Study Of Binding Affinity Model Of Per-and Polyfluoroalkyl Substances To Proteins And Their Adverse Effects On Mice Pancreas

Per-and polyfluoroalkyl substances(PFAS)are of great concern because of wide distribution in the environment and their adverse effects on animal,plant and human health.With the development of research,PFAS have been proven a variety of biological toxicity(e.g.,hepatotoxicity,reproductive toxicity,developmental toxicity,neurotoxicity,and carcinogenicity).As a result,chemical manufacturers around the world have developed a series of PFAS alternatives for production needs.Although researchers have demonstrated a few toxic effects of PFAS alternatives,it still lacks knowledge about the toxicity mechanisms.According to reports,PFAS alternatives can bind to some target molecules in organisms(e.g.,transport proteins,nuclear receptors,and cell membranes)and affect the organs health(e.g.,the liver,kidney,and pancreas).This study will focus on predicting the potential toxic effects of PFAS alternatives on pancreatic health by studying the interaction between PFAS alternatives and pancreatic protein,and then verify on mice models.In this study,the predicted values of binding affinities between 28 PFAS alternatives and several proteins were calculated by molecular docking,and then the quantitative structure-activity relationship(QSAR)model of binding affinity between PFAS alternatives and proteins was established.Moreover,the hierarchical induction model was further used to establish the comprehensive binding affinity model of PFAS alternatives.Finally,the Kronecker-RLS model was established to predict the binding affinity under the multi-dimensional characteristics of molecules and proteins.The factors that affect the integrative binding affinity of PFAS alternatives were the relative negative charge,the capacity factor at-0.2.By predicting the binding affinity of PFAS alternatives to GPR40 protein,it was found that PFAS alternatives had potential toxic effects on pancreatic health.Protein-binding interactions of PFAS alternatives may provide new insights into the toxicity mechanism.This study focused on the adverse effects of 3 PFAS alternatives(perfluoroohexane sulfonic acid,perfluoroobutane sulfonic acid,and sodium pperfluorous nonenoxybenzene sulfonate)on pancreatic health in mice.The toxicity of PFAS alternatives were elucidated by histopathology,immunity,endoplasmic reticulum stress,16 s RNA sequencing of gut microbiota,and short-chain fatty acid targeting metabolomics.Sodium p-perfluorous nonenoxybenzene sulfonate conducted the greatest adverse effect to pancreas.It was suggested that the pancreas may be the target toxic organ of PFAS alternatives,and this research provided evidence for further expansion of toxic effects of PFAS alternatives.In conclusion,this study proved the toxicity and mechanisms of PFAS alternatives,compared the different toxicity of PFAS alternatives,and provided experimental evidence for the subsequent development of regulatory measures.