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      Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification

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          Abstract

          Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach.

          Abstract

          In this Expert Consensus Statement, the authors define 10 key characteristics (KCs) for endocrine-disrupting chemicals. They further describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs.

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          Most cited references136

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          Bisphenol A and human health: a review of the literature.

          There is growing evidence that bisphenol A (BPA) may adversely affect humans. BPA is an endocrine disruptor that has been shown to be harmful in laboratory animal studies. Until recently, there were relatively few epidemiological studies examining the relationship between BPA and health effects in humans. However, in the last year, the number of these studies has more than doubled. A comprehensive literature search found 91 studies linking BPA to human health; 53 published within the last year. This review outlines this body of literature, showing associations between BPA exposure and adverse perinatal, childhood, and adult health outcomes, including reproductive and developmental effects, metabolic disease, and other health effects. These studies encompass both prenatal and postnatal exposures, and include several study designs and population types. While it is difficult to make causal links with epidemiological studies, the growing human literature correlating environmental BPA exposure to adverse effects in humans, along with laboratory studies in many species including primates, provides increasing support that environmental BPA exposure can be harmful to humans, especially in regards to behavioral and other effects in children. Copyright © 2013 Elsevier Inc. All rights reserved.
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            How Ligands Illuminate GPCR Molecular Pharmacology

            G protein-coupled receptors (GPCRs), which are modulated by a variety of endogenous and synthetic ligands, represent the largest family of druggable targets in the human genome. Recent structural and molecular studies have both transformed and expanded classical concepts of receptor pharmacology and begun to illuminate the distinct mechanisms by which structurally, chemically, and functionally diverse ligands modulate GPCR function. These molecular insights into ligand engagement and action have enabled new computational methods and accelerated the discovery of novel ligands and tool compounds —especially for understudied and orphan GPCRs. These advances promise to streamline the development of GPCR-targeted medications.
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              Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist.

              The increase in the number of reports of abnormalities in male sex development in wildlife and humans coincided with the introduction of 'oestrogenic' chemicals such as DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) into the environment. Although these phenotypic alterations are thought to be mediated by the oestrogen receptor, they are also consistent with inhibition of androgen receptor-mediated events. Here we report that the major and persistent DDT metabolite, p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), has little ability to bind the oestrogen receptor, but inhibits androgen binding to the androgen receptor, androgen-induced transcriptional activity, and androgen action in developing, pubertal and adult male rats. The results suggest that abnormalities in male sex development induced by p,p'-DDE and related environmental chemicals may be mediated at the level of the androgen receptor.
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                Author and article information

                Contributors
                mlamerrill@ucdavis.edu
                Journal
                Nat Rev Endocrinol
                Nat Rev Endocrinol
                Nature Reviews. Endocrinology
                Nature Publishing Group UK (London )
                1759-5029
                1759-5037
                12 November 2019
                12 November 2019
                2020
                : 16
                : 1
                : 45-57
                Affiliations
                [1 ]ISNI 0000 0004 1936 9684, GRID grid.27860.3b, Department of Environmental Toxicology, , University of California, ; Davis, CA USA
                [2 ]ISNI 0000 0001 0742 0364, GRID grid.168645.8, Department of Environmental Health Science, School of Public Health and Health Sciences, , University of Masschusetts, ; Amherst, MA USA
                [3 ]ISNI 0000 0001 2181 7878, GRID grid.47840.3f, School of Public Health, , University of California, ; Berkeley, CA USA
                [4 ]ISNI 0000000098234542, GRID grid.17866.3e, California Pacific Medical Center Research Institute, Sutter Hospital, ; San Francisco, CA USA
                [5 ]ISNI 0000000121590079, GRID grid.36193.3e, Environmental Directorate, Organisation for Economic Co-operation and Development, ; Paris, France
                [6 ]ISNI 0000 0001 2173 6074, GRID grid.40803.3f, Department of Biological Sciences, , North Carolina State University, ; Raleigh, NC USA
                [7 ]ISNI 0000000405980095, GRID grid.17703.32, International Agency for Research on Cancer, World Health Organization, ; Lyon, France
                [8 ]ISNI 0000 0001 0724 6933, GRID grid.7728.a, Department of Life Sciences, , Brunel University, ; London, UK
                [9 ]ISNI 0000 0001 2146 2763, GRID grid.418698.a, Office of the Science Advisor, United States Environmental Protection Agency, ; Washington, DC USA
                [10 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, , University of California, San Francisco, ; San Francisco, CA USA
                [11 ]ISNI 0000 0001 0481 6099, GRID grid.5012.6, Institute of Data Science, , Maastricht University, ; Maastricht, Netherlands
                [12 ]ISNI 0000 0001 0746 5933, GRID grid.140139.e, Center for Health and Environmental Risk Research, National Institute for Environmental Studies, ; Ibaraki, Japan
                [13 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, Receptor Biology, Section Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Science, ; Durham, NC USA
                [14 ]ISNI 0000 0004 1936 9924, GRID grid.89336.37, Division of Pharmacology and Toxicology, , University of Texas at Austin, ; Austin, TX USA
                [15 ]ISNI 0000 0001 0704 4602, GRID grid.428205.9, Office of the Director, Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency, ; Sacramento, CA USA
                [16 ]ISNI 0000 0001 0742 0364, GRID grid.168645.8, Biology Department, , University of Masschusetts, ; Amherst, MA USA
                Author information
                http://orcid.org/0000-0002-5720-5862
                http://orcid.org/0000-0001-7489-3188
                http://orcid.org/0000-0002-0414-2167
                http://orcid.org/0000-0003-1278-2890
                http://orcid.org/0000-0001-7825-1262
                http://orcid.org/0000-0001-9055-9729
                http://orcid.org/0000-0003-3622-1297
                http://orcid.org/0000-0002-7765-418X
                http://orcid.org/0000-0001-5549-6793
                http://orcid.org/0000-0002-7485-2658
                Article
                273
                10.1038/s41574-019-0273-8
                6902641
                31719706
                92b86370-27ae-4d7e-a574-2e348f62c294
                © Springer Nature Limited 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 October 2019
                Categories
                Consensus Statement
                Custom metadata
                © Springer Nature Limited 2020

                endocrinology,risk factors,chemical safety
                endocrinology, risk factors, chemical safety

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