Sex differences in rat liver carcinogenesis are known following exposure to several hepatocarcinogens, including 2-acetylaminofluorene (2-AAF) and aflatoxin B1 (AFB1). Furthermore, hormones are important modifiers of rat liver carcinogenesis. Most previous studies focus on the importance of sex hormones in this process. Results from our laboratory indicates that also pituitary hormones are capable of modifying liver carcinogenesis. We hypothesize that sex hormones influence rat liver carcinogenesis via a hypothalamo-pituitary-liver axis, as we have previously demonstrated for the sex differentiated hepatic metabolism of steroid hormones. The mechanism by which hormones influence the various stages of rat liver carcinogenesis are unknown. Do the sex differences occur during initiation and/or during promotion? Is the sexual dimorphism in response to carcinogen treatment due to a sexually differentiated metabolism of the carcinogen, leading to differences in mutagenicity and/or toxicity of the carcinogen or are other mechanisms also involved? Our aim is to try to answer these questions by investigating the effects of pituitary hormones on early and later stages of liver carcinogens in the rat in vivo, as well on the in vitro rat liver metabolism of hepatocarcinogens, especially 2-AAF. The following experiments will be carried out concerning pituitary regulation of chemical carcinogenesis in rat liver in vivo: 1. Effects of continuous infusion of bovine GH and ovine prolactin on the 2-AAF selection in the RM-model. 2. Will neonatal and adult castration of male rats, with or without testosterone substitution, alter the response to 2-AAF selection in the RH-model? 3. Effects of in vivo inhibition of the N-OH-2-AAF sulfotransferase on the 2-AAF selection in the RM-model. 4. Influence of pituitary hormones on the initiation of rat liver carcinogenesis with AFB1 and 2-AAF. 5. Effects of hypophysectomy, with or without hormonal substitution, on the promotion/progression of rat liver carcinogenesis. 6. Studies concerning sex differences in, and hormonal regulation of, the mitoinhibitory and toxic effects of 2-AAF. A deeper knowledge concerning mechanisms behind hormonal control of liver carcinogenesis may be of relevance also for the understanding of the pathogenesis of other hormone dependent cancers such as breast and prostatic carcinoma.
