Jin Qian, Lin Yuxin, Wei Yue, Liu Zhanbiao, Cao Manzhu, Chen Xuejun, Li Liqin
State Key Laboratory of Chemistry for NBC Hazards Protection, Beijing, China.
Arch Toxicol. 2025 Jul 21. doi: 10.1007/s00204-025-04131-y.
Soman, a highly lethal organophosphorus compound (OP), is notorious for its rapid induction of irreversible acetylcholinesterase binding through accelerated aging. Although subacute soman exposure has been specifically implicated in cognitive deficits, the molecular pathways driving these impairments remain poorly characterized, highlighting a significant research gap. This study aims to comprehensively elucidate the effects of soman exposure on cognitive impairment by analyzing proteome and lipidome alterations in the hippocampal tissue of guinea pigs administered a sublethal dose (11 µg/kg) of soman. A molecular network based on lipidomic and proteomics data was constructed to investigate the key molecules. The study demonstrates that subcutaneous exposure to low-dose soman for 14 consecutive days in guinea pigs impairs learning and memory. We further observed that soman exposure induces damage to both the hippocampal neurons and the mitochondrial ultrastructure in the brains of these animals. The study revealed that subacute soman exposure significantly altered the endocannabinoid system, characterized by disrupted biosynthesis and metabolism of 2-arachidonoylglycerol (2-AG), with a significant down-regulation of 2-AG lipid metabolism pathways, as well as a significant up-regulation of cannabinoid receptor 1 (CB1R) pathways. Notably, the disruption of 2-AG biosynthesis and metabolism is primarily attributed to the upregulation of the activities of three key enzymes, DAGLα, MAGL, and ABHD6. The activation of CB1R negatively feedback-regulate the cAMP/PKA pathway which further leads to dysregulation of mitochondrial homeostasis and reduced energy metabolism. Pharmacodynamic evaluations demonstrated that reversible MAGL inhibitor and ABHD6 inhibitor effectively elevate 2-AG levels in cerebral organoid models, subsequently restoring mitochondrial energy metabolism. This research expands the current understanding of soman's systemic neurotoxicity, particularly its capacity to modulate endocannabinoid-mediated cognitive processes. Our results provide mechanistic insights into soman-induced cognitive deficits and associated health risks. Importantly, elevating 2-AG levels may serve as an effective strategy for preventing and treating soman-induced memory impairment.
梭曼是一种极具致死性的有机磷化合物（OP），因其通过加速老化迅速诱导不可逆的乙酰胆碱酯酶结合而声名狼藉。尽管亚急性梭曼暴露与认知缺陷有明确关联，但导致这些损伤的分子途径仍未得到充分表征，这凸显了一个重大的研究空白。本研究旨在通过分析给予亚致死剂量（11微克/千克）梭曼的豚鼠海马组织中的蛋白质组和脂质组变化，全面阐明梭曼暴露对认知障碍的影响。构建了一个基于脂质组学和蛋白质组学数据的分子网络来研究关键分子。该研究表明，豚鼠连续14天皮下暴露于低剂量梭曼会损害学习和记忆。我们进一步观察到，梭曼暴露会导致这些动物大脑中的海马神经元和线粒体超微结构受损。该研究表明，亚急性梭曼暴露显著改变了内源性大麻素系统，其特征是2-花生四烯酸甘油酯（2-AG）的生物合成和代谢受到破坏，2-AG脂质代谢途径显著下调，以及大麻素受体1（CB1R）途径显著上调。值得注意的是，2-AG生物合成和代谢的破坏主要归因于三种关键酶DAGLα、MAGL和ABHD6活性的上调。CB1R的激活对cAMP/PKA途径进行负反馈调节，这进一步导致线粒体稳态失调和能量代谢降低。药效学评估表明，可逆性MAGL抑制剂和ABHD6抑制剂可有效提高脑类器官模型中的2-AG水平，随后恢复线粒体能量代谢。这项研究扩展了我们目前对梭曼全身神经毒性的理解，特别是其调节内源性大麻素介导的认知过程的能力。我们的结果为梭曼诱导的认知缺陷和相关健康风险提供了机制性见解。重要的是，提高2-AG水平可能是预防和治疗梭曼诱导的记忆损伤的有效策略。
