Genotoxicity of multi-walled carbon nanotubes at occupationally relevant doses.
Sargent-LM; Reynolds-SH; Lowry-D; Kashon-ML; Benkovic-SA; Salisbury-JL; Hubbs-AF; Young-S-H; Siegrist-KJ; Keane-MJ; Mastovich-J; Bunker-K; Sturgeon-J; Cena-L; Dinu-CZ
Proc Am Assoc Cancer Res 2012 Mar; 53:1320
Carbon nanotubes represent a creative alternative for applications in medicine as therapeutic vectors, imaging and controlled release of active molecules. Although the low density and small size of carbon nanotubes makes respiratoty exposures to workers likely during the production or use of commercial products, the potential genotoxicity of multi-walled carbon nanotubes has not been investigated. We have previously shown mitotic spindle aberrations in cultured primary and immortalized human airway epithelial cells exposed to single-walled carbon nanotubes (SWCNT). In order to investigate whether genetic damage was unique to SWCNT, we examined mitotic spindle aberrations following dosing of cells to multi-walled carbon nanotubes (MWCNT) at concentrations anticipated in the workplace. Immortalized and primary respiratory epithelial cells were exposed to 0.024, 0.24, 2.4, and 24 microg/cm2 carbon nanotubes. The minimal dose of MWCNT considered for this research was based on the permissible exposure limit for particles with an aerodynamic diameter of less than 5 microns (Occupation Safety and Health Administration). MWCNT induced a dose response of disrupted centrosomes, mirotic spindles and aneuploid chromosome number. The data further showed that monopolar mitotic spindles comprised 95% of the disrupted mitoses. The monopolar phenotype of the distupted mitotic spindles is in sharp contrast to the multipolar spindle of SWCNT-induced disruption. Three-dimensional reconstructions showed carbon nanotubes integrated with the microtubules, the DNA and within the centrosome structure. The lower doses did not cause cytotoxicity or apoptosis 24 hours after exposure; however, after 72 hours. significant cytotoxicity was observed in the MWCNT-exposed cells. Disruption of the centrosome is common in many solid tumors including lung cancer. The resulting aneuploidy is a key event in the progression of cancer and is correlated with tumor stage. Our results demonstrate significant disruption of the mitotic spindle by MWCNT at occupationally relevant doses. These results suggest caution should be used in the handling and processing of carbon nanotubes.
Nanotechnology; Gene-mutation; Genotoxic-effects; Therapeutic-agents; Respiratory-irritants; Laboratory-testing; Humans; Cell-alteration; Cell-cultures; Dose-response; Cell-damage; Particle-aerodynamics; Permissible-concentration-limits; Chromosome-damage; Chromosome-disorders; Mitosis; DNA-damage; Cytotoxicity; Lung-cancer; Tumors
Proceedings of the American Association for Cancer Research