Binding and Activation of Estrogen-Related Receptor γ: A Novel Molecular Mechanism for the Estrogenic Disruption Effects of DDT and Its Metabolites

• Published in: Environmental science & technology Vol. 56; no. 17; pp. 12358 - 12367
• Main Authors: Wang, Li, Qie, Yu, Yang, Yu, Zhao, Qiang
• Format: Journal Article
• Language: English
• Published: Easton American Chemical Society 06.09.2022
• Subjects: Binding; Breast cancer; Cell cycle; Cell proliferation; Conformation; Disruption; Ecotoxicology and Public Health; Estrogen receptors; Estrogens; Ethanol; Fluorescence; Fluorescence polarization; Metabolites; Receptors; Xenoestrogens; DDT and its metabolites; signaling pathway; estrogenic effects; agonistic activity; ERRγ
• ISSN: 0013-936X; 1520-5851
• DOI: 10.1021/acs.est.1c08624

DDT and its metabolites (DDTs) can induce estrogenic effects. Previous mechanistic investigations mainly concentrated on activating the genomic transcription of estrogen receptor (ER) pathways. Here, we identified whether estrogen-related receptor γ (ERRγ), an orphan nuclear receptor, is a potential target of DDTs by receptor binding, transcriptional activity, and receptor-mediated pathway assays. Fluorescence polarization-based binding assays showed that all eight DDTs bound to ERRγ directly, with K d values ranging from 0.73–168.82 μM. Among them, 2,2-bis­(4-chlorophenyl)­ethanol (4,4′-DDOH) exhibited the highest binding affinity, which was 2.5-fold stronger than GSK4716, a well-known ERRγ agonist. Eight DDTs exhibited agonistic activity toward the ERRγ pathway, with 4,4′-DDOH showing the strongest potency. In silico studies revealed that DDTs tended to bind with ERRγ in the agonistic conformation. Using a SKBR3 breast cancer cell model, we further found that nanomolar or micromolar levels of DDTs significantly activated the ERRγ pathway in cells and induced cell proliferation through the ERRγ-modulated cell cycle. These results indicated that the binding and activation of DDTs to ERRγ might serve as molecular initiating events for subsequent ERRγ-mediated signaling pathways and adverse outcomes. Overall, our results demonstrated that ERRγ might be a crucial pathway involved in the estrogenic disruption effects of DDTs.