Mechanisms Underlying the Varied Mammary Carcinogenicity of the Environmental Pollutant 6‑Nitrochrysene and Its Metabolites (−)‑[<i>R</i>,<i>R</i>]- and (+)‑[<i>S</i>,<i>S</i>]‑1,2-Dihydroxy-1,2-dihydro-6-nitrochrysene in the Rat

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 (±)-<i>trans</i>-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 (−)-[<i>R</i>,<i>R</i>]- and (+)-[<i>S</i>,<i>S</i>]-1,2-DHD-6-NC and compared their <i>in vivo</i> mutagenicity and carcinogenicity in the mammary glands of female transgenic (BigBlue F344 × Sprague–Dawley)­F1 rats harboring <i>lacI</i>/<i>cII</i> and Sprague–Dawley rats, respectively. Both [<i>R</i>,<i>R</i>]- and [<i>S</i>,<i>S</i>]-isomers exerted similar mutagenicity and carcinogenicity but were less potent than 6-NC. Additional <i>in vivo</i> and <i>in vitro</i> 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