The cause of most breast cancers remains unknown. Widespread environmental agents (e.g., nitropolycyclic aromatic hydrocarbons [NO2-PAH]) that are known to induce mammary cancer in rodents must be regarded as potential human carcinogens;a representative example is 6-nitrochrysene (6-NC). Studies proposed in this competitive renewal focus on understanding the mechanisms that can account for the remarkable mammary carcinogenicity of 6-NC in rats. We previously showed that trans 1,2-dihydroxy-1,2-dihydro-6- nitrochrysene (1,2-DHD-6-NC) is the proximate carcinogen and characterized the structures of DNA adducts in the rat mammary gland;these adducts were derived not only from simple nitroreduction but also from a combination of ring oxidation and nitroreduction of 6-NC. The structures of these adducts are consistent with the type of mutation spectra observed in the lacl reporter gene in the same target organ in vivo;some of the mutation spectra are identical to those observed in p53 gene in human breast cancer. In the present application, we hypothesize that structural characteristics of certain DNA adducts derived from 6-NC can account for its carcinogenic potency. To test our hypothesis, we will carry out the synthesis of ample materials of 6-NC, and its putative ultimate carcinogenic forms [R,R]- and [S,S]-1,2-DHD-6-NHOH-C, DNA adducts and oligonucelotides containing lesions at hot spots in the p53 and ras gene. Mammary carcinogenesis, mutation frequency, mutation spectra, DNA adducts formation and DNA repair will be assessed. Nothing is known about the repair by mammalian nucleotides excision repair (NER) enzymes of DNA adducts derived from the metabolites of 6-NC either in vitro or in vivo. Furthermore, there is no information about the time dependence after exposure of cells or mammalian tissues and the relative abundance of 6-NC-adducts in different base sequence contexts and how efficiently they are removed by NER process. If not removed by DNA repair mechanisms, it is not established how fast, after exposure, the mutations develop. These issues will be addressed in this project. The proposed studies are requisite to our understanding of the potential risks to the development of breast cancer associated with exposure to 6-NC, a typical NO2-PAH.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035519-25
Application #
7901003
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Johnson, Ronald L
Project Start
1983-07-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
25
Fiscal Year
2010
Total Cost
$304,309
Indirect Cost
Name
Pennsylvania State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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
Boyiri, Telih; Guttenplan, Joseph; Khmelnitsky, Michael et al. (2004) Mammary carcinogenesis and molecular analysis of in vivo cII gene mutations in the mammary tissue of female transgenic rats treated with the environmental pollutant 6-nitrochrysene. Carcinogenesis 25:637-43
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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