Abstract
BACKGROUND: Hexavalent chromium Cr(VI), a well-established human carcinogen, induces systemic toxicity affecting reproductive, neurological, hepatic, and immune systems. The broad spectrum of its toxicity implies mechanisms of action that transcend organ-specific or cell type-restricted pathways. Protein interactions have been proposed as a mechanism underlying Cr(VI) toxicity and carcinogenicity. OBJECTIVE AND METHODS: To address gaps in understanding the molecular effect of Cr(VI), particularly the distinct roles of its two stable oxidation states-Cr(VI) and the trivalent form Cr(III) -we employed high-resolution mass spectrometry to identify the protein targets, compare valence-state-specific interactions (Cr(VI) vs. Cr(III)), and map the specific amino acid residues involved. RESULTS AND CONCLUSIONS: In synthesized histone peptides, we demonstrated that it is Cr(III), rather than Cr(VI), that directly binds to acetylated lysine residues. Further, in cellular models exposed to Cr(VI), we identified 15 Cr-binding proteins, all of which were acetylated, with site-specific information of interacting amino acids. Collectively, these findings provide new evidence that Cr(III), generated via intracellular reduction of Cr(VI), directly binds to post-translationally modified proteins on acetylated lysine residues. This work advances a molecular mechanism wherein Cr(VI) exerts toxicity via its reduced trivalent form, Cr(III), highlighting the critical putative role of protein acetylation in mediating Cr-induced damage.