Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway
Abstract
Dioxins such as 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) are common environmental contaminants known to regulate several genes via activation of the transcription factor aryl hydrocarbon receptor (AhR) associated with the development of numerous adverse biological effects. However, comparatively little is known about the molecular mechanisms by which dioxins display their toxic effects in vertebrates. The 5' untranslated region of the hepatocellular Reduced folate carrier (Rfc1; Slc19a1) exhibits AhR binding sites termed dioxin responsive elements (DRE) that have as yet only been found in the promoter region of prototypical TCDD target genes. Rfc1 mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) plays an essential role in physiological folate homeostasis and MTX cancer chemotherapy. In order to determine whether this carrier represents a target gene of dioxins we have investigated the influence of TCDD on functional Rfc1 activity in rat liver. Pre-treatment of rats with TCDD significantly diminished hepatocellular Rfc1 uptake activity in a time- and dose-dependent manner. In further mechanistic studies we demonstrated that this reduction was due to TCDD-dependent activation of the AhR signalling pathway. We additionally showed that binding of the activated receptor to DRE motifs in the Rfc1 promoter resulted in downregulation of Rfc1 gene expression andmore »
- Authors:
-
- Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig (Germany)
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig (Germany)
- Molecular Cell Therapy, Center for Biotechnology and Biomedicine, Faculty of Medicine, University of Leipzig, Leipzig (Germany)
- Publication Date:
- OSTI Identifier:
- 21451176
- Resource Type:
- Journal Article
- Journal Name:
- Toxicology and Applied Pharmacology
- Additional Journal Information:
- Journal Volume: 246; Journal Issue: 1-2; Other Information: DOI: 10.1016/j.taap.2010.04.020; PII: S0041-008X(10)00164-X; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; CARCINOGENESIS; CARDIOVASCULAR DISEASES; CARRIERS; DIOXIN; GENES; METHOTREXATE; RATS; RECEPTORS; TOXICITY; TRANSCRIPTION FACTORS; ANIMALS; ANTIMETABOLITES; DISEASES; DRUGS; HETEROCYCLIC COMPOUNDS; MAMMALS; MEMBRANE PROTEINS; ORGANIC COMPOUNDS; ORGANIC OXYGEN COMPOUNDS; PATHOGENESIS; PROTEINS; RODENTS; VERTEBRATES
Citation Formats
Halwachs, Sandra, Lakoma, Cathleen, Gebhardt, Rolf, Schaefer, Ingo, Seibel, Peter, and Honscha, Walther. Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway. United States: N. p., 2010.
Web. doi:10.1016/j.taap.2010.04.020.
Halwachs, Sandra, Lakoma, Cathleen, Gebhardt, Rolf, Schaefer, Ingo, Seibel, Peter, & Honscha, Walther. Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway. United States. https://doi.org/10.1016/j.taap.2010.04.020
Halwachs, Sandra, Lakoma, Cathleen, Gebhardt, Rolf, Schaefer, Ingo, Seibel, Peter, and Honscha, Walther. 2010.
"Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway". United States. https://doi.org/10.1016/j.taap.2010.04.020.
@article{osti_21451176,
title = {Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway},
author = {Halwachs, Sandra and Lakoma, Cathleen and Gebhardt, Rolf and Schaefer, Ingo and Seibel, Peter and Honscha, Walther},
abstractNote = {Dioxins such as 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) are common environmental contaminants known to regulate several genes via activation of the transcription factor aryl hydrocarbon receptor (AhR) associated with the development of numerous adverse biological effects. However, comparatively little is known about the molecular mechanisms by which dioxins display their toxic effects in vertebrates. The 5' untranslated region of the hepatocellular Reduced folate carrier (Rfc1; Slc19a1) exhibits AhR binding sites termed dioxin responsive elements (DRE) that have as yet only been found in the promoter region of prototypical TCDD target genes. Rfc1 mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) plays an essential role in physiological folate homeostasis and MTX cancer chemotherapy. In order to determine whether this carrier represents a target gene of dioxins we have investigated the influence of TCDD on functional Rfc1 activity in rat liver. Pre-treatment of rats with TCDD significantly diminished hepatocellular Rfc1 uptake activity in a time- and dose-dependent manner. In further mechanistic studies we demonstrated that this reduction was due to TCDD-dependent activation of the AhR signalling pathway. We additionally showed that binding of the activated receptor to DRE motifs in the Rfc1 promoter resulted in downregulation of Rfc1 gene expression and reduced carrier protein levels. As downregulation of pivotal Rfc1 activity results in functional folate deficiency associated with an elevated risk of cardiovascular diseases or carcinogenesis, our results indicate that deregulation of this essential transport pathway represents a novel regulatory mechanism how dioxins display their toxic effects through the Ah receptor.},
doi = {10.1016/j.taap.2010.04.020},
url = {https://www.osti.gov/biblio/21451176},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1-2,
volume = 246,
place = {United States},
year = {Thu Jul 15 00:00:00 EDT 2010},
month = {Thu Jul 15 00:00:00 EDT 2010}
}