Toxicity of TiO2 Nanoparticles: Validation of Alternative Models

Leroux, M.; Doumandji, Zahra; Chézeau, Laëtitia; Gaté, Laurent; Nahle, Sara; Hocquel, Romain; Zhernovkov, Vadim; Migot, Sylvie; Ghanbaja, Jafar; Bonnet, Céline; Schneider, Raphaël; Rihn, Bertrand; Ferrari, Luc; Joubert, O.

doi:10.3390/ijms21144855

Cited by 13 publications

(8 citation statements)

References 117 publications

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“…As demonstrated by Leroux et al air-liquid interface compared to submerged cultures more closely mimics gene expression levels upon TiO2 nanoparticle exposure to that in vivo. 40,41 Here, Calu-3 cells showed the least cytotoxic effects upon ZnO exposure, which aligns well with comparable other studies of submerged cultures. 42 Most importantly, the type of barrier cell severely affected the nanotoxicological results in the current study.…”

Section: Discussion and Prospectssupporting

confidence: 91%

The Cultivation Modality and Barrier Maturity Modulate the Toxicity of Industrial Zinc Oxide and Titanium Dioxide Nanoparticles on Nasal, Buccal, Bronchial, and Alveolar Mucosa Cell-Derived Barrier Models

Stuetz¹,

Reihs²,

Neuhaus³

et al. 2023

Preprint

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As common industrial by-products, airborne engineered nanomaterials are considered important environmental toxicants to monitor due to their potential health risks to humans and animals. The main uptake routes of airborne nanoparticles are nasal and/or oral inhalation, which are known to enable the transfer of nanomaterials into the blood stream resulting in rapid distribution in the body. Consequently, mucosal barriers present in nose, buccal and lung have been identified and intensively studied as the key tissue barrier to nanoparticle translocation. Despite decades of research, surprisingly little is known about the differences among various mucosa tissue types to tolerate nanoparticle exposures. One limitation in comparing nanotoxicological data sets can be linked to a lack of harmonization and standardization of cell-based assays, where a) different cultivation conditions such as air-liquid interface or submerged cultures, b) varying barrier maturity and c) diverse media substitutes have been used. The current comparative nanotoxicological study therefore aims at analyzing the toxic effects of nanomaterials on four human mucosa barrier models including nasal (RPMI2650), buccal (TR146), alveolar (A549), and bronchial (Calu-3) mucosal cell lines to better understand the modulating effects of tissue maturity, cultivation conditions and tissue type using standard Transwell cultivations at liquid-liquid and air-liquid interfaces. Overall, cell size, confluency, tight junction localization, and cell viability as well as barrier formation using 50% and 100% confluency was monitored using trans-epithelial-electrical resistance (TEER) measurements and Presto Blue assays of immature (e.g. 5 days) and mature (e.g. 22 days) cultures in the presence and absence of corticosteroids such as hydrocortisone. Results of our study show that cellular responses to increasing nanoparticle exposures are highly cell type specific, where bronchial mucosal cell barriers models cultivated under ALI conditions showed less tolerance to acute ZnO nanoparticle exposures. Additionally, stronger toxicities are found using early mucosa barriers compared to later barrier models being maturated under air-liquid cultivation conditions.

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Section: Discussion and Prospectssupporting

confidence: 91%

The Cultivation Modality and Barrier Maturity Modulate the Toxicity of Industrial Zinc Oxide and Titanium Dioxide Nanoparticles on Nasal, Buccal, Bronchial, and Alveolar Mucosa Cell-Derived Barrier Models

Stuetz¹,

Reihs²,

Neuhaus³

et al. 2023

Preprint

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“…Even though both constitute viable and well-established models, in our opinion future studies must investigate a variety of human mucosa models in more comprehensive comparative studies, as highlighted by our current study, using more physiological approaches such as ALI protocols. As demonstrated by Leroux et al air-liquid interface compared to submerged cultures more closely mimics gene expression levels upon TiO 2 nanoparticle exposure to that in vivo [ 76 , 77 ]. Here, Calu-3 cells showed the least cytotoxic effects upon ZnO exposure, which aligns well with comparable other studies of submerged cultures [ 78 ].…”

Section: Discussion and Prospectsmentioning

confidence: 99%

The Cultivation Modality and Barrier Maturity Modulate the Toxicity of Industrial Zinc Oxide and Titanium Dioxide Nanoparticles on Nasal, Buccal, Bronchial, and Alveolar Mucosa Cell-Derived Barrier Models

