Laboratory animals have been extensively used to study the mechanisms of cutaneous tumorigenesis by polyaromatic hydrocarbons; but the significance of these studies on human skin is unknown. We have been successful in establishing human skin xenograft, using neonatal foreskins, on nude mice further immunosuppressed by splenectomy. Our several years of experience in studying the metabolism of BP as well as BPDE- DNA adducts in human cells in vitro, permits us to extend our studies to the in vivo system of human skin xenografts. We proposed to undertake a detailed investigation of the metabolism of BP in the epidermis and dermis of the xenograft. The organic soluble metabolites will be extracted with ethyl acetate, separated by HPLC and identified and quantitated using authentic standards. Modification of the DNA in the epidermal cells and dermal cells will be measured by the 32P post-labelling method. Persistence of the adducts over a period of time will also be investigated. The metabolism, DNA modification and persistence of adducts, in the dermis and epidermis of human xenografts when treated with B(a)P in the presence of benzamide and its analogues will also be studied. Benzamide, a poly-ADP-ribose polymerase inhibitor, has been shown, by us, to interfere with the formation of critical DNA bases to form site specific DNA adducts, without affecting the extent of DNA modification. We expect that the above mentioned studies should provide us with information on how suspect environmental genobiotics act on human cells in a functional tissue system on a surrogate host permitting us further insight into mechanisms of human environmental induced genotoxicity.
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