DNA ADDUCTS AS MOLECULAR DOSIMETERS OF GENOTOXINS

暴露于遗传毒性剂可能发生在各种职业和 环境来源。 这些试剂的酶促活化导致 形成亲电体，其随后可反应形成DNA 加合物 DNA加合物的形成被认为是重要的 在人类致癌基因的激活和癌症的起始中起作用。 在 这些研究我们将研究苯的活化形成DNA损伤。 这项建议的具体目的是进行调查; 1. DNA加合物和8-氧代脱氧鸟苷的形成和修复 B6 C3 F1小鼠的骨髓和外周血白细胞， 苯本身或与其它试剂组合。 2. 骨髓细胞DNA损伤的形成 B6 C3 F1小鼠以及与项目4和5合作的血液祖细胞 细胞和外周血培养物将在体外用苯处理 代谢物。 3. 与项目9，DNA加合物之间的剂量反应关系， 水生动物的形成和生殖及发育反应 有机体， 4. 大蓝B6 C3 F1骨髓中lacI突变的形成 用苯处理的小鼠。 5. 与项目3，以优化程序的结构 通过32 P-后标记检测DNA加合物的鉴定， 苯形成的DNA加合物的结构鉴定 代谢物。 这些研究将使人们更好地了解DNA的应用 加合物测量作为暴露于遗传毒性的分子剂量计 剂.

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.