ArticleChemical research in toxicology2013
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.
Article in Chemical research in toxicology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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12 authors at 3 institutions in 2 countries.
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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.
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