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Open AccessArticle

Impact of Endocytosis and Lysosomal Acidification on the Toxicity of Copper Oxide Nano- and Microsized Particles: Uptake and Gene Expression Related to Oxidative Stress and the DNA Damage Response

Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany
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Nanomaterials 2020, 10(4), 679; https://doi.org/10.3390/nano10040679
Received: 6 February 2020 / Revised: 23 March 2020 / Accepted: 30 March 2020 / Published: 3 April 2020
(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles)
The toxicity of the copper oxide nanoparticles (CuO NP) has been attributed to the so-called “Trojan horse”-type mechanism, relying on the particle uptake and extensive intracellular release of copper ions, due to acidic pH in the lysosomes. Nevertheless, a clear distinction between extra- and intracellular-mediated effects is still missing. Therefore, the impact of the endocytosis inhibitor hydroxy-dynasore (OH-dyn), as well as bafilomycin A1 (bafA1), inhibiting the vacuolar type H+-ATPase (V-ATPase), on the cellular toxicity of nano- and microsized CuO particles, was investigated in BEAS 2 B cells. Selected endpoints were cytotoxicity, copper uptake, glutathione (GSH) levels, and the transcriptional DNA damage and (oxidative) stress response using the high-throughput reverse transcription quantitative polymerase chain reaction (RT-qPCR). OH-dyn markedly reduced intracellular copper accumulation in the cases of CuO NP and CuO MP; the modulation of gene expression, induced by both particle types affecting especially HMOX1, HSPA1A, MT1X, SCL30A1, IL8 and GADD45A, were completely abolished. BafA1 lowered the intracellular copper concentration in case of CuO NP and strongly reduced transcriptional changes, while any CuO MP-mediated effects were not affected by bafA1. In conclusion, the toxicity of CuO NP depended almost exclusively upon dynamin-dependent endocytosis and the intracellular release of redox-active copper ions due to lysosomal acidification, while particle interactions with cellular membranes appeared to be not relevant. View Full-Text
Keywords: copper oxide nanoparticles; genomic stability; gene expression profiling; high-throughput RT-qPCR; endocytosis; cellular copper uptake; lysosomal acidification; Trojan horse-type mechanism copper oxide nanoparticles; genomic stability; gene expression profiling; high-throughput RT-qPCR; endocytosis; cellular copper uptake; lysosomal acidification; Trojan horse-type mechanism
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Strauch, B.M.; Hubele, W.; Hartwig, A. Impact of Endocytosis and Lysosomal Acidification on the Toxicity of Copper Oxide Nano- and Microsized Particles: Uptake and Gene Expression Related to Oxidative Stress and the DNA Damage Response. Nanomaterials 2020, 10, 679.

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