Histone markers identify the mode of action for compounds positive in the TK6 micronucleus assay

Mutation Research. Genetic Toxicology and Environmental Mutagenesis
Jennifer CheungPamela L Heard

Abstract

The in vitro micronucleus assay with TK6 cells is frequently used as part of the genotoxicity testing battery for pharmaceuticals. Consequently, follow-up testing strategies are needed for positive compounds to determine their mode of action, which would then allow for deployment of appropriate in vivo follow-up strategies. We have chosen 3 micronucleus positive compounds, the clastogen etoposide, the aneugen noscapine and the cytotoxicant tunicamycin to evaluate different approaches to determine their aneugenic or clastogenic properties. Each of the three compounds were evaluated following 4 and 24h of continuous treatment by flow cytometry for micronucleus induction, the aneugenicity markers phosphorylated-histone 3 (p-H3) and polyploidy, the clastogenicity marker γH2AX and the apoptosis marker cleaved caspase 3. They were further evaluated by Western blot for mono-ubiquitinated and γH2AX. Results show that the clastogen etoposide produced a dose related increase in γH2AX and mono-ubiquitinated H2AX and a dose related decrease in p-H3 positive mitotic cells. Conversely, the aneugen produced increases in p-H3 and polyploidy with no significant increases seen in mono-ubiquitinated H2AX or γH2AX. Lastly, the cytotoxicant tunicam...Continue Reading

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Citations

Jan 15, 2016·Environmental and Molecular Mutagenesis·Steven M BryceStephen D Dertinger
Apr 2, 2016·Pharmacognosy Research·Oluwatosin Adekunle AdaramoyeOlufunke Elizabeth Ola-Davies
Jul 2, 2016·Environmental and Molecular Mutagenesis·Derek T BernackiStephen D Dertinger
Nov 7, 2017·Toxicological Sciences : an Official Journal of the Society of Toxicology·Steven M BryceStephen D Dertinger
Jul 12, 2019·Environmental and Molecular Mutagenesis·Daniel J SmartPatrick Vanscheeuwijck
Feb 11, 2020·Environmental and Molecular Mutagenesis·Shuchang TianStephen D Dertinger
Jul 11, 2019·Archives of Toxicology·B KoppMarc Audebert
Apr 4, 2017·Environmental and Molecular Mutagenesis·Steven M BryceStephen D Dertinger
May 16, 2018·EFSA Journal·UNKNOWN EFSA Panel on Contaminants in the Food Chain (CONTAM)Christiane Vleminckx

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