Effects of Testosterone on Cell Proliferation and Apoptosis in BBN-Induced Mouse Urinary Bladder Carcinogenesis

Human bladder cancer is nearly 3 times more common in men than in women. In general, the sex difference in incidence of human bladder carcinoma is considered to be due to industrial and environmental carcinogens or other factors, though there is no clear evidence supporting this. We suspected that the sex difference in incidence of bladder carcinoma might be due to the effects of testosterone. We investigated the effects of testosterone on mouse bladder arcinogenesis by using immunohistochemical staining and terminal-deoxynucleotidyl-transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL). A total of 94 four-week-old male mice were divided into 3 groups. In Group I, castration was carried out, then 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was administered until the end of the experiment. In Group II, 0.05% BBN was administered similarly, without castration. In Group III, 0.05% BBN was administered similarly, without castration, and 3 mg/kg of testosterone was injected intramuscularly weekly from the beginning of the experiment. All mice were cystectomized at the end of the experimental period to investigate the incidence of bladder cancer, and immunohistochemical staining and TUNEL were performed to examine the correlation between cell proliferation and apoptosis. Among the 3 groups, occurrence of bladder tumor was most frequent in Group III, and tumor induction time was the shortest. The proliferation index for tumors significantly increased as the stage and grade progressed. On the other hand, the apoptotic index for tumors significantly decreased. The proliferation index was the highest in Group III and the lowest in Group I. A significant difference in the proliferation index was observed among the 3 groups. No significant difference was observed in the apoptotic index among the 3 groups. Our results indicate that the effect of testosterone on mouse bladder carcinogenesis is more significantly related to cell proliferation than to suppression of apoptosis, with the result that testosterone promotes the occurrence of BBN-induced mouse bladder carcinomas.