Associations and mechanistic insights of multiple metal exposure and hypothyroidism: Evidence from population data and network toxicology

Disturbances in essential or toxic metal levels within the human body may disrupt thyroid homeostasis. However, existing studies on the associations between metal exposure and hypothyroidism have reported inconsistent findings, and the underlying mechanisms remain unclear. We aimed to evaluate the associations of multiple metal exposure with hypothyroidism and investigate the mechanisms using network toxicology analysis. Urinary concentrations of 13 metals were determined in 2916 participants using inductively coupled plasma mass spectrometry based on a cross-sectional study in Henan Province. The associations between metal exposure and hypothyroidism were assessed by generalized linear models, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) methods. Network toxicology analysis, including pathway enrichment and protein-protein interaction analyses, was conducted to identify potential hub genes and potential mechanistic pathways of metal-induced hypothyroidism. Urinary levels of Aluminum (Al) and Manganese (Mn) were significantly positively associated with hypothyroidism, while urinary levels of Selenium (Se) were negatively associated with hypothyroidism (all P < 0.05). In the WQS model, mixed metal exposure was positively associated with hypothyroidism (OR = 1.334, 95% CI: 1.086 ∼ 1.639), which was further supported by the BKMR model. Network toxicology analysis revealed Al, Mn, and Se-related hypothyroidism pathways, including lipid metabolism, PI3K-Akt signaling pathway, and apoptosis. Hub genes such as TNF, IL6, CASP3, and JUN were identified by Maximal clique centrality. Our findings suggest that exposure to Al, Mn, and Se was associated with hypothyroidism. The potential pathways involve lipid metabolism, the PI3K-Akt signaling pathway, and apoptosis.