Nylander-French Leena A, Wu Michael C, French John E, Boyer Jayne C, Smeester Lisa, Sanders Alison P, Fry Rebecca C
CIH Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, CB #7431, Chapel Hill, NC 27599-7431, USA.
Department of Biostatistics, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Toxicol Lett. 2014 Dec 1;231(2):217-26. doi: 10.1016/j.toxlet.2014.10.024. Epub 2014 Oct 22.
DNA methylation may mediate inter-individual responses to chemical exposure and, thus, modify biomarker levels of exposure and effects. We analyzed inter-individual differences in inhalation and skin exposure to 1,6-hexamethylene diisocyanate (HDI) and urine biomarker 1,6-hexamethylene diamine (HDA) levels in 20 automotive spray-painters. Genome-wide 5-methyl cytosine (CpG) DNA methylation was assessed in each individual's peripheral blood mononuclear cells (PBMC) DNA using the Illumina 450K CpG array. Mediation analysis using linear regression models adjusted for age, ethnicity, and smoking was conducted to identify and assess the association between HDI exposure, CpG methylation, and urine HDA biomarker levels. We did not identify any CpGs common to HDI exposure and biomarker level suggesting that CpG methylation is a mediator that only partially explains the phenotype. Functional significance of genic- and intergenic-CpG methylation status was tested using protein-protein or protein-DNA interactions and gene-ontology enrichment to infer networks. Combined, the results suggest that methylation has the potential to affect HDI mass transport, permeation, and HDI metabolism. We demonstrate the potential use of PBMC methylation along with quantitative exposure and biomarker data to guide further investigation into the mediators of occupational exposure and biomarkers and its role in risk assessment.
DNA甲基化可能介导个体对化学物质暴露的反应，从而改变暴露和效应的生物标志物水平。我们分析了20名汽车喷漆工吸入和皮肤接触1,6-己二异氰酸酯（HDI）的个体差异以及尿生物标志物1,6-己二胺（HDA）水平。使用Illumina 450K CpG芯片对每个个体外周血单核细胞（PBMC）DNA中的全基因组5-甲基胞嘧啶（CpG）DNA甲基化进行评估。采用针对年龄、种族和吸烟情况进行调整的线性回归模型进行中介分析，以确定和评估HDI暴露、CpG甲基化与尿HDA生物标志物水平之间的关联。我们未发现HDI暴露和生物标志物水平共有的任何CpG，这表明CpG甲基化是一种仅部分解释该表型的中介因素。利用蛋白质-蛋白质或蛋白质-DNA相互作用以及基因本体富集来推断网络，测试基因内和基因间CpG甲基化状态的功能意义。综合来看，结果表明甲基化有可能影响HDI的质量转运、渗透和HDI代谢。我们证明了PBMC甲基化与定量暴露及生物标志物数据结合使用的潜力，以指导对职业暴露和生物标志物的中介因素及其在风险评估中的作用进行进一步研究。
