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 umol/kg PCB126 dose in vehicle was given at various time points resulting in exposures of 9 hr, 18 hr, 36 hr, 3 days, 6 days, and 12 days. Mild hepatic vacuolar change was seen as early as 36 hours 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.

Assessment of the Mitigative Capacity of Dietary Zinc on PCB126 Hepatotoxicity and the Contribution of Zinc to Toxicity

“…4, 27, 40 Hepatic copper was increased in a dose dependent fashion, whereas zinc, selenium, and manganese were decreased (Figure 5). The zinc deficient diet did cause lower hepatic zinc levels whereas zinc supplementation did not increase levels.…”

“…Previous investigations have shown that PCB126 exposure causes decreases in hepatic zinc. 27 In addition, zinc is important in the toxicity of other liver specific agents, like carbon tetrachloride and acetaminophen, since both deficiency and supplementation alter their toxicity. On the basis of these findings, the authors hypothesized that zinc deficiency would exacerbate PCB126 mediated liver injury and supplementation mitigate.…”

“…Previous studies have demonstrated an increase in other antioxidant enzymes after exposure to PCB126, in particular metallothionein, glutathione transferase, and total glutathione peroxidase. 6, 27 …”

Identification of lipidomic markers of chronic 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) exposure in the male rat liver

“…One hallmark of PCB 126 exposure is liver steatosis in rodent models (Klaren et al, 2015; Lai et al, 2010a; Lai et al, 2011; Lai et al, 2012). For example, histological examinations revealed that acute intraperitoneal exposure to PCB 126 caused a gradual increase in hepatic lipid levels, with lipid levels being significantly higher compared to controls of days 6 and 12 after exposure (Gadupudi et al, 2016; Klaren et al, 2015). These changes were accompanied by diffuse vacuolar changes that are apparent as early as 18 h after PCB 126 exposure.…”

“…Exposure to PCB 126 causes wasting syndrome and alters redox and metal homeostasis in rodent models (Klaren et al, 2015; Lai et al, 2010a; Lai et al, 2011; Lai et al, 2012) by mechanisms involving the AhR (van den Berg et al, 2006). PCB 126 exposure also decreases hepatic glucose levels, followed by a decrease in peroxisomal fatty acid oxidation in male rats (Gadupudi et al, 2016).…”