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Abstract:

Risk assessment from exposure to spindle inhibitors should take into account the possibility of threshold concentration-response curves for aneuploidy induction. We analysed concentration-dependent induction of chromosome nondisjunction by well known spindle poisons (colchicine, carbendazim, mebendazole and nocodazole) and a reference clastogen, methyl methanesulphonate (MMS) in vitro in human lymphocytes; and integrated these findings with earlier results of chromosome loss in micronuclei. Chromosome non-disjunction was estimated on cytokinesis-blocked lymphocytes after simultaneous fluorescent in situ hybridization labelling with two chromosome-specific centromeric probes (chromosomes 1 and 17). The frequencies of spontaneous non-disjunction showed important inter-individual variations and were surprisingly high (7.04-15.39%). Lower concentrations of aneugens did not induce a statistically significant increase of non-disjunction frequencies over the respective control levels, whereas higher concentrations clearly induced a concentration-dependent increase in the non-disjunction frequencies with the four aneugens tested. On the contrary, even at high concentrations, MMS induced a slight increase in the frequency of non-disjunction but without being statistically significant when compared with the control frequencies. We estimated the inflection points, the first statistically significant concentrations, the last non-statistically significant concentrations and the number of events from concentration-response curves of chromosome non-disjunction and chromosome loss. A threshold-type of concentration-response for non-disjunction is highly probable for colchicine and nocodazole. For carbendazim and mebendazole the inflection point fell above the first statistically significant concentrations. But since it is obvious from dose-response curves where the inflection point/ threshold lies, it appears that the model might be picking up some irregularities (possibly due to experimental variability in the dose-response curve at concentrations greater than the threshold). For accurate estimation of the threshold, analysis of more concentrations or more cells might be needed. Our data strongly indicate that in cultured human lymphocytes chromosome non-disjunction is a major mechanism of aneuploidy induction by spindle inhibitors and since non-disjunction occurs at lower concentration than chromosome loss, the aneuploidy threshold should be estimated on the basis of non-disjunction rather than on micronuclei frequencies (chromosome loss).

Registro:

Documento: Artículo
Título:Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors in vitro in human lymphocytes
Autor:Elhajouji, A.; Tibaldi, F.; Kirsch-Volders, M.
Filiación:Anthropogenetics Laboratory, Vrije Universiteit Brussel, Pleinlaan 2, 1050-Brussels, Belgium
Instituto de Calculo, University of Buenos Aires, Argentina
Palabras clave:carbendazim; colchicine; mebendazole; mesylic acid methyl ester; nocodazole; aneuploidy; article; chromosome; chromosome 1; chromosome 17; chromosome loss; genotoxicity; human; human cell; lymphocyte; micronucleus; priority journal; Adult; Aneuploidy; Benzimidazoles; Carbamates; Chromosomes, Human; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 17; Colchicine; Dose-Response Relationship, Drug; Female; Humans; Lymphocytes; Male; Mebendazole; Methyl Methanesulfonate; Micronucleus Tests; Mitotic Spindle Apparatus; Mutagens; Mutation; Nocodazole
Año:1997
Volumen:12
Número:3
Página de inicio:133
Página de fin:140
DOI: http://dx.doi.org/10.1093/mutage/12.3.133
Título revista:Mutagenesis
Título revista abreviado:MUTAGENESIS
ISSN:02678357
CODEN:MUTAE
CAS:Benzimidazoles; Carbamates; Colchicine, 64-86-8; Mebendazole, 31431-39-7; mecarzole, 10605-21-7; Methyl Methanesulfonate, 66-27-3; Mutagens; Nocodazole, 31430-18-9
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02678357_v12_n3_p133_Elhajouji

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Citas:

---------- APA ----------
Elhajouji, A., Tibaldi, F. & Kirsch-Volders, M. (1997) . Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors in vitro in human lymphocytes. Mutagenesis, 12(3), 133-140.
http://dx.doi.org/10.1093/mutage/12.3.133
---------- CHICAGO ----------
Elhajouji, A., Tibaldi, F., Kirsch-Volders, M. "Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors in vitro in human lymphocytes" . Mutagenesis 12, no. 3 (1997) : 133-140.
http://dx.doi.org/10.1093/mutage/12.3.133
---------- MLA ----------
Elhajouji, A., Tibaldi, F., Kirsch-Volders, M. "Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors in vitro in human lymphocytes" . Mutagenesis, vol. 12, no. 3, 1997, pp. 133-140.
http://dx.doi.org/10.1093/mutage/12.3.133
---------- VANCOUVER ----------
Elhajouji, A., Tibaldi, F., Kirsch-Volders, M. Indication for thresholds of chromosome non-disjunction versus chromosome lagging induced by spindle inhibitors in vitro in human lymphocytes. MUTAGENESIS. 1997;12(3):133-140.
http://dx.doi.org/10.1093/mutage/12.3.133