Humans are continually exposed to a wide variety of chemicals, some of which may act as initiators, promoters, cocarcinogens and/or complete carcinogens. Current evidence suggests that covalent modification of DNA plays a central role in the mechanism of tumor initiation by diverse classes of carcinogenic agents including polycyclic aromatic hydrocarbons (PAH). However, it remains to be determined which DNA-adducts are most important; whether DNA-adducts are removed efficiently or inefficiently thus introducing errors in the DNA; or whether DNA- adducts must persist in the DNA for long periods of time for tumor initiation. The proposed research is designed to further investigate the role of PAH DNA-adduct removal and persistence in relation to skin tumor initiation in mice. Mouse skin is a well known target tissue for PAH and is a widely studied model system for skin carcinogenesis.
The specific aims of the proposal are as follows. The quantitative relationship between the formation of specific hydrocarbon DNA-adducts (especially dAdo adducts) and skin tumor-initiation will be determined. The extent and time course of unscheduled DNA synthesis induced by a variety of PAHs will be examined. We will also examine the rates of removal of specific DNA-adducts (especially dAdo adducts) in relation to skin tumor-initiating potency. Furthermore, we will continue to explore the formation, removal, and persistence of hydrocarbon DNA-adducts in epidermal subpopulations in relation to the biphasic disappearance of DNA-adducts in mouse epidermis. We will further examine the role of DNA replication at the time of tumor initiation by determining the quantitative relationship between specific adduct formation and inhibition of epidermal DNA synthesis and through the use of DNA synthesis inhibitors. Finally, to learn more about the biological, biochemical and molecular effects of specific PAH DNA-adducts, we will prepare site directed dAdo adducts from anti BPDE to be incorporated into a bacterial vector. This approach will allow us to test the hypothesis that specific hydrocarbon DNA-adducts are required early after application for skin tumor initiation.
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