Lead-driven synergistic interactions in environmental metal (loid) mixtures: Systemic inflammation mediating autism spectrum disorder risk in Chinese children

Environmental metal (loid) exposure, particularly to lead (Pb), constitutes a growing concern for potential associations with autism spectrum disorder (ASD). Current risk assessments may underestimate neurodevelopmental impacts due to co-exposure interactions, while systemic inflammation's mediating role in Pb-ASD relationships remains poorly characterized. This case-control study quantified serum concentrations of eight metal (loid)s via inductively coupled plasma mass spectrometry (ICP-MS) in 81 ASD cases and 402 typically developing (TD) Chinese children. Logistic regression demonstrated significantly elevated ASD risk with increasing Pb exposure quartiles (Q3 vs. Q1: OR = 2.64, 95 % CI 1.42-4.89; Q4 vs. Q1: OR = 6.85, 95 % CI 3.24-14.48; P_trend < 0.001). Restricted cubic spline analysis confirmed a positive nonlinear dose-response relationship between log-transformed Pb levels and ASD risk (P_non-linear = 0.004, P_overall < 0.001). Multi-pollutant mixture analyses identified Pb as the predominant contributor to ASD risk in both quantile g-computation (weight = 0.5099) and Bayesian kernel machine regression (PIP = 1.00) models, with evidence of significant cobalt (Co)-Pb interaction. Mediation analyses indicated systemic inflammation indices (SIRI, SII) partially mediated the Pb-ASD association (15.8 % and 8.6 %, respectively). These findings identify Pb as a principal determinant of metal (loid)-associated ASD risk, with inflammatory pathways contributing to its neurotoxicity. The observed Co-Pb interaction warrants investigation into co-exposure neurotoxicity mechanisms.