Hepatocarcinogenesis represents an ongoing process which can be divided into initiation, promotion, and progression, all of which require a number of carcinogenic dose- and time-dependent events. The basophilic foci are the first morphologic entities which develop during the phase of promotion, and represent the earliest putative precursors of the late emerging carcinomas. The kinetics of hepatocarcinogenesis induced in the intact infant mouse by a single diethylnitrosamine (DEN) treatment indicated that twice as many time-dependent events were required for the development of hepatocellular carcinomas than basophilic foci. The process of hepatocarcinogenesis proceeds at a faster rate in male than in female mice. The change in the androgen/estrogen (A/E) ratio by gonadectomy can modify the onset and the rate of development of the basophilic foci and the hepatocellular carcinomas. The high A/E ratio accelerates, while the low ratio delays the development of hepatocellular adenomas and carcinomas.
The specific aim of the proposed studies is to test the hypothesis that sex hormonal environment modifies the kinetics of hepatocarcinogenesis by influencing the time-dependent events by its effect upon the growth rate and the rate of progression of the basophilic foci and the subsequent lesions to carcinomas. It is anticipated that orchidectomy in conjunction with estrogen treatment and ovariectomy with testosterone treatment would modulate carcinogenesis more effectively than gonadectomy per se. The experimental model, which has been developed and defined in our laboratory, may test the above hypothesis by exploring the effects of the change in the hormonal environment on the number, size, volume, morphologic nature, and the time at which specified lesions emerge in relation to the carcinogenic dose. B6C3F1 mice will be treated with single dose levels of DEN at 15 days of age and one-half of the males and females will be gonadectomized at 4 weeks. One subset of orchidectomized males will be administered estrogen, and one set of ovariectomized females will be treated with testosterone. Groups of animals will be killed at specified time intervals and dose-response, time-response, time-dose relationships, and the growth of the basophilic foci, hepatatocellular adenomas and carcinomas will be evaluated. The stereologic morphometric quantitation of lesions will be conducted by direct analysis of the microscopic images by means of a digitizercomputer system using a specially developed statistical program for estimating lesions in 3-dimensional space from observations on 2-dimensional planes.
