National Institute of Occupational Health, NO-0033 Oslo, Norway.
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, NO-0316 Oslo, Norway.
Int J Mol Sci. 2021 May 19;22(10):5349. doi: 10.3390/ijms22105349.
There is little in vitro data available on long-term effects of TiO exposure. Such data are important for improving the understanding of underlying mechanisms of adverse health effects of TiO. Here, we exposed pulmonary epithelial cells to two doses (0.96 and 1.92 µg/cm) of TiO for 13 weeks and effects on cell cycle and cell death mechanisms, i.e., apoptosis and autophagy were determined after 4, 8 and 13 weeks of exposure. Changes in telomere length, cellular protein levels and lipid classes were also analyzed at 13 weeks of exposure. We observed that the TiO exposure increased the fraction of cells in G1-phase and reduced the fraction of cells in G2-phase, which was accompanied by an increase in the fraction of late apoptotic/necrotic cells. This corresponded with an induced expression of key apoptotic proteins i.e., BAD and BAX, and an accumulation of several lipid classes involved in cellular stress and apoptosis. These findings were further supported by quantitative proteome profiling data showing an increase in proteins involved in cell stress and genomic maintenance pathways following TiO exposure. Altogether, we suggest that cell stress response and cell death pathways may be important molecular events in long-term health effects of TiO.
关于 TiO 暴露的长期影响，目前仅有少量的体外数据。这些数据对于加深理解 TiO 对健康产生不良影响的潜在机制非常重要。在此，我们将肺上皮细胞暴露于两种剂量（0.96 和 1.92μg/cm）的 TiO 中 13 周，并在暴露 4、8 和 13 周后测定细胞周期和细胞死亡机制（即凋亡和自噬）的变化。在暴露 13 周时，还分析了端粒长度、细胞蛋白水平和脂质类别的变化。我们观察到 TiO 暴露增加了 G1 期细胞的比例，降低了 G2 期细胞的比例，同时晚期凋亡/坏死细胞的比例增加。这伴随着关键凋亡蛋白 BAD 和 BAX 的表达诱导，以及几种涉及细胞应激和凋亡的脂质类别的积累。这些发现得到定量蛋白质组谱数据的进一步支持，该数据显示 TiO 暴露后与细胞应激和基因组维护途径相关的蛋白增加。总的来说，我们认为细胞应激反应和细胞死亡途径可能是 TiO 对长期健康影响的重要分子事件。
