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High-dose intranasal application of titanium dioxide nanoparticles induces the systemic uptakes and allergic airway inflammation in asthmatic mice.

ABSTRACT: BACKGROUND:Titanium dioxide nanoparticles (TiO2 NPs) have a wide range of applications in several industrial and biomedical domains. Based on the evidence, the workers exposed to inhaled nanosized TiO2 powder are more susceptible to the risks of developing respiratory diseases. Accordingly, this issue has increasingly attracted the researchers' interest in understanding the consequences of TiO2 NPs exposure. Regarding this, the present study was conducted to analyze the local effects of TiO2 NPs on allergic airway inflammation and their uptake in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation. METHODS:For the purpose of the study, female BALB/c mice with or without asthma were intranasally administered with TiO2 NPs. The mice were subjected to histological assessment, lung function testing, scanning electron microscopy (SEM), inductively coupled plasma mass spectrometry (ICP-MS), and NP uptake measurement. In addition, T helper (Th) 1/Th2 cytokines were evaluated in the lung homogenate using the enzyme-linked immunosorbent assay. RESULTS:According to the results, the mice receiving OVA alone or OVA plus TiO2 NPs showed eosinophilic infiltrates and mucus overproduction in the lung tissues, compared to the controls. Furthermore, a significant elevation was observed in the circulating Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13 after NP exposure. The TiO2 NPs were taken up by alveolar macrophages at different time points. As the results of the SEM and ICP-MS indicated, TiO2 NPs were present in most of the organs in both asthmatic and non-asthmatic mice. CONCLUSION:Based on the findings of the current study, intranasally or inhalation exposure to high-dose nanosized TiO2 particles appears to exacerbate the allergic airway inflammation and lead to systemic uptake in extrapulmonary organs. These results indicate the very important need to investigate the upper limit of intranasally or inhalation exposure to nanosized TiO2 particles in occupational and environmental health policy.

SUBMITTER: Abdulnasser Harfoush S

PROVIDER: S-EPMC7331175 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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High-dose intranasal application of titanium dioxide nanoparticles induces the systemic uptakes and allergic airway inflammation in asthmatic mice.

Abdulnasser Harfoush Shaza S Hannig Matthias M Le Duc Dung DD Heck Sebastian S Leitner Maximilian M Omlor Albert Joachim AJ Tavernaro Isabella I Kraegeloh Annette A Kautenburger Ralf R Kickelbick Guido G Beilhack Andreas A Bischoff Markus M Nguyen Juliane J Sester Martina M Bals Robert R Dinh Quoc Thai QT

Respiratory research 20200702 1

<h4>Background</h4>Titanium dioxide nanoparticles (TiO<sub>2</sub> NPs) have a wide range of applications in several industrial and biomedical domains. Based on the evidence, the workers exposed to inhaled nanosized TiO<sub>2</sub> powder are more susceptible to the risks of developing respiratory diseases. Accordingly, this issue has increasingly attracted the researchers' interest in understanding the consequences of TiO<sub>2</sub> NPs exposure. Regarding this, the present study was conducted ...[more]

PMID: 32616045

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Project description:Titanium dioxide nanoparticles (TiO2NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies; however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO2NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO2NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO2NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO2NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO2NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO2NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO2NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO2NP-mediated respiratory toxicity.

Project description:Pulmonary exposure to high doses of nanoparticles (NP) leads to well characterized lung toxicity in addition to long-term NP retention. However, pulmonary NP accumulation and toxicity following low dose exposures are not well described. In the present study we sought to: (1) investigate particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO2) and (2) determine the effects of long-term particle accumulation on pulmonary systems. Female C57BL/6 mice were exposed to rutile nano-TiO2 (primary size of 20.6 nm and surface area of 107.7 m2/g) via single intratracheal instillations of 18, 54 and 162 µg/mouse and sampled 1, 3 and 28 days post-exposure. The deposition of nano-TiO2 in the lungs was assessed using Nanoscale Hyperspectral Microscope. DNA microarrays, pathway-specific real-time RT-PCR (qPCR) and gene-specific qPCR arrays, and tissue protein analyses were employed to characterize pulmonary responses. Hyperspectral mapping showed dose-dependent retention of nano-TiO2 in the lungs up to 28 days post-exposure time. Retention did not correlate with the extent of inflammatory neutrophil influx into the lungs. DNA microarray analysis showed altered expression of approximately 3000 genes across all treatment groups (±1.3 fold; p<0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein levels. Although the low dose exposure failed to induce observable inflammation, significant changes in the expression of genes and proteins associated with inflammation were observed. Moreover, diminished (or absent) neutrophil influx in the low and medium dose groups was correlated with negative regulation of genes associated with ion homeostasis and muscle regulation. Gene expression changes for several inflammatory mediators have previously been noted in mice exposed to the same nano-TiO2 via inhalation. Our results suggest that retention of nano-TiO2 in the absence of inflammation and effective clearance can perturb calcium and ion homeostasis, and affect smooth muscle activities over time.

Project description:Pulmonary exposure to high doses of nanoparticles (NP) leads to well characterized lung toxicity in addition to long-term NP retention. However, pulmonary NP accumulation and toxicity following low dose exposures are not well described. In the present study we sought to: (1) investigate particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO2) and (2) determine the effects of long-term particle accumulation on pulmonary systems. Female C57BL/6 mice were exposed to rutile nano-TiO2 (primary size of 20.6 nm and surface area of 107.7 m2/g) via single intratracheal instillations of 18, 54 and 162 M-BM-5g/mouse and sampled 1, 3 and 28 days post-exposure. The deposition of nano-TiO2 in the lungs was assessed using Nanoscale Hyperspectral Microscope. DNA microarrays, pathway-specific real-time RT-PCR (qPCR) and gene-specific qPCR arrays, and tissue protein analyses were employed to characterize pulmonary responses. Hyperspectral mapping showed dose-dependent retention of nano-TiO2 in the lungs up to 28 days post-exposure time. Retention did not correlate with the extent of inflammatory neutrophil influx into the lungs. DNA microarray analysis showed altered expression of approximately 3000 genes across all treatment groups (M-BM-11.3 fold; p<0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein levels. Although the low dose exposure failed to induce observable inflammation, significant changes in the expression of genes and proteins associated with inflammation were observed. Moreover, diminished (or absent) neutrophil influx in the low and medium dose groups was correlated with negative regulation of genes associated with ion homeostasis and muscle regulation. Gene expression changes for several inflammatory mediators have previously been noted in mice exposed to the same nano-TiO2 via inhalation. Our results suggest that retention of nano-TiO2 in the absence of inflammation and effective clearance can perturb calcium and ion homeostasis, and affect smooth muscle activities over time. This experiment consists of three different dosages of TiO2, e.g., low (18 ug), medium (54 ug) and high (162 ug), and one control. There are 3 time points for each treatment and control group, e.g., day 1, day 3 and day 28. Each dose or time point has 5-6 biological replicates. There are total 65 samples (arrays)

Dataset Information

High-dose intranasal application of titanium dioxide nanoparticles induces the systemic uptakes and allergic airway inflammation in asthmatic mice.

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High-dose intranasal application of titanium dioxide nanoparticles induces the systemic uptakes and allergic airway inflammation in asthmatic mice.

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