The goals of this investigation are to determine whether isocaloric diets high in n-3 relative to n-6-fatty acids will have the chemopreventive effect in mouse skin carcainogenesis of reducing tumor initiation and promotion. It will be determined whether isocaloric diets containing 10% fat as either high n-6, n- 3, both or predominately saturated fatty acids alter tumor response to a metabolism-requiring carcinogen, 7,12- dimethylbenz(a)anthrene (DMBA) and a direct acting carcinogen, N-methyl-N-nitro-N-nitrosoquanidine (MNNG). Dietary effects on carcinogen binding to DNA and metabolite profiles in the epidermis will also be measured. The effect of these diets will also be studied with respect to tumor promotion, using 12-0- tetradecanyolphorbol-13-acetate (TPA) and benzoyl peroxide, as well as several parameters believed to be important to the promotion process: hyperplasia, inflammation and ornithine decarboxylase induction. Since it is expected that high n-6 fatty acid diets will enhance promotion, tumor experiments will be done in which the major arachidonate metabolites are applied to mice on the high n-3 fatty acid diets to attempt to partially restore promotion. Studies will also be carried out to determine whether the fatty acid effects seen above are epidermal in origin rather than due to changes in systemic parameters such as the immune system. This will be done by culturing mouse epidermal cells in a defined medium containing n-6 and/or n-3 fatty acids and measuring several parameters of growth and differentiation. Finally, it will also be determined if the different fatty acid diets affect the responsiveness of the immune system to challenge. Several parameters will be measured: delayed hypersensitivity, mitogen responsiveness, mixed lymphocyte reactions and natural killer cell activity.
