Exposure to organochlorine pesticides and mortality risk among individuals with diabetes: A prospective cohort analysis and network pharmacology study

Emerging evidence suggests a potential link between organochlorine pesticides (OCPs) and diabetes, yet their impact on mortality risk among diabetic individuals is poorly understood. This longitudinal study assessed 1846 diabetic participants from the National Health and Nutrition Examination Surveys (2003-2016) with mortality follow-up extending to December 31, 2019. Serum levels of seven OCPs and metabolites were quantified using gas chromatography-high resolution mass spectrometry. An environmental risk score (ERS) was derived using LASSO regression to represent mixed OCP exposure. Over a median follow-up of 90.00 months, 467 out of 1846 diabetic individuals died, with 144 attributed to heart disease and 90 to cancer. Elevated serum concentrations of OCPs, particularly oxychlordane and trans-nonachlor, significantly correlated with increased risks of all-cause mortality (hazard ratio [HR]= 1.37, 95 % CI: 1.27-1.48 and HR= 1.42, 95 % CI: 1.32-1.53) and heart disease mortality (HR= 1.38, 95 % CI 1.27-1.49 and HR= 1.43, 95 % CI: 1.31-1.55). Additionally, oxychlordane was associated with cancer mortality (HR= 1.36, 95 % CI: 1.26-1.47). Notably, mixed OCP exposure, characterized by an innovative ERS, consistently predicted mortality risks, with restricted cubic spline curves illustrating a linear dose-response relationship. Additionally, sensitivity analyses confirmed the robustness of these findings against unmeasured confounders. Mechanistic investigations through network pharmacology identified 30 key proteins, including MAPK14, CREBBP, and EGFR. Gene Ontology and KEGG pathway analyses suggested potential mechanisms involving HIF-1 signaling, TNF signaling, and calcium signaling pathways. Our findings suggest a significant association between exposure to certain OCPs and increased mortality risks among diabetic populations, emphasizing the need for public health strategies to mitigate environmental pollutant exposure in diabetes management.