Long-term exposure of A549 cells to titanium dioxide nanoparticles induces DNA damage and sensitizes cells towards genotoxic agents

Armand, Lucie; Tarantini, Adeline; Béal, David; Biola-Clier, Mathilde; Bobyk, Laure; Sorieul, S.; Pernet‐Gallay, Karin; Marie-Desvergne, Caroline; Lynch, Iseult; Herlin‐Boime, Nathalie; Carrière, Marie

doi:10.3109/17435390.2016.1141338

Cited by 105 publications

(68 citation statements)

References 41 publications

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“…In the present study, a significant increase of both DNA damages and MN frequencies was observed in the HUVECs exposed to the TiO 2 ‐NPs, with a clear dose‐effect relationship (Figures and ). This is consistent with the findings of other groups in human lymphocytes, BEAS‐2B, A549, HepG2, and HEK293 cells in vitro and in the mice PBMCs, liver cells, and lung cells in vivo . Moreover, a very similar manner of dose‐dependent and size‐dependent effects was found as our previous work did in apoptosis assay, indicating that the genotoxicity of TiO 2 ‐NPs has taken an important role in this apoptotic event in HUVECs tested.…”

Section: Discussionsupporting

confidence: 93%

“…New recently, a number of ENPs assessed were reported to induce genotoxic responses, such as DNA strand breakages, chromosomal fragmentation, point mutations, oxidative DNA adducts, and alterations in gene expression profiles, in vitro and/or in vivo . Also, TiO 2 ‐NPs were found to elicit a significant increase of oxidative DNA damage in human lymphocytes, BEAS‐2B, A549, HepG2, and HEK293 cells in vitro and in the mice PBMCs, liver cells, and lung cells in vivo, and micronuclei and chromosomal aberrations in both plant and human lymphocytes . In the literature, however, the observed genotoxic potencies of ENPs were cell‐type‐dependent; inconsistent and even contradictory consequences were often obtained in different types of cells .…”

Section: Introductionmentioning

confidence: 99%

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The size‐dependent genotoxic potentials of titanium dioxide nanoparticles to endothelial cells

Liao

Chen

Liu

et al. 2019

Environmental Toxicology

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Despite intensive research activities, there are still many major knowledge gaps over the potential adverse effects of titanium dioxide nanoparticles (TiO2‐NPs), one of the most widely produced and used nanoparticles, on human cardiovascular health and the underlying mechanisms. In the present study, alkaline comet assay and cytokinesis‐block micronucleus test were employed to determine the genotoxic potentials of four sizes (100, 50, 30, and 10 nm) of anatase TiO2‐NPs to human umbilical vein endothelial cells (HUVECs) in culture. Also, the intracellular redox statuses were explored through the measurement of the levels of reactive oxygen species (ROS) and reduced glutathione (GSH) with kits, respectively. Meanwhile, the protein levels of nuclear factor erythroid 2‐related factor 2 (Nrf2) were also detected by western blot. The results showed that at the exposed levels (1, 5, and 25 μg/mL), all the four sizes of TiO2‐NPs could elicit an increase of both DNA damage and MN frequency in HUVECs in culture, with a positive dose‐dependent and negative size‐dependent effect relationship (T100 < T50 < T30 < T10). Also, increased levels of intracellular ROS, but decreased levels of GSH, were found in all the TiO2‐NP‐treated groups. Intriguingly, a very similar manner of dose‐dependent and size‐dependent effect relationship was observed between the ROS test and both comet assay and MN test, but contrary to that of GSH assay. Correspondingly, the levels of Nrf2 protein were also elevated in the TiO2‐NP‐exposed HUVECs, with an inversely size‐dependent effect relationship. These findings indicated that induction of oxidative stress and subsequent genotoxicity might be an important biological mechanism by which TiO2‐NP exposure would cause detrimental effects to human cardiovascular health.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

The size‐dependent genotoxic potentials of titanium dioxide nanoparticles to endothelial cells

Liao

Chen

Liu

et al. 2019

Environmental Toxicology

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“…found that TiO 2 NPs induced a high level of ROS formation in a dose-dependent manner in Caco-2 cells after 6 h, but did not induce IL-8 release or cytotoxicity 57 . Long-term (two months) exposure to low concentrations (1–50 μg/mL) of TiO 2 NPs did not affect viability of A549 alveolar epithelial cells, but initiated oxidative damage to DNA and resulted in accumulated intracellular NPs 58 . The reduction in TER in this study was likely related to ROS formation, as cellular oxidative stress has been shown to activate redox-responsive signaling that disrupts TJ proteins 59 .…”

