Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines.

Abstract

The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degrees of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Exposure to 1% O2 prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity.

• Authors: Sabine U Vorrink, Paul L Severson, Mikhail V Kulak, Bernard W Futscher, Frederick E Domann
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 274 Issue 3 Pg. 408-16 (Feb 01 2014) ISSN: 1096-0333 [Electronic] United States
• PMID: 24355420 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• AHR protein, human
• ARNT protein, human
• Basic Helix-Loop-Helix Transcription Factors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Polychlorinated Dibenzodioxins
• RNA, Messenger
• Receptors, Aryl Hydrocarbon
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Polychlorinated Biphenyls
• CYP1A1 protein, human
• Cytochrome P-450 CYP1A1
• 3,4,5,3',4'-pentachlorobiphenyl

Topics

• Aryl Hydrocarbon Receptor Nuclear Translocator (genetics, metabolism)
• Basic Helix-Loop-Helix Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Cell Hypoxia (drug effects)
• Cytochrome P-450 CYP1A1 (antagonists & inhibitors, genetics, metabolism)
• Hep G2 Cells
• Hepatocytes (drug effects, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Liver (cytology, drug effects, metabolism)
• Polychlorinated Biphenyls (toxicity)
• Polychlorinated Dibenzodioxins (toxicity)
• Promoter Regions, Genetic
• Protein Binding
• RNA, Messenger (genetics, metabolism)
• Receptors, Aryl Hydrocarbon (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Skin (cytology, drug effects, metabolism)
• Transcriptional Activation