The in vitro MN assay in 2011: origin and fate,biological significance,protocols, high throughput methodologies and toxicological relevance |
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Authors: | Micheline Kirsch-Volders Gina Plas Azeddine Elhajouji Magdalena Lukamowicz Laetitia Gonzalez Kim Vande Loock Ilse Decordier |
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Institution: | (1) Laboratorium voor Cellulaire Genetica, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium;(2) Novartis Institutes for Biomedical Research, Translational Sciences, Preclinical Safety, Genetic Toxicology and Safety Pharmacology, MUT-2881.5.38, 4002 Basel, Switzerland; |
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Abstract: | Micronuclei (MN) are small, extranuclear bodies that arise in dividing cells from acentric chromosome/chromatid fragments
or whole chromosomes/chromatids lagging behind in anaphase and are not included in the daughter nuclei at telophase. The mechanisms
of MN formation are well understood; their possible postmitotic fate is less evident. The MN assay allows detection of both
aneugens and clastogens, shows simplicity of scoring, is widely applicable in different cell types, is internationally validated,
has potential for automation and is predictive for cancer. The cytokinesis-block micronucleus assay (CBMN) allows assessment
of nucleoplasmic bridges, nuclear buds, cell division inhibition, necrosis and apoptosis and in combination with FISH using
centromeric probes, the mechanistic origin of the MN. Therefore, the CBMN test can be considered as a “cytome” assay covering
chromosome instability, mitotic dysfunction, cell proliferation and cell death. The toxicological relevance of the MN test
is strong: it covers several endpoints, its sensitivity is high, its predictivity for in vivo genotoxicity requires adequate
selection of cell lines, its statistical power is increased by the recently available high throughput methodologies, it might
become a possible candidate for replacing in vivo testing, it allows good extrapolation for potential limits of exposure or
thresholds and it is traceable in experimental in vitro and in vivo systems. Implementation of in vitro MN assays in the test
battery for hazard and risk assessment of potential mutagens/carcinogens is therefore fully justified. |
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