Use of An In Silico Knowledge Discovery Approach To Translate Mechanistic Studies of Silver Nanoparticles-Induced Toxicity From In Vitro To In Vivo

Abstract

Background: Silver nanoparticles (AgNPs) are considered a double-edged sword that demonstrates beneficial and harmful effects depending on their dimensions and surface coating types. However, mechanistic reports regarding size- and coating-dependent effects of AgNPs remain inadequate in vitro and in vivo. In keeping with the 3Rs principles, we adopted an in silico decision tree-based knowledge-discovery-in-databases process to offer a multilayered view of AgNPs toxicity and translate our research from cell-based phenomenological observations to further in vitro and in vivo mechanistic explorations.Results: Cell viability assessment results was used to create a tree model for predicting toxicity evoked by four AgNP types: SCS, LCS, SAS, and LAS. This model ranked toxicity-relevant parameters in the order: dose > cell type > AgNP type ≥ exposure time. As suggested by the model, we chose a less responsive cell line to conduct further investigations. LCS among others was more capable of comprising viability of this cell line and could trigger higher levels of apoptosis and autophagy at a subcytotoxic dose. Even though at a cytotoxic dose, it was yet unable to evoke necrosis. Longer exposure to a noncytotoxic dose of LCS induced G2/M cell cycle arrest and senescence rather than eliciting apoptosis and autophagy. After a single intraperitoneal injection, SCS was found to be more toxic to mice than SAS, both of which could be deposited in various target organs (e.g., spleen, liver, and kidneys). Morphological observation, together with serum biochemical and histological analyses, indicated that AgNPs could produce pancreatic toxicity, apart from leading to hepatic inflammation. Conclusions: Our integrated in vitro, in silico, and in vivo study demonstrated that AgNPs could exert toxicity in dose-, cell/organ type- and particle type-dependent manners. More importantly, a single injection of lethal-dose AgNPs (i.e., SCS and SAS) could incur severe damage to pancreas and raise blood glucose levels at the early phase of exposure.