These gene expression profiles can be linked with specific tissue changes using microdissection techniques. Again, emphasis on developmental characteristics is important. Such characteristics include temporal aspects of gene expression and multiple organisms, organs, and tissues of interest. Functional genomics databases on expressed genes are particularly relevant for developmental toxicologists. Expressed sequence tags (ESTs), ORFs, and the time and place of expression of each gene in the embryo and on the function of encoded proteins (specific function or categorization by motifs) would be essential information. For example, signal transduction pathways and the interactions of pathways are in the process of being summarized on the Web site www.stke.org. Journal articles, as well as methods protocols, will be posted (announced in Science, April 1999). Likewise, databases on human polymorphisms and disease associations, human and mouse mutants, including all the targeted disruption mutants and phenotypes in mice, would be important. Online access to databases listing all known human genetic syndromes relevant for development would also be essential.
Within a decade, most genes encoding components of signaling pathways and genetic regulatory circuits important in development will probably be identified in humans and mice (the extensive synteny among vertebrates will be valuable here), and their times and places of expression will be known. Many human polymorphisms will be identified and correlated with heritable diseases. At levels 1 and 2 of the model system toxicity assays, this database information will be useful for choosing proteins to use in simple biochemical or cell assays or to modify in test animals, such as Drosophila. It is safe to say that almost any human gene and, hence, its encoded protein, can be put into such an animal assay. The question will be which proteins are most relevant to the identification of developmental toxicants in humans. If 100,000 assays can be done per year at level 1 and 10,000 at level 2, the results would have to be preserved in an immense database. Over the same period, all genes for proteins of the major toxicokinetic pathways of chemical uptake, distribution, metabolic conversion, and elimination in humans, mice, and rats will probably be identified, as will polymorphisms of these genes. This information will be preserved in databases, and should be widely available. Catalogs of phenotypes of mouse null mutants for individual genes in the heterozygous and homozygous states, and in combination with other gene disruption, will be useful for comparison with phenotypes of human birth defects in order to gain inferences about what is affected in human development. The level 2 and 3 model system assays for developmental defects will draw from these genomic databases and contribute to them. Several of the databases of epidemiological characterizations will benefit as well.
Chemical databases might be more difficult to organize than genome databases. Whereas there are about 140,000 genes in humans, the universe of possible chemicals is unlimited (the number of possible human allele combinations is also unlimited). New compounds can always be synthesized, and their effects on developmental mechanisms are rarely predictable, at least so far. Also, a new