Lead exposure increases the risk of retinal vein occlusion: a population-based analysis and investigation of PRICKLE4/PLCXD1-mediated endothelial cell mechanisms

Background Retinal vein occlusion (RVO) is one of a leading cause of blindness with complex etiology. This study aims to investigate the relationship between blood heavy metal concentrations and RVO, and explored transcriptomic effects of lead on endothelial cells. Methods Using the 2005-2008 NHANES data, individuals ≥40 years with fundus and heavy metal testing were analyzed. Multivariate logistic regression model was used to evaluate the relationship between blood lead, cadmium, mercury and RVO, with multi‑exposure modeling for combined effects. RNA sequencing was performed on HUVECs treated with 10 μM or 30 μM lead nitrate versus controls, followed by qRT‑PCR validation and functional enrichment analysis. Results Of 5,415 participants, 32 had RVO. The blood lead concentration in the RVO group was significantly higher than that in the control group ( p < 0.001). In the fully adjusted model, higher blood lead levels were associated with increased odds of RVO (continuous model, p = 0.0111; top vs. bottom tertile: p = 0.0198).Cadmium and mercury showed no significant association. Multiple exposure analysis further confirmed that blood lead showed a stable risk contribution in the context of multiple exposure. RNA sequencing identified 166 common differentially expressed genes; PRICKLE4 and PLCXD1 expression changes were validated. Enrichment analysis revealed Wnt signaling pathway involvement, with PRICKLE4 linked to Wnt and PLCXD1 to phosphoric diester hydrolase activity. Discussion These findings suggest lead may promote RVO by disrupting Wnt signaling and phosphodiesterase‑related pathways in endothelial cells, offering novel mechanistic insights.