MECHANISMS OF HEPATIC TUMOR PROMOTION BY PCB'S

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It is well established that polychlorinated biphenyls (PCBs) are efficacious inducers of hepatocellular carcinomas in rodents. Both PCB mixtures and individual PCB congers have promoting activity in two- stage hepatocarcinogenesis, but the mechanism of their promoting activity is unclear. One possible mechanism is that these agents are increasing oxidative stress in the liver, which could lead to lipid peroxidation, oxidative DNA damage, or changes in gene expression. Several transcription factors, including NF-kappaB and AP-1, can be activated at least in part by oxidative stress. We have shown that PCBs increase the hepatic DNA binding activities of both NF-kappaB and AP- 1, particularly after chronic administration. In this project we propose to test the hypothesis that these transcription factors are important in the promoting activity of PCBs. We will examine 1) the mechanisms, such as increased oxidative stress, by which PCBs activated NF-kappaB and AP- 1; 2) the importance of hepatic Kupffer cells in the activation of NF- kappaB and AP-1, the induction of cell proliferation, and the promotion of pre-neoplastic lesions by PCBs; 3) the consequences of NF-kappaB activation by analyzing downstream targets of these transcription factors after the administration of PCBs; and 4) if the loss of the p50 subunit of NF-kappaB will influence the promoting activity of PCBs. These studies will show if NF-kappaB activation is necessary for the promoting activity of PCBs and will elucidate the mechanism by which NF-kappaB activation influences hepatic tumor promotion by PCBs.