polymorphisms, and the Environmental Genome Project has such identification as a goal, as do the National Cancer Institute and various pharmaceutical companies. Genotype-environment interactions are suspected to underlie a variety of developmental defects, and identification of human polymorphism will shed light on those interactions.
As these polymorphic genes are identified, experiments are being done to eliminate them by targeted inactivation in the mouse and to assess the animal’s sensitivity or resistance to various chemicals. Studies are also being done to observe the protective or sensitizing effects of overexpression and ectopic expression of enzymes encoded by these genes. The committee supports this work enthusiastically.
The information about individual differences in the metabolism of exogenous chemicals is being extended to research on model organisms (the mouse, Drosophila, and C. elegans), because the validity of animal test results for predicting human toxicity depends not only upon an understanding of the toxicodynamics of the animals’ developmental process but also on an understanding of the drug-metabolizing capacity of the animal and how it is similar or dissimilar to that of humans.
1.3.2. Individual toxicodynamic differences in developmental components.
Another large domain of possible human variability concerns genetic differences in components of developmental processes. Toxicants might interact with these components. Although signaling pathways and genetic regulatory circuits are particularly attractive for study, there is little information on their genetic differences at this time compared with that on DMEs. However, many mouse mutants in genes encoding such components show developmental defects similar to those in humans, and a few human polymorphisms of components are known to correlate with disease (e.g., Patched mutations and a predisposition to basal-cell carcinoma) and predisposition to developmental defects from certain toxicants (e.g., TGF and tobacco smoke). Some signaling component polymorphisms behave as complex traits with sensitivity to genetic background (e.g., APC mutants in mice represent a Wnt pathway intermediate). Gene locations for many signaling components will soon be known through genetic studies of mouse and zebrafish development, cancer databases, and genome studies. This information will be deposited in widely accessible databases on the Internet.
The current experimental situation is favorable for determining the relationship between mutations in these components and susceptibility to toxicants. Mice offer an opportunity for a survey of the importance of genetic background for toxicant sensitivity and for toxicant specificity of effects. Genetic variants, usually produced by targeted gene knockout (but also by gene replacement to make hypomorphs and gain-of-function types and ectopic expression types), can be made with relative ease in mice, which can be used in developmental toxicity studies. When a null allele of any of a variety of kinds of signaling components is