Nitropolycyclic aromatic hydrocarbons (Nitro-PAHs) have been detected in numerous environmental sources. 1-Nitropyrene (1-NP), a rodent carcinogen, is the major component in this class. However, 4-NP was the strongest tumorigen among the three possible isomers (1-NP, 2-NP, and 4-NP). Clearly, the position of the nitro group is a critical factor determining their tumorigenic activities. We will continue our studies aimed at establishing the biochemical basis for the varied tumorigenic activities and assessing the potential of these compounds as human carcinogens (cf Aim 1). Our interest in 6-nitrochrysene (6-NC) was stimulated by its remarkable tumorigenic activity in the newborn mouse lung, which far exceeds that of its parent hydrocarbon (chrysene) and approximates that of certain ultimate carcinogenic metabolites of PAHs, e.g. anti-7,8- dihydroxy-9,10-epoxy-7,8,9,1O-tetra-hydrobenzo[a]pyrene (BPDE). Further studies are required to determine the role of the nitro group and understand the basis for the varied tumorigenicity between 6-NC and chrysene (cf Aim 2). On the basis of our findings and those described in the literature, we hypothesized that the nitro group may alter the levels and/or structures of DNA adducts -which, in turn, may account for the remarkable tumorigenic activities of 6-NC when compared to chrysene. In a recent study, we also demonstrated that 6-NC is the most potent Nitro-PAH as a rat mammary carcinogen following intramammary administration; its activity far exceeds that of BPDE. The biochemical and molecular basis for mammary cancer induction preferably by a route that better mimics human exposure to 6-NC need to be evaluated (cf Aim 3). To achieve our ,goals and to test our hypothesis, our specific aims are: 1.a. To characterize 4-NP-DNA adducts in rat mammary epithelial cells and compare to those of 1-NP and 2-NP, b. To establish complete metabolic profiles of 1-NP, 2-NP, and 4-NP under identical conditions in the rat, c. To compare the metabolism of 1-NP, 2-NP, and 4-NP by human liver and lung microsomes; 2. To determine the relationship between adducts structure derived from 6- NC and chrysene and mutation efficiency using site-specific mutagenesis experiments. 3.a. To determine the carcinogenic potency of 6-NC in rat mammary glands by oral administration, b. To establish the biochemical basis for mammary tumor induction by 6-NC, c. To determine the type and frequency of mutations in ras and p53 genes in mammary tumors following the oral administration of 6-NC.

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National Cancer Institute (NCI)
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Chemical Pathology Study Section (CPA)
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Johnson, Ronald L
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Sun, Yuan-Wan; Guttenplan, Joseph B; Cooper, Timothy et al. (2013) Mechanisms underlying the varied mammary carcinogenicity of the environmental pollutant 6-nitrochrysene and its metabolites (-)-[R,R]- and (+)-[S,S]-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene in the rat. Chem Res Toxicol 26:547-54
Krzeminski, Jacek; Kropachev, Konstantin; Reeves, Dara et al. (2013) Adenine-DNA adduct derived from the nitroreduction of 6-nitrochrysene is more resistant to nucleotide excision repair than guanine-DNA adducts. Chem Res Toxicol 26:1746-54
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