likely to be two main kinds of differences: (1) differences in the steps by which the active or activated toxicant is introduced to the embryo or fetus, and (2) differences in the components of developmental processes, making the toxicant have more effect or less effect on developmental function and resulting in a more severe or less severe developmental defect. Enough is now known about absorption, distribution, metabolism, and excretion, especially regarding drug-metabolizing enzymes (DMEs), to make systematic comparisons between humans and rodents possible. Many components of signaling pathways and genetic regulation, which are central to development, are also now known in test animals and humans, and those components could be compared systematically as well.

As summarized by Malakoff (2000), the use of mice in biomedical research and drug testing is expected to increase dramatically in the next few years, especially as the sequencing of the mouse genome approaches completion, and the increased use of mice will create opportunities in developmental toxicology.

Gene-Deletion Transgenics for the Study of DMEs

Only within the last 5 years have transgenic methodologies been brought to bear on the reciprocal relationship between the animal’s genetic constitution and its susceptibility to developmental toxicants. A particularly important and approachable set of genes are those encoding enzymes that metabolize exogenous chemicals. As discussed in Chapter 5, there are two major categories, the oxidizing enzymes (mostly P450 proteins) and the conjugation enzymes. There might be tens of these enzymes that metabolize most chemicals and hundreds more that metabolize a few chemicals each. In addition, several known transcription factors activate the expression of genes encoding these enzymes, and some of these factors themselves bind exogenous chemicals.

Much remains to be learned about the role of the various enzymes in generating and removing active toxicants, and the gene-deletion approach in the mouse has great advantages. At least in some cases the knockout mice are viable and fertile. One pioneering example in which gene-deletion transgenics was used concerns the dioxin-inducible mouse gene battery (Nebert and Duffy 1997), a group of genes believed to play an important role in developmental toxicity. Much more of this analysis can and should be done, both to understand the role of these enzymes in potentiation and detoxification and to define human and mouse differences for better-informed extrapolations of animal-test data.

Overexpression Transgenics for the Study of DMEs

Another approach to the study of developmental toxicity using transgenic animals is to overexpress, or ectopically express, a gene of interest in the embryo and fetus. For example, one could ask whether overexpression or ectopic expression of a gene encoding a particular oxidizing or conjugating enzyme either sensitizes or protects the embryo and fetus from the adverse effects of developmental



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