基于核磁共振的代谢组学对邻苯二甲酸二丁酯的毒性研究

发布时间：2018-01-20 05:15

本文关键词： 邻苯二甲酸二丁酯核磁共振代谢组学毒性　出处：《广东药科大学》2017年硕士论文　论文类型：学位论文

【摘要】：邻苯二甲酸二丁酯(DBP)作为增塑剂已在各个领域广泛使用,但其潜在的毒性同样受到大众的关注。本课题以分子生物学与生物化学的理论为基础,采用核磁共振代谢组学方法,与病理组织学检查与血浆生化分析等传统毒理学方法。研究经DBP染毒情况下大鼠生物体液中的内源性代谢物的动态变化情况,说明机体内产生的代谢应答与内在组织损伤之间的关系,进而阐述DBP的毒性作用机理。代谢组学数据的模式识别分析结果显示,DBP染毒后大鼠各生物体液中的内源性代谢产物的变化情况相比对照组具有显著性的差异。血浆生化指标分析结果表明肝肾功能受损,病理组织学检查也说明睾丸、肝肾组织有损伤。并且血浆生化分析及病理组织学检查得出的结果与体内代谢物的差异情况与表现出统一性。DBP染毒剂量组与对照组比较,产生的内源性代谢物的变化情况主要包括:(1)血浆中乳酸、丙酮酸水平升高;脂质蛋白、β-羟丁酸盐、糖蛋白、柠檬酸、葡萄糖、磷酸肌酸、不饱和脂肪酸、酪氨酸和苯丙氨酸水平下降。(2)尿液中亮氨酸、异亮氨酸、缬氨酸、β-羟基丁酸、丙氨酸、赖氨酸、乙酸盐、马尿酸和色氨酸的水平升高;乳酸、糖蛋白、蛋氨酸、丙酮、α-酮戊二酸、谷氨酰胺、柠檬酸、丙二酸盐、胆碱、氧化三甲胺(TMAO)、牛磺酸、肌酸、肌酸酐、β-葡萄糖、顺乌头酸、异柠檬酸、苹果酸和甲酸盐水平下降。(3)粪样中的亮氨酸、异亮氨酸、色氨酸、缬氨酸、丙氨酸、乙酸盐、赖氨酸和腺嘌呤的水平升高;乳酸、糖蛋白、蛋氨酸、α-酮戊二酸、谷氨酰胺、丙二酸盐、胆碱、氧化三甲胺、牛磺酸、肌酸、β-葡萄糖、苹果酸和甲酸盐水平下降。并且,大鼠机体内这些代谢物的差异变化情况存在剂量和时间的毒效关系。参考卫生毒理学、病理组织学和生物化学等理论进行分析,得出DBP导致的代谢物差异变化可相对的造成机体某些代谢途径发生紊乱,其中包括三羧酸循环(柠檬酸循环)、糖类代谢,蛋白质代谢和脂质代谢等,且还提示体内肠道菌群存在失衡的情况。并且这些生化代谢途径的紊乱与DBP的毒性作用呈一定程度的相关性。本研究能够全面监测DBP毒性作用的产生、发展及蓄积的整个过程,从整体水平上系统阐述DBP引起的毒性作用机制,为环境化学物质的毒理学研究提供新方法。
[Abstract]:Dibutyl phthalate (DBP) as a plasticizer has been widely used in various fields, but its potential toxicity is also concerned by the public. This topic is based on the theory of molecular biology and biochemistry. The dynamic changes of endogenous metabolites in the biological fluid of rats exposed to DBP were studied by traditional toxicological methods such as nuclear magnetic resonance metabonomics, histopathology and plasma biochemical analysis. The relationship between metabolic response and internal tissue damage was explained, and the toxic mechanism of DBP was explained. The results of pattern recognition analysis of metabolomics data showed that. The changes of endogenous metabolites in the fluid of rats exposed to DBP were significantly different from those in the control group. The results of plasma biochemical index analysis showed that the liver and kidney function was damaged. Histopathological examination also indicates that the testicles. The results of biochemical analysis and histopathology of plasma were different from those of metabolites in the body and showed the unity between the group treated with DBP and the control group. The changes of endogenous metabolites mainly included the increase of lactate and pyruvate levels in plasma. The levels of lipid protein, 尾 -hydroxybutyrate, glycoprotein, citric acid, glucose, creatine phosphate, unsaturated fatty acid, tyrosine and phenylalanine decreased in urine. The levels of 尾 -hydroxybutyric acid, alanine, lysine, acetate, hippuric acid and tryptophan increased. Lactic acid, glycoprotein, methionine, acetone, 伪 -ketoglutaric acid, glutamine, citric acid, malonate, choline, trimethylamine oxide TMAOO, taurine, creatine, creatinine, 尾 -glucose. The levels of leucine, isoleucine, tryptophan, valine, alanine, acetate, lysine and adenine in fecal samples decreased. Levels of lactic acid, glycoprotein, methionine, 伪 -ketoglutaric acid, glutamine, malonate, choline, trimethylamine oxide, taurine, creatine, 尾 -glucose, malic acid and formate decreased. The difference of these metabolites in the body of rats was related to dose and time. The results were analyzed with reference to the theories of health toxicology, histopathology and biochemistry. It is concluded that the difference of metabolites caused by DBP can cause disorder of some metabolic pathways, including tricarboxylic acid cycle (citric acid cycle), carbohydrate metabolism, protein metabolism and lipid metabolism. It is also suggested that there is imbalance in intestinal flora in vivo, and the disturbance of these biochemical metabolic pathways is related to the toxicity of DBP to some extent. This study can comprehensively monitor the production of toxic effects of DBP. In order to provide a new method for toxicological study of environmental chemicals, the mechanism of toxicity induced by DBP is systematically expounded in the whole process of development and accumulation.
【学位授予单位】：广东药科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R114

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