MOLECULAR BIOMARKERS OF EXPOSURE/ENVIRONMENTAL CARCINOMA

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The overall objective of this research program is the systematic development of qualitative and quantitative data bases relating markers of exposure and biologically effective dose (carcinogen adducts in blood proteins and cellular DNA) to selected markers of biological response (mutations or other DNA sequence changes in specific genes; alterations in suppressor gene activity) and the induction of tumors in well characterized animal models of chemical carcinogenesis. Studies in experimental models will utilize analytical procedures and approaches that will be directly applicable in parallel studies in cells and tissues of humans environmentally exposed to the same chemical carcinogens and mutagens. The program will focus on four carcinogens to which human exposure at low levels is essentially unavoidable, and that have been identified as established risk factors for human cancers through epidemiologic evidence (aflatoxin B1, 4-aminobiphenyl) or suspected risk factors on the basis of their carcinogenicity in animals (methylIQx and urethane). The program will consist of five interactive projects within three areas of emphasis. Project I, Molecular dosimetry of carcinogens and mutagens concerns protein and DNA adducts as markers of systemic and biologically effective doses. In the second area of emphasis, alterations in gene structure as markers of early biological effects, three related projects involve studies of in vivo mutations occurring within specific gene sequences. Project II will analyze Mutational pathways in carcinogenesis: spontaneous and carcinogen-induced mutation in rat liver. Project III has the objective of evaluating relationships between specific DNA adduct structures and mutations within defined DNA sequence contexts through characterization of Specificity of mutagenesis by 4-aminobiphenyl and other aromatic N-aromatic compounds. Project IV will focus on Structural alterations in specific oncogene and tumor suppressor gene sequences in chemical carcinogenesis. the third area of emphasis changes in tumor suppressor gene function as markers of early biological effects, consists of Project V, in which Alterations of tumor suppressor gene activity in chemical carcinogenesis will be investigated. The initial phase of the program, which will build upon an extensive information base already created for certain elements of the program by prior collaborative research efforts of this group of investigators, will emphasize generation of specific critical data elements not yet available in experimental animal models. Concurrently, applications of the same approaches to studies in exposed humans already in progress through existing collaborations will be continued and expanded whenever possible. Comprehensive comparisons of dose relatedness and other characteristics of responses in the experimental systems with the same parameters in exposed human subjects will greatly enhance assessment of health hazards resulting from environmental exposures to these carcinogens.