{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:31Z","timestamp":1787028571663,"version":"build-2736575974"},"reference-count":62,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T00:00:00Z","timestamp":1756512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Canada\u2019s Chemicals Management Plan"},{"name":"Environmental Health Science and Research Bureau"},{"name":"New Substances Assessment and Control Bureau of Health Canada"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 (Al2O3) NPs, and titanium dioxide (TiO2) 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 TiO2 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 TiO2 NPs, but not soluble CuO NPs, impaired the organization of F-actin and \u03b1-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.<\/jats:p>","DOI":"10.3390\/ijms26178451","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T15:02:57Z","timestamp":1756825377000},"page":"8451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Acute Toxicity of Metal Oxide Nanoparticles\u2014Role of Intracellular Localization In Vitro in Lung Epithelial Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0827-997X","authenticated-orcid":false,"given":"Andrey","family":"Boyadzhiev","sequence":"first","affiliation":[{"name":"Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada"},{"name":"Biology Department, Faculty of Science, University of Ottawa, Ottawa, ON K1N 9A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Halappanavar","sequence":"additional","affiliation":[{"name":"Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada"},{"name":"Biology Department, Faculty of Science, University of Ottawa, Ottawa, ON K1N 9A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.3762\/bjnano.6.181","article-title":"Nanotechnology in the Real World: Redeveloping the Nanomaterial Consumer Products Inventory","volume":"6","author":"Vance","year":"2015","journal-title":"Beilstein J. 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