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

2019-11-05

Airborne lower-chlorinated PCBs are vulnerable to metabolisation 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. In the present study, the authors investigated for the first time the potential endocrine disruption effects of PCB sulfates through oestrogen-related receptor ? (ERR?) 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 ERR? with the Kd (dissociation constant) values ranging from not available (NA) to 3.2??M 4′-OH-PCB 12 showed the highest binding affinity with Kd value of 3.2??M, which was comparable to that of a synthetic ERR? agonist GSK4716. The effects of the thirteen chemicals on the ERR? transcriptional activity were determined by using the luciferase reporter gene assay. It was found that the PCBs/OH-PCBs/PCB sulfates acted as agonists for ERR?, with the lowest observed effective concentration reaching 3??M. The binding affinity and agonistic activity of PCBs towards ERR? 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 Glu316 and Arg247 while PCBs and PCB sulfates could not, which might be the main factor impacting the binding affinity and agonistic activity. Overall, ERR? is a novel target for lower-chlorinated PCBs and their metabolites.

Authors: Cao LY, Ren XM, Guo LH.
; Full Source: Environmental Pollution. 2019 Nov;254(Pt B):113088. doi: 10.1016/j.envpol.2019.113088. Epub 2019 Aug 27.