Advances in the Use of Zebrafish in Developmental Toxicology: Linking Genetics, Behavior, and High-Throughput Testing Strategies

Heightened concerns about adverse effects from exposures to the thousands of chemicals in use and present as persistent contaminants in humans and the environment have led to efforts to implement more predictive-based approaches to characterize the toxicity of chemicals in use and promote the design of chemicals with reduced bioactivity. While the zebrafish has been used for many years in environmental toxicology and the biomedical sciences, it has emerged more recently as an integral model to develop more robust and efficient testing strategies. This article describes major advances in genetic tools and testing approaches that have positioned the zebrafish as a key in vivo model in chemical safety evaluations particularly related to teratogenicity. Many toxic responses to chemicals have been shown to be shared among fish and mammals owing to their generally well-conserved development, cellular networks, and organ systems. These shared responses have been observed for chemicals that impair endocrine functioning, development, and reproduction, as well as those that elicit cardiotoxicity and carcinogenicity, among many other diseases. High-throughput screening platforms with embryonic zebrafish now enable the screening of large chemical libraries for bioactivity providing opportunities for biological effects testing early in product development. A compelling attribute of the zebrafish centers on being able to characterize toxicity mechanisms across multiple levels of biological organization from the genome to receptor interactions and cellular processes leading to phenotypic perturbations such as developmental deformities. Along with these predictive approaches, a number of behavioral testing strategies have emerged to further assess perturbed nervous system responses to chemical exposures. Finally, there is a growing recognition of the links between human and wildlife health and the need for approaches that allow for assessment of real world multichemical exposures. The zebrafish is poised to be an important model in bridging these two conventionally separate areas of toxicology and characterizing the biological effects of chemical mixtures.