Reproductive toxicology, developmental toxicology, ovary, reproductive biology
Jean Spencer Felton Award for Excellence in Scientific Writing, 2017, Western Occupational and Environmental Medicine Association
Diplomate, American Board of Internal Medicine, 1996, 2006
American Board of Preventive Medicine in Occupational and Environmental Medicine, 2000, 2010, 2020
National Research Council, Subcommittee for the Review of the Risk Assessment of Methyl Bromide, Jul 99-May 00.
U.S. Environmental Protection Agency Science Advisory Board Environmental Health Committee, Oct 00-Sep 06.
Center for the Evaluation of Risks to Human Reproduction, National Toxicology Program, Expert Panel on 1- and 2-Bromopropane, Sept 01-Jan 02.
Center for the Evaluation of Risks to Human Reproduction, National Toxicology Program, Chair of Expert Panel on Styrene, Jan-Jun 05.
California Environmental Contaminant Biomonitoring Program Scientific Guidance Panel. Member, Aug 2007-present. Chair May 2010-2015
California Developmental and Reproductive Toxicant Identification Committee, 2012-present
CURRENT RESEARCH INTERESTS
Our research aims to elucidate the mechanisms by which toxicants and ionizing radiation disrupt reproductive function and to uncover protective mechanisms that prevent reproductive dysfunction.
ANTIOXIDANT PROTECTIVE MECHANISMS IN THE OVARY
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. 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. 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 is an early event in the induction of apoptosis in cultured follicles or granulosa cells by dimethylbenzanthracene, a polycyclic aromatic hydrocarbon pollutant, and by the anticancer drug cyclophosphamide and ionizing radiation. 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.
To study the roles of GSH in the ovary in vivo, we turned to 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 very low ovarian GSH concentrations resulting in poor oocyte quality, early preimplantation embryonic mortality with small litter sizes, and accelerated onset of ovarian senescence. Ongoing studies are dissecting the mechanisms by which GSH deficiency decreases oocyte quality and developmental potential and accelerates ovarian aging.
DEVELOPMENTAL BASIS OF ACCELERATED OVARIAN AGING AND OVARIAN CANCER
We discovered that prenatal exposure to the environmental pollutant benzo[a]pyrene (BaP) destroyed ovarian germ cells, accelerated reproductive senescence, and caused epithelial ovarian cancer in the female offspring. Furthermore, Gclm deficiency potentiated the transplacental gonadotoxicity of BaP. Gclm null females were more sensitive than Gclm wild type littermates to germ cell depletion and ovarian tumorigenesis by prenatal BaP. Prenatal BaP also impaired spermatogenesis in the male offspring and again Gclm deficient embryos were more sensitive than wild type embryos, but we found that the fetal testis was less sensitive than the fetal ovary to BaP toxicity. We are continuing to investigate the interactions between genetic deficiencies in antioxidant capacity and toxicant exposure in ovarian toxicity, reproductive aging and ovarian cancer.
EFFECTS OF SPACE RADIATION ON THE OVARY
Our newest project investigates the effects of charged particles, which are components of space radiation, on the ovary. We found that charged iron particles rapidly induced DNA strand breaks, oxidative lipid and protein damage, and apoptosis in ovarian follicles leading to dose-dependent depletion of ovarian follicles, premature ovarian failure, and high prevalence of epithelial ovarian tumors later in life. Our results show that the ovary is exquisitely sensitive to charged iron and oxygen particles, with a very low doses of 0.05 Gray depleting the ovarian follicle reserve by 50% or more. Ongoing studies are further investigating the mechanisms by which charged particles destroy ovarian follicles and cause ovarian tumors.
Glutathione Deficiency Decreases Mouse Oocyte Lipid Droplet Stores and Increases Oxidative Stress, Reducing Oocyte Competence. 2022. Malott KF, Reshel S, Ortiz L, Chen J, Lim J, Luderer U. Biology of Reproduction online
Exposure to Environmentally Relevant Concentrations of Ambient Fine Particulate Matter (PM2.5) Depletes the Ovarian Follicle Reserve and Causes Sex-Dependent Cardiovascular Changes in Apolipoprotein E Null Mice. 2022 Luderer U, Lim J, Ortiz L, Nguyen JD, Shin JH, Allen BD, Liao LS, Malott K, Perraud V, Wingen L, Arechavala RJ, Bliss B, Herman DA, Kleinman MT. Particle and Fibre Toxicology. 19:5 Open access
Sex Difference in Embryonic Gonad Transcriptomes and Benzo[a]pyrene Metabolite Levels after Transplacental Exposure. 2022 Lim J, Ramesh A, Shioda T, Leon Parada K, Luderer U. Endocrinology 163(1). Epub ahead of print, November 3, 2021. doi: 10.1210/endocr/bqab228
Toxicant effects on mammalian oocyte mitochondria. 2021 Malott KF, Luderer U. Biology of Reproduction. 104(4): 784-793. https://doi.org/10.1093/biolre/ioab002 (online
