Long-term exposures to low doses of cobalt nanoparticles induce cell transformation enhanced by oxidative damage.
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.
Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona , Bellaterra , Spain and.
Balasubramanyam
B
Annangi
Jordi
J
Bach
Gerard
G
Vales
Laura
L
Rubio
Ricard
R
Marcos
Alba
A
Hernández
D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D003035:Cobalt / Q000008:administration & dosage / Q000633:toxicity*; D004249:DNA Damage / Q000502:physiology*; D045647:DNA Glycosylases / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D008137:Longitudinal Studies; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D036401:Toxicity Tests, Chronic / Q000379:methods
D017382:Reactive Oxygen Species; D003035:Cobalt; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse
Mechanistic toxicology; nanotoxicology; risk assessment