Study of TiO ₂ P25 nanoparticles genotoxicity on lung, blood and liver cells in lung overload and non-overload conditions after repeated respiratory exposure in rats

Abstract

Inhaled titanium dioxide (TiO2) nanoparticles (NPs) can have negative health effects, and have been shown to cause respiratory tract cancer in rats. Inflammation has been linked to oxidative stress, and both have been described as possible mechanisms for genotoxicity of NPs, but rarely examined side-by-side in animal studies. In the present study, a wide range of complementary endpoints have been performed to study TiO2 P25 NP-induced genotoxicity in lung overload and non-overload conditions. Additionally, lung burden, inflammation, cytotoxicity and oxidative stress have also been evaluated in order to link genotoxicity with these responses. To assess quick and delayed responses after recovery, endpoints were evaluated at two time points: 2 h and 35 days after three repeated instillations. This study confirmed the previously described lung overload threshold at approximately 200-300 cm2 of lung burden for total particle surface area lung deposition or 4.2 µl/kg for volume-based cumulative lung exposure dose, above which lung clearance is impaired and inflammation is induced. Our results went on to show that these overload doses induced delayed genotoxicity in lung, associated with persistent inflammation only at the highest dose. The lowest tested doses had no toxicity or genotoxicity effects in the lung. In blood, no lymphocyte DNA damage, erythrocytes chromosomal damage or gene mutation could be detected. Our data also demonstrated that only overload doses induced liver DNA lesions irrespective of the recovery time. Tested doses of TiO2 P25 NPs did not induce glutathione changes in lung, blood or liver at both recovery times.

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

“…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 . 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 and animal models . 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found that the four sizes of nano‐TiO 2 could induce significant DNA damages and micronuclei in human BEAS‐2B cells (unpublished data).…”

“…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). These findings indicated that the intracellular approach of apoptosis may be an important pathway involved in the EC apoptosis due to nano-TiO 2 exposure.…”

Genotoxicity and Gene Expression in the Rat Lung Tissue Following Instillation and Inhalation of Different Variants of Amorphous Silica Nanomaterials (aSiO2 NMs)

“…induced an in ammatory response in mice BAL uid not associated with signi cant genotoxic effects in lung epithelial cells. At the same time, Relier, et al [103] found that only under overload conditions (three instillations of 10 mg/kg) TiO 2 _NM105 (rutile-anatase) induced delayed genotoxicity in lung, associated with persistent in ammation. In the present study, only rats exposed for ve consecutive days to the highest dose of TiO 2 _NM105 aerosols exhibited an increase in the DNA damage of total lung cells, which is consistent with its high oxidative stress potential based on the high levels of protein carbonylation found in the lung tissue of the exposed animals.…”

Are Titania Photocatalysts and Titanium Implants Safe? Review on the Toxicity of Titanium Compounds

“…To better understand how titania affects human health, animal models, in particular rats or other rodents (mice and hamsters), have been used as exemplary for commercial titania, as presented by Relier et al [ 97 ]. Accordingly, obtained data allow us to compare various conditions of TiO 2 exposure and multiple exposure routes, and help to assess the model of action, even when the animal model of the organ injury does not correspond to the human organ injury or identification of conserved gene expression across organisms.…”