title: Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure.
abstract: Polychlorinated Biphenyls (PCBs) are industrial chemicals that have become a persistent threat to human health due to ongoing exposure. A subset of PCBs, known as dioxin-like PCBs, pose a special threat given their potent hepatic effects. Micronutrients, especially Cu, Zn and Se, homeostatic dysfunction is commonly seen after exposure to dioxin-like PCBs. This study investigates whether micronutrient alteration is the byproduct of the ongoing hepatotoxicity, marked by lipid accumulation, or a concurrent, yet independent event of hepatic damage. A time course study was carried out using male Sprague-Dawley rats with treatments of PCB126, the prototypical dioxin-like PCB, resulting in 6 different time points. Animals were fed a purified diet, based on AIN-93G, for three weeks to ensure micronutrient equilibration. A single IP injection of either tocopherol-stripped soy oil vehicle (5 mL/kg) or 5 μmol/kg PCB126 dose in vehicle was given at various time points resulting in exposures of 9h, 18 h, 36 h, 3 days, 6 days, and 12 days. Mild hepatic vacuolar change was seen as early as 36 h with drastic changes at the later time points, 6 and 12 days. Micronutrient alterations, specifically Cu, Zn, and Se, were not seen until after day 3 and only observed in the liver. No alterations were seen in the duodenum, suggesting that absorption and excretion may not be involved. Micronutrient alterations occur with ROS formation, lipid accumulation, and hepatomegaly. To probe the mechanistic underpinnings, alteration of gene expression of several copper chaperones was investigated; only metallothionein appeared elevated. These data suggest that the disruption in micronutrient status is a result of the hepatic injury elicited by PCB126 and is mediated in part by metallothionein.
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, Iowa, USA; Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa, USA.
authors.forename: W D
authors.initials: WD
authors.lastname: Klaren
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, Iowa, USA; Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Gadupudi
authors.affiliation: State Hygienic Laboratory, University of Iowa, Ankeny, Iowa, USA.
authors.forename: B
authors.initials: B
authors.lastname: Wels
authors.affiliation: State Hygienic Laboratory, University of Iowa, Ankeny, Iowa, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Simmons
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Olivier
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, Iowa, USA; Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, Iowa, USA. Electronic address: larry-robertson@uiowa.edu.
authors.forename: L W
authors.initials: LW
authors.lastname: Robertson
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003300:Copper / Q000378:metabolism; D018450:Disease Progression; D004785:Environmental Pollutants / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006529:Hepatomegaly / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018977:Micronutrients / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism; D018570:Risk Assessment; D012643:Selenium / Q000378:metabolism; D013997:Time Factors; D015032:Zinc / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D018977:Micronutrients; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D003300:Copper; D011078:Polychlorinated Biphenyls; D012643:Selenium; D015032:Zinc; C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: AhR; Homeostasis; Metals; Micronutrients; PCB126; Time Course