Archives of Toxicology

, Volume 87, Issue 11, pp 1975–1987 | Cite as

Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum

  • Zhong-Ze Fang
  • Kristopher W. Krausz
  • Naoki Tanaka
  • Fei Li
  • Aijuan Qu
  • Jeffrey R. Idle
  • Frank J. GonzalezEmail author
Organ Toxicity and Mechanisms


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.


Trichloroethylene Dichloroacetate Trichloroacetate PPARα Metabolomics Toxicity 



Acetyl-CoA acyltransferase 1a


Acyl-CoA dehydrogenase, long chain


Acyl-CoA dehydrogenase, C-4 to C-12 straight chain


Acyl-CoA oxidase


Acyl-CoA thioesterase 1


Alanine transaminase


Alkaline phosphatase


Aspartate aminotransferase


Carnitine palmitoyltransferase 1a


Carnitine palmitoyltransferase 2


Cytochrome P450 4a10




Eukaryotic translation elongation factor


Enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase


International Agency for Cancer Research




Mass spectrometry


Nuclear magnetic resonance




Peroxisome proliferator chemicals


Peroxisome proliferator-activated receptor


Quantitative polymerase chain reaction


Template-activating factor








Ultra-performance liquid chromatography


[4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid



This work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

Conflict of interest

The authors have declared that there are no conflicts of interest.

Supplementary material

204_2013_1053_MOESM1_ESM.pdf (1.5 mb)
Supplementary material 1 (PDF 1523 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg (Outside the USA) 2013

Authors and Affiliations

  • Zhong-Ze Fang
    • 1
  • Kristopher W. Krausz
    • 1
  • Naoki Tanaka
    • 1
  • Fei Li
    • 1
  • Aijuan Qu
    • 1
  • Jeffrey R. Idle
    • 1
  • Frank J. Gonzalez
    • 1
    Email author
  1. 1.Laboratory of Metabolism, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA

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