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
-
摘要: 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250 μ g·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。Abstract: 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 250 μg·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.
-
Key words:
- bisphenol A /
- mice /
- metabolics /
- plasma /
- biological targets
-
-
Geens T, Goeyens L, Covaci A. Are potential sources for human exposure to bisphenol-A overlooked?[J]. International Journal of Hygiene and Environmental Health, 2011, 214(5):339-347 Geens T, Apelbaum T Z, Goeyens L, et al. Intake of bisphenol A from canned beverages and foods on the Belgian market[J]. Food Additives and Contaminants, 2010, 27(11):1627-1637 Rice C, Birnbaum L S, Cogllano J, et al. Exposure assessment for endocrine disruptors:Some considerations in the design of studies[J]. Environmental Health Perspectives, 2003, 111(13):1683-1690 Arnold S F, Collins B M, Robinson M K, et al. Differential interaction of natural and synthetic estrogens with extracellular binding proteins in a yeast estrogen screen[J]. Steroids, 1996, 61(11):642-646 郑丽舒, 金一和, 靳翠红, 等. 双酚A和β-六氯环己烷对小鼠雌激素活性的实验研究[J]. 中国公共卫生, 2002, 18(8):922-924 Zheng L S, Jin Y H, Jin C H, et al. Experimental study of BPA and β-HCH on estrogenic activity of mice[J]. China Public Health, 2002, 18(8):922-924(in Chinese)
Kavlock R J, Daston G P, DeRosa C, et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors:A report of the U.S. EPA-sponsored workshop[J]. Environmental Health Perspectives, 1996, 104(s4):715-740 刘秀清. 婴幼儿配方乳粉中壬基酚污染检测与风险控制[J]. 现代农业科技, 2016(21):260-261 Liu X Q.Nonylphenol pollution detection and control in infant formula milk powder[J]. Modern Agricultural Science and Technology, 2016 (21):260-261(in Chinese)
Lu Y Y, Chen M L, Sung F C, et al. Daily intake of 4-nonylphenol in Taiwanese[J]. Environment International, 2007, 33(7):903-910 林奕云, 郑家概, 付强, 等. DSPE-UPLC-MS-MS测定畜禽产品中壬基酚和双酚A[J]. 食品工业, 2016, 37(6):279-284 Lin Y Y, Zheng J G, Fu Q, et al. Determination of nonylphenol and bisphenol A in animal products by DSPE-UPLC-MS/MS[J]. The Food Industry, 2016, 37(6):279-284(in Chinese)
Gyllenhammar I, Glynn A, Darnerud P O, et al. 4-Nonylphenol and bisphenol A in Swedish food and exposure in Swedish nursing women[J]. Environment International, 2012, 43:20-28 Niu Y, Zhang J, Duan H, et al. Bisphenol A and nonylphenol in foodstuffs:Chinese dietary exposure from the 2007 total diet study and infant health risk from formulas[J]. Food Chemistry, 2015, 167:320-325 Geens T, Aerts D, Berthot C, et al. Diet and dietary exposure to bisphenol A were reviewed[J]. Food Chemical Toxicity, 2012, 50(10):3725-3740 Wei Y, Han C, Geng Y, et al. Maternal exposure to bisphenol A during pregnancy interferes testis development of F1 male mice[J]. Environmental Science and Pollution Research, 2019, 14(4):1-14 Jiang X, Yin L, Zhang N, et al. Bisphenol A induced male germ cell apoptosis via IFNbeta-XAF1-XIAP pathway in adult mice[J]. Toxicology and Applied Pharmacology, 2018, 355:247-256 Zhang Y, Han L,Yang H, et al. Bisphenol A affects cell viability involved in autophagy and apoptosis in goat testis sertoli cell[J]. Toxicology and Applied Pharmacology, 2017, 55:137-147 Birla H, Keswani C, Rai S N, et al. Neuroprotective effects of Withania somnifera in BPA induced-cognitive dysfunction and oxidative stress in mice[J]. Behavioral and Brain Functions, 2019, 15(1):9 Xu W, Guo G, Li J, et al. Activation of Bcl-2-Caspase-9 apoptosis pathway in the testis of asthmatic mice[J]. PLoS One, 2016, 11:e0149353 Misra B B. Metabolomics tools to study links between pollution and human health:An exposomics perspective[J]. Current Pollution