Silver Nanoparticle-Induced Autophagic-Lysosomal Disruption and NLRP3-Inflammasome Activation in HepG2 Cells is Size-Dependent

Toxicological Sciences : an Official Journal of the Society of Toxicology
Anurag MishraPeter L Goering

Abstract

Silver nanoparticles (AgNPs) are incorporated into medical and consumer products to exploit their excellent antimicrobial properties; however, potential mechanisms of toxicity of AgNPs in mammalian cells are not fully understood. The objective of this study was to determine the mechanism of size- and concentration-dependent cytotoxicity of AgNPs in human liver derived hepatoma (HepG2) cells. Mechanisms of toxicity were explored at sub-cytotoxic concentrations (≤ 10 µg/ml AgNPs) and autophagy induction, lysosomal activity, inflammasome-dependent caspase-1 activation and apoptosis were examined. Using enhanced dark-field light microscopy hyperspectral imaging, electron microscopy, and EDS, AgNPs were shown to rapidly accumulate in cytoplasmic vesicles for up to 24 hr exposure and 10nm AgNPs exhibited the highest uptake and accumulation. Autophagy and enhanced lysosomal activity were induced at non-cytotoxic concentrations (1 µg/ml; primary particle size:10nm>50nm>100nm), whereas increased caspase-3 activity (associated with apoptosis) was observed at cytotoxic concentrations (10, 25 and 50 µg/ml). Sub-cytotoxic concentrations of AgNPs enhanced expression of LC3B, a pro-autophagic protein, CHOP, an apoptosis inducing ER-stress pro...Continue Reading

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