Silver Nanoparticles Induced RNA Polymerase-Silver Binding and RNA Transcription Inhibition in Erythroid Progenitor Cells

Abstract

Due to its antimicrobial activity, nanosilver (nAg) has become the most widely used nanomaterial. Thus far, the mechanisms responsible for nAg-induced antimicrobial properties and nAg-mediated toxicity to organisms have not been clearly recognized. Silver (Ag) ions certainly play a crucial role, and the form of nanoparticles can change the dissolution rate, bioavailability, biodistribution, and cellular uptake of Ag. However, whether nAg exerts direct "particle-specific" effects has been under debate. Here we demonstrated that nAg exhibited a robust inhibition on RNA polymerase activity and overall RNA transcription through direct Ag binding to RNA polymerase, which is separated from the cytotoxicity pathway induced by Ag ions. nAg treatment in vitro resulted in reduced hemoglobin concentration in erythroid cells; in vivo administration of nAg in mice caused profound reduction of hemoglobin content in embryonic erythrocytes, associated with anemia in the embryos.Embryonic anemia and general proliferation deficit due to the significant inhibition on RNA synthesis, at least partially, accounted for embryonic developmental retardation upon nAg administration. To date, there is no conclusive answer to the sources of nAg-mediated toxicity: Ag ions or "particlespecific" effects, or both. We here demonstrated that both Ag ions and nAg particles simultaneously existed inside cells, demonstrating the "Trojan horse" effects of nAg particles in posing biological impacts on erythroid cells. Moreover, our results suggested that "particle-specific" effects could be the predominant mediator in eliciting biological influences on erythroid cells under relatively low concentrations of nAg exposure. The combined data highlighted the inhibitory effect of nAg on RNA polymerase activity through a direct reciprocal interaction.

Nanosilver Incurs an Adaptive Shunt of Energy Metabolism Mode to Glycolysis in Tumor and Nontumor Cells

“…23 The transmission electron microscopy (TEM) imaging revealed that silver nanoparticles were spherical and homogeneously dispersed (Figure 2A), and the average diameter was 25 nm, as evidenced by a histogram of measured size ( Figure 2B). An absorption peak was observed around 400 nm, as characterized by the absorption spectrum analysis ( Figure 2C).…”

“…35À37 In agreement with these results, we recently demonstrated that nAg particles with smaller size showed greater effects on inhibiting globin expression in erythroid cells than those with larger size, and nAg particles with spherical shape ARTICLE revealed enhanced capability to suppress globin expression compared to those in plate shape. 23 We next studied the molecular bases underlying the energy mode change in response to nAg. Since smallsized nAg showed greater effects on driving energy mode shift than those with larger size or in plate shape and HEK293T appeared to be more sensitive to nAgconducted energy mode change as discussed above, we embarked on the molecular mechanisms using HEK293T cells and 25 nm sphere-like nAg in the following experiments.…”

“…23 Electrons are transferred in a finely tuned way between electron donors and ARTICLE electron acceptors along the respiratory chain complexes, which drives protons to move from the mitochondrial matrix into the intermembrane space and thus generates a proton gradient across the inner mitochondrial membrane, where released energy is converted into ATP. Ag ions have great capability to attract electrons, which will likely disturb electron transfer along mitochondrial respiratory chain.…”

Silver nanoparticle-induced hemoglobin decrease involves alteration of histone 3 methylation status

“…AgNPs were characterized by transmission electron microscopy (TEM, Hitachi H7500, Japan), and the hydrodynamic diameter and zeta potential in cell culture media were determined with a Zetasizer (Malvern Nano series, Malvern, U.K.). The rate of Ag ion dissolution was carried out at different time points, as described previously [26].…”

Speciation Analysis of Labile and Total Silver(I) in Nanosilver Dispersions and Environmental Waters by Hollow Fiber Supported Liquid Membrane Extraction

“…9 While it is generally believed that the free/labile metal ions are responsible for the toxicity of metals in environment, and the metal ions associated with matrix (such as particles and nature organic matter) are not bioavailable, 10−12 the case for nanoparticles is much more complicated because the particles could enter the cells by a Trojan-horse type mechanism. 13,14 Therefore, determination of nanoparticulate and ionic species of metals in metal/metal oxide nanomaterial dispersions and environment waters is crucial for exploiting the applications, as well as for understanding and elucidating the environmental transportation, transformation, and toxicity properties of these materials. 15−18 Various techniques, such as centrifugation, 19 centrifugal ultrafiltration, 20 dialysis, 21 ultrafiltration, 22,23 cloud point extraction, 24−26 and magnetic solid phase extraction, 27 were proposed for the separation and determination of nanoparticulate and ionic metals in various samples.…”