Structure-Dependent Hematological Effects of Per- and Polyfluoroalkyl Substances on Activation of Plasma Kallikrein-Kinin System Cascade

Per- and polyfluoroalkyl substances (PFASs) are a global concern because of their ubiquitous occurrence and high persistence in human blood, and increasing amounts of unidentified fluorinated compounds are now becoming new exposure issues. This study aims to investigate the structure-related effects of PFASs on the activation of the plasma kallikrein-kinin system (KKS). The effects of 20 PFASs and the related long-chain aliphatic compounds were screened, and their binding affinities for the initial zymogen, Hagmen factor XII (FXII) in the KKS, were evaluated by molecular docking analysis. PFASs were demonstrated to activate the KKS in a structure-dependent mode. More specifically, PFASs with longer carbon chain length, higher fluorine atom substitution degree, and terminal acid group exhibited relatively higher activities in activating the KKS. The binding affinities of PFASs with FXII determined their capabilities for inducing KKS activation. The alternative binding modes of PFASs with FXII, together with van der Waals and hydrogen bonds, specifically accommodated the distinctive chemical structures. To our knowledge, PFASs, for the first time, were found to induce the activation of the KKS in plasma, and their chemical structure-related effects would be extremely important for risk assessment on emerging PFASs in addition to the listing in Stockholm Convention.