Recently a new class of chemicals, the nitrated polycyclic aromatic hydrocarbons (nitro-PAH), have been found to be ubiquitous environmental pollutants. Identified sources for nitro-PAH production include diesel combustion, urban area atmospheres, coal combustion emissions, and possibly cigarette smoke. Some of these compounds are highly mutagenic in short-term mutation assays and several of these compounds including 1-nitropyrene and 3-nitrofluoranthene, two of the more abundant compounds, have been shown to be carcinogenic in animals. Thus, due to the widespread occurrence of these compounds, of prime importance should be to determine to what extent the nitro-PAH contribute to the etiology of human cancers. In previous work, we have shown that in three short-term mutation assays, 1-nitropyrene induces one type of DNA adduct, and the presence of this DNA adduct correlates with the extent of mutagenicity. However, when 1-nitropyrene is incubated with DNA and rat liver microsomes, at least six DNA adducts are detected. Therefore, it is not known how many, or which DNA adduct(s) are responsible for the carcinogenicity noted in laboratory animals. One other abundant nitro-PAH is 3-nitrofluoranthene. This compound is more mutagenic than 1-nitropyrene in short-term mutation assays both in the presence and absence of added liver microsomal fractions, and has been shown to be carcinogenic in laboratory animals. However, neither the metabolic fate in vitro or in vivo, nor the nature of the DNA adduct(s) is currently known. In this proposal, five specific aims will be addressed in order to understand the metabolism of 1-nitropyrene and 3-nitrofluoranthene. We will also investigate DNA adduct formation and attempt to determine how these processes relate to the carcinogenicity noted in laboratory animals in an attempt to project the potential risk to humans.
The specific aims are: 1-Nitropyrene (1) Determine the identity (identities) of the in vivo DNA adduct(s) using Sprague Dawley rats and [3H]1-nitropyrene, (2) Determine the persistence of this (these) adduct(s) in vivo. 3-Nitrofluoranthene (3) Determine the identity of metabolites produced following in vitro incubation with rat liver microsomes, (4) Quantitate the mutagenicity of these metabolites in Salmonella typhimurium, (5) Determine the identity of the DNA adduct(s) in vitro using Salmonella typhimurium and in vivo using Sprague Dawley rats.
