Imatinib has deleterious effects on differentiating spermatogonia while sparing spermatogonial stem cell self renewal

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2011-05, Vol.31 (4), p.454-463
• Main Authors: Heim, Crystal, Minniear, Kayla, Dann, Christina Tenenhaus
• Format: Article
• Language: English
• Subjects: Animal Testing Alternatives; Animals; Antineoplastic Agents - toxicity; Benzamides; Biological and medical sciences; Cell Proliferation - drug effects; Cells, Cultured; Coculture Techniques; Differentiation; Drug test; Embryology: invertebrates and vertebrates. Teratology; Fertility; Fundamental and applied biological sciences. Psychology; Imatinib Mesylate; Male; Medical sciences; Mice; Mice, Nude; Molecular Targeted Therapy - adverse effects; Piperazines - toxicity; Protein Kinase Inhibitors - toxicity; Proto-Oncogene Proteins c-kit - antagonists & inhibitors; Proto-Oncogene Proteins c-kit - metabolism; Pyrimidines - toxicity; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor beta - metabolism; Self renewal; Spermatogenesis - drug effects; Spermatogonia; Spermatogonia - drug effects; Spermatogonia - enzymology; Spermatogonia - pathology; Spermatogonia - transplantation; Spermatogonial stem cells; Stem Cell Transplantation; Stem Cells - drug effects; Stem Cells - enzymology; Stem Cells - pathology; Teratology. Teratogens; Time Factors; Toxicity Tests; Toxicology
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2010.12.056

Imatinib mesylate is among a growing number of effective cancer drugs that provide molecularly targeted therapy; however, imatinib causes reproductive defects in rodents. The availability of an in vitro system for screening the effect of drugs on spermatogenesis would be beneficial. The imatinib targets, KIT and platelet derived growth factor receptor beta (PDGFRB), were shown here to be expressed in “germline stem” (GS) cell cultures that contain spermatogonia, including spermatogonial stem cells (SSCs). GS cell cultures were utilized to determine whether imatinib affects SSC self renewal or differentiation. GS cells grown in imatinib retained self renewal based on multiple assays, including transplantation. However, growth in imatinib led to decreased numbers of differentiated spermatogonia and reduced culture growth consistent with the known requirement for KIT in survival and proliferation of spermatogonia. These results build upon the in vivo studies and support the possibility of utilizing GS cell cultures for preclinical drug tests.