Antioxidant Supplementation Partially Rescues Accelerated Depletion of Ovarian Reserve, but Not Oocyte Quality, of Glutathione-Deficient Gclm-/- Mice. 2020 Lim J, Ali S, Liao LS, Nguyen ES, Ortiz L, Reshel S, Luderer U. Biology of Reproduction. 102(5): 1065-1079. https://doi.org/10.1093/biolre/ioaa009 (online
Reproductive Hazards of Space Travel in Women and Men. Mishra B, Luderer U. Nature Reviews Endocrinology. Published online 14 October 2019. (online
Key Characteristics of Female Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Data in Hazard Assessment. 2019. Luderer U, Eskenazi B, Hauser R, Korach KS, McHale CM, Moran F, Rieswijk L, Solomon G, Udagawa O, Zhang L, Zlatnik M, Zeise L, Smith MT. Environmental Health Perspectives. 127(7). DOI: 10.1289//EHP4971 (online
(Link to webinar on Key Characteristics of Reproductive Toxicants
In Utero Exposure to Benzo[a]pyrene Induces Ovarian Mutations at Doses that Deplete Ovarian Follicles in Mice. 2019. Luderer U, Meier MJ, Lawson GW, Beal MA, Yauk CL, Marchetti F. Environmental and Molecular Mutagenesis. 60(5):410-420. DOI: 10.1002/em.22261 (online
Glutathione Deficiency Sensitizes Cultured Embryonic Mouse Ovaries to Benzo[a]pyrene-Induced Germ Cell Apoptosis. 2018. Lim J, Luderer U. Toxicology and Applied Pharmacology. 352:38-45. (online
Charged Iron Particles Are Potent Inducers of Epithelial Ovarian Tumors. Mishra B, Lawson GW, Ripperdan R, Ortiz L, Luderer U. Radiation Research. 2018. 190(2):142-150. (online
Associations between Urinary Biomarkers of Polycyclic Aromatic Hydrocarbon Exposure and Reproductive Function in Women. Luderer U, Christensen F, Johnson WO, She J, Ip HSI, Zhou J, Alvaran J, Krieg EF Jr, Kesner JS. Environment International. 2017; 100: 110-120. PMC5291797
Ovarian Effects of Prenatal Exposure to Benzo[a]pyrene: Roles of Embryonic and Maternal Glutathione Status. Luderer U, Myers MB, Banda M, McKim KL, Ortiz L, Parsons BL. Reproductive Toxicology. 2017, 69:187-195 (online
Very Low Doses of Heavy Oxygen Ion Radiation Induce Apoptosis in Ovarian Follicles, Causing Premature Ovarian Failure. Mishra B, Ripperdan R, Ortiz L, Luderer U. Reproduction. 2017, 154(2):123-133 (online
Transitions in Pregnancy Planning in Women Recruited for a Large Prospective Cohort Study. Luderer U, Li T, Fine JP, Hamman RF, Stanford JB, Baker D. Human Reproduction, 2017, 32(6):1325-1333. (online
Effects of Deletion of the Transcription Factor Nrf2 and Benzo[a]pyrene Treatment on Ovarian Follicles and Ovarian Surface Epithelial Cells in Mice. Lim J, Ortiz L, Nakamura BN, Hoang YD, Banuelos J, Flores VN, Chan JY, Luderer U. Reproductive Toxicology. 2015; 58: 24-32. Epub August 3, 2015. DOI: 10.1016/j.reprotox.2015.07.080. (online
Exposure to Charged Iron Particles Typical of Space Radiation Induces Premature Ovarian Failure in Mice. Mishra B., Ortiz L, Luderer U. Human Reproduction. 2016; 31(8): 1816-26. DOI: 10.1093/humrep/dew126
Greater Sensitivity of the Mouse Fetal Ovary than the Fetal Testis to Benzo[a]pyrene-Induced Germ Cell Death. Lim J, Kong W, Lu M, Luderer U. Toxicological Sciences. 2016. 152(2): 372-81. DOI: 10.1093/toxsci/kfw083.
Glutamate Cysteine Ligase Modifier Subunit (Gclm) Null Mice Have Increased Ovarian Oxidative Stress and Accelerated Age-Related Ovarian Failure. Lim J, Nakamura BN, Mohar I, Kavanagh TJ, Luderer U. Endocrinology. 2015; 156(9):3329-3343. Epub June 17, 2015. DOI: 10.1210/en.2015-1206
Spatial Characterization of Bioenergetics and Metabolism of Primordial to Preovulatory Follicles in Whole Ex Vivo Murine Ovary. Cinco R, Digman MA, Gratton R, Luderer U. Biology of Reproduction. Epub on September 28, 2016. DOI:10.1095/biolreprod.116.142141
In Utero Exposure to Benzo[a]pyrene Increases Adiposity and Causes Hepatic Steatosis in Female Mice, and Glutathione Deficiency Is Protective. Ortiz L, Nakamura BN, Li X, Blumberg B, Luderer U. Toxicology Letters. 2013; 223(2):260-7. (online
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; 121: 84-94. DOI: 10.1016/j.envres.2012.11.001
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):908-917. (online
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. (online
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 (online
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
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.
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
Additional publications: (online
Developmental Gene-Environment Interactions and Premature Ovarian Failure
NASA 80NSSC19K1620 Ovarian Cancer and Space Radiation.
NIH R21HD097541 Interactions of Glutathione, Reactive Oxygen Species, and Lipids on Oocyte Mitochondrial Function
Society of Toxicology
American College of Occupational and Environmental Medicine
Society for the Study of Reproduction
Cellular and Molecular Biosciences
Environmental Health Sciences
Center for Occupational & Environmental Health
Chao Family Comprehensive Cancer Center