Biological and Tumor-Promoting Effects of Dioxin-like and Non-Dioxin-like Polychlorinated Biphenyls in Mouse Liver After Single or Combined Treatment

被引：26

作者：

Rignall, Benjamin ^{[1
]}

Grote, Konstanze ^{[2
]}

Gavrilov, Alina ^{[1
]}

Weimer, Marc ^{[3
]}

Kopp-Schneider, Annette ^{[3
]}

Krause, Eberhard ^{[4
]}

Appel, Klaus E. ^{[5
]}

Buchmann, Albrecht ^{[1
]}

Robertson, Larry W. ^{[6
]}

Lehmler, Hans-Joachim ^{[6
]}

Kania-Korwel, Izabela ^{[6
]}

Chahoud, Ibrahim ^{[7
]}

Schwarz, Michael ^{[1
]}

机构：

[1] Univ Tubingen, Dept Toxicol, D-72074 Tubingen, Germany

[2] Charite, Dept Expt Med, D-13353 Berlin, Germany

[3] German Canc Res Ctr, Cent Unit Biostat, D-69120 Heidelberg, Germany

[4] Leibniz Inst Mol Pharmacol FMP, D-13125 Berlin, Germany

[5] Fed Inst Risk Assessment, Unit Food Toxicol, D-14195 Berlin, Germany

[6] Univ Iowa, Coll Publ Hlth, Dept Occupat & Environm Hlth, Iowa City, IA USA

[7] Charite, Inst Clin Pharmacol & Toxicol, D-13353 Berlin, Germany

来源：

TOXICOLOGICAL SCIENCES | 2013年 / 133卷 / 01期

关键词：

PCB126; PCB153; tumor promotion; Cyp1a1; Cyp2b10; ALTERED HEPATIC FOCI; SPRAGUE-DAWLEY RATS; BETA-CATENIN; RISK-ASSESSMENT; RECEPTOR CAR; MICE; HEPATOCARCINOGENESIS; INDUCTION; PCBS; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN;

D O I：

10.1093/toxsci/kft034

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

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 similar to 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.

引用

页码：29 / 41

页数：13