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A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells

Eleanor C. Wilde, Katherine Chapman Orcid Logo, Leanne M. Stannard, Anna L. Seager, Katja Brüsehafer, Ume-Kulsoom Shah, James A. Tonkin, M. Rowan Brown, Jatin R. Verma, Ann T. Doherty, George E. Johnson, Shareen H. Doak, Gareth J. S. Jenkins, George Johnson Orcid Logo, Gareth Jenkins Orcid Logo, Rowan Brown Orcid Logo

Archives of Toxicology, Volume: 92, Issue: 2, Pages: 935 - 951

Swansea University Authors: Katherine Chapman Orcid Logo, George Johnson Orcid Logo, Gareth Jenkins Orcid Logo, Rowan Brown Orcid Logo

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DOI (Published version): 10.1007/s00204-017-2102-y

Abstract

Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-tes...

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Published in: Archives of Toxicology
ISSN: 0340-5761 1432-0738
Published: Springer Science and Business Media LLC 2018
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URI: https://cronfa.swan.ac.uk/Record/cronfa36828
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spelling 2020-06-19T13:02:00.0152596 v2 36828 2017-11-20 A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells 19e7d85eec17117858d867ec0c9f575e 0000-0001-6668-0705 Katherine Chapman Katherine Chapman true false 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false a44095d26187304e903da7ca778697b6 0000-0002-5437-8389 Gareth Jenkins Gareth Jenkins true false d7db8d42c476dfa69c15ce06d29bd863 0000-0003-3628-2524 Rowan Brown Rowan Brown true false 2017-11-20 MEDS Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens’ adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention. Journal Article Archives of Toxicology 92 2 935 951 Springer Science and Business Media LLC 0340-5761 1432-0738 Carcinogenesis, In vitro, Genotoxicity, Multiple-endpoint, Carcinogenicity testing 1 2 2018 2018-02-01 10.1007/s00204-017-2102-y COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2020-06-19T13:02:00.0152596 2017-11-20T09:56:01.7046283 Faculty of Science and Engineering School of Engineering and Applied Sciences - Uncategorised Eleanor C. Wilde 1 Katherine Chapman 0000-0001-6668-0705 2 Leanne M. Stannard 3 Anna L. Seager 4 Katja Brüsehafer 5 Ume-Kulsoom Shah 6 James A. Tonkin 7 M. Rowan Brown 8 Jatin R. Verma 9 Ann T. Doherty 10 George E. Johnson 11 Shareen H. Doak 12 Gareth J. S. Jenkins 13 George Johnson 0000-0001-5643-9942 14 Gareth Jenkins 0000-0002-5437-8389 15 Rowan Brown 0000-0003-3628-2524 16 36828__7144__f7552491f3fd43ff9275077c8bb23177.pdf wilde2017.pdf 2017-11-20T09:58:13.5200000 Output 3607198 application/pdf Version of Record true 2017-11-20T00:00:00.0000000 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License false eng http://creativecommons.org/licenses/by/4.0/
title A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
spellingShingle A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
Katherine Chapman
George Johnson
Gareth Jenkins
Rowan Brown
title_short A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
title_full A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
title_fullStr A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
title_full_unstemmed A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
title_sort A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
author_id_str_mv 19e7d85eec17117858d867ec0c9f575e
37d0f121db69fd09f364df89e4405e31
a44095d26187304e903da7ca778697b6
d7db8d42c476dfa69c15ce06d29bd863
author_id_fullname_str_mv 19e7d85eec17117858d867ec0c9f575e_***_Katherine Chapman
37d0f121db69fd09f364df89e4405e31_***_George Johnson
a44095d26187304e903da7ca778697b6_***_Gareth Jenkins
d7db8d42c476dfa69c15ce06d29bd863_***_Rowan Brown
author Katherine Chapman
George Johnson
Gareth Jenkins
Rowan Brown
author2 Eleanor C. Wilde
Katherine Chapman
Leanne M. Stannard
Anna L. Seager
Katja Brüsehafer
Ume-Kulsoom Shah
James A. Tonkin
M. Rowan Brown
Jatin R. Verma
Ann T. Doherty
George E. Johnson
Shareen H. Doak
Gareth J. S. Jenkins
George Johnson
Gareth Jenkins
Rowan Brown
format Journal article
container_title Archives of Toxicology
container_volume 92
container_issue 2
container_start_page 935
publishDate 2018
institution Swansea University
issn 0340-5761
1432-0738
doi_str_mv 10.1007/s00204-017-2102-y
publisher Springer Science and Business Media LLC
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Uncategorised{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Uncategorised
document_store_str 1
active_str 0
description Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens’ adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention.
published_date 2018-02-01T07:14:11Z
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