Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum.
Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum.
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DOI：
10.1007/s00204-013-1053-1
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发表时间：
2013-11
影响因子：
6.1
通讯作者：
Gonzalez FJ
中科院分区：
文献类型：
--
作者：
Fang ZZ;Krausz KW;Tanaka N;Li F;Qu A;Idle JR;Gonzalez FJ
三氯乙烯（TCE）诱导的肝毒性和致癌作用被认为部分是通过激活过氧化物酶体增殖物激活受体α（PPARα）介导的。然而，TCE的两种代谢产物，二氯乙酸酯（DCA）和三氯乙酸酯（TCA）对TCE毒性的贡献仍不清楚。本研究的目的是确定小鼠暴露于TCE后血清和尿液中的代谢产物谱，以帮助确定对TCE暴露的代谢反应以及DCA和TCA对TCE毒性的贡献。对C57 BL/6小鼠给予TCE、TCA或DCA，并对尿液和血清进行基于超高效液相色谱-电喷雾电离四极杆飞行时间质谱（UPLC-ESI-QTOFMS）的整体代谢组学分析。通过搜索代谢组学数据库并与真实标准品进行比较来鉴定离子，并使用多反应监测进行定量。定量聚合酶链反应的mRNA，生化分析，肝组织学也进行了。TCE暴露导致尿液中参与脂肪酸代谢的代谢物减少，这是由于PPARα靶基因表达改变所致。TCE处理还诱导血清中磷脂稳态的改变，如血清溶血磷脂酰胆碱18：0和18：1以及磷脂酰胆碱代谢物的增加所揭示的。TCA给药显示TCE暴露后尿液和血清中的代谢产物谱相似，这与TCA比DCA给药更稳健地诱导PPARα靶基因表达相关。这些数据显示了对TCE暴露的代谢反应，并证明TCA是在尿液和血清中观察到的TCE诱导的代谢物变化的主要贡献者。
Trichloroethylene (TCE)-induced liver toxicity and carcinogenesis is believed to be mediated in part by activation of the peroxisome proliferator-activated receptor α (PPARα). However, the contribution of the two TCE metabolites, dichloroacetate (DCA) and trichloroacetate (TCA) to the toxicity of TCE, remains unclear. The aim of the present study was to determine the metabolite profiles in serum and urine upon exposure of mice to TCE, to aid in determining the metabolic response to TCE exposure and the contribution of DCA and TCA to TCE toxicity. C57BL/6 mice were administered TCE, TCA, or DCA, and urine and serum subjected to ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based global metabolomics analysis. The ions were identified through searching metabolomics databases and by comparison with authentic standards, and quantitated using multiple reactions monitoring. Quantitative polymerase chain reaction of mRNA, biochemical analysis, and liver histology were also performed. TCE exposure resulted in a decrease in urine of metabolites involved in fatty acid metabolism, resulting from altered expression of PPARα target genes. TCE treatment also induced altered phospholipid homeostasis in serum, as revealed by increased serum lysophosphatidylcholine 18:0 and 18:1, and phosphatidylcholine metabolites. TCA administration revealed similar metabolite profiles in urine and serum upon TCE exposure, which correlated with a more robust induction of PPARα target gene expression associated with TCA than DCA treatment. These data show the metabolic response to TCE exposure and demonstrate that TCA is the major contributor to TCE-induced metabolite alterations observed in urine and serum.
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影响因子：
4.4
作者：
Patterson, Andrew D.;Slanar, Ondrej;Krausz, Kristopher W.;Li, Fei;Hoefer, Constance C.;Perlik, Frantisek;Gonzalez, Frank J.;Idle, Jeffrey R.
通讯作者：
Idle, Jeffrey R.
影响因子：
10.4
作者：
Bull RJ
通讯作者：
Bull RJ
影响因子：
4.3
作者：
Park, Seul-Ki;Nam, Suk-Woo;Lee, Mi-Young
通讯作者：
Lee, Mi-Young
影响因子：
3.8
作者：
Evans, M. V.;Chiu, W. A.;Caldwell, J. C.
通讯作者：
Caldwell, J. C.
影响因子：
4.5
作者：
Laughter, AR;Dunn, CS;Corton, JC
通讯作者：
Corton, JC