OXIDATIVE INJURY TO DNA AND NON-GENOTOXIC CARCINOGENESIS

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The goal of this project is to characterize mutation spectra in strain A heterozygous B6C3F(1) transgenic mice using a lambda ZAP/lacI shuttle vector after treatment with selected non-genotoxic chemical agents, including both nonperoxisomal and peroxisomal proliferation inducers. Endogenous oxidative injury to cellular DNA is extensive. This damage may contribute to spontaneous mutation rates that may result in "initiated" cells. These "initiated cells" may be fixed and clonally expanded (multistage carcinogenesis) by cellular proliferation induced by exposure to non-genotoxic toxic chemicals resulting in an increase in tumor incidence at the site(s) of toxic injury that caused the cellular proliferation. By using a new transgenic mouse that employs a lambda shuttle vector with lacI target gene we propose to expose transgenic mice to selected non-genotoxic mouse carcinogens. After appropriate treatment regimens the transgene will be recovered from treated mice by exposing the isolated mouse tissue genomic DNA to in vitro packaging extracts and culturing the rescued phage. Phage with mutations in the lacI target gene form colored plaques, while non-mutated target gene form colorless plaques. Precise identification of adduct(s) and/or mutations shall be determined and correlated with agents known to induce DNA damage (prooxidants, peroxisome proliferators, etc.) and nongenotoxic and non-carcinogenic chemical treatments. Using this research strategy we should be able to provide some insight on endogenous oxidative damage to DNA and non-gentoxic carcinogenesis.