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Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters
Örebro University, School of Science and Technology. (MOD)
Örebro University, School of Science and Technology. (MOD)ORCID iD: 0000-0003-3302-7106
Örebro University, School of Science and Technology. (MOD)
Örebro University, School of Science and Technology.
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2015 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 74, p. 60-70Article in journal (Refereed) Published
Abstract [en]

Brominated flame-retardants (BFRs) are used in industrial products to reduce the risk of fire. However, their continuous release into the environment is a concern as they are often persistent, bioaccumulating and toxic. Information on the impact these compounds have on human health and wildlife is limited and only a few of them have been identified to disrupt hormone receptor functions. In the present study we used in silico modeling to determine the interactions of selected BFRs with the human androgen receptor (AR). Three compounds were found to dock into the ligand-binding domain of the human AR and these were further tested using in vitro analysis. 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) were observed to act as AR antagonists. These BFRs have recently been detected in the environment, in house dust and in aquatic animals. The compounds have been detected at high concentrations in both blubber and brain of seals and we therefore also assessed their impact on the expression of L-type amino acid transporter system (LAT) genes, that are needed for amino acid uptake across the blood-brain barrier, as disruption of LAT gene function has been implicated in several brain disorders. The three BFRs down-regulated the expression of AR target genes that encode for prostate specific antigen (PSA), 5. α-reductases and β-microseminoprotein. The potency of PSA inhibition was of the same magnitude as the common prostate cancer drugs, demonstrating that these compounds are strong AR antagonists. Western blot analysis of AR protein showed that ATE, BATE and DPTE decreased the 5. α-dihydrotestosterone-induced AR protein levels, further confirming that these BFRs act as AR antagonists. The transcription of the LAT genes was altered by the three BFRs, indicating an effect on amino-acid uptake across cellular membranes and blood-brain barrier. This study demonstrated that ATE, BATE and DPTE are potent AR antagonists and the alterations in LAT gene transcription suggest that these compounds can affect neuronal functions and should be considered as potential neurotoxic and endocrine disrupting compounds.

Place, publisher, year, edition, pages
2015. Vol. 74, p. 60-70
Keywords [en]
Gene regulation; Human; PSA; LAT
National Category
Environmental Sciences
Research subject
Biology
Identifiers
URN: urn:nbn:se:oru:diva-41508DOI: 10.1016/j.envint.2014.09.002ISI: 000346681700008PubMedID: 25454221Scopus ID: 2-s2.0-84908626070OAI: oai:DiVA.org:oru-41508DiVA, id: diva2:780553
Funder
Knowledge Foundation, 20110183
Note

Funding Agency:

Örebro University J61900

Available from: 2015-01-14 Created: 2015-01-14 Last updated: 2017-12-05Bibliographically approved
In thesis
1. 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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Banjop-Kharlygdoh, JoubertPradhan, AjayAsnake, SolomonOlsson, Per-Erik

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