Childhood dyslexia risk elevated by heavy metal mixtures from e-waste: A machine learning-driven mixture modeling study.

Environmental heavy metal mixtures from informal e-waste recycling are potential neurotoxicants, but their link to developmental dyslexia remains unclear. This study aimed to investigate whether exposure to heavy metal mixtures in an e-waste recycling environment is associated with dyslexia risk, to identify key contributing metals and their interactions, and to explore potential biological mechanisms. This two-stage study in Guiyu, China-a major global e-waste recycling area-involved initial screening of 2520 primary-school children for dyslexia, followed by a case-control analysis including 66 dyslexic cases and 132 controls. Eleven urinary metals were quantified using inductively coupled plasma mass spectrometry (ICP-MS). We applied an XGBoost model with SHapley Additive exPlanations (SHAP) to identify essential sociodemographic, behavioral, and environmental covariates. These covariates informed further analyses with mixture models: adaptive elastic net (AENET) with environmental risk scores (ERS), weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). All mixture models demonstrated robust, dose-dependent associations between mixed-metal exposure and increased dyslexia risk (highest vs. lowest quartile odds ratios: ERS = 11.00; WQS = 14.98; qgcomp = 1.56), primarily driven by chromium (Cr), nickel (Ni), and lead (Pb). BKMR analyses further confirmed synergistic interactions among Cr, Ni, and Pb, moderated by antagonistic effects from zinc (Zn). Integrative bioinformatics identified neuroinflammation, oxidative stress, and epigenetic disruptions as critical mechanistic pathways, highlighting Interleukin 1 Beta (IL1B), Estrogen Receptor 1 (ESR1), Microtubule Associated Protein Tau (MAPT), and Albumin (ALB) as central molecular hubs. Additionally, rutin emerged as a potential candidate for mitigating metal-induced neurotoxicity. Our findings draw attention to the significant dyslexia risk posed by mixed-metal exposures near e-waste recycling areas, emphasizing the urgent need for targeted environmental remediation, proactive public health interventions, and routine dyslexia screening.