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Sulfur mustard (SM), a chemical warfare agent, is a strong alkylatingcompound that readily reacts with numerous biomolecules. The goal of thepresent work was to define and validate new biomarkers of exposure to SM thatcould be easily accessible in urine or plasma. Because investigations using SMare prohibited by the Organization for the Prohibition of Chemical Weapons, weworked with 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM.We developed an ultra-high-pressure liquid chromatography - tandem massspectrometry approach (UHPLC-MS/MS) to the conjugate of CEES to glutathione andtwo of its metabolites, the cysteine and the N-acetyl-cysteine conjugates. TheN7-guanine adduct of CEES (N7Gua-CEES) was also targeted. After synthesizingthe specific biomarkers, a solid phase extraction protocol and a UHPLC-MS/MSmethod with isotopic dilution were optimized. We were able to quantifyN7Gua-CEES in the DNA of HaCaT keratinocytes and of explants of human skinexposed to CEES. N7Gua-CEES was also detected in the culture medium of thesetwo models, together with the glutathione and the cysteine conjugates. Incontrast, the N-acetyl-cysteine conjugate was not detected. The method was thenapplied to plasma from mice cutaneously exposed to CEES. All four markers couldbe detected. Our present results thus validate both the analytical techniqueand the biological relevance of new, easily quantifiable biomarkers of exposureto CEES. Because CEES behaves very similarly to SM, the results are promisingfor application to this toxic of interest.

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