Cargando…

Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action

Current in vitro genotoxicity tests can produce misleading positive results, indicating an inability to effectively predict a compound’s subsequent carcinogenic potential in vivo. Such oversensitivity can incur unnecessary in vivo tests to further investigate positive in vitro results, supporting th...

Descripción completa

Detalles Bibliográficos
Autores principales: Chapman, Katherine E., Wilde, Eleanor C., Chapman, Fiona M., Verma, Jatin R., Shah, Ume-Kulsoom, Stannard, Leanne M., Seager, Anna L., Tonkin, James A., Brown, M. Rowan, Doherty, Ann T., Johnson, George E., Doak, Shareen H., Jenkins, Gareth J. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811515/
https://www.ncbi.nlm.nih.gov/pubmed/32910239
http://dx.doi.org/10.1007/s00204-020-02902-3
_version_ 1783637514359144448
author Chapman, Katherine E.
Wilde, Eleanor C.
Chapman, Fiona M.
Verma, Jatin R.
Shah, Ume-Kulsoom
Stannard, Leanne M.
Seager, Anna L.
Tonkin, James A.
Brown, M. Rowan
Doherty, Ann T.
Johnson, George E.
Doak, Shareen H.
Jenkins, Gareth J. S.
author_facet Chapman, Katherine E.
Wilde, Eleanor C.
Chapman, Fiona M.
Verma, Jatin R.
Shah, Ume-Kulsoom
Stannard, Leanne M.
Seager, Anna L.
Tonkin, James A.
Brown, M. Rowan
Doherty, Ann T.
Johnson, George E.
Doak, Shareen H.
Jenkins, Gareth J. S.
author_sort Chapman, Katherine E.
collection PubMed
description Current in vitro genotoxicity tests can produce misleading positive results, indicating an inability to effectively predict a compound’s subsequent carcinogenic potential in vivo. Such oversensitivity can incur unnecessary in vivo tests to further investigate positive in vitro results, supporting the need to improve in vitro tests to better inform risk assessment. It is increasingly acknowledged that more informative in vitro tests using multiple endpoints may support the correct identification of carcinogenic potential. The present study, therefore, employed a holistic, multiple-endpoint approach using low doses of selected carcinogens and non-carcinogens (0.001–770 µM) to assess whether these chemicals caused perturbations in molecular and cellular endpoints relating to the Hallmarks of Cancer. Endpoints included micronucleus induction, alterations in gene expression, cell cycle dynamics, cell morphology and bioenergetics in the human lymphoblastoid cell line TK6. Carcinogens ochratoxin A and oestradiol produced greater Integrated Signature of Carcinogenicity scores for the combined endpoints than the “misleading” in vitro positive compounds, quercetin, 2,4-dichlorophenol and quinacrine dihydrochloride and toxic non-carcinogens, caffeine, cycloheximide and phenformin HCl. This study provides compelling evidence that carcinogens can successfully be distinguished from non-carcinogens using a holistic in vitro test system. Avoidance of misleading in vitro outcomes could lead to the reduction and replacement of animals in carcinogenicity testing. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00204-020-02902-3) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-7811515
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-78115152021-01-25 Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action Chapman, Katherine E. Wilde, Eleanor C. Chapman, Fiona M. Verma, Jatin R. Shah, Ume-Kulsoom Stannard, Leanne M. Seager, Anna L. Tonkin, James A. Brown, M. Rowan Doherty, Ann T. Johnson, George E. Doak, Shareen H. Jenkins, Gareth J. S. Arch Toxicol Genotoxicity and Carcinogenicity Current in vitro genotoxicity tests can produce misleading positive results, indicating an inability to effectively predict a compound’s subsequent carcinogenic potential in vivo. Such oversensitivity can incur unnecessary in vivo tests to further investigate positive in vitro results, supporting the need to improve in vitro tests to better inform risk assessment. It is increasingly acknowledged that more informative in vitro tests using multiple endpoints may support the correct identification of carcinogenic potential. The present study, therefore, employed a holistic, multiple-endpoint approach using low doses of selected carcinogens and non-carcinogens (0.001–770 µM) to assess whether these chemicals caused perturbations in molecular and cellular endpoints relating to the Hallmarks of Cancer. Endpoints included micronucleus induction, alterations in gene expression, cell cycle dynamics, cell morphology and bioenergetics in the human lymphoblastoid cell line TK6. Carcinogens ochratoxin A and oestradiol produced greater Integrated Signature of Carcinogenicity scores for the combined endpoints than the “misleading” in vitro positive compounds, quercetin, 2,4-dichlorophenol and quinacrine dihydrochloride and toxic non-carcinogens, caffeine, cycloheximide and phenformin HCl. This study provides compelling evidence that carcinogens can successfully be distinguished from non-carcinogens using a holistic in vitro test system. Avoidance of misleading in vitro outcomes could lead to the reduction and replacement of animals in carcinogenicity testing. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00204-020-02902-3) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-09-10 2021 /pmc/articles/PMC7811515/ /pubmed/32910239 http://dx.doi.org/10.1007/s00204-020-02902-3 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Genotoxicity and Carcinogenicity
Chapman, Katherine E.
Wilde, Eleanor C.
Chapman, Fiona M.
Verma, Jatin R.
Shah, Ume-Kulsoom
Stannard, Leanne M.
Seager, Anna L.
Tonkin, James A.
Brown, M. Rowan
Doherty, Ann T.
Johnson, George E.
Doak, Shareen H.
Jenkins, Gareth J. S.
Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action
title Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action
title_full Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action
title_fullStr Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action
title_full_unstemmed Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action
title_short Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action
title_sort multiple-endpoint in vitro carcinogenicity test in human cell line tk6 distinguishes carcinogens from non-carcinogens and highlights mechanisms of action
topic Genotoxicity and Carcinogenicity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811515/
https://www.ncbi.nlm.nih.gov/pubmed/32910239
http://dx.doi.org/10.1007/s00204-020-02902-3
work_keys_str_mv AT chapmankatherinee multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT wildeeleanorc multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT chapmanfionam multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT vermajatinr multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT shahumekulsoom multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT stannardleannem multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT seagerannal multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT tonkinjamesa multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT brownmrowan multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT dohertyannt multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT johnsongeorgee multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT doakshareenh multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction
AT jenkinsgarethjs multipleendpointinvitrocarcinogenicitytestinhumancelllinetk6distinguishescarcinogensfromnoncarcinogensandhighlightsmechanismsofaction