Document Detail


The AhR is constitutively activated and affects granulosa cell features in the human cell line KGN.
MedLine Citation:
PMID:  20823264     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A well-balanced activity of the aryl hydrocarbon receptor (AhR) is necessary for normal ovarian function. As known from murine AhR knock-out (KO) models, the AhR is involved in folliculogenesis, gonadotrophin receptor expression, proliferation of granulosa cells and intraovarian estrogen signalling. Highly potent, non-physiological ligands such as the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) lead to a blockade of ovulation, estrogen receptor degradation and reduction of estrogen levels. Estrogen synthesis is a typical function of granulosa cells and essential for normal cyclicity and fertility. We employed the human granulosa cell line KGN to further characterize AhR signalling and AhR function in granulosa cell physiology. Real-time PCR quantification of the target genes Cyp1a1 and Cyp1b1 and reporter gene assays after stimulation with TCDD or beta-naphthoflavone (BNF) or inhibition with alpha-naphthoflavone (ANF) or 3'-methoxy-4'-nitroflavone (3,4-MNF) of the AhR demonstrated constitutive activity and functionality of AhR pathway in KGN granulosa cells. In untreated KGN cells, AhR protein was exclusively detected in the nuclear fraction. TCDD stimulation affected the gonadotrophin receptor but not estrogen receptor β (ERβ) protein expression. Additionally, the constitutively activated AhR suppressed aromatase expression and estrogen synthesis (enzyme-linked immunoassay, ELISA) and enhanced proliferation [Bromodeoxyuridine (BrdU) ELISA] of KGN cells. Activation of the AhR by BNF did not override this inhibitory effect on estrogen synthesis or proliferation. In conclusion, the AhR pathway is constitutively activated and functional in human KGN granulosa cells. It is a potential target for endocrine disruption by exogenous ligands and subsequent dysfunction of granulosa cells.
Authors:
Katja Horling; Anne Navarrete Santos; Bernd Fischer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-07
Journal Detail:
Title:  Molecular human reproduction     Volume:  17     ISSN:  1460-2407     ISO Abbreviation:  Mol. Hum. Reprod.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-20     Completed Date:  2011-05-05     Revised Date:  2014-01-08    
Medline Journal Info:
Nlm Unique ID:  9513710     Medline TA:  Mol Hum Reprod     Country:  England    
Other Details:
Languages:  eng     Pagination:  104-14     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aromatase / genetics
Aryl Hydrocarbon Hydroxylases / genetics
Benzoflavones / pharmacology
Cell Line
Cell Proliferation
Cytochrome P-450 CYP1A1 / genetics
Enzyme-Linked Immunosorbent Assay
Estrogens / biosynthesis
Female
Flavonoids / pharmacology
Granulosa Cells / drug effects,  metabolism*
Humans
Ovary / metabolism
Polymerase Chain Reaction
Receptors, Aryl Hydrocarbon / antagonists & inhibitors,  genetics*,  metabolism*
Receptors, Estrogen / genetics,  metabolism
Receptors, Gonadotropin / genetics,  metabolism
Signal Transduction*
Tetrachlorodibenzodioxin / pharmacology
beta-Naphthoflavone / pharmacology
Chemical
Reg. No./Substance:
0/3'-methoxy-4'-nitroflavone; 0/Benzoflavones; 0/Estrogens; 0/Flavonoids; 0/Receptors, Aryl Hydrocarbon; 0/Receptors, Estrogen; 0/Receptors, Gonadotropin; 604-59-1/alpha-naphthoflavone; 6051-87-2/beta-Naphthoflavone; DO80M48B6O/Tetrachlorodibenzodioxin; EC 1.14.14.1/Aromatase; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/Cytochrome P-450 CYP1A1; EC 1.14.14.1/cytochrome P-450 CYP1B1

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