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Hypomethylation of LINE-1 repeat elements and global loss of DNA hydroxymethylation in vapers and smokers.

Vapers 和吸烟者中 LINE-1 重复元件的低甲基化和 DNA 羟甲基化的整体丢失。

  • 影响因子:4.73
  • DOI:10.1080/15592294.2020.1724401
  • 作者列表:"Caliri AW","Caceres A","Tommasi S","Besaratinia A
  • 发表时间:2020-01-29

:The outbreak of vaping-related severe lung injuries and deaths and the epidemic of teen vaping in the United States underscores the urgent need for determining the biological consequences of electronic cigarette (e-cig) use. We have investigated the association between vaping and epigenetic changes by quantifying DNA methylation levels in Long Interspersed Nucleotide Element 1 (LINE-1) and global DNA hydroxymethylation (5-hmC) levels and measuring the expression level of enzymes catalyzing the respective processes in peripheral blood of exclusive e-cig users, smokers, and controls, matched for age, gender, and race (n = 15, each group). Both vapers and smokers showed significant loss of methylation in LINE-1 repeat elements in comparison to controls (P = 0.00854 and P = 0.03078, respectively). Similarly, vapers and smokers had significant reductions in 5-hmC levels relative to controls (P = 0.04884 and P = 0.0035, respectively). Neither the LINE-1 methylation levels nor the global 5-hmC levels were different between vapers and smokers. There was a direct correlation between methylation levels in the LINE-1 elements and global 5-hmC levels in the study subjects (r = 0.31696, P = 0.03389). Inverse and statistically-significant correlations were found between both the LINE-1 methylation levels and the global 5-hmC levels and various vaping/smoking metrics in the study subjects. There were modest but not statistically-significant changes in transcription of DNA methyltransferases and ten-eleven translocation enzymes in both vapers and smokers relative to controls. Our findings support follow up genome-wide investigations into the epigenetic effects of vaping, which may help clarify the health risks or potential benefits of e-cig use vs. smoking.


: 美国 vaping 相关严重肺损伤和死亡的爆发以及青少年 vaping 的流行强调了确定电子烟 (e-cig) 的生物后果的迫切需要使用。我们通过定量长穿插核苷酸元件 1 (LINE-1) 和整体 DNA 羟甲基化 (5-hmC) 中的 DNA 甲基化水平,研究了 vaping 和表观遗传变化之间的关联。水平和测量独家 e-cig 使用者、吸烟者和对照者外周血中催化各自过程的酶的表达水平,年龄匹配,性别、种族 (n = 15,每组)。与对照组相比,vapers 和吸烟者在 LINE-1 重复元件中均显示出显著的甲基化丢失 (分别为 P = 0.00854 和 P = 0.03078)。同样,相对于对照组,vapers 和吸烟者的 5-hmC 水平显著降低 (分别为 P = 0.04884 和 P = 0.0035)。Vapers 和吸烟者之间的 LINE-1 甲基化水平和全球 5-hmC 水平都没有差异。在研究对象中,LINE-1 元件中的甲基化水平与整体 5-hmC 水平之间存在直接相关性 (r = 0.31696,P = 0.03389)。在研究对象中,LINE-1 甲基化水平和全球 5-hmC 水平与各种 vaping/吸烟指标之间发现了反向和统计学上显著的相关性。相对于对照组,vapers 和吸烟者的 DNA 甲基转移酶和 ten-11 转位酶的转录有适度但无统计学意义的变化。我们的研究结果支持随访全基因组研究 vaping 的表观遗传效应,这可能有助于阐明使用 e-cig 相对于吸烟的健康风险或潜在益处。



作者列表:["De Cunto G","Brancaleone V","Riemma MA","Cerqua I","Vellecco V","Spaziano G","Cavarra E","Bartalesi B","D'Agostino B","Lungarella G","Cirino G","Lucattelli M","Roviezzo F"]

METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.

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作者列表:["Bernstein DM","Toth B","Rogers RA","Kling DE","Kunzendorf P","Phillips JI","Ernst H"]

METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

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作者列表:["Zaragosi LE","Deprez M","Barbry P"]

METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.

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