Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
Environ Res. 2023 Jan 15;217:114797. doi: 10.1016/j.envres.2022.114797. Epub 2022 Nov 12.
Environmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window.
This study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort.
We repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data.
We included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease.
This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.
环境金属暴露与多种有害健康终点相关。DNA 甲基化（DNAm）可能为这些关系背后的机制提供深入了解。趾甲金属是非侵入性生物标志物，反映了中期时间暴露窗口。
本研究在纵向队列 Normative Aging Study 中检查了老年男性白细胞 DNAm 和趾甲砷（As）、镉（Cd）、铅（Pb）、锰（Mn）和汞（Hg）的变化。
我们反复采集血液和趾甲样本。我们使用 Illumina HumanMethylation450 K BeadChip 测量白细胞中的 DNAm。我们首先进行中位数回归，以评估每个个体趾甲金属对三个水平上 DNAm 的影响：单个胞嘧啶-磷酸-鸟嘌呤（CpG）位点、区域和途径。然后，我们应用贝叶斯核机器回归（BKMR）评估金属混合物对 DNAm 的联合和个体影响。使用基于独立自由度方法的多重检验校正识别显著的 CpG，该方法考虑了 DNAm 数据中使用解释数据 >95%变化的主要成分的有效自由度。
我们纳入了 1999 年至 2013 年间的 564 名受试者（754 次就诊）。差异甲基化 CpG 位点、区域和途径的数量因金属而异。例如，我们发现了六个与 As 相关的显著途径、三个与 Cd 相关的途径和一个与 Mn 相关的途径。与 As 相关的途径与癌症（如皮肤癌）和心血管疾病有关，而与 Cd 相关的途径与肺癌有关。金属混合物也与 47 个显著的 CpG 位点以及主要与癌症和心血管疾病相关的途径相关。
本研究提供了一种方法来理解观察到的趾甲金属与不良健康终点之间关系的潜在表观遗传机制。
