title: Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum.
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.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
authors.forename: Aijuan
authors.initials: A
authors.lastname: Qu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA. gonzalef@mail.nih.gov.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000652:urine*; D002851:Chromatography, High Pressure Liquid; D003999:Dichloroacetic Acid / Q000378:metabolism / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism; D006529:Hepatomegaly / Q000139:chemically induced / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D008660:Metabolism / Q000187:drug effects*; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D015999:Multivariate Analysis; D010743:Phospholipids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization; D014238:Trichloroacetic Acid / Q000378:metabolism*; D014241:Trichloroethylene / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D005227:Fatty Acids; D010743:Phospholipids; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D003999:Dichloroacetic Acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase