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This study was to investigate the combined toxicity of silica nanoparticles (SiNPs) and methylmercury (MeHg) on cardiovascular system in zebrafish (Danio rerio) embryos. Ultraviolet absorption analysis showed that the co-exposure system had high absorption and stability. The dosages used in this study were based on the NOAEL level. Zebrafish embryos exposed to the co-exposure of SiNPs and MeHg did not show any cardiovascular malformation or atrioventricular block, but had an inhibition effect on bradycardia. Using o-Dianisidine for erythrocyte staining, the cardiac output of zebrafish embryos was decreased gradually in SiNPs, MeHg, co-exposure groups, respectively. Co-exposure of SiNPs and MeHg enhanced the vascular endothelial damage in Tg(fli-1:EGFP) transgenic zebrafish line. Moreover, the co-exposure significantly activated the oxidative stress and inflammatory response in neutrophils-specific Tg(mpo:GFP) transgenic zebrafish line. This study suggested that the combined toxic effects of SiNPs and MeHg on cardiovascular system had more severe toxicity than the single exposure alone., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The multinucleation effect of silica nanoparticles (SiNPs) had been determined in our previous studies, but the relative mechanisms of multinucleation and how the multinucleated cells are generated were still not clear. This extensional study was conducted to investigate the mechanisms underlying the formation of multinucleated cells after SiNPs exposure. We first investigated cellular multinucleation, then performed time-lapse confocal imaging to certify whether the multinucleated cells resulted from cell fusion or abnormal cell division. Our results confirmed for the first time that there are three patterns contributing to the SiNPs-induced multinucleation in HepG2 cells: cell fusion, karyokinesis without cytokinesis, and cytokinesis followed by fusion. The chromosomal passenger complex (CPC) deficiency and cell cycle arrest in G1/S and G2/M checkpoints may be responsible for the cell aberrant cytokinesis. The activated MAPK/ERK1/2 signaling and decreased mitosis related proteins might be the underlying mechanism of cell cycle arrest and thus multinucleation. In summary, we confirmed the hypothesis that aberrant cytokinesis and cell fusion resulted in multinucleation in HepG2 cells after SiNPs exposure. Since cell fusion and multinucleation were involved in genetic instability and tumor development, this study suggests the potential ability of SiNPs to induce cellular genetic instability. These findings raise concerns with regard to human health hazards and environmental risks with SiNPs exposure.

Despite the widespread application of silica nanoparticles (SiNPs) in industrial, commercial, and biomedical fields, their response to human cells has not been fully elucidated. Overall, little is known about the toxicological effects of SiNPs on the cardiovascular system. In this study, SiNPs with a 58 nm diameter were used to study their interaction with human umbilical vein endothelial cells (HUVECs). Dose- and time-dependent decrease in cell viability and damage on cell plasma-membrane integrity showed the cytotoxic potential of the SiNPs. SiNPs were found to induce oxidative stress, as evidenced by the significant elevation of reactive oxygen species generation and malondialdehyde production and downregulated activity in glutathione peroxidase. SiNPs also stimulated release of cytoprotective nitric oxide (NO) and upregulated inducible nitric oxide synthase (NOS) messenger ribonucleic acid, while downregulating endothelial NOS and ET-1 messenger ribonucleic acid, suggesting that SiNPs disturbed the NO/NOS system. SiNP-induced oxidative stress and NO/NOS imbalance resulted in endothelial dysfunction. SiNPs induced inflammation characterized by the upregulation of key inflammatory mediators, including IL-1β, IL-6, IL-8, TNFα, ICAM-1, VCAM-1, and MCP-1. In addition, SiNPs triggered the activation of the Nrf2-mediated antioxidant system, as evidenced by the induction of nuclear factor-κB and MAPK pathway activation. Our findings demonstrated that SiNPs could induce oxidative stress, inflammation, and NO/NOS system imbalance, and eventually lead to endothelial dysfunction via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling. This study indicated a potential deleterious effect of SiNPs on the vascular endothelium, which warrants more careful assessment of SiNPs before their application.

Although nanoparticles have a great potential for biomedical applications, there is still a lack of a correlative safety evaluation on the cardiovascular system. This study is aimed to clarify the biological behavior and influence of silica nanoparticles (Nano-SiO2) on endothelial cell function. The results showed that the Nano-SiO2 were internalized into endothelial cells in a dose-dependent manner. Monodansylcadaverine staining, autophagic ultrastructural observation, and LC3-I/LC3-II conversion were employed to verify autophagy activation induced by Nano-SiO2, and the whole autophagic process was also observed in endothelial cells. In addition, the level of nitric oxide (NO), the activities of NO synthase (NOS) and endothelial (e)NOS were significantly decreased in a dose-dependent way, while the activity of inducible (i)NOS was markedly increased. The expression of C-reactive protein, as well as the production of proinflammatory cytokines (tumor necrosis factor α, interleukin [IL]-1β, and IL-6) were significantly elevated. Moreover, Nano-SiO2 had an inhibitory effect on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Our findings demonstrated that Nano-SiO2 could disturb the NO/NOS system, induce inflammatory response, activate autophagy, and eventually lead to endothelial dysfunction via the PI3K/Akt/mTOR pathway. This indicates that exposure to Nano-SiO2 is a potential risk factor for cardiovascular diseases.

The toxic effects of silica nanoparticles (SiNPs) are raising concerns due to its widely applications in biomedicine. However, current information about the epigenetic toxicity of SiNPs is insufficient. In this study, the epigenetic regulation of low-dose exposure to SiNPs was evaluated in human bronchial epithelial BEAS-2B cells over 30 passages. Cell viability was decreased in a dose- and passage-dependent manner. The apoptotic rate, the expression of caspase-9 and caspase-3, were significantly increased induced by SiNPs. HumanMethylation450 BeadChip analysis identified that the PI3K/Akt as the primary apoptosis-related pathway among the 25 significant altered processes. The differentially methylated sites of PI3K/Akt pathway involved 32 differential genes promoters, in which the CREB3L1 and Bcl-2 were significant hypermethylated. The methyltransferase inhibitor, 5-aza, further verified that the DNA hypermethylation status of CREB3L1 and Bcl-2 were associated with downregulation of their mRNA levels. In addition, mitochondrial-mediated apoptosis was triggered by SiNPs via the downregulation of PI3K/Akt/CREB/Bcl-2 signaling pathway. Our findings suggest that long-term low-dose exposure to SiNPs could lead to epigenetic alterations. [ABSTRACT FROM AUTHOR]

Recently, amorphous silicon nanoparticles (SNPs) are widely used in a variety of fields, especially in biological and medical science. Thus, the adverse effect of these nanoparticles should be carefully investigated. The multinucleation effect of SNPs was firstly reported in our previous studies, while the relative mechanism is still unclear. Therefore, the purpose of this study is to investigate the mechanisms with regard to the formation of multinucleated cells. Two sizes of amorphous SNPs (Nano-Si64 and Nano-Si46) are carefully characterized. Cytotoxicity and rate of multinucleated cells are firstly determined after human hepatic L-02 cells are treated with two SNPs for 24 h. Then cell fusion and abnormal mitosis, two ways could form multinucleated cells, are investigated, respectively. Results indicated that SNPs produce a dose-dependent and size-related multinucleation effect in L-02 cells. Abnormal mitosis instead of cell fusion is the main reason for the formation of multinucleated cells caused by SNPs. Both two SNPs could affect the quantity and distribution of cytoskeleton through extra ROS and Ca2+ leading to abnormal mitosis and cytokinesis. Additionally, chromosome damage resulting in corresponding G2/M cell cycle arrest should be another aspect, which finally leads to the formation of multinucleated cells in L-02 cell line. [ABSTRACT FROM AUTHOR]