RNA sequencing analysis shows that titanium dioxide nanoparticles induce endoplasmic reticulum stress, which has a central role in mediating plasma glucose in mice

Hu, Hailong; Li, Li; Guo, Qin; Zong, He; Yan, Yichao; Yao, Yin; Wang, Yu; Oh, Yuri; Feng, Yujie; Wu, Qiong; Gu, Ning

doi:10.1080/17435390.2018.1446560

Cited by 46 publications

(68 citation statements)

References 33 publications

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“…Based on previous studies, we designed an experiment to examine TiO 2 NP‐induced ER stress and ROS generation . Our results showed that GRP78 and CHOP mRNA and protein expression, mRNA and protein ratios of XBP1‐s/t, and protein ratio of ATF6 (90/50 kD) were significantly increased from week 5, indicating that ER stress is induced at this time.…”

Section: Discussionmentioning

confidence: 87%

“…In earlier studies on mice treated with 0, 10, 20, 50, 100, and 200 mg/kg b.w. TiO 2 NPs, concentrations of 50, 100, and 200 mg/kg led to elevation of plasma glucose . At an adult intake of 0.36 mg/kg b.w.…”

Section: Discussionmentioning

confidence: 99%

“…The predominant mechanism underlying the biological toxicity of TiO 2 NPs in humans and animals is proposed to be increased accumulation of ROS but remains to be established. A recent study showed that oral administration of TiO 2 NPs led to not only elevated ROS in mice but also ER stress . The consequences of ER stress are multifaceted and its intermediates either activate or deactivate vital genes related to ROS generation, such as the mitochondrial respiratory chain, arachidonic acid pathway, cytochrome P450 (CYP) family, glucose oxidase, amino acid oxidases, xanthine oxidase, NADPH/NADPH oxidases, and NO synthases .…”

Section: Discussionmentioning

confidence: 99%

“…Notably, inhibition of ROS in TiO 2 NP‐treated mice with resveratrol (Res) and vitamin E (Ve) resulted in suppression of plasma glucose levels in mice . Recent usage of RNA sequencing (RNA‐seq) technology to establish the toxicity mechanisms of TiO 2 NPs led to the unexpected finding that oral administration of these NPs not only promotes ROS levels in mice but also induces endoplasmic reticulum (ER) stress . ER stress is closely related to generation of ROS .…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

Fan

Yao

et al. 2019

Environmental Toxicology

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Titanium dioxide nanoparticles (TiO2 NPs) are reported to increase plasma glucose levels in mice at specific doses. The production and accumulation of reactive oxygen species (ROS) is potentially the most important factor underlying the biological toxicity of TiO2 NPs but the underlying mechanisms are unclear at present. Data from genome‐wide analyses showed that TiO2 NPs induce endoplasmic reticulum (ER) stress and ROS generation, leading to the inference that TiO2 NP‐induced ER stress contributes to enhancement of ROS in mice. Resveratrol (Res) effectively relieved TiO2 NP‐induced ER stress and ROS generation by ameliorating expression of a common set of activated genes for both processes, signifying that ER stress and ROS are closely related. TiO2 NP‐induced ER stress occurred earlier than ROS generation. Upon treatment with 4‐phenylbutyric acid to relieve ER stress, plasma glucose levels tended toward normal and TiO2 NP increased ROS production was inhibited. These results suggest that TiO2 NP‐induced ER stress promotes the generation of ROS, in turn, triggering increased plasma glucose levels in mice. In addition, Res that displays the ability to reduce ER stress presents a dietary polyphenol antioxidant that can effectively prevent the toxicological effects of TiO2 NPs on plasma glucose metabolism.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

Fan

Yao

et al. 2019

Environmental Toxicology

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“…In a previous study, Hu et al showed that TiO 2 NPs activated a monooxygenase system in mice, as an exogenous compound . Cytochrome P450s, such as Cyp2b9, Cyp2c70, and Cyp4a14, participate in xenobiotic biodegradation and play a primary role in the monooxygenase system .…”

Section: Discussionmentioning

confidence: 99%

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice

Zhang

et al. 2019

Environmental Toxicology

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Titanium dioxide nanoparticles (TiO2 NPs) are authorized food additives, and children have the highest exposure. Therefore, children are likely more susceptible to the adverse effects of TiO2 NPs than adults. Previous study showed that oral administration of 50 mg/kg body weight (bw) TiO2 NPs increase plasma glucose in mice. However, few studies have directly compared the adverse effects of exposure to TiO2 NPs on plasma glucose metabolism of different age groups. In this study, the developing (age 3 weeks) and adult mice (age 10 weeks) were orally administered with 50 mg/kg bw TiO2 NPs per day. The TiO2 NPs induced hyperglycemia earlier in the developing mice than in the adult mice. Then mechanisms were analyzed after mice were oral administration of TiO2 NPs for 8 weeks and 26 weeks, respectively. Results showed that the treatment with TiO2 NPs activated xenobiotic biodegradation in livers of both developing and adult mice at the early stage. However, only in the developing mice, TiO2 NPs induced endoplasmic reticulum (ER) stress in livers and increased reactive oxygen species in livers and sera in the early stage. The ER stress and ROS activated an inflammation response and mitogen‐activated protein kinase pathways, thereby inducing insulin resistance in the livers of developing mice at the early stage. The response of the adult mice was delayed, and these changes were observed in the late stage of the study. The results of this study all suggest that children are more susceptible than adults to the toxicity of orally administered TiO2 NPs.

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Toxic effects and involved molecular pathways of nanoparticles on cells and subcellular organelles

Liu¹,

Tang

2019

J of Applied Toxicology

108

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Owing to the increasing application of engineered nanoparticles (NPs), besides the workplace, human beings are also exposed to NPs from nanoproducts through the skin, respiratory tract, digestive tract and vein injection. This review states pathways of cellular uptake, subcellular distribution and excretion of NPs. The uptake pathways commonly include phagocytosis, micropinocytosis, clathrin‐ and caveolae‐mediated endocytosis, scavenger receptor‐related pathway, clathrin‐ or caveolae‐independent pathway, and direct penetration or insertion. Then the ability of NPs to decrease cell viability and metabolic activity, change cell morphology, and destroy cell membrane, cytoskeleton and cell function was presented. In addition, the lowest dose decreasing cell metabolic viability compared with the control or IC50 of silver, titanium dioxide, zinc oxide, carbon black, carbon nanotubes, silica, silicon NPs and cadmium telluride quantum dots to some cell lines was gathered. Next, this review attempts to increase our understanding of NP‐caused adverse effects on organelles, which have implications in mitochondrial dysfunction, endoplasmic reticulum stress and lysosomal rupture. In particular, the disturbance of mitochondrial biogenesis and mitochondrial dynamic fusion‐fission, mitophagy and cytochrome c‐dependent apoptosis are involved. In addition, prolonged endoplasmic reticulum stress will result in apoptosis. Rupture of the lysosomal membrane was associated with inflammation, and both induction of autophagy and blockade of autophagic flow can result in cytotoxicity. Finally, the network mechanism of the combined action of multiple organelle dysfunction, apoptosis, autophagy and oxidative stress was discussed.

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RNA sequencing analysis shows that titanium dioxide nanoparticles induce endoplasmic reticulum stress, which has a central role in mediating plasma glucose in mice

Cited by 46 publications

References 33 publications

Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice

Toxic effects and involved molecular pathways of nanoparticles on cells and subcellular organelles

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