Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2571134 | Toxicology and Applied Pharmacology | 2008 | 7 Pages |
Abstract
Polychlorinated biphenyls (PCBs) are persistent and ubiquitous environmental chemicals that bioaccumulate and have hepatic tumor promoting activity in rodents. The present study examined the effect of deleting the p50 subunit of NF-κB on the hepatic tumor promoting activity of 2,2â²,4,4â²,5,5â²-hexachlorobiphenyl (PCB-153) in mice. Both wild-type and p50â/â male mice were injected i.p. with diethylnitrosamine (DEN, 90 mg/kg) and then subsequently injected biweekly with 20 i.p. injections of PCB-153 (300 μmol/kg/injection). p50 deletion decreased the tumor incidence in both PCB- and vehicle-treated mice, whereas PCB-153 slightly (P = 0.09) increased the tumor incidence in wild-type and p50â/â mice. PCB-153 increased the total tumor volume in both wild-type and p50â/â mice, but the total tumor volume was not affected by p50 deletion in either PCB- or vehicle-treated mice. The volume of tumors that were positive for glutamine synthetase (GS), which is indicative of mutations in the beta-catenin gene, was increased in both wild-type and p50â/â mice administered PCB-153 compared to vehicle controls, and inhibited in p50â/â mice compared to wild-type mice (in both PCB- and vehicle-treated mice). The volume of tumors that were negative for GS was increased in p50â/â mice compared to wild-type mice but was not affected by PCB-153. PCB-153 increased cell proliferation in normal hepatocytes in wild-type but not p50â/â mice; this increase was inhibited in p50â/â mice. In hepatic tumors, the rate of cell proliferation was much higher than in normal hepatocytes, but was not affected by PCB treatment or p50 deletion. The rate of apoptosis, as measured by the TUNEL assay, was not affected by PCB-153 or p50 deletion in normal hepatocytes. In hepatic tumors, the rate of apoptosis was lower than in normal hepatocytes; PCB-153 slightly (P = 0.10) increased apoptosis in p50â/â but not wild-type mice; p50 deletion had no effect. Taken together, these data indicate that the absence of the NF-κB p50 subunit inhibits the promoting activity of PCB-153 and alters the proliferative and apoptotic changes in mouse liver in the response to PCBs.
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Authors
Howard P. Glauert, Job C. Tharappel, Subhashis Banerjee, Nelson L.S. Chan, Izabela Kania-Korwel, Hans-Joachim Lehmler, Eun Y. Lee, Larry W. Robertson, Brett T. Spear,