Background

Associations of arsenic (As) with the sum of 5-mC and 5-hmC levels have been reported; however, As exposure-related differences of the separated 5-mC and 5-hmC markers have rarely been studied.

Methods

In this study, we evaluated the association of arsenic exposure biomarkers and 5-mC and 5-hmC in 30 healthy men (43–55 years) from the Aragon Workers Health Study (AWHS) (Spain) and 31 healthy men (31–50 years) from the Folic Acid and Creatinine Trial (FACT) (Bangladesh). We conducted 5-mC and 5-hmC profiling using Infinium MethylationEPIC arrays, on paired standard and modified (ox-BS in AWHS and TAB in FACT) bisulfite converted blood DNA samples.

Results

The median for the sum of urine inorganic and methylated As species (ΣAs) (μg/L) was 12.5 for AWHS and 89.6 for FACT. The median of blood As (μg/L) was 8.8 for AWHS and 10.2 for FACT. At a statistical significance p-value cut-off of 0.01, the differentially methylated (DMP) and hydroxymethylated (DHP) positions were mostly located in different genomic sites. Several DMPs and DHPs were consistently found in AWHS and FACT both for urine ΣAs and blood models, being of special interest those attributed to the DIP2C gene. Three DMPs (annotated to CLEC12A) for AWHS and one DHP (annotated to NPLOC4) for FACT remained statistically significant after false discovery rate (FDR) correction. Pathways related to chronic diseases including cardiovascular, cancer and neurological were enriched.

Conclusions

While we identified common 5-hmC and 5-mC signatures in two populations exposed to varying levels of inorganic As, differences in As-related epigenetic sites across the study populations may additionally reflect low and high As-specific associations. This work contributes a deeper understanding of potential epigenetic dysregulations of As. However, further research is needed to confirm biological consequences associated with DIP2C epigenetic regulation and to investigate the role of 5-hmC and 5-mC separately in As-induced health disorders at different exposure levels.

中文翻译：

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来自孟加拉国和西班牙的两个不同人群的砷暴露和人类血液 DNA 甲基化和羟甲基化概况

背景

已经报道了砷 (As) 与 5-mC 和 5-hmC 水平之和的关联；然而，很少研究分离的 5-mC 和 5-hmC 标记与暴露相关的差异。

方法

在这项研究中，我们评估了来自阿拉贡工人健康研究 (AWHS)（西班牙）的 30 名健康男性（43-55 岁）和 31 名健康男性（31-50年）来自叶酸和肌酐试验 (FACT)（孟加拉国）。我们使用 Infinium MethylationEPIC 阵列对配对的标准和修饰（AWHS 中的 ox-BS 和 FACT 中的 TAB）亚硫酸氢盐转化的血液 DNA 样本进行了 5-mC 和 5-hmC 分析。

结果

AWHS 尿液无机砷和甲基化砷总和 (ΣAs) (μg/L) 的中位数为 12.5，FACT 为 89.6。AWHS 的血液 As (μg/L) 中位数为 8.8，FACT 为 10.2。在统计显着性 p 值截止值为 0.01 时，差异甲基化 (DMP) 和羟甲基化 (DHP) 位置主要位于不同的基因组位点。在尿样和血液模型的 AWHS 和 FACT 中始终发现了几种 DMP 和 DHP，尤其是归因于 DIP2C 基因的那些。用于 AWHS 的三个 DMP（注释为CLEC12A）和一个 DHP（注释为NPLOC4) 对于 FACT 在错误发现率 (FDR) 校正后仍然具有统计学意义。丰富了与心血管、癌症和神经系统等慢性疾病相关的通路。

结论

虽然我们在暴露于不同水平无机砷的两个人群中确定了常见的 5-hmC 和 5-mC 特征，但研究人群中与砷相关的表观遗传位点的差异可能还反映了低和高的砷特异性关联。这项工作有助于更深入地了解 As 的潜在表观遗传失调。然而，需要进一步的研究来确认与DIP2C表观遗传调控相关的生物学后果，并分别研究 5-hmC 和 5-mC 在不同暴露水平的砷诱导的健康障碍中的作用。