From environmental exposure to retinal pathology: epidemiological and mechanistic insights into multi-metal driven ocular diseases.

With aging and environmental pollution, heavy metal exposure has become a growing concern for age-related eye diseases. However, the relationship between heavy metals and age-related macular degeneration (AMD), cataracts, glaucoma, and diabetic retinopathy (DR) remains unclear. This study investigates the association between urinary heavy metals and these eye diseases, focusing on the molecular mechanisms of cadmium (Cd) in driving AMD. Data from the 2005-2008 NHANES (n = 1865) were analyzed using multivariable logistic regression, weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), restricted cubic spline (RCS) modeling, and sensitivity analyses. Potential molecular mechanisms of Cd in AMD were explored via intersection gene screening, protein-protein interaction network construction, and GO/KEGG enrichment analyses. In single-metal exposure models, Cd was significantly associated with AMD (OR = 1.563, 95% CI: 1.177-2.077, P = 0.00205), Co with cataract (OR = 1.386), U with glaucoma (OR = 1.300), and As with DR (OR = 1.214). In the WQS model, only AMD remained significantly associated with the overall metal mixture (OR = 1.89, 95% CI: 1.22-2.91, P = 0.0041). BKMR identified Cd as the most influential contributor to AMD (PIP = 0.523). The exposure-response curve for Cd and AMD demonstrated an upward trend, with the risk of AMD increasing as Cd exposure levels rose. Additionally, the overall metal mixture was positively associated with AMD risk. Subgroup and RCS analyses confirmed the stability of results, with no significant interaction across demographic subgroups. Sensitivity analyses further validated the findings: the highest quartile of Cd exposure was associated with increased AMD risk (OR = 2.45), and a significant dose-response trend was observed (P for trend = 0.0187). The association remained robust after excluding outliers (OR = 1.31, P = 0.0483).Mechanistically, Cd may induce retinal pigment epithelium damage via oxidative stress (SIRT1/TP53 axis), inflammation (TLR4/NF-κB pathway and pro-inflammatory cytokines), dysregulated apoptosis (BCL2/BAX imbalance), and hypoxia-induced metabolic disruption (HIF-1 signaling). Cd is an independent risk factor for AMD, likely acting through multiple toxic pathways. The effects of U, Co, and As may depend on exposure thresholds or confounders. These findings highlight the need for stricter Cd control and targeted antioxidant or anti-inflammatory strategies for age-related eye disease prevention and treatment.