Sex hormones and pituitary hormones are known to modify chemical carcinogenesis in mammals. The hormones may act at the initiation stage or at the promotion stage of carcinogenesis. In rainbow trout, 17 beta-estradiol has been shown to be a promoter of aflatoxin B1-induced carcinogenesis. However, in this species, little or no information is available regarding the effects of hormones especially those of pituitary origin at other stages of chemical carcinogenesis. Can hormones modify the activation and detoxication of carcinogens in trout as in mammals? Can the binding of carcinogens to trout liver DNA be modified by hormone pretreatment? These are some of the questions to be addressed in this project. The applicant hypothesizes that in the rainbow trout different peptide hormones and glucocorticoids affect the metabolism and covalent binding index of carcinogens by regulating the expression and activities of enzymes involved in activation and detoxication of chemical carcinogens. This hypothesis will be tested by carrying out experiments with the following specific aims: 1) Examine the effect of in vivo administration of ACTH, gonadotropin, thyroxine, growth hormone, and cortisol on the in vitro metabolism of aflatoxin B1 (AFB1), dimethylnitrosamine (DMN), and 7,12-dimethylbenz(a)anthracene (DMBA) by microsomal and mitochondrial preparations of liver and head kidney from rainbow trout. 2) Determine whether the hormones affect the expression of cytochrome P450 mRNAs or P450 isozymes involved in AFB1, DMN, and DMBA metabolism in trout liver. 3) Determine the influence of glucocorticoids and growth hormone on the induction of hepatic cytochrome P450 in trout treated with beta-napthoflavone ( BNF); dexamethasone or pregnenolone 16 beta-carbonitrile (PCN); or phenobarbital (PB). 4) Determine the effect in vitro of cortisol on the hepatic microsomal cytochrome P450 dependent metabolism of AFB1, DMN, and DMBA in trout. 5) Determine the role of hormones on the levels and activities of cytosolic and microsomal glutathione S-transferase (GSH-t) in trout liver. 6) Determine the effect of the hormones on the excretion and in vivo binding of AFB1, DMN, and DMBA to DNA and protein in liver of trout. 7) Assess the effect of hormones on hepatic tumor incidence in trout given AFB1. These studies should provide the necessary information regarding the role of hormones on chemical carcinogenesis in trout and should improve out understanding of some of the mechanisms by which hormones modify carcinogenesis in this animal model.
