ToxSci Advance Access published online on January 18, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm003
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Expression of Zebrafish Aromatase cyp19a and cyp19b Genes in Response to the Ligands of Estrogen Receptor and Aryl Hydrocarbon Receptor
ER AND AHR EFFECTS ON CYP19 EXPRESSION
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* Eawag, Swiss Federal Institute of Aquatic Science and Technology, 8600, Dübendorf, Switzerland
Unité d'évaluation des risques écotoxicologiques, Direction des Risques Chroniques, Institut National de l'Environnement Industriel et des Risques (INERIS), BP 2, F-60550 Verneuil-en-Halatte, France
Endocrinologie Moléculaire de la Reproduction, UMRCNRS 6026, Campus de Beaulieu, Université de Rennes 1, 35042 Rennes Cedex, France
Centre for Fish and Wildlife Health, University of Bern, Länggass-strasse 122, Post Box 8466, 3001, Bern, Switzerland
2 To whom correspondence should be addressed: Rik I. L. Eggen, Eawag, Überlandstrasse 133, Postfach 611, CH 8600, Dübendorf, Switzerland. E-mail : eggen{at}eawag.ch Phone: +41 (0) 44 823 5320 Fax: +41 (0) 44 823 5311
Received December 21, 2006; accepted January 8, 2007
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Abstract |
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Many endocrine disrupting chemicals act via estrogen receptor (ER) or aryl hydrocarbon receptor (AhR). To investigate the interference between ER and AhR, we studied the effects of 17ß-estradiol (E2) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the expression of zebrafish cyp19a (zfcyp19a) and cyp19b (zfcyp19b) genes, encoding aromatase P450, an important steroidogenic enzyme. In vivo (mRNA quantification in exposed zebrafish larvae) and in vitro (activity of zfcyp19-luciferase reporter genes in cell cultures in response to chemicals and zebrafish transcription factors) assays were used. None of the treatments affected zfcyp19a, excluding the slight upregulation by E2 observed in vitro. Strong upregulation of zfcyp19b by E2 in both assays was downregulated by TCDD. This effect could be rescued by the addition of an AhR antagonist. Anti-estrogenic effect of TCDD on the zfcyp19b expression in the brain was also observed on the protein level, assessed by immunohistochemistry. TCDD alone did not affect zfcyp19b expression in vivo or promoter activity in the presence of zebrafish AhR2 and AhR nuclear translocator 2b (ARNT2b) in vitro. However, in the presence of zebrafish ER
, AhR2 and ARNT2b, TCDD led to a slight upregulation of promoter activity, which was eliminated by either an ER or AhR antagonist. Studies with mutated reporter gene constructs indicated that both mechanisms of TCDD action in vitro were independent of dioxin responsive elements (DREs) predicted in the promoter. This study shows the usefulness of in vivo zebrafish larvae and in vitro zfcyp19b reporter gene assays for evaluation of estrogenic chemical actions, provides data on the functionality of DREs predicted in zfcyp19 promoters and shows the effects of crosstalk between ER and AhR on zfcyp19b expression. The anti-estrogenic effect of TCDD demonstrated raises further concerns about the neuroendocrine effects of AhR ligands.
1 Both authors contributed equally to this work
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