The etiology of most breast cancers remains obscure. A significant portion of breast cancer incidence in the U.S. is related to environmental factors and lifestyle, including diet. An example of a class of environmental mammary carcinogens is the nitropolynuclear aromatic hydrocarbons (NO2-PAH). The National Agency for Research on Cancer listed some NO2-PAH as possibly carcinogenic to humans. However, the actual risk associated with human exposure to NO2-PAH has not been clearly defined. In order to evaluate risks, we focused our efforts on understanding the mechanistic basis for tumor induction by 6-nitrochrysene (6-NC) and mono-nitropyrene (mono-NP) isomers (1-, 2- and 4-NP). Studies proposed in the present application are a logical extension of our findings. Accordingly, we formulated the following hypotheses and the Specific Aims to test them. (1) We hypothesize that 1,2-dihydroxy- 1,2-dihydro-6-nitrochrysene (l,2-DHD-6-NC) or 1,2-dihydroxy-1,2-dihydroxy-6-aminochrysene (1,2-DHD-6-AC) is the proximate mammary carcinogen and 1,2-dihydroxy-1,2-dihydro-6-hydroxylamino-chrysene (1,2-DHD-6-NHOH) is the ultimate carcinogenic form. To test our hypothesis, we will carry out the following: (a) synthesis of DNA adducts derived from 1,2-DHA-6-NHOH, (b) synthesis of ample materials of metabolites derived from 6-NC and comparison of their relative potency as mammary carcinogens by intramammary administration in rats, (c) determine the type and frequency of mutations in the p53 gene in rat mammary tumors. (2) We have shown that NO2-PAH derived DNA adduct formation is necessary but is not sufficient for carcinogenesis. Clearly, there are gaps in our understanding of the role of DNA adducts in mammary carcinogenesis. Thus, we will determine the relationships between: (a) the nature and levels of DNA adducts, (b) mutation frequency and spectra and (c) mammary carcinogenicity induced by 6-NC using rats harboring the lacI reporter gene. Our hypothesis is that the major DNA adduct derived from l,2-DHD-6-NHOH is responsible for the type and frequency of mutations in both the lacI gene and in the p53 gene. (3) To translate our ongoing studies of NO2-PAH in rodents, we propose to pursue similar studies in cultured human mammary tissues. We propose to employ normal (MCF-1OA) and cancer cell lines (MCF-7) to determine: (a) the metabolic capacity of the target organ (human breast tissues) and (b) the form of P450 isozymes involved in the activation of these carcinogens. The proposed study will also provide an experimental approach to the identification of relevant DNA adducts detected in humans; toward this end a pilot study will be initiated to determine the possible presence of NO2-PAH-derived DNA adducts in human breast tissues. (4) The hypothesis to be tested here is that certain covalent modification of genomic DNA by ultimate carcinogenic metabolites derived from 6-NC and mono-NP represents a type of cellular damage that can be responsible for an increased expression of the tumor suppressor protein p53.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Chemical Pathology Study Section (CPA)
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Johnson, Ronald L
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Pennsylvania State University
Schools of Medicine
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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
Krzeminski, Jacek; Kropachev, Konstantin; Kolbanovskiy, Marina et al. (2011) Inefficient nucleotide excision repair in human cell extracts of the N-(deoxyguanosin-8-yl)-6-aminochrysene and 5-(deoxyguanosin-N(2)-yl)-6-aminochrysene adducts derived from 6-nitrochrysene. Chem Res Toxicol 24:65-72
Sun, Yuan-Wan; Guttenplan, Joseph B; Khmelnitsky, Michael et al. (2009) Stereoselective metabolism of the environmental mammary carcinogen 6-nitrochrysene to trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene by aroclor 1254-treated rat liver microsomes and their comparative mutation profiles in a laci mammary epithelial cell li Chem Res Toxicol 22:1992-7
Sun, Yuan-Wan; Herzog, Christopher R; Krzeminski, Jacek et al. (2007) Effects of the environmental mammary carcinogen 6-nitrochrysene on p53 and p21(Cip1) protein expression and cell cycle regulation in MCF-7 and MCF-10A cells. Chem Biol Interact 170:31-9
Guttenplan, Joseph B; Zhao, Zhong-lin; Kosinska, Wieslawa et al. (2007) Comparative mutational profiles of the environmental mammary carcinogen, 6-nitrochrysene and its metabolites in a lacI mammary epithelial cell line. Carcinogenesis 28:2391-7
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Sun, Yuan-Wan; Guengerich, F Peter; Sharma, Arun K et al. (2004) Human cytochromes P450 1A1 and 1B1 catalyze ring oxidation but not nitroreduction of environmental pollutant mononitropyrene isomers in primary cultures of human breast cells and cultured MCF-10A and MCF-7 cell lines. Chem Res Toxicol 17:1077-85
El-Bayoumy, Karam; Sharma, Arun K; Lin, Jyh-Ming et al. (2004) Identification of 5-(deoxyguanosin-N2-yl)- 1,2-dihydroxy-1,2-dihydro-6-aminochrysene as the major DNA lesion in the mammary gland of rats treated with the environmental pollutant 6-nitrochrysene. Chem Res Toxicol 17:1591-9
Amin, Shantu; Lin, Jyh-Ming; Krzeminski, Jacek et al. (2003) Metabolism of benzo[c]chrysene and comparative mammary gland tumorigenesis of benzo[c]chrysene bay and fjord region diol epoxides in female CD rats. Chem Res Toxicol 16:227-31

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