Circulating miRs-183-5p, -206-3p and -381-3p may serve as novel biomarkers for 4,4’-methylene diphenyl diisocyanate exposure

<b>Background:</b> Occupational exposure to the most widely used diisocyanate, 4,4’-methylene diphenyl diisocyanate (MDI), is a cause of occupational asthma (OA). Early recognition of MDI exposure and sensitization is essential for the prevention of MDI-OA. <b>Objective:</b> Identify circulating microRNAs (miRs) as novel biomarkers for early detection of MDI exposure and prevention of MDI-OA. <b>Materials and methods:</b> Female BALB/c mice were exposed to one of three exposure regimens: dermal exposure to 1% MDI in acetone; nose-only exposure to 4580 ± 1497 μg/m³ MDI-aerosol for 60 minutes; or MDI dermal exposure/sensitization followed by MDI-aerosol inhalation challenge. Blood was collected and miRCURY™ miRs qPCR Profiling Service was used to profile circulate miRs from dermally exposed mice. Candidate miRs were identified and verified from mice exposed to three MDI-exposure regimens by TaqMan^® miR assays. <b>Results:</b> Up/down-regulation patterns of circulating mmu-miRs-183-5p, -206-3p and -381-3p were identified and verified. Circulating mmu-miR-183-5p was upregulated whereas mmu-miRs-206-3p and -381-3p were downregulated in mice exposed via all three MDI exposure regimens. <b>Discussion and conclusion:</b> Upregulation of circulating miR-183-5p along with downregulation of circulating miRs-206-3p and -381-3p may serve as putative biomarkers of MDI exposure and may be considered as potential candidates for validation in exposed human worker populations.

<b>背景：</b>职业暴露于目前应用最广泛的二异氰酸酯类物质——4,4'-二苯基甲烷二异氰酸酯（4,4’-methylene diphenyl diisocyanate, MDI），是引发职业性哮喘（occupational asthma, OA）的诱因之一。早期识别MDI暴露及其致敏状态，对于预防MDI相关职业性哮喘（MDI-OA）至关重要。<b>目的：</b>筛选循环微RNA（circulating microRNAs, miRs）作为新型生物标志物，用于早期检测MDI暴露并预防MDI-OA。<b>材料与方法：</b>将雌性BALB/c小鼠随机分为3种暴露方案组：丙酮溶剂中1% MDI的皮肤暴露组；仅鼻部暴露于浓度为4580 ± 1497 μg/m³的MDI气溶胶60分钟组；以及先进行MDI皮肤暴露/致敏，随后给予MDI气溶胶吸入激发的联合暴露组。采集小鼠血液样本，采用miRCURY™ 微RNA定量PCR芯片分析服务，对皮肤暴露组小鼠的循环微RNA进行表达谱分析。通过TaqMan® 微RNA检测试剂盒，对3种MDI暴露方案组小鼠的候选微RNA进行筛选与验证。<b>结果：</b>本研究筛选并验证了循环小鼠源mmu-miR-183-5p、mmu-miR-206-3p以及mmu-miR-381-3p的表达调控模式。在三种MDI暴露方案的小鼠中，循环mmu-miR-183-5p均呈现上调表达，而mmu-miR-206-3p与mmu-miR-381-3p均呈现下调表达。<b>讨论与结论：</b>循环miR-183-5p的上调表达，联合miR-206-3p与miR-381-3p的下调表达，可作为MDI暴露的推定生物标志物，有望成为后续在暴露职业人群中开展验证研究的潜在候选靶点。