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Crystalline silica particles cause rapid NLRP3-dependent mitochondrial depolarization and DNA damage in airway epithelial cells.
Particle and Fibre Toxicology ( IF 10 ) Pub Date : 2020-08-10 , DOI: 10.1186/s12989-020-00370-2
Rongrong Wu 1 , Johan Högberg 1 , Mikael Adner 1 , Patricia Ramos-Ramírez 1 , Ulla Stenius 1 , Huiyuan Zheng 1
Affiliation  

Respirable crystalline silica causes lung carcinomas and many thousand future cancer cases are expected in e.g. Europe. Critical questions are how silica causes genotoxicity in the respiratory epithelium and if new cases can be avoided by lowered permissible exposure levels. In this study we investigate early DNA damaging effects of low doses of silica particles in respiratory epithelial cells in vitro and in vivo in an effort to understand low-dose carcinogenic effects of silica particles. We find DNA damage accumulation already after 5–10 min exposure to low doses (5 μg/cm2) of silica particles (Min-U-Sil 5) in vitro. DNA damage was documented as increased levels of γH2AX, pCHK2, by Comet assay, AIM2 induction, and by increased DNA repair (non-homologous end joining) signaling. The DNA damage response (DDR) was not related to increased ROS levels, but to a NLRP3-dependent mitochondrial depolarization. Particles in contact with the plasma membrane elicited a Ser198 phosphorylation of NLRP3, co-localization of NLRP3 to mitochondria and depolarization. FCCP, a mitochondrial uncoupler, as well as overexpressed NLRP3 mimicked the silica-induced depolarization and the DNA damage response. A single inhalation of 25 μg silica particles gave a similar rapid DDR in mouse lung. Biomarkers (CC10 and GPRC5A) indicated an involvement of respiratory epithelial cells. Our findings demonstrate a novel mode of action (MOA) for silica-induced DNA damage and mutagenic double strand breaks in airway epithelial cells. This MOA seems independent of particle uptake and of an involvement of macrophages. Our study might help defining models for estimating exposure levels without DNA damaging effects.

中文翻译:

结晶二氧化硅颗粒导致气道上皮细胞中快速依赖NLRP3的线粒体去极化和DNA损伤。

可吸入的结晶二氧化硅会引起肺癌,预计在欧洲等成千上万的未来癌症病例。关键问题是二氧化硅如何在呼吸道上皮中引起遗传毒性,以及是否可以通过降低允许的暴露水平避免新的病例。在这项研究中,我们研究了低剂量的二氧化硅颗粒在体外和体内对呼吸道上皮细胞的早期DNA破坏作用,旨在了解二氧化硅颗粒的低剂量致癌作用。我们发现在体外暴露于低剂量(5μg/ cm2)的二氧化硅颗粒(Min-U-Sil 5)5-10分钟后,DNA损伤积累已经开始。通过彗星试验,AIM2诱导和通过增加的DNA修复(非同源末端连接)信号传导,DNA损伤被记录为γH2AX,pCHK2的水平升高。DNA损伤反应(DDR)与ROS水平升高无关,而与NLRP3依赖的线粒体去极化有关。与质膜接触的颗粒引起NLRP3的Ser198磷酸化,NLRP3到线粒体的共定位和去极化。线粒体解偶联剂FCCP以及过表达的NLRP3模仿了二氧化硅诱导的去极化和DNA损伤反应。一次吸入25μg二氧化硅颗粒会在小鼠肺部产生类似的快速DDR。生物标志物(CC10和GPRC5A)表明呼吸道上皮细胞受累。我们的发现证明了二氧化硅引起的DNA损伤和气道上皮细胞诱变性双链断裂的新型作用模式(MOA)。该MOA似乎独立于颗粒摄取和巨噬细胞的参与。
更新日期:2020-08-10
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