ToxSci Advance Access originally published online on June 16, 2006
Toxicological Sciences 2006 93(1):34-40; doi:10.1093/toxsci/kfl041
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PCB 153, a Non-dioxin–like Tumor Promoter, Selects for ß-Catenin (Catnb)–Mutated Mouse Liver Tumors
* Department of Toxicology, University of Tuebingen, 72074 Tuebingen, Germany; Graduate Center for Nutritional Sciences, and Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40506; Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa 52242-5000; and ¶ Federal Institute for Risk Assessment, Center for Experimental Toxicology, 14195 Berlin, Germany
Received April 11, 2006; accepted June 15, 2006
Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants which act as liver tumor promoters in rodents and can be classified as either dioxin-like or non-dioxin (phenobarbital [PB])–like inducers of cytochrome P-450. Since we have previously shown that tumor promotion by PB leads to clonal outgrowth of ß-catenin (Catnb)–mutated but not Ha-ras–mutated mouse liver tumors, we were interested to know whether the non-dioxin–like tumor promoter 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) shows the same selective pressure during tumor promotion. Male B6129SF2/J mice were given a single injection of N-nitrosodiethylamine (90 mg/kg body weight) at 9 weeks of age, followed by 39 weeks of treatment with PCB 153 (20 biweekly ip injections of 300 µmol/kg body weight) or corn oil as a control. Animals were killed 15 weeks after the last PCB 153 injection and liver tumors were identified by immunohistochemical staining of glutamine synthetase (GS) and analyzed for Catnb, Ha-ras, and B-raf mutations. Quantitative analyses revealed that GS-positive tumors were much larger and more frequent in livers from PCB 153–treated mice than in control animals, whereas GS-negative tumors were similar in both groups. Almost 90% (34/38) of all tumors from PCB 153–treated animals contained Catnb mutations, which compares to 
45% (17/37) of tumors in the control group. Ha-ras– and B-raf–mutated liver tumors were rare and not significantly different between treatment groups. These results clearly indicate that PCB 153 strongly selects for Catnb-mutated, GS-positive liver tumors, which is similar to the known action of PB, a prototypical tumor promoter in rodent liver.
Key Words: polychlorinated biphenyls; tumor promotion; mouse liver; ß-catenin; Catnb mutations.
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