Xuedan Xu

Environmental metal exposure is associated with adverse health outcomes, yet the relationship between long non-coding RNAs (lncRNAs) and metal exposure remains poorly understood. This study aimed to explore plasma lncRNA expression profiles in relation to multi-metal exposure, examine tissue enrichment patterns, and annotate pathway-level enrichment. We 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 enrichment patterns were explored using the tissue specificity index (TSI), and correlations between plasma and leukocyte lncRNA expression were examined using linear regression models. Functional pathways were analyzed through Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA). Linear 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 significantly correlated with leukocyte expression. GO enrichment classified the lncRNAs into two categories, one enriched in RNA processing and the other in vesicle transport. GSEA further showed enrichment of RNA processing-related lncRNAs in oxidative stress-related pathways and vesicle organization-related lncRNAs in secretory pathways. Our findings provided new insights into the health effects of environmental metal exposures and identified metal-associated lncRNA signals that may inform future hypothesis-driven research.