Journal article
Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines
Toxicology and applied pharmacology, Vol.274(3), pp.408-416
02/01/2014
DOI: 10.1016/j.taap.2013.12.002
PMCID: PMC3919493
PMID: 24355420
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.
•Significant crosstalk exists between AhR and HIF-1α signaling.•Hypoxia perturbs PCB 126 induced AhR function and target gene expression.•PCB 126 mediated activation of AhR activity inhibits HIF-1α signaling.•AhR binding to CYP1A1 and CYP1B1 promoters is inhibited by hypoxia.•ARNT overexpression relieves hypoxic inhibition of AhR function.
Details
- Title: Subtitle
- Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines
- Creators
- Sabine U Vorrink - Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USAPaul L Severson - Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ, USAMikhail V Kulak - Department of Surgery, The University of Iowa, Iowa City, IA, USABernard W Futscher - Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ, USAFrederick E Domann - Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Toxicology and applied pharmacology, Vol.274(3), pp.408-416
- DOI
- 10.1016/j.taap.2013.12.002
- PMID
- 24355420
- PMCID
- PMC3919493
- NLM abbreviation
- Toxicol Appl Pharmacol
- ISSN
- 0041-008X
- eISSN
- 1096-0333
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health (NIH), award: P42 ES013661-5099, P42 ES004940-5083, P50 ES006694, 2T32 ES007091-31; name: SRP Training Core, award: P42 ES013661-5110
- Language
- English
- Date published
- 02/01/2014
- Academic Unit
- Pathology; Surgery; Radiation Oncology; Iowa Superfund Research Program
- Record Identifier
- 9984046830702771
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