Genotoxicity of inorganic lead salts and disturbance of microtubule function

Bonacker, Daniela, Stoiber, Thomas, Böhm, Konrad J., Prots, Irina, Wang, Minsheng, Unger, Eberhard, Thier, Ricarda, Bolt, Hermann M., & Degen, Gisela H. (2005) Genotoxicity of inorganic lead salts and disturbance of microtubule function. Environmental and Molecular Mutagenesis, 45(4), pp. 346-353.

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Lead compounds are known genotoxicants, principally affecting the integrity of chromosomes. Lead chloride and lead acetate induced concentration-dependent increases in micronucleus frequency in V79 cells, starting at 1.1 μM lead chloride and 0.05 μM lead acetate. The difference between the lead salts, which was expected based on their relative abilities to form complex acetato-cations, was confirmed in an independent experiment. CREST analyses of the micronuclei verified that lead chloride and acetate were predominantly aneugenic (CREST-positive response), which was consistent with the morphology of the micronuclei (larger micronuclei, compared with micronuclei induced by a clastogenic mechanism). The effects of high concentrations of lead salts on the microtubule network of V79 cells were also examined using immunofluorescence staining. The dose effects of these responses were consistent with the cytotoxicity of lead(II), as visualized in the neutral-red uptake assay. In a cell-free system, 20-60 μM lead salts inhibited tubulin assembly dose-dependently. The no-observed-effect concentration of lead(II) in this assay was 10 μM. This inhibitory effect was interpreted as a shift of the assembly/disassembly steady-state toward disassembly, e.g., by reducing the concentration of assembly-competent tubulin dimers. The effects of lead salts on microtubule-associated motor-protein functions were studied using a kinesin-gliding assay that mimics intracellular transport processes in vitro by quantifying the movement of paclitaxel-stabilized microtubules across a kinesin-coated glass surface. There was a dose-dependent effect of lead nitrate on microtubule motility. Lead nitrate affected the gliding velocities of microtubules starting at concentrations above 10 μM and reached half-maximal inhibition of motility at about 50 μM. The processes reported here point to relevant interactions of lead with tubulin and kinesin at low dose levels.

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ID Code: 77444
Item Type: Journal Article
Refereed: Yes
Keywords: Acetate, Aneugenicity, Chloride, Clastogenicity, Genotoxicity, Kinesin, Lead, Micronucleus assay, Motor protein, Nitrate, Tubulin, acetic acid, aneugen, cation, centromere antibody, clastogen, lead acetate, lead chloride, molecular motor, neutral red, paclitaxel, animal cell, article, cell free system, cell motility, cell structure, concentration response, controlled study, CREST analysis, cytotoxicity, immunofluorescence, intracellular transport, micronucleus, microtubule, microtubule assembly, nonhuman, protein function, staining, steady state, Animals, Cell Line, Cell Nucleus, Cell Proliferation, Cell Survival, Cricetinae, Dose-Response Relationship, Drug, Micronuclei, Chromosome-Defective, Micronucleus Tests, Microscopy, Electron, Transmission, Microtubules, Nitrates, Organometallic Compounds, Tubulin Modulators
DOI: 10.1002/em.20100
ISSN: 0893-6692
Divisions: Current > Schools > School of Clinical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Copyright Owner: Copyright 2005 Wiley-Liss, Inc.
Deposited On: 21 Oct 2014 00:00
Last Modified: 22 Oct 2014 04:09

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