Single is not combined: the role of Co and Ni bioavailability on toxicity mechanisms in liver and brain cells

The two trace elements cobalt (Co) and nickel (Ni) are widely distributed in the environment due to the increasing industrial application, for example in lithium-ion batteries. Both metals are known to cause detrimental health impacts to humans when overexposed and both are supposed to be a risk factor for various diseases. The individual toxicity of Co and Ni has been partially investigated, however the underlying mechanisms, as well as the interactions of both remain unknown.In this study, we focused on the treatment of liver carcinoma (HepG2) and astrocytoma (CCF-STTG1) cells as a model for the target sites of these two metals. We investigated their effects in single and combined exposure on cell survival, cell death mechanisms, bioavailability, and the induction of oxidative stress. The combination of CoCl2 and NiCl2 resulted in higher Co levels with subsequent decreased amount of Ni compared to the individual treatment. Only CoCl2 and the combination of both metals led to RONS induction and increased GSSG formation, while apoptosis and necrosis seem to be involved in the cell death mechanisms of both CoCl2 and NiCl2. Collectively, this study demonstrates cell-type specific toxicity, with HepG2 representing the more sensitive cell line. Importantly, combined exposure to CoCl2 and NiCl2 is more toxic than single exposure, which may originate partly from the respective cellular Co and Ni content. Our data imply that the major mechanism of joint toxicity is associated with oxidative stress. More studies are needed to assess toxicity after combined exposure to elements such as Co and Ni to advance an improved hazard prediction for less artificial and more real-life exposure scenarios.