Association Between Per- and Polyfluoroalkyl Substances and All-Cause Mortality in Diabetic Patients: Insights from a National Cohort Study and Toxicogenomic Analysis

Per- and polyfluoroalkyl substances (PFAS) are a group of environmental contaminants associated with various health risks: however, their relationship with all-cause mortality in individuals with diabetes remains unclear. A total of 1256 participants from the National Health and Nutrition Examination Survey (NHANES) were included to explore the association between seven PFAS compounds and all-cause mortality in diabetic patients. Preliminary logistic regression identified three PFAS compounds (perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS], and 2-(N-methyl-PFOSA) acetate acid [MPAH]) as significantly associated with mortality in the diabetic population. The optimal cut-off values for PFOS, PFOA, and MPAH were determined using the X-tile algorithm, and participants were categorized into high- and low-exposure groups. Kaplan&ndash:Meier survival curves and multivariable Cox proportional hazards regression models were used to assess the relationship between PFAS levels and mortality risk. The results showed that high levels of PFOS were significantly associated with increased all-cause mortality risk in diabetic patients (hazard ratio [HR]: 1.55, 95% confidence interval [CI]: 1.06&ndash:2.29), while PFOA and MPAH showed no significant associations. To explore mechanisms underlying the PFOS&ndash:mortality link, toxicogenomic analysis identified 95 overlapping genes associated with PFOS exposure and diabetes-related mortality using the Comparative Toxicogenomics Database (CTD) and GeneCards. Functional enrichment analysis revealed key biological processes, such as glucose homeostasis and response to peptide hormone, with pathways including the longevity regulating pathway, apoptosis, and p53 signaling pathway. Protein&ndash:protein interaction network analysis identified 10 hub genes, and PFOS was found to upregulate or downregulate their mRNA expression, protein activity, or protein expression, with notable effects on mRNA levels. These findings suggest that PFOS exposure contributes to increased mortality risk in diabetic patients through pathways related to glucose metabolism, apoptosis, and cellular signaling. Our study provides new insights into the association between PFAS and all-cause mortality in diabetes, highlighting the need for large-scale cohort studies and further in vivo and in vitro experiments to validate these findings.