Computational evidence of cancer and reproductive toxicological potential from short-chain PFAS exposure through network toxicology and docking approaches.

Abstract

Short-chain per- and polyfluoroalkyl substances (PFAS) are increasingly being used as substitutes for long-chain PFAS due to their lower bioaccumulation potential. However, their persistence and mobility can lead to toxicity and pose significant long-term health risks. Hence, the present study aims to investigate the toxicity and the molecular mechanisms associated with cancer and reproductive toxicity linked to short-chain PFAS based on network toxicology and molecular docking. The short-chain PFAS representatives used in this study include PFBA, PFBS, PFHxA, and PFHpA. The predicted biological targets for PFBA, PFBS, PFHxA, and PFHpA are 6, 2, 20, and 34, respectively. Potential targets from the disease library were identified and analyzed for protein-protein interactions and pathway enrichment. The top five targets were selected for molecular docking studies to examine interactions. Molecular docking indicated strong interactions between biological targets and pollutants, mainly through hydrogen bonds and salt bridges. Short-chain PFAS representatives have shown strong interaction with proteins such as HDAC3 (-6.133 kcal/mol), SHBG (-6.176 kcal/mol), PPARD (-6.355 kcal/mol and -6.205 kcal/mol), and FABP4 (-6.091 kcal/mol). This study also used molecular dynamics (MD) simulations to validate interactions, revealing significant dynamic behavior between proteins and ligands. Fourteen proteins linked to short-chain PFAS were associated with cancer and reproductive toxicity, with many targets common across diseases. Notably, PFHxA and PFHpA share several target proteins, suggesting similar effects in the body. Overall, the study provides an overview of the biological targets of short-chain PFAS and their potential health impacts.