Genotoxicity and Gene Expression in the Rat Lung Tissue Following Instillation and Inhalation of Different Variants of Amorphous Silica Nanomaterials (aSiO2 NMs)

Abstract

Background: Synthetic amorphous silica (SAS) has been widely used in several industrial and consumer applications for decades and considered safe for humans. However, several reports on the in vitro and in vivo toxicity of amorphous silica nanomaterials (aSiO2 NMs) have been questioning its safety at the nanoscale. In the present study, we investigated the influence of the physicochemical properties (size and surface chemistry) on in vivo pulmonary toxicity using four variants of aSiO2 NMs (SiO2_15_Unmod, SiO2_15_Amino, SiO2_7 and SiO2_40). We focused on alterations in lung DNA and protein integrity, and gene expression following intratracheal instillation in rats. Additionally, a short-term inhalation study (STIS) was carried out for SiO2_7, using TiO2_NM105 as a benchmark NM.Results: Overall, single intratracheal instillation of all tested NMs did not cause a significant increase of DNA strand breaks in the rat lung. However, a significant but slight increase of oxidative DNA damage in rats exposed to the highest instilled dose (0.36 mg/rat) of SiO2_15_ Amino was observed at 21 days post-exposure. In turn, exposure to SiO2_7 or SiO2_40 markedly increased oxidative DNA lesions in the rat lung cells in every tested dose at 3 days post-exposure, even though in a dose-independent manner. Nevertheless, this damage seems to be repaired since no changes compared to controls were observed in the recovery groups. In STIS, a significant increase of DNA strand breaks in the lung cells of rats exposed to 0.5 mg/m3 of SiO2_7 or to 50 mg/m3 of TiO2_NM105 was observed at both assessed time-points. The gene expression changes detected suggest that oxidative stress and/or inflammation pathways are likely implicated in the induction of (oxidative) DNA damage.Conclusions: Overall, all tested aSiO2 NMs were not associated with marked in vivo toxicity following instillation or STIS. Under our experimental conditions, pyrogenic aSiO2 NMs (SiO2_7 and SiO2_40) showed a higher genotoxic potential compared to colloidal aSiO2 (SiO2_15_Unmod and SiO2_15_Amino). Overall, genotoxicity findings for SiO2_7 from instillation and STIS are concordant, however changes in STIS animals were more permanent/difficult to revert.