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Hepatotoxicity and the role of the gut-liver axis in rats after oral administration of titanium dioxide nanoparticles.

ABSTRACT: BACKGROUND:Due to its excellent physicochemical properties and wide applications in consumer goods, titanium dioxide nanoparticles (TiO2 NPs) have been increasingly exposed to the environment and the public. However, the health effects of oral exposure of TiO2 NPs are still controversial. This study aimed to illustrate the hepatotoxicity induced by TiO2 NPs and the underlying mechanisms. Rats were administered with TiO2 NPs (29?nm) orally at exposure doses of 0, 2, 10, 50?mg/kg daily for 90?days. Changes in the gut microbiota and hepatic metabolomics were analyzed to explore the role of the gut-liver axis in the hepatotoxicity induced by TiO2 NPs. RESULTS:TiO2 NPs caused slight hepatotoxicity, including clear mitochondrial swelling, after subchronic oral exposure at 50?mg/kg. Liver metabolomics analysis showed that 29 metabolites and two metabolic pathways changed significantly in exposed rats. Glutamate, glutamine, and glutathione were the key metabolites leading the generation of energy-related metabolic disorders and imbalance of oxidation/antioxidation. 16S rDNA sequencing analysis showed that the diversity of gut microbiota in rats increased in a dose-dependent manner. The abundance of Lactobacillus_reuteri increased and the abundance of Romboutsia decreased significantly in feces of TiO2 NPs-exposed rats, leading to changes of metabolic function of gut microbiota. Lipopolysaccharides (LPS) produced by gut microbiota increased significantly, which may be a key factor in the subsequent liver effects. CONCLUSIONS:TiO2 NPs could induce slight hepatotoxicity at dose of 50?mg/kg after long-term oral exposure. The indirect pathway of the gut-liver axis, linking liver metabolism and gut microbiota, played an important role in the underlying mechanisms.

SUBMITTER: Chen Z

PROVIDER: S-EPMC6935065 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Hepatotoxicity and the role of the gut-liver axis in rats after oral administration of titanium dioxide nanoparticles.

Chen Zhangjian Z Zhou Di D Han Shuo S Zhou Shupei S Jia Guang G

Particle and fibre toxicology 20191227 1

<h4>Background</h4>Due to its excellent physicochemical properties and wide applications in consumer goods, titanium dioxide nanoparticles (TiO<sub>2</sub> NPs) have been increasingly exposed to the environment and the public. However, the health effects of oral exposure of TiO<sub>2</sub> NPs are still controversial. This study aimed to illustrate the hepatotoxicity induced by TiO<sub>2</sub> NPs and the underlying mechanisms. Rats were administered with TiO<sub>2</sub> NPs (29 nm) orally at ex ...[more]

PMID: 31881974

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Project description:OBJECTIVE: The aim of this study was to obtain kinetic data that can be used in human risk assessment of titanium dioxide nanomaterials. METHODS: Tissue distribution and blood kinetics of various titanium dioxide nanoparticles (NM-100, NM-101, NM-102, NM-103, and NM-104), which differ with respect to primary particle size, crystalline form and hydrophobicity, were investigated in rats up to 90 days post-exposure after oral and intravenous administration of a single or five repeated doses. RESULTS: For the oral study, liver, spleen and mesenteric lymph nodes were selected as target tissues for titanium (Ti) analysis. Ti-levels in liver and spleen were above the detection limit only in some rats. Titanium could be detected at low levels in mesenteric lymph nodes. These results indicate that some minor absorption occurs in the gastrointestinal tract, but to a very limited extent.Both after single and repeated intravenous (IV) exposure, titanium rapidly distributed from the systemic circulation to all tissues evaluated (i.e. liver, spleen, kidney, lung, heart, brain, thymus, reproductive organs). Liver was identified as the main target tissue, followed by spleen and lung. Total recovery (expressed as % of nominal dose) for all four tested nanomaterials measured 24 h after single or repeated exposure ranged from 64-95% or 59-108% for male or female animals, respectively. During the 90 days post-exposure period, some decrease in Ti-levels was observed (mainly for NM-100 and NM-102) with a maximum relative decrease of 26%. This was also confirmed by the results of the kinetic analysis which revealed that for each of the investigated tissues the half-lifes were considerable (range 28-650 days, depending on the TiO(2)-particle and tissue investigated). Minor differences in kinetic profile were observed between the various particles, though these could not be clearly related to differences in primary particle size or hydrophobicity. Some indications were observed for an effect of crystalline form (anatase vs. rutile) on total Ti recovery. CONCLUSION: Overall, the results of the present oral and IV study indicates very low oral bioavailability and slow tissue elimination. Limited uptake in combination with slow elimination might result in the long run in potential tissue accumulation.

Project description:BackgroundSilicon dioxide nanoparticles (SiO2NPs) are widely used as additive in the food industry with controversial health risk. Gut microbiota is a new and hot topic in the field of nanotoxicity. It also contributes a novel and insightful view to understand the potential health risk of food-grade SiO2NPs in children, who are susceptible to the toxic effects of nanoparticles.MethodsIn current study, the young mice were orally administrated with vehicle or SiO2NPs solution for 28 days. The effects of SiO2NPs on the gut microbiota were detected by 16S ribosomal RNA (rRNA) gene sequencing, and the neurobehavioral functions were evaluated by open field test and Morris water maze. The level of inflammation, tissue integrity of gut and the classical indicators involved in gut-brain, gut-liver and gut-lung axis were all assessed.ResultsOur results demonstrated that SiO2NPs significantly caused the spatial learning and memory impairments and locomotor inhibition. Although SiO2NPs did not trigger evident intestinal or neuronal inflammation, they remarkably damaged the tissue integrity. The microbial diversity within the gut was unexpectedly enhanced in SiO2NPs-treated mice, mainly manifested by the increased abundances of Firmicutes and Patescibacteria. Intriguingly, we demonstrated for the first time that the neurobehavioral impairments and brain damages induced by SiO2NPs might be distinctively associated with the disruption of gut-brain axis by specific chemical substances originated from gut, such as Vipr1 and Sstr2. Unapparent changes in liver or lung tissues further suggested the absence of gut-liver axis or gut-lung axis regulation upon oral SiO2NPs exposure.ConclusionThis study provides a novel idea that the SiO2NPs induced neurotoxic effects may occur through distinctive gut-brain axis, showing no significant impact on either gut-lung axis or gut-liver axis. These findings raise the exciting prospect that maintenance and coordination of gastrointestinal functions may be critical for protection against the neurotoxicity of infant foodborne SiO2NPs.

Dataset Information

Hepatotoxicity and the role of the gut-liver axis in rats after oral administration of titanium dioxide nanoparticles.

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Hepatotoxicity and the role of the gut-liver axis in rats after oral administration of titanium dioxide nanoparticles.

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