title: From the Cover: Does the Assessment of Nondisjunction Provide a More Sensitive Assay for the Detection of Aneugens?
abstract: The detection of aneugenic chemicals is important due to the implications of aneuploidy for human health. Aneuploidy can result from chromosome loss or nondisjunction due to chromosome mis-segregation at anaphase. Frequently, aneugens are detected using the in vitro micronucleus assay (IVM), with either centromere or kinetochore labeling. However, this method does not consider nondisjunction, the suggested predominant mechanism of spindle poison induced aneugenicity in primary human lymphocytes. Therefore, the IVM may be relatively insensitive in detecting aneuploidy. To investigate whether chromosome distribution analysis, specifically of nondisjunction, using chromosome-specific centromeric probes provides a more sensitive assay for aneugen detection, six reference aneugens with differing modes of action were tested on human lymphoblastoid TK6 cells. The results show that chromosome loss is a substantial part of the process leading to aneuploidy in TK6 cells. This differs from previous studies on human lymphocytes where nondisjunction has been described as the major mechanism of aneugenicity. However, in the current study more cells and types of aneugenic damage were analyzed. Although compound specific effects on nondisjunction were identified, chromosome distribution analysis did not provide increased sensitivity for the detection of aneugens: For the six reference aneugens examined, chromosome loss was shown at the same concentrations or lower than nondisjunction, even when nondisjunction levels were comparatively high. Therefore, in TK6 cells methods that detect chromosome loss, eg, the IVM, provide a more sensitive technique for the detection of aneugens than the measurement of nondisjunction.
authors.affiliation: AstraZeneca, Innovative Medicines and Early Development, Drug Safety and Metabolism (Discovery Safety), Unit 310-Darwin Building, Cambridge, UK.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Elloway
authors.affiliation: AstraZeneca, Innovative Medicines and Early Development, Drug Safety and Metabolism (Discovery Safety), Unit 310-Darwin Building, Cambridge, UK.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Davies
authors.affiliation: AstraZeneca, Innovative Medicines and Early Development, Drug Safety and Metabolism (Discovery Safety), AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Hayes
authors.affiliation: AstraZeneca, Innovative Medicines and Early Development, Drug Safety and Metabolism (Discovery Safety), Unit 310-Darwin Building, Cambridge, UK.
authors.forename: Ann T
authors.initials: AT
authors.lastname: Doherty
mesh_terms: D024422:Aneugens / Q000633:toxicity*; D000782:Aneuploidy; D002461:Cell Line, Transformed; D002877:Chromosomes, Human; D048749:Cytokinesis / Q000187:drug effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015162:Micronucleus Tests; D009630:Nondisjunction, Genetic / Q000187:drug effects*
chemical_list: D024422:Aneugens
keywords: aneugen; nondisjunction; micronuclei