Plastic additives, such as phthalates and organophosphate esters (OPEs), are ubiquitous environmental contaminants. Their widespread use, coupled with low recycling rates, leads to significant environmental pollution and potential human exposure via ingestion, inhalation, and skin contact. PAEs are widely used plasticizers, while OPEs serve as flame retardants and plasticizers. While individual studies have linked PAEs or OPEs to diabetes, the impact of their combined exposure and the modifying role of dietary antioxidants remain unclear. Previous research suggests a link between PAE exposure, oxidative stress, insulin resistance, and diabetes, with some evidence suggesting that antioxidants might mitigate these effects. This study aimed to (1) analyze the association between combined PAEs and OPEs exposure and diabetes; (2) investigate whether antioxidant diets modify this association; and (3) identify potential biological mechanisms using the AOP framework.

Prior research has established links between individual plastic additives and various health problems. Studies have shown associations between PAEs or OPEs and adverse reproductive outcomes, childhood asthma, and neurodevelopmental deficits. Regarding diabetes, some studies have reported positive correlations between PAE exposure and increased risk, with variations based on the specific PAE metabolite and the population studied. Research also suggests that PAE exposure may increase oxidative stress, a factor in insulin resistance and diabetes. Furthermore, some studies indicate that higher antioxidant levels, such as serum β-carotene, may weaken the association between PAE exposure and insulin resistance. However, the impact of combined PAE and OPE exposure on diabetes and the modifying effect of dietary antioxidants have been largely unexplored.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES) 2011–2018, encompassing 2824 adult participants after exclusions for age, pregnancy, and missing data. Fifteen chemicals (10 PAEs and 5 OPEs) were measured in urine, adjusting for urinary creatinine to account for urine dilution. A composite dietary antioxidant index (CDAI) was calculated based on the intake of vitamins A, C, and E, selenium, zinc, and carotenoids. The association between individual chemicals and diabetes was analyzed using survey-weighted logistic regression. To assess the cumulative risk of diabetes from combined PAE and OPE exposure, an environmental risk score (ERS) was calculated using the adaptive elastic net (adENET) method, employing five-fold cross-validation to mitigate bias. Quantile g-computation was used to evaluate the combined effect of PAEs and OPEs on diabetes, considering both crude and adjusted models. The interaction between ERS and CDAI on diabetes risk was evaluated using weighted logistic regression and quantile g-computation. Finally, an adverse outcome pathway (AOP) analysis was performed using the comparative toxicogenomics database (CTD), disease gene network (DisGeNET), and MalaCards databases to identify potential mechanisms linking TCPP and TCEP exposure to diabetes.

A higher ERS was significantly associated with an increased risk of diabetes (OR per 1-SD increment: 1.25, 95% CI: 1.13–1.39). This association interacted significantly with CDAI (Pinteraction = 0.038), with a stronger effect observed in the low CDAI group (ORlow: 1.83, 95% CI: 1.37–2.55) compared to the high CDAI group (ORhigh: 1.28, 95% CI: 1.15–1.45). Quantile g-computation confirmed the positive association between higher combined exposure and diabetes (OR: 1.27, 95% CI: 1.05–2.87). However, this association was attenuated when dietary antioxidants were included (OR: 1.09, 95% CI: 0.85–2.34), indicating a modifying effect of dietary antioxidants. AOP analysis identified TCPP and TCEP as key chemicals potentially causing diabetes through effects on glucose metabolism and insulin signaling pathways. Specifically, TCPP may disrupt fatty acid beta-oxidation, affecting glucose metabolism, while TCEP may affect insulin signaling pathways.

This study provides evidence of a significant association between co-exposure to PAEs and OPEs and increased diabetes risk. The modifying effect of dietary antioxidants suggests that nutritional interventions may help mitigate this risk. The AOP analysis offers potential mechanistic insights into how TCPP and TCEP might contribute to diabetes through disruption of glucose metabolism and insulin signaling. These findings are consistent with previous research indicating that PAEs can induce oxidative stress and inflammation, factors known to contribute to diabetes. The interaction between ERS and CDAI suggests that a diet rich in antioxidants could be a protective factor against the diabetogenic effects of these plastic additives. However, further research is needed to confirm these findings and explore other potential mechanisms.

Combined exposure to PAEs and OPEs increases diabetes risk, an effect modified by dietary antioxidant intake. TCPP and TCEP are implicated in potential mechanisms involving glucose metabolism and insulin signaling. Future research should focus on longitudinal studies to establish causality, explore a wider range of plastic chemicals, investigate the specific roles of different antioxidant nutrients, and examine the interaction between genetic predispositions and environmental exposures in diabetes development.

This study's cross-sectional design limits the ability to establish causality between exposure and diabetes. Unmeasured confounders and residual confounding may affect the observed associations. The study did not differentiate between type 1 and type 2 diabetes, potentially limiting interpretation of the specific mechanisms involved. Finally, the AOP analysis relies on publicly available databases, and findings require validation through further experimental research.