Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 10). Testicular toxicity of adriamycin observed 2 and 4 weeks after a single intravenous administration.
The present study was performed to clarify whether toxic effects of the antitumor drug, adriamycin (ADR) on the male genital organ can be adequately detected 2 and 4 weeks after a single intravenous administration in the rat. ADR was intravenously administered once to 10 Crj:CD (SD) male rats/group aged 6 weeks (4-week group) and 8 weeks (2-week group) at doses of 0, 2 and 6 mg/kg. The rats were sacrificed at the age of 10 weeks. For comparison 10 rats/group were killed 2 weeks after a single intravenous administration at the age of 4 weeks (immature group). Saline was administered to control rats. Histopathological examination and a quantitative morphometry were carried out after measurement of testes weights at necropsy. In rats of the 4-week and 2-week groups, mean absolute testicular weight in all groups was significantly decreased. However, changes in mean relative weight were not evident in the 2-week group. Disappearance of seminiferous epithelial cells was observed histopathologically in rats dosed with 2 and 6 mg/kg in the 2-week group. The change was more severe in the 4-week group, when reduction of spermatogenesis and giant cells were also observed at 6 mg/kg. The quantitative morphometry in the 2-week group showed decreases in the numbers of spermatogonia and spermatocytes in stages X and XII at 2 mg/kg, and in the numbers of spermatogonia in all stages and spermatocytes in all stages except stage V at 6 mg/kg. Moreover, the numbers of spermatogonia and spermatocytes in all stages and spermatids in stages II-III and V were decreased with dose related manner in the 4-week group. In contrast, no obvious change in testes weights was apparent in the immature group. However, the numbers of spermatogonia and spermatocytes in all stages were decreased at 6 mg/kg. In conclusion, testicular toxicity of ADR could be detected 2 weeks after a single administration. Susceptibility of the testes of immature rats to ADR might be less than that of older animals.
Tsunenari
I
I
Department of Toxicology & Safety Assessment, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Hyogo 666-0193, Japan.
Kawachi
M
M
Matsumaru
T
T
Katsuki
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D006403:Hematologic Tests; D007275:Injections, Intravenous; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; 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; D004317:Doxorubicin