toxicants. Expression of transgenes can be driven by ubiquitous, constitutive promoters, such as β-actin, to induce expression in most, if not all, cells of the embryo. Alternatively, transgene expression can be limited to specific tissues by using tissue-specific promoters. Finally, transgene expression can be limited to specific stages of development and specific tissues by using one of several inducible expression systems such as the Cre-recombinase described above.

Transgenes as Biomarkers for the Activation of Stress, Checkpoint, and Apoptosis Pathways

Transgenic mice might also play a role in testing drugs and chemicals for potential developmental toxicity (see further discussion in Chapters 8 and 9). As scientists learn more about normal development and about the mechanisms of developmental toxicity, in part from studies using gene deletion or overexpression approaches, sufficient information should become available to construct transgenic mouse lines designed to contain biomarkers of the animal’s toxic response to a chemical. For example, a transgenic mouse could be constructed that contained a transgene consisting of the heat-shock promoter linked to an appropriate reporter gene, as has been done in Drosophila. This reporter, in turn, could be used to determine whether specific drugs and chemicals induce a stress response, which is often associated with developmental toxicity. Such a biomarker transgene could be used for in vivo developmental toxicity studies, or cells from appropriate tissues could be used for in vitro testing. Other stress and checkpoint pathways could be connected to reporter genes as well, as could components of apoptosis.

Signaling Pathways as Developmental Targets of Toxicants

As noted above, the mouse is at present the animal of choice for the selective knockout or replacement of genes. A large number of genes encoding components of many signaling pathways have now been eliminated, one at a time, as summarized in Chapter 6 (Tables 6-4 and 6-5), and the phenotypes of the single-gene homozygous null mutants have been examined. Surprisingly, many of these mutants achieve advanced development, living past birth, and some reach fertile adulthood. Many have discrete developmental defects. The current explanation of the viability of these mutants is that vertebrates have large, partially diversified families of genes for most signaling components, and the genes, which are expressed at different times and places in the embryo and fetus, encode proteins of partially redundant function. Defects tend to occur at times and places where there is no overlap of expression. A number of double and triple mutants have been made as well, and they have more severe effects.

Sensitized test mice can certainly be prepared for the testing of toxicant effects on development (i.e., mice with a particular pathway operating at or near the limiting rate in a designated developing tissue). Animals can also be prepared with lacZ or GFP reporter genes to give enhanced readout of effects on pathways.



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