Effects of multiple doses of cyclophosphamide on mouse testes: Accessing the germ cells lost, and the functional damage of stem cells

• Published in: Reproductive toxicology (Elmsford, N.Y.) Vol. 32; no. 4; pp. 395 - 406
• Main Authors: Drumond, Ana Luiza, Weng, Connie C., Wang, Gensheng, Chiarini-Garcia, Helio, Eras-Garcia, Leticia, Meistrich, Marvin L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.12.2011; Elsevier
• Subjects: Animals; Antineoplastic Agents, Alkylating - administration & dosage; Apoptosis; Biological and medical sciences; Cell Differentiation - drug effects; Cell Survival - drug effects; Cyclophosphamide; Cyclophosphamide - administration & dosage; Embryology: invertebrates and vertebrates. Teratology; Fundamental and applied biological sciences. Psychology; In Situ Nick-End Labeling; Male; Medical sciences; Mice; Mice, Inbred C57BL; Seminiferous Epithelium - cytology; Sperm Count; Spermatogenesis - drug effects; Spermatogonia - cytology; Spermatogonia - drug effects; Spermatogonia - transplantation; Spermatogonial stem cells; Teratology. Teratogens; Testis; Testis - cytology; Testis - drug effects; Toxicology; p.o; Testis; Cyclophosphamide; CY; Expt; i.p; HRLM; Mice; Pl and preL; Spermatogonial stem cells; GCNA-1; SHC; Antineoplastic agent; Stem cell; Rodentia; Germinal cell; Testicle; Male genital system; Multiple dose; Alkylating agent; Oxazaphosphinane derivatives; Vertebrata; Mammalia; Mouse; Nitrogen mustard; Animal; Lesion
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2011.09.010

► Effects of cyclophosphamide in stem spermatogonia. ► Recovery of spermatogenesis evaluated in situ and after transplantation. ► Stem cells showed good recovery in situ. ► Poor recovery after transplantation. ► Cyclophosphamide caused stem cell depletion and functional damage. Spermatogenesis is sensitive to the chemotherapeutic drug cyclophosphamide, which decreases the patients’ sperm count. Since the recovery of fertility is dependent on regeneration from stem cells, in the present study we evaluated the ability of cyclophosphamide-exposed stem spermatogonia from mice to regenerate spermatogenesis in situ and after transplantation. When seven doses of cyclophosphamide were given at 4-day intervals, the differentiating germ cells were largely eliminated but ∼50% of the undifferentiated type A spermatogonia remained. We monitored the recovery and found that sperm production recovered to 64% of control within the time expected. When the cyclophosphamide-surviving spermatogonia were transplanted into recipient mice, recovery of spermatogenesis from the cyclophosphamide-exposed donor cells was observed, but was reduced when compared to cells from cryptorchid donors. Thus, multidose regimens of cyclophosphamide did not eliminate the stem spermatogonia, but resulted in cell loss and residual damage.