Investigation of molecular mechanisms in silver nanoparticle-induced cytotoxicity from gene to metabolite level

The aim of this study was to explore the mechanisms in silver nanoparticle (AgNP)-induced cytotoxicity from gene to metabolite levels through an integrative analysis of transcriptomics and metabolomics results. First, transcriptome sequencing technology revealed 1365, 1241, and 2790 genes differentially expressed within human dermal fibroblasts (HDFs) after 4, 8, and 24 h of exposure to silver nanoparticles, which were involved in 250, 248, and 280 biological pathways. Then, by comparing with the metabolomics results, 7 metabolic pathways (purine metabolism pathway, glycerophospholipid metabolism pathway, etc.), with 9 key upstream genes (ADCY4, SPHK1, etc.) and 8 downstream metabolites (xanthine, choline, etc.) jointly involved were found relate to AgNP-induced cytotoxicity. Finally, the results of the validation experiments revealed that AgNPs exerted the toxic effects through these pathways, inducing oxidative stress, affecting energy metabolism, arresting the cell cycle, disrupting the cytoskeleton, inhibiting cell proliferation, and triggering apoptosis.