Landscape of Nucleic Acid Modifications Induced by Chemical Warfare Agents

Nucleic acids are one of the key cellular targets for chemical exposure and stress responses, and nucleic acid modification induced by chemical toxicants represents a core research area in toxicology. Toxicant-induced nucleic acid modifications are categorized into two interconnected pathways. First is the exogenous modifications arising from direct covalent or noncovalent interactions between toxicants or their reactive metabolites and nucleic acids. Second is the endogenous modifications generated secondarily through toxicant-triggered oxidative stress, lipid peroxidation, inflammation, endogenous alkylation, and epigenetic or epitranscriptomic dysregulation. Taking prototypical electrophilic agents, chemical warfare agents (CWAs), as the focal point, this review maps a comprehensive landscape of nucleic acid modification induced by CWAs, mainly including exogenous monoadducts, cross-links, and endogenous oxidative damage and regulatory modifications. We systematically elucidate the chemical reactivity, structural diversity, and toxicokinetic behaviors of key lesions, further exploring the differential roles of these lesions as exposure or effect biomarkers and their contribution to adverse biological outcomes induced by CWAs. For different CWAs, bifunctional reactions producing DNA-DNA and DNA-protein cross-links constitute the most cytotoxic lesions, and single-base adducts represent the predominant and best-characterized modifications. In this context, nucleic acid adductomics has emerged as an untargeted strategy for comprehensively profiling diverse induced lesions at the molecular level. Mass spectrometry (MS) serves as the core analytical platform for adductomics, enabling structural identification and accurate picogram-level quantification of nucleic acid adducts. Meanwhile, next-generation sequencing (NGS) achieves high-resolution localization of endogenous modifications in certain contexts, although its applicability to bulky and chemically complex lesions remains technically challenging. It is expected that the combination of MS and NGS will unlock the capability to dissect the inherent relationship between specific modification sites, gene function perturbation, and resultant toxicological effects.