Abstract
Dioxins and dioxin-like compounds encompass a group of structurally related heterocyclic compounds that bind to and activate the aryl hydrocarbon receptor (AhR). The prototypical dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic industrial byproduct that incites numerous adverse physiological effects. Global commercial production of the structurally similar polychlorinated biphenyls (PCBs), however, commenced early in the 20th century and continued for decades; dioxin-like PCBs therefore contribute significantly to total dioxin-associated toxicity. In this study, PCB 126, the most potent dioxin-like PCB, was evaluated with respect to its direct effects on hepatic glucose metabolism using primary mouse hepatocytes. Overnight treatment with PCB 126 reduced hepatic glycogen stores in a dose-dependent manner. Additionally, PCB 126 suppressed forskolin-stimulated gluconeogenesis from lactate. These effects were independent of acute toxicity, as PCB 126 did not increase lactate dehydrogenase release nor affect lipid metabolism or total intracellular ATP. Interestingly, provision of cells with glycerol instead of lactate as the carbon source completely restored hepatic glucose production, indicating specific impairment in the distal arm of gluconeogenesis. In concordance with this finding, PCB 126 blunted the forskolin-stimulated increase in phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels without affecting glucose-6-phosphatase expression. Myricetin, a putative competitive AhR antagonist, reversed the suppression of PEPCK induction by PCB 126. Furthermore, other dioxin-like PCBs demonstrated similar effects on PEPCK expression in parallel with their ability to activate AhR. It therefore appears that AhR activation mediates the suppression of PEPCK expression by dioxin-like PCBs, suggesting a role for these pollutants as disruptors of energy metabolism.
Highlights
polychlorinated biphenyls (PCBs) are a group of bicyclic chlorinated hydrocarbons that are lipophilic and highly resistant to physical, chemical, and enzymatic breakdown [1]
To directly determine the effect of dioxin-like PCBs on hepatic glycogen levels, primary mouse hepatocytes were incubated with varying doses of PCB 126 for 16 h; PCB 126 was selected as the reference PCB for this study due to its toxic equivalence factor (TEF)
PCB 126 had no effect on basal or insulin-stimulated lipogenesis from glucose (Figure 1E), indicating that this agent does not interfere with lipid metabolism in cultured hepatocytes under the stated conditions
Summary
PCBs are a group of bicyclic chlorinated hydrocarbons that are lipophilic and highly resistant to physical, chemical, and enzymatic breakdown [1]. The term dioxin-like refers to structural and physiological similarities to the prototypical dioxin TCDD, a highly toxic byproduct of certain industrial processes. TCDD and its congeners, including dioxin-like PCBs, are thought to exert their toxic effects primarily through activation of the aryl hydrocarbon receptor (AhR), a widely expressed nuclear transcription factor that binds a broad range of xenobiotics [6]. Unliganded AhR resides in the cytosol; binding of a productive ligand induces translocation into the nucleus, where AhR dimerizes with the aryl hydrocarbon receptor nuclear translocator, binds to xenobiotic response elements of its target genes, and induces transcription. The putative mechanism of dioxin-induced toxicity is a combination of high specificity for AhR binding and persistent AhR activation secondary to poor metabolism of dioxins by the CYPs, leading to a range of organ- and species-dependent maladaptive responses (reviewed in [7])
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