ToxSci Advance Access originally published online on January 18, 2007
Toxicological Sciences 2007 96(2):255-267; doi:10.1093/toxsci/kfm003
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Expression of Zebra Fish Aromatase cyp19a and cyp19b Genes in Response to the Ligands of Estrogen Receptor and Aryl Hydrocarbon Receptor
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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, 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, 3001 Bern, Switzerland
2 To whom correspondence should be addressed at Eawag, Überlandstrasse 133, Postfach 611, CH 8600, Dübendorf, Switzerland. Fax: +41 (0) 44 823-5311. E-mail: eggen{at}eawag.ch.
Received September 15, 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 zebra fish cyp19a (zfcyp19a) and cyp19b (zfcyp19b) genes, encoding aromatase P450, an important steroidogenic enzyme. In vivo (mRNA quantification in exposed zebra fish larvae) and in vitro (activity of zfcyp19-luciferase reporter genes in cell cultures in response to chemicals and zebra fish 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. Antiestrogenic 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 zebra fish AhR2 and AhR nuclear translocator 2b (ARNT2b) in vitro. However, in the presence of zebra fish 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 zebra fish 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 cross talk between ER and AhR on zfcyp19b expression. The antiestrogenic effect of TCDD demonstrated raises further concerns about the neuroendocrine effects of AhR ligands.
Key Words: endocrine disruption; aromatase CYP19; zebra fishestrogen receptor; aryl hydrocarbon receptor; gene expression/regulation.
1 Both authors contributed equally to this work.
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