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      Bisphenol-C is the strongest bifunctional ERα-agonist and ERβ-antagonist due to magnified halogen bonding

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          Abstract

          We reported that bisphenol AF (BPAF) works as an agonist for estrogen receptor (ER) ERα but as an antagonist for ERβ. Similar results were observed for bisphenol E analogs (BPE-X) such as BPE-F, BPE-Cl, and BPE-Br, each consisting of a series of a tri-halogenated methyl group CX 3 in the central alkyl moiety. It was demonstrated that the electrostatic halogen bond based on the dispersion force of halogen atoms is a major driving force in the activities of bifunctional ERα-agonist and ERβ-antagonist. Since the chlorine atoms present in bisphenol C (BPC) exist in a π-π conjugated system due to the presence of an adjacent C = C double bond, we intended to prove that BPC is also a bifunctional ERα-agonist and ERβ-antagonist exhibiting greatly enhanced agonist/antagonist activities. BPC was evaluated for its ability to activate ERα and ERβ in the luciferase reporter gene assay using HeLa cells. With high receptor-binding ability to both ERs, BPC was found to be fully active for ERα but inactive for ERβ. BPC’s definite antagonist activity in ERβ was revealed by its inhibitory activity against 17β-estradiol. Thus, BPC is a bifunctional ERα-agonist and ERβ-antagonist. These agonist/antagonist activities were discovered to be extremely high among series of halogen-containing bisphenol compounds. This comparative structure-activity study revealed that the ascending order of ERα-agonist and ERβ-antagonist activities was BPE-F ≪ BPE-Cl ≲ BPAF < BPE-Br ≪ BPC. The highly intensified receptor interaction of BPC is attributable to the presence of an n-π-π-n conjugation system mediated through the >C = CCl 2 double bond.

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          A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding

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            EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals.

            The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.
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              Estrogen receptors: how do they signal and what are their targets.

              During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ER alpha and ER beta) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: SoftwareRole: Validation
                Role: SoftwareRole: Validation
                Role: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                9 February 2021
                2021
                : 16
                : 2
                : e0246583
                Affiliations
                [1 ] Laboratory of Structure-Function Biochemistry, Department of Chemistry, Faculty of Science, Kyushu University, Fukuoka, Japan
                [2 ] Department of Applied Microbial Technology, Faculty of Biotechnology and Life Sciences, Sojo University, Kumamoto, Japan
                [3 ] Faculty of Arts and Science, Kyushu University, Fukuoka, Japan
                [4 ] Division of Biology, Department of Earth System of Science, Faculty of Science, Fukuoka University, Fukuoka, Japan
                [5 ] Risk Science Research Institute, Fukuoka, Japan
                University of Parma, ITALY
                Author notes

                Competing Interests: The authors declare that no competing interests exist.

                Author information
                https://orcid.org/0000-0003-3162-429X
                Article
                PONE-D-20-33235
                10.1371/journal.pone.0246583
                7872235
                33561155
                5b08afc0-db83-4a78-9116-2e6249ca1418
                © 2021 Liu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 October 2020
                : 7 January 2021
                Page count
                Figures: 9, Tables: 3, Pages: 22
                Funding
                Funded by: Japan Society for the Promotion of Science (JSPS) KAKENHI
                Award ID: JP25740024; JP15K00557; 19K12340
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science (JSPS) KAKENHI
                Award ID: JP22221005; JP15H01741
                Award Recipient :
                Funded by: Health and Labour Sciences Research Grant for Research on the Risk of Chemical Substances from the Ministry of Health, Labour, and Welfare of Japan
                Award ID: H20-Chemistry-General-003
                Award Recipient :
                This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI; grant nos. JP25740024, JP15K00557, and 19K12340 (to X.L.) and JP22221005 and JP15H01741 (to Y.S.). This work was also supported in part by a Health and Labour Sciences Research Grant for Research on the Risk of Chemical Substances from the Ministry of Health, Labour, and Welfare of Japan, under contract/grant no. H20-Chemistry-General-003 (to Y.S.).
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                Particle Physics
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