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-kappaB.
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-kappaB) activation and increased hepatocyte proliferation in PCB-treated rats. In this study, the role of NF-kappaB in hepatocyte proliferation and apoptosis after PCB administration was analyzed in wild-type mice and in mice deficient in the NF-kappaB p50 subunit (p50-/-). In a 2-day study, mice received a single intraperitoneal (ip) injection of corn oil or PCB-153. Hepatic NF-kappaB 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-kappaB 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-kappaB p50 subunit alters the proliferative and apoptotic changes in mouse liver in the response to PCB-153.
Lu
Zijing
Z
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington 40536, USA.
Lee
Eun Y
EY
Robertson
Larry W
LW
Glauert
Howard P
HP
Spear
Brett T
BT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D049109:Cell Proliferation / Q000187:drug effects*; D016213:Cyclins / Q000096:biosynthesis; D024202:Electrophoretic Mobility Shift Assay; D022781:Hepatocytes / Q000187:drug effects*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000235:genetics*; D052002:NF-kappa B p50 Subunit; D023282:Nuclease Protection Assays; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification
D016213:Cyclins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D011078:Polychlorinated Biphenyls; D001973:Bromodeoxyuridine; C014024:2,4,5,2',4',5'-hexachlorobiphenyl