Repeated low-level exposure to sarin results to hippocampus dysfunction. Metabonomics involves a holistic analysis of a set of metabolites in an organism in the search for a relationship between these metabolites and physiological or pathological changes. The objective of the present study was to evaluate the effects of repeated exposure to low-level sarin on the metabonomics in hippocampus of a guinea pig model. Guinea pigs were divided randomly into control and sarin treated groups (n = 14). Guinea pigs in the control group received saline; while the sarin-treated group received 0.4×LD50 (16.8 μg/kg) sarin. Daily injections (a total of 14 days) were administered sc between the shoulder blades in a volume of 1.0 ml/kg body weight. At the end of the final injection, 6 animals in each group were chosen for Morris water maze test. The rest guinea pigs (n = 8 for each group) were sacrificed by decapitation, and hippocampus were dissected for analysis. Compared with the control-group, the escape latency in sarin-group was significantly (p < 0.05) longer while the crossing times were significantly decreased in the Morris water task (p < 0.05). Sarin inhibited activities of acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in hippocampus. The AChE activity of hippocampus from sarin-treated groups is equivalent to 59.9 ± 6.4%, and the NTE activity of hippocampus from sarin-groups is equivalent to 78.1 ± 8.3% of that from control-group. Metabolites were identified and validated. A total of 14 variables were selected as potential biomarkers. Phospholipids [phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA), phosphatidylglycerol (PG), phosphatidylinositol (PI), Lysophosphatidylethanolamine (LysoPE or LPE)] and sphingolipids (SPs) [sphinganine (SA), phytosphingosine (PSO) and sphinganine-1-phosphate (SA1P)] were clearly modified. In conclusion, repeated low-dose exposures to sarin disrupted the homeostasis of phospholipid and sphingolipid metabolism in guinea pig hippocampus and may lead to a neuronal-specific function disorders. Identified metabolites such as SA1P need to be studied more deeply on their biological function that against sarin lesions. In future research, we should pay more attention to characterize the physiological roles of lipid metabolism enzymes as well as their involvement in pathologies induced by repeated low-level sarin exposure.

中文翻译：

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反复低剂量暴露于沙林破坏了豚鼠海马体内磷脂和鞘脂代谢的稳态

反复低水平接触沙林会导致海马功能障碍。代谢组学涉及对生物体内的一组代谢物进行整体分析，以寻找这些代谢物与生理或病理变化之间的关系。本研究的目的是评估反复接触低浓度沙林对豚鼠模型海马代谢组学的影响。豚鼠被随机分为对照组和沙林治疗组（n = 14）。对照组豚鼠接受生理盐水；而沙林治疗组接受 0.4×LD50 (16.8 μg/kg) 沙林。每日注射（共 14 天）在肩胛骨之间以 1.0 ml/kg 体重的体积进行皮下注射。在最后一次注射结束时，每组选择6只动物进行Morris水迷宫试验。其余豚鼠（每组 n = 8）被斩首处死，并解剖海马进行分析。与对照组相比，沙林组的逃逸潜伏期显着延长（p < 0.05），而莫里斯水任务的穿越时间显着减少（p < 0.05）。沙林抑制海马中乙酰胆碱酯酶 (AChE) 和神经病变靶标酯酶 (NTE) 的活性。沙林组海马AChE活性相当于59.9±6.4%，沙林组海马NTE活性相当于对照组的78.1±8.3%。代谢物被鉴定和验证。总共选择了 14 个变量作为潜在的生物标志物。磷脂 [磷脂酰胆碱 (PC)、磷脂酰乙醇胺 (PE)、磷脂酸 (PA)、磷脂酰甘油 (PG)、磷脂酰肌醇 (PI)、溶血磷脂酰乙醇胺 (LysoPE 或 LPE)] 和鞘脂 (SP) [鞘氨醇 (SA)、植物鞘氨醇 (PSO) 和 1-磷酸鞘氨醇 (SA1P)] 总之，反复低剂量暴露于沙林破坏了豚鼠海马体内磷脂和鞘脂代谢的稳态，并可能导致神经元特异性功能障碍。需要更深入地研究已鉴定的代谢物，如 SA1P，它们对沙林病灶的生物学功能。在未来的研究中，我们应该更加关注脂质代谢酶的生理作用以及它们在反复低水平沙林暴露引起的病理中的参与。溶血磷脂酰乙醇胺 (LysoPE 或 LPE)] 和鞘脂 (SP) [鞘氨醇 (SA)、植物鞘氨醇 (PSO) 和 1-磷酸鞘氨醇 (SA1P)] 被明显修饰。总之，反复低剂量暴露于沙林破坏了豚鼠海马体内磷脂和鞘脂代谢的稳态，并可能导致神经元特异性功能障碍。需要更深入地研究已鉴定的代谢物，如 SA1P，它们对沙林病灶的生物学功能。在未来的研究中，我们应该更加关注脂质代谢酶的生理作用以及它们在反复低水平沙林暴露引起的病理中的参与。溶血磷脂酰乙醇胺 (LysoPE 或 LPE)] 和鞘脂 (SP) [鞘氨醇 (SA)、植物鞘氨醇 (PSO) 和 1-磷酸鞘氨醇 (SA1P)] 被明显修饰。总之，反复低剂量暴露于沙林破坏了豚鼠海马体内磷脂和鞘脂代谢的稳态，并可能导致神经元特异性功能障碍。需要更深入地研究已鉴定的代谢物，如 SA1P，它们对沙林病灶的生物学功能。在未来的研究中，我们应该更加关注脂质代谢酶的生理作用以及它们在反复低水平沙林暴露引起的病理中的参与。反复低剂量接触沙林会破坏豚鼠海马体内磷脂和鞘脂代谢的稳态，并可能导致神经元特异性功能障碍。需要更深入地研究已鉴定的代谢物，如 SA1P，它们对沙林病灶的生物学功能。在未来的研究中，我们应该更加关注脂质代谢酶的生理作用以及它们在反复低水平沙林暴露引起的病理中的参与。反复低剂量接触沙林会破坏豚鼠海马体内磷脂和鞘脂代谢的稳态，并可能导致神经元特异性功能障碍。需要更深入地研究已鉴定的代谢物，如 SA1P，它们对沙林病灶的生物学功能。在未来的研究中，我们应该更加关注脂质代谢酶的生理作用以及它们在反复低水平沙林暴露引起的病理中的参与。