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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.
MedLine Citation:
PMID:  23461617     Owner:  NLM     Status:  Publisher    
The mechanisms that can account for the remarkable mammary carcinogenicity of the environmental pollutant 6-nitrochrysene (6-NC) in the rat remain elusive. In our previous studies, we identified several 6-NC-derived DNA adducts in the rat mammary gland; one major adduct was derived from (±)-trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene (1, 2-DHD-6-NC). In the present study, we resolved the racemic (±)-1, 2-DHD-6-NC into (-)-[R,R]- and (+)-[S,S] -1,2-DHD-6-NC and compared their in vivo mutagenicity and carcinogenicity in the mammary glands of female transgenic (BigBlue F344 × Sprague-Dawley)F1 rats harboring lacI/cII and Sprague-Dawley rats, respectively. Both [R,R]- and [S,S]-isomers exerted similar mutagenicity and carcinogenicity but were less potent than 6-NC. Additional in vivo and in vitro studies were then performed to explore possible mechanisms that can explain the higher potency of 6-NC than 1, 2-DHD-6-NC. Using ELISA, we found that neither 6-NC nor 1, 2-DHD-6-NC increased the levels of several inflammatory cytokines in plasma obtained from rats 24 h after treatment. In MCF-7 cells, as determined by immunoblotting, the effects of 6-NC and 1, 2-DHD-6-NC on protein expression (p53, Akt, p38, JNK, c-myc, bcl-2, PCNA, and ERβ) were comparable; however, the expressions of AhR and ERα proteins were decreased by 6-NC but not 1, 2-DHD-6-NC. The expression of both receptors was decreased in mammary tissues of rats treated with 6-NC. Our findings suggest that the differential effects of 6-NC and 1, 2-DHD-6-NC on AhR and ERα could potentially account for the higher carcinogenicity of the parent compound in the rat mammary gland.
Yuan-Wan Sun; Joseph B Guttenplan; Timothy Cooper; Jacek Krzeminski; Cesar Aliaga; Telih Boyiri; Wieslawa Kosinska; Zhong-Lin Zhao; Kun-Ming Chen; Arthur Berg; Shantu G Amin; Karam El-Bayoumy
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-3-5
Journal Detail:
Title:  Chemical research in toxicology     Volume:  -     ISSN:  1520-5010     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-3-6     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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