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- Genotoxicity and Gene Expression in the Rat Lung Tissue following Instillation and Inhalation of Different Variants of Amorphous Silica Nanomaterials (aSiO2 NM)Publication . Brandão, Fátima; Costa, Carla; Bessa, Maria João; Dumortier, Elise; Debacq-Chainiaux, Florence; Hubaux, Roland; Salmon, Michel; Laloy, Julie; Stan, Miruna S.; Hermenean, Anca; Gharbia, Sami; Dinischiotu, Anca; Bannuscher, Anne; Hellack, Bryan; Haase, Andrea; Fraga, Sónia; Teixeira, JoãoSeveral reports on amorphous silica nanomaterial (aSiO2 NM) toxicity have been questioning their safety. Herein, we investigated the in vivo pulmonary toxicity of four variants of aSiO2 NM: 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 single intratracheal instillation in rats. Additionally, a short-term inhalation study (STIS) was carried out for SiO2_7, using TiO2_NM105 as a benchmark NM. In the instillation study, a significant but slight increase in oxidative DNA damage in rats exposed to the highest instilled dose (0.36 mg/rat) of SiO2_15_Amino was observed in the recovery (R) group. Exposure to SiO2_7 or SiO2_40 markedly increased oxidative DNA lesions in rat lung cells of the exposure (E) group at every tested dose. This damage seems to be repaired, since no changes compared to controls were observed in the R groups. In STIS, a significant increase in DNA strand breaks of the lung cells exposed to 0.5 mg/m3 of SiO2_7 or 50 mg/m3 of TiO2_NM105 was observed in both groups. The detected gene expression changes suggest that oxidative stress and/or inflammation pathways are likely implicated in the induction of (oxidative) DNA damage. Overall, all tested aSiO2 NM were not associated with marked in vivo toxicity following instillation or STIS. The genotoxicity findings for SiO2_7 from instillation and STIS are concordant; however, changes in STIS animals were more permanent/difficult to revert.
- Comparative assessment of the acute toxicity of commonly used metal nanoparticles in two in vitro models of human barriersPublication . Pires, J.; Moreira, L.; Teixeira, João; Fraga, SóniaMetal nanoparticles (M-NP) have application in several areas such as industry, environment, agriculture, and biomedicine. Consequently, human exposure to these nanosized materials is increasing, which raises serious concerns regarding their safety to the human health and the environment. Biological barriers are important lines of defence to xenobiotics, thus expected targets for M-NP. The present study investigated the in vitro toxicity of different types of M-NP in two cell models of biological barriers: human intestinal (Caco-2) and trophoblastic (BeWo clone b30) epithelial cells. Cells were exposed for 24 h to varied concentrations (0.8-48 µg/cm2) of M NP of different chemical composition (Au, Ag, TiO2), primary size (10, 30 and 60 nm), capping (citrate, PEG) and crystal structure (rutile, anatase) and toxicity assessed by determining changes in cell morphology, metabolic activity, plasma membrane integrity, generation of intracellular reactive oxygen species (ROS) and intracellular ATP levels. Our data show that the potential toxicity of the tested M-NPs is similar for both cell lines with AgNPs > AuNPs > TiO2NPs, being the effects more visible at higher concentrations. The influence of the size in the cytotoxic-induced effects was more evident for AgNP than for AuNP, with the smaller NP causing more toxicity, being the BeWo cells more sensitive to these M-NP. In addition, PEG-capping effectively attenuated AuNP-induced toxicity both in Caco-2 and BeWo cells. Only cells exposed to AgNP exhibited significant increased levels of ROS. Thus, our data support that the physicochemical properties of the nanomaterials, in this particular case of M-NP, is an important determinant of their cytotoxicity and that intestinal and trophoblastic cells exhibit different sensitivity to the tested M-NP. Future studies would be useful to further explore the effects of M-NP in the human barriers
- Multiparametric in vitro genotoxicity assessment of different variants of amorphous silica nanomaterials in rat alveolar epithelial cellsPublication . Brandão, Fátima; Costa, Carla; Bessa, Maria João; Valdiglesias, Vanessa; Hellack, Bryan; Haase, Andrea; Fraga, Sónia; Teixeira, João PauloThe hazard posed to human health by inhaled amorphous silica nanomaterials (aSiO2 NM) remains uncertain. Herein, we assessed the cyto- and genotoxicity of aSiO2 NM variants covering different sizes (7, 15, and 40 nm) and surface modifications (unmodified, phosphonate-, amino- and trimethylsilyl-modified) on rat alveolar epithelial (RLE-6TN) cells. Cytotoxicity was evaluated at 24 h after exposure to the aSiO2 NM variants by the lactate dehydrogenase (LDH) release and WST-1 reduction assays, while genotoxicity was assessed using different endpoints: DNA damage (single- and double-strand breaks [SSB and DSB]) by the comet assay for all aSiO2 NM variants; cell cycle progression and γ-H2AX levels (DSB) by flow cytometry for those variants that presented higher cytotoxic and DNA damaging potential. The variants with higher surface area demonstrated a higher cytotoxic potential (SiO2_7, SiO2_15_Unmod, SiO2_15_Amino, and SiO2_15_Phospho). SiO2_40 was the only variant that induced significant DNA damage on RLE-6TN cells. On the other hand, all tested variants (SiO2_7, SiO2_15_Unmod, SiO2_15_Amino, and SiO2_40) significantly increased total γ-H2AX levels. At high concentrations (28 µg/cm2), a decrease in G0/G1 subpopulation was accompanied by a significant increase in S and G2/M sub-populations after exposure to all tested materials except for SiO2_40 which did not affect cell cycle progression. Based on the obtained data, the tested variants can be ranked for its genotoxic DNA damage potential as follows: SiO2_7 = SiO2_40 = SiO2_15_Unmod > SiO2_15_Amino. Our study supports the usefulness of multiparametric approaches to improve the understanding on NM mechanisms of action and hazard prediction.