Stuetz

Reihs

Neuhaus

et al. 2023

IJMS

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As common industrial by-products, airborne engineered nanomaterials are considered important environmental toxins to monitor due to their potential health risks to humans and animals. The main uptake routes of airborne nanoparticles are nasal and/or oral inhalation, which are known to enable the transfer of nanomaterials into the bloodstream resulting in the rapid distribution throughout the human body. Consequently, mucosal barriers present in the nose, buccal, and lung have been identified and intensively studied as the key tissue barrier to nanoparticle translocation. Despite decades of research, surprisingly little is known about the differences among various mucosa tissue types to tolerate nanoparticle exposures. One limitation in comparing nanotoxicological data sets can be linked to a lack of harmonization and standardization of cell-based assays, where (a) different cultivation conditions such as an air-liquid interface or submerged cultures, (b) varying barrier maturity, and (c) diverse media substitutes have been used. The current comparative nanotoxicological study, therefore, aims at analyzing the toxic effects of nanomaterials on four human mucosa barrier models including nasal (RPMI2650), buccal (TR146), alveolar (A549), and bronchial (Calu-3) mucosal cell lines to better understand the modulating effects of tissue maturity, cultivation conditions, and tissue type using standard transwell cultivations at liquid-liquid and air-liquid interfaces. Overall, cell size, confluency, tight junction localization, and cell viability as well as barrier formation using 50% and 100% confluency was monitored using trans-epithelial-electrical resistance (TEER) measurements and resazurin-based Presto Blue assays of immature (e.g., 5 days) and mature (e.g., 22 days) cultures in the presence and absence of corticosteroids such as hydrocortisone. Results of our study show that cellular viability in response to increasing nanoparticle exposure scenarios is highly compound and cell-type specific (TR146 6 ± 0.7% at 2 mM ZnO (ZnO) vs. ~90% at 2 mM TiO2 (TiO2) for 24 h; Calu3 93.9 ± 4.21% at 2 mM ZnO vs. ~100% at 2 mM TiO2). Nanoparticle-induced cytotoxic effects under air-liquid cultivation conditions declined in RPMI2650, A549, TR146, and Calu-3 cells (~0.7 to ~0.2-fold), with increasing 50 to 100% barrier maturity under the influence of ZnO (2 mM). Cell viability in early and late mucosa barriers where hardly influenced by TiO2 as well as most cell types did not fall below 77% viability when added to Individual ALI cultures. Fully maturated bronchial mucosal cell barrier models cultivated under ALI conditions showed less tolerance to acute ZnO nanoparticle exposures (~50% remaining viability at 2 mM ZnO for 24 h) than the similarly treated but more robust nasal (~74%), buccal (~73%), and alveolar (~82%) cell-based models.

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“…The study exhibited the toxicity induced by titanium dioxide NPs inadequately expressed genes involved in various cellular functions and approached the ALI system for cytotoxicity study. 281 The proximity of carbon NPs or ultrafine particles in air pollution is the foremost reason for a lung infection and even stimulates lung fibrosis. However, the mechanism of action to provoke pulmonary fibrosis remains unclear until now.…”

Section: Toxicity Of Inhaled Nanoparticlesmentioning

confidence: 99%

“…The Fischer 344 rats were exposed to NPs inhalation via aerosolization technique at a concentration of 10 mg/m 3 , followed by an immediate gene expression study performed to check the cytotoxic potentiality of titanium dioxide NPs on NR8383 cells. The study exhibited the toxicity induced by titanium dioxide NPs inadequately expressed genes involved in various cellular functions and approached the ALI system for cytotoxicity study …”

Section: Toxicity Of Inhaled Nanoparticlesmentioning

confidence: 99%

Nanoparticle-Based Drug Delivery System: The Magic Bullet for the Treatment of Chronic Pulmonary Diseases

Pramanik

Mohanto

Manne³

et al. 2021

Mol. Pharmaceutics

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Chronic pulmonary diseases encompass different persistent and lethal diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), asthma, and lung cancers that affect millions of people globally. Traditional pharmacotherapeutic treatment approaches (i.e., bronchodilators, corticosteroids, chemotherapeutics, peptide-based agents, etc.) are not satisfactory to cure or impede diseases. With the advent of nanotechnology, drug delivery to an intended site is still difficult, but the nanoparticle’s physicochemical properties can accomplish targeted therapeutic delivery. Based on their surface, size, density, and physical-chemical properties, nanoparticles have demonstrated enhanced pharmacokinetics of actives, achieving the spotlight in the drug delivery research field. In this review, the authors have highlighted different nanoparticle-based therapeutic delivery approaches to treat chronic pulmonary diseases along with the preparation techniques. The authors have remarked the nanosuspension delivery via nebulization and dry powder carrier is further effective in the lung delivery system since the particles released from these systems are innumerable to composite nanoparticles. The authors have also outlined the inhaled particle’s toxicity, patented nanoparticle-based pulmonary formulations, and commercial pulmonary drug delivery devices (PDD) in other sections. Recently advanced formulations employing nanoparticles as therapeutic carriers for the efficient treatment of chronic pulmonary diseases are also canvassed.

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Toxicity of TiO2 Nanoparticles: Validation of Alternative Models

Cited by 13 publications

References 117 publications

The Cultivation Modality and Barrier Maturity Modulate the Toxicity of Industrial Zinc Oxide and Titanium Dioxide Nanoparticles on Nasal, Buccal, Bronchial, and Alveolar Mucosa Cell-Derived Barrier Models

The Cultivation Modality and Barrier Maturity Modulate the Toxicity of Industrial Zinc Oxide and Titanium Dioxide Nanoparticles on Nasal, Buccal, Bronchial, and Alveolar Mucosa Cell-Derived Barrier Models

The Cultivation Modality and Barrier Maturity Modulate the Toxicity of Industrial Zinc Oxide and Titanium Dioxide Nanoparticles on Nasal, Buccal, Bronchial, and Alveolar Mucosa Cell-Derived Barrier Models

Nanoparticle-Based Drug Delivery System: The Magic Bullet for the Treatment of Chronic Pulmonary Diseases

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