Use of an in silico knowledge discovery approach to determine 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 understanding of the size- and coating-dependent effects of AgNPs in vitro and in vivo remains elusive. We adopted an in silico decision tree-based knowledge-discovery-in-databases process to prioritize the factors affecting the toxic potential of AgNPs, which included exposure dose, cell type and AgNP type (i.e., size and surface coating), and exposure time. This approach also contributed to effective knowledge integration between cell-based phenomenological observations and in vitro/in vivo mechanistic explorations. Results The consolidated cell viability assessment results were used to create a tree model for generalizing cytotoxic behavior of the four AgNP types: SCS, LCS, SAS, and LAS. The model ranked the toxicity-related parameters in the following order of importance: exposure dose > cell type > particle size > exposure time ≥ surface coating. Mechanistically, larger AgNPs appeared to provoke greater levels of autophagy in vitro, which occurred during the earlier phase of both subcytotoxic and cytotoxic exposures. Furthermore, apoptosis rather than necrosis majorly accounted for compromised cell survival over the above dosage range. Intriguingly, exposure to non-cytotoxic doses of AgNPs induced G2/M cell cycle arrest and senescence instead. At the organismal level, SCS following a single intraperitoneal injection was found more toxic to BALB/c mice as compared to SAS. Both particles could be deposited in various target organs (e.g., spleen, liver, and kidneys). Morphological observation, along 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 revealed that AgNPs exerted 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.

Silver nanoparticles induce cytotoxicity by releasing Ag + from the lysosome and increasing lysosomal membrane permeability

“…Previous studies have demonstrated that AgNPs exhibit different forms of cytotoxicity. For instance, AgNPs can generate ROS by activating the IKK/NF-κB signal pathway, leading to cell apoptosis [30]; They can also damage the cytoskeleton, DNA, or DNA repair enzymes [31,32], upregulate autophagy-related genes [33,34], trigger p53-dependent [35] or mitochondrial-dependent [17,36] apoptosis pathways, among others. The diverse cytotoxic effects of AgNPs have long confused researchers seeking to understand their actual cytotoxic mechanism.…”

Toxic Effects and Mechanisms of Silver and Zinc Oxide Nanoparticles on Zebrafish Embryos in Aquatic Ecosystems

“…More recently, we also prioritized the factors affecting the toxic potential of AgNPs, which included exposure dose/time, cell type, and the size and surface coating of AgNPs. Using an in silico decision tree-based knowledge discovery-in-databases process, the toxicity-related parameters are ranked as follows: exposure dose > cell type > particle size > exposure time ≥ surface coating [47]. AgNPs with larger particle sizes appeared to induce higher levels of autophagy during the earlier phase of both subcytotoxic and cytotoxic exposures in the in vitro cell culture models, whereas apoptosis, but not necrosis, accounted for the compromised cell survival over the same dosage range [47].…”

“…Using an in silico decision tree-based knowledge discovery-in-databases process, the toxicity-related parameters are ranked as follows: exposure dose > cell type > particle size > exposure time ≥ surface coating [47]. AgNPs with larger particle sizes appeared to induce higher levels of autophagy during the earlier phase of both subcytotoxic and cytotoxic exposures in the in vitro cell culture models, whereas apoptosis, but not necrosis, accounted for the compromised cell survival over the same dosage range [47]. In addition, we determined the skin toxicity and the potential mechanisms of ZnONPs combined with UVB exposure and the preventive effect of a well-known antioxidant, pterostilbene.…”

Safety and Toxicity Implications of Multifunctional Drug Delivery Nanocarriers on Reproductive Systems In Vitro and In Vivo

“…Various studies on toxicological outcomes of nanomaterials in reproductive cellular systems and tissues of females majorly implicate metals and/or metallic oxides, carbon-based nanoparticles, and cadmium and/or selenium core–based quantum dots (see Table 1 for details of all these types of nanoparticles) ( Yin et al, 2005 ). In vivo and in vitro results demonstrated that various size ranges of nanoparticles can well penetrate into the various female germline cellular compartments and get accumulated inside those, which can then start the various cellular reactions including but not limited to the production of reactive oxygen species, DNA damage, apoptotic cell deaths, inflammatory responses, and inhibiting the various signal transduction mechanisms ( Mao et al, 2022 ).…”