Comparison of the DNA damage response in BEAS-2B and A549 cells exposed to titanium dioxide nanoparticles.
For some decades production of titanium dioxide nanoparticle (TiO2-NP) has been increasing at a considerable rate; concerns as to the toxicity of these particles upon inhalation have been raised. Indeed, TiO2-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 TiO2-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, TiO2-NPs effects on cytotoxicity, genotoxicity, DNA repair activity and DNA repair gene expression were investigated in both cell lines upon exposure to 1-100 µg/mL of anatase/rutile, 21 nm TiO2-NPs. Our results show that TiO2-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 TiO2-NP induces indirect genotoxicity in lung cells, via modulation of DNA repair processes, and shed some light on the mechanisms behind this effect.
Laboratoire Lésions des Acides Nucléiques, Université Grenoble Alpes, INAC, SYMMES, 38000 Grenoble, France.|Laboratoire Lésions des Acides Nucléiques, CEA, INAC, SYMMES, 38000 Grenoble, France.
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Biola-Clier
Laboratoire Lésions des Acides Nucléiques, Université Grenoble Alpes, INAC, SYMMES, 38000 Grenoble, France.|Laboratoire Lésions des Acides Nucléiques, CEA, INAC, SYMMES, 38000 Grenoble, France.
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Beal
Laboratoire Lésions des Acides Nucléiques, Université Grenoble Alpes, INAC, SYMMES, 38000 Grenoble, France.|Laboratoire Lésions des Acides Nucléiques, CEA, INAC, SYMMES, 38000 Grenoble, France.
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Caillat
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Libert
Laboratoire Lésions des Acides Nucléiques, Université Grenoble Alpes, INAC, SYMMES, 38000 Grenoble, France.|Laboratoire Lésions des Acides Nucléiques, CEA, INAC, SYMMES, 38000 Grenoble, France.
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Armand
CEA, IRAMIS, NIMBE, LEDNA, 91191 Gif sur Yvette, France and.
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Herlin-Boime
LXRepair, Parvis Louis Néel, 38000 Grenoble, France.
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Sauvaigo
Laboratoire Lésions des Acides Nucléiques, Université Grenoble Alpes, INAC, SYMMES, 38000 Grenoble, France.|Laboratoire Lésions des Acides Nucléiques, CEA, INAC, SYMMES, 38000 Grenoble, France.
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Douki
Laboratoire Lésions des Acides Nucléiques, Université Grenoble Alpes, INAC, SYMMES, 38000 Grenoble, France, marie.carriere@cea.fr.|Laboratoire Lésions des Acides Nucléiques, CEA, INAC, SYMMES, 38000 Grenoble, France.
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Carriere
D000072283:A549 Cells; D002460:Cell Line; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D045643:DNA Repair Enzymes / Q000187:drug effects* / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D009152:Mutagenicity Tests; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D014025:Titanium / Q000633:toxicity*
C009495:titanium dioxide; D004247:DNA; D014025:Titanium; D045643:DNA Repair Enzymes