Long crocidolite asbestos fibers cause polyploidy by sterically blocking cytokinesis

Abstract

Asbestos has been described as a physical carcinogen in that its carcinogenic effects appear to be related primarily to fiber dimensions. It has been hypothesized that long asbestos fibers may interfere with chromosome distribution during cell division, causing genomic changes that lead to cell transformation and neoplastic progression. Using high-resolution time-lapse light microscopy and serial-section electron microscopy, we have followed individual crocidolite asbestos fibers through the later stages of cell division in LLC-MK2 epithelial cells, and have detailed for the first time their effect on cytokinesis. We found that long fibers (15-55 microgram), trapped by the cleavage furrow, sterically blocked cytokinesis, sometimes resulting in the formation of a binucleated cell. The ends of blocking fibers were usually found within invaginations of the newly formed nuclei. Nuclear envelope-fiber attachment was evident when a chromatin strand ran with the fiber into the intercellular bridge. Such strands may break, causing chromosome structural rearrangements. Our data are the first to show that individual crocidolite fibers can cause genomic changes by sterically blocking cytokinesis and that fiber length and affinity for the nuclear envelope are important factors. Such genomic changes may be among the initial events leading to asbestos-induced cancers.

Pulmonary Toxicity of Intratracheally Instilled Multiwall Carbon Nanotubes in Male Fischer 344 Rats

“…Shvedova et al 11) suggested possible interference with the mitotic spindle on the basis of their histopathological observation of an anaphase bridge in a dividing macrophage containing SWCNT in the lung of mice exposed by inhalation to SWCNT aerosol. Further evidence in support of this was provided by the formation of polyploidy by sterical blocking of cytokinesis in cultured LLC-MK 2 cells exposed in vitro to long crocidolite asbestos fibers 34) . Since the MWCNT fibers used in the present study were long and thin 22) , like asbestos fibers, well-dispersed in the lung tissues and biopersistent, MWCNT might act upon the lung like asbestos fibers, as suggested by Poland et al 7) .…”

Molecular Alterations at 9q33.1 and Polyploidy in Asbestos-Related Lung Cancer

“…We also analyzed the ploidy level of the tumors using several centromere FISH probes and were able to detect more frequent polyploidy in the tumors of exposed (48%) than in those of nonexposed (29%) patients. Indeed, asbestos has been shown to induce polyploidy by sterically blocking cytokinesis in vitro (17).…”

Characteristics of Multiwall Carbon Nanotubes for an Intratracheal Instillation Study with Rats

“…Indeed, the length of asbestos fibers is known to be a critically important determinant for asbestos-induced carcinogenesis 14,15) . In vitro exposure of cultured LLC-MK 2 cells to long crocidolite asbestos fibers was reported to induce formation of binucleated cells leading to polyploidy, resulting from sterical blocking of cytokinesis by long fibers 17) . Another key factor for pathogenic, asbestos-like behavior is whether MWCNT is persistent in the lung and pleural cavity in the same manner as in the case of asbestos fibers suggested by Donaldson and Tran 18) .…”