Cobalt nanoparticles induce lung injury, DNA damage and mutations in mice.
Cobalt nanoparticles induce lung injury, DNA damage and mutations in mice.
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DOI：
10.1186/s12989-017-0219-z
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发表时间：
2017-09-18
影响因子：
10
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Wan R;Mo Y;Zhang Z;Jiang M;Tang S;Zhang Q
我们和其他研究小组已经证明，暴露于钴纳米颗粒（Nano-Co）会引起氧化应激和炎症，这与遗传毒性和致癌作用密切相关。然而，很少有研究报告纳米钴诱导的体内遗传毒性作用。在这里，我们提出，纳米钴可能具有高的遗传毒性作用，由于它们的小尺寸和高表面积，具有高的能力，引起氧化应激和炎症。 使用gpt δ转基因小鼠作为我们的体内研究模型。分别于染毒后第1、3、7、28天行支气管肺泡灌洗（BAL），测定BALF中中性粒细胞数、CXCL 1/KC水平、LDH活性和总蛋白浓度。取小鼠肺组织行H&E染色，Ki-67、PCNA和γ-H2 AX免疫组化染色。8-通过OxiSelect™氧化性DNA损伤ELISA试剂盒测定小鼠肺的基因组DNA中的OHdG水平，并且还通过6-TG选择、菌落PCR和DNA测序在Nano-Co暴露后四个月在小鼠肺中测定gpt基因中的突变频率和突变谱。小鼠暴露于Nano-Co（50 μg/只）导致广泛的急性肺部炎症和肺损伤，其表现为BALF中中性粒细胞数量、CXCL 1/KC水平、LDH活性和总蛋白浓度增加，以及肺泡腔和间质组织中大量中性粒细胞和巨噬细胞浸润。在Nano-Co暴露后第7天，在小鼠肺中的细支气管上皮细胞和增生的II型肺细胞中也观察到细胞增殖标记物Ki-67和PCNA以及DNA损伤标记物γ-H2 AX的免疫染色增加。暴露后4个月，观察到广泛的间质纤维化和间质细胞增殖，炎性细胞浸润肺泡隔。此外，纳米钴引起小鼠肺组织基因组DNA中8-OHdG水平升高。与对照相比，Nano-Co还诱导了更高的突变频率，并且最常见的突变是G：C至T：A颠换，这可以通过Nano-Co诱导的8-OHdG形成增加来解释。我们的研究表明，暴露于纳米钴引起氧化应激，肺部炎症和损伤，细胞增殖，这进一步导致DNA损伤和DNA突变。这些发现对于理解纳米颗粒暴露的潜在健康影响具有重要意义。
We and other groups have demonstrated that exposure to cobalt nanoparticles (Nano-Co) caused oxidative stress and inflammation, which have been shown to be strongly associated with genotoxic and carcinogenic effects. However, few studies have reported Nano-Co-induced genotoxic effects in vivo. Here, we propose that Nano-Co may have high genotoxic effects due to their small size and high surface area, which have high capacity for causing oxidative stress and inflammation. gpt delta transgenic mice were used as our in vivo study model. They were intratracheally instilled with 50 μg per mouse of Nano-Co. At day 1, 3, 7 and 28 after exposure, bronchoalveolar lavage (BAL) was performed and the number of neutrophils, CXCL1/KC level, LDH activity and concentration of total protein in the BAL fluid (BALF) were determined. Mouse lung tissues were collected for H&E staining, and Ki-67, PCNA and γ-H2AX immunohistochemical staining. 8-OHdG level in the genomic DNA of mouse lungs was determined by an OxiSelect™ Oxidative DNA Damage ELISA Kit, and mutant frequency and mutation spectrum in the gpt gene were also determined in mouse lungs at four months after Nano-Co exposure by 6-TG selection, colony PCR, and DNA sequencing. Exposure of mice to Nano-Co (50 μg per mouse) resulted in extensive acute lung inflammation and lung injury which were reflected by increased number of neutrophils, CXCL1/KC level, LDH activity and concentration of total protein in the BALF, and infiltration of large amount of neutrophils and macrophages in the alveolar space and interstitial tissues. Increased immunostaining of cell proliferation markers, Ki-67 and PCNA, and the DNA damage marker, γ-H2AX, was also observed in bronchiolar epithelial cells and hyperplastic type II pneumocytes in mouse lungs at day 7 after Nano-Co exposure. At four months after exposure, extensive interstitial fibrosis and proliferation of interstitial cells with inflammatory cells infiltrating the alveolar septa were observed. Moreover, Nano-Co caused increased level of 8-OHdG in genomic DNA of mouse lung tissues. Nano-Co also induced a much higher mutant frequency as compared to controls, and the most common mutation was G:C to T:A transversion, which may be explained by Nano-Co-induced increased formation of 8-OHdG. Our study demonstrated that exposure to Nano-Co caused oxidative stress, lung inflammation and injury, and cell proliferation, which further resulted in DNA damage and DNA mutation. These findings have important implications for understanding the potential health effects of nanoparticle exposure.
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影响因子：
16
作者：
Choe KN;Moldovan GL
通讯作者：
Moldovan GL
DOI：
10.1016/j.mrgentox.2009.06.009
发表时间：
2009-08
影响因子：
1.9
作者：
Albino, Anthony P.;Jorgensen, Ellen D.;Rainey, Patrick;Gillman, Gene;Clark, T. Jeffrey;Gietl, Diana;Zhao, Hong;Traganos, Frank;Darzynkiewicz, Zbigniew
通讯作者：
Darzynkiewicz, Zbigniew
影响因子：
10.4
作者：
DONALDSON, K;BROWN, GM;LI, XY
通讯作者：
LI, XY
影响因子：
9.3
作者：
Hwang, Do Won;Lee, Dong Soo;Kim, Soonhag
通讯作者：
Kim, Soonhag
影响因子：
3.8
作者：
Driscoll, KE;Costa, DL;Schlesinger, RB
通讯作者：
Schlesinger, RB