Silica nanomaterials induce organ injuries by Ca2+-ROS-initiated disruption of the endothelial barrier and triggering intravascular coagulation

Abstract

Background: The 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. Methods:The study was conducted in cultured human umbilical vein endothelial cells (HUVECs) and adult female Balb/c mice using several techniques.Results: In 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 concentrationdependent 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 Ca 2+ release activated Ca 2+ (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.

<p>Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice</p>

“…We reported recently that the toxicity of SiNP-100 on HUVECs is higher than that of SiNP-20. 33 This may be associated with the faster sedimentation of SiNP-100 onto the cell surface than that of SiNP-20, as identified using the in vitro Sedimentation, Diffusion and Dosimetry (ISDD) model. 33,34 In addition, other physical characteristics of nanoparticles, such as the zeta potential, may also contribute to the biotoxicity of nanoparticles.…”

“…33 This may be associated with the faster sedimentation of SiNP-100 onto the cell surface than that of SiNP-20, as identified using the in vitro Sedimentation, Diffusion and Dosimetry (ISDD) model. 33,34 In addition, other physical characteristics of nanoparticles, such as the zeta potential, may also contribute to the biotoxicity of nanoparticles. The zeta potential predicts the physical stability of the nanosuspension, the higher the absolute value of zeta potential, the higher the dispersion of nanoparticles in a solution.…”

<p>The Size-dependent Cytotoxicity of Amorphous Silica Nanoparticles: A Systematic Review of in vitro Studies</p>

“…By comparison, 30 nm particles did not decrease the cell viability, owing to the tendency of agglomeration over time. Wang et al 76 demonstrated that both 20 nm and 100 nm aSiNPs decreased the cell viability of HUVECs in a concentration-dependent manner from the minimal toxic concentration (50 μg/mL), whereas 100 nm aSiNPs was found to be more toxic than 20 nm aSiNPs. An in vitro sedimentation, diffusion and dosimetry (ISDD) model was introduced to estimate the aSiNPs sedimentations onto the cell surface, and results suggested that 100 nm aSiNPs reached to the cell surface more efficiently than 20 nm aSiNPs over time, larger aSiNPs thus have a higher effective exposure concentration than smaller particles.…”

Transcriptomic‐based toxicological investigations of ethanol to human umbilical vein endothelial cells

“…It was confirmed that both concentrations of ethanol downregulated key genes related with calcium signaling pathway (Figure 6). Interestingly, previous studies also found that dysfunction in calcium signaling is involved in endothelial dysfunction (Cheriyan et al, 2020; Li et al, 2020; Wang et al, 2020). Key genes related with PI3K‐Akt signaling pathway were also downregulated by ethanol, but 50‐mM ethanol appeared to be more effectively compared with 5‐mM ethanol (Figure 7).…”