The objective of this research program is to determine the mechanisms) by which several nonalternant polycyclic aromatic hydrocarbons (PAH) are activated to carcinogens. This research program will focus on the environmental pollutants: benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)fluoranthene, indeno-(1,2,3-cd)pyrene, and 2- and 3-methylfluoranthene. Several new methods will be developed for elucidating the mechanism(s) of action of these nonalternant PAH. We will use a combination of the classical fluorine-probe approach with 32P post- labelling of DNA adducts as formed in vivo in mouse skin to determine those positions in these molecules which are critically associated with their genotoxic activity. With synthetic standards and 32P post-labelling, we will determine the extent to which suspect proximate and ultimate carcinogenic metabolites contribute to the DNA adducts formed from their parent hydrocarbon. The chemical nature of the post-labelled DNA adducts formed will be partially established by their chromatographic properties on HPLC and their retention using immobilized boronate chromatography. The possibility that differences in DNA adduct formation or persistence are correlated with know sex differences in tumorigenic activity will also be determined. Bioassays in newborn mice and initiation promotion bioassays on mouse skin will be among the principal in vivo bioassays which will be employed to evaluate suspect proximate and ultimate carcinogenic metabolites. This research program will provide data essential for analysis of their DNA adducts in peripheral lymphocytes as well as establish the appropriate methodology for the analysis of the principal hemoglobin bound adducts of these nonalternant PAH. The methods which developed in this research program will be of general use in elucidating the mechanism of action of other genotoxic agents and in developing suitable indices of human exposure.
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