Estrogen-related receptor γ is a novel target for Lower-Chlorinated Polychlorinated Biphenyls and their hydroxylated and sulfated metabolites

Airborne lower-chlorinated PCBs are vulnerable to metabolization to PCB sulfates through further sulfation of the hydroxylated metabolites (OH-PCBs). However, studies on the toxic effects and mechanisms of PCB sulfates are still very limited. Here, we investigated for the first time the potential endocrine disruption effects of PCB sulfates through estrogen-related receptor gamma (ERR gamma) in comparison with their OH-PCBs precursors and PCB parent compounds. The binding affinity of thirteen PCBs/OH-PCBs/PCB sulfates was measured by using fluorescence competitive binding assays based on fluorescence polarization (FP). All of the tested chemicals could bind to ERRy with the K-d (dissociation constant) values ranging from not available (NA) to 3.2 mu M 4'-OH-PCB 12 showed the highest binding affinity with K-d value of 3.2 mu M, which was comparable to that of a synthetic ERR gamma agonist GSK4716. The effects of the thirteen chemicals on the ERR gamma transcriptional activity were determined by using the luciferase reporter gene assay. We found the PCBs/OH-PCBs/PCB sulfates acted as agonists for ERR gamma, with the lowest observed effective concentration reaching 3 mu M. The binding affinity and agonistic activity of PCBs towards ERR gamma were both enhanced after hydroxylation, while further sulfation of OH-PCBs decreased the activity instead. Molecular docking simulation showed that OH-PCBs had lower binding energy than the corresponding PCBs and PCB sulfates, indicating that OH-PCBs had higher binding affinity theoretically. In addition, OH-PCBs could form hydrogen bonds with amino acids G1u316 and Arg247 while PCBs and PCB sulfates could not, which might be the main factor impacting the binding affinity and agonistic activity. Overall, ERR gamma is a novel target for lower-chlorinated PCBs and their metabolites. (C) 2019 Elsevier Ltd. All rights reserved.