ToxSci Advance Access originally published online on June 16, 2004
Toxicological Sciences 2004 81(1):35-42; doi:10.1093/toxsci/kfh193
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Toxicological Sciences vol. 81 no. 1 © Society of Toxicology 2004; all rights reserved.
Effect of 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB-153) on Hepatocyte Proliferation and Apoptosis in Mice Deficient in the p50 Subunit of the Transcription Factor NF-
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* Graduate Center for Nutritional Sciences, Department of Pathology and Laboratory Medicine, Graduate Center for Toxicology, Department of Nutrition and Food Science, and ¶ Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536
Received January 21, 2004; accepted May 18, 2004
Polychlorinated biphenyls (PCBs) are a group of synthetic chemicals that induce and promote liver tumors in rodents. We previously showed hepatic nuclear factor kappaB (NF-
B) activation and increased hepatocyte proliferation in PCB-treated rats. In this study, the role of NF-B in hepatocyte proliferation and apoptosis after PCB administration was analyzed in wild-type mice and in mice deficient in the NF-B p50 subunit (p50–/–). In a 2-day study, mice received a single intraperitoneal (ip) injection of corn oil or PCB-153. Hepatic NF-B DNA binding activity and cell proliferation were increased by PCB-153 in wild-type mice but not in p50–/– mice. In a 21-day study, mice received six ip injections of corn oil or PCB-153 (twice weekly for 3 weeks) and were euthanized 4 days after the last injection. In this study, NF-B DNA binding activity was not increased after PCB-153 treatment in wild-type or p50–/– mice. Cell proliferation was significantly increased in the wild-type mice treated with PCB-153; in the p50–/– mice treated with PCB-153, cell proliferation was greater than in untreated mice but less than in wild-type mice treated with PCB-153. The livers of p50–/– mice showed greater apoptosis than those of wild-type mice; PCB-153 decreased apoptosis in p50–/– mice, with higher inhibition in the 21-day study than in the 2-day study. RNase protection assays indicated that PCB-153 decreased the mRNA level of cyclin A2, B1, B2, and C in the 2-day study, but not in the 21-day study; however, it did not affect cyclin D1 and D2 mRNA levels at either time point. Cyclin D1 protein levels were not affected by PCB-153. Taken together, these data indicate that the absence of the NF-B p50 subunit alters the proliferative and apoptotic changes in mouse liver in the response to PCB-153.
Key Words: PCBs; NF-B; hepatocytes; apoptosis; cell proliferation.
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