Certain aspects of hepatocarcinogenesis in the infant mouse model

The studies related to the kinetics of hepatocarcinogenesis and the effect of sex hormones upon hepatocarcinogenesis have been presented. The objective was to clarify the carcinogen- and time-dependent events leading to the development of liver tumors and the role of sex hormones regarding the rate of development of focal and nodular liver lesions. Kinetics of hepatocarcinogenesis were evaluated in B6C3F1 mice using the mathematical-graphic approach. Low-dose levels (0.0, 0.3125, 0.625, 1.25, 2.5, and 5.0 micrograms/g body weight) of diethylnitrosamine (DEN) were injected once intraperitoneally into 15-day-old males. Subgroups of 8 to 20 animals were killed from each treatment level at 4 to 6 week intervals. In addition, a series of male and female mice was administered 2.5 micrograms DEN/kg body weight and a fraction of each sex was gonadectomized. The analysis of dose-response data showed first order kinetics (single event) regarding the induction of intermediate basophilic foci (IBF) and hepatocellular carcinomas (HCC). The difference in the transformation probabilities between these two lesions was of 3 orders of magnitude, indicating a qualitative difference between the original events. Time-dose kinetics showed that twice as many time-dependent events were required for the development of HCC than for the development of IBF. Therefore, the carcinogen influenced not only the nature and degree of initiation of hepatocytes but also programmed the rate of cascading events, and the time being the limiting factor of morphologic expression. In relation to the role of sex hormones, the study demonstrated that the male hormonal environment accelerated and the female hormonal environment delayed the rate of focal morphologic expression and neoplastic progression.