Étude au niveau pulmonaire du profil d’expression de gènes et de protéines chez le rat exposé par inhalation à un aérosol de particules nanostructurées de dioxyde de titane

Abstract : Due to the growing use of nanomaterials in various industrial processes, the number of workers potentially exposed is increasing even though the toxicological properties of these compounds are not completely known. Since nanoparticles (NP) may get aerosolized, inhalation represents their main route of occupational exposure. Then, inhalation studies of nanomaterial toxicity in animal models appear to be the most relevant approach to assess their hazards. In this work, we studied the short and long term pulmonary toxicological properties of inhaled titanium dioxide (TiO2) nanostructured aerosol (NSA), using conventional (broncho-alveolar lavage (BAL) analyses, lung and lymph nodes histopathology); and high content molecular toxicological approaches (transcriptomics and proteomics analyses). Fischer 344 rats were exposed to 10 mg/m3 of TiO2 nanostructured aerosol by nose-only inhalation, 6h/day, 5 days/week for 4 weeks. Biological samples were collected immediately and up to 180 post-exposure days. Exposure to TiO2 NSA resulted in a strong acute pulmonary inflammation. This response was characterized by a neutrophil influx, the presence of particle-laden macrophages in the alveolar lumen, as well as overexpression of genes and proteins involved in inflammatory and immune responses, complement and coagulation cascades, oxidative stress. Some overexpressed genes were also involved in DNA damage and fibrosis; and some overexpressed proteins in proteasome and cytoskeleton organization. In the BAL supernatant, the increased level of histones and other neutrophilic extracellular trap (NET) -associated proteins suggests the release of these traps in the alveolar space. This possible NET release occurs in an inflammatory context but in the absence of significant histopathological changes. Very few studies reported this unexpected process related to exposure to nanomaterials. Six months after the end of exposure (long-term response), inflammation had decreased in line with the decrease of titanium lung burden (a surrogate for TiO2 pulmonary deposition), but many genes and proteins remained differentially expressed. The physiopathological consequences of the molecular changes reported here are not fully known, but these results should raise concern about the long-term pulmonary effects of inhaled low toxicity NP such as TiO2. Altogether, this work shows that there is a good relationship between cytological and histopathological changes in one hand and gene as well as protein expression profile modifications in the other hand. However, in some cases transcriptomics or proteomics could be more sensitive than conventional methods to identify new toxicological properties or to better understand the underlying molecular mechanisms of chemicals toxicity. Our study along with others could also be helpful to identify biomarkers of exposure or predict the long-term adverse effects of nanomaterials
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Laëtitia Chezeau. Étude au niveau pulmonaire du profil d’expression de gènes et de protéines chez le rat exposé par inhalation à un aérosol de particules nanostructurées de dioxyde de titane. Toxicologie. Université de Lorraine, 2018. Français. ⟨NNT : 2018LORR0226⟩. ⟨tel-02078672⟩

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