Epidemiologic and animal model studies suggest that dietary intake of certain types of fat plays a role in the risk of colon cancer development. The long term objective is to understand the modulating effects of amount and types of fat differing in fatty acid composition in colon tumor promotion and progression. Specifically, it is proposed to investigate the mechanism(s) of types and amount of dietary fat such as corn oil (CO) and menhaden fish oil (FO) rich in omega-6 and omega-3 fatty acids, respectively and mixed lipid high in saturated fats. Recent studies indicate that high intake of certain dietary fats has been associated with an alteration in the production of secondary bile acids, diacylglycerols (DAG) and fatty acids in the colonic contents which could enter the colonic mucosa and activate several cellular events including protein kinase C (PKC), arachidonic acid metabolism and ras p21, to cite a few. These biochemical and molecular events induced by types and amount of dietary fat became a basis to conduct in-depth studies. Specifically, it is proposed to determine the effect of diets high and low in CO and high in FO and mixed lipids on the production of DAG by the gut microflora, fatty acid composition of colonic luminal (fecal) DAGs, colonic mucosal and tumor up-regulation and down- regulation of PKC isozymes, cyclooxygenase isozymes, and farnesyl protein transferase during promotion and progression stages of colon carcinogenesis. At 5 weeks of age, groups of male F344 rats will be fed low-fat AIN-76A diet containing CO (LFCO). At 7 weeks of age, groups of animals will be treated with two weekly s.c. doses of azoxymethane (AOM) or normal saline (vehicle and one day later, they will be transferred to high fat diets containing CO (HFCO) or FO (HFF0). One group will be continued on LFCO diet. Then the groups of animals will be sacrificed at weeks 1, 12, 36 and 50 after AOM or saline treatment. Prior to sacrifice, daily stool samples for one week will be collected from each animal and analyzed for fecal DAG mass and their fatty acid composition. Cecal contents will be used to determine the production of DAG by intestinal microflora. Colon mucosa harvested at weeks 1, 12, 36 and 50 and colon tumors will be used to determine the isoforms of PKC, cyclooxygenase 1 and 2, and farnesyl-protein transferase. These biochemical and molecular parameters of animals treated with AOM or saline and fed the experimental diets will be analyzed statistically to determine the significance of difference. It is hoped that the results generated from the proposed mechanistic study will strengthen the rationale for primary and secondary prevention of colon cancer through dietary modulation.
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