title: PCB 126 perturbs hypoxia-induced HIF-1α activity and glucose consumption in human HepG2 cells.
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.
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Sabine U
authors.initials: SU
authors.lastname: Vorrink
authors.affiliation: Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Ehab H
authors.initials: EH
authors.lastname: Sarsour
authors.affiliation: Department of Pathology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA, USA.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Robertson
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Prabhat C
authors.initials: PC
authors.lastname: Goswami
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA; Department of Pathology, The University of Iowa, Iowa City, IA, USA. Electronic address: frederick-domann@uiowa.edu.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Domann
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D004965:Estrogen Antagonists; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls; D005947:Glucose; C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: Cellular metabolism; Hepatocytes; Low oxygen environments; Nuclear localization; Polychlorinated biphenyls