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ToxSci Advance Access published online on December 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh020
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received August 8, 2003; accepted October 20, 2003
© 2003 Society of Toxicology

Neurotoxicology

The Use of Zebrafish Mutants to Identify Secondary Target Effects of Acetylcholine Esterase Inhibitors

Martine Behra 1, Christelle Etard 2, Xavier Cousin 3, and Uwe Strähle 2*

1 Institut de Genetique et de Biologie Moleculaire et Cellulaire, 1 rue Laurent Fries, BP10142, 67404 Illkirch, France
2 Institut de Genetique et de Biologie Moleculaire et Cellulaire, 1 rue Laurent Fries, BP10142, 67404 Illkirch, France; Forschungszentrum Karlsruhe, PO Box 3640, D-76021 Karlsruhe, Germany
3 Unite Différenciation Cellulaire et Croissance - INRA, 2 place Viala, 34060 Montpellier, France

* To whom correspondence should be addressed. E-mail: uwe{at}igbmc.u-strasbg.fr.


  Abstract

We are confronted with a large and steadily growing number of bioactive compounds, including drugs, pesticides and industrial by-products. The assessment of target specificity and potential toxic effect on human health and the environment generates a strong demand for robust and cost-effective models with high predictive power. Here, we investigate the potential of the zebrafish embryo as a whole-organism, vertebrate model to assess the specificity of compounds that are known to inhibit Acetylcholinesterase (AChE). Inhibitors of AChE are widely used as drugs and pesticides. By application of simple assays and comparison with the phenotype of embryos with genetic lesions in the ache gene, we demonstrate that only one of the AChE inhibitors (galanthamine) reproduces the phenotype of ache mutant embryos. The other compounds produced additional effects indicating secondary targets. Our work demonstrates the power of a genetic system for toxicological evaluations. The combination of genetics and transgenesis with the other experimental virtues of the zebrafish embryo, such as small size and low cost, offers a whole organism platform for medium to high throughput compound testing.

Key Words: zebrafish, acetylcholinesterase, inhibitors, animal model, secondary drug targets .


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