be advantageous. Also, there are now a number of mutants for components of signaling pathways (e.g., BMP2, Nodal, and Cripto).

One of the original hopes for the study of zebrafish was that it would permit the genetic dissection of behaviors, including learning. In principle, the transparency of the embryo offers the opportunity for simultaneous assay of neuronal activity. Several behaviors are established early during development. For example, the embryo becomes motile and will respond to touch within the first day of postfertilization (Saint-Amant and Drapeau 1998), and eyes follow a striped drum (termed the optokinetic response) by 3 days (Brockerhoff et al. 1995). Screens have already identified genes that modify these activities (Brockerhoff et al. 1995; Granato et al. 1996). Mutations that perturb locomotory behavior have been shown to affect a variety of sites, including receptors, the CNS, or muscle (Granato et al. 1996). Rhythmic activity, such as circadian rhythms (Cahill et al. 1998) and cardiac pacemaking (Baker et al. 1997), are embryonic in their time of onset and can be dissected by genetics (Baker et al. 1997). Whether these behaviors may be modified is not known, but modification would provide a means to garner genes for learning, addiction, and memory. The effects of chemicals on the development of these behaviors remain to be examined, but the availability of specific behavioral assays is at hand.

A radiation hybrid map of the zebrafish genome has been completed, the map coverage being 81.9% of the genome. The map is based on a panel of 94 radiation hybrids (Geisler et al. 1999). A large-scale insertional mutagenesis screen in the zebrafish, with the goal of isolating about 1,000 embryonic mutations, is under way (Amsterdam et al. 1999). This approach is similar to the Nobel Prize-winning approach of isolating a large number of Drosophilia mutants—described in an earlier chapter.

Mouse

Transgenic Animals and Developmental Toxicology

Mice and rats have long been the mammals of choice for toxicological tests. Their advantage over the previously discussed model organisms is their similarity, as mammals, to humans. An advantage of mice over rats is the advanced state of the procedures for genetic manipulation and the large number of mutant and inbred strains already available. The disadvantage of mice and rats, compared with the other model organisms presented above, is their expense. To use them to test tens of thousands of compounds under a range of exposure conditions or in combinations is not feasible. Thus far, little use has been made of sensitized strains and reporter strains to improve toxicant detection and to learn more about mechanisms of toxicity.

Furthermore, little analysis has been done on the differences between mice and humans that lower the validity of cross-species extrapolations. There are



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement