Exposure to fine particulate matter (PM) is associated with the neurodegenerative diseases. Coke oven emissions (COEs) in occupational environment are important sources of PM. However, its neurotoxicity is still unclear. Therefore, evaluating the toxicological effects of COE on the nervous system is necessary. In the present study, we constructed mouse models of COE exposure by tracheal instillation. Mice exposed to COE showed signs of cognitive impairment. This was accompanied by a decrease in miR-145a-5p and an increase in SIK1 expression in the hippocampus, along with synaptic structural damage. Our results demonstrated that COE-induced miR-145a-5p downregulation could increase the expression of SIK1 and phosphorylated SIK1, inhibiting the cAMP/PKA/CREB pathway by activating PDE4D, which was associated with reduced synaptic structural plasticity. Furthermore, restoring of miR-145a-5p expression based on COE exposure in HT22 cells could partially reversed the negative effects of COE exposure through the SIK1/PDE4D/cAMP axis. Collectively, our findings link epigenetic regulation with COE-induced neurotoxicity and imply that miR-145a-5p could be an early diagnostic marker for neurological diseases in patients with COE occupational exposure.

中文翻译：

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miR-145a-5p/SIK1/cAMP依赖性突触结构可塑性改变导致焦炉排放引起的认知障碍


接触细颗粒物 (PM) 与神经退行性疾病有关。职业环境中的焦炉排放（COE）是PM的重要来源。然而，其神经毒性仍不清楚。因此，评估COE对神经系统的毒理学影响是必要的。在本研究中，我们通过气管滴注构建了 COE 暴露的小鼠模型。接触 COE 的小鼠表现出认知障碍的迹象。伴随着海马中 miR-145a-5p 的减少和 SIK1 表达的增加，以及突触结构损伤。我们的结果表明，COE诱导的miR-145a-5p下调可以增加SIK1和磷酸化SIK1的表达，通过激活PDE4D抑制cAMP/PKA/CREB通路，这与突触结构可塑性降低有关。此外，基于 HT22 细胞中 COE 暴露恢复 miR-145a-5p 表达可以通过 SIK1/PDE4D/cAMP 轴部分逆转 COE 暴露的负面影响。总的来说，我们的研究结果将表观遗传调控与 COE 诱导的神经毒性联系起来，这意味着 miR-145a-5p 可能是 COE 职业暴露患者神经系统疾病的早期诊断标志物。