We have shown some forms of Se reduce DNA binding and formation of specific adducts when 7,12- dimethylbenz(a)anthracene (DMBA) is added to cultures of rat mammary epithelial and mouse embryo cells. Such results are consistent with data showing Se is able to inhibit the initiation phase of DMBA carcinogenesis. The proposed studies will determine if similar effects are observed in the intact rat given supplemental Se, what factors modify the response to Se and to correlate these adduct patterns with ultimate tumor formation. Studies using isolated mammary cells from rats fed identical diets will be used to establish a valid in vitro/ in vivo model and for evaluation of the mechanism by which selenium inhibits the initiation phase of carcinogenesis. A variety of in vivo and in vivo/ in vitro studies will evaluate the quantity and form of dietary Se and dose of DMBA on binding and adduct formation in mammary tissue. A post label 32p assay will be developed for the sensitive determination of DNA adducts. The decrease in anti- dihydrodiol adducts caused by Se appears to relate to reduced induction of enzyme(s). Additional studies will examine the effects of selenium upon the metabolism profiles of DMBA to help locate specific sites were Se may inhibit. Metabolites of DMBA and related compounds will be used to verify the site appearing most affected by Se. Sufficient rats will be fed the experimental diets and given DMBA to allow for comparison of specific changes in binding and adduct pattern during initiation upon the final tumor incidence and total tumor number. These studies will also correlate the influence of selective changes in DMBA metabolites and in the adducts that bind to DNA with ultimate mammary tumor development. These studies will likely have broad implications with various carcinogens requiring metabolic activation.
