基于高分辨质谱研究双酚A对小鼠血浆代谢谱的影响

Effect of Bisphenol A on the Plasma Metabolic Spectrum in Mice Based on Quadrupole Orbitrap Mass Spectrometry

观察不同染毒剂量的双酚A(BPA)对C57BL6小鼠血浆代谢谱的影响,探讨其可能的毒性机制,并探寻毒性相关生物靶点。将小鼠随机分为对照组及1、10、50和250μg·kg^-1组。利用高分辨质谱技术结合主成分分析、偏最小二乘分析等方法对血浆数据进行分析,发现对照组与各剂量组基本分离,并随染毒剂量的增加,各组逐渐偏离对照组,提示小鼠机体具有发生紊乱的趋势;运用Pathway Analysis数据库对差异性代谢物进行拓扑分析;运用Cytoscape和Metscape进行代谢产物的相关性分析和模块化分析。从血浆中筛选出27种差异代谢物,发现BPA的干预作用可能与亚油酸代谢、花生四烯酸代谢、丙氨酸、天冬氨酸和谷氨酸代谢、丙酮酸代谢、鞘脂类代谢和磷酸肌醇代谢等通路有关;对血浆差异性代谢产物的相关性分析和模块化分析结果表明,7个模块之间关系密切,BPA的干预作用可能与血浆7个模块代谢物的差别相关;BPA染毒14 d后,其毒性作用机制可能与丙酮酸、花生四烯酸、亮氨酸和亚油酸等生物靶点的异常相关,丙酮酸、花生四烯酸、亮氨酸和亚油酸等生物靶点可作为BPA引起机体毒性的标志物。

The changes of the plasma metabolic spectrum in C57BL6 mice were observed after exposure to different doses of bisphenol A(BPA)in order to investigate the possible mechanism of its toxic side effects,and to identify its toxicity-related biological targets.Mice were randomly assigned to receive BPA at doses of 0(control group),1,10,50,and 250μg·kg^-1.The plasma data were analyzed using UHPLC-MS technology combined with principal component and partial least squares analyses.The results revealed differences between the control group and each BPA group,with the effect becoming more pronounced with increasing doses.Topological analysis of the different metabolites was conducted using the Pathway Analysis database.Cytoscape and Metscape were used to analyze the correlation and modularization of metabolites.In total,27 different metabolites were screened from plasma,and BPA treatment was revealed to affect linoleic acid metabolism;arachidonic acid metabolism;alanine,aspartic acid,and glutamic acid metabolism;pyruvate metabolism;sphingolipid metabolism;phosphoinositol metabolism;and other pathways.Correlation analysis of plasma differential metabolites revealed that the seven modules are closely related,whereas modularization analysis illustrated that the intervention effect of BPA may be related to differences in the seven module metabolites of plasma.The results indicated that the toxicity mechanism of BPA after 14 days of exposure may be related to abnormalities in the metabolism of pyruvic acid,arachidonic acid,leucine,linoleic acid,and other biological targets.These biological targets can thus be used as markers of BPA-related toxicity.