Circulating Exosomal MicroRNA Profiles Associated with Heavy Metal Exposure and Short Stature in Children

Heavy metal exposure is increasingly linked to impaired childhood growth, but the biological mechanisms are poorly understood. Here, we assessed associations between heavy metal exposure and growth impairment (idiopathic short stature [ISS] and growth hormone deficiency [GHD]) in 36 children (24 cases, 12 controls, males 41.7%), identifying related alterations in circulating exosomal miRNAs. Blood/urine concentrations of nine metals, including Pb, As, and Hg were measured, and serum exosomal miRNAs were profiled via sequencing. Elevated heavy metal exposure was associated with significantly increased proportions of ISS and GHD. Specifically, high blood Pb was associated with ISS (p = 0.01) and high urinary As with overall short stature (p = 0.03). Elevated urinary Hg showed a marginal association with GHD (p = 0.07). Differentially expressed miRNAs were identified: hsa-miR-4488 was downregulated in high-Pb and ISS groups, whereas hsa-miR-133a-3p and hsa-miR-4516 were upregulated in high urinary Hg/As and GHD groups. Predicted targets of these miRNAs involved growth hormone (GH)–insulin-like growth factor-1 (IGF-1) signaling and endochondral ossification. In conclusion, Pb, As, and Hg exposures were associated with impaired growth in children. The dysregulation of related miRNAs suggests biological mechanisms involving both local growth-plate dysfunction and GH-IGF1 signaling disruption.