Year of Publication
Polychlorinated biphenyls (PCBs) are nongenotoxic hepatic tumor promoters. PCBs have been shown to cause oxidative stress, but the exact mechanism by which PCBs exert their tumor promoting activity is not clear. In our study, PCB-153, a non-coplanar congener, caused a transient increase in hepatic NF-B DNA binding activity and cell proliferation, while PCB-77, a coplanar congener, showed no effect. Our second study using a mouse model that was deficient in the p50 subunit of NF-kB (p50-/-) showed that NF-kB contributes to the changes in hepatocyte proliferation and apoptosis in response to PCB-153 treatment: a single dose of PCB-153 increased hepatic NF-B activity and cell proliferation in wild type mice, but not in the p50-/- mice; longer-term treatment with PCB-153 increased cell proliferation in p50-/- mice, but this increase was less than that in the wild type. In addition, p50-/- livers had more apoptosis than in the wild type, and PCB-153 inhibited apoptosis in the p50-/- livers. p50-/- livers had less cyclin D1 protein than the wild type, but that the mRNA levels were same. Bcl-xL protein was not changed by PCB-153, and wild type and p50-/- mice had the same level of Bcl-xL protein. In the third study, PCB-77 caused an increase in hepatic NF-kB DNA binding activity and cell proliferation during the promotion stage, and this increase was blocked by dietary supplementation of vitamin E, but the number and volume of placental glutathione S-transferase (PGST)-positive foci were slightly, though insignificantly, increased in the same animals. The apparent conflict could be due to different effect in different cells: high level vitamin E significantly inhibited PCB-77-induced cell proliferation in normal hepatocytes, while this inhibitory effect was much less in the PGST-positive hepatocytes. In conclusion, our studies show that a non-coplanar PCB can cause an increase in hepatic NF-kB DNA binding activity in rats and mice, and this increase contributes to the change in cell proliferation and apoptosis. Dietary vitamin E supplementation did not show protective effect on the formation of altered hepatic foci that were promoted by PCBs, although vitamin E supplementation decreased PCBs-induced hepatic NF-kB activation and cell proliferation.
Lu, Zijing, "THE ROLE OF NF-kB ACTIVATION IN HEPATIC TUMOR PROMOTION BY POLYCHOLORINATED BIPHENYLS (PCBs)" (2002). University of Kentucky Doctoral Dissertations. 399.