Modification Of Polychlorinated Biphenyls To Molecules With Lower Estrogen Activity And Environmental Risk Assessment Of Their Metabolites Based On The 3D-QSAR Model

Polychlorinated biphenyls(PCBs)are a typical type of persistent organic pollutants(POPs),which are widely distributed in the environment and difficult to be degraded.Polychlorinated biphenyls and their transformation products not only have significant environmental persistence,long-distance migration,high biological toxicity and high biological enrichment,but also their endocrine disrupting properties can not be ignored.Among them,estrogen activity is the most significant,which can cause serious harm to the normal metabolism of reproductive,nervous and endocrine systems of organisms.In recent years,the environmental endocrine disruptor of PCBs,mainly due to estrogen activity,has attracted extensive attention from scientists.Existing studies generally focus on the experimental methods for the determination of estrogen activity of PCBs homologues,but there are few studies on the risk regulation and mechanism of action of reducing estrogen activity of PCBs homologues.In this study,the estrogen-activity values(pREC20)of 209 PCBs were predicted using a three-dimensional quantitative structure-activity relationship(3D-QSAR)model constructed by density functional theory(DFT).According to the information provided by the three-dimensional isopotential map,the molecular modification scheme of PCBs with low-estrogen-active was developed,and the functional and POPs characteristics of the modified PCBs were evaluated comprehensively.The 2D-QSAR model and molecular docking technology were used to explore the influencing factors of estrogen activity of PCBs before and after modification.The molecular dynamics method was used to regulate the binding ability of PCBs molecules with estrogen receptors by changing the external environmental conditions,and further affect the expression of estrogen activity.The experimental values of estrogen activity(pREC20)of 11 known PCBs molecules were selected as the dependent variable and the structural parameters as the independent variable.The 3D-QSAR model was constructed by combining the comparative molecular similarity index analysis(CoMSIA).It was used to predict the pREC20 value of the remaining 198 PCBs,so as to establish the relationship between estrogen activity and the molecular structure of PCBs.The PCB-44 with the highest pREC20 value in the data source was determined as the target molecule.According to the three-dimensional isopotential map,the sites and substituent groups that had a greater influence on the estrogen activity of PCB-44 molecule were obtained,and 50 kinds of new PCB-44 molecules with low estrogen activity were designed.The results show that the cross validation coefficient q2 of CoMSIA model was 0.665(>0.5).the correlation coefficient R2 of non-cross-validation was 0.991(>0.9),the cross test coefficient Rpred2 of external prediction set was 0.902(>0.6).indicating that the established model had strong stability and good predictive ability.According to the three-dimensional isopotential map of CoMSIA.the electrostatic field effect and hydrophobic field effect were the main factors affecting the pREC20 value of PCBs homologs.A total of 50 new PCBs molecules were designed by introducing less electronegative than Cl and hydrophilic groups into the positions respectively for single and double substitution where the estrogen activity of the target molecule was significantly affected.In addition,the estrogen activity was decreased to varying degrees(the reduction range was 0.6%-38.7%).The POPs properties of the seven modified PCB-44 molecular derivatives were significantly reduced under the condition that the functionality remained unchanged(the maximum reduction was 43.09%in bioenrichment,68.09%in environmental persistence,30.73%in long-distance migration,and 17.98%in biotoxicity).The molecular docking results of PCBs before and after modification with human estrogen-α receptor(hERα,PDB ID:2AYR,2Q70,1ERR,2Q6J and 2IOK)showed that the decrease of hydrophobic action caused by the hydrophobic amino acid residues and hydrophobic substituents at the binding site between PCBs derivatives and hERa was the main reason for the decrease of binding force and estrogen-α activity.The shorter the mean distance between the hydrophobic substituents of PCBs derivatives and the hydrophobic amino acid residues at the hERa binding site,and the greater the number of hydrophobic amino acid residues,the greater the estrogenic activity of PCBs derivatives.Therefore,by adding xylitol,mannitol,tannin,anthocyanin and other additives to change the external environmental conditions to weaken the hydrophobic interaction between PCBs molecules and estrogen receptor,thus reducing the binding ability of PCBs molecules and estrogen receptor,the risk of estrogen activity generated by residual PCBs molecules in the environment can be effectively regulated.In addition,based on the metabolic mechanism of PCBs molecules and their derivatives in organisms,the metabolites that may be generated during the transformation process were deduced.The established 3D-QSAR model was used to predict the estrogen activity and POPs characteristics of PCBs molecules before and after modification and their metabolites,so as to evaluate their potential environmental risks.The results showed that the estrogen activity and POPs properties of the molecular biological metabolites of the modified PCBs derivatives were higher than their parent molecules,indicating that the designed environmentally friendly PCBs derivatives still had certain environmental risks in the biological metabolism process.Therefore,in the modification of environmentally friendly PCBs molecules,the biological metabolic pathway simulation of the derivative molecules can be used as one of the screening conditions to avoid their potential environmental risks.