Although many compounds appear effective in cell based testing, they frequently fail in large animal toxicity testing. Furthermore, compounds that do not produce immediate lethality induce subsequent organ or tissue specific toxicity. Current methods for embryo toxicity testing in mammals include culture assays using either rat or mouse embryos, and in utero assays in which compounds are injected in the peritoneum of a pregnant mouse or rat. Although the whole-embryo mouse and rat culture technique is a validated method for toxicity testing in vertebrates, this method is complicated and only a limited number of expensive assays can be performed. New reproducible, rapid, inexpensive and highly predictive vertebrate animal models are needed. This Phase I SBIR aims to validate the zebrafish (Danio rerio) as a whole animal model for drug toxicity testing. Inherent advantages of this model include the low cost to generate and maintain embryos, rapid embryogenesis, and a morphological and molecular basis for tissue and organ development that is similar to that found in humans. In the proposed assay, changes in the expression of zebrafish genes involved in the toxicity response will be analyzed using in situ hybridization.
The zebrafish assay will provide a rapid and inexpensive molecular approach for toxicity testing and screening of drugs, including anti-cancer drugs. The worldwide market for drug screening, toxicity testing and pharmacogenomics exceeds $1 B.
