1-Nitropyrene (1-NP) is considered one of the major components found in numerous environmental sources and is tumorigenic in mouse lung and liver, in rat mammary glands in hamster trachea and lung. 6-Nitrochrysene (6-NC), which is carcinogenic in newborn mouse lung and liver, is the most active compound tested in this assay, more active than benzo[a]pyrene. In rat mammary glands and in newborn mouse liver and lung, multiple DNA adducts were detected following administration of 1-NP. In contrast one major adduct was detected in newborn mouse liver and lung following administration of 6-NC. Based on our results we hypothesized that the major metabolic activation pathway of 1-NP in newborn mice occurs via nitroreduction and in Sprague-Dawley rats via ring oxidation; both pathways are essential for the metabolic activation of 6-NC in newborn mice. In order to clearly define the biological activities of these compounds, assess the possible risks associated with human exposure, and test our hypothesis our aims are: 1) Elucidate the structures of the major DNA adducts detected in newborn mouse liver and lung and in rat liver and mammary glands following the administration of 1-NP; 2) Compare the tumorigenic activity of 1-NP and its ring oxidized metabolites in a) Newborn mice, b) Newborn female Sprague-Dawley rats; 3) Develop sensitive analytical methods for detecting urinary metabolites of 1-NP in humans; 4) Compare the tumorigenic activities of 6-NC and its metabolites derived from nitroreduction and ring oxidation in newborn female Sprague-Dawley rats; 5) Compare the tumorigenic activities of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-aminochrysene (1,2-DHD-3,4-oxide-6-AC) and 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene (1,2-DHD-3,4-oxide-C) in newborn mice; 6) Establish the relationship between the levels of DNA adducts in newborn mouse lung and liver and the capacity for tumor induction by 1,2-DHD-3,4-oxide-6-AC and 1,2-DHD-3,4-oxide-C.
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