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.

Continuousin vitroexposure of intestinal epithelial cells to E171 food additive causes oxidative stress, inducing oxidation of DNA bases but no endoplasmic reticulum stress

“…Cellular responses to continuous vs. acute exposure to NPs have also been compared in other studies. Some of these studies report similar or higher responses in continuously-exposed cells compared to acutely-exposed cells (Annangi, 2015;Kocbek, 2010;, while others indicate lower or A c c e p t e d M a n u s c r i p t different types of responses in continuously-exposed cells (Annangi, 2016;Aude-Garcia, 2016;Comfort, 2014). A diminished and altered response is always reported for cells continuously exposed to sub-lethal concentrations of NPs that are prone to dissolution or physico-chemical transformation, such as ZnO-NPs (Annangi, 2016) or Ag-NPs (Aude-Garcia, 2016;Comfort, 2014).…”

Investigation on cobalt‐oxide nanoparticles cyto‐genotoxicity and inflammatory response in two types of respiratory cells

“…Genotoxic and/or oxidative effects of Co‐NPs have been shown on A549 cells (Wan et al ., ) and in other kind of cells such as Balb/3T3 mouse fibroblasts (Ponti et al ., ), mouse embryonic fibroblast (MEF) (Annangi et al ., ), human T cells (Jiang et al ., ) and peripheral human lymphocytes (Colognato et al ., ; Chattopadhyay et al ., ).…”

Carcinogenic activity of PbS quantum dots screened using exosomal biomarkers secreted from HEK293 cells

“…65 Cobalt nanoparticles increased carcinogenic risk following long-term exposure. 66 Based on these previous studies and our results, carcinogenic activity should be given more importance while evaluating nanomaterial toxicity.…”