Upregulation of epithelial metallothioneins by metal-rich ultrafine particulate matter from an underground railway
Upregulation of epithelial metallothioneins by metal-rich ultrafine particulate matter from an underground railway
Airborne particulate matter (PM) is a leading cause of mortality and morbidity. However, understanding of the range and mechanisms of effects of PM components is poor. PM generated in underground railways is rich in metals, especially iron. In the ultrafine (UFPM; <0.1 µm diameter) fraction, the combination of small size and metal enrichment poses an unknown health risk. This study aimed to analyse transcriptomic responses to underground UFPM in primary bronchial epithelial cells (PBECs), a key site of PM deposition. The oxidation state of iron in UFPM from an underground station was determined by x-ray absorption near edge structure (XANES) spectroscopy. Antioxidant response was assayed using a reporter cell line transfected with an antioxidant response element (ARE)-luciferase construct. Differentiated PBECs were exposed to UFPM for 6 h or 24 h for RNA-Seq and RT-qPCR analysis. XANES showed predominance of redox-active Fe3O4, with ROS generation confirmed by induction of ARE-luciferase expression. 6 h exposure of PBECs to UFPM identified 52 differentially expressed genes (DEGs), especially associated with epithelial maintenance, whereas 24 h exposure yielded 23 DEGs, particularly involved with redox homeostasis and metal binding. At both timepoints, there was upregulation of members of the metallothionein family, low molecular weight proteins with antioxidant activity whose main function is binding and homeostasis of zinc and copper ions, but not iron ions. This upregulation was partially inhibited by metal chelation or ROS scavenging. These data suggest differential regulation of responses to metal-rich UFPM depending on exposure period, and highlight novel pathways and markers of PM exposure, with the role of metallothioneins warranting further investigation.
particulate matter, air pollution, metals, transcriptomics, oxidative stress, epithelium, airway
1070-1082
Loxham, Matthew
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Woo, Jeongmin
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Singhania, Akul
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Smithers, Natalie P.
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Yeomans, Alison
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Packham, Graham
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Crainic, Alina-Mariana
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Cook, Richard
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Cassee, Flemming R.
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Woelk, Christopher H.
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Davies, Donna
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1 July 2020
Loxham, Matthew
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Woo, Jeongmin
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Singhania, Akul
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Smithers, Natalie P.
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Yeomans, Alison
b47f0dfe-596f-4cef-b4b6-2233b7cdd899
Packham, Graham
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Crainic, Alina-Mariana
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Cook, Richard
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Cassee, Flemming R.
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Woelk, Christopher H.
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Davies, Donna
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Loxham, Matthew, Woo, Jeongmin, Singhania, Akul, Smithers, Natalie P., Yeomans, Alison, Packham, Graham, Crainic, Alina-Mariana, Cook, Richard, Cassee, Flemming R., Woelk, Christopher H. and Davies, Donna
(2020)
Upregulation of epithelial metallothioneins by metal-rich ultrafine particulate matter from an underground railway.
Metallomics, 12 (7), .
(doi:10.1039/d0mt00014k).
Abstract
Airborne particulate matter (PM) is a leading cause of mortality and morbidity. However, understanding of the range and mechanisms of effects of PM components is poor. PM generated in underground railways is rich in metals, especially iron. In the ultrafine (UFPM; <0.1 µm diameter) fraction, the combination of small size and metal enrichment poses an unknown health risk. This study aimed to analyse transcriptomic responses to underground UFPM in primary bronchial epithelial cells (PBECs), a key site of PM deposition. The oxidation state of iron in UFPM from an underground station was determined by x-ray absorption near edge structure (XANES) spectroscopy. Antioxidant response was assayed using a reporter cell line transfected with an antioxidant response element (ARE)-luciferase construct. Differentiated PBECs were exposed to UFPM for 6 h or 24 h for RNA-Seq and RT-qPCR analysis. XANES showed predominance of redox-active Fe3O4, with ROS generation confirmed by induction of ARE-luciferase expression. 6 h exposure of PBECs to UFPM identified 52 differentially expressed genes (DEGs), especially associated with epithelial maintenance, whereas 24 h exposure yielded 23 DEGs, particularly involved with redox homeostasis and metal binding. At both timepoints, there was upregulation of members of the metallothionein family, low molecular weight proteins with antioxidant activity whose main function is binding and homeostasis of zinc and copper ions, but not iron ions. This upregulation was partially inhibited by metal chelation or ROS scavenging. These data suggest differential regulation of responses to metal-rich UFPM depending on exposure period, and highlight novel pathways and markers of PM exposure, with the role of metallothioneins warranting further investigation.
Text
Metallomics Transcriptomics
- Accepted Manuscript
Text
Loxham Upregulation of epithelial metallothioneins by metal-rich UFPM from underground
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Accepted/In Press date: 18 March 2020
e-pub ahead of print date: 16 April 2020
Published date: 1 July 2020
Additional Information:
Funding Information:
The authors thank A. John F. Boere, Daan L. A. C. Leseman, and Paul H. B. Fokkens from the Centre for Sustainability, Environment and Health, National Institute for Public Health and the Environment (RIVM), Netherlands, for valuable assistance with collecting ultrafine particulate matter from the underground railway station, Dr Robert A. Ridley and Graham A. Berreen (Brooke Laboratory, Faculty of Medicine, University of Southampton, UK) for help with the culture of PBECs, Dr Kamran Tariq (Faculty of Medicine, University of Southampton) for provision of bronchial brushings, Dr Timothy Hinks (Faculty of Medicine, University of Southampton (now at Nuffield Department of Medicine, University of Oxford)) for providing PBEC donor information, and Professor Roland Wolf (University of Dundee, UK) for the kind gift of the ARE reporter construct. ML is funded by a BBSRC Future Leader Fellowship (BB/P011365/1) and a National Institute for Health Research Southampton Biomedical Research Centre Senior Research Fellowship, and also a research grant from the Asthma, Allergy, and Inflammation Research (AAIR) Charity.
Publisher Copyright:
© The Royal Society of Chemistry.
Keywords:
particulate matter, air pollution, metals, transcriptomics, oxidative stress, epithelium, airway
Identifiers
Local EPrints ID: 438941
URI: http://eprints.soton.ac.uk/id/eprint/438941
ISSN: 1756-5901
PURE UUID: af36e2ec-41b2-4413-8afa-7cf77e6d7fb2
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Date deposited: 27 Mar 2020 17:30
Last modified: 16 Apr 2024 04:02
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Contributors
Author:
Jeongmin Woo
Author:
Akul Singhania
Author:
Natalie P. Smithers
Author:
Alison Yeomans
Author:
Alina-Mariana Crainic
Author:
Flemming R. Cassee
Author:
Christopher H. Woelk
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