Advances in analytical methods have made it possible to quantitate DNA adducts in a variety of tissues and cells of experimental animals and humans and to begin to relate these biomarkers to extent of exposure and potential risk for cancer. These DNA adducts arise from exogenous exposure to chemicals as well as from endogenous processes. Modulation of the repair pathways that exist for both exogenous and endogenous DNA adducts by environmental exposure to xenobiotics could play an important role in the induction of neoplasia in experimental animals exposed to Maximum Tolerated Doses, and in individuals exposed to hazardous wastes. The long range goal of this project is to examine the formation and repair of both endogenous and exogenous DNA adducts associated with environmental chemical exposures in order to identify mechanisms that are of critical importance for the accurate prediction of human risk for cancer. We will determine if exposure to environmental carcinogens (1,1,2-trichloroethylene, 1,1,2,2- tetrachloroethylene, 1,1,2-trichloroethane, chloroform, and carbon tetrachloride) induces or modulates the formation and/or repair of cyclic DNA adducts. These studies will quantitate adducts that are formed by direct alkylation of DNA by the test chemical, as well as similar adducts that arise from oxidative stress such as lipid peroxidation. We will examine dose-response relationships for adduct formation and repair to determine if important nonlinearities exist that could affect cancer risk assessments. We will continue to develop ultrasensitive and highly specific methods for quantitating DNA adducts. In collaboration with the Chemistry Core, we will further develop applications of mass spectrometry to DNA adducts. Differences in DNA repair could greatly affect age, tissue and cell type susceptibilities to mutagenesis and carcinogenesis. We will measure the expression of N-methylpurine-DNA-glycosylase (MPG) mRNA in a variety of tissues and cells from rodents and humans using quantitative RT/PCR. The effect of exposure to environmental carcinogens on MPG activity will be examined and correlated with DNA adducts. Since MPG excises adducted bases, the utility of monitoring urinary excretion of etheno adducts as an index of exposure will be investigated. We will determine the molecular dose of the dinitrotoluene DNA adducts and the extent of cell proliferation, and relate these effects to hepatocyte initiation. This effort will provide critical information on dose- response, ranging from the bioassay doses and extending down two orders of magnitude. Data from this research project will greatly improve the scientific bases needed to improve the accuracy of biologically-based low dose risk estimates for these important Superfund chemicals.
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