Media type: E-Article Title: Inhibitory effect of cadmium on estrogen signaling in zebrafish brain and protection by zinc Contributor: Chouchene, Lina; Pellegrini, Elisabeth; Gueguen, Marie‐Madeleine; Hinfray, Nathalie; Brion, François; Piccini, Benjamin; Kah, Olivier; Saïd, Khaled; Messaoudi, Imed; Pakdel, Farzad imprint: Wiley, 2016 Published in: Journal of Applied Toxicology Language: English DOI: 10.1002/jat.3285 ISSN: 0260-437X; 1099-1263 Origination: Footnote: Description: <jats:title>Abstract</jats:title><jats:p>The present study was conducted to assess the effects of Cd exposure on estrogen signaling in the zebrafish brain, as well as the potential protective role of Zn against Cd‐induced toxicity. For this purpose, the effects on transcriptional activation of the estrogen receptors (ERs), aromatase B (Aro‐B) protein expression and molecular expression of related genes were examined <jats:italic>in vivo</jats:italic> using wild‐type and transgenic zebrafish embryos. For <jats:italic>in vitro</jats:italic> studies, an ER‐negative glial cell line (U251MG) transfected with different zebrafish ER subtypes (ERα, ERβ1 and ERβ2) was also used. Embryos were exposed either to estradiol (E<jats:sub>2</jats:sub>), Cd, E<jats:sub>2</jats:sub>+Cd or E<jats:sub>2</jats:sub>+Cd+Zn for 72 h and cells were exposed to the same treatments for 30 h. Our results show that E<jats:sub>2</jats:sub> treatment promoted the transcriptional activation of ERs and increased Aro‐B expression, at both the protein and mRNA levels. Although exposure to Cd, does not affect the studied parameters when administered alone, it significantly abolished the E<jats:sub>2</jats:sub>‐stimulated transcriptional response of the reporter gene for the three ER subtypes in U251‐MG cells, and clearly inhibited the E<jats:sub>2</jats:sub> induction of Aro‐B in radial glial cells of zebrafish embryos. These inhibitory effects were accompanied by a significant downregulation of the expression of <jats:italic>esr1</jats:italic>, <jats:italic>esr2a</jats:italic>, <jats:italic>esr2b</jats:italic> and <jats:italic>cyp19a1b</jats:italic> genes compared to the E<jats:sub>2</jats:sub>‐treated group used as a positive control. Zn administration during simultaneous exposure to E<jats:sub>2</jats:sub> and Cd strongly stimulated zebrafish ERs transactivation and increased Aro‐B protein expression, whereas mRNA levels of the three ERs as well as the <jats:italic>cyp19a1b</jats:italic> remained unchanged in comparison with Cd‐treated embryos. In conclusion, our results clearly demonstrate that Cd acts as a potent anti‐estrogen <jats:italic>in vivo</jats:italic> and <jats:italic>in vitro</jats:italic>, and that Cd‐induced E<jats:sub>2</jats:sub> antagonism can be reversed, at the protein level, by Zn supplement. Copyright © 2016 John Wiley & Sons, Ltd.</jats:p>