Epidemiological data reveal that the incidence of liver cancer is markedly higher in men than women. To clarify the mechanism responsible for the induction of higher incidence of liver tumors in male animals, we investigated the modifying effect of sex hormones in diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis. F344 male rats (n=120) were divided into two experiments, experiment I (Exp I) and experiment II (Exp II). In each experiment, 60 rats were randomly allocated into four groups. The mini-osmotic pumps containing doses of 47.5 mg (Exp I) or 23.75 mg (Exp II) of DEN were inserted into the abdominal cavity of each animal to initiate liver carcinogenesis. Animals in group 2 were castrated one week prior to DEN treatment, and animals in groups 3 and 4 were treated with 1 or 10 µg of estradiol-3-benzoate (EB), respectively, one week prior to DEN treatment. Animals in group 1 were treated with DEN alone and sham-operated at the same time. All animals were sacrificed 26 weeks after DEN treatment. In Exp I, liver tumor incidence of group 3 decreased significantly compared with that of group 1 (p<0.05), and tumor multiplicities of groups 2, 3 and 4 were decreased significantly compared to that of group 1 (p<0.01). In Exp II, tumor incidence of group 3 was significantly different (p<0.05) when compared to that of group 1. Immunohistochemical expression of ERα was shown in normal appearing cells, but not in tumor cells. Western blot analysis confirmed that ERα expression was higher in normal liver tissue compared to tumor tissues. Taken together, we conclude that castration or EB treatment has an inhibitory effect in DEN-induced hepatocarcinogenesis in F344 rats. The reason for ERα loss in tumor cells should be further elucidated.

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