Induction of aneuploidy by single‐walled carbon nanotubes

Sargent, Linda M.; Shvedova, Anna A.; Hubbs, Ann F.; Salisbury, Jeffrey L.; Benkovic, Stanley A.; Kashon, Michael L.; Lowry, David T.; Murray, Ashley R.; Kisin, Elena R.; Friend, Sherri; McKinstry, K. T.; Battelli, Lori; Reynolds, Steven H.

doi:10.1002/em.20529

Cited by 154 publications

(157 citation statements)

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“…5a). These results may also provide the possible explanation for the genotoxicity induced by SWNTs 40 . Furthermore, metaphases spreads in treated groups were also prepared and stained with DAPI and Giemsa, respectively.…”

Section: Dna-damage Response Triggered By Swnts Occurred At Telomerementioning

confidence: 71%

Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres

et al. 2012

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Both human telomeric G-rich and C-rich DnA have been considered as specific drug targets for cancer therapy. However, due to i-motif structure instability and lack of specific binding agents, it remains unclear whether stabilization of telomeric i-motif can inhibit telomerase activity. single-walled carbon nanotubes (sWnTs) have been reported as the first ligand that can selectively stabilize human telomeric i-motif DnA. Here we report that sWnTs can inhibit telomerase activity through stabilization of i-motif structure. The persistence of i-motif and the concomitant G-quadruplex eventually leads to telomere uncapping and displaces telomerebinding proteins from telomere. The dysfunctional telomere triggers DnA damage response and elicits upregulation of p16 and p21 proteins. This is the first example that sWnTs can inhibit telomerase activity and interfere with the telomere functions in cancer cells. These results provide new insights into understanding the biomedical effects of sWnTs and the biological importance of i-motif DnA.

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Section: Dna-damage Response Triggered By Swnts Occurred At Telomerementioning

confidence: 71%

Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres

et al. 2012

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“…Fragmentation of the centrosome can be induced by a number of mechanisms including global DNA damage [49], inhibition of mitotic spindle motor movement or activity [50,51], or by inhibiting the processing of misfolded centrosome proteins [52]. Levels of SWCNT four-fold higher than used in this experiment induce DNA breakage in only 8% of the cells [40]. This level of DNA damage would not result in centrosome fragmentation and this global DNA damage is unlikely to be the cause of fragmentation.…”

Section: Discussionmentioning

confidence: 85%

“…Secondary antibodies were Rhodamine Red goat anti-rabbit IgG and Alexa 488 goat anti-mouse IgG (Invitrogen, Carlsbad, CA). Small aggregates of SWCNT (carbon nanoropes) appeared as black structures in differential interference contrast (DIC) imaging due to absorbance of light [39][40][41]. The morphology of the mitotic spindle and centrosome, and the relationship with carbon nanoropes, was analyzed in the BEAS-2B cells using a laser scanning confocal microscope (LSM 510, Carl Zeiss MicroImaging Inc., Thornwood, NY) as previously described [25].…”

Section: Mitotic Spindle and Centrosome Morphology Analysismentioning

confidence: 99%

Single-walled carbon nanotube-induced mitotic disruption

Sargent

Hubbs

Young

et al. 2012

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Carbon nanotubes were among the earliest products of nanotechnology and have many potential applications in medicine, electronics, and manufacturing. The low density, small size, and biological persistence of carbon nanotubes create challenges for exposure control and monitoring and make respiratory exposures to workers likely. We have previously shown mitotic spindle aberrations in cultured primary and immortalized human airway epithelial cells exposed to 24, 48 and 96 μg/cm 2 single-walled carbon nanotubes (SWCNT). To investigate mitotic spindle aberrations at concentrations anticipated in exposed workers, primary and immortalized human airway epithelial cells were exposed to SWCNT for 24-72 h at doses equivalent to 20 weeks of exposure at the Permissible Exposure Limit for particulates not otherwise regulated. We have now demonstrated fragmented centrosomes, disrupted mitotic spindles and aneuploid chromosome number at those doses. The data further demonstrated multipolar mitotic spindles comprised 95% of the disrupted mitoses. The increased multipolar mitotic spindles were associated with an increased number of cells in the G2 phase of mitosis, indicating a mitotic checkpoint response. Nanotubes were observed in association with mitotic spindle microtubules, the centrosomes and condensed chromatin in cells exposed to 0.024, 0.24, 2.4 and 24 μg/cm 2 SWCNT. Three- Conflict of interest statementThe authors declare that there are no conflicts of interest. Appendix A. Supplementary dataSupplementary data associated with this article can be found, in the online version, at doi:10.1016/j.mrgentox.2011.11.017. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript dimensional reconstructions showed carbon nanotubes within the centrosome structure. The lower doses did not cause cytotoxicity or reduction in colony formation after 24 h; however, after three days, significant cytotoxicity was observed in the SWCNT-exposed cells. Colony formation assays showed an increased proliferation seven days after exposure. Our results show significant disruption of the mitotic spindle by SWCNT at occupationally relevant doses. The increased proliferation that was observed in carbon nanotube-exposed cells indicates a greater potential to pass the genetic damage to daughter cells. Disruption of the centrosome is common in many solid tumors including lung cancer. The resulting aneuploidy is an early event in the progression of many cancers, suggesting that it may play a role in both tumorigenesis and tumor progression. These results suggest caution should be used in the handling and processing of carbon nanotubes.

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“…Some nanomaterials have been shown to disrupt normal cell processes including cell division (mitosis) resulting in genotoxicity including aneuploidy (abnormal chromosome number) (Sargent et al 2009(Sargent et al 2011. Some CNT can also cause rapid development of pulmonary fibrosis by a different mechanism (i.e., acting as a lung basement membrane, encouraging lung fibroblast growth) (Wang et al 2010).…”

Section: Discussion and Next Stepsmentioning

confidence: 99%

Development of risk-based nanomaterial groups for occupational exposure control

et al. 2012

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Given the almost limitless variety of nanomaterials, it will be virtually impossible to assess the possible occupational health hazard of each nanomaterial individually. The development of science-based hazard and risk categories for nanomaterials is needed for decision-making about exposure control practices in the workplace. A possible strategy would be to select representative (benchmark) materials from various mode of action (MOA) classes, evaluate the hazard and develop risk estimates, and then apply a systematic comparison of new nanomaterials with the benchmark materials in the same MOA class. Poorly soluble particles are used here as an example to illustrate quantitative risk assessment methods for possible benchmark particles and occupational exposure control groups, given mode of action and relative toxicity. Linking such benchmark particles to specific exposure control bands would facilitate the translation of health hazard and quantitative risk information to the development of effective exposure control practices in the workplace. A key challenge is obtaining sufficient dose-response data, based on standard testing, to systematically evaluate the nanomaterials' physical-chemical factors influencing their biological activity. Categorization processes involve both science-based analyses and default assumptions in the absence of substance-specific information. Utilizing data and information from related materials may facilitate initial determinations of exposure control systems for nanomaterials.

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Induction of aneuploidy by single‐walled carbon nanotubes

Cited by 154 publications

References 47 publications

Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres

Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres

Single-walled carbon nanotube-induced mitotic disruption

Development of risk-based nanomaterial groups for occupational exposure control

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