Molecular Modification And Mechanism Of PBDEs With Lower Estrogenic Activities And More Environmental Friendliness

Polybrominated diphenyl ethers(PBDEs)are a class of brominated flame retardants widely used in textiles,electronic products,plastic products and building materials.PBDEs have been identified as persistent organic pollutants(POPs)due to their significant biotoxicity,persistence,long-range transport potentials and bioconcentration.PBDEs are also endocrine disruptors that have marked estrogenic activities,which can cause damage to adipose tissue,reproductive development and central nervous system in humans and other organisms.The endocrine disrupting effects of PBDEs,especially estrogenic effects,have become a hot topic among environmental researches.Previous studies focused on the experimental determination and mechanism of PBDEs estrogenic activities,and lacked the regulation in estrogenic activities of PBDEs.Therefore,this study first constructed a 3D-QSAR model to predict the estrogenic activities of 209 PBDE congeners.The pharmacophore model and resolution V of the 210-3 fractional factorial design were used to design modified PBDE molecules with decreased estrogenic activities,and their POP-related and biodegradation-related flame-retardant properties were evaluated.The docking of modified PBDE molecules with human estrogen receptor(hER?)were used to explore the influencing factors of estrogenic activities of PBDE molecules.The experimental data of estrogenic activities(pEC50)of 17 PBDEs was used to establish a 3D-QSAR model by comparative molecular similarity index analysis(CoMSIA).The target PBDE molecules BDE-47,BDE-99,BDE-100,BDE-183,and BDE-209 were modified to decrease their estrogenic activities.The results showed that the established 3D-QSAR model gave a cross-validated correlation coefficient(q2)of 0.682(i.e.,>0.5),a non-cross-validated correlation coefficient(r2)of 0.980(i.e.,>0.9)and a correlation coefficient for the test set predictions(r2pred)of 0.724(i.e.,>0.6),indicating that the model had a good predictive ability.The mono-substituted and bis-substituted positions significantly affecting estrogenic activities of target molecules were determined by the resolution V of the 210-3 fractional factorial design,and the pharmacophore model revealed that the hydrophobic groups were considerable as the substituted groups for the target PBDE molecules.Accordingly,mono-and di-substitutions and hydrophobic substituent groups gave 40 modified molecules with decreased estrogenic activities,including modified BDE-47 and BDE-99 with pEC50 decreased by>10%and modified BDE-100,BDE-183,and BDE-209 with pEC50 decreased by>20%.The modified molecules had similar flame-retardancy to the unmodified molecules,lower biotoxicities(by a maximum of 17.27%),persistences(by a maximum of 55.68%),long-range transport potentials(by 0.72%-18.47%)and bioconcentration(by 4.28%-23.91%),and higher biodegradability.Additionally,the docking of modified PBDE molecules with hERa(PDB IDs:1A52,1ERE,2QA8 and 3ERD)was carried out to analyze the scoring functions and binding conformations.The results revealed that hydrophobic interactions were found to be the main factors affecting estrogenic activities of PBDE molecules.The average distances between the hydrophobic substituents and hydrophobic residues negatively correlated with the estrogenic activities of PBDE molecules,which can explain the differences in estrogenic activities of PBDE molecules mediated by hERa.The ortho substitutions for PBDEs could be influential to decrease the estrogenic activity.