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Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations

Leanne M Stannard, Ann Doherty, Katherine Chapman Orcid Logo, Shareen Doak Orcid Logo, Gareth Jenkins Orcid Logo, Leanne Stannard

Mutagenesis, Volume: 39, Issue: 1, Pages: 13 - 23

Swansea University Authors: Katherine Chapman Orcid Logo, Shareen Doak Orcid Logo, Gareth Jenkins Orcid Logo, Leanne Stannard

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DOI (Published version): 10.1093/mutage/gead025

Abstract

Cadmium chloride (CdCl2) is a known genotoxic carcinogen, with a mechanism of action thought to partly involve the generation of reactive oxygen species (ROS). We applied here a multi-endpoint approach in vitro to explore the impact of CdCl2 on both the genome and on wider cell biology pathways rele...

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Published in: Mutagenesis
ISSN: 0267-8357 1464-3804
Published: Oxford University Press (OUP) 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa64199
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We applied here a multi-endpoint approach in vitro to explore the impact of CdCl2 on both the genome and on wider cell biology pathways relevant to cancer. Multi-endpoint approaches are believed to offer greater promise in terms of understanding the holistic effects of carcinogens in vitro. This richer understanding may help better classification of carcinogens as well as allowing detailed mechanisms of action to be identified. We found that CdCl2 caused DNA damage (micronuclei; MN) in both TK6 and NH32 cells in a dose dependent manner after 4 hours exposure (plus 23 hours recovery), with lowest observable effect levels (LOELs) for MN induction of 1μM (TK6) and 1.6μM (NH32). This DNA damage induction in TK6 cells was ROS dependent as pre-treatment with the antioxidant N Acetyl Cysteine (1mM), abrogated this effect. However, DCFDA was not capable of detecting the ROS induced by CdCl2. The use of NH32 cells allowed an investigation of the role of p53 as they are a p53 null cell line derived from TK6. NH32 showed a 10-fold increase in MN in untreated cells and a similar dose dependent effect after CdCl2 treatment. In TK6 cells, CdCl2 also caused activation of p53 (accumulation of total and phosphorylated p53), imposition of cell cycle checkpoints (G2/M) and intriguingly the production of smaller and more eccentric (elongated) cells. Overall, this multi-endpoint study suggests a carcinogenic mechanism of CdCl2 involving ROS generation, oxidative DNA damage and p53 activation, leading to cell cycle abnormalities and impacts of cell size and shape. 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spelling v2 64199 2023-08-31 Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations 19e7d85eec17117858d867ec0c9f575e 0000-0001-6668-0705 Katherine Chapman Katherine Chapman true false 8f70286908f67238a527a98cbf66d387 0000-0002-6753-1987 Shareen Doak Shareen Doak true false a44095d26187304e903da7ca778697b6 0000-0002-5437-8389 Gareth Jenkins Gareth Jenkins true false 4a21f43a6d275fb4908405b05e60dc5f Leanne Stannard Leanne Stannard true false 2023-08-31 BMS Cadmium chloride (CdCl2) is a known genotoxic carcinogen, with a mechanism of action thought to partly involve the generation of reactive oxygen species (ROS). We applied here a multi-endpoint approach in vitro to explore the impact of CdCl2 on both the genome and on wider cell biology pathways relevant to cancer. Multi-endpoint approaches are believed to offer greater promise in terms of understanding the holistic effects of carcinogens in vitro. This richer understanding may help better classification of carcinogens as well as allowing detailed mechanisms of action to be identified. We found that CdCl2 caused DNA damage (micronuclei; MN) in both TK6 and NH32 cells in a dose dependent manner after 4 hours exposure (plus 23 hours recovery), with lowest observable effect levels (LOELs) for MN induction of 1μM (TK6) and 1.6μM (NH32). This DNA damage induction in TK6 cells was ROS dependent as pre-treatment with the antioxidant N Acetyl Cysteine (1mM), abrogated this effect. However, DCFDA was not capable of detecting the ROS induced by CdCl2. The use of NH32 cells allowed an investigation of the role of p53 as they are a p53 null cell line derived from TK6. NH32 showed a 10-fold increase in MN in untreated cells and a similar dose dependent effect after CdCl2 treatment. In TK6 cells, CdCl2 also caused activation of p53 (accumulation of total and phosphorylated p53), imposition of cell cycle checkpoints (G2/M) and intriguingly the production of smaller and more eccentric (elongated) cells. Overall, this multi-endpoint study suggests a carcinogenic mechanism of CdCl2 involving ROS generation, oxidative DNA damage and p53 activation, leading to cell cycle abnormalities and impacts of cell size and shape. This study shows how the integration of multiple cell biology endpoints studied in parallel in vitro can help mechanistic understanding of how carcinogens disrupt normal cell biology. Journal Article Mutagenesis 39 1 13 23 Oxford University Press (OUP) 0267-8357 1464-3804 1 1 2024 2024-01-01 10.1093/mutage/gead025 http://dx.doi.org/10.1093/mutage/gead025 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2024-04-03T10:39:55.7349934 2023-08-31T12:04:00.8233077 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Leanne M Stannard 1 Ann Doherty 2 Katherine Chapman 0000-0001-6668-0705 3 Shareen Doak 0000-0002-6753-1987 4 Gareth Jenkins 0000-0002-5437-8389 5 Leanne Stannard 6 64199__29875__5e54859a45614a82a60dcd21af70d020.pdf 64199VoR.pdf 2024-04-03T10:39:18.8204587 Output 858154 application/pdf Version of Record true This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. false eng http://creativecommons.org/licenses/by/4.0/
title Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations
spellingShingle Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations
Katherine Chapman
Shareen Doak
Gareth Jenkins
Leanne Stannard
title_short Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations
title_full Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations
title_fullStr Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations
title_full_unstemmed Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations
title_sort Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations
author_id_str_mv 19e7d85eec17117858d867ec0c9f575e
8f70286908f67238a527a98cbf66d387
a44095d26187304e903da7ca778697b6
4a21f43a6d275fb4908405b05e60dc5f
author_id_fullname_str_mv 19e7d85eec17117858d867ec0c9f575e_***_Katherine Chapman
8f70286908f67238a527a98cbf66d387_***_Shareen Doak
a44095d26187304e903da7ca778697b6_***_Gareth Jenkins
4a21f43a6d275fb4908405b05e60dc5f_***_Leanne Stannard
author Katherine Chapman
Shareen Doak
Gareth Jenkins
Leanne Stannard
author2 Leanne M Stannard
Ann Doherty
Katherine Chapman
Shareen Doak
Gareth Jenkins
Leanne Stannard
format Journal article
container_title Mutagenesis
container_volume 39
container_issue 1
container_start_page 13
publishDate 2024
institution Swansea University
issn 0267-8357
1464-3804
doi_str_mv 10.1093/mutage/gead025
publisher Oxford University Press (OUP)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
url http://dx.doi.org/10.1093/mutage/gead025
document_store_str 1
active_str 0
description Cadmium chloride (CdCl2) is a known genotoxic carcinogen, with a mechanism of action thought to partly involve the generation of reactive oxygen species (ROS). We applied here a multi-endpoint approach in vitro to explore the impact of CdCl2 on both the genome and on wider cell biology pathways relevant to cancer. Multi-endpoint approaches are believed to offer greater promise in terms of understanding the holistic effects of carcinogens in vitro. This richer understanding may help better classification of carcinogens as well as allowing detailed mechanisms of action to be identified. We found that CdCl2 caused DNA damage (micronuclei; MN) in both TK6 and NH32 cells in a dose dependent manner after 4 hours exposure (plus 23 hours recovery), with lowest observable effect levels (LOELs) for MN induction of 1μM (TK6) and 1.6μM (NH32). This DNA damage induction in TK6 cells was ROS dependent as pre-treatment with the antioxidant N Acetyl Cysteine (1mM), abrogated this effect. However, DCFDA was not capable of detecting the ROS induced by CdCl2. The use of NH32 cells allowed an investigation of the role of p53 as they are a p53 null cell line derived from TK6. NH32 showed a 10-fold increase in MN in untreated cells and a similar dose dependent effect after CdCl2 treatment. In TK6 cells, CdCl2 also caused activation of p53 (accumulation of total and phosphorylated p53), imposition of cell cycle checkpoints (G2/M) and intriguingly the production of smaller and more eccentric (elongated) cells. Overall, this multi-endpoint study suggests a carcinogenic mechanism of CdCl2 involving ROS generation, oxidative DNA damage and p53 activation, leading to cell cycle abnormalities and impacts of cell size and shape. This study shows how the integration of multiple cell biology endpoints studied in parallel in vitro can help mechanistic understanding of how carcinogens disrupt normal cell biology.
published_date 2024-01-01T10:39:53Z
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