Elucidating the associations and molecular mechanisms of perfluoroalkyl substances exposure with type 2 diabetes and its complications: A multifaceted approach

BACKGROUND: Environmental pollutants, such as perfluoroalkyl substances (PFASs), have been implicated in various human diseases. Despite growing evidence from observational studies linking PFASs to type 2 diabetes (T2D), results have been inconsistent. This study aims to investigate the relationships between PFASs exposure and the onset of T2D and its complications, and to elucidate the underlying molecular mechanisms. METHODS: Mendelian randomization (MR) analysis was conducted to evaluate the relationships between PFASs exposure and the onset of T2D and its complications. PFASs data were sourced from the GWAS Catalog, while T2D and its complications data were retrieved from the FinnGen database. Network toxicology was utilized to investigate the potential molecular mechanisms underlying the significant associations between compounds and diseases. Molecular docking and molecular dynamics simulations were employed to verify the binding stability between the compounds and their core target genes. RESULTS: PFOS exhibited a statistically significant positive association with the risk of diabetic retinopathy (DR) (P < 0.05, OR > 1). 200 intersection targets were obtained, among which EGFR, ESR1, and MMP9 were identified as core targets. Molecular docking and molecular dynamics simulations indicated that PFOS had strong binding affinity with these core targets. Additionally, PFOS might influence DR by mainly modulating the FoxO signaling pathway. CONCLUSIONS: PFOS is significantly associated with DR. EGFR, ESR1, and MMP9 have been identified as core targets associated with DR. These findings may elucidate the mechanisms by which environmental pollutants contribute to the development of DR.