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Androgen receptors and endocrine disrupting substances
Örebro universitet, Akademin för naturvetenskap och teknik.
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

 

Ort, förlag, år, upplaga, sidor
Örebro: Örebro universitet , 2010. , s. 64
Serie
Örebro Studies in Life Science ; 5
Nyckelord [en]
Androgen receptor, Brominated flame retardant, TBECH, Endocrine disruptor
Nationell ämneskategori
Biologiska vetenskaper Naturvetenskap
Forskningsämne
Biologi
Identifikatorer
URN: urn:nbn:se:oru:diva-9679ISBN: 978-91-7668-714-7 (tryckt)OAI: oai:DiVA.org:oru-9679DiVA, id: diva2:292809
Disputation
2010-02-26, Hörsal P2, Örebro, 10:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-02-10 Skapad: 2010-02-09 Senast uppdaterad: 2017-10-18Bibliografiskt granskad
Delarbeten
1. Molecular cloning and characterization of a nuclear androgen receptor activated by 11-ketotestosterone
Öppna denna publikation i ny flik eller fönster >>Molecular cloning and characterization of a nuclear androgen receptor activated by 11-ketotestosterone
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2005 (Engelska)Ingår i: Reproductive biology and endocrinology, ISSN 1477-7827, Vol. 3:37Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
Biologi
Identifikatorer
urn:nbn:se:oru:diva-8835 (URN)10.1186/1477-7827-3-37 (DOI)16107211 (PubMedID)
Tillgänglig från: 2009-12-18 Skapad: 2009-12-18 Senast uppdaterad: 2017-10-18Bibliografiskt granskad
2. Zebrafish androgen receptor: isolation, molecular, and biochemical characterization
Öppna denna publikation i ny flik eller fönster >>Zebrafish androgen receptor: isolation, molecular, and biochemical characterization
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2008 (Engelska)Ingår i: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 78, nr 2, s. 361-369Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Androgens play an important role in male sexual differentiation and development. They exert their function by binding to and activating the androgen receptor (Ar), a member of the steroid hormone receptor superfamily. Here, we report on the isolation and characterization of zebrafish Ar. The complete transcript of zebrafish ar is 5.3 kb long encoding a putative polypeptide of 868 amino acids. Our experimental and bioinformatic analysis has found a single ar locus in zebrafish. Phylogenetic analysis using the ligand-binding domain showed that the zebrafish Ar clustered with its cyprinid orthologs to form a separate group, which was closer to the beta clade than to the alpha clade. Tissue-specific expression analysis revealed that the ar mRNA was expressed ubiquitously in all adult tissues tested, with sexually dimorphic expression in the gonad and muscle. While the ar transcript was maternally deposited into the embryo, signs of zygotic expression could be detected as early as 24 h after fertilization, and the expression level increased substantially afterwards. When analyzed during gonad development, the expression level of ar mRNA at 4 wk after fertilization was similar in both developing gonads but later became higher in the transforming testis, suggesting a potential role during male gonad differentiation. We also combined theoretical modeling with in vitro experiments to show that the zebrafish Ar is preferentially activated by 11-ketotestosterone.

