Nitropolynuclear aromatic hydrocarbons (NPAH) are widespread environmental carcinogens which may pose a significant human health hazard. 1-Nitropyrene (1-NP) is one of the most frequently detected of the carcinogenic NPAH and 6-nitrochrysene (6-NC) is one of the most tumorigenic of the NAPH. It is not known whether the observed tumorigenicity of 1-NP in newborn Sprague-Dawley rats and of 6-NC in newborn mice is due primarily to nitroreduction, ring oxidation or a combination of both pathways. Based on our results and those obtained by others, our hypothesis is that the major metabolic activation pathway of 1-NP and 6-NC is ring oxidation followed by nitroreduction. This pathway would yield several electrophilic intermediates and multiple DNA adducts would be expected. Therefore structural elucidation of those adducts is mandatory in order to understand the specific role of each adduct in carcinogenesis by 1-NP and 6-NC. Thus the proposed methods to test our hypothesis are as follows: (1) We will establish the further metabolic transformation of known mutagenic ring oxidized metabolites of 1-NP particularly with respect to formation of intermediates which can bind to DNA. The structures of the major DNA adducts formed from (3H)1-NP in rat breast (target organ), liver and colon will be elucidated and will be compared with those formed from (3H)1-aminopyrene and (3H)1-nitrosopyrene since the latter compounds are weak or inactive breast carcinogens as compared to 1-NP; (2) The pattern of 6-NC metabolism and DNA adducts profiles in newborn mice will be established and the results will be compared with those of chrysene since the latter compound is inactive as a tumorigen in the liver and lung of newborn mice; (3) Structural elucidation of the electrophilic intermediates and DNA adducts derived from 1-NP and 6-NC will be based on spectral analysis and/or independent synthesis. The results of this study are essential in understanding carcinogenesis induced by 1-NP and 6-NC in rats and mice respectively. In addition new DNA-adducts will be provided as markers in order to be used in assays to study the actual exposure of humans to 1-NP and 6-NC.
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