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The brominated flame retardant TBECH activates the zebrafish (Danio rerio) androgen receptor, alters gene transcription and causes developmental disturbances
Örebro University, School of Science and Technology.ORCID iD: 0000-0003-3302-7106
Örebro University, School of Science and Technology.
Örebro University, School of Science and Technology.
Örebro University, School of Science and Technology.ORCID iD: 0000-0001-7336-6335
2013 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 142, p. 63-72Article in journal (Refereed) Published
Abstract [en]

Tetrabromoethylcyclohexane (TBECH) is a brominated flame retardant that has been shown to be a potent agonist to the human androgen receptor (AR). However, while it is present in the environment, it is not known if it interacts with AR from aquatic species. The present study was therefore aimed at improving our understanding of how TBECH affects aquatic animals using zebrafish as a model organism. In silica modeling demonstrated that TBECH diastereomers bind to the zebrafish androgen receptor (zAR) and in vitro and in vivo data showed that TBECH has androgenic properties. Deleterious effects of TBECH were studied on embryonic and juvenile zebrafish and qRT-PCR analysis in vitro and in vivo was performed to determine TBECH effects on gene regulation. TBECH was found to delay hatching at 1 mu M and 10 mu M doses while morphological abnormalities and juvenile mortality was observed at 10 mu M. The qRT-PCR analysis showed alterations of multiple genes involved in chondrogenesis (cartilage development), metabolism and stress response. Thus, TBECH induces androgenic activity and has negative effects on zebrafish physiology and therefore its impact on the environment should be carefully monitored. (C) 2013 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
2013. Vol. 142, p. 63-72
Keywords [en]
Androgens, Endocrine, Endocrine disruptor, Gene regulation
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:oru:diva-32902DOI: 10.1016/j.aquatox.2013.07.018ISI: 000328093900007PubMedID: 23958786OAI: oai:DiVA.org:oru-32902DiVA, id: diva2:683127
Funder
Knowledge FoundationAvailable from: 2014-01-02 Created: 2014-01-02 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Interaction of brominated flame retardants with the chicken and zebrafish androgen receptors
Open this publication in new window or tab >>Interaction of brominated flame retardants with the chicken and zebrafish androgen receptors
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The survival of organisms depends on their ability to use different signaling pathways to adapt to the environment. The endocrine system consists of glands that release hormones to the blood stream. Male reproductive functions are regulated by androgens through interactions with the androgen receptor (AR). AR has been characterized in chicken and zebrafish where they use testosterone and 11-ketotestosterone as their primary androgens, respectively. AR function has been disturbed by different endocrine disrupting compounds (EDCs) present in the environment causing detrimental effects on avian and fish species. Brominated flame retardants (BFRs) are a group of EDCs that are ubiquitous in the environment. Molecular modeling techniques using computer simulations such as docking and molecular dynamics are a useful tool in the identification of EDCs. The capacity to test thousands of compounds at once has helped in the early identification of EDCs that interact with AR. Two groups of BFRs, the 1,2-dibromo-4- cyclohexane diastereomers (TBECH) and the compounds synthesized from 2, 4, 6-tribromophenol, allyl 2,4,6-tribromophenyl ether (ATE), 2-bromoallyl 2,4,6- tribromophenyl ether (BATE) and 2,3-dibromopropyl 2,4,6-tribromophenyl ether (DPTE) interact and alter AR activity in human in vitro studies. As models for avian and fish species, chicken and zebrafish were used to test these BFRs. TBECH diastereomers were able to bind to the AR, estrogen receptors and thyroid receptors in the chicken and to the AR in zebrafish. ATE, BATE and DPTE were also able to interact with the chicken AR and zebrafish AR. Activation studies using cell lines showed that TBECH diastereomers acted as agonists to the cAR and zAR while ATE, BATE and DPTE acted as antagonists. The BFRs also altered multiple signaling pathways such as the apoptotic, antiapoptotic, immune, drug metabolizing and DNA methylation systems and in vivo studies resulted in physiological effects on zebrafish.

Place, publisher, year, edition, pages
Örebro: Örebro university, 2015. p. 70
Series
Örebro Studies in Life Science ; 12
Keywords
DBE-DBCH, TBP-AE, TBP-BAE, TBP-DBPE, gene transcription
National Category
Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-42881 (URN)978-91-7529-067-6 (ISBN)
Public defence
2015-04-29, Hörsalen, Musikhögskolan, Örebro universitet, Fakultetsgatan 1, Örebro, 10:00 (English)
Opponent
Supervisors
Available from: 2015-02-23 Created: 2015-02-23 Last updated: 2017-10-17Bibliographically approved
2. Modulation of androgen receptor function by brominated flame retardants
Open this publication in new window or tab >>Modulation of androgen receptor function by brominated flame retardants
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Örebro: Örebro university, 2015. p. 78
Series
Örebro Studies in Biology, ISSN 1650-8793 ; 13
Keywords
DBE-DBCH, TBP-AE, TBP-BAE, TBP-DBPE, androgen receptor, endocrine disrupters, brominated flame retardant
National Category
Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-43881 (URN)978-91-7529-082-9 (ISBN)
Public defence
2015-06-05, Hörsalen, Musikhögskolan, Örebro universitet, Fakultetsgatan 1, Örebro, 10:00 (English)
Opponent
Supervisors
Available from: 2015-03-26 Created: 2015-03-26 Last updated: 2017-10-17Bibliographically approved

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Pradhan, AjayKharlyngdoh, Joubert BanjopAsnake, SolomonOlsson, Per-Erik

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