Long-term exposures to low doses of cobalt nanoparticles induce cell transformation enhanced by oxidative damage

Abstract

A weak aspect of the in vitro studies devoted to get information on the toxic, genotoxic and carcinogenic properties of nanomaterials is that they are usually conducted under acute-exposure and high-dose conditions. This makes difficult to extrapolate the results to human beings. To overcome this point, we have evaluated the cell transforming ability of cobalt nanoparticles (CoNPs) after long-term exposures (12 weeks) to sub-toxic doses (0.05 and 0.1 µg/mL). To get further information on whether CoNPs-induced oxidative DNA damage is relevant for CoNPs carcinogenesis, the cell lines selected for the study were the wild-type mouse embryonic fibroblast (MEF Ogg1^+/+) and its isogenic Ogg1 knockout partner (MEF Ogg1^−/−), unable to properly eliminate the 8-OH-dG lesions from DNA. Our initial short-term exposure experiments demonstrate that low doses of CoNPs are able to induce reactive oxygen species (ROS) and that MEF Ogg1^−/− cells are more sensitive to CoNPs-induced acute toxicity and oxidative DNA damage. On the other hand, long-term exposures of MEF cells to sub-toxic doses of CoNPs were able to induce cell transformation, as indicated by the observed morphological cell changes, significant increases in the secretion of metalloproteinases (MMPs) and anchorage-independent cell growth ability, all cancer-like phenotypic hallmarks. Interestingly, such changes were significantly dependent on the cell line used, the Ogg1^−/− cells being particularly sensitive. Altogether, the data presented here confirms the potential carcinogenic risk of CoNPs and points out the relevance of ROS and Ogg1 genetic background on CoNPs-associated effects.

• Mechanistic toxicology
• nanotoxicology
• risk assessment

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article. B.A. was supported by a post-doctoral fellowship from the Universitat Autònoma de Barcelona (UAB). J.B., G.V. and L.R. were supported by UAB PIF fellowships. This work was supported by the “Generalitat de Catalunya” (2009SGR-725), the “UAB” (APOSTA-2011) and the Spanish Ministry of Education and Science (SAF2011-23146).