Research on the hepatotoxicity mechanism of citrate-modified silver nanoparticles based on metabolomics and proteomics

Abstract

Citrate-modified silver nanoparticles (AgNP-cit) have received extensive attention due to their excellent antimicrobial properties. However, these particles tend to migrate in vivo, thereby entering the blood circulatory system in granular form and accumulating in the liver, causing toxic reactions. However, the mechanism underlying AgNP-cit toxicity is not yet clear. Thus, we adopted a tandem mass tag (TMT)-labeled quantitative proteomics and metabolomics approach to identify proteins and small molecule metabolites associated with AgNP-cit-induced liver damage and constructed interaction networks between the differentially expressed proteins and metabolites to explain the AgNP-cit toxicity mechanism. AgNP-cit resulted in abnormal purine metabolism mainly by affecting xanthine and other key metabolites along with pyruvate kinase and other bodily proteins, leading to oxidative stress. AgNP-cit regulated the metabolism of amino acids and glycerol phospholipids through glycerol phospholipids, CYP450 enzymes and other key proteins, causing liver inflammation. Via alanine, isoleucine, L-serine dehydratase/L-threonine deaminase and other proteins, AgNP-cit altered the metabolism of glycine, serine and threonine, cysteine and methionine, affecting oxidation and deamination, and ultimately leading to liver damage. This work clearly explains toxic reactions induced by AgNP-cit from three perspectives, oxidative stress, inflammatory response, and oxidation and deamination, thus providing an experimental basis for the safe application of nanomaterials.

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“…Likewise, amino acids have been minimally extended, and in opposition, creatine and phosphocreatine remained unaffected. The cholesterol esters of polyunsaturated fatty acids and PPC have been decreased [139,140]. On the contrary, from the previous literature, AgNPs-and Ag+-treated metabolome signatures delivered plenty similar landscapes, although a few variances were noted.…”

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“…were the mechanism for DON-induced hepatotoxicity. Recent literature suggested that CYP450s are involved in oxidative stress, apoptosis and in ammatory response against foreign particles [39,40].…”

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“…A low‐dose, long‐term exposure of human bronchial epithelial cells to AgNPs may induce fibrosis and epithelial‐mesenchymal transition, a process associated with cancer progression . Citrate‐modified AgNPs resulted in abnormalities in purine metabolism in rats . The intestinal microbiota may also be affected, since AgNPs may induce microbial alterations similar to those related to inflammatory diseases in rat guts .…”

“…[24] Citrate-modified AgNPs resulted in abnormalities in purine metabolism in rats. [25] The intestinal microbiota may also be affected, since AgNPs may induce microbial alterations similar to those related to inflammatory diseases in rat guts. [26] Actually, Tian et al [27] reported that lactobacilli were more susceptible than two common pathogens (Escherichia coli and Staphylococcus aureus) to AgNPs.…”