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Dietary Manganese Modulates PCB126 Toxicity, Metal Status, and MnSOD in the Rat
Bingxuan Wang1, William D Klaren1, Brian R Wels2
1*The Interdisciplinary Graduate Program in Human Toxicology and.
Abstract:
PCB126 (3,3',4,4',5-pentachlorobiphenyl) is a potent aryl hydrocarbon receptor agonist and induces oxidative stress. Because liver manganese (Mn) levels decrease in response to PCB126, a Mn dietary study was designed to investigate the role of Mn in PCB126 toxicity. Male Sprague Dawley rats received diets containing 0, 10, or 150 ppm added Mn for 3 weeks, followed by a single ip injection of corn oil or PCB126 (5 µmol/kg body weight). After 2 weeks, Mn, Cu, Zn, and Fe levels in the heart, liver, and liver mitochondria, and Mn-containing superoxide dismutase (MnSOD) and metallothionein mRNA, MnSOD protein, and MnSOD activity were determined. Mn levels in liver, heart, and liver mitochondria were strongly decreased by the Mn-deficient diet. Small effects on Fe levels and a stepwise increase in MnSOD activity with dietary Mn were also visible. PCB126 caused profound changes in Cu (up), Zn, Fe, and Mn (down) in liver, but not in heart, and differing effects (Cu, Zn, and Fe up, Mn down) in liver mitochondria. Liver MnSOD and metallothionein mRNA levels and MnSOD protein were increased but MnSOD activity was decreased by PCB126. PCB126-induced liver enlargement was dose-dependently reduced with increasing dietary Mn. These changes in metals homeostasis and MnSOD activity in liver but not heart may be a/the mechanism of PCB126 liver-specific toxicity. Specifically, transport of Fenton metals (Cu, Fe) into and Mn out of the mitochondria, a probable mechanism for lower MnSOD activity, may be a/the cause of PCB126-induced oxidative stress. The role of metallothioneins needs further evaluation. Dietary Mn slightly alleviated PCB126-induced toxicities.
Insights
Dietary manganese (Mn) supplementation reduced liver enlargement and toxicity caused by PCB126, a potent aryl hydrocarbon receptor agonist. This suggests Mn plays a key role in mitigating PCB126-induced liver damage and oxidative stress.
Area of Science:
- Environmental Toxicology
- Nutritional Biochemistry
- Hepatotoxicity
Background:
- Polychlorinated biphenyl 126 (PCB126) is an aryl hydrocarbon receptor agonist known to induce oxidative stress.
- Previous observations indicate that PCB126 exposure leads to decreased manganese (Mn) levels in the liver.
- The specific role of Mn in PCB126 toxicity remains unclear.
Purpose of the Study:
- To investigate the protective role of dietary manganese (Mn) in PCB126-induced toxicity.
- To examine the effects of PCB126 on metal homeostasis and oxidative stress markers in rats fed varying Mn diets.
- To elucidate the mechanisms underlying PCB126-induced liver-specific toxicity.
Main Methods:
- Male Sprague Dawley rats were fed diets with 0, 10, or 150 ppm added Mn for three weeks.
- Following dietary treatment, rats received an intraperitoneal injection of either corn oil or PCB126.
- Liver and heart tissues, including mitochondria, were analyzed for metal content (Mn, Cu, Zn, Fe), Mn-containing superoxide dismutase (MnSOD) and metallothionein mRNA, MnSOD protein levels, and MnSOD activity.
Main Results:
- PCB126 exposure significantly altered metal levels in the liver and liver mitochondria, decreasing Mn while increasing Cu, Zn, and Fe.
- Dietary Mn supplementation dose-dependently reduced PCB126-induced liver enlargement and alleviated toxic effects.
- PCB126 increased MnSOD and metallothionein mRNA and MnSOD protein, but decreased MnSOD activity, an effect partially mitigated by dietary Mn.
Conclusions:
- Dietary manganese partially alleviates PCB126-induced liver toxicity, suggesting a crucial role for Mn in mitigating PCB126-induced oxidative stress.
- Alterations in metal homeostasis, particularly the transport of Fenton metals into and Mn out of mitochondria, may underlie PCB126's hepatotoxicity and reduced MnSOD activity.
- Further research is warranted to fully understand the role of metallothioneins in this context.
