Association Between Multiple Plasma Metals and Plasma LncRNA: Profile and Signature Pathways in Chinese Population

BackgroundEnvironmental metal exposure is associated with adverse health outcomes, yet the involvement of long non‐coding RNAs (lncRNAs) in these mechanisms remains poorly understood.ObjectivesThis study aimed to explore plasma lncRNA expression profiles in relation to multi‐metal exposure, determine their tissue origins, and elucidate functional pathways.MethodsWe measured 23 plasma metals using inductively coupled plasma‐mass spectrometry (ICP‐MS) and profiled lncRNAs via high‐throughput gene chip technology in 160 healthy Chinese adults. Associations were assessed using linear regression (FDR<0.05), the two‐way orthogonal partial least squares (O2PLS) model and quantile g‐computation to evaluate mixture effects. Tissue origins were inferred using tissue specificity index (TSI), and potential leukocyte origins were evaluated by linear regression models. Functional pathways were analyzed through Gene Ontology Biological Process (GOBP) analysis and Gene Set Enrichment Analysis (GSEA).ResultsLinear regression identified nine metals associated with 1047 lncRNAs. Lead, nickel, and vanadium exhibited strong intercorrelations and were jointly associated with 300 lncRNAs. Both O2PLS and quantile g-computation revealed that a mixture of 11 metals was associated with decreased expression of three specific lncRNAs. Tissue‐specific analysis indicated enrichment of Pb–Ni–V–related lncRNAs in the pituitary and brain. Seven of these lncRNAs were traced to leukocytes based on correlations between plasma and leukocyte expression levels. Functional analysis identified two clusters: RNA‐processing lncRNAs linked to oncogenesis, and vesicle‐transport lncRNAs associated with secretory and fibrotic processes.ConclusionsOur study provides novel mechanistic insights into environmental metal toxicity and identifies specific plasma lncRNAs as potential biomarkers for advancing exposure assessment and risk detection.