Parental arsenic exposure and tissue-specific DNA methylation in Bangladeshi infants with spina bifida

An emerging hypothesis linking arsenic toxicity involves altered epigenetic mechanisms, such as DNA methylation. In this study, we examined the relationship between parents’ arsenic exposure and DNA methylation in tissues obtained from 28 infants with spina bifida from Bangladesh. We analyzed arsenic in parents’ toenails using inductively coupled plasma mass spectrometry (ICP-MS). DNA methylation was measured in infants’ dural tissue, buccal swabs, and whole blood using the Illumina Infinium MethylationEPIC BeadChip. We performed epigenome-wide association analyses (EWAS) and tested differentially methylated regions (DMRs). In EWAS, DNA methylation at cg24039697 in dural tissue was positively associated (β = 0.59, <i>p</i> = 7.6 × 10⁻⁹) with father’s toenail arsenic concentrations, adjusting for covariates. We did not identify any CpG sites related to father’s arsenic exposure in the other tissues, or any CpG sites related to mother’s arsenic exposure. Gene ontology analysis identified many biological pathways of interest, including the Wnt signaling pathways. We identified several DMRs across the tissues related to arsenic exposure that included probes mapping to genes that have previously been identified in studies of neural tube defects. This study emphasizes the potential impact of arsenic exposure in fathers, often understudied in epidemiological studies, on DNA methylation in a unique neurological tissue specific to spina bifida.

目前一项新兴假说认为，砷毒性与表观遗传调控机制的改变存在关联，例如DNA甲基化（DNA methylation）。本研究针对孟加拉国28名脊柱裂（spina bifida）患儿的离体组织，探讨了父母砷暴露与子代DNA甲基化水平之间的关联。研究采用电感耦合等离子体质谱法（inductively coupled plasma mass spectrometry, ICP-MS）检测了父母趾甲中的砷含量。本研究采用Illumina Infinium MethylationEPIC BeadChip芯片，对患儿的硬脑膜组织、口腔拭子样本及全血中的DNA甲基化水平进行了检测。本研究开展了表观全基因组关联分析（epigenome-wide association analyses, EWAS），并对差异甲基化区域（differentially methylated regions, DMRs）进行了验证。在表观全基因组关联分析中，经协变量校正后，患儿硬脑膜组织中cg24039697位点的DNA甲基化水平与父亲趾甲砷浓度呈显著正相关（β=0.59，p=7.6×10⁻⁹）。在其余两类组织中，未发现与父亲砷暴露相关的CpG位点，亦未发现与母亲砷暴露相关的CpG位点。基因本体富集分析（Gene ontology analysis）筛选出多个值得关注的生物学通路，其中包括Wnt信号通路。本研究在各类组织中筛选出多个与砷暴露相关的差异甲基化区域，这些区域的探针所靶向的基因，曾在神经管缺陷相关研究中被报道过。本研究凸显了父亲砷暴露——这一在流行病学研究中常被忽视的暴露因素——对脊柱裂特异性神经组织DNA甲基化水平的潜在影响。