Potential mechanisms and modifications of dietary antioxidants on the associations between co-exposure to plastic additives and diabetes

BACKGROUND: The association of plastic additive mixture exposure with diabetes and the modifying effects of dietary antioxidants are unclear. METHODS: Using NHANES 2011–2018 data, urinary phthalates and organophosphate esters (OPEs) were analyzed as exposures. Co-exposure effects were assessed via environmental risk score (ERS) derived from adaptive elastic net and by quantile g-computation; a cross-validated ERS (ERS_CV) was also constructed. Dietary antioxidant intake was summarized by the composite dietary antioxidant index (CDAI). Potential biological mechanisms were explored using an adverse outcome pathway (AOP) framework integrating public databases. RESULTS: Fifteen chemicals (10 phthalates, 5 OPEs) were measured in 2824 adults. Higher ERS was associated with greater diabetes odds (OR per 1-SD ERS: 1.25, 95% CI: 1.13–1.39), with effect modification by CDAI (ORlow: 1.83, 95% CI: 1.37–2.55; ORhigh: 1.28, 95% CI: 1.15–1.45; Pinteraction = 0.038). Quantile g-computation showed a positive mixture association (OR: 1.27, 95% CI: 1.05–2.87), whereas adding dietary antioxidants attenuated the association (OR: 1.09, 95% CI: 0.85–2.34). AOP analyses implicated TCPP and TCEP in disrupting glucose metabolism and insulin signaling leading to diabetes. CONCLUSIONS: Co-exposure to phthalates and OPEs is positively associated with diabetes, and an antioxidative diet modifies this association. AOPs suggest plausible mechanistic pathways.