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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

Abstract

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.

Keywords

Trichloroethylene Dichloroacetate Trichloroacetate PPARα Metabolomics Toxicity 

Abbreviations

Acaa1a

Acetyl-CoA acyltransferase 1a

Acadl

Acyl-CoA dehydrogenase, long chain

Acadm

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

Acox

Acyl-CoA oxidase

Acot1

Acyl-CoA thioesterase 1

ALT

Alanine transaminase

ALP

Alkaline phosphatase

AST

Aspartate aminotransferase

Cpt1a

Carnitine palmitoyltransferase 1a

Cpt2

Carnitine palmitoyltransferase 2

Cyp4a10

Cytochrome P450 4a10

DCA

Dichloroacetate

eEF

Eukaryotic translation elongation factor

Ehhadh

Enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase

IACR

International Agency for Cancer Research

LPC

Lysophosphatidylcholine

MS

Mass spectrometry

NMR

Nuclear magnetic resonance

PC

Phosphatidylcholine

PP

Peroxisome proliferator chemicals

PPAR

Peroxisome proliferator-activated receptor

qPCR

Quantitative polymerase chain reaction

TAF

Template-activating factor

TCA

Trichloroacetate

TCE

Trichloroethylene

TG

Triglyceride

UPLC

Ultra-performance liquid chromatography

Wy-14,643

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

Notes

Acknowledgments

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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