Information on the toxicity of carbon nanotubes is still fragmentary but indicates that these particles can induce adverse effects. We previously demonstrated in rats that, when purified multi-wall carbon nanotubes (MWCNT) reach the lung, they are biopersistent and induce lung inflammation as well as fibrosis. The present study was designed to address the genotoxic potential of this material in the same species. In vivo, micronuclei (MN) were assessed in type II pneumocytes 3 days after a single intra-tracheal administration of MWCNT (0.5 or 2 mg). We also used the cytokinesis-block micronucleus assay in rat lung epithelial cells exposed in vitro to MWCNT (10, 25, 50 mug/ml). Finally, we applied a human pancentromeric fluorescent probe (fluorescent in situ hybridization assay) to differentiate clastogenic and/or aneugenic mechanisms in a human epithelial cell line (MCF-7). In vivo, we found a significant and dose-dependent increase in micronucleated pneumocytes after a single administration of MWCNT ( approximately a 2-fold increase at the highest dose). In vitro, we observed a significant increase of MN in epithelial cells after exposure to MWCNT (up to a 2-fold increase at the cytotoxic dose of 50 mug/ml). Finally, we found that MWCNT induced both centromere-positive and -negative MN in MCF-7 cells. Overall, this study provides the first evidence of the potential of MWCNT to induce clastogenic as well as aneugenic events.
Inhalation of hard metal dust (WC-Co particles) has been associated with an increased risk for lung cancer in occupational settings. In vitro, WC-Co was genotoxic in human lymphocytes producing DNA strand breaks and micronuclei. The aim of the present study was to evaluate the in vivo genotoxic effects of WC-Co dust in rat type II pneumocytes. DNA breaks/alkali-labile sites (alkaline comet assay) and chromosome/genome mutations (micronucleus test) were assessed after a single intra-tracheal (i.t.) instillation of WC-Co, including dose-effect and time trend relationships. In addition, the alkaline comet assay was performed on cells obtained after broncho-alveolar lavage (BAL) and on peripheral blood mononucleated cells (PBMC). As pulmonary toxicity parameters, protein content, lactate dehydrogenase activity, total and differential cell count in BAL fluid were evaluated in parallel. In type II pneumocytes, WC-Co induced a statistically significant increase in tail DNA (12 h time point) and in micronuclei (72 h) after a single treatment with 16.6 mg WC-Co/kg body wt, a dose that produced mild pulmonary toxicity. This observation provides the first evidence of the in vivo mutagenic potential of hard metal dust. In PBMC, no increase in DNA damage or micronuclei was observed. This study indicates the potential to detect chromosome/genome mutations (micronuclei) in relevant target cells (type II pneumocytes) after i.t. instillation of a particle mixture.
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