Toxic mechanisms of copper oxide nanoparticles in epithelial kidney cells

CuO NPs have previously been reported as toxic to a range of cell cultures including kidney epithelial cells from the frog, Xenopus laevis (A6). Here we examine the molecular mechanisms affecting toxicity of Cu in different forms and particle sizes. A6 cells were exposed to ionic Cu (Cu2+) or CuO particles of three different sizes: CuO NPs of 6 nm (NP6), larger Poly-dispersed CuO NPs of <100 nm (Poly) and CuO Micro particles of <5 μm (Micro), at 200 μM, equal to 12.7 mg Cu/L. Poly was significantly more toxic than NP6, Micro and Cu2+ to A6 cells, causing DNA damage, decreased cell viability and levels of reduced glutathione (GSH) and eventually cell death. We show that ROS (Reactive Oxygen Species) generation plays a key role and occurs early in Poly toxicity as Poly-induced DNA damage and cell death could be mitigated by the antioxidant NAC (N-acetyl-cysteine). Here we propose a model of the sequence of events explaining Poly toxicity. Briefly, the events include: cellular uptake, most likely via endocytosis, production of ROS, which cause DNA damage that activates a signaling pathway which eventually leads to cell death, mainly via apoptosis.