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. 2022 Aug 3;19(1):53.
doi: 10.1186/s12989-022-00484-9.

Landscape of lipidomic metabolites in gut-liver axis of Sprague-Dawley rats after oral exposure to titanium dioxide nanoparticles

Zhangjian Chen  1   2 , Shuo Han  1   2 , Pai Zheng  1   2 , Jiahe Zhang  1   2 , Shupei Zhou  3 , Guang Jia  4
Affiliations

Landscape of lipidomic metabolites in gut-liver axis of Sprague-Dawley rats after oral exposure to titanium dioxide nanoparticles

Zhangjian Chen et al. Part Fibre Toxicol. .

Abstract

Background: The application of titanium dioxide nanoparticles (TiO2 NPs) as food additives poses a risk of oral exposure that may lead to adverse health effects. Even though the substantial evidence supported liver as the target organ of TiO2 NPs via oral exposure, the mechanism of liver toxicity remains largely unknown. Since the liver is a key organ for lipid metabolism, this study focused on the landscape of lipidomic metabolites in gut-liver axis of Sprague Dawley (SD) rats exposed to TiO2 NPs at 0, 2, 10, 50 mg/kg body weight per day for 90 days.

Results: TiO2 NPs (50 mg/kg) caused slight hepatotoxicity and changed lipidomic signatures of main organs or systems in the gut-liver axis including liver, serum and gut. The cluster profile from the above biological samples all pointed to the same key metabolic pathway and metabolites, which was glycerophospholipid metabolism and Phosphatidylcholines (PCs), respectively. In addition, absolute quantitative lipidomics verified the changes of three PCs concentrations, including PC (16:0/20:1), PC (18:0/18:0) and PC (18:2/20:2) in the serum samples after treatment of TiO2 NPs (50 mg/kg). The contents of malondialdehyde (MDA) in serum and liver increased significantly, which were positively correlated with most differential lipophilic metabolites.

Conclusions: The gut was presumed to be the original site of oxidative stress and disorder of lipid metabolism, which resulted in hepatotoxicity through the gut-liver axis. Lipid peroxidation may be the initial step of lipid metabolism disorder induced by TiO2 NPs. Most nanomaterials (NMs) have oxidation induction and antibacterial properties, so the toxic pathway revealed in the present study may be primary and universal.

Keywords: Gut-liver axis; Lipid peroxidation; Lipidomics; Nanotoxicity; Titanium dioxide nanoparticles.

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Conflict of interest statement

The authors declare that they have no competing financial interests.

Figures

Fig. 1
Fig. 1
Effect of TiO2 nanoparticles on lipid metabolism in liver of rats. A Multivariate analysis of untargeted metabolomic data by OPLS-DA model showed the significant overall difference in metabolites of positive and negative ion modes between the TiO2 NPs treated group (50 mg/kg) and the control group. B Volcano plot was mapped to distinguish differential metabolites between different groups, taking VIP > 1 and p < 0.05 as the demarcation standard. C The concentrations of well-matched differential lipophilic metabolite in hepatic tissues were shown in heatmap and analyzed by hierarchical clustering, which revealed the change characteristics of metabolites among the experimental groups. D KEGG pathway analysis of differential metabolites between the control and treated group was shown in bubble chart. The names of significant pathways were labeled in the graph with p < 0.05 or Pathway Impact > 0.1. Glycerophospholipid metabolism pathway was significantly changed in liver by oral exposure to TiO2 NPs
Fig. 2
Fig. 2
Effect of TiO2 nanoparticles on lipid metabolism in gut of rats. A Multivariate analysis of untargeted metabolomic data by OPLS-DA model showed the significant overall difference in metabolites of feces between the TiO2 NPs treated group (50 mg/kg) and the control group. B Volcano plot was mapped to distinguish differential metabolites between different groups, taking VIP > 1 and p < 0.05 as the demarcation standard. C The concentrations of well-matched differential lipophilic metabolite in feces were shown in heatmap and analyzed by hierarchical clustering. D KEGG pathway analysis showed that oral exposure to TiO2 NPs induced significant changes of Glycerophospholipid metabolism pathway in feces of rats
Fig. 3
Fig. 3
Correlation of lipophilic metabolites differentially expressed between the TiO2 NPs treated and control group in liver, serum and feces of rats. A Correlation analysis of differential metabolites from different sources showed that there was a wide correlation between them. B The number of significantly related metabolites (p < 0.05) between each metabolite and other metabolites was counted, according to three sources. It showed that the three metabolites with the most significant correlation with other metabolites were phosphatidylcholines (PCs)
Fig. 4
Fig. 4
Relative expressions of phosphatidylcholines (PCs) in liver, serum and feces of rats after oral exposure to TiO2 NPs. A Total relative expression of all identified PCs from different sources showed no significant difference between the 50 mg/kg TiO2 NPs treated group and the control group. B Total relative expression of differentially expressed PCs significantly increased in feces and decreased in liver. C Fold changes of differentially expressed PCs between the 50 mg/kg TiO2 NPs treated group and the control group. The three PCs with the most significant correlation with other metabolites were labelled in red box. The changes of PCs were mainly manifested in some subclasses. Significant difference compared with the control group (∗ p < 0.05)
Fig. 5
Fig. 5
Absolute quantitative lipidomics verified changes of the concentrations of PCs in serum. Compared with the control group, the concentration of three kinds of PCs in serum of the 50 mg/kg TiO2 NPs treated group changed significantly. PC(16:0/20:1) increased significantly, while PC(18:0/18:0) and PC(18:2/20:2) decreased significantly. Significant difference compared with the control group (∗ p < 0.05)
Fig. 6
Fig. 6
Lipid peroxidation induced by oral exposure to TiO2 NPs. A The concentration of malondialdehyde (MDA) increased significantly in liver tissue of rats in the TiO2 NPs treated groups (10 and 50 mg/kg) compared to the control group. B The concentration of malondialdehyde (MDA) also increased significantly in serum of rats in the TiO2 NPs treated groups (50 mg/kg)
Fig. 7
Fig. 7
The correlation between the level of MDA and differential metabolites induced by oral exposure to TiO2 NPs in serum and liver. A MDA was significantly correlated with 11 kinds of differential metabolites in liver (p < 0.05), 7 of which were positively correlated. B MDA was significantly correlated with 21 kinds of differential metabolites in serum (p < 0.05), 20 of which were positively correlated. Lipid peroxidation was closely related to abnormal lipid metabolism induced by oral exposure to TiO2 NPs
Fig. 8
Fig. 8
The toxic pathway of hepatotoxicity induced by oral exposure to TiO2 NPs through lipid metabolism disorders in gut-liver axis. Due to limited intestinal absorption and strong oxidation induction ability of TiO2 NPs, the gut microbiota was presumed to be the original site of oxidative stress and disorders of lipid metabolism. In fact, TiO2 NPs changed lipidomic signatures of main organs or systems in the gut-liver axis including liver, serum and gut. The cluster profile from the above biological samples all pointed to the same key metabolic pathway and metabolites, which was glycerophospholipid metabolism and Phosphatidylcholines (PCs), respectively. Lipid peroxidation characterized by the increase of malondialdehyde (MDA) may be the initial step of lipid metabolism disorders, which resulted in hepatic fatty degeneration and liver function changes, leading to hepatotoxicity. Most nanomaterials (NMs) have oxidation induction and antibacterial properties, so this toxic pathway may be primary and universal
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