Taylor Laura W, French John E, Robbins Zachary G, Nylander-French Leena A
Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Nutrition Research Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Front Genet. 2021 Jul 14;12:700636. doi: 10.3389/fgene.2021.700636. eCollection 2021.
Isocyanates are respiratory and skin sensitizers that are one of the main causes of occupational asthma globally. Genetic and epigenetic markers are associated with isocyanate-induced asthma and, before asthma develops, we have shown that genetic polymorphisms are associated with variation in plasma and urine biomarker levels in exposed workers. Inter-individual epigenetic variance may also have a significant role in the observed biomarker variability following isocyanate exposure. Therefore, we determined the percent methylation for CpG islands from DNA extracted from mononuclear blood cells of 24 male spray-painters exposed to 1,6-hexamethylene diisocyanate (HDI) monomer and HDI isocyanurate. Spray-painters' personal inhalation and skin exposure to these compounds and the respective biomarker levels of 1,6-diaminohexane (HDA) and trisaminohexyl isocyanurate (TAHI) in their plasma and urine were measured during three repeated industrial hygiene monitoring visits. We controlled for inhalation exposure, skin exposure, age, smoking status, and ethnicity as covariates and performed an epigenome-wide association study (EWAS) using likelihood-ratio statistical modeling. We identified 38 CpG markers associated with differences in isocyanate biomarker levels (Bonferroni < 0.05). Annotations for these markers included 18 genes: ALG1, ANKRD11, C16orf89, CHD7, COL27A, FUZ, FZD9, HMGN1, KRT6A, LEPR, MAPK10, MED25, NOSIP, PKD1, SNX19, UNC13A, UROS, and ZFHX3. We explored the functions of the genes that have been published in the literature and used GeneMANIA to investigate gene ontologies and predicted protein-interaction networks. The protein functions of the predicted networks include keratinocyte migration, cell-cell adhesions, calcium transport, neurotransmitter release, nitric oxide production, and apoptosis regulation. Many of the protein pathway functions overlap with previous findings on genetic markers associated with variability both in isocyanate biomarker levels and asthma susceptibility, which suggests there are overlapping protein pathways that contribute to both isocyanate toxicokinetics and toxicodynamics. These predicted protein networks can inform future research on the mechanism of allergic airway sensitization by isocyanates and aid in the development of mitigation strategies to better protect worker health.
异氰酸酯是呼吸道和皮肤致敏剂，是全球职业性哮喘的主要病因之一。遗传和表观遗传标记与异氰酸酯诱发的哮喘有关，在哮喘发病之前，我们已经表明基因多态性与接触工人血浆和尿液生物标志物水平的变化有关。个体间的表观遗传差异在异氰酸酯暴露后观察到的生物标志物变异性中也可能起重要作用。因此，我们测定了24名接触1,6 - 己二异氰酸酯（HDI）单体和HDI异氰脲酸酯的男性喷漆工单核血细胞DNA中CpG岛的甲基化百分比。在三次重复的工业卫生监测访问期间，测量了喷漆工个人对这些化合物的吸入和皮肤接触情况，以及他们血浆和尿液中1,6 - 二氨基己烷（HDA）和三氨基己基异氰脲酸酯（TAHI）的相应生物标志物水平。我们将吸入暴露、皮肤暴露、年龄、吸烟状况和种族作为协变量进行控制，并使用似然比统计模型进行全表观基因组关联研究（EWAS）。我们鉴定出38个与异氰酸酯生物标志物水平差异相关的CpG标记（Bonferroni < 0.05）。这些标记的注释包括18个基因：ALG1、ANKRD11、C16orf89、CHD7、COL27A、FUZ、FZD9、HMGN1、KRT6A、LEPR、MAPK10、MED25、NOSIP、PKD1、SNX19、UNC13A、UROS和ZFHX3。我们探索了文献中已发表的基因的功能，并使用GeneMANIA研究基因本体和预测的蛋白质相互作用网络。预测网络的蛋白质功能包括角质形成细胞迁移、细胞间粘附、钙转运、神经递质释放一氧化氮产生和细胞凋亡调节。许多蛋白质途径功能与先前关于与异氰酸酯生物标志物水平和哮喘易感性变异性相关的遗传标记的研究结果重叠，这表明存在重叠的蛋白质途径，它们对异氰酸酯的毒代动力学和毒效动力学都有贡献。这些预测的蛋白质网络可为未来关于异氰酸酯引起气道过敏致敏机制的研究提供信息，并有助于制定缓解策略以更好地保护工人健康。
