Biological and tumor-promoting effects of dioxin-like and non-dioxin-like polychlorinated biphenyls in mouse liver after single or combined treatment

• Published in: Toxicological sciences 2013-05, Vol.133 (1), p.29-41
• Main Authors: Rignall, Benjamin, Grote, Konstanze, Gavrilov, Alina, Weimer, Marc, Kopp-Schneider, Annette, Krause, Eberhard, Appel, Klaus E, Buchmann, Albrecht, Robertson, Larry W, Lehmler, Hans-Joachim, Kania-Korwel, Izabela, Chahoud, Ibrahim, Schwarz, Michael
• Format: Article
• Language: English
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases - biosynthesis; Blotting, Western; Cocarcinogenesis; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P450 Family 2; Diethylnitrosamine - toxicity; Dioxins - pharmacokinetics; Dioxins - toxicity; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Induction; Immunohistochemistry; Liver - drug effects; Liver - enzymology; Liver - metabolism; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - enzymology; Male; Mice; Mice, Inbred C3H; Polychlorinated Biphenyls - pharmacokinetics; Polychlorinated Biphenyls - toxicity; Steroid Hydroxylases - biosynthesis
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kft034

To assess the impact of a mixture containing dioxin-like and non-dioxin-like polychlorinated biphenyls (PCBs), male mice were initiated with N-nitroso-diethylamine and subsequently treated with PCB126, an Ah-Receptor agonist, and PCB153, acting via activation of the constitutive androstane receptor. The two congeners were given at two dose levels: the low dose was adjusted to induce ~150-fold increases in cytochrome P450 (Cyp)1a1 (PCB126) and Cyp2b10 mRNAs (PCB153), and the high dose was chosen as twice the low dose. To keep the liver PCB levels constant, mice were given initial loading doses followed by weekly maintenance doses calculated on the basis of the PCBs' half-lives. Mice were treated with the individual congeners (low and high dose) or with a mixture consisting of the low doses of the 2 PCBs. The following results were obtained: (1) the 2 PCBs produced dose-dependent increases in Cyp1a1 and Cyp2b10 mRNA, protein, and activity when given individually; (2) combined treatment caused more than additive effects on Cyp1a1 mRNA expression, protein level, and ethoxyresurofin activity; (3) changes in the levels of several proteins were detected by proteome analysis in livers of PCB-treated mice; (4) besides these biological responses, the individual PCBs caused no significant increase in the number of glucose-6-phospatase (G6Pase)-deficient neoplastic lesions in liver, whereas a moderate significant effect occurred in the combination group. These results suggest weak but significant response-additive effects of the 2 PCBs when given in combination. They also suggest that the Cyp biomarkers tend to overestimate the carcinogenic response produced by the PCBs in mouse liver.