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OBJECTIVE: To screen the serum biomarkers in workers occupationally exposed to titanium dioxide nanoparticles(TiO_2 NPs) using metabolomics technology. METHODS: Using a typical sampling method, 56 workers who have occupationally exposed to TiO_(2 )in a TiO_2 NPs manufacturer were selected as the exposure group and 44 employees without occupational exposure to TiO_2 were selected as the control group. The high performance liquid chromatography-mass spectrometry technology was used to perform non-targeted metabolomics detection. The difference in serum metabolite profiles of the TiO_2 NPs exposure group and the control group were analyzed. Key differential metabolites and potential biomarkers were screened. The sensitivity and specificity of biomarkers were assessed through receiver operating characteristic(ROC) curve.RESULTS: We detected a total of 1 492 mass spectrum peaks in serum samples by serum metabolomics analysis, and 413 well-matched metabolites were obtained after annotation and identification. The results of principal component analysis and orthogonal partial least squares discriminant analysis showed that a total of 296 differentially expressed metabolites were found in the serum of individuals of the exposure group compared with the control group(all P<0.01). Among them the relative expression of metabolites increased in 265 species and decreased in 31 species. The ROC analysis results showed that the area under the ROC curve of five metabolites exceeded 0.900, and these metabolites included tanacetol A,(5 E)-2-hydroxy-4-oxobenzopenta-5-en-1-ylacetic acid, triterpene saponins organic compounds, 9,10,13-trihydroxystearic acid, and liquoric acid. The multiple linear regression analysis showed that the relative expression of all the five metabolites were positively correlated with occupational exposure to TiO_2 NPs after adjusting for the influence of confounding factors such as gender, age, body mass index, smoking and drinking(all P<0.01). CONCLUSION: Occupational exposure to TiO_2 NPs could induce changes in serum metabolite profiles. The metabolites represented by tanacetol A in serum can be used as potential biomarkers for indicating occupational exposure to TiO_2 NPs.
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OBJECTIVE@#To explore the effects and related mechanisms of oral exposure titanium dioxide nanoparticles (TiO2 NPs) for 90 days on the intestinal and the gut microbiota of rats, through fecal metabolomics.@*METHODS@#Twelve 4-week-old clean-grade Sprague Dawley (SD) rats were randomly de-vided into 2 groups by body weight, treated with TiO2 NPs at dose of 0 or 50 mg/kg body weight everyday respectively for 90 days. The solution of each infection was freshly prepared and shocked fully by ultrasonic. Characterization of the particle size, crystal form, purity, and specific surface area of TiO2 NPs was conducted. And the fresh feces of the rats were collected on the 90th day. After lyophilized and hydrophilic phase extraction, ultra performance liquid chromatography-Q-exactive orbitrap-high-resolution mass spectrometry system (UPLC-QEMS) was utilized for non-targeted determination of fecal meta-bolites. The metabolites were identified and labeled through Compound Discoverer 3.0 software, and used for subsequent metabolomics analysis. Bioinformatics analysis was carried out including unsupervised principal component analysis and supervised orthogonal projection to latent structure discriminant analysis for the differential metabolites between the two groups. The differential metabolites were followed-up for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.@*RESULTS@#Compared with the control group, the body weight of the rats was significantly reduced (P<0.05) in the treatment group. A total of 22 metabolites in fecal metabolomics showed significant changes. Among them, xanthine, 1-methyladenine, 3-hydroxypyridine, methionine sulfoxide, pyridoxine, 1,5-isoquinolinediol, N-acetylornithine, N-acetyl-D-galactosamine, L-citrulline, L-methionine, leucine, DL-tryptophan, L-ornithine, 4-methyl-5-thiazoleethanol, and L-glutamic acid totaled 15 metabolites increased significantly. N-acetylhistamine, D-pipecolinic acid, imidazolelactic acid, L-valine, 2,3,4,6-tetramethylpyrazine, caprolactam, and histamine totaled 7 metabolites decreased significantly. N-acetylhistamine, L-valine and methionine sulfoxide were changed more than 16 times. Analysis of KEGG pathway revealed that the two metabolic pathways arginine biosynthesis and aminoacyl-tRNA biosynthesis were significantly changed (false discover rate < 0.05, pathway impact > 0.1).@*CONCLUSION@#Oral exposure to TiO2 NPs for 90 days could disrupt the metabolism of the intestine and gut microbiota, causing significant changes in metabolites and metabolic pathways which were related to inflammatory response, oxidative stress, glucose homeostasis, blood system and amino acid homeostasis in rat feces. It is suggested that the toxic effect of TiO2 NPs on rats may be closely related to intestinal and gut microbiota metabolism.
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Animais , Ratos , Administração Oral , Fezes , Metaboloma , Nanopartículas Metálicas , Ratos Sprague-Dawley , TitânioRESUMO
OBJECTIVE@#To explore the effect of subchronic combined oral exposure of titanium dioxide nanoparticles and glucose on levels of serum folate and vitamin B12 in young SD rats.@*METHODS@#At first, the physical and chemical properties of titanium dioxide nanoparticles, such as particle size, shape, crystal form and agglomeration degree in solution system, were characterized in detail. Eighty 4-week-old young SD rats were randomly divided into 8 groups (10 rats in each group, half male and half female). The rats were exposed to titanium dioxide nanoparticles through intragastric administration at 0, 2, 10 and 50 mg/kg body weight with or without 1.8 g/kg glucose daily for 90 days. At last, the concentrations of serum folate and vitamin B12 were detected.@*RESULTS@#Titanium dioxide nanoparticles were anatase crystals, closely spherical shape, with an average particle size of (24±5) nm. In male young rats, compared with the control group, the serum folate concentration was significantly increased when exposed to titanium dioxide nanoparticles (10 mg/kg) and glucose. The difference was statistically significant (P<0.05). However, in female and male young rats, compared with glucose (1.8 g/kg) exposure group, titanium dioxide nanoparticles (50 mg/kg) and glucose significantly reduced the serum folate concentration. The difference was statistically significant (P<0.05). Through statistical analysis of factorial design and calculation of interaction, obvious antagonistic effect was observed between titanium dioxide nanoparticles and glucose on the serum folate concentration in the young female SD rats. The combined oral exposure of titanium dioxide nanoparticles and glucose had little effect on the concentration of serum vitamin B12 in the young SD rats, with no significant interaction between the two substances. It was only found that titanium dioxide nanoparticles (2 mg/kg) and glucose significantly increased the serum vitamin B12 concentration, compared with glucose (1.8 g/kg) exposure group. The difference was statistically significant (P<0.05).@*CONCLUSION@#Subchronic combined oral exposure of titanium dioxide nanoparticles and glucose had an obvious antagonistic effect on serum folate concentrations in young SD rats.