Exosomal miRNAs as Participators of Hexavalent Chromium-Induced Genotoxicity and Immunotoxicity: A Two-Stage Population Study

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