Analysis of the biological response of mouse liver (Mus musculus) exposed to As2O3 based on integrated -omics approaches
Analysis of the biological response of mouse liver (Mus musculus) exposed to As2O3 based on integrated -omics approaches
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DOI：
10.1039/c3mt00186e
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发表时间：
2013-01-01
期刊：
影响因子：
3.4
通讯作者：
Gomez-Ariza, J. L.
中科院分区：
文献类型：
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作者：
Garcia-Sevillano, M. A.;Garcia-Barrera, T.;Gomez-Ariza, J. L.
以肝脏为靶器官，采用有机和无机质谱技术研究了小鼠对无机砷暴露的生化反应。采用金属组学、代谢组学和氧化还原蛋白质组学方法，研究了口服三价无机砷（3 mg/kg体重/天）7天后的毒理学效应。将ICP-MS检测的分子排阻色谱（SEC）与阴离子交换色谱（AEC）结合，以表征暴露小鼠的生物学反应。另一方面，使用正和负采集模式（ESI+/ESI-）对极性和亲脂性浸提液进行的直接输注质谱法（DI-ESI-QTOF-MS）提供了有关通过偏最小二乘判别分析（PLS-DA）鉴定的内源性代谢物的时间依赖性变化的信息。最后，该研究还补充了与氧化应激相关的酶的上调/下调的评估，如超氧化物歧化酶（SOD），谷胱甘肽还原酶（GR），过氧化氢酶（CAT）和过氧化物酶与金属毒性问题。结果表明，慢性砷暴露后，肝脏中无机砷甲基化可达到饱和点。另一方面，SEC-ICP-MS偶联提供了与砷暴露相关的含金属蛋白质和代谢物的信息（金属组学），这些信息与整体代谢的变化（代谢组学）相关，还考虑了它们对蛋白质氧化还原状态和蛋白质表达的影响（氧化还原蛋白质组学）。我们的研究表明，砷引起生化途径的改变，如能量代谢（如糖酵解，克雷布斯循环），氨基酸代谢，胆碱代谢和膜磷脂降解（细胞凋亡）。这项工作说明了有机质谱法用于As 2 O3诱导的生化效应的代谢组学研究的高度可靠性，无机质谱法用于暴露小鼠肝脏中砷生物甲基化的金属组学和形态评估，氧化还原蛋白质组学用于评估不同蛋白质（如超氧化物歧化酶（SOD））中酶活性的抑制，过氧化氢酶（CAT）和谷胱甘肽还原酶（GR）由这种元素引起。总之，整合金属组学，代谢组学和氧化还原蛋白质组学的结果提供了一个更全面的评价生物反应的实验处理暴露于有毒金属。
Organic and inorganic mass spectrometries were used to investigate the biochemical response of mice (Mus musculus) to inorganic arsenic exposure using liver as the target organ. The toxicological effects of trivalent inorganic arsenic after oral administration (3 mg kg(-1) body weight and per day) were investigated over a period of 7 days using metallomics, metabonomics and redox proteomics approaches. Size-exclusion chromatography (SEC) with ICP-MS detection was combined with anion exchange chromatography (AEC) to characterize the biological response of the exposed mice. On the other hand, direct infusion mass spectrometry (DI-ESI-QTOF-MS) of polar and lipophilic extracts using positive and negative modes of acquisition (ESI+/ESI-) provided information about time-dependent changes in endogenous metabolites identified by Partial Least Square-Discriminant Analysis (PLS-DA). Finally, the study has been complemented with the evaluation of up/down-regulation of enzymes related to oxidative stress such as superoxide dismutase (SOD), glutathione reductase (GR), catalase (CAT) and peroxidases in connection with metal toxicity issues. The results show that the inorganic arsenic methylation in the liver may reach the saturation point upon chronic exposure to the element. On the other hand, SEC-ICP-MS coupling provided information about metal containing-proteins and metabolites related to arsenic exposure (metallomics) which has been correlated with the changes in the global metabolism (metabonomics), also considering their consequences on the redox status of protein and protein expression (redox proteomics). Our study shows that arsenic causes biochemical pathway alterations, such as energy metabolism (e.g. glycolysis, Krebs cycle), amino acid metabolism, choline metabolism and degradation of membrane phospholipids (apoptosis). This work illustrates the high reliability of the integrated use of organic mass spectrometry for the metabonomic study of biochemical effects induced by As2O3, with inorganic mass spectrometry for metallomic and speciation assessment of arsenic biomethylation in the liver of exposed mice, and redox proteomics to evaluate inhibition of enzymatic activity in different proteins such as superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) caused by this element. In conclusion, the integration of metallomics, metabolomics and redox proteomics results provides a more comprehensive evaluation about the biological response in experiments dealing with exposure to toxic metals.