Comparison of the DNA damage response in BEAS-2B and A549 cells exposed to titanium dioxide nanoparticles

Mathilde Biola-Clier 1, 2 David Béal 1, 2 Sylvain Caillat 1, 2 S. Libert 3 L. Armand 1, 2 Nathalie Herlin-Boime 4 Sylvie Sauvaigo 3 Thierry Douki 1, 2 Marie Carrière 1, 2
2 CIBEST - Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie
SYMMES - SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé : DRF/INAC/SYMMES
4 LEDNA - Laboratoire Edifices Nanométriques
NIMBE UMR 3685 - Nanosciences et Innovation pour les Matériaux, la Biomédecine et l'Energie (ex SIS2M)
Abstract : For some decades production of titanium dioxide nanoparticle (TiO$_2$-NP) has been increasing at a considerable rate; concerns as to the toxicity of these particles upon inhalation have been raised. Indeed, TiO$_2$-NPs have been shown to induce significant genotoxicity and to adversely affect both major DNA repair mechanisms: base excision repair (BER) and nucleotide excision repair (NER). The aims of the present study were to (i) compare the genotoxicity of TiO$_2$-NPs and their impact on DNA repair processes on A549 alveolar carcinoma and BEAS-2B normal bronchial lung cell lines and (ii) delve deeper into the mechanisms leading to these effects. To achieve these goals, TiO$_2$-NPs effects on cytotoxicity, genotoxicity, DNA repair activity and DNA repair gene expression were investigated in both cell lines upon exposure to 1–100 $\mu$g/mL of anatase/rutile, 21 nm TiO$_2$-NPs. Our results show that TiO$_2$-NPs induce comparable cytotoxic and genotoxic responses in BEAS-2B and A549 cells. Functional response to DNA damage is observed in both cell lines and consists of an overall downregulation in DNA repair processes. When evaluating the relative importance of the two DNA repair pathways, we observed a lower impact on BER compared with NER activities, suggesting that repair of oxidatively generated DNA damage is still triggered in these cells. This response becomes measureable at 4 h of exposure in BEAS-2B but only after 48 h of exposure in A549 cells. The delayed response in A549 cells is due to an initial overall and intense downregulation of the genes encoding DNA repair proteins. This overall downregulation correlates with increased methylation of DNA repair gene promoters and downregulation of NRF2 and BRCA1, which may thus be considered as upstream regulators. These results strengthen the evidence that TiO$_2$-NP induces indirect genotoxicity in lung cells, via modulation of DNA repair processes, and shed some light on the mechanisms behind this effect.
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Mathilde Biola-Clier, David Béal, Sylvain Caillat, S. Libert, L. Armand, et al.. Comparison of the DNA damage response in BEAS-2B and A549 cells exposed to titanium dioxide nanoparticles. Mutagenesis, Oxford University Press (OUP), 2016, 32, pp.161-172. ⟨http://mutage.oxfordjournals.org/content/early/2016/11/01/mutage.gew055.abstract⟩. ⟨10.1093/mutage/gew055⟩. ⟨cea-01424852⟩

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