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Molecular mechanism of DNA damage induced by titanium dioxide nanoparticles in toll-like receptor 3 or 4 expressing human hepatocarcinoma cell lines.

El-Said KS, Ali EM, Kanehira K, Taniguchi A - J Nanobiotechnology (2014)

Bottom Line: Our results showed evidence for elevated oxidative stress, including the generation of reactive oxygen species (ROS), with increased hydrogen peroxide levels, decreased glutathione peroxidase, and reduced glutathione and activated caspase-3 levels in cells exposed for 48 h to 10 μg/ml TiO2 NPs.These effects were enhanced by TLR4 and reduced by TLR3 over-expression.Our results indicated that TiO2 NPs induced ROS, and the above molecules are implicated in the genotoxicity induced by TiO2 NPs.

View Article: PubMed Central - PubMed

Affiliation: Cell-Material Interaction Group, Biomaterial Unit, Nano-Bio Field, Interaction Center for Material Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS), Tsukuba, Japan. SAMYELSAIDALI.Karim@nims.go.jp.

ABSTRACT

Background: Titanium dioxide nanoparticles (TiO2 NPs) are widely used in the biological sciences. The increasing use of TiO2 NPs increases the risk of humans and the environment being exposed to NPs. We previously showed that toll-like receptors (TLRs) play an important role in the interactions between NPs and cells. Our previous results indicated that TLR4 increased the DNA damage response induced by TiO2 NPs, due to enhanced NP uptake into the cytoplasm, whereas TLR3 expression decreased the DNA damage response induced by TiO2 NPs because of NP retention in the endosome. In this study, we explored the molecular mechanism of the DNA damage response induced by TiO2 NPs using TLR3 or TLR4 transfected cells. We examined the effect of TLR3 or TLR4 over-expression on oxidative stress and the effect of DNA damage induced by TiO2 NPs on gene expression levels.

Results: Our results showed evidence for elevated oxidative stress, including the generation of reactive oxygen species (ROS), with increased hydrogen peroxide levels, decreased glutathione peroxidase, and reduced glutathione and activated caspase-3 levels in cells exposed for 48 h to 10 μg/ml TiO2 NPs. These effects were enhanced by TLR4 and reduced by TLR3 over-expression. Seventeen genes related to DNA double-strand breaks and apoptosis were induced, particularly IP6K3 and ATM.

Conclusion: Our results indicated that TiO2 NPs induced ROS, and the above molecules are implicated in the genotoxicity induced by TiO2 NPs.

No MeSH data available.


Related in: MedlinePlus

A schematic representation of mitochondrial ROS implicated in DNA damage and apoptosis induced by TiO2NP exposure, with and without TLR4 over-expression. The figure shows the site of induction and inhibition of respiratory complexes and oxidative stress molecules involved in ROS generation in HepG2 cells exposed to TiO2 NPs with and without TLR4 over-expression. (+) indicate the sites of activation and (-) show the sites of inhibition.
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Fig8: A schematic representation of mitochondrial ROS implicated in DNA damage and apoptosis induced by TiO2NP exposure, with and without TLR4 over-expression. The figure shows the site of induction and inhibition of respiratory complexes and oxidative stress molecules involved in ROS generation in HepG2 cells exposed to TiO2 NPs with and without TLR4 over-expression. (+) indicate the sites of activation and (-) show the sites of inhibition.

Mentions: The purpose of this study was to examine the molecular mechanism of DNA damage caused by exposure to TiO2 NPs (10 μg/ml). A high concentration of TiO2 NPs should amplify the effects of the NPs and thus aid examination of their mechanism of action. The interactions of NPs with cells resulted in the generation of ROS, and the resultant oxidative stress may cause DNA fragmentation [35,36]. We found a significant increase in ROS generation in cells exposed to TiO2 NPs, which is consistent with our previous report of DNA damage responses in TiO2 NP-exposed cells [32]. In this paper, the results indicated that TiO2 NPs induced oxidative stress in cells, which can cause oxidative DNA damage and lead to the activation of p53 tumor suppressors and bcl-2 apoptotic factors. Additionally, oxidative stress can affect the mitochondria, the richest source of ROS, in which oxygen is metabolized and converted to O2− by several components of the mitochondrial respiratory chain (Figure 8).Figure 8


Molecular mechanism of DNA damage induced by titanium dioxide nanoparticles in toll-like receptor 3 or 4 expressing human hepatocarcinoma cell lines.

