Abstract

Background:

The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals.

Objectives:

We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm.

Methods:

We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45–74 years of age who participated in the Strong Heart Study in 1989–1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and in silico protein–protein interaction networks to explore the biological relevance of the findings.

Results:

At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In in silico protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smoking-DMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm.

Conclusions:

Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. https://doi.org/10.1289/EHP6345

中文翻译：

---

强心研究中成年人的镉、吸烟和人类血液 DNA 甲基化谱。

 抽象的

 背景：

烟草中个别环境毒物的表观遗传效应在很大程度上仍未得到探索。镉 (Cd) 与吸烟相关的健康影响有关，与其他金属相比，其在烟草烟雾中的浓度较高。

 目标：

我们研究了镉和吸烟暴露与人类血液 DNA 甲基化 (DNAm) 谱的关联。我们还评估了研究结果对相关甲基化途径的影响以及吸烟导致的镉暴露的潜在贡献，以解释吸烟与位点特异性 DNAm 之间的关联。

 方法：

我们对尿液镉和自我报告的吸烟（当前和以前与从不吸烟，以及累积吸烟剂量）和使用 Illumina Infinium Human MmethylationEPIC (Illumina Inc.) 测量的 790,026 个 CpG（甲基化位点）中的血液 DNAm 进行了全表观基因组关联研究。 ）平台上有 2,325 名 45-74 岁的成年人参加了 1989-1991 年的强心脏研究。在中介分析中，我们估计了与吸烟相关的 DNAm 变化量，这些变化量可以独立归因于吸烟引起的尿液镉浓度的增加。我们还进行了富集分析和计算机模拟蛋白质-蛋白质相互作用网络，以探索研究结果的生物学相关性。

 结果：

在错误发现率 (FDR) 校正水平为 0.05 时，我们发现了 Cd 的 6 个差异甲基化位置 (DMP)；目前和以前的吸烟状况分别为 288 和 17；香烟包年为 77 年。这些 DMP 的富集分析显示分别富集了 58 个和 6 个基因本体论和京都基因和基因组百科全书基因集，包括癌症和心血管疾病的生物途径。在计算机模拟的蛋白质到蛋白质网络中，我们观察到 DNAm 通路中的关键蛋白质与 Cd-和吸烟-DMP 直接或间接相关。在对 Cd 和当前吸烟均显着的 DMP 中（注释为 PRSS23、AHRR、F2RL3、RARA 和 2q37.1），我们发现 Cd 对吸烟相关 DNAm 的贡献具有统计显着性。

 结论：

除了复制众所周知的吸烟表观遗传特征之外，我们还发现了与吸烟相关的新型 DMP。此外，与吸烟相关的镉暴露增加与 DNAm 差异相关。我们的综合分析支持镉与吸烟相关健康影响之间的生物学联系，包括镉通过表观遗传变化部分导致吸烟毒性的可能性。 https://doi.org/10.1289/EHP6345