Abstract
Nanomaterials are useful for their characteristic properties and are commonly used in various fields. Nanosized-magnetite (MGT) is widely utilized in medicinal and industrial fields, whereas their toxicological properties are not well documented. A safety assessment is thus urgently required for MGT, and genotoxicity is one of the most serious concerns. In the present study, we examined genotoxic effects of MGT using mice and revealed that DNA damage analyzed by a comet assay in the lungs of imprinting control region (ICR) mice intratracheally instilled with a single dose of 0.05 or 0.2 mg/animal of MGT was approximately two- to three-fold higher than that of vehicle-control animals. Furthermore, in gpt delta transgenic mice, gpt mutant frequency (MF) in the lungs of the group exposed to four consecutive doses of 0.2 mg MGT was significantly higher than in the control group. Mutation spectrum analysis showed that base substitutions were predominantly induced by MGT, among which G:C to A:T transition and G:C to T:A transversion were the most significant. To clarify the mechanism of mutation caused by MGT, we analyzed the formation of DNA adducts in the lungs of mice exposed to MGT. DNA was extracted from lungs of mice 3, 24, 72 and 168 h after intratracheal instillation of 0.2 mg/body of MGT, and digested enzymatically. 8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and lipid peroxide-related DNA adducts were quantified by stable isotope dilution liquid chromatography-mass spectrometry (LC-MS/MS). Compared with vehicle control, these DNA adduct levels were significantly increased in the MGT-treated mice. In addition to oxidative stress- and inflammation related-DNA adduct formations, inflammatory cell infiltration and focal granulomatous formations were also observed in the lungs of MGT-treated mice. Based on these findings, it is suggested that inflammatory responses are probably involved in the genotoxicity induced by MGT in the lungs of mice.
Highlights
Magnetite nanoparticles (MGT), a form of iron oxide (Fe3O4) nanoparticles have been widely exploited since the simplicification of synthesis, mainly because of their unique magnetic properties.Applications include use in printing inks and magnetic recording media [1]
In order to characterize and ascertain the properties of MGT used in the present study, the particle appearance, dispersed diameter and zeta potential were determined
In addition to the in vivo genotoxicity, we showed MGT to be mutagenic in the lungs of mice, using gpt delta transgenic mice
Summary
Magnetite nanoparticles (MGT), a form of iron oxide (Fe3O4) nanoparticles have been widely exploited since the simplicification of synthesis, mainly because of their unique magnetic properties. Exposure of cultured mammalian cells to MGT induces cytotoxicity and genotoxicity [10,11,12], and an inflammatory response and the generation of reactive oxygen species (ROS) [8,11]. Expression of inflammation related genes and formation of microgranulomas are two of the indicators for a chronic inflammatory response [19] Based on this information, it is suggested that MGTs might increase the inflammatory response in both cultured mammalian cells and animals, and induce toxicity. We evaluated the in vivo genotoxicity, including DNA damage and mutagenicity, of MGT in the lungs of both wild-type and transgenic mice to obtain fundamental data to elucidate the health risk of MGT. Aiming at examining the mechanisms involved in genotoxicity induced by MGT, oxidative and lipid peroxide-related DNA adduct analysis was performed.
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