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An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens

Katherine Chapman Orcid Logo, Ume-kulsoom Shah Orcid Logo, Jessica Fletcher Orcid Logo, George Johnson Orcid Logo, Shareen Doak Orcid Logo, Gareth Jenkins Orcid Logo

Mutagenesis, Volume: 39, Issue: 2, Pages: 69 - 77

Swansea University Authors: Katherine Chapman Orcid Logo, Ume-kulsoom Shah Orcid Logo, Jessica Fletcher Orcid Logo, George Johnson Orcid Logo, Shareen Doak Orcid Logo, Gareth Jenkins Orcid Logo

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DOI (Published version): 10.1093/mutage/geae004

Abstract

Chemical safety testing plays a crucial role in product and pharmacological development, as well as chemoprevention; however, in vitro genotoxicity safety tests do not always accurately predict the chemicals that will be in vivo carcinogens. If chemicals test positive in vitro for genotoxicity but n...

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Published in: Mutagenesis
ISSN: 0267-8357 1464-3804
Published: Oxford University Press (OUP) 2024
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The endpoints were used to observe cellular responses to 18 chemicals within the following categories: genotoxic carcinogens, non-genotoxic carcinogens, toxic non-carcinogens, and misleading in vitro positive and negative agents. The number of endpoints significantly altered for each chemical was considered, alongside the holistic Integrated Signature of Carcinogenicity score, derived from the sum of fold changes for all endpoints. Following the calculation of an overall score from these measures, carcinogens exhibited greater potency than non-carcinogens. Genotoxic carcinogens were generally more potent than non-genotoxic carcinogens. This novel approach therefore demonstrated potential for correctly predicting whether chemicals with unknown mechanism may be considered carcinogens. Overall, while further validation is recommended, the test demonstrates potential for the identification of carcinogenic compounds. 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spelling v2 65653 2024-02-19 An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens 19e7d85eec17117858d867ec0c9f575e 0000-0001-6668-0705 Katherine Chapman Katherine Chapman true false bcef4e069220a4b85f8a2c0cc3059487 0000-0002-0594-580X Ume-kulsoom Shah Ume-kulsoom Shah true false 25b51eb7a9fb4c1779b6b4b3a7ac3f1d 0000-0002-4911-2711 Jessica Fletcher Jessica Fletcher true false 37d0f121db69fd09f364df89e4405e31 0000-0001-5643-9942 George Johnson George Johnson true false 8f70286908f67238a527a98cbf66d387 0000-0002-6753-1987 Shareen Doak Shareen Doak true false a44095d26187304e903da7ca778697b6 0000-0002-5437-8389 Gareth Jenkins Gareth Jenkins true false 2024-02-19 BMS Chemical safety testing plays a crucial role in product and pharmacological development, as well as chemoprevention; however, in vitro genotoxicity safety tests do not always accurately predict the chemicals that will be in vivo carcinogens. If chemicals test positive in vitro for genotoxicity but negative in vivo, this can contribute to unnecessary testing in animals used to confirm erroneous in vitro positive results. Current in vitro tests typically evaluate only genotoxicity endpoints, which limits their potential to detect non-genotoxic carcinogens. The frequency of misleading in vitro positive results can be high, leading to a requirement for more informative in vitro tests. It is now recognized that multiple-endpoint genotoxicity testing may aid more accurate detection of carcinogens and non-carcinogens. The objective of this review was to evaluate the utility of our novel, multiple-endpoint in vitro test, which uses multiple cancer-relevant endpoints to predict carcinogenic potential. The tool assessed micronucleus frequency, p53 expression, p21 expression, mitochondrial respiration, cell cycle abnormalities and, uniquely, cell morphology changes in human lymphoblastoid cell lines, TK6 and MCL-5. The endpoints were used to observe cellular responses to 18 chemicals within the following categories: genotoxic carcinogens, non-genotoxic carcinogens, toxic non-carcinogens, and misleading in vitro positive and negative agents. The number of endpoints significantly altered for each chemical was considered, alongside the holistic Integrated Signature of Carcinogenicity score, derived from the sum of fold changes for all endpoints. Following the calculation of an overall score from these measures, carcinogens exhibited greater potency than non-carcinogens. Genotoxic carcinogens were generally more potent than non-genotoxic carcinogens. This novel approach therefore demonstrated potential for correctly predicting whether chemicals with unknown mechanism may be considered carcinogens. Overall, while further validation is recommended, the test demonstrates potential for the identification of carcinogenic compounds. Adoption of the approach could enable reduced animal use in carcinogenicity testing. Journal Article Mutagenesis 39 2 69 77 Oxford University Press (OUP) 0267-8357 1464-3804 carcinogenicity, genotoxicity, micronucleus assay, multiple-endpoint, in vitro 12 3 2024 2024-03-12 10.1093/mutage/geae004 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University SU Library paid the OA fee (TA Institutional Deal) This work was supported by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) (Grant number NC/K500033/1) and the UK Environmental Mutagen Society. 