Exosomal\nmiRNAs as Participators of Hexavalent Chromium-Induced\nGenotoxicity and Immunotoxicity: A Two-Stage Population Study

Genotoxic\nand immunosuppressive characteristics are central to\nthe carcinogenic profile of hexavalent chromium [Cr(VI)], with dysregulation\nof circulating exosomal miRNA potentially acting as oncogenes or tumor\nsuppressors or participating in the carcinogenic landscape of heavy\nmetals through immunomodulation. In this two-stage epidemiological\ninvestigation, we unveiled for the first time the perturbations of\nexosomal miRNAs among individuals exposed to Cr(VI), alongside their\nsignificant correlations with biomarkers of genetic injury (γ-H2AX\npositivity in circulating lymphocytes and the urinary 8-OHdG levels)\nand immunological indicators (immunosuppressive PD-1 expression),\nwhich was supported by validation in an external cohort. Employing\na support vector machine model, we discerned that exosomal miRNAs,\nparticularly miR-4467, miR-345-5p, miR-144-3p, and miR-206, exhibited\na remarkable capacity to delineate the genetic damage stratum within\nthe population with high precision, and the target genes predicted\nof these miRNAs further elucidated their intricate regulatory interplay\nwith the effector biomarkers. Additionally, employing a Bayesian mediation\nframework, we observed the intermediary function of miR-4467 in the\nnexus between chromium exposure and the escalation of urinary 8-OHdG\nlevels (mediation effect: 0.47, <i>P</i> < 0.05). Although\nour findings suggested a link between extracellular miRNAs and immunosuppressive\nbiomarkers, this association did not achieve validation in the external\ncohort, possibly due to population heterogeneity. Collectively, this\nstudy advanced our understanding of the epigenetic orchestration of\nhealth hazards of Cr(VI) by exosomal miRNAs, shedding light on their\nexpression signatures and their intricate interplay with Cr(VI)-induced\ngenetic and immunological perturbations, thus providing novel perspectives\non the toxic pathways of heavy metals.