Boyadzhiev Andrey, Halappanavar Sabina
Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada.
Biology Department, Faculty of Science, University of Ottawa, Ottawa, ON K1N 9A4, Canada.
Int J Mol Sci. 2025 Aug 30;26(17):8451. doi: 10.3390/ijms26178451.
Endocytic uptake and lysosomal localization are suggested to be the key mechanisms underlying the toxicity of metal oxide nanoparticles (MONPs), with dissolution in the acidic milieu driving the response. In this study, we aimed to investigate if MONPs of varying solubility are similarly sequestered intracellularly, including in lysosomes and the role of the acidic lysosomal milieu on toxicity induced by copper oxide (CuO) nanoparticles (NPs), nickel oxide (NiO) NPs, aluminum oxide (AlO) NPs, and titanium dioxide (TiO) NPs of varying solubility in FE1 lung epithelial cells. Mitsui-7 multi-walled carbon nanotubes (MWCNTs) served as contrasts against particles. Enhanced darkfield hyperspectral imaging (EDF-HSI) with fluorescence microscopy was used to determine their potential association with lysosomes. The v-ATPase inhibitor Bafilomycin A1 (BaFA1) was used to assess the role of lysosomal acidification on toxicity. The results showed co-localization of all MONPs with lysosomes, with insoluble TiO NPs showing the greatest co-localization. However, only acute toxicity induced by soluble CuO NPs was affected by the presence of BaFA1, showing a 14% improvement in relative survival. In addition, all MONPs were found to be associated with large actin aggregates; however, treatment with insoluble TiO NPs, but not soluble CuO NPs, impaired the organization of F-actin and α-tubulin. These results indicate that MONPs are sequestered similarly intracellularly; however, the nature or magnitude of their toxicity is not similarly impacted by it. Future studies involving a broader variety of NPs are needed to fully understand the role of differential sequestration of NPs on cellular toxicity.
内吞摄取和溶酶体定位被认为是金属氧化物纳米颗粒（MONPs）毒性的关键机制，其在酸性环境中的溶解驱动了这一反应。在本研究中，我们旨在调查不同溶解度的MONPs是否在细胞内被类似地隔离，包括在溶酶体中，以及酸性溶酶体环境对不同溶解度的氧化铜（CuO）纳米颗粒（NPs）、氧化镍（NiO） NPs、氧化铝（AlO） NPs和二氧化钛（TiO） NPs在FE1肺上皮细胞中诱导的毒性的作用。三井-7多壁碳纳米管（MWCNTs）用作颗粒的对照。结合荧光显微镜的增强暗场高光谱成像（EDF-HSI）用于确定它们与溶酶体的潜在关联。V-ATP酶抑制剂巴弗洛霉素A1（BaFA1）用于评估溶酶体酸化对毒性的作用。结果显示所有MONPs都与溶酶体共定位，不溶性TiO NPs的共定位程度最高。然而，只有可溶性CuO NPs诱导的急性毒性受BaFA1存在的影响，相对存活率提高了14%。此外，发现所有MONPs都与大的肌动蛋白聚集体相关；然而，用不溶性TiO NPs处理而非可溶性CuO NPs处理会破坏F-肌动蛋白和α-微管蛋白的组织。这些结果表明MONPs在细胞内被类似地隔离；然而，它们毒性的性质或程度并未受到类似影响。需要开展涉及更广泛种类纳米颗粒的未来研究，以充分了解纳米颗粒差异隔离对细胞毒性的作用。
