Identifying Metabolic Perturbations and Toxic Effects of Rac-Metalaxyl and Metalaxyl-M in Mice Using Integrative NMR and UPLC-MS/MS Based Metabolomics
Identifying Metabolic Perturbations and Toxic Effects of Rac-Metalaxyl and Metalaxyl-M in Mice Using Integrative NMR and UPLC-MS/MS Based Metabolomics
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使用基于 NMR 和 UPLC-MS/MS 的综合代谢组学鉴定 Rac-Metalaxyl 和 Metalaxyl-M 在小鼠中的代谢扰动和毒性作用
DOI：
10.3390/ijms20215457
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发表时间：
2019-11
影响因子：
5.6
通讯作者：
He Lin
中科院分区：
文献类型：
--
作者：
Zhang Ping;Wang Sheng;He Yuhan;Xu Yangyang;Shi Dongmei;Yang Furong;Yu Weizhong;Zhu Wentao;He Lin
虽然代谢紊乱是低剂量毒性效应的敏感指标，但从代谢特征分析的角度来看，外消旋甲霜灵和甲霜灵-M在哺乳动物中的代谢机制仍不清楚。本研究采用基于代谢组学的核磁共振（NMR）和超高效液相色谱-串联质谱（UPLC-MS/MS）技术，对外消旋甲霜灵和精甲霜灵在小鼠体内的代谢紊乱和毒性作用进行了研究。分别在外消旋甲霜灵和甲霜灵-M暴露后测定组织学、基于NMR的非靶向尿液特征、多变量模式识别、代谢物鉴定、途径分析、基于UPLC-MS/MS的靶向血清氨基酸和色氨酸途径分析。组织学研究表明，在相同的暴露剂量下，甲霜灵-M诱导小鼠肝细胞炎症、坏死和空泡化的程度高于rac-甲霜灵。采用偏最小二乘判别分析（PLS-DA）直接分离外消旋甲霜灵和精甲霜灵引起的代谢扰动。代谢物鉴定和代谢途径分析表明，外消旋甲霜灵主要引起10种尿液代谢物的变化和4种代谢途径的波动。然而，甲霜灵-M引起19种尿液代谢物的变化和6种途径的波动。外消旋甲霜灵和精甲霜灵在相同暴露水平下引起的血清氨基酸和色氨酸途径代谢物的变化也不同。这些结果可以提供具体的见解外消旋甲霜灵和甲霜灵-M的代谢扰动和毒性作用，并有助于提供可用的数据外消旋甲霜灵和甲霜灵-M的健康风险评估在代谢组学水平。
Although metabolic perturbations are sensitive indicators for low-dose toxic effects, the metabolic mechanisms affected by rac-metalaxyl and metalaxyl-M in mammals from a metabolic profiling perspective remain unclear. In this study, the metabolic perturbations and toxic effects of rac-metalaxyl and metalaxyl-M in mice were carefully investigated using integrative nuclear magnetic resonance (NMR) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) based metabolomics. Histopathology, NMR-based untargeted urine profile, multivariate pattern recognition, metabolite identification, pathway analysis, UPLC-MS/MS based targeted serum amino acids, and tryptophan pathway analysis were determined after rac-metalaxyl and metalaxyl-M exposure, individually. Histopathology indicated that metalaxyl-M induced greater hepatocellular inflammatory, necrosis, and vacuolation in mice than rac-metalaxyl at the same exposure dosage. The metabolic perturbations induced by rac-metalaxyl and metalaxyl-M were directly separated using partial least-squares discriminant analysis (PLS-DA). Furthermore, metabolite identification and pathway analysis indicated that rac-metalaxyl mainly induced ten urine metabolite changes and four pathway fluctuations. However, metalaxyl-M induced 19 urine metabolite changes and six pathway fluctuations. Serum amino acids and tryptophan pathway metabolite changes induced by rac-metalaxyl and metalaxyl-M were also different even at the same exposure level. Such results may provide specific insight into the metabolic perturbations and toxic effects of rac-metalaxyl and metalaxyl-M, and contribute to providing available data for health risk assessments of rac-metalaxyl and metalaxyl-M at a metabolomics level.
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影响因子：
3.5
作者：
Phang, James M.;Donald, Steven P.;Liu, Yongmin
通讯作者：
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影响因子：
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Hua-Dong Xu;Junsong Wang;Ming-hui Li;Yan Liu;Ting Chen;Ai-Qun Jia
影响因子：
3.5
作者：
A. Willis;H. Bender;G. Steel;D. Valle
通讯作者：
A. Willis;H. Bender;G. Steel;D. Valle
影响因子：
11.4
作者：
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通讯作者：
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