Reports, 2019, 22(5):1-19 Yu K, Yi S, Li B, et al. An integrated meta-omics approach reveals substrates involved in synergistic interactions in a bisphenol A (BPA)-degrading microbial community[J]. Microbiome, 2019, 16(7):1-13 Xie W P, Zhang W P, Ren J, et al Metabonomics indicates inhibition of fatty acid synthesis, beta-oxidation and the TCA cycle in triclocarban-induced cardiac metabolic alterations in male mice[J]. Journal of Agricultural and Food Chemistry, 2018, 66(6):1533-1542 Zhou L L, Zhang W P, Chen H M, et al. Short-term effects of tributyl phosphate exposure on the metabolism of liver and susceptibility to hepatic encephalopathy in male mice[J]. Science of the Total Environment, 2017, 603-604:77-85 Shen G L, Zhou L L, Liu W, et al. Di(2-ethylhexyl)phthalate alters the synthesis and β-oxidation of fatty acids and hinders ATP supply in mouse testes via UPLC-Q-Exactive Orbitrap MS-based metabonomics study[J]. Journal of Agricultural and Food Chemistry, 2017, 65(24):5056-5063 Wishart D S, Tzur D, Knox C. HMDB:The human metabolome database[J]. Nucleic Acids Research, 2007, 35:521-526 Ogata H, Goto S, Kanehisa M, et al. KEGG:Kyoto encyclopedia of genes and genomes[J]. Nucleic Acids Research, 2000, 28(1):27-30 Kanehisa M, Araki M, Goto S, et al. KEGG for linking genomes to life and the environment[J]. Nucleic Acids Research, 2008, 36(1):480-484 Steuer R, Kurths J, Fiehn O. Observing and interpreting correlations in metabolomic networks[J]. Bioinformatics, 2003, 19(8):1019-1026 郭冰冰, 蒋新液, 裴晶晶, 等. 谷氨酰胺对高脂饮食诱导C57BL/6J小鼠肥胖和胰岛素抵抗的影响[J]. 中国病理生理杂志, 2018, 34(9):1720-1723 Guo B B, Jiang X Y, Pei J J, et al. Effect of L-glutamine on obesity and insulin resistance in high-fat diet induced C57BL/6J mice[J]. Chinese Journal of Pathophysiology, 2018, 34(9):1720-1723(in Chinese)
Murphy C J, Newsholme P. Importance of glutamine metabolism in murine macrophages and human monocytes to L-arginine biosynthesis and rates of nitrite or urea production[J]. Clinical Science, 1998, 95(4):397-407 Perlman J M. Summary proceedings from the neurology group on hypoxic-ischemic encephalopathy[J]. Pediatrics, 2006, 117(3 Pt 2):S28-S33 Bak L K, Schousboe A, Waagepetersen H S. The glutamate/GABA-glutamine cycle:Aspects of transport, neurotransmitter homeostasis and ammonia transfer[J]. Journal of Neurochemistry, 2006, 98(3):614-653 Somashekar B S, Kamarajan P, Danciu T, et al. Magic angle spinning NMR-based metabolic profiling of head and neck squamous cell carcinoma tissues[J]. Journal of Proteome Research, 2011, 10(11):5232-5241 De Lorenzo A, Petroni M L, Masala S. Effect of acute and chronic branched-chain amino acids on energy metabolism and muscle performance[J]. Diabetes, Nutrition & Metabolism, 2003, 16(5-6):291-297 Itoh T, Quastel J H. Ribonucleic acid biosynthesis in adult and infant rat brain in vitro[J]. Science,1969, 164(3875):79-80 Tieu K, Perier C, Caspersen C, et al. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease[J]. Journal of Clinical Investigation, 2003, 112(6):892-901 Li T, Chen Y, Gua C, et al. Elevated circulating trimethylamine N-oxide levels contribute to endotelial dysfunction in aged ratsthrough vascular inflammation and oxidative stress[J]. Frontiers in Physiology, 2017, 8:350 Wang Z, Tang W H, Buffa J A, et al. Prognostic value of choline and betaine depends on intestinal microbiota generated metabolite trimethylamine-N-oxide[J]. European Heart Journal, 2014, 35(14):904-910 Birla H, Keswani C, Rai S N, et al. Neuroprotective effects of Withania somnifera in BPA induced cognitive dysfunction and oxidative stress in mice[J]. Behavioral and Brain Functions, 2019, 15(1):9 -
点击查看大图
计量
- 文章访问数: 2178
- HTML全文浏览数: 2178
- PDF下载数: 115
- 施引文献: 0
下载:
