Platelet mitochondrial DNA methylation mediates the association of bisphenol, phthalate, and paraben exposures with type 2 diabetes mellitus: An exploratory nested case-control study

Exposure to environmental pollutants has been found to be associated with epigenetic modifications of platelet mitochondria, which may influence the risk of type 2 diabetes mellitus (T2DM). However, research on the relationship between exposure to environmental endocrine disrupting chemicals (EDCs) and T2DM remains very limited at the molecular level of mitochondrial epigenetic alterations. This study aims to investigate the impact of mixed exposure to bisphenols (BPs), phthalates (PAEs), and parabens (PBs) on T2DM and platelet mitochondrial DNA (mtDNA) methylation, using a nested case-control study design. Levels of BPs, PAEs, and PBs metabolites were quantified using high-performance liquid chromatography-mass spectrometry (HPLC-MS). We used weighted quantile sum (WQS) and bayesian kernel machine regression (BKMR) models to assess the association between individual and mixed exposure to multiple EDCs and T2DM. Methylation levels of mitochondrial coding genes were measured by bisulfite pyrosequencing. In logistic regression models, MT-COX1 methylation levels were significantly negatively associated with T2DM risk, whereas MT-COX3 methylation levels were significantly positively associated. Both WQS and BKMR models indicated that mixed exposure to BPs, PAEs, and PBs was positively linked to T2DM, with DnPrP and DEHP identified as the primary contributors. Mediation analysis demonstrated that MT-COX3 methylation significantly mediated the associations of DEP, DMP, DEHP, DnPrP, DAlP, and MP with T2DM. Our findings indicate that both individual and mixed exposure to PAEs and PBs are positively associated with T2DM risk. Platelet mtDNA methylation mediates the association between EDCs exposure and T2DM risk, suggesting its potential utility as a biomarker. • Mixed exposure to BPs, PAEs, and PB markedly elevates T2DM risk in the elderly. • Platelet mtDNA COX1 and COX3 methylation significantly associated with T2DM. • MT-COX3 methylation mediated the relationship between EDCs and T2DM risk.