Section: Discussionmentioning

confidence: 88%

Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine

et al. 2017

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Ingestion of titanium dioxide (TiO2) nanoparticles from products such as agricultural chemicals, processed food, and nutritional supplements is nearly unavoidable. The gastrointestinal tract serves as a critical interface between the body and the external environment, and is the site of essential nutrient absorption. The goal of this study was to examine the effects of ingesting the 30 nm TiO2 nanoparticles with an in vitro cell culture model of the small intestinal epithelium, and to determine how acute or chronic exposure to nano-TiO2 influences intestinal barrier function, reactive oxygen species generation, proinflammatory signaling, nutrient absorption (iron, zinc, fatty acids), and brush border membrane enzyme function (intestinal alkaline phosphatase). A Caco-2/HT29-MTX cell culture model was exposed to physiologically relevant doses of TiO2 nanoparticles for acute (four hours) or chronic (five days) time periods. Exposure to TiO2 nanoparticles significantly decreased intestinal barrier function following chronic exposure. Reactive oxygen species (ROS) generation, proinflammatory signaling, and intestinal alkaline phosphatase activity all showed increases in response to nano-TiO2. Iron, zinc, and fatty acid transport were significantly decreased following exposure to TiO2 nanoparticles. This is because nanoparticle exposure induced a decrease in absorptive microvilli in the intestinal epithelial cells. Nutrient transporter protein gene expression was also altered, suggesting that cells are working to regulate the transport mechanisms disturbed by nanoparticle ingestion. Overall, these results show that intestinal epithelial cells are affected at a functional level by physiologically relevant exposure to nanoparticles commonly ingested from food.

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“…29 It is now known that the intracellular approach of apoptosis is mainly initiated by the induction of p53 as a response to DNA damage induced by genotoxic agents. 29 A number of studies have shown that nano-TiO 2 can induce DNA damage and adversely affect both major DNA repair mechanisms: base excision repair and nucleotide excision repair, showing a genotoxic potential to human cells 10,31,[42][43][44][45] and animal models. 24,46,47 We also found that the four sizes of nano-TiO 2 could induce significant DNA damages and micronuclei in human BEAS-2B cells (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

The size‐dependent apoptotic effect of titanium dioxide nanoparticles on endothelial cells by the intracellular pathway

Zeng

Feng

Wu-xiang

et al. 2018

Environmental Toxicology

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Concerns over the health risk of the widely distributed, commonly used titanium dioxide nanoparticles (nano-TiO ) are increasing worldwide. Yet, up-to-now, our understanding in their potential effects on the cardiovascular system is very limited and the toxicological mechanisms are still unclear. In the present study, the CCK-8 assay was performed to determine the cytotoxicity of four sizes (10, 30, 50, and 100 nm) of anatase nano-TiO on human umbilical vein endothelial cells (HUVECs) in culture, and the flow cytometry was employed to investigate the potential of these nano-TiO to induce the apoptosis of HUVECs. The apoptotic pathway was also probed through the determination of the protein expression and activation of p53, Bax, Bcl-2, caspases-9, -7, -3, and PARP by western blot. The results showed that at the administrative levels (1, 5, 25 μg/mL), all the four sizes of nano-TiO could significantly inhibit the viability of HUVECs and elicit significant apoptosis in them, compared with the negative control (P < .05, P < .01). Moreover, the apoptotic rates of HUVECs were increased respectively with the elevating levels and decreasing sizes of the administrative nano-TiO , showing a clear dose- and size-dependent effect relationships. Interestingly, the increasing phosphorylation of p53, decreasing ratio of Bcl-2/Bax, and enhancing activation of the downstream proteins caspase-9, -7, -3, and PARP, were also observed with the decreasing sizes of the administrative nano-TiO in the western blot, indicating that the intracellular approach of apoptosis, the p53-caspase pathway, is the major way of the nano-TiO -mediated apoptosis in HUVECs in culture and that the size is an important parameter that may determine the potential of nano-TiO to induce cellular response. In conclusion, these results suggested that high levels of nano-TiO exposure may pose potential risks to human cardiovascular health by inducing cardiovascular EC apoptosis.

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Long-term exposure of A549 cells to titanium dioxide nanoparticles induces DNA damage and sensitizes cells towards genotoxic agents

Cited by 105 publications

References 41 publications

The size‐dependent genotoxic potentials of titanium dioxide nanoparticles to endothelial cells

The size‐dependent genotoxic potentials of titanium dioxide nanoparticles to endothelial cells

Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine

The size‐dependent apoptotic effect of titanium dioxide nanoparticles on endothelial cells by the intracellular pathway

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