The overall goal of the proposed research is to determine in a specific target tissue, such as mouse skin, the early critical events in polycyclic aromatic hydrocarbon (PAH) carcinogenesis. We will continue to use as our model system the initiation-promotion protocol for the induction of skin tumors in mice. Pursuant to this goal, we will investigate: 1) The activation and detoxification of benzo(a)pyrene (BP) and 7,12-dimethylbenz(a)anthracene (DMBA) in mouse epidermis both in vivo and epidermal cells in culture from inbred strains of mice selectively bred for susceptibility and resistance to two-stage carcinogenesis using either DMBA-TPA or BP-TPA; 2) the interaction and persistence of binding of BP, DMBA, and their ultimate carcinogenic forms to nuclear macromolecules (DNA, RNA and protein) of various subpopulations of epidermal cells; the specificity of interaction of PAH's to subpopulations of epidermal cells will be mainly assessed through the use of carcinogenc (+)-anti diol-epoxide of BP [(+)-anti-BPDE] and the noncarcinogenic (-)-anti diol-epoxide of BP [(-)-anti-BPDE]. We will also make use of the skin tumor sensitive and resistant strains of mice in these studies. 3) The skin tumor initiating and promoting activities of various metabolites of PAH's especially BP and DMBA; 4) the reason(s) for the altered sensitivity to skin carcinogenesis in the inbred strains of mice; is the altered sensitivity related to tumor initiation and/or promotion? The proposed studies should give us a better understanding of PAH carcinogenesis by a) giving insight into what metabolite(s) of carcinogenic PAH's are responsible for their skin tumor initiating and promoting activities, b) some insight into the genetics of skin carcinogenesis, c) some insight into the critical population of epidermal cells involved in skin carcinogenesis and d) some insight into the critical macromolecule(s) within the target cells.
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