title: Age-related testicular toxicity of mGluR5 negative allosteric modulators appears to be unrelated to testis drug transporter maturity.
abstract: Testicular degeneration was observed in exploratory toxicity studies in Wistar rats treated with several mGluR5 negative allosteric modulators. To determine if these testis effects were influenced by animal age, these compounds were administered to male Wistar rats of different ages (8, 10, and 12 weeks old) for 2 weeks followed by evaluation of male reproductive organ weights, testis histopathology, and inhibin B levels. Overall, seminiferous tubule degeneration was observed in 2/15, 5/15, and 0/15 compound treated rats from the 8, 10, and 12 week old cohorts and inhibin B was decreased in 8 and 10 week old animals, but not in 12 week old rats, suggesting that there is an age-related component to this testis toxicity. The gene expression profiles of drug transporters in the testis of rats aged PND 38 through PND 91 were very similar, indicating that immaturity of these transporters is an unlikely factor contributing to the age-related toxicity.
authors: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT, United States. Electronic address: Sarah.Campion@pfizer.com.
authors: Sarah N
authors: SN
authors: Campion
authors: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT, United States.
authors: John M
authors: JM
authors: Marcek
authors: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT, United States.
authors: Steven W
authors: SW
authors: Kumpf
authors: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT, United States.
authors: Robert E
authors: RE
authors: Chapin
authors: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT, United States.
authors: Christopher
authors: C
authors: Houle
authors: Drug Safety Research and Development, Pfizer Worldwide Research & Development, Groton, CT, United States.
authors: Gregg D
authors: GD
authors: Cappon
mesh_terms: D000375:Aging; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D007265:Inhibins / Q000097:blood; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*; D012741:Sexual Maturation; D013737:Testis / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology
chemical_list: C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; C422364:inhibin B; D007265:Inhibins
keywords: Drug transporter; Immaturity; Rat; Testis; mGluR5