Arsenic (As) is a toxic metalloid element that causes lung cancer and multiple non-malignant respiratory diseases. The toxicity of arsenic is mediated in part by epigenetic mechanisms, such as alterations in DNA methylation. While increasing studies have highlighted the potential importance of arsenic exposure to DNA methylation patterns and the subsequent risks for arsenic toxicity, there has been little focus on DNA hydroxymethylation—a negative regulation mechanism of DNA methylation. Therefore, this study aimed to investigate the relationship between genomic DNA methylation/hydroxymethylation and lung injury in arsenicosis populations. First, an increased risk of lung injury and exacerbation of lung function impairment in the arsenicosis population was confirmed. Levels of 5-methylcytosine/deoxycytidine (5 mC/dC), 5-hydroxymethylcytosine/deoxycytidine (5 hmC/dC) and 5 hmC/5 mC in genomic DNA of peripheral blood were decreased in the arsenicosis population compared to in the control. Additionally, multivariate logistic regression models showed an increased risk of chest digital radiography (DR) abnormalities when 5 hmC/dC and 5 hmC/5 mC levels were lower (OR = 3.12 and 3.96, all P < 0.001). For 3 years follow-up, regression analysis showed that a decline in 5 hmC/dC was significantly associated with the decline of lung function parameters [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and maximal mid-expiratory flow (MMEF); β = 0.167, 0.122 and 0.073, respectively; all P < 0.05]. Using the receiver operating characteristic (ROC) curve, a combination of 5 hmC/5 dC and 5 hmC/5 mC obtained the highest value for distinguishing lung injury in all subjects (AUC = 0.82, P < 0.01). In contrast, in arsenicosis subjects, 5 hmC/dC was better at distinguishing lung injury (AUC = 0.84, P < 0.01). Together, the results revealed that a decrease in genomic DNA hydroxymethylation markers was associated with lung injury in coal-burning arsenicosis populations. Genomic DNA hydroxymethylation could be a novel biomarker for identifying the risk of lung injury caused by coal-burning arsenicosis.

砷 (As) 是一种有毒的类金属元素，可导致肺癌和多种非恶性呼吸道疾病。砷的毒性部分由表观遗传机制介导，例如 DNA 甲基化的改变。虽然越来越多的研究强调了砷暴露于 DNA 甲基化模式的潜在重要性以及随后的砷毒性风险，但很少关注 DNA 羟甲基化——一种 DNA 甲基化的负调控机制。因此，本研究旨在探讨砷中毒人群基因组 DNA 甲基化/羟甲基化与肺损伤的关系。首先，证实了砷中毒人群肺损伤和肺功能损害恶化的风险增加。5-甲基胞嘧啶/脱氧胞苷的水平 (5 mC/dC)，与对照组相比，砷中毒人群外周血基因组 DNA 中的 5-羟甲基胞嘧啶/脱氧胞苷 (5 hmC/dC) 和 5 hmC/5 mC 降低。此外，多变量逻辑回归模型显示，当 5 hmC/dC 和 5 hmC/5 mC 水平较低时（OR = 3.12 和 3.96，所有P < 0.001)。对于 3 年的随访，回归分析表明，5 hmC/dC 的下降与肺功能参数的下降显着相关 [用力肺活量 (FVC)、1 秒用力呼气量 (FEV1) 和最大呼气中流量（MMEF）；β = 0.167、0.122 和 0.073，分别；所有P < 0.05]。使用受试者工作特征（ROC）曲线，5 hmC/5 dC 和 5 hmC/5 mC 的组合在所有受试者中获得了区分肺损伤的最高值（AUC = 0.82，P < 0.01）。相比之下，在砷中毒受试者中，5 hmC/dC 在区分肺损伤方面更好（AUC = 0.84，P <0.01)。总之，结果表明，基因组 DNA 羟甲基化标志物的减少与燃煤砷中毒人群的肺损伤有关。基因组 DNA 羟甲基化可能是一种新的生物标志物，用于识别由燃煤砷中毒引起的肺损伤风险。