Ort, förlag, år, upplaga, sidor
Champaign, Ill.: Society for the Study of Reproduction, 2008
Nyckelord
Androgens/*metabolism/pharmacology, Animals, Chromosome Mapping, Cloning; Molecular, Computer Simulation, DNA; Complementary/genetics, Female, Gene Expression, Gonads/growth & development, Male, Molecular Sequence Data, Phylogeny, RNA; Messenger/metabolism, Receptors; Androgen/agonists/*classification/*genetics, Sequence Homology; Amino Acid, Testosterone/analogs & derivatives/pharmacology, Transcription; Genetic, Transfection, Zebrafish/genetics/*growth & development, Zebrafish Proteins/*genetics
Nationell ämneskategori
Naturvetenskap Biologiska vetenskaper
Forskningsämne
biologi
Identifikatorer
urn:nbn:se:oru:diva-3557 (URN)10.1095/​biolreprod.107.062018 (DOI)17942797 (PubMedID)
Tillgänglig från: 2008-12-09 Skapad: 2008-12-09 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
3. Identification of the brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an androgen agonist
Öppna denna publikation i ny flik eller fönster >>Identification of the brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane as an androgen agonist
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2006 (Engelska)Ingår i: Journal of medicinal chemistry, ISSN 0022-2623, Vol. 49, nr 25, s. 7366-7372Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
Binding, Competitive, Cell Line, Tumor, Cyclohexanes/*chemistry/toxicity, Endocrine Disruptors/*chemistry/toxicity, Flame Retardants/*toxicity, Humans, Ligands, Models, Molecular, Receptors, Androgen/*agonists/*chemistry
Nationell ämneskategori
Naturvetenskap Biologiska vetenskaper
Forskningsämne
Biologi
Identifikatorer
urn:nbn:se:oru:diva-3562 (URN)10.1021/jm060713d (DOI)17149866 (PubMedID)
Tillgänglig från: 2008-12-09 Skapad: 2008-12-09 Senast uppdaterad: 2017-10-18Bibliografiskt granskad
4. Diastereomers of the Brominated Flame Retardant 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane Induce Androgen Receptor Activation in the HepG2 Hepatocellular Carcinoma Cell Line and the LNCaP Prostate Cancer Cell Line
Öppna denna publikation i ny flik eller fönster >>Diastereomers of the Brominated Flame Retardant 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane Induce Androgen Receptor Activation in the HepG2 Hepatocellular Carcinoma Cell Line and the LNCaP Prostate Cancer Cell Line
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2009 (Engelska)Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 117, nr 12, s. 1853-1859Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Reported incidences of prostate cancer and masculinization of animals indicate a release of compounds with androgenic properties into the environment. Large numbers of environmental pollutants have been screened to identify such compounds; however, not until recently was 1,2-dibromo-4-(1,2-dibromoethyl)cyclohex​ane (TBECH) identified as the first potent activator of the human androgen receptor (hAR). TBECH has been found in beluga whales and bird eggs and has also been found to be maternally transferred in zebrafish.

Objectives: In the present study we investigated interaction energies between TBECH diastereomers (α, β, γ, and δ) and the hAR, and their ability to activate the receptor and induce prostate-specific antigen (PSA) expression in vitro.

Methods: We performed computational modeling to determine interaction energies between the ligand and the AR ligand-binding site, and measured in vitro competitive binding assays for AR by polarization fluorometry analysis. We used enzyme-linked immunosorbent assays to determine PSA activity in LNCaP and HepG2 cells.

Results: We found the γ and δ diastereomers to be more potent activators of hAR than the α and β diastereomers, which was confirmed in receptor binding studies. All TBECH diastereomers induced PSA expression in LNCaP cells even though the AR present in these cells is mutated (T877A). Modeling studies of LNCaP AR revealed that TBECH diastereomers bound to the receptor with a closer distance to the key amino acids in the ligand-binding domain, indicating stronger binding to the mutated receptor.

Conclusions: The present study demonstrates the ability of TBECH to activate the hAR, indicating that it is a potential endocrine disruptor.

Ort, förlag, år, upplaga, sidor
National Institute of Environmental Health Science, 2009
Nyckelord
androgen, brominated flame retardant, endocrine disruptor
Nationell ämneskategori
Naturvetenskap Kemi Miljövetenskap Biologiska vetenskaper
Forskningsämne
Biologi
Identifikatorer
urn:nbn:se:oru:diva-9678 (URN)10.1289/ehp.0901065 (DOI)000272474600026 ()20049203 (PubMedID)2-s2.0-75349109314 (Scopus ID)
Tillgänglig från: 2010-02-09 Skapad: 2010-02-09 Senast uppdaterad: 2017-12-12Bibliografiskt granskad

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