Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, 30322, USA.
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, 30322, USA.
Food Chem Toxicol. 2018 Jun;116(Pt B):272-280. doi: 10.1016/j.fct.2018.04.042. Epub 2018 Apr 21.
Disrupted polyamine metabolism with elevated putrescine is associated with neuronal dysfunction. Manganese (Mn) is an essential nutrient that causes neurotoxicity in excess, but methods to evaluate biochemical responses to high Mn are limited. No information is available on dose-response effects of Mn on putrescine abundance and related polyamine metabolism. The present research was to test the hypothesis that Mn causes putrescine accumulation over a physiologically adequate to toxic concentration range in a neuronal cell line. We used human SH-SY5Y neuroblastoma cells treated with MnCl under conditions that resulted in cell death or no cell death after 48 h. Putrescine and other metabolites were analyzed by liquid chromatography-ultra high-resolution mass spectrometry. Putrescine-related pathway changes were identified with metabolome-wide association study (MWAS). Results show that Mn caused a dose-dependent increase in putrescine over a non-toxic to toxic concentration range. MWAS of putrescine showed positive correlations with the polyamine metabolite N8-acetylspermidine, methionine-related precursors, and arginine-associated urea cycle metabolites, while putrescine was negatively correlated with γ-aminobutyric acid (GABA)-related and succinate-related metabolites (P < 0.001, FDR < 0.01). These data suggest that measurement of putrescine and correlated metabolites may be useful to study effects of Mn intake in the high adequate to UL range.
多胺代谢紊乱伴精胺升高与神经元功能障碍有关。锰 (Mn) 是一种必需的营养物质，过量会导致神经毒性，但评估过量 Mn 生化反应的方法有限。目前尚无关于 Mn 对精胺丰度和相关多胺代谢的剂量-反应影响的信息。本研究旨在检验以下假设：在神经元细胞系中，Mn 在生理适宜至毒性浓度范围内引起精胺积累。我们使用 MnCl 处理人 SH-SY5Y 神经母细胞瘤细胞，48 小时后观察细胞死亡或无细胞死亡的情况。通过液相色谱-超高分辨率质谱分析精胺和其他代谢物。通过代谢组学全关联研究 (MWAS) 鉴定与精胺相关的途径变化。结果表明，Mn 在无毒至毒性浓度范围内引起精胺的剂量依赖性增加。MWAS 分析表明，精胺与多胺代谢物 N8-乙酰亚精胺、蛋氨酸相关前体和精氨酸相关尿素循环代谢物呈正相关，而精胺与 γ-氨基丁酸 (GABA) 相关和琥珀酸相关代谢物呈负相关 (P < 0.001, FDR < 0.01)。这些数据表明，测量精胺和相关代谢物可能有助于研究高适宜摄入量至 UL 范围内 Mn 摄入的影响。
