title: Does dietary copper supplementation enhance or diminish PCB126 toxicity in the rodent liver?
abstract: Copper is essential for the function of the mitochondrial electron transport chain and several antioxidant proteins. However, in its free form copper can participate in Fenton-like reactions that produce reactive hydroxyl radicals. Aryl-hydrocarbon receptor (AhR) agonists, including the most potent polychlorinated biphenyl (PCB) congener, 3,3',4,4',5-pentachlorobiphenyl (PCB126), increase copper levels in rodent livers. This is accompanied by biochemical and toxic changes. To assess the involvement of copper in PCB toxicity, male Sprague-Dawley rats were fed an AIN-93G diet with differing dietary copper levels: low (2 ppm), adequate (6 ppm), and high (10 ppm). After three weeks, rats from each group were given a single ip injection of corn oil (control), 1, or 5 μmol/kg body weight PCB126. Two weeks following injections, biochemical and morphological markers of hepatic toxicity, trace metal status, and hepatic gene expression of metalloproteins were evaluated. Increasing dietary copper was associated with elevated tissue levels of copper and ceruloplasmin. In the livers of PCB126-treated rats, the hallmark signs of AhR activation were present, including increased cytochrome P450 and lipid levels and decreased glutathione. In addition, a doubling of hepatic copper levels was seen, and overall metal homeostasis was disturbed, resulting in decreased hepatic selenium, manganese, zinc, and iron. Expression of key metalloproteins was either decreased (cytochrome c oxidase), unchanged (ceruloplasmin and CuZnSOD), or increased (tyrosinase and metallothioneins 1 and 2) with exposure to PCB126. Increases in metallothionein may contribute/reflect the increased copper seen. Alterations in dietary copper did not amplify or abrogate the hepatic toxicity of PCB126. PCB126 toxicity, i.e., oxidative stress and steatosis, is clearly associated with disturbed metal homeostasis. Understanding the mechanisms of this disturbance may provide tools to prevent liver toxicity by other AhR agonists.
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, University of Iowa , UI Research Park, #219 IREH, Iowa City, Iowa 52242-5000, USA.
authors.forename: Ian K
authors.initials: IK
authors.lastname: Lai
authors.forename: William D
authors.initials: WD
authors.lastname: Klaren
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.forename: Brian
authors.initials: B
authors.lastname: Wels
authors.forename: Donald L
authors.initials: DL
authors.lastname: Simmons
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.forename: Wanda M
authors.initials: WM
authors.lastname: Haschek
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ludewig
authors.forename: Larry W
authors.initials: LW
authors.lastname: Robertson
mesh_terms: D000818:Animals; D003300:Copper / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D003300:Copper; D011078:Polychlorinated Biphenyls