Genotoxicity assessment of intravenously injected titanium dioxide nanoparticles in gpt delta transgenic mice

Suzuki, Tetsuya; Miura, Nobuhiko; Hojo, Rieko; Yanagiba, Yukie; Suda, Megumi; Hasegawa, Tatsuya; Miyagawa, Munéyuki; Wang, Rui-Sheng

doi:10.1016/j.mrgentox.2016.03.007

Cited by 28 publications

(24 citation statements)

References 27 publications

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“…We recently examined the genotoxicity of TiNPs using male gpt Delta C57BL/6J mice by intravenous injection of TiNPs, once a week for 4 consecutive weeks, and reported that TiNPs did not exhibit genotoxicity in the liver and bone marrow under the experimental conditions used (Suzuki et al, 2016). In the present study, however, we confirmed the testicular toxicity induced by TiNPs (Miura et al, 2014).…”

Section: Introductionsupporting

confidence: 67%

High sensitivity of testicular function to titanium nanoparticles

et al. 2017

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-Titanium dioxide nanoparticles (TiNPs) present toxicity in organs such as the liver, lung, and intestine. The testis has also been reported as a target organ of TiNPs. We recently reported that TiNPs had no genotoxic effect in the liver and bone marrow, while showing clear testicular dysfunction. In this paper, therefore, we systematically compared the sensitivity of hepatic function using biochemical markers and testicular function against TiNPs. Male C57BL/6J mice were injected intravenously with TiNPs (Aeroxide-P25, at doses of 0.1, 1, 2, and 10 mg/kg body weight) once per week for 4 consecutive weeks. Mice were sacrificed three days after the last injection. Body weights, liver weights, and testicular-related organ weights were not found to be changed by TiNP treatment. Moreover, TiNPs caused no hepatic damage, as evaluated by alanine aminotransferase and aspartate aminotransferase indexes. The testicular function, however, was clearly impaired by TiNP treatment; reduction in two sperm motion parameters (motile percent and progressive percent) and sperm numbers in cauda epididymides was seen. We observed Ti accumulation in the liver but not in the testis, as well as no change in plasma levels of sex hormones related to spermatogenesis. Our findings indicate that the testis is highly sensitive to TiNPs, as compared to the liver. We believe that, when considering the biological effects of TiNPs, testicular function (especially motility ability) may be a sensitive indicator.

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Section: Introductionsupporting

confidence: 67%

High sensitivity of testicular function to titanium nanoparticles

et al. 2017

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“…In our study, it is noteworthy that no DNA damage, either as DNA strand breaks or oxidative DNA damage, was detected in PP despite the nuclear translocation of Ti elements after 7 days of oral treatment, hence demonstrating the absence of genotoxicity in vivo at low doses. Numerous studies have evaluated the genotoxicity of TiO 2 7, mainly following pulmonary, dermal or intravenous exposure, and discrepancies exist regarding the potential for genotoxicity for TiO 2 -NPs in vivo 73334. Importantly, TiO 2 -NPs have been recently reported to be non-genotoxic in the peripheral blood and the liver in mice exposed intravenously to 2, 5 or 50 mg/kg of BW per week for 4 consecutive weeks, as shown using various sensitive methods, including alkaline comet assays such as those used herein34.…”

Section: Discussionmentioning

confidence: 99%

Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon

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Boutet-Robinet

Cartier

et al. 2017

Sci Rep

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Food-grade titanium dioxide (TiO2) containing a nanoscale particle fraction (TiO2-NPs) is approved as a white pigment (E171 in Europe) in common foodstuffs, including confectionary. There are growing concerns that daily oral TiO2-NP intake is associated with an increased risk of chronic intestinal inflammation and carcinogenesis. In rats orally exposed for one week to E171 at human relevant levels, titanium was detected in the immune cells of Peyer’s patches (PP) as observed with the TiO2-NP model NM-105. Dendritic cell frequency increased in PP regardless of the TiO2 treatment, while regulatory T cells involved in dampening inflammatory responses decreased with E171 only, an effect still observed after 100 days of treatment. In all TiO2-treated rats, stimulation of immune cells isolated from PP showed a decrease in Thelper (Th)-1 IFN-γ secretion, while splenic Th1/Th17 inflammatory responses sharply increased. E171 or NM-105 for one week did not initiate intestinal inflammation, while a 100-day E171 treatment promoted colon microinflammation and initiated preneoplastic lesions while also fostering the growth of aberrant crypt foci in a chemically induced carcinogenesis model. These data should be considered for risk assessments of the susceptibility to Th17-driven autoimmune diseases and to colorectal cancer in humans exposed to TiO2 from dietary sources.

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“…The TiO 2 -P25 suspension was prepared as previously described [17]. Eight-week-old male gpt delta mice were randomly divided into four groups, with 6 mice per group.…”

Section: Preparation Of the Tio 2 Np Suspension And Its Administratiomentioning

confidence: 99%

“…Liver samples taken at day 90 after the final injection of TiO 2 -P25 were analyzed using a JEM-2100F transmission electron microscope (JEOL, Tokyo, Japan) as previously described [17].…”

Section: Observation Of Hepatocyte Ultrastructure By Temmentioning

confidence: 99%

“…Several studies in mice and rats have reported conflicting results of various genotoxic endpoint analyses [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Recently, we reported that TiO 2 NPs have no genotoxic effects in the liver and erythrocytes when intravenously injected into gpt delta mice [17], but there are still reports about their positive effect [18,19]. Thus, the genotoxicity of TiO 2 NPs remains unclear [20,21].…”

Section: Introductionmentioning

confidence: 99%

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Genotoxicity assessment of titanium dioxide nanoparticle accumulation of 90 days in the liver of gpt delta transgenic mice

et al. 2020

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Backgound: A variety of in vivo and in vitro studies to assess the genotoxicity of titanium dioxide nanoparticles (TiO 2 NPs) have been reported, but the results are inconsistent. Recently, we reported that TiO 2 NPs exhibit no genotoxic effects in the liver and erythrocytes during a relatively brief period following intravenous injection into mice. However, there is no information about long-term genotoxicity due to TiO 2 NP accumulation in tissues. In this study, we investigated the long-term mutagenic effects of TiO 2 NPs and the localization of residual TiO 2 NPs in mouse liver after multiple intravenous injections.Results: Male gpt delta C57BL/6 J mice were administered with various doses of TiO 2 NPs weekly for 4 consecutive weeks. The long-term mutagenic effects on the liver were analyzed using gpt and Spi − mutation assays 90 days after the final injection. We also quantified the amount of titanium in the liver using inductively coupled plasma mass spectrometry and observed the localization of TiO 2 NPs in the liver using transmission electron microscopy. Although TiO 2 NPs were found in the liver cells, the gpt and Spi − mutation frequencies in the liver were not significantly increased by the TiO 2 NP administration. Conclusions:These results clearly show that TiO 2 NPs have no mutagenic effects on the liver, even though the particles remain in the liver long-term.

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Genotoxicity assessment of intravenously injected titanium dioxide nanoparticles in gpt delta transgenic mice

Cited by 28 publications

References 27 publications

High sensitivity of testicular function to titanium nanoparticles

High sensitivity of testicular function to titanium nanoparticles

Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon

Genotoxicity assessment of titanium dioxide nanoparticle accumulation of 90 days in the liver of gpt delta transgenic mice

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