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Magnetite Nanoparticles Induce Genotoxicity in the Lungs of Mice via Inflammatory Response

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Microscopic findings in the lungs of gpt delta mice intratracheally instilled with MGT.Representative histopathology of the lungs of: (a) a control mouse given vehicle (once a week for 4 weeks; killed at 22 weeks of age); and (b,c) a mouse given multiple doses of 0.2 mg MGT (killed at 22 weeks of age). The brown-colored material is MGT.
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nanomaterials-04-00175-f004: Microscopic findings in the lungs of gpt delta mice intratracheally instilled with MGT.Representative histopathology of the lungs of: (a) a control mouse given vehicle (once a week for 4 weeks; killed at 22 weeks of age); and (b,c) a mouse given multiple doses of 0.2 mg MGT (killed at 22 weeks of age). The brown-colored material is MGT.

Mentions: There were no obvious histopathological changes in the lungs of vehicle-treated control mice (Figure 4a). In mice given multiple MGT administrations (0.2 mg weekly for 4 weeks), macrophage phagocytising MGT were recruited diffusely in the alveolar lumina and occasionally also in the alveolar interstitium (Figure 4b,c). Inflammatory cell infiltration (mainly lymphocytes) occurred in the alveolar interstitium and around vascular vessels or bronchioles, with granulations being scattered (Figure 4b,c). In addition, swelling of Type II alveolar epithelial cells and hyperplasia of bronchial epithelial cells were also observed (Figure 4b,c). Similar findings, but with a smaller degree of particle accumulation and granuloma formation, were observed in the lungs of mice that received a low-dose MGT instillation (data not shown).


Magnetite Nanoparticles Induce Genotoxicity in the Lungs of Mice via Inflammatory Response
Microscopic findings in the lungs of gpt delta mice intratracheally instilled with MGT.Representative histopathology of the lungs of: (a) a control mouse given vehicle (once a week for 4 weeks; killed at 22 weeks of age); and (b,c) a mouse given multiple doses of 0.2 mg MGT (killed at 22 weeks of age). The brown-colored material is MGT.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5304606&req=5

nanomaterials-04-00175-f004: Microscopic findings in the lungs of gpt delta mice intratracheally instilled with MGT.Representative histopathology of the lungs of: (a) a control mouse given vehicle (once a week for 4 weeks; killed at 22 weeks of age); and (b,c) a mouse given multiple doses of 0.2 mg MGT (killed at 22 weeks of age). The brown-colored material is MGT.
Mentions: There were no obvious histopathological changes in the lungs of vehicle-treated control mice (Figure 4a). In mice given multiple MGT administrations (0.2 mg weekly for 4 weeks), macrophage phagocytising MGT were recruited diffusely in the alveolar lumina and occasionally also in the alveolar interstitium (Figure 4b,c). Inflammatory cell infiltration (mainly lymphocytes) occurred in the alveolar interstitium and around vascular vessels or bronchioles, with granulations being scattered (Figure 4b,c). In addition, swelling of Type II alveolar epithelial cells and hyperplasia of bronchial epithelial cells were also observed (Figure 4b,c). Similar findings, but with a smaller degree of particle accumulation and granuloma formation, were observed in the lungs of mice that received a low-dose MGT instillation (data not shown).

View Article: PubMed Central - PubMed

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.

No MeSH data available.