Wang B, Wels BR, Klaren WD, Wang K, Robertson LW, Ludewig G. Regulation of MnSOD by the AhR agonist PCB126: The role of dietary manganese. Society of Toxicology Annual Meeting, San Francisco, Ca, 2012. Also presented at Superfund Annual Meeting, Lexington, Ky, 2012.
PCB126 is the most potent aryl hydrocarbon receptor (AhR) agonist among all polychlorinated biphenyls, which are persistent organic pollutants. PCB126 has been shown to increase reactive oxygen species including superoxide radicals in vivo and in vitro. MnSOD is one of the most efficient antioxidant enzymes, converting superoxide to hydrogen peroxide. However, its activity was reduced by PCB126, thereby probably aggravating the oxidative stress. To elucidate the mechanisms of PCB126’s modulation of MnSOD expression, we conducted dose- and time-response and a manganese dietary study of PCB126 effects in male Sprague Dawley rats. The expression and activity of hepatic MnSOD was determined. Several redox-sensitive transcription factors of MnSOD as well as post-translational modifications of the protein were also studied. The results show a dose-and time-dependent elevation of MnSOD mRNA and protein. The transcriptional induction of MnSOD is consistent with an observed increase of Nrf2 binding activity and the direct binding of AhR to the promoter region of MnSOD, which contains two core XRE sequences. However, MnSOD activity was reduced by PCB126, which could not be accounted for by acetylation, nitration or phosphorylation of the protein. Dietary Mn supplementation enhanced the increase in MnSOD mRNA but did not reverse the loss of its activities by PCB126, even though it significantly reduced the PCB126-driven liver hypertrophy. Mn supplementation also elevated the Mn concentration in the liver, which was nevertheless decreased by PCB126 both in the whole liver and in liver mitochondria. In conclusion, we discovered that the complex regulation of hepatic MnSOD expression by PCB126 occurred at both transcriptional and post-translational levels. Mn supplementation is protective, although far from complete, against PCB126-induced toxicities.