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目的应用核磁共振氢谱(~1H NMR)筛选邻苯二甲酸二丁酯(DBP)在大鼠血浆内差异表达的小分子代谢物,从分子水平和物质、能量代谢的角度探究DBP在体内的代谢变化及可能的毒性作用机制。方法取无特定病原体级SD雄性大鼠24只,随机分为对照组和低、中、高剂量组,分别给予剂量为0、500、1 000和1 500 mg/kg体质量的DBP灌胃染毒,每日1次,共2周。染毒结束后,收集各组大鼠血浆进行~1H NMR分析,运用主成分分析、偏最小二乘法判别分析和正交偏最小二乘法显著性分析法对血浆代谢产物图谱进行模式识别,筛选差异代谢物,采用变量重要性投影准则筛选生物标志物。结果共筛选出12个差异代谢物,上述代谢物水平与DBP染毒剂量存在剂量-效应关系。与对照组比较,高剂量组大鼠血浆中高密度脂蛋白、低密度脂蛋白、羟丁酸盐、糖蛋白、柠檬酸、葡萄糖、磷酸肌酸、不饱和脂肪酸、酪氨酸和苯丙氨酸的水平均下降(P<0.05),乳酸和丙酮酸的水平均升高(P<0.05)。结论 DBP可导致机体氨基酸代谢、脂代谢及能量代谢紊乱。
OBJECTIVE To screen small-molecule metabolites differentially expressed in rat plasma by 1H-NMR spectroscopy and to investigate the effect of DBP in vivo on the molecular level and substance and energy metabolism Metabolic changes and possible toxicological mechanisms. Methods Twenty-four male SD rats without specific pathogen were randomly divided into control group and low, medium and high dose groups, and were given DBP gavage at doses of 0, 500, 1 000 and 1 500 mg / kg respectively Toxic, 1 day, a total of 2 weeks. At the end of exposure, the plasma of rats in each group was collected for ~ 1H NMR analysis. The principal component analysis, partial least square discriminant analysis and orthogonal partial least-squares significant analysis were used to identify the patterns of plasma metabolites, and the differences were screened Metabolites were selected using variable importance projection criteria for biomarkers. Results A total of 12 differential metabolites were screened. The above metabolite levels were dose-dependently correlated with DBP dose. Compared with the control group, high-density lipoprotein, low density lipoprotein, hydroxybutyrate, glycoprotein, citric acid, glucose, creatine phosphate, unsaturated fatty acid, tyrosine and phenylalanine (P <0.05), the levels of lactate and pyruvate increased (P <0.05). Conclusion DBP can lead to amino acid metabolism, lipid metabolism and energy metabolism disorders.