Lung recovery from DNA damage induced by graphene oxide is dependent on size, dose and inflammation profile.
Lung recovery from DNA damage induced by graphene oxide is dependent on size, dose and inflammation profile.
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DOI：
10.1186/s12989-022-00502-w
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发表时间：
2022-09-21
影响因子：
10
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中科院分区：
文献类型：
--
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任何新材料安全性评估的一个关键方面是对它们在体内的遗传毒性的评估。氧化石墨烯(GO)已被研究用于许多有前途的应用，但人们对其安全性仍有担忧，特别是在吸入后。在这里，我们测试了GO横向尺寸，比较微米(LGO)和纳米(USGO)GO片断，是否在小鼠肺DNA双链断裂的形成中发挥作用。我们使用空间分辨率和差异细胞类型分析来测量在单次或多次暴露后，上皮细胞和免疫细胞中的DNA损伤。在两种情况下，GO诱导的DNA损伤都是大小和剂量相关的。单次高剂量染毒后，USGO和LGO均可引起肺实质明显的DNA损伤，但仅在急性期(p <； 0.05；p <； 0.01)。随后，两个GO在第7天和第28天的肺快速恢复。在评估GO反复暴露后的慢性影响时，只有高剂量的LGO才能引起肺泡上皮细胞的长期DNA损伤(84天，p <； 0.05)。无论大小，低剂量的GO在重复暴露后没有引起任何明显的DNA损伤。对我们的重复暴露数据进行多参数相关分析表明，短暂或持续的炎症和氧化应激与恢复或持续的DNA损伤有关。对于USGO，从DNA损伤中恢复与从急性炎症中有效恢复相关(即显著分泌SAA3，p <； 0.001；中性粒细胞浸润，p <； 0.01)。相比之下，LGO在肺中的持续存在与多核巨噬细胞的长期存在(长达84天，p <； 0.05)、潜在的炎症(IL-1α分泌长达28天，p <； 0.05)以及84天的持续DNA损伤有关。总体而言，这些结果突出了所使用的暴露情景的重要性。我们发现，由于持续的肺部炎症，LGO在重复暴露后比一次暴露有更大的遗传毒性。这些发现在人类健康风险评估的背景下非常重要，并有助于建立在工作场所安全使用石墨烯材料的建议。网上版载有补充材料，可在10.1186/s12989-022-00502-w查阅。
A key aspect of any new material safety assessment is the evaluation of their in vivo genotoxicity. Graphene oxide (GO) has been studied for many promising applications, but there are remaining concerns about its safety profile, especially after inhalation. Herein we tested whether GO lateral dimension, comparing micrometric (LGO) and nanometric (USGO) GO sheets, has a role in the formation of DNA double strand breaks in mouse lungs. We used spatial resolution and differential cell type analysis to measure DNA damages in both epithelial and immune cells, after either single or repeated exposure. GO induced DNA damages were size and dose dependent, in both exposure scenario. After single exposure to a high dose, both USGO and LGO induced significant DNA damage in the lung parenchyma, but only during the acute phase response (p < 0.05 for USGO; p < 0.01 for LGO). This was followed by a fast lung recovery at day 7 and 28 for both GOs. When evaluating the chronic impact of GO after repeated exposure, only a high dose of LGO induced long-term DNA damages in lung alveolar epithelia (at 84 days, p < 0.05). Regardless of size, low dose GO did not induce any significant DNA damage after repeated exposure. A multiparametric correlation analysis of our repeated exposure data revealed that transient or persistent inflammation and oxidative stress were associated to either recovery or persistent DNA damages. For USGO, recovery from DNA damage was correlated to efficient recovery from acute inflammation (i.e., significant secretion of SAA3, p < 0.001; infiltration of neutrophils, p < 0.01). In contrast, the persistence of LGO in lungs was associated to a long-lasting presence of multinucleated macrophages (up to 84 days, p < 0.05), an underlying inflammation (IL-1α secretion up to 28 days, p < 0.05) and the presence of persistent DNA damages at 84 days. Overall these results highlight the importance of the exposure scenario used. We showed that LGO was more genotoxic after repeated exposure than single exposure due to persistent lung inflammation. These findings are important in the context of human health risk assessment and toward establishing recommendations for a safe use of graphene based materials in the workplace. The online version contains supplementary material available at 10.1186/s12989-022-00502-w.
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影响因子：
5
作者：
Kim YH;Jo MS;Kim JK;Shin JH;Baek JE;Park HS;An HJ;Lee JS;Kim BW;Kim HP;Ahn KH;Jeon K;Oh SM;Lee JH;Workman T;Faustman EM;Yu IJ
通讯作者：
Yu IJ
影响因子：
2.8
作者：
Bengtson, Stefan;Kling, Kirsten;Madsen, Anne Mette;Noergaard, Asger W.;Jacobsen, Nicklas Raun;Clausen, Per Axel;Alonso, Beatriz;Pesquera, Amaia;Zurutuza, Amaia;Ramos, Raphael;Okuno, Hanako;Dijon, Jean;Wallin, Hakan;Vogel, Ulla
通讯作者：
Vogel, Ulla
影响因子：
5.9
作者：
de Sousa, Marcelo;Visani de Luna, Luis Augusto;Alves, Oswaldo Luiz
通讯作者：
Alves, Oswaldo Luiz
影响因子：
3.7
作者：
Azqueta A;Dusinska M
通讯作者：
Dusinska M
影响因子：
10.2
作者：
Burgum MJ;Clift MJD;Evans SJ;Hondow N;Tarat A;Jenkins GJ;Doak SH
通讯作者：
Doak SH