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Prior PCB exposure suppresses hypoxia-induced up-regulation of glycolytic enzymes in Fundulus heteroclitus

University of British Columbia - Vancouver, Vancouver, British Columbia, Canada
Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology (Impact Factor: 2.83). 11/2004; 139(1-3):23-9. DOI: 10.1016/j.cca.2004.08.015
Source: PubMed

ABSTRACT Increased activity of the glycolytic enzymes is a conserved feature of the cellular response to hypoxia, and may represent a protective mechanism by which cells can survive short-term hypoxic exposure. Gene induction by hypoxia involves a dimer of the hypoxia inducible factor (HIF)-1 alpha and the nuclear cofactor HIF-1 beta, also called the aryl hydrocarbon receptor nuclear translocator (ARNT), which is also involved in induction of genes in response to aryl hydrocarbon exposure. To assess the possibility of interaction between these pathways, we examined changes in the activity of the glycolytic enzymes in response to hypoxia and polychlorinated biphenyl (PCB) exposure in the liver of a teleost fish, Fundulus heteroclitus. After 3 days of hypoxic exposure (dissolved oxygen levels between 1.5 and 2.0 mg/L), there were significant increases in the activity of six glycolytic enzymes (PGI, ALD, TPI, PGK, PGM and LDH). In contrast, intraperitoneal injection of 1 microg/g body weight of PCB #77 (3,3',4,4'-tetrachlorobiphenyl) caused significant decreases in glycolytic enzyme activity after 7 days of exposure. When fish were injected with PCB #77 and then (4 days later) exposed to hypoxia for 3 days as before, we observed no induction of the glycolytic enzymes. This suggests that there is an antagonistic interaction between exposure to PCBs and hypoxia in F. heteroclitus. Prior PCB exposure could make these fish less tolerant of environmental hypoxia.

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    • "Few studies have assessed the effects of PCB exposure on the hypoxia signaling pathway. A study by Kraemer and Schulte assessed the effect of PCB 77, another dioxin-like PCB, on hypoxia-induced glycolytic enzyme activity in fish and found that PCB treatment decreased enzyme activity (Kraemer and Schulte, 2004). However, it is not known if PCB 126 affects hypoxia-regulated responses of HIF-1␣. "
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    ABSTRACT: Aerobic organisms strongly depend on the availability of oxygen for respiration and countless other metabolic processes to maintain cellular homeostasis. Under certain conditions, the amount of available oxygen can be limited. To support survival in environments with limited oxygen supply, hypoxia-inducible factors (HIFs) reprogram vital components of cellular metabolism. HIF-1α is an important mediator of acute and adaptive responses to hypoxic stress. Interestingly, the heterodimeric partner required by HIF-1α to function as transcription factor, known as ARNT, is also an essential part of the aryl hydrocarbon receptor (AhR) transcription factor complex. Thus, via ARNT a crosstalk exists between these two pathways that might affect HIF-1α-mediated processes. In this study we sought to assess the effect of the AhR agonist PCB 126 on HIF-1α activity as well as on HIF-1α-regulated targets involved in cellular metabolism in human HepG2 cells. Our results show that PCB 126 reduced HIF-1α localization to the nucleus. Furthermore, in an in vivo setting, rats exposed to parenteral PCB 126 also displayed reduced hepatocyte nuclear localization of HIF-1α. Additionally, HepG2 cells exposed to PCB 126 displayed reduced hypoxia-regulated HRE-luciferase reporter gene expression as well as a reduction in glucose consumption in conditions of hypoxia. In summary, this study reveals that HIF-1α-regulated cellular metabolic processes are negatively affected by PCB 126 which might ultimately affect adaptive responses and cell survival in hypoxic environments.
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    • "In this regard, it has been discussed by others that hypoxia promote a transient increase in blood glucose due to a delayed utilization rate during the switch on substrate fuel preferences , namely from protein and lipids to carbohydrates (Haman et al., 1997; Vianen et al., 2002; Speers-R oesch et al., 2010 ). It is interesting to mention that a previous study by Kraemer and Schulte (2004), detected that PCBs pre-treatm ent inhibits the hypoxia-me diated induction on some glycolyti c enzymes of Fundulus heteroclitus . Conceivably, BaP-treatment may be interfere d with the hypoxia-mediated change in energy substrates to fuel glycolysis, resulting in the transient glucose increase detected in our study. "
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    • "Studies have also shown that hypoxia may increase the toxicity of exposures to PAHs, dioxins, and PCBs, leading to potential CITS 102, 103. Exposures to these chemical classes may also hinder the ability of species to respond to increased hypoxia under climate change (TICS scenario) 104. Interactions between hypoxia and contaminants demonstrate the complexity of direct and indirect parameters altered by GCC that could impair the health of aquatic organisms and populations. "
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