A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure

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2019
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Hochgesand, Sabrine
John, Harald
Steinritz, Dirk
Schmidt, Annette
Mangerich, Aswin
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Despite its worldwide ban, the warfare agent sulfur mustard (SM) still represents a realistic threat, due to potential release in terroristic attacks and asymmetric conflicts. Therefore, the rigorous and quantitative detection of SM exposure is crucial for diagnosis, health risk assessment, and surveillance of international law. Alkylation adducts of nucleic acids can serve as valuable toxicologically relevant 'biomarkers of SM exposure'. Here, we developed a robust and versatile bioanalytical platform based on isotope dilution UPLC-MS/MS to quantify major SM-induced DNA and RNA adducts, as well as adducts induced by the monofunctional mustard 2-chloroethyl ethyl sulfide. We synthesized 15N/13C-labeled standards, which allowed absolute quantitation with full chemical specificity and subfemtomole sensitivities. DNA and RNA mono-alkylation adducts and crosslinks were carefully analyzed in a dose- and time-dependent manner in various matrices, including human cancer and primary cells, derived of the main SM-target tissues. Nucleic acid adducts were detected up to 6 days post-exposure, indicating long persistence, which highlights their toxicological relevance and proves their suitability as forensic and medical biomarkers. Finally, we investigated ex vivo-treated rat skin biopsies and human blood samples, which set the basis for the implementation into the method portfolio of Organization for the Prohibition of Chemical Weapons-designated laboratories to analyze authentic samples from SM-exposed victims.

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570 Biowissenschaften, Biologie
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Sulfur mustard, S-lost, Mass spectrometry, DNA damage, Biomarker
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ISO 690ZUBEL, Tabea, Sabrine HOCHGESAND, Harald JOHN, Dirk STEINRITZ, Annette SCHMIDT, Alexander BÜRKLE, Aswin MANGERICH, 2019. A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure. In: Archives of Toxicology. 2019, 93(1), pp. 61-79. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-018-2324-7
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@article{Zubel2019-01spect-43579,
  year={2019},
  doi={10.1007/s00204-018-2324-7},
  title={A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure},
  number={1},
  volume={93},
  issn={0340-5761},
  journal={Archives of Toxicology},
  pages={61--79},
  author={Zubel, Tabea and Hochgesand, Sabrine and John, Harald and Steinritz, Dirk and Schmidt, Annette and Bürkle, Alexander and Mangerich, Aswin}
}
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