title: 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.
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.
authors: Departments of †Biochemistry and Molecular Biology, ‡Comparative Medicine, §Pharmacology, and ∥Public Health Sciences, College of Medicine, Pennsylvania State University , Hershey, Pennsylvania 17033, United States.
authors: Yuan-Wan
authors: YW
authors: Sun
authors: Joseph B
authors: JB
authors: Guttenplan
authors: Timothy
authors: T
authors: Cooper
authors: Jacek
authors: J
authors: Krzeminski
authors: Ceaser
authors: C
authors: Aliaga
authors: Telih
authors: T
authors: Boyiri
authors: Wieslawa
authors: W
authors: Kosinska
authors: Zhong-Lin
authors: ZL
authors: Zhao
authors: Kun-Ming
authors: KM
authors: Chen
authors: Arthur
authors: A
authors: Berg
authors: Shantu
authors: S
authors: Amin
authors: Karam
authors: K
authors: El-Bayoumy
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002911:Chrysenes / Q000633:toxicity*; D016207:Cytokines / Q000097:blood; D018736:DNA Adducts; D004785:Environmental Pollutants / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
chemical_list: D002273:Carcinogens; D002911:Chrysenes; D016207:Cytokines; D018736:DNA Adducts; D004785:Environmental Pollutants; D047628:Estrogen Receptor alpha; D018336:Receptors, Aryl Hydrocarbon; C035986:6-nitrochrysene; C042316:1,2-dihydro-1,2-dihydroxy-6-nitrochrysene