HORMONAL REGULATION OF CARCINOGENESIS IN TROUT

DESCRIPTION: 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.