Genotoxicity of inorganic lead salts and disturbance of microtubule function

Abstract

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 microM lead chloride and 0.05 microM 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 microM lead salts inhibited tubulin assembly dose-dependently. The no-observed-effect concentration of lead(II) in this assay was 10 microM. 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 microM and reached half-maximal inhibition of motility at about 50 microM. The processes reported here point to relevant interactions of lead with tubulin and kinesin at low dose levels.

Evaluation of peripheral blood neutrophil leucocytes in lead-exposed workers

“…Lead acts directly by inhibiting neutrophil chemotactic activity both in vivo and in vitro (Governa et al 1987(Governa et al , 1988. Furthermore, it can interfere with their cell membrane fluidity in vivo (Valentino et al 1982) and with their cytoplasmic microtubular network in vitro (Bonacker et al 2005).…”

Chronic Exposure to Lead Chromate Causes Centrosome Abnormalities and Aneuploidy in Human Lung Cells

“…On the other hand, it is possible that lead ions could contribute to lead chromate-induced centrosome amplification. Studies show that lead ions do enter the cell after lead chromate exposure (17), and a recent study by Bonacker et al showed that soluble lead ions disrupt microtubule function and formation (34). However, lead's effect on centrosome function is unknown.…”

Lead-induced genotoxicity to Vicia faba L. roots in relation with metal cell uptake and initial speciation

“…According to Johnson (1998) lead and its compounds are capable of interfering with the spindle apparatus of dividing cells thus leading to genotoxicity. Bonacker et al (2005) thought that the micronuclei induced by lead ions are most often associated with processes involving reactive oxygen generated by redox shuttling. Oxidative stress as a result of metal toxicity is also described to play a major role in DNA-damage induction (Halliwel, 1990).…”