Multiple-endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non-carcinogens an
- PDF / 1,082,303 Bytes
- 16 Pages / 595.276 x 790.866 pts Page_size
- 102 Downloads / 201 Views
GENOTOXICITY AND CARCINOGENICITY
Multiple‑endpoint in vitro carcinogenicity test in human cell line TK6 distinguishes carcinogens from non‑carcinogens and highlights mechanisms of action Katherine E. Chapman1 · Eleanor C. Wilde1 · Fiona M. Chapman1 · Jatin R. Verma1 · Ume‑Kulsoom Shah1 · Leanne M. Stannard1 · Anna L. Seager1 · James A. Tonkin2 · M. Rowan Brown2 · Ann T. Doherty3 · George E. Johnson1 · Shareen H. Doak1 · Gareth J. S. Jenkins1 Received: 19 June 2020 / Accepted: 2 September 2020 © The Author(s) 2020
Abstract 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. Keywords In vitro · Carcinogenicity testing · Genotoxicity · Multiple endpoints
Introduction This publication is dedicated to the memory of Dr. Ellie Verma (née Wilde) (1990–2019), who contributed to this project. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02902-3) contains supplementary material, which is available to authorized users. * Katherine E. Chapman [email protected] 1
In Vitro Toxicology Group, Institute of Life Science 1, Swansea University Medical School, Swansea University, Singleton Campus, Swansea SA2 8PP, UK
2
College of Engineering, Swansea University, Bay Campus, Swansea SA1 8EN, UK
3
Discovery Safety, AstraZeneca, DSM, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK
Thousands of new chemical entities (NCEs) are generated each year, and all require initial safety testing to predict their human health implications. Exp
Data Loading...