El-Said KS, Ali EM, Kanehira K, Taniguchi A - J Nanobiotechnology (2014)

A schematic representation of mitochondrial ROS implicated in DNA damage and apoptosis induced by TiO2NP exposure, with and without TLR4 over-expression. The figure shows the site of induction and inhibition of respiratory complexes and oxidative stress molecules involved in ROS generation in HepG2 cells exposed to TiO2 NPs with and without TLR4 over-expression. (+) indicate the sites of activation and (-) show the sites of inhibition.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4260178&req=5

Fig8: A schematic representation of mitochondrial ROS implicated in DNA damage and apoptosis induced by TiO2NP exposure, with and without TLR4 over-expression. The figure shows the site of induction and inhibition of respiratory complexes and oxidative stress molecules involved in ROS generation in HepG2 cells exposed to TiO2 NPs with and without TLR4 over-expression. (+) indicate the sites of activation and (-) show the sites of inhibition.
Mentions: The purpose of this study was to examine the molecular mechanism of DNA damage caused by exposure to TiO2 NPs (10 μg/ml). A high concentration of TiO2 NPs should amplify the effects of the NPs and thus aid examination of their mechanism of action. The interactions of NPs with cells resulted in the generation of ROS, and the resultant oxidative stress may cause DNA fragmentation [35,36]. We found a significant increase in ROS generation in cells exposed to TiO2 NPs, which is consistent with our previous report of DNA damage responses in TiO2 NP-exposed cells [32]. In this paper, the results indicated that TiO2 NPs induced oxidative stress in cells, which can cause oxidative DNA damage and lead to the activation of p53 tumor suppressors and bcl-2 apoptotic factors. Additionally, oxidative stress can affect the mitochondria, the richest source of ROS, in which oxygen is metabolized and converted to O2− by several components of the mitochondrial respiratory chain (Figure 8).Figure 8

Bottom Line: Our results showed evidence for elevated oxidative stress, including the generation of reactive oxygen species (ROS), with increased hydrogen peroxide levels, decreased glutathione peroxidase, and reduced glutathione and activated caspase-3 levels in cells exposed for 48 h to 10 μg/ml TiO2 NPs.These effects were enhanced by TLR4 and reduced by TLR3 over-expression.Our results indicated that TiO2 NPs induced ROS, and the above molecules are implicated in the genotoxicity induced by TiO2 NPs.

View Article: PubMed Central - PubMed

Affiliation: Cell-Material Interaction Group, Biomaterial Unit, Nano-Bio Field, Interaction Center for Material Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS), Tsukuba, Japan. SAMYELSAIDALI.Karim@nims.go.jp.

ABSTRACT

Background: Titanium dioxide nanoparticles (TiO2 NPs) are widely used in the biological sciences. The increasing use of TiO2 NPs increases the risk of humans and the environment being exposed to NPs. We previously showed that toll-like receptors (TLRs) play an important role in the interactions between NPs and cells. Our previous results indicated that TLR4 increased the DNA damage response induced by TiO2 NPs, due to enhanced NP uptake into the cytoplasm, whereas TLR3 expression decreased the DNA damage response induced by TiO2 NPs because of NP retention in the endosome. In this study, we explored the molecular mechanism of the DNA damage response induced by TiO2 NPs using TLR3 or TLR4 transfected cells. We examined the effect of TLR3 or TLR4 over-expression on oxidative stress and the effect of DNA damage induced by TiO2 NPs on gene expression levels.

Results: Our results showed evidence for elevated oxidative stress, including the generation of reactive oxygen species (ROS), with increased hydrogen peroxide levels, decreased glutathione peroxidase, and reduced glutathione and activated caspase-3 levels in cells exposed for 48 h to 10 μg/ml TiO2 NPs. These effects were enhanced by TLR4 and reduced by TLR3 over-expression. Seventeen genes related to DNA double-strand breaks and apoptosis were induced, particularly IP6K3 and ATM.

Conclusion: Our results indicated that TiO2 NPs induced ROS, and the above molecules are implicated in the genotoxicity induced by TiO2 NPs.

No MeSH data available.


Related in: MedlinePlus