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Journal of Peking University (Health Sciences) ›› 2020, Vol. 52 ›› Issue (3): 457-463. doi: 10.19723/j.issn.1671-167X.2020.03.010

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Effects of titanium dioxide nanoparticles on fecal metabolome in rats after oral administration for 90 days

Shuo HAN,Zhang-jian CHEN,Di ZHOU,Pai ZHENG,Jia-he ZHANG,Guang JIA()   

  1. Department of Occupational and Environmental Health Sciences, Peking University School of Public Health, Beijing 100191, China
  • Received:2020-02-06 Online:2020-06-18 Published:2020-06-30
  • Contact: Guang JIA E-mail:jiaguangjia@bjmu.edu.cn
  • Supported by:
    National Science and Technology Major Project of the Ministry of Science and Technology of China(2017YFC1600204);National Natural Science Foundation of China(81703257)

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Abstract:

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.

Key words: Titanium dioxide nanoparticles, Metabolomics, Feces, Rats, Sprague-Dawley

CLC Number: 

  • R994.4

Figure 1

Changes in body weight of TiO2 NPs (50 mg/kg) treatment and control group *P<0.05, #P<0.01, compared with control group."

Figure 2

Heat map of metabolite concentrations in the TiO2 NPs treatment and control group Each row represents a metabolite, each column represents a sample, and the color of each grid represents the relative concentration of metabolites in each row. This figure shows the distribution of metabolites in the treatment and control group after TiO2 NPs intervention."

Figure 3

PCA score (A) and OPLS-DA score (B) graphs of metabolites in samples of the TiO2 NPs treatment group and the control group"

Figure 4

V-score plot of the metabolite in OPLS-DA model The abscissa represents the size of the difference between the groups, and the ordinate represents the reliability of the difference between the groups. Based on p (corr) [1]>0.3, The red dot indicates that the metabolite concentration is significantly higher in the treatment group than the control group, and the blue dot indicates that the metabolite concentration is significantly lower."

Table 1

Details of differential metabolites"

Super class Metabolite name Molecular formula Relative
molecular mass		 HMDB ID KEGG ID Log change fold
(log2N)
Organoheterocyclic compounds Xanthine C5H4N4O2 152.110 9 HMDB0000292 C00385 2.857 1
Organoheterocyclic compounds 1-methyladenine C6H7N5 149.153 3 HMDB0011599 C02216 2.045 8
Organoheterocyclic compounds 3-hydroxypyridine C5H5NO 95.099 3 2.191 9
Organoheterocyclic compounds Pyridoxine C8H11NO3 169.177 8 HMDB0000239 C00314 2.149 2
Organic acids and derivatives Methionine sulfoxide C5H11NO3S 165.210 0 HMDB0002005 C02989 7.581 8
Organoheterocyclic compounds 1,5-isoquinolinediol C9H7NO2 161.160 0 2.502 5
Organic acids and derivatives N-acetylornithine C7H14N2O3 174.197 7 HMDB0003357 C00437 0.564 7
Organic oxygen compounds N-acetyl-D-galactosamine C8H15NO6 221.207 8 HMDB0000853 C05021 2.558 6
Organic acids and derivatives L-citrulline C6H13N3O3 175.185 7 HMDB0000904 C00327 1.895 0
Organic acids and derivatives L-methionine C5H11NO2S 149.211 0 HMDB0000696 C00073 1.370 4
Organic acids and derivatives Leucine C6H13NO2 131.172 9 HMDB0000687 C00123 0.754 9
Organoheterocyclic compounds DL-tryptophan C11H12N2O2 204.225 2 HMDB0013609 C00525 -0.140 4
Organic acids and derivatives L-ornithine C5H12N2O2 132.161 0 HMDB0000214 C00077 0.503 8
Organoheterocyclic compounds 4-methyl-5-thiazoleethanol C6H9NOS 143.207 0 HMDB0032985 C04294 1.259 6
Organic acids and derivatives L-glutamic acid C5H9NO4 147.129 3 HMDB0000148 C00025 0.714 0
Organic nitrogen compounds Histamine C5H9N3 111.145 1 HMDB0000870 C00388 -1.004 3
Organoheterocyclic compounds Caprolactam C6H11NO 113.157 6 HMDB0062769 C06593 -8.288 4
Organoheterocyclic compounds 2,3,5,6-tetramethylpyrazine C8H12N2 136.194 3 HMDB0036584 -1.740 2
Organic acids and derivatives L-valine C5H11NO2 117.146 3 HMDB0000883 C00183 -4.354 5
Organoheterocyclic compounds Imidazolelactic acid C6H8N2O3 156.139 3 HMDB0002320 C05132 -2.948 3
Organic acids and derivatives D-pipecolinic acid C6H11NO2 129.157 0 HMDB0005960 -1.898 0
Organic acids and derivatives N-acetylhistamine C7H11N3O 153.181 7 HMDB0013253 C05135 -8.991 5

Figure 5

KEGG pathway analysis results of differential metabolites The abscissa represents the degree of pathway impact obtained from the topology analysis. The size of the point is positively related to the pathway impact value of the path. The ordinate represents the negative logarithm of the P value obtained from the path enrichment analysis, and the yellow-red color gradient of the point is positively related to the negative logarithm of the P value of the pathway change. Significantly changed pathway names are marked in the figure."

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