Weight of evidence approach using a TK gene mutation assay with human TK6 cells for follow-up of positive results in Ames tests: a collaborative study by MMS/JEMS
Abstract Background Conflicting results between bacterial mutagenicity tests (the Ames test) and mammalian carcinogenicity tests might be due to species differences in metabolism, genome structure, and DNA repair systems. Mutagenicity assays using human cells are thought to be an advantage as follow...
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2021-03-01
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Series: | Genes and Environment |
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Online Access: | https://doi.org/10.1186/s41021-021-00179-1 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Manabu Yasui Takayuki Fukuda Akiko Ukai Jiro Maniwa Tadashi Imamura Tsuneo Hashizume Haruna Yamamoto Kaori Shibuya Kazunori Narumi Yohei Fujiishi Emiko Okada Saori Fujishima Mika Yamamoto Naoko Otani Maki Nakamura Ryoichi Nishimura Maya Ueda Masayuki Mishima Kaori Matsuzaki Akira Takeiri Kenji Tanaka Yuki Okada Munehiro Nakagawa Shuichi Hamada Akihiko Kajikawa Hiroshi Honda Jun Adachi Kentaro Misaki Kumiko Ogawa Masamitsu Honma |
spellingShingle |
Manabu Yasui Takayuki Fukuda Akiko Ukai Jiro Maniwa Tadashi Imamura Tsuneo Hashizume Haruna Yamamoto Kaori Shibuya Kazunori Narumi Yohei Fujiishi Emiko Okada Saori Fujishima Mika Yamamoto Naoko Otani Maki Nakamura Ryoichi Nishimura Maya Ueda Masayuki Mishima Kaori Matsuzaki Akira Takeiri Kenji Tanaka Yuki Okada Munehiro Nakagawa Shuichi Hamada Akihiko Kajikawa Hiroshi Honda Jun Adachi Kentaro Misaki Kumiko Ogawa Masamitsu Honma Weight of evidence approach using a TK gene mutation assay with human TK6 cells for follow-up of positive results in Ames tests: a collaborative study by MMS/JEMS Genes and Environment TK6 assay Human lymphoblastoid TK6 cells Ames test Follow-up Weight of evidence approach Toxicoproteomics |
author_facet |
Manabu Yasui Takayuki Fukuda Akiko Ukai Jiro Maniwa Tadashi Imamura Tsuneo Hashizume Haruna Yamamoto Kaori Shibuya Kazunori Narumi Yohei Fujiishi Emiko Okada Saori Fujishima Mika Yamamoto Naoko Otani Maki Nakamura Ryoichi Nishimura Maya Ueda Masayuki Mishima Kaori Matsuzaki Akira Takeiri Kenji Tanaka Yuki Okada Munehiro Nakagawa Shuichi Hamada Akihiko Kajikawa Hiroshi Honda Jun Adachi Kentaro Misaki Kumiko Ogawa Masamitsu Honma |
author_sort |
Manabu Yasui |
title |
Weight of evidence approach using a TK gene mutation assay with human TK6 cells for follow-up of positive results in Ames tests: a collaborative study by MMS/JEMS |
title_short |
Weight of evidence approach using a TK gene mutation assay with human TK6 cells for follow-up of positive results in Ames tests: a collaborative study by MMS/JEMS |
title_full |
Weight of evidence approach using a TK gene mutation assay with human TK6 cells for follow-up of positive results in Ames tests: a collaborative study by MMS/JEMS |
title_fullStr |
Weight of evidence approach using a TK gene mutation assay with human TK6 cells for follow-up of positive results in Ames tests: a collaborative study by MMS/JEMS |
title_full_unstemmed |
Weight of evidence approach using a TK gene mutation assay with human TK6 cells for follow-up of positive results in Ames tests: a collaborative study by MMS/JEMS |
title_sort |
weight of evidence approach using a tk gene mutation assay with human tk6 cells for follow-up of positive results in ames tests: a collaborative study by mms/jems |
publisher |
BMC |
series |
Genes and Environment |
issn |
1880-7062 |
publishDate |
2021-03-01 |
description |
Abstract Background Conflicting results between bacterial mutagenicity tests (the Ames test) and mammalian carcinogenicity tests might be due to species differences in metabolism, genome structure, and DNA repair systems. Mutagenicity assays using human cells are thought to be an advantage as follow-up studies for positive results in Ames tests. In this collaborative study, a thymidine kinase gene mutation study (TK6 assay) using human lymphoblastoid TK6 cells, established in OECD TG490, was used to examine 10 chemicals that have conflicting results in mutagenicity studies (a positive Ames test and a negative result in rodent carcinogenicity studies). Results Two of 10 test substances were negative in the overall judgment (20% effective as a follow-up test). Three of these eight positive substances were negative after the short-term treatment and positive after the 24 h treatment, despite identical treatment conditions without S9. A toxicoproteomic analysis of TK6 cells treated with 4-nitroanthranilic acid was thus used to aid the interpretation of the test results. This analysis using differentially expressed proteins after the 24 h treatment indicated that in vitro specific oxidative stress is involved in false positive response in the TK6 assay. Conclusions The usefulness of the TK6 assay, by current methods that have not been combined with new technologies such as proteomics, was found to be limited as a follow-up test, although it still may help to reduce some false positive results (20%) in Ames tests. Thus, the combination analysis with toxicoproteomics may be useful for interpreting false positive results raised by 24 h specific reactions in the assay, resulting in the more reduction (> 20%) of false positives in Ames test. |
