Association of toxic heavy metal mixture exposure with schizophrenia risk: Potential role of carbon metabolic dysregulation

The mechanisms underlying the contribution of toxic heavy metals to the risk of schizophrenia (SCZ) are not fully understood. This study aims to uncover molecular signatures of toxic heavy metal exposure via transcriptomics and metabolomics, and further reveal potential pathways linking exposure to toxic heavy metals to schizophrenia through mediation analysis. First, logistic regression, Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS), and quantile g-computation (qgcomp) were used to assess the association between single and mixed toxic heavy metal exposure and SCZ risk. Subsequently, Orthogonal Two-Level Partial Least Squares (O2PLS) and Data Integration Analysis for Biomarker discovery using Latent Components (DIABLO) were used for integrated multi-omics to identify toxic heavy metal-related differentially expressed genes (DEGs) and metabolites. Finally, chain mediation models assessed the chain mediating roles of genes and metabolites in the relationship between mixed heavy metal exposure and SCZ. Logistic regression analysis preliminary revealed Cr and Pb exposure were associated with an increased schizophrenia risk (Pb: OR 1.81, 95 % CI 1.13-2.88; Cr: OR 2.28, 95 % CI 1.07-4.83), and As exposure with a decreased risk (OR 0.46, 95 % CI 0.30-0.98). Mixture models (BKMR, WQS, qgcomp) yielded preliminary evidence of revealed a positive correlation between exposure to toxic heavy metal mixtures and SCZ risk, with Pb being the primary contributor. Pathway enrichment analysis revealed that transcriptomic and metabolomic data related to toxic heavy metals were enriched in pathways involving tryptophan, glucose, and folate-mediated one-carbon metabolism. The combined O2PLS and DIABLO models identified five DEGs and metabolites associated with toxic heavy metal exposure. Additionally, our preliminary chain mediation analysis generated hypothesis-driven evidence that five DEGs and three metabolites may potentially mediate the impact of toxic heavy metal exposure on SCZ risk, highlighting potential molecular pathways significant for prevention and treatment strategies in high-risk populations.