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Interaction of brominated flame retardants with the chicken and zebrafish androgen receptors
Örebro universitet, Institutionen för naturvetenskap och teknik.
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Örebro: Örebro university , 2015. , s. 70
Serie
Örebro Studies in Life Science ; 12
Nyckelord [en]
DBE-DBCH, TBP-AE, TBP-BAE, TBP-DBPE, gene transcription
Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
Biologi
Identifikatorer
URN: urn:nbn:se:oru:diva-42881ISBN: 978-91-7529-067-6 (tryckt)OAI: oai:DiVA.org:oru-42881DiVA, id: diva2:790143
Disputation
2015-04-29, Hörsalen, Musikhögskolan, Örebro universitet, Fakultetsgatan 1, Örebro, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-02-23 Skapad: 2015-02-23 Senast uppdaterad: 2017-10-17Bibliografiskt granskad
Delarbeten
1. 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH)-mediated steroid hormone receptor activation and gene regulation in chicken LMH cells
Öppna denna publikation i ny flik eller fönster >>1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH)-mediated steroid hormone receptor activation and gene regulation in chicken LMH cells
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2014 (Engelska)Ingår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 33, nr 4, s. 891-899Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Hoboken: Wiley-Blackwell, 2014
Nyckelord
Endocrine disruptor, Diastereomer, Enantiomer, Quantitative polymerase chain reaction (qPCR), Gene regulation
Nationell ämneskategori
Miljövetenskap
Forskningsämne
Miljövetenskap; Biologi
Identifikatorer
urn:nbn:se:oru:diva-34941 (URN)10.1002/etc.2509 (DOI)000333538700020 ()2-s2.0-84897431931 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet
Anmärkning

Funding Agency:

Örebro University

Tillgänglig från: 2014-05-05 Skapad: 2014-05-05 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
2. The brominated flame retardant TBECH activates the zebrafish (Danio rerio) androgen receptor, alters gene transcription and causes developmental disturbances
Öppna denna publikation i ny flik eller fönster >>The brominated flame retardant TBECH activates the zebrafish (Danio rerio) androgen receptor, alters gene transcription and causes developmental disturbances
2013 (Engelska)Ingår i: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 142, s. 63-72Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
Androgens, Endocrine, Endocrine disruptor, Gene regulation
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:oru:diva-32902 (URN)10.1016/j.aquatox.2013.07.018 (DOI)000328093900007 ()23958786 (PubMedID)
Forskningsfinansiär
KK-stiftelsen
Tillgänglig från: 2014-01-02 Skapad: 2014-01-02 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
3. The brominated flame retardants TBP-AE and TBP-DBPE antagonize the chicken androgen receptor and alter gene expression in chicken LMH cells
Öppna denna publikation i ny flik eller fönster >>The brominated flame retardants TBP-AE and TBP-DBPE antagonize the chicken androgen receptor and alter gene expression in chicken LMH cells
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord
EDC, Avian, signaling pathways, ATE, BATE, DPTE, TBECH
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:oru:diva-43909 (URN)
Tillgänglig från: 2015-03-27 Skapad: 2015-03-27 Senast uppdaterad: 2017-10-17Bibliografiskt granskad
4. In silico and biological analysis of anti-androgen activity of the brominated flame retardants ATE, BATE and DPTE in zebrafish
Öppna denna publikation i ny flik eller fönster >>In silico and biological analysis of anti-androgen activity of the brominated flame retardants ATE, BATE and DPTE in zebrafish
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nyckelord
Brominated flame retardants, stereoidgenesis, gene regulation, hatch, teratogenesis
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:oru:diva-43911 (URN)
Tillgänglig från: 2015-03-27 Skapad: 2015-03-27 Senast uppdaterad: 2017-10-17Bibliografiskt granskad

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