Synergistic effects of bisphenol A and its substitutes with latent insulin resistance on childhood blood pressure and the potential role of lipid metabolism.

Childhood hypertension is a growing public health concern, predisposing affected individuals to long-term cardiovascular complications. The cardiovascular and metabolic effects of exposure to bisphenol A (BPA) substitutes, emerging endocrine-disrupting chemicals, remain poorly understood in children. This study investigated associations between childhood BPA substitutes exposure and blood pressure, focusing on the modifying role of latent insulin resistance (LIR) and potential lipid metabolic pathways. A total of 747 children from a prospective cohort in Xiamen, China, were included. Associations between repeated bisphenol measurements and blood pressure were assessed using mixed-effects models and generalized estimating equations. A random subsample underwent lipidomic profiling; participants were grouped by bisphenol exposure and triglyceride-glucose (TyG) index. Differentially expressed lipids were identified, tested for associations with blood pressure, and analyzed by enrichment and mediation approaches. Exposure to bisphenol AF and AP was positively associated with higher systolic blood pressure z-scores (β = 0.075 and 0.144, both P < 0.001) and with increased risk of elevated and high blood pressure (OR = 1.218 and 1.364, P < 0.001 and = 0.002; OR = 1.281 and 1.539, both P < 0.001). Children with concurrently higher bisphenol AF or AP exposure and TyG exhibited lipid dysregulation, which was associated with increased childhood blood pressure. Dysregulated lipids were predominantly enriched in lysoglycerophospholipids and lipid-mediated signaling pathways. Specific lipids, including two glycerolipids and five glycerophospholipids, potentially mediated the association between bisphenol AF/AP × LIR and blood pressure, with indirect effects ranging from 0.114 to 0.626. In conclusion, bisphenol AP and AF were significantly associated with elevated childhood blood pressure. LIR amplified these adverse effects, partly through lipidomic perturbations, highlighting glycerophospholipid and glycerolipid metabolism as potential pathways underlying this association.