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Glutathione conjugates of the mercapturic acid pathway and guanine adduct as biomarkers of exposure to CEES, a sulfur mustard analog

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Abstract

Sulfur mustard (SM), a chemical warfare agent, is a strong alkylating compound that readily reacts with numerous biomolecules. The goal of the present work was to define and validate new biomarkers of exposure to SM that could be easily accessible in urine or plasma. Because investigations using SM are prohibited by the Organisation for the Prohibition of Chemical Weapons, we worked with 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM. We developed an ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) approach to the conjugate of CEES to glutathione and two of its metabolites: the cysteine and the N-acetylcysteine conjugates. The N7-guanine adduct of CEES (N7Gua-CEES) was also targeted. After synthesizing the specific biomarkers, a solid-phase extraction protocol and a UHPLC-MS/MS method with isotopic dilution were optimized. We were able to quantify N7Gua-CEES in the DNA of HaCaT keratinocytes and of explants of human skin exposed to CEES. N7Gua-CEES was also detected in the culture medium of these two models, together with the glutathione and the cysteine conjugates. In contrast, the N-acetylcysteine conjugate was not detected. The method was then applied to plasma from mice cutaneously exposed to CEES. All four markers could be detected. Our present results thus validate both the analytical technique and the biological relevance of new, easily quantifiable biomarkers of exposure to CEES. Because CEES behaves very similar to SM, the results are promising for application to this toxic of interest.

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Funding

This work was supported by the “Agence de l’Innovation de Défense” (French Defence Ministry) and the “NRBC” program of CEA.

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Authors and Affiliations

  1. Univ. Grenoble Alpes, CEA, CNRS, IRIG, SyMMES, 38000, Grenoble, France

    Marie Roser, David Béal, Camille Eldin, Leslie Gudimard & Thierry Douki

  2. Institut de Recherche Biomédicale des Armées (IRBA), 91223, Brétigny-sur-Orge, France

    Fanny Caffin, Fanny Gros-Désormeaux & Christophe Piérard

  3. Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, Université Paris-Saclay, CEA, INRAE, 91191, Gif-sur-Yvette, France

    Daniel Léonço, François Fenaille & Christophe Junot

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Roser, M., Béal, D., Eldin, C. et al. Glutathione conjugates of the mercapturic acid pathway and guanine adduct as biomarkers of exposure to CEES, a sulfur mustard analog. Anal Bioanal Chem 413, 1337–1351 (2021). https://doi.org/10.1007/s00216-020-03096-4

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