Synthetic phenolic antioxidant exposure and type 2 diabetes: Joint effects of genetic risk and healthy lifestyle

Background: Synthetic Phenolic Antioxidants (SPAs) are widely used food and industrial additives, but their potential diabetogenic effects remain unclear. Whether genetic susceptibility and lifestyle modify the association between SPA exposure and Type 2 Diabetes Mellitus (T2DM) is largely unknown. 

Objective: This study aimed to assess associations of single and mixed SPAs exposure with T2DM and glycemic biomarkers, and further explore the joint modifying roles of genetic susceptibility and healthy lifestyle, so as to provide evidence for early prevention of T2DM. 

Methods: We conducted a 1:1 age- and sex-matched nested case–control study of 407 incident T2DM cases and 407 controls from a rural cohort in Henan Province, China. Urinary SPAs were measured using ultra-high-performance liquid chromatography–tandem mass spectrometry. Conditional logistic regression and restricted cubic spline models were used to evaluate associations of individual SPAs with T2DM and glycemic biomarkers. Mixture effects were assessed using quantile g-computation and advanced Bayesian kernel machine regression. Joint effects were further evaluated according to Weighted Genetic Risk Score (wGRS) and Healthy Lifestyle Score (HLS). 

Results: BHT-COOH and BHT-CHO were the predominant urinary SPAs. Higher exposure to both compounds was positively associated with T2DM, fasting plasma glucose, and insulin, with non-linear dose–response relationships. Mixture analyses consistently showed that combined SPA exposure was associated with increased T2DM risk, mainly driven by BHTCOOH and BHT-CHO. Higher genetic susceptibility was associated with greater T2DM risk, whereas a healthier lifestyle was associated with lower risk. Importantly, high SPA exposure was associated with a substantially greater T2DM risk among individuals with high genetic susceptibility or an unhealthy lifestyle. In contrast, low SPA exposure combined with lower genetic risk or a healthier lifestyle was associated with the lowest risk. Estimated exposure levels remained below corresponding health-based reference values. 

Conclusions: SPA exposure, particularly BHT-COOH and BHT-CHO, may contribute to T2DM risk and impaired glycemic homeostasis. Genetic susceptibility and lifestyle may modify these associations, suggesting that reducing environmental SPA exposure together with maintaining a healthy lifestyle may be particularly beneficial for populations at elevated genetic risk. 

Keywords: Synthetic Phenolic Antioxidants, Type 2 Diabetes Mellitus, Genetic Risk, Healthy Lifestyle, Mixed Exposure. 

Xuan Chen is a postgraduate student majoring in environmental and occupational health. Her research focuses on associations between environmental chemical exposure and chronic non‑communicable diseases, particularly type 2 diabetes. She takes part in the Chinese rural population cohort study and is mainly engaged in data management and statistical analysis for environmental risk‑factor research.