Investigating the association between bisphenols and diabetes: Evidence from epidemiological and bioinformatics

Bisphenol A (BPA), widely employed in the manufacture of plastics, has been associated with the development of numerous diseases. Bisphenol F (BPF) and bisphenol S (BPS) have been introduced as common substitutes for BPA; however, their safety profiles remain contentious, particularly regarding potential associations with diabetes risk. This study aimed to evaluate the relationship between exposure to bisphenols (BPs) and the prevalence of diabetes among U.S. adults using data from the National Health and Nutrition Examination Survey (NHANES), and to investigate the molecular mechanisms underlying BPF-induced diabetes through integrated network toxicology, molecular docking, and mediation analysis. After adjusting for confounders including sex, age, race, and education level, a statistically significant association was observed between BPF exposure and diabetes prevalence (OR = 1.04, P = 0.032). Stratified analyses revealed age-dependent metabolic heterogeneity: BPF exposure exhibited a linear association with diabetes in individuals under 50 years (OR = 1.05, P = 0.042), while a non-linear association was observed in those aged 50 and above (P-overall = 0.000876; P-nonlinear = 0.031). Network toxicology and molecular docking analyses indicated that BPF may impair insulin resistance and lipid metabolism by interacting with key proteins (FN1, GAPDH, TP53) through stable hydrogen bonding and π-π stacking, with binding affinities ranging from -5.1 to -7.0 kcal/mol. Mediation analysis suggested a potential suppressive effect of triglycerides on the association between BPF and diabetes in older adults (≥50 years), although the indirect effect was not statistically significant (IE = -0.008, 95 % CI: -0.019-0.003, P = 0.142). The negative mediation proportion (-12.1 %) indicated that the positive direct effect of BPF on diabetes (DE = 0.073, 95 % CI: 0.007-0.14, P = 0.031) was masked by triglycerides. These findings provide novel epidemiological and mechanistic insights into the link between BPF exposure and diabetes risk, underscoring the necessity for rigorous safety assessment of BPA substitutes in consumer plastics.