Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 12). Effects of cyclophosphamide on spermatogenesis.
To determine what is an appropriate administration period for evaluation of the testicular toxicity of cyclophosphamide, the compound was administered orally to male Crj:(CD)SD rats at doses of 5, 10, 20 and 40 mg/kg/day for 2 weeks and at doses of 2.5, 5 and 10 mg/kg/day for 4 weeks. All animals in the 2-week treatment group given 40 mg/kg/day died during the treatment period. After repeated dosing, weights of testes and epididymides did not change significantly in either 2-week or 4-week treatment groups. On conventional histopathological examination, changes in spermatogonia were too subtle to allow simple quantitative evaluation. Therefore the quantitative analysis described by Matsui et al. (1995) was employed. After 4-weeks treatment all types of germ cells decreased significantly in all stages of seminiferous tubules examined in the 10 mg/kg/day group. Spermatogonia type A in all stage seminiferous tubules examined and spermatogonia type B in stage V seminiferous tubules decreased significantly in the 5 mg/kg/day group. With 2-weeks treatment, spermatogonia type A in all stage seminiferous tubules examined were similarly decreased significantly in 10 mg/kg/day or more groups. Spermatogonia type B and pachytene spermatocytes in stage V, preleptotene spermatocytes in stage VII and zygotene spermatocytes in stage XII were decreased in 20 mg/kg/day group. Sertoli cells and the Leydig cells and epididymides were not affected in any treatment group. In conclusion, testicular toxicity induced by cyclophosphamide could be detectable after 2-weeks as well as after 4-weeks treatment if precise histopathological examination including quantitative analysis of spermatocytes are conducted.
Watanabe
T
T
Department of Toxicology, Fuji Research Laboratories, Kowa Co., Ltd., 332-1 Ohnoshinden, Fuji-city, Shizuoka 417-8650, Japan.
Yamaguchi
N
N
Akiba
T
T
Tanaka
M
M
Takimoto
M
M
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002452:Cell Count; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012670:Seminiferous Epithelium / Q000187:drug effects / Q000473:pathology; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D018675:Toxicity Tests; D015430:Weight Gain / Q000187:drug effects
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide