Dataset Information

Amorphous silica nanoparticles induce tumorigenesis via regulating ATP5H/SOD1-related oxidative stress, oxidative phosphorylation and EIF4G2/PABPC1-associated translational initiation.

ABSTRACT: Background:Recent studies indicate amorphous silica nanoparticles (SiNPs), one of the widely applied nanomaterials, have potential toxicity in humans and induces cell malignant transformation. However, its carcinogenic mechanisms remain poorly understood. This study's purpose was to investigate the underlying toxic mechanisms of amorphous SiNPs on human lung epithelial cells model by using microarray data. Methods:Microarray dataset GSE82062 was collected from Gene Expression Omnibus database, including three repeats of Beas-2B exposed to amorphous SiNPs for 40 passages and three repeats of passage-matched control Beas-2B cells. Differentially expressed genes (DEGs) were identified using linear models for microarray data method. Protein-protein interaction (PPI) network was constructed using data from the STRING database followed by module analysis. The miRwalk2 database was used to predict the underlying target genes of differentially miRNAs. Function enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. Results:A total of 323 genes were identified as DEGs, including 280 downregulated (containing 12 pre-miRNAs) and 43 upregulated genes (containing 29 pre-miRNAs). Function enrichment indicated these genes were involved in translational initiation (i.e., eukaryotic translation initiation factor 4 gamma 2 (EIF4G2), poly (A) binding protein cytoplasmic 1 (PABPC1)), response to reactive oxygen species (i.e., superoxide dismutase 1 (SOD1)) and oxidative phosphorylation (i.e., ATP5H). PABPC1 (degree = 15), ATP5H (degree = 11) and SOD1 (degree = 8)] were proved to be hub genes after PPI-module analyses. ATP5H/SOD1 and EIF4G2/PABPC1 were overlapped with the target genes of differentially expressed pre-miR-3648/572/661 and pre-miR-4521. Conclusions:Amorphous SiNPs may induce tumorigenesis via influencing ATP5H/SOD1-related oxidative stress, oxidative phosphorylation and EIF4G2/PABPC1-associated translational initiation which may be regulated by miR-3648/572/661 and miR-4521, respectively.

SUBMITTER: Xie D

PROVIDER: S-EPMC6404658 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Amorphous silica nanoparticles induce tumorigenesis via regulating ATP5H/SOD1-related oxidative stress, oxidative phosphorylation and EIF4G2/PABPC1-associated translational initiation.

Xie Dongli D Zhou Yang Y Luo Xiaogang X

PeerJ 20190304

<h4>Background</h4>Recent studies indicate amorphous silica nanoparticles (SiNPs), one of the widely applied nanomaterials, have potential toxicity in humans and induces cell malignant transformation. However, its carcinogenic mechanisms remain poorly understood. This study's purpose was to investigate the underlying toxic mechanisms of amorphous SiNPs on human lung epithelial cells model by using microarray data.<h4>Methods</h4>Microarray dataset GSE82062 was collected from Gene Expression Omni ...[more]

PMID: 30863671

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Project description:BackgroundThe regulatory definition(s) of nanomaterials (NMs) frequently uses the term 'agglomerates and aggregates' (AA) despite the paucity of evidence that AA are significantly relevant from a nanotoxicological perspective. This knowledge gap greatly affects the safety assessment and regulation of NMs, such as synthetic amorphous silica (SAS). SAS is used in a large panel of industrial applications. They are primarily produced as nano-sized particles (1-100?nm in diameter) and considered safe as they form large aggregates (>?100?nm) during the production process. So far, it is indeed believed that large aggregates represent a weaker hazard compared to their nano counterpart. Thus, we assessed the impact of SAS aggregation on in vitro cytotoxicity/biological activity to address the toxicological relevance of aggregates of different sizes.ResultsWe used a precipitated SAS dispersed by different methods, generating 4 ad-hoc suspensions with different aggregate size distributions. Their effect on cell metabolic activity, cell viability, epithelial barrier integrity, total glutathione content and, IL-8 and IL-6 secretion were investigated after 24?h exposure in human bronchial epithelial (HBE), colon epithelial (Caco2) and monocytic cells (THP-1). We observed that the de-aggregated suspension (DE-AGGR), predominantly composed of nano-sized aggregates, induced stronger effects in all the cell lines than the aggregated suspension (AGGR). We then compared DE-AGGR with 2 suspensions fractionated from AGGR: the precipitated fraction (PREC) and the supernatant fraction (SuperN). Very large aggregates in PREC were found to be the least cytotoxic/biologically active compared to other suspensions. SuperN, which contains aggregates larger in size (>?100?nm) than in DE-AGGR but smaller than PREC, exhibited similar activity as DE-AGGR.ConclusionOverall, aggregation resulted in reduced toxicological activity of SAS. However, when comparing aggregates of different sizes, it appeared that aggregates >?100?nm were not necessarily less cytotoxic than their nano-sized counterparts. This study suggests that aggregates of SAS are toxicologically relevant for the definition of NMs.

Project description:BackgroundInhalation of crystalline silica is known to cause an inflammatory reaction and chronic exposure leads to lung fibrosis and can progress into the disease, silicosis. Cultured macrophages bind crystalline silica particles, phagocytose them, and rapidly undergo apoptotic and necrotic death. The mechanism by which particles are bound and internalized and the reason particles are toxic is unclear. Amorphous silica has been considered to be a less toxic form, but this view is controversial. We compared the uptake and toxicity of amorphous silica to crystalline silica.Methodology/principal findingsAmorphous silica particles are phagocytosed by macrophage cells and a single internalized particle is capable of killing a cell. Fluorescent dextran is released from endo-lysosomes within two hours after silica treatment and Caspase-3 activation occurs within 4 hours. Interestingly, toxicity is specific to macrophage cell lines. Other cell types are resistant to silica particle toxicity even though they internalize the particles. The large and uniform size of the spherical, amorphous silica particles allowed us to monitor them during the uptake process. In mCherry-actin transfected macrophages, actin rings began to form 1-3 minutes after silica binding and the actin coat disassembled rapidly following particle internalization. Pre-loading cells with fluorescent dextran allowed us to visualize the fusion of phagosomes with endosomes during internalization. These markers provided two new ways to visualize and quantify particle internalization. At 37 °C the rate of amorphous silica internalization was very rapid regardless of particle coating. However, at room temperature, opsonized silica is internalized much faster than non-opsonized silica.Conclusions/significanceOur results indicate that amorphous and crystalline silica are both phagocytosed and both toxic to mouse alveolar macrophage (MH-S) cells. The pathway leading to apoptosis appears to be similar in both cases. However, the result suggests a mechanistic difference between Fc?RIIA receptor-mediated and non-opsonized silica particle phagocytosis.

Dataset Information

Amorphous silica nanoparticles induce tumorigenesis via regulating ATP5H/SOD1-related oxidative stress, oxidative phosphorylation and EIF4G2/PABPC1-associated translational initiation.

Publications

Amorphous silica nanoparticles induce tumorigenesis via regulating ATP5H/SOD1-related oxidative stress, oxidative phosphorylation and EIF4G2/PABPC1-associated translational initiation.

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