Mechanisms Underlying the Varied Mammary Carcinogenicity of the Environmental Pollutant 6-Nitrochrysene and Its Metabolites (鈭?-[R,R]- and (+)-[S,S]-1,2-Dihydroxy-1,2-dihyd

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• 作者：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
• 刊名：Chemical Research in Toxicology
• 出版年：2013
• 出版时间：April 15, 2013
• 年：2013
• 卷：26
• 期：4
• 页码：547-554
• 全文大小：400K
• 年卷期：v.26,no.4(April 15, 2013)
• ISSN：1520-5010

文摘

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 (卤)-trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene (1,2-DHD-6-NC). In the present study, we resolved the racemic (卤)-1,2-DHD-6-NC into (鈭?-[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 脳 Sprague鈥揇awley)F1 rats harboring lacI/cII and Sprague鈥揇awley 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 ER尾) were comparable; however, the expressions of AhR and ER伪 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 ER伪 could potentially account for the higher carcinogenicity of 6-NC in the rat mammary gland.