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      Bisphenol A causes reproductive toxicity, decreases dnmt1 transcription, and reduces global DNA methylation in breeding zebrafish (Danio rerio)

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          ABSTRACT

          Bisphenol A (BPA) is a commercially important high production chemical widely used in epoxy resins and polycarbonate plastics, and is ubiquitous in the environment. Previous studies demonstrated that BPA activates estrogenic signaling pathways associated with adverse effects on reproduction in vertebrates and that exposure can induce epigenetic changes. We aimed to investigate the reproductive effects of BPA in a fish model and to document its mechanisms of toxicity. We exposed breeding groups of zebrafish ( Danio rerio) to 0.01, 0.1, and 1 mg/L BPA for 15 d. We observed a significant increase in egg production, together with a reduced rate of fertilization in fish exposed to 1 mg/L BPA, associated with significant alterations in the transcription of genes involved in reproductive function and epigenetic processes in both liver and gonad tissue at concentrations representing hotspots of environmental contamination (0.1 mg/L) and above. Of note, we observed reduced expression of DNA methyltransferase 1 ( dnmt1) at environmentally relevant concentrations of BPA, along with a significant reduction in global DNA methylation, in testes and ovaries following exposure to 1 mg/L BPA. Our findings demonstrate that BPA disrupts reproductive processes in zebrafish, likely via estrogenic mechanisms, and that environmentally relevant concentrations of BPA are associated with altered transcription of key enzymes involved in DNA methylation maintenance. These findings provide evidence of the mechanisms of action of BPA in a model vertebrate and advocate for its reduction in the environment.

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          JASPAR: an open-access database for eukaryotic transcription factor binding profiles.

          The analysis of regulatory regions in genome sequences is strongly based on the detection of potential transcription factor binding sites. The preferred models for representation of transcription factor binding specificity have been termed position-specific scoring matrices. JASPAR is an open-access database of annotated, high-quality, matrix-based transcription factor binding site profiles for multicellular eukaryotes. The profiles were derived exclusively from sets of nucleotide sequences experimentally demonstrated to bind transcription factors. The database is complemented by a web interface for browsing, searching and subset selection, an online sequence analysis utility and a suite of programming tools for genome-wide and comparative genomic analysis of regulatory regions. JASPAR is available at http://jaspar. cgb.ki.se.
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            Ensembl BioMarts: a hub for data retrieval across taxonomic space

            For a number of years the BioMart data warehousing system has proven to be a valuable resource for scientists seeking a fast and versatile means of accessing the growing volume of genomic data provided by the Ensembl project. The launch of the Ensembl Genomes project in 2009 complemented the Ensembl project by utilizing the same visualization, interactive and programming tools to provide users with a means for accessing genome data from a further five domains: protists, bacteria, metazoa, plants and fungi. The Ensembl and Ensembl Genomes BioMarts provide a point of access to the high-quality gene annotation, variation data, functional and regulatory annotation and evolutionary relationships from genomes spanning the taxonomic space. This article aims to give a comprehensive overview of the Ensembl and Ensembl Genomes BioMarts as well as some useful examples and a description of current data content and future objectives. Database URLs: http://www.ensembl.org/biomart/martview/; http://metazoa.ensembl.org/biomart/martview/; http://plants.ensembl.org/biomart/martview/; http://protists.ensembl.org/biomart/martview/; http://fungi.ensembl.org/biomart/martview/; http://bacteria.ensembl.org/biomart/martview/
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              The DNA methyltransferases of mammals.

              T Bestor (2000)
              The biological significance of 5-methylcytosine was in doubt for many years, but is no longer. Through targeted mutagenesis in mice it has been learnt that every protein shown by biochemical tests to be involved in the establishment, maintenance or interpretation of genomic methylation patterns is encoded by an essential gene. A human genetic disorder (ICF syndrome) has recently been shown to be caused by mutations in the DNA methyltransferase 3B (DNMT3B) gene. A second human disorder (Rett syndrome) has been found to result from mutations in the MECP2 gene, which encodes a protein that binds to methylated DNA. Global genome demethylation caused by targeted mutations in the DNA methyltransferase-1 (Dnmt1) gene has shown that cytosine methylation plays essential roles in X-inactivation, genomic imprinting and genome stabilization. The majority of genomic 5-methylcytosine is now known to enforce the transcriptional silence of the enormous burden of transposons and retroviruses that have accumulated in the mammalian genome. It has also become clear that programmed changes in methylation patterns are less important in the regulation of mammalian development than was previously believed. Although a number of outstanding questions have yet to be answered (one of these questions involves the nature of the cues that designate sites for methylation at particular stages of gametogenesis and early development), studies of DNA methyltransferases are likely to provide further insights into the biological functions of genomic methylation patterns.
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                Author and article information

                Journal
                Epigenetics
                Epigenetics
                KEPI
                kepi20
                Epigenetics
                Taylor & Francis
                1559-2294
                1559-2308
                July 2016
                27 April 2016
                27 April 2016
                : 11
                : 7
                : 526-538
                Affiliations
                [a ]Biosciences, College of Life & Environmental Sciences, Geoffrey Pope Building, University of Exeter , Exeter, EX4 4QD, United Kingdom
                [b ]University of Exeter Medical School, RILD building, University of Exeter , Exeter, EX2 5DW, United Kingdom
                [c ]Centre for Environment, Fisheries and Aquaculture Science (Cefas) , Barrack Road, The Nothe, Weymouth, Dorset, DT4 8UB, United Kingdom
                [d ]Institute of Psychiatry, Psychology & Neuroscience (IoPPN) , King's College London, Denmark Hill, London, SE5 8AF, UK
                Author notes
                Correspondence Address Email: ll292@ 123456exeter.ac.uk . Email: e.santos@ 123456exeter.ac.uk

                Supplemental data for this article can be accessed on the publisher's website.

                Article
                1182272
                10.1080/15592294.2016.1182272
                4939919
                27120497
                73e34254-ceba-4201-8f16-b7812824db19
                © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                : 22 February 2016
                : 18 April 2016
                : 19 April 2016
                Page count
                Figures: 7, Tables: 0, References: 74, Pages: 13
                Categories
                Research Paper

                Genetics
                aquatic,endocrine,methylation,plasticizers,teleost,vertebrate,waste
                Genetics
                aquatic, endocrine, methylation, plasticizers, teleost, vertebrate, waste

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