Search

Abstract Background With the large-scale production and application of amorphous silica nanoparticles (aSiNPs), its adverse health effects are more worthy of our attention. Our previous research has demonstrated for the first time that aSiNPs induced cytokinesis failure, which resulted in abnormally high incidences of multinucleation in vitro, but the underlying mechanisms remain unclear. Therefore, the purpose of this study was firstly to explore whether aSiNPs induced multinucleation in vivo, and secondly to investigate the underlying mechanism of how aSiNPs caused abnormal cytokinesis and multinucleation. Methods Male ICR mice with intratracheal instillation of aSiNPs were used as an experimental model in vivo. Human hepatic cell line (L-02) was introduced for further mechanism study in vitro. Results In vivo, histopathological results showed that the rate of multinucleation was significantly increased in the liver and lung tissue after aSiNPs treatment. In vitro, immunofluorescence results manifested that aSiNPs directly caused microfilaments aggregation. Following mechanism studies indicated that aSiNPs increased ROS levels. The accumulation of ROS further inhibited the PI3k 110β/Aurora B pathway, leading to a decrease in the expression of centralspindlin subunits MKLP1 and CYK4 as well as downstream cytokines regulation related proteins Ect2, Cep55, CHMP2A and RhoA. Meanwhile, the particles caused abnormal co-localization of the key mitotic regulatory kinase Aurora B and the centralspindlin complex by inhibiting the PI3k 110β/Aurora B pathway. PI3K activator IGF increased the phosphorylation level of Aurora B and improved the relative ratio of the centralspindlin cluster. And ROS inhibitors NAC reduced the ratio of multinucleation, alleviated the PI3k 110β/Aurora B pathway inhibition, and then increased the expression of MKLP1, CYK4 and cytokinesis-related proteins, whilst NAC restored the clustering of the centralspindlin. Conclusion This study demonstrated that aSiNPs led to multinucleation formation both in vivo and in vitro. ASiNPs exposure caused microfilaments aggregation and inhibited the PI3k 110β/Aurora B pathway through excessive ROS, which then hindered the centralspindlin cluster as well as restrained the expression of centralspindlin subunits and cytokinesis-related proteins, which ultimately resulted in cytokinesis failure and the formation of multinucleation.

The extensive application of amorphous silica nanoparticles (aSiNPs) in recent years has resulted in unavoidable human exposure in daily life, thus raising widespread concerns regarding the safety of aSiNPs on human health. The particle size is one of the important characteristics of nanomaterials that could influence their toxicity. For the reason that particles with smaller sizes possess larger surface area, which may lead to higher surface activity and biological reactivity. However, due to the complexity of experimental conditions and biological systems, the relationship between the particle size and the toxic effect of aSiNPs remains unclear. Therefore, this systematic review aims to investigate how particle size influences the toxic effect of aSiNPs in vivo and to analyze the relevant experimental factors affecting the size-dependent toxicity of aSiNPs in vivo. We found that 83.8% of 35 papers included in the present review came to the conclusion that smaller-sized aSiNPs exhibited stronger toxicity, though a few papers (6 papers) put forward different opinions. The reasons for smaller aSiNPs manifested greater toxicity were summarized. In addition, certain important experimental factors could influence the size-dependent effects and in vivo toxicity of aSiNPs, such as the synthesis method of aSiNPs, disperse medium of aSiNPs, administration route of aSiNPs, species or strain of experimental animals, sex of experimental animals, aggregation/agglomeration and protein corona of aSiNPs.