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Identification of the brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an androgen agonist
Örebro University, Department of Natural Sciences.
Örebro University, Department of Natural Sciences.
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2006 (English)In: Journal of medicinal chemistry, ISSN 0022-2623, Vol. 49, no 25, p. 7366-7372Article in journal (Refereed) Published
Abstract [en]

To investigate androgen receptor (AR) activation by exogenous compounds, we used a combination of experimental analysis and theoretical modeling to compare a set of brominated flame retardants (BFRs) to dihydrotestosterone (DHT) with regard to ligand docking, AR binding, and AR activation in human hepatocellular liver carcinoma cells, as well as interacting energy analysis. Modeling of receptor docking was found to be a useful first step in predicting the potential to translocate to the ligand pocket of the receptor, and the computed interaction energy was found to correlate with the observed binding affinity. Flexible alignment studies of the BFR compounds demonstrated that 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (BCH) closely overlap DHT. Combining the theoretical modeling with in vitro ligand-binding and receptor-activation assays, we show that BCH binds to and activates the human AR. The remaining BFRs did not successfully interact with the ligand pocket, were not able to replace a synthetic androgen from the receptor, and failed to activate the receptor.

Place, publisher, year, edition, pages
2006. Vol. 49, no 25, p. 7366-7372
Keyword [en]
Binding, Competitive, Cell Line, Tumor, Cyclohexanes/*chemistry/toxicity, Endocrine Disruptors/*chemistry/toxicity, Flame Retardants/*toxicity, Humans, Ligands, Models, Molecular, Receptors, Androgen/*agonists/*chemistry
National Category
Natural Sciences Biological Sciences
Research subject
Biology
Identifiers
URN: urn:nbn:se:oru:diva-3562DOI: 10.1021/jm060713dPubMedID: 17149866OAI: oai:DiVA.org:oru-3562DiVA, id: diva2:137860
Available from: 2008-12-09 Created: 2008-12-09 Last updated: 2017-10-18Bibliographically approved
In thesis
1. Androgen receptors and endocrine disrupting substances
Open this publication in new window or tab >>Androgen receptors and endocrine disrupting substances
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Throughout the animal kingdom, organisms are dependent on substances such as steroid hormones to help them maintain internal balances. Examples of important tasks that are under regulation of steroid hormones are somatic and gonadal development, sexual performance and behavior (both social and sexual) as well as sex differentiation. Balance in the biology of reproduction is important for all organisms, and is sensitive to alterations and disturbances. If the environment is altered in a manner that lead to higher estrogenic or androgenic levels, the sex ratio of organisms that do not rely on genetic differences in the sex differentiation, will be biased towards more females or males in the population. It has been known for some time that there are pollutants in the environment that affect steroid pathways, such as the estrogenic and thyroid systems, but not much has been known about the androgenic systems. Examples of populations being masculinized have been recorded, and estrogenic compounds have been known to act as antiandrogens, but not until recently the first androgen agonist was identified. We used a combination of in vitro and computational modeling to identify the brominated flame retardant, 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane, as a potent androgen agonist to the human androgen receptor.

In addition to this we cloned and characterized the androgen receptor from, a frequently used model organism, zebrafish (Danio rerio) as a receptor primarily activated by 11-ketotestosterone. This is a feature the zebrafish share with several other teleost fishes, such as the three-spined stickleback. Thus fish androgen receptors differ from most mammalian androgen receptors, where dihydrotestosterone is the most potent activator.

 

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2010. p. 64
Series
Örebro Studies in Life Science ; 5
Keyword
Androgen receptor, Brominated flame retardant, TBECH, Endocrine disruptor
National Category
Biological Sciences Natural Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-9679 (URN)978-91-7668-714-7 (ISBN)
Public defence
2010-02-26, Hörsal P2, Örebro, 10:15 (English)
Opponent
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Available from: 2010-02-10 Created: 2010-02-09 Last updated: 2017-10-18Bibliographically approved

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Larsson, AndersEriksson, Leif A.Olsson, Per-Erik

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