2024-04-30T16:44:40.2089771 2024-02-19T12:22:04.9476106 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Katherine Chapman 0000-0001-6668-0705 1 Ume-kulsoom Shah 0000-0002-0594-580X 2 Jessica Fletcher 0000-0002-4911-2711 3 George Johnson 0000-0001-5643-9942 4 Shareen Doak 0000-0002-6753-1987 5 Gareth Jenkins 0000-0002-5437-8389 6 65653__29899__a7b1c066771a45c993444f27dd5638df.pdf 65653.pdf 2024-04-03T15:58:22.0985312 Output 3759203 application/pdf Version of Record true This is an Open Access article distributed under the terms of the Creative Commons Attribution License. true eng https://creativecommons.org/licenses/by/4.0/
title An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens
spellingShingle An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens
Katherine Chapman
Ume-kulsoom Shah
Jessica Fletcher
George Johnson
Shareen Doak
Gareth Jenkins
title_short An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens
title_full An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens
title_fullStr An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens
title_full_unstemmed An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens
title_sort An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens
author_id_str_mv 19e7d85eec17117858d867ec0c9f575e
bcef4e069220a4b85f8a2c0cc3059487
25b51eb7a9fb4c1779b6b4b3a7ac3f1d
37d0f121db69fd09f364df89e4405e31
8f70286908f67238a527a98cbf66d387
a44095d26187304e903da7ca778697b6
author_id_fullname_str_mv 19e7d85eec17117858d867ec0c9f575e_***_Katherine Chapman
bcef4e069220a4b85f8a2c0cc3059487_***_Ume-kulsoom Shah
25b51eb7a9fb4c1779b6b4b3a7ac3f1d_***_Jessica Fletcher
37d0f121db69fd09f364df89e4405e31_***_George Johnson
8f70286908f67238a527a98cbf66d387_***_Shareen Doak
a44095d26187304e903da7ca778697b6_***_Gareth Jenkins
author Katherine Chapman
Ume-kulsoom Shah
Jessica Fletcher
George Johnson
Shareen Doak
Gareth Jenkins
author2 Katherine Chapman
Ume-kulsoom Shah
Jessica Fletcher
George Johnson
Shareen Doak
Gareth Jenkins
format Journal article
container_title Mutagenesis
container_volume 39
container_issue 2
container_start_page 69
publishDate 2024
institution Swansea University
issn 0267-8357
1464-3804
doi_str_mv 10.1093/mutage/geae004
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
document_store_str 1
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description Chemical safety testing plays a crucial role in product and pharmacological development, as well as chemoprevention; however, in vitro genotoxicity safety tests do not always accurately predict the chemicals that will be in vivo carcinogens. If chemicals test positive in vitro for genotoxicity but negative in vivo, this can contribute to unnecessary testing in animals used to confirm erroneous in vitro positive results. Current in vitro tests typically evaluate only genotoxicity endpoints, which limits their potential to detect non-genotoxic carcinogens. The frequency of misleading in vitro positive results can be high, leading to a requirement for more informative in vitro tests. It is now recognized that multiple-endpoint genotoxicity testing may aid more accurate detection of carcinogens and non-carcinogens. The objective of this review was to evaluate the utility of our novel, multiple-endpoint in vitro test, which uses multiple cancer-relevant endpoints to predict carcinogenic potential. The tool assessed micronucleus frequency, p53 expression, p21 expression, mitochondrial respiration, cell cycle abnormalities and, uniquely, cell morphology changes in human lymphoblastoid cell lines, TK6 and MCL-5. The endpoints were used to observe cellular responses to 18 chemicals within the following categories: genotoxic carcinogens, non-genotoxic carcinogens, toxic non-carcinogens, and misleading in vitro positive and negative agents. The number of endpoints significantly altered for each chemical was considered, alongside the holistic Integrated Signature of Carcinogenicity score, derived from the sum of fold changes for all endpoints. Following the calculation of an overall score from these measures, carcinogens exhibited greater potency than non-carcinogens. Genotoxic carcinogens were generally more potent than non-genotoxic carcinogens. This novel approach therefore demonstrated potential for correctly predicting whether chemicals with unknown mechanism may be considered carcinogens. Overall, while further validation is recommended, the test demonstrates potential for the identification of carcinogenic compounds. Adoption of the approach could enable reduced animal use in carcinogenicity testing.
published_date 2024-03-12T16:44:39Z
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