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

Yuan Wan Sun, Joseph B. Guttenplan, Timothy Cooper, Jacek Krzeminski, Ceaser Aliaga, Telih Boyiri, Wieslawa Kosinska, Zhong Lin Zhao, Kun Ming Chen, Arthur Berg, Shantu Amin, Karam El-Bayoumy

Research output: Contribution to journalArticlepeer-review

Abstract

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 6-NC in the rat mammary gland.

Original languageEnglish (US)
Pages (from-to)547-554
Number of pages8
JournalChemical research in toxicology
Volume26
Issue number4
DOIs
StatePublished - Apr 15 2013

ASJC Scopus subject areas

  • Toxicology

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