MONOCLONAL ANTIBODIES SPECIFIC FOR CYCLIC DNA ADDUCTS

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Humans are exposed to a variety of carcinogens and potential carcinogens including acrolein, crotonaldehyde, N-nitrosopyrrolidine, cyclophosphamide, glyoxal, methylglyoxal, N-nitrosomorpholine, N-nitrosodiethanolamine, misonidazole, vinyl chloride, chloracetaldehyde and ethyl carbamate. These compounds are present in the environment, food chain and occupational or medical settings. Exposure to these compounds can lead to the formation of cyclic nucleoside adducts in DNA and or RNA. Current analytical methods are inadequate to detect these adducts in tissues of persons exposed to these compounds. Recently, sensitive immunoassays have been developed for the detection of a number of DNA adducts. Some of these assays have been used to screen humans exposed to environmental carcinogenes. In this project we intend to develop monoclonal antibodies specific for 6 cyclic nucleoside adducts which are formed by the above mentioned compounds. These monoclonal antibodies will be used in the development of sensitive immunoblotting assays for the detection of these adducts in DNA from tissues of animals, and eventually humans, exposed to these compounds. The applicability of these assays to human studies will be demonstrated by assaying DNA isolated from peripheral blood and liver of F344 rats exposed to these compounds. These experiments will establish the level of exposure to these compounds necessary for the formation of detectable levels of DNA adduct and establish the validity of using DNA from peripheral blood white cells as an indicator of exposure to these compounds. The development of these highly sensitive immunoassays represents a valuable approach toward 1) understanding the mechanisms of adduct formation and their role in tumor formation and 2) monitoring and controlling such exposures and preventing their deleterious effects.