BACKGROUND Lead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels-validated measures of cumulative exposure-require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles-obtainable via Illumina 450K or IlluminaEPIC bead-chip assays. METHODS We developed and tested two methylation-based biomarkers from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the biomarkers using elastic nets. Results were validated in a NAS subset, reporting specificity, and sensitivity. FINDINGS Participants were 73 years old on average (standard deviation, SD = 6), with moderate lead levels of (mean ± SD patella: 27 ± 18 µg/g; tibia:21 ± 13 µg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r = 0.62 patella, r = 0.59 tibia) and had low mean square error (MSE) (MSE = 0.68 patella, MSE = 0.53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across patella and tibia bones (p > 0.05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74 and 73% for patella and tibia lead levels, respectively, with 70% sensitivity. INTERPRETATION DNA methylation-based lead biomarkers are novel tools that can be used to reconstruct decades' worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative exposure.

中文翻译：

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成年人体内累积铅暴露的血液DNA甲基化生物标志物。

背景技术铅是一种普遍存在的有毒物质，它遵循三部分动力学，在骨骼中具有最长的半衰期。通过ella骨和胫骨铅水平验证的累积暴露量，需要专门的X射线荧光光谱法才能在全球范围内使用。我们开发了微创生物标志物，可使用血液DNA甲基化谱图反映个体累积的铅暴露量，可通过Illumina 450K或IlluminaEPIC磁珠芯片检测获得。方法我们从348名规范性衰老研究（NAS）老年男性中开发并测试了两种基于甲基化的生物标记。通过稳健的回归分析，我们选择了与骨铅水平密切相关的甲基化位点，并使用弹性网构建了生物标记。结果在NAS子集中进行了验证，报告了特异性和敏感性。结果参与者平均年龄73岁（标准差，SD = 6），铅水平中等（平均±骨：27±18 µg / g；胫骨：21±13 µg / g）。骨和胫骨中基于铅的甲基化生物标记分别包含59和138个DNA甲基化位点。估计的铅水平与实际测量值显着相关（r = 0.62 pat骨，r = 0.59胫骨），均方差（MSE）低（MSE = 0.68 pat骨，MSE = 0.53胫骨）。across骨和胫骨之间的估计铅含量和实际铅含量的平均值和分布无显着差异（p> 0.05）。基于甲基化的生物标记物区分高暴露（>中位数）铅的参与者，其骨和胫骨铅水平的特异性分别为74％和73％，敏感性为70％。