topic |
TK6 assay Human lymphoblastoid TK6 cells Ames test Follow-up Weight of evidence approach Toxicoproteomics |
url |
https://doi.org/10.1186/s41021-021-00179-1 |
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doaj-28a26d2c8a28419a8e0d701873581be02021-03-11T12:48:45ZengBMCGenes and Environment1880-70622021-03-0143111910.1186/s41021-021-00179-1Weight of evidence approach using a TK gene mutation assay with human TK6 cells for follow-up of positive results in Ames tests: a collaborative study by MMS/JEMSManabu Yasui0Takayuki Fukuda1Akiko Ukai2Jiro Maniwa3Tadashi Imamura4Tsuneo Hashizume5Haruna Yamamoto6Kaori Shibuya7Kazunori Narumi8Yohei Fujiishi9Emiko Okada10Saori Fujishima11Mika Yamamoto12Naoko Otani13Maki Nakamura14Ryoichi Nishimura15Maya Ueda16Masayuki Mishima17Kaori Matsuzaki18Akira Takeiri19Kenji Tanaka20Yuki Okada21Munehiro Nakagawa22Shuichi Hamada23Akihiko Kajikawa24Hiroshi Honda25Jun Adachi26Kentaro Misaki27Kumiko Ogawa28Masamitsu Honma29Division of Genetics and Mutagenesis, National Institute of Health SciencesTokyo Laboratory, BoZo Research Center Inc.Division of Genetics and Mutagenesis, National Institute of Health SciencesAstraZeneca KKIna Research Inc.Scientific Product Assessment Center, R&D Group, Japan Tobacco Inc.Scientific Product Assessment Center, R&D Group, Japan Tobacco Inc.Scientific Product Assessment Center, R&D Group, Japan Tobacco Inc.Yakult Central InstituteYakult Central InstituteYakult Central InstituteChemicals Evaluation and Research Institute, JapanAstellas Pharma Inc.Astellas Pharma Inc.Tokyo Laboratory, BoZo Research Center Inc.Tokyo Laboratory, BoZo Research Center Inc.Genotoxicology Laboratory, BioSafety Research Center Inc.Chugai Pharmaceutical Co., LtdChugai Pharmaceutical Co., LtdChugai Pharmaceutical Co., LtdChugai Pharmaceutical Co., LtdToxicology Research Department, Teijin Institute for Bio-medical Research, Teijin Pharma LimitedNonclinical Research Center, LSI Medience CorporationTokyo Laboratory, BoZo Research Center Inc.Nonclinical Research Center, LSI Medience CorporationR&D Safety Science Research, Kao CorporationLaboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and NutritionSchool of Nursing, University of ShizuokaDivision of Pathology, National Institute of Health SciencesDivision of Genetics and Mutagenesis, National Institute of Health SciencesAbstract Background Conflicting results between bacterial mutagenicity tests (the Ames test) and mammalian carcinogenicity tests might be due to species differences in metabolism, genome structure, and DNA repair systems. Mutagenicity assays using human cells are thought to be an advantage as follow-up studies for positive results in Ames tests. In this collaborative study, a thymidine kinase gene mutation study (TK6 assay) using human lymphoblastoid TK6 cells, established in OECD TG490, was used to examine 10 chemicals that have conflicting results in mutagenicity studies (a positive Ames test and a negative result in rodent carcinogenicity studies). Results Two of 10 test substances were negative in the overall judgment (20% effective as a follow-up test). Three of these eight positive substances were negative after the short-term treatment and positive after the 24 h treatment, despite identical treatment conditions without S9. A toxicoproteomic analysis of TK6 cells treated with 4-nitroanthranilic acid was thus used to aid the interpretation of the test results. This analysis using differentially expressed proteins after the 24 h treatment indicated that in vitro specific oxidative stress is involved in false positive response in the TK6 assay. Conclusions The usefulness of the TK6 assay, by current methods that have not been combined with new technologies such as proteomics, was found to be limited as a follow-up test, although it still may help to reduce some false positive results (20%) in Ames tests. Thus, the combination analysis with toxicoproteomics may be useful for interpreting false positive results raised by 24 h specific reactions in the assay, resulting in the more reduction (> 20%) of false positives in Ames test.https://doi.org/10.1186/s41021-021-00179-1TK6 assayHuman lymphoblastoid TK6 cellsAmes testFollow-upWeight of evidence approachToxicoproteomics |