Oxidative stress- and mitochondrial dysfunction-mediated cytotoxicity by silica nanoparticle in lung epithelial cells from metabolomic perspective

Quantities of researches have demonstrated silica nanoparticles (SiNPs) exposure inevitably induced damage to respiratory system, nonetheless, knowledge of its toxicological behavior and metabolic interactions with the cellular machinery that determines the potentially deleterious outcomes are limited and poorly elucidated. Here, the metabolic responses of lung bronchial epithelial cells (BEAS-2B) under SiNPs exposure were investigated using ultra performance liquid chromatography-mass spectrum (UPLC-MS)-based metabolomics research. Results revealed that even with low cytotoxicity, SiNPs disturbed global metabolism. Five metabolic pathways were significantly perturbed, in particular, oxidative stress- and mitochondrial dysfunction-related GSH metabolism and pantothenate and coenzyme A (CoA) biosynthesis, where the identified metabolites glutathione (GSH), glycine, beta-alanine, cysteine, cysteinyl-glycine and pantothenic acid were included. In support of the metabolomics profiling, SiNPs caused abnormality in mitochondrial structure and mitochondrial dysfunction, as evidenced by the inhibition of cellular respiration and ATP production. Moreover, SiNPs triggered oxidative stress as confirmed by the dose-dependent ROS generation, down-regulated nuclear factor erythroid 2-related factor 2 (NRF2) signaling, together with GSH depletion in SiNPs-treated BEAS-2B cells. Oxidative DNA damage and cell membrane dis-integrity were also detected in response to SiNPs exposure, which was correspondingly in agreed with the elevated 8-hydroxyguanosine (8-OHdG) and decreased phospholipids screened through metabolic analysis. Thereby, we successfully used the metabolomics approaches to manifest SiNPs-elicited toxicity through oxidative stress, mitochondrial dysfunction, DNA damage and rupture of membrane integrity in BEAS-2B cells. Overall, our study provided novel insights into the mechanism underlying SiNPs-induced pulmonary toxicity. (C) 2021 Published by Elsevier Ltd.

Automated summary

Our study investigated the metabolic responses of lung bronchial epithelial cells (BEAS-2B) under silica nanoparticles (SiNPs) exposure using UPLC-MS-based metabolomics research. The results showed that even with low cytotoxicity, SiNPs disturbed global metabolism and perturbed five metabolic pathways, leading to oxidative stress, mitochondrial dysfunction, DNA damage, and membrane integrity rupture in BEAS-2B cells. This study provided novel insights into the mechanisms underlying SiNPs-induced pulmonary toxicity.