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Molecular cloning and characterization of a nuclear androgen receptor activated by 11-ketotestosterone
Örebro University, Department of Natural Sciences.ORCID iD: 0000-0001-7336-6335
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2005 (English)In: Reproductive biology and endocrinology, ISSN 1477-7827, Vol. 3:37Article in journal (Refereed) Published
Abstract [en]

Although 11-ketotestosterone is a potent androgen and induces male secondary sex characteristics in many teleosts, androgen receptors with high binding affinity for 11-ketotestosterone or preferential activation by 11-ketotestosterone have not been identified. So, the mechanism by which 11-ketotestosterone exhibits such high potency remains unclear. Recently we cloned the cDNA of an 11-ketotestosterone regulated protein, spiggin, from three-spined stickleback renal tissue. As spiggin is the only identified gene product regulated by 11-ketotestosterone, the stickleback kidney is ideal for determination of the mechanism of 11-ketotestosterone gene regulation. A single androgen receptor gene with two splicing variants, belonging to the androgen receptor-beta subfamily was cloned from stickleback kidney. A high affinity, saturable, single class of androgen specific binding sites, with the characteristics of an androgen receptor, was identified in renal cytosolic and nuclear fractions. Measurement of ligand binding moieties in the cytosolic and nuclear fractions as well as to the recombinant receptor revealed lower affinity for 11-ketotestosterone than for dihydrotestosterone. Treatment with different androgens did not up-regulate androgen receptor mRNA level or increase receptor abundance, suggesting that auto-regulation is not involved in differential ligand activation. However, comparison of the trans-activation potential of the stickleback androgen receptor with the human androgen receptor, in both human HepG2 cells and zebrafish ZFL cells, revealed preferential activation by 11-ketotestosterone of the stickleback receptor, but not of the human receptor. These findings demonstrate the presence of a receptor preferentially activated by 11-ketotestosterone in the three-spined stickleback, so far the only one known in any animal.

Place, publisher, year, edition, pages
2005. Vol. 3:37
National Category
Biological Sciences
Research subject
Biology
Identifiers
URN: urn:nbn:se:oru:diva-8835DOI: 10.1186/1477-7827-3-37PubMedID: 16107211OAI: oai:DiVA.org:oru-8835DiVA: diva2:281954
Available from: 2009-12-18 Created: 2009-12-18 Last updated: 2016-12-13Bibliographically 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. 64 p.
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
Supervisors
Available from: 2010-02-10 Created: 2010-02-09 Last updated: 2011-05-11Bibliographically approved

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