1H NMR Based Metabolomics Studies of the Toxicity of Titanium Dioxide Nanoparticles in Zebrafish (Danio rerio)

摘要

Introduction Nanoparticles (NPs) are defined as natural, incidental, or manufactured materials with at least one of their three dimensions in the range of 1–100?nm.1, 2 The physicochemical properties of NPs are much different from those of the fine particle (FP) forms. Titanium commonly exists in an oxidized and metallic form, with TiO2 and TiCl4 being the most widely used in industry. TiO2 finds application in paints, coatings, plastics, papers, inks, medicines, pharmaceuticals, and food products. TiO2‐NPs are used in sunscreens and cosmetics, and as photocatalytic agents because of their high stability, as well as anticorrosive and photocatalytic properties.3-5 Titanium has been used in bone replacement materials such as dental implants, bone fracture plates, and artificial joints as it possesses good qualities of physicochemical stability, mechanical integrity, biocompatibility, and corrosion resistance. Since pure titanium is an inert material, additional surface modifications are required for enhancing bone apposition and soft tissue integration.6, 7 The formation of a nanotubular layer of TiO2‐NPs on titanium implants has been used to acquire a high surface‐to‐volume ratio to facilitate more cell adhesions.8 In the field of drug carriers, TiO2‐NPs have been studied as a photo‐sensitizer to achieve ultraviolet (UV) light‐triggered drug release.9, 10 Unlike their FP analogues, TiO2‐NPs are reported to induce cytotoxicity via generation of reactive oxygen species (ROS), mitochondrial depolarization, plasma membrane leakage, intracellular calcium influx, and cytokine release.11-13 However, the potential mechanisms by which the TiO2‐NPs exert their cytotoxic effects are still controversial. The zebrafish (Danio rerio) has been gaining popularity as a model organism for biological and biomedical research because they have similar organ systems to mammals and are easily bred in large numbers with a relatively low maintenance cost.14-17 1H–nuclear magnetic resonance (NMR)‐based metabolomics measures fluctuations in low molecular weight metabolites such as amino acids and sugars in response to external drugs or environmental stress.18 In the present study, we applied 1H NMR spectroscopy with univariate and multivariate statistics to analyze the metabolomic profiles of zebrafish following exposure to TiO2‐NPs.