Abstract
Despite advances in the preparation of metal oxide (MO) nanoparticles (NPs) as catalysts for various applications, concerns about the biosafety of these particles remain. In this study, we prepared transition metal-doped cerium oxide (TM@CeO2; TM = Cr, Mn, Fe, Co, or Ni) nanoparticles and investigated the mechanism underlying dopant-dependent toxicity in HaCaT human keratinocytes. We show that doping with Cr or Co but not Fe, Mn, or Ni increased the toxicity of CeO2 NPs in dose- and time-dependent manners and led to apoptotic cell death. Interestingly, while both undoped and transition metal-doped NPs increased intracellular reactive oxygen species (ROS), toxic Cr@CeO2 and Co@CeO2 NPs failed to induce the expression of NRF2 (nuclear factor erythroid 2-related factor 2) as well as its downstream target genes involved in the antioxidant defense system. Moreover, activation of NRF2 transcription was correlated with dynamic changes in H3K4me3 and H3K27me3 at the promoter of NRF2, which was not observed in cells exposed to Cr@CeO2 NPs. Furthermore, exposure to relatively non-toxic Fe@CeO2 NPs, but not the toxic Cr@CeO2 NPs, resulted in increased binding of MLL1 complex, a major histone lysine methylase mediating trimethylation of histone H3 lysine 4, at the NRF2 promoter. Taken together, our findings strongly suggest that failure of cells to respond to oxidative stress is critical for dopant-dependent toxicity of CeO2 NPs and emphasize that careful evaluation of newly developed NPs should be preceded before industrial or biomedical applications.
Highlights
Metal oxide nanoparticles (MONPs) have been used for various chemical and biological applications, for example, as chemical sensors, biosensors, drug delivery agents, and for cancer therapy and in electrochemical reactions, due to their unique physicochemical properties [1,2,3,4]
In vitro and in vivo studies have suggested that induction of reactive oxygen species (ROS) by MONPs predominantly underlies their toxicities by causing oxidative stress and inflammation, leading to intracellular component damage and aberrant expressions of genes associated with cellular homeostasis [7,15]
To investigate the effects of transition metal doping on the toxicity of CeO2 NPs, we first analyzed the crystal structure of TM@CeO2 NPs by X-ray diffraction (XRD) and transmission electron microscopy (TEM)
Summary
Metal oxide nanoparticles (MONPs) have been used for various chemical and biological applications, for example, as chemical sensors, biosensors, drug delivery agents, and for cancer therapy and in electrochemical reactions, due to their unique physicochemical properties [1,2,3,4]. Most studies have reported at best modest toxic effects or even protective effects [33,34,35], some have suggested CeO2 NPs may be toxic and cause cell death, presumably due to oxidative stress (e.g., reactive oxygen species (ROS) production), DNA damage, alterations in cell signaling, and deregulated gene expression [36,37,38,39]. NPs induces oxidative stresses, increases nuclear NRF2 level, and eventually causes cell death [38] It has been reported CeO2 NPs have protective effects due to the transcriptional and posttranscriptional activation of NRF2 signaling [47,48], and yet others have reported CeO2 NPs exposure resulted in no significant change or even a reduction in NRF2 level [49,50]. Our comparative analysis provides evidence that transcriptional activation of the NRF2 gene and dynamic changes in H3K4me and H3K27me histone modifications play a critical role in dopant-dependent toxicity of TM@CeO2 NPs
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