DNA ADDUCTS AS MOLECULAR DOSIMETERS OF GENOTOXINS

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Exposure to genotoxic agents can occur from av variety of occupational and environmental sources. Enzymatic activation of these agents results in the formation of electrophiles which can subsequently react to form DNA adducts. The formation of DNA adducts is believed to play an important role in the activation of human oncogenes and the initiation of cancer. In these studies we will study the activation of benzene to form DNA damage. The specific aims of this proposal are to investigate; 1. the formation and repair of DNA adducts, and 8-oxodeoxyguanosine in bone marrow and peripheral blood leukocytes of B6C3F1 mice treated with benzene by itself or in combination with other agents. 2. the formation of DNA damage in myeloid fractions of bone marrow of B6C3F1 mice and in collaboration with Projects 4 and 5 blood progenitor cells and peripheral blood cultures will be treated in vitro with benzene metabolites. 3. with Project 9, the dose response relationships between DNA adduct formation and reproductive, and developmental responses in aquatic organisms., 4. the formation of lacI mutations in the bone marrow ob Big Blue B6C3F1 mice treated with benzene. 5. with project 3, to optimize the procedures for structural identification of DNA adducts detected by 32P-postlabeling and identification of the structures of the DNA adducts formed by the benzene metabolites. These studies will provide a better understanding of the application of DNA adduct measurements as a molecular dosimeter for exposure to genotoxic agents.