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1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH)-mediated steroid hormone receptor activation and gene regulation in chicken LMH cells
Örebro University, School of Science and Technology.
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.
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2014 (English)In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 33, no 4, p. 891-899Article in journal (Refereed) Published
Abstract [en]

The incorporation of brominated flame retardants into industrial and household appliances has increased their occurrence in the environment, resulting in deleterious effects on wildlife. With the increasing restraints on available compounds, there has been a shift to using brominated flame retardants that has seen the production of alternative brominated flame retardants such as 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH), which has been detected in the environment. In previous in silico and in vitro studies the authors have shown that TBECH can activate both the human androgen receptor (hAR) and the zebrafish AR (zAR) suggesting that it is a potential endocrine disruptor. The present study was aimed at determining the interaction of TBECH with the chicken AR (cAR). In the present study, TBECH bound to cAR, but in vitro activation assay studies using the chicken LMH cell line showed it had a potency of only 15% compared with testosterone. Sequence difference between ARs from different species may contribute to the different responses to TBECH. Further quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) analysis showed that TBECH interacted with and altered the expression of both thyroid receptors and estrogen receptors. In addition, the qRT-PCR analysis showed that TBECH altered the transcription pattern of genes involved in inflammatory, apoptotic, proliferative, DNA methylation, and drug-metabolizing pathways. This demonstrates that TBECH, apart from activating cAR, can also influence multiple biological pathways in the chicken.

Place, publisher, year, edition, pages
Hoboken: Wiley-Blackwell, 2014. Vol. 33, no 4, p. 891-899
Keywords [en]
Endocrine disruptor, Diastereomer, Enantiomer, Quantitative polymerase chain reaction (qPCR), Gene regulation
National Category
Environmental Sciences
Research subject
Enviromental Science; Biology
Identifiers
URN: urn:nbn:se:oru:diva-34941DOI: 10.1002/etc.2509ISI: 000333538700020Scopus ID: 2-s2.0-84897431931OAI: oai:DiVA.org:oru-34941DiVA, id: diva2:715550
Funder
Swedish Research Council
Note

Funding Agency:

Örebro University

Available from: 2014-05-05 Created: 2014-05-05 Last updated: 2017-12-05Bibliographically 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

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Asnake, SolomonPradhan, AjayBanjop-Kharlyngdoh, JoubertModig, CarinaOlsson, Per-Erik

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