title: Zinc oxide nanoparticles interfere with zinc ion homeostasis to cause cytotoxicity.
abstract: The toxicological effects of zinc oxide nanoparticles (ZnO-NPs) are attracting increasing concern as the field of nanotechnology progresses. Although the literature suggests that toxicity of ZnO-NPs may be related to their dissolution, the mechanism for ZnO-NP perturbation of cytosolic zinc concentration ([Zn(2+)](c)) homeostasis remains obscure. Using FluoZin-3 and RhodZin-3, this study investigated changes in both [Zn(2+)](c) and mitochondrial free Zn(2+) concentration ([Zn(2+)](m)) under conditions of ZnO-NP treatment in vivo and in vitro. In human leukemia Jurkat cells and human lung carcinoma H1355 cells, ZnO-NP treatment resulted in an elevation of both [Zn(2+)](c) and [Zn(2+)](m). In H1355 cells, ZnO-NP treatment induced depolarization of mitochondrial membrane potential, as well as caspase-3 activation and lactic dehydrogenase (LDH) release. In our in vivo experiments, when rats were exposed to ZnO-NPs, higher [Zn(2+)](c) and [Zn(2+)](m) were recorded in both broncho-alveolar lavage (BAL) cells and white blood cells isolated from ZnO-NP-exposed rats, compared with high efficiency particulate air-filter-protected controls LDH levels were also elevated in the BAL of ZnO-NP-exposed rats compared with controls. A mechanical toxicological pathway for ZnO-NP toxicity is suggested by these results: an elevation in [Zn(2+)](c) resulting from ZnO-NP dissolution in the intracellular endosome; cytosolic Zn(2+) sequestration by mitochondria; and elevated [Zn(2+)](m) leading to mitochondrial dysfunction, caspase activation, and cell apoptosis. We conclude that exposure to ZnO-NPs interferes with the homeostasis of [Zn(2+)](c,) and that elevated [Zn(2+)](c) results in cell apoptosis.
authors: Department of Microbiology, Soochow University, Taipei, Taiwan, Republic of China.
authors: Yi-Yun
authors: YY
authors: Kao
authors: Yi-Chun
authors: YC
authors: Chen
authors: Tsun-Jen
authors: TJ
authors: Cheng
authors: Yin-Mei
authors: YM
authors: Chiung
authors: Pei-Shan
authors: PS
authors: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis; D006801:Humans; D019570:Inhalation Exposure; D019169:Jurkat Cells; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015034:Zinc Oxide / Q000378:metabolism / Q000633:toxicity*
chemical_list: D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; D053148:Caspase 3; D015034:Zinc Oxide