pH-dependent toxicity of high aspect ratio ZnO nanowires in macrophages due to intracellular dissolution.
High-aspect ratio ZnO nanowires have become one of the most promising products in the nanosciences within the past few years with a multitude of applications at the interface of optics and electronics. The interaction of zinc with cells and organisms is complex, with both deficiency and excess causing severe effects. The emerging significance of zinc for many cellular processes makes it imperative to investigate the biological safety of ZnO nanowires in order to guarantee their safe economic exploitation. In this study, ZnO nanowires were found to be toxic to human monocyte macrophages (HMMs) at similar concentrations as ZnCl(2). Confocal microscopy on live cells confirmed a rise in intracellular Zn(2+) concentrations prior to cell death. In vitro, ZnO nanowires dissolved very rapidly in a simulated body fluid of lysosomal pH, whereas they were comparatively stable at extracellular pH. Bright-field transmission electron microscopy (TEM) showed a rapid macrophage uptake of ZnO nanowire aggregates by phagocytosis. Nanowire dissolution occurred within membrane-bound compartments, triggered by the acidic pH of the lysosomes. ZnO nanowire dissolution was confirmed by scanning electron microscopy/energy-dispersive X-ray spectrometry. Deposition of electron-dense material throughout the ZnO nanowire structures observed by TEM could indicate adsorption of cellular components onto the wires or localized zinc-induced protein precipitation. Our study demonstrates that ZnO nanowire toxicity in HMMs is due to pH-triggered, intracellular release of ionic Zn(2+) rather than the high-aspect nature of the wires. Cell death had features of necrosis as well as apoptosis, with mitochondria displaying severe structural changes. The implications of these findings for the application of ZnO nanowires are discussed.
Multi-Imaging Centre, Department of Physiology, Development and Neuroscience/Anatomy Building, University of Cambridge, Downing Street, Cambridge CB3 2DY, United Kingdom.
Karin H
KH
Müller
Jaideep
J
Kulkarni
Michael
M
Motskin
Angela
A
Goode
Peter
P
Winship
Jeremy N
JN
Skepper
Mary P
MP
Ryan
Alexandra E
AE
Porter
D001692:Biological Transport; D032701:Biomimetics; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005110:Extracellular Space / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects*; D008853:Microscopy; D057054:Molecular Imaging; D009000:Monocytes / Q000166:cytology; D053770:Nanowires / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism; D015034:Zinc Oxide / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*
D015032:Zinc; D015034:Zinc Oxide