Superfund Research Program

Mechanisms of Hepatic Tumor Promotion by PCBs

Project Leader: Howard P. Glauert
Grant Number: P42ES007380
Funding Period: 1997 - 2005

Project-Specific Links

Final Progress Reports

Year:   2004  1999 

The persistence and biomagnification of polychlorinated biphenyls (PCBs), as well as the presence of these compounds in human adipose tissue and breast milk, raise concerns about the health consequences of long-term exposure to these environmental pollutants. The various toxic effects reported for PCB commercial products include liver hypertrophy and hepatocellular carcinoma. Many previous studies, that describe the potent promoting activities of numerous commercial PCB formulations and single congeners, have led to the general view that carcinogenicity of PCBs and related compounds is due to their activity as promoters. The mechanism of the promoting activity of PCBs, however, has not been determined. One possible mechanism is that PCBs are inducing oxidative stress in the liver. Project investigators have demonstrated that PCBs activate the transcription factors NF-kB and AP-1, which are activated at least in part by oxidative stress. The researchers therefore hypothesize that these transcription factors are important in the promoting activity of PCBs.

Project investigators have examined whether or not PCBs induce oxidative stress in the liver in the form of lipid peroxidation and activation of active oxygen-related transcription factors (NF-kB and AP-1). Two different types of PCBs--PCB-77 and PCB-153--increased lipid peroxidation in the form of thiobarbituric acid reactive substances (TBARS). Short-term treatment with PCB-153 but not PCB-77 increased the DNA binding activity of NF-kB; after promotion by either of these PCBs, however, the DNA binding activity of NF-kB was enhanced. AP-1 activity was increased after promotion but not after short-term treatment.

Results show that PCBs induce oxidative stress in the form of lipid peroxidation and transcription factor activation. These results imply that decreasing PCB-induced oxidative stress may be protective against PCB-induced carcinogenesis.