Multi-omics approaches confirm metal ions mediate the main toxicological pathways of metal-bearing nanoparticles in lung epithelial A549 cells

The toxicity of silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) has been associated with their dissolution or ability to release metal ions while the toxicity of cerium dioxide (CeO2) NPs has been related to their ability to induce or reduce oxidative stress dependent on their surface redox state. To examine the underlying biochemical mechanisms, multiple omics technologies were applied to characterise the responses at the molecular level in cells exposed to various metal-based particles and their corresponding metal ions. Human lung epithelial carcinoma cells (A549) were exposed to various Ag, ZnO, and CeO2 NPs, Ag and ZnO micro-sized particles (MPs), Ag ions (Ag+) and zinc ions (Zn2+) over a 24 h time course. Molecular responses at exposure levels that caused ∼20% cytotoxicity were characterised by direct infusion mass spectrometry lipidomics and polar metabolomics and by RNAseq transcriptomics. All Ag, Zn and ZnO exposures resulted in significant metabolic and transcriptional responses and the great majority of these molecular changes were common to both ionic and NP exposures and characteristic of metal ion exposure. The low toxicity CeO2 NPs elicited few molecular changes, showing slight evidence of oxidative stress for only one of the four CeO2 NPs tested. The multiple omics analyses highlight the main pathways implicated in metal ion-mediated effects. These results can be used to establish adverse outcome pathways as well as strategies to group nanomaterials for risk assessment.