Abstract
BackgroundThe growing use of silica nanoparticles (SiNPs) in many fields raises human toxicity concerns. We studied the toxicity of SiNP-20 (particle diameter 20 nm) and SiNP-100 (100 nm) and the underlying mechanisms with a focus on the endothelium both in vitro and in vivo.MethodsThe study was conducted in cultured human umbilical vein endothelial cells (HUVECs) and adult female Balb/c mice using several techniques.ResultsIn vitro, both SiNP-20 and SiNP-100 decreased the viability and damaged the plasma membrane of cultured HUVECs. The nanoparticles also inhibited HUVECs migration and tube formation in a concentration-dependent manner. Both SiNPs induced significant calcium mobilization and generation of reactive oxygen species (ROS), increased the phosphorylation of vascular endothelial (VE)-cadherin at the site of tyrosine 731 residue (pY731-VEC), decreased the expression of VE-cadherin expression, disrupted the junctional VE-cadherin continuity and induced F-actin re-assembly in HUVECs. The injuries were reversed by blocking Ca2+ release activated Ca2+ (CRAC) channels with YM58483 or by eliminating ROS with N-acetyl cysteine (NAC). In vivo, both SiNP-20 and SiNP-100 (i.v.) induced multiple organ injuries of Balb/c mice in a dose (range 7–35 mg/kg), particle size, and exposure time (4–72 h)-dependent manner. Heart injuries included coronary endothelial damage, erythrocyte adhesion to coronary intima and coronary coagulation. Abdominal aorta injury exhibited intimal neoplasm formation. Lung injuries were smaller pulmonary vein coagulation, bronchiolar epithelial edema and lumen oozing and narrowing. Liver injuries included multifocal necrosis and smaller hepatic vein congestion and coagulation. Kidney injuries involved glomerular congestion and swelling. Macrophage infiltration occurred in all of the observed organ tissues after SiNPs exposure. SiNPs also decreased VE-cadherin expression and altered VE-cadherin spatial distribution in multiple organ tissues in vivo. The largest SiNP (SiNP-100) and longest exposure time exerted the greatest toxicity both in vitro and in vivo.ConclusionsSiNPs, administrated in vivo, induced multiple organ injuries, including endothelial damage, intravascular coagulation, and secondary inflammation. The injuries are likely caused by upstream Ca2+-ROS signaling and downstream VE-cadherin phosphorylation and destruction and F-actin remodeling. These changes led to endothelial barrier disruption and triggering of the contact coagulation pathway.
Highlights
The growing use of silica nanoparticles (SiNPs) in many fields raises human toxicity concerns
Dynamic light scattering (DLS) experiments showed that the hydrodynamic sizes of Silica nanomaterials (SiNPs) were with two diameters: 20 nm (SiNP-20) and SiNP-100 were respectively 35.4 ± 1.2 nm and 120.8 ± 1.0 nm in water, and were 40.2 ± 1.5 nm and 160.2 ± 1.4 nm in serumcontaining culture medium (Fig. 1c)
Our present study suggests that reactive oxygen species (ROS) are signaling molecules mediating the endothelial toxicity of SiNPs, because scavenging ROS by N-acetyl cysteine (NAC) improved the destruction of vascular endothelial (VE)-cadherin (Fig. 6d)
Summary
The growing use of silica nanoparticles (SiNPs) in many fields raises human toxicity concerns. SiNPs have wide applications because of their unique properties and have been used in fields such as microelectronics [2], material science and industry [3], agriculture, food and consumer products (including cosmetics) [4,5,6,7], and medicine (drug delivery, diagnostic and medicine imaging and engineering) [8, 9]. The cellular mechanisms include DNA damage, cell cycle arrest, immunotoxicity, autophagy, oxidative stress, and dysfunction of endothelial cells and blood cells. Cell type is another variable related to SiNPs cytotoxicity. Alternative mechanisms may cause SiNPs cytotoxicity including endoplasmic reticulum stress-associated apoptosis [11], mitochondrial pathway-mediated apoptosis [12], reactive oxygen species (ROS)-associated intracellular acidosis [13], and transient receptor potential (TRP) ion channelassociated event [14]
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