Silica nanoparticles administered at the maximum tolerated dose induce genotoxic effects through an inflammatory reaction while gold nanoparticles do not
Silica nanoparticles administered at the maximum tolerated dose induce genotoxic effects through an inflammatory reaction while gold nanoparticles do not
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DOI：
10.1016/j.mrgentox.2012.03.012
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发表时间：
2012-06-14
影响因子：
1.9
通讯作者：
Pfuhler, Stefan
中科院分区：
文献类型：
--
作者：
Downs, Thomas R.;Crosby, Meredith E.;Pfuhler, Stefan
虽然对纳米颗粒材料（NP）的遗传毒性数据的收集和对潜在作用机制的了解正在稳步增加，但目前的标准试验是否适合适当表征潜在风险仍存在很大的不确定性。我们研究了NP在体内彗星/微核（MN）组合试验和体外MN试验中对人血的影响。我们还将其他终点纳入体内研究中，以努力描述主要机制和次要机制。无定形二氧化硅NP（15和55 nm）因其已知的反应性而被选择，而金纳米/微米颗粒（2、20和200 nm）因其宽的尺寸范围和较低的反应性而被选择。在处死前48、24和4 h连续3次静脉注射给雄性Wistar大鼠，测定肝、肺和血细胞DNA损伤和循环网织红细胞微核。金纳米/微粒在体外和体内对MN诱导是阴性的，并且在所有组织中对DNA损伤的诱导是阴性的。然而，当在其最大耐受剂量（MTD）下进行试验时，二氧化硅颗粒引起DNA损伤和微核网织红细胞的小幅但可重现的增加。在较低剂量下未观察到遗传毒性效应，体外MN试验也为阴性。我们假设二氧化硅纳米颗粒通过释放炎性细胞衍生的氧化剂引发继发性遗传毒性效应。类似于对结晶二氧化硅（石英）所述的。这种机制得到了肝脏中嗜酸性浸润、坏死和凋亡细胞增加以及MTD时血浆中炎症标志物TNF-α和IL-6诱导的支持。这些结果在二氧化硅NP和石英对照之间相当一致，从而加强了二氧化硅NP可以以类似的阈值方式起作用的论点。观察到的特征支持炎症驱动的继发性遗传毒性机制。(C)2012爱思唯尔有限公司版权所有。
While the collection of genotoxicity data and insights into potential mechanisms of action for nano-sized particulate materials (NPs) are steadily increasing, there is great uncertainty whether current standard assays are suitable to appropriately characterize potential risks. We investigated the effects of NPs in an in vivo Comet/micronucleus (MN) combination assay and in an in vitro MN assay performed with human blood. We also incorporated additional endpoints into the in vivo study in an effort to delineate primary from secondary mechanisms. Amorphous silica NPs (15 and 55 nm) were chosen for their known reactivity, while gold nano/microparticles (2, 20, and 200 nm) were selected for their wide size range and lower reactivity. DNA damage in liver, lung and blood cells and micronuclei in circulating reticulocytes were measured after 3 consecutive intravenous injections to male Wistar rats at 48, 24 and 4h before sacrifice. Gold nano/microparticles were negative for MN induction in vitro and in vivo, and for the induction of DNA damage in all tissues. Silica particles, however, caused a small but reproducible increase in DNA damage and micronucleated reticulocytes when tested at their maximum tolerated dose (MTD). No genotoxic effects were observed at lower doses, and the in vitro MN assay was also negative. We hypothesize that silica NPs initiate secondary genotoxic effects through release of inflammatory cell-derived oxidants. similar to that described for crystalline silica (quartz). Such a mechanism is supported by the occurrence of increased neutrophilic infiltration, necrosis, and apoptotic cells in the liver, and induction of inflammatory markers TNF-alpha and IL-6 in plasma at the MTDs. These results were fairly consistent between silica NPs and the quartz control, thereby strengthening the argument that silica NPs may act in a similar, thresholded manner. The observed profile is supportive of a secondary genotoxicity mechanism that is driven by inflammation. (C) 2012 Elsevier B.V. All rights reserved.