Centers for Disease Control and Prevention, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA.
Sci Rep. 2019 Jan 24;9(1):471. doi: 10.1038/s41598-018-36712-6.
Occupational exposure to silica has been observed to cause pulmonary fibrosis and lung cancer through complex mechanisms. Telomeres, the nucleoprotein structures with repetitive (TTAGGG) sequences at the end of chromosomes, are a molecular "clock of life", and alterations are associated with chronic disease. The shelterin complex (POT1, TRF1, TRF2, Tin2, Rap1, and POT1 and TPP1) plays an important role in maintaining telomere length and integrity, and any alteration in telomeres may activate DNA damage response (DDR) machinery resulting in telomere attrition. The goal of this study was to assess the effect of silica exposure on the regulation of the shelterin complex in an animal model. Male Fisher 344 rats were exposed by inhalation to Min-U-Sil 5 silica for 3, 6, or 12 wk at a concentration of 15 mg/m for 6 hr/d for 5 consecutive d/wk. Expression of shelterin complex genes was assessed in the lungs at 16 hr after the end of each exposure. Also, the relationship between increased DNA damage protein (γH2AX) and expression of silica-induced fibrotic marker, αSMA, was evaluated. Our findings reveal new information about the dysregulation of shelterin complex after silica inhalation in rats, and how this pathway may lead to the initiation of silica-induced pulmonary fibrosis.
职业性暴露于二氧化硅被观察到通过复杂的机制引起肺纤维化和肺癌。端粒是染色体末端具有重复（TTAGGG）序列的核蛋白结构，是生命的分子“时钟”，其改变与慢性疾病有关。 shelterin 复合物（POT1、TRF1、TRF2、Tin2、Rap1 以及 POT1 和 TPP1）在维持端粒长度和完整性方面发挥着重要作用，端粒的任何改变都可能激活 DNA 损伤反应（DDR）机制，导致端粒磨损。本研究的目的是评估二氧化硅暴露对动物模型中 shelterin 复合物调节的影响。雄性 Fisher 344 大鼠通过吸入暴露于 Min-U-Sil 5 二氧化硅中，浓度为 15mg/m，每天暴露 6 小时，每周连续 5 天，持续 3、6 或 12 周。在每次暴露结束后 16 小时评估肺中 shelterin 复合物基因的表达。还评估了 DNA 损伤蛋白（γH2AX）的增加与二氧化硅诱导的纤维化标志物 αSMA 的表达之间的关系。我们的研究结果揭示了二氧化硅吸入后大鼠 shelterin 复合物失调的新信息，以及该途径如何引发二氧化硅诱导的肺纤维化的发生。
