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
5201 California Ave, 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 and MPH, University of Washington, Seattle, WA

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. Many known ovarian toxicants are conjugated by the tripeptide glutathione (GSH), and GSH is also a critical detoxification mechanism for reactive oxygen species. The ovary contains moderate concentrations of glutathione, and ovarian GSH concentrations change with estrous cycle stage. However, the roles and regulation of glutathione in the ovary are not well understood. Therefore, work in the laboratory has focused on understanding the role(s) of glutathione in ovarian follicles and investigating the hormonal regulation of ovarian glutathione synthesis. We have shown that GSH synthesis in the ovary is regulated by modulation of the expression of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH synthesis, by the gonadotropins, LH and FSH. We have observed that ovarian GSH synthesis is up-regulated by gonadotropins in a follicle stage-specific and GCL subunit-specific manner. We also observed that GSH synthesis is down-regulated in apoptotic follicles. We therefore hypothesized that follicular GSH is a survival factor for ovarian follicles and that depletion of ovarian GSH will cause follicles to undergo apoptotic degeneration (atresia). We showed that depletion of GSH using buthionine sulfoximine treatment significantly increased the percentage of atretic follicles in the ovaries of adult female rats. Using cultured primary preovulatory rat follicles, we showed that the anti-apoptotic effects of FSH on preovulatory follicles are mediated in part by FSH-induced upregulation of follicular glutathione synthesis and suppression of reactive oxygen species. Ongoing studies are investigating the roles of gluathione in spontaneous and toxicant-induced follicular survival and apoptosis in vivo using genetically-modified mouse models and in vitro using cultured follicles and granulosa cells.


EFFECTS OF IN UTERO HEPTACHLOR EXPOSURE ON REPRODUCTIVE SYSTEM DEVELOPMENT
A second area of focus in the laboratory is the developing reproductive system. In utero exposure to various environmental and occupational toxicants, including some organochlorine pesticides, alters reproductive system development by hormonal mechanisms. The cyclodiene organochlorine insecticide heptachlor has not been studied in this regard, but heptachlor does alter sex steroid metabolism, and one of its metabolites binds to estrogen receptors in vitro. In addition, a well-characterized mass human exposure to this insecticide occurred when the milk supply on the Hawaiian island of Oahu was contaminated with heptachlor in 1981-82. Dr. Luderer is a co-investigator on a US Environmental Protection Agency research grant to study reproductive function in young Oahu adults who were exposed to heptachlor while in utero during the contamination episode.

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, In press. doi: 10.1095/biolreprod.107.060368

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 In Press.

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

Calls on reproductive and developmental toxicants to a regional poison center, Luderer U, Burgess JL, Polifka JE, Robertson WO, Veterinary and Human Toxicology., 1999, 41: 42-46

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

Differential gonadotropin responses to N-methyl-D,L-aspartate in intact and castrated male rats., Strobl FJ, Luderer U, Besecke L, Wolfe A, Schwartz NB, Levine JE, Biology of Reproduction, 1993, 48:867-873