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Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes
Open accessAbstract
Bisphenol A (BPA) is an industrial compound and a well known endocrine-disrupting chemical with estrogenic activity. The widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Here we report that the mechanisms by which BPA and two congeners, bisphenol AF and bisphenol C (BPC), bind to and activate estrogen receptors (ER) α and β differ from that used by 17β-estradiol. We show that bisphenols act as partial agonists of ERs by activating the N-terminal activation function 1 regardless of their effect on the C-terminal activation function 2, which ranges from weak agonism (with BPA) to antagonism (with BPC). Crystallographic analysis of the interaction between bisphenols and ERs reveals two discrete binding modes, reflecting the different activities of compounds on ERs. BPA and 17β-estradiol bind to ERs in a similar fashion, whereas, with a phenol ring pointing toward the activation helix H12, the orientation of BPC accounts for the marked antagonist character of this compound. Based on structural data, we developed a protocol for in silico evaluation of the interaction between bisphenols and ERs or other members of the nuclear hormone receptor family, such as estrogen-related receptor γ and androgen receptor, which are two known main targets of bisphenols. Overall, this study provides a wealth of tools and information that could be used for the development of BPA substitutes devoid of nuclear hormone receptor-mediated activity and more generally for environmental risk assessment.
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“In these experiments, the protein data bank (PDB) entries 3OLL, 3UUD and 2AM9 were used for ERβ, ERα and AR, respectively [84,85,86]. These crystal structures were specifically selected as they are in ligand-bound states and therefore their conformations would allow ligand docking into the ligand-binding site.”
From Phytoecdysteroids and Anabolic Effect of Atriplex dimorphostegia: UPLC-PDA-MS/MS Profiling, In Silico and In Vivo Models (2023) · cites this paper as [86]
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Cited by
Sorted by citations
Potential Mechanisms of Bisphenol A (BPA) Contributing to Human Disease
Cimmino, I., Fiory, F., Perruolo, G., Miele, C., Bèguinot, F., Formisano, P., & Oriente, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165761 · Cited by 508
“between BPA and ERα, demonstrating that this compound binds ERα through 42 van der Waals interactions, instead of the 51 involved in E2-ERα binding [6].”
BackgroundEscher, B. I., Allinson, M., Altenburger, R., Bain, P. A., Balaguer, P., Busch, W., Crago, J., Denslow, N. D., Dopp, E., Hilscherová, K., et al. (2013) · Environmental Science & Technology · doi:10.1021/es403899t · Cited by 477
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“In this regard, when BPS was tested in HELN cells stably transfected with AF-1 deleted hERs, deletion of the A/B domain in hERβ markedly altered its transactivation potency, indicating that BPS is dependent on AF-1 (Delfosse et al., 2012).”
BackgroundOccurrence and profiles of bisphenol analogues in municipal sewage sludge in China
Song, S., Song, M., Zeng, L., Wang, T., Liu, R., Ruan, T., & Jiang, G. (2013) · Environmental Pollution · doi:10.1016/j.envpol.2013.11.023 · Cited by 293
“However, individual BPs showed varied estrogenicity properties, which were elucidated as discrete binding modes between BP analogues and corresponding nuclear hormone receptors (Delfosse et al., 2012).”
BackgroundXue, J., Wu, Q., Sakthivel, S., Pavithran, P. V., Jayakumar, R. V., & Kannan, K. (2014) · Environmental Research · doi:10.1016/j.envres.2014.12.007 · Cited by 272
“BPs can be used as additives or raw materials in plastic linings for food containers and thermo-sensitive coatings for papers (Delfosse et al., 2012).”
Background
Metadata
- Authors
- Delfosse, V., Grimaldi, M., Pons, J.-L., Boulahtouf, A., le Maire, A., Cavailles, V., Labesse, G., Bourguet, W., & Balaguer, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Centre de Biochimie Structurale, Institut National de la Santé et de la Recherche Médicale U1054, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5048, Universités Montpellier 1 and 2, 34090 Montpellier, France; and
- Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé et de la Recherche Médicale U896, Centre Régional de Lutte contre le Cancer Val d’Aurelle Paul Lamarque, Université Montpellier 1, 34298 Montpellier, France
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-08-27
- Volume
- 109
- Issue
- 37
- Pages
- 14930-14935
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3443136
- OpenAlex
- W2140633565
- Cited by
- 405
- References
- 45
- Citations by year
- 2026: 28 · 2025: 33 · 2024: 26 · 2023: 33 · 2022: 34 · 2021: 40 · 2020: 38 · 2019: 35 · 2018: 25 · 2017: 26 · 2016: 19 · 2015: 25 · 2014: 23 · 2013: 20
- FWCI
- 15.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- bisphenol A, bisphenol AF, bisphenol C, estrogen receptor alpha, estrogen receptor beta, endocrine disruptors, partial agonists, estrogen receptor antagonism, crystal structure, estrogen-related receptor gamma, androgen receptor, nuclear receptors, BPA substitutes, risk assessment, virtual screening
- MeSH terms
- Bisphenol A Compounds, Animals, Benzhydryl Compounds, Cell Line, Chromatography, Gel, Crystallography, Dose-Response Relationship, Drug, Estradiol, Fluorescence Polarization, Humans, Luciferases, Models, Molecular, Phenols, Oncorhynchus mykiss, Receptors, Cytoplasmic and Nuclear, Reverse Transcriptase Polymerase Chain Reaction, Estrogen Receptor alpha, Estrogen Receptor beta, Endocrine Disruptors
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