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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
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
1756-5901
1070-1082
Loxham, Matthew
8ef02171-9040-4c1d-8452-2ca34c56facb
Woo, Jeongmin
f31ed6e0-741c-4ccf-8e14-3b4f92bac2b7
Singhania, Akul
322f628d-5374-49ec-b7d7-13bb3885d636
Smithers, Natalie P.
63ead01b-6515-4f82-a963-884f572af872
Yeomans, Alison
b47f0dfe-596f-4cef-b4b6-2233b7cdd899
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Crainic, Alina-Mariana
a8df3e5f-a738-4683-acc8-c75433c88cd0
Cook, Richard
06f8322d-81be-4f82-9326-19e55541c78f
Cassee, Flemming R.
9ec4238b-6a04-4e9c-9680-d0394168faa4
Woelk, Christopher H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Loxham, Matthew
8ef02171-9040-4c1d-8452-2ca34c56facb
Woo, Jeongmin
f31ed6e0-741c-4ccf-8e14-3b4f92bac2b7
Singhania, Akul
322f628d-5374-49ec-b7d7-13bb3885d636
Smithers, Natalie P.
63ead01b-6515-4f82-a963-884f572af872
Yeomans, Alison
b47f0dfe-596f-4cef-b4b6-2233b7cdd899
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Crainic, Alina-Mariana
a8df3e5f-a738-4683-acc8-c75433c88cd0
Cook, Richard
06f8322d-81be-4f82-9326-19e55541c78f
Cassee, Flemming R.
9ec4238b-6a04-4e9c-9680-d0394168faa4
Woelk, Christopher H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38

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), 1070-1082. (doi:10.1039/d0mt00014k).

Record type: Article

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.

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Accepted/In Press date: 18 March 2020
e-pub ahead of print date: 16 April 2020
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
ORCID for Matthew Loxham: ORCID iD orcid.org/0000-0001-6459-538X
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991

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Date deposited: 27 Mar 2020 17:30
Last modified: 18 Feb 2021 17:23

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Contributors

Author: Matthew Loxham ORCID iD
Author: Jeongmin Woo
Author: Akul Singhania
Author: Natalie P. Smithers
Author: Alison Yeomans
Author: Graham Packham ORCID iD
Author: Alina-Mariana Crainic
Author: Richard Cook
Author: Flemming R. Cassee
Author: Donna Davies ORCID iD

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