Characterization of inter-tissue and inter-strain variability of TCE glutathione conjugation metabolites DCVG, DCVC, and NAcDCVC in the mouse

ABSTRACT

Trichloroethylene (TCE) is a ubiquitous environmental toxicant that is a liver and kidney carcinogen. Conjugation of TCE with glutathione (GSH) leads to formation of nepthrotoxic and mutagenic metabolites postulated to be critical for kidney cancerdevelopment; however, relatively little is known regarding their tissue levels as previous analytical methods for their detection lacked sensitivity. Here, an LC-MS/MS-based method for simultaneous detection of S-(1,2-dichlorovinyl)-glutathione (DCVG), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAcDCVC) in multiple mouse tissues was developed. This analytical method is rapid, sensitive (limits of detection (LOD) 3–30 fmol across metabolites and tissues), and robust to quantify all three metabolites in liver, kidneys, and serum. The method was used to characterize inter-tissue and inter-strain variability in formation of conjugative metabolites of TCE. Single oral dose of TCE (24, 240 or 800 mg/kg) was administered to male mice from 20 inbred strains of Collaborative Cross. Inter-strain variability in the levels of DCVG, DCVC, and NAcDCVC (GSD = 1.6–2.9) was observed. Whereas NAcDCVC was distributed equally among analyzed tissues, highest levels of DCVG were detected in liver and DCVC in kidneys. Evidence indicated that inter-strain variability in conjugative metabolite formation of TCE might affect susceptibility to adverse health effects and that this method might aid in filling data gaps in human health assessment of TCE.

Acknowledgements

The authors wish to thank Ms. Oksana Kosyk and Mr. Abhishek Venkatratnam for technical assistance with the in-life portion of this study. We also thank Drs. Terry Wade and Thomas McDonald for access to the analytical instruments and fruitful discussions of the method development phase of this project

Funding

This work was supported, in part, by a cooperative agreement STAR RD83561202 from US EPA, and by a grant from the National Institute of Environmental Health Sciences, P42 ES027704. The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of NIH or EPA.

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Additional information

Funding

This work was supported, in part, by a cooperative agreement STAR RD83561202 from US EPA, and by a grant from the National Institute of Environmental Health Sciences, P42 ES027704. The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of NIH or EPA.