morgan MS, Brodkin, CA, Kalman DA, Faustman EM. Reproductive Endocrine Effects of Acute Toluene Exposure in Men and Women, Occupational and Environmental Medicine. 1999, 56:657-666.

Luderer U, Burgess JL, Polifka JE, Robertson WO. Calls on Reproductive and Developmental Toxicants to a Regional Poison Center. Veterinary and Human Toxicology. 1999, 41: 42-46.

Luderer U, Strobl FJ, Levine JE, Schwartz NB. Differential Gonadotropin Responses to N-methyl-D,L-aspartate in Metestrous, Proestrous and Ovariectomized Rats. Biology of Reproduction. 1993, 48:857-866.