Using dietary strategies to explore mechanisms of hepatic toxicity caused by 3,3',4,4',5-Pentachlorobiphenyl (PCB 126) in an animal model

Abstract

This doctoral dissertation work strived to contribute to the ever expanding knowledge about the mechanisms of polychlorinated biphenyl (PCB) toxicity using dietary strategies. PCBs are a family of persistent environmental pollutants with a wide range of toxicity. The toxicity of PCBs is largely dependent on the congener’s chlorination pattern. Of particular interest to this work was 3,3’,4,4’,5pentachlorobiphenyl (PCB 126), the most potent of the dioxin-like PCB congeners. I hypothesized that in vivo PCB 126 toxicity would be ameliorated by dietary selenium supplementation, lowered dietary copper, and dietary N-acetylcysteine (NAC) supplementation. Dioxin-like PCBs are known for diminishing hepatic selenium and seleniumdependent glutathione peroxidase (SeGPx), an antioxidant enzyme. In the first study, PCB 126 caused a dose-dependent decrease in hepatic selenium and SeGPx. Supplemental dietary selenium significantly increased hepatic selenium and SeGPx, and decreased incidence of liver apoptosis in these rats. The results from this study support the concept that selenium plays a protective role, and differences in liver injuries of these rats may be reflected in their selenium status. The dose-dependent increase in hepatic copper caused by PCB 126 was a subject of interest and concern in the next study. Lowering dietary copper levels without negatively affecting the function of the essential antioxidant enzyme copper zinc superoxide dismutase did not result in reduction of PCB 126-induced toxicity. Copper metabolism was unlikely a main target of PCB 126 toxicity as increasing dietary copper did not significantly increase hepatic copper levels. Hepatic copper is highly regulated and likely does not play a significant role in PCB 126-induced toxicity. The effectiveness of NAC on restoring glutathione status and reducing PCB 126 toxicity was tested in the final study. While NAC did not restore glutathione status, NAC