dependent upon each specific pathway. The signaling pathways and genetic regulatory circuits used in the development of the fruit fly and nematode organs are largely the same as those used in human organ formation but are used in different combinations and express different genes to form species-specific organs. At information level 2, the fruit fly organ can be used for assaying for chemical effects on conserved signaling pathways and gene regulation. In addition, some fruit fly organs are now thought to have deep evolutionary similarities to particular vertebrate organs, including human organs, in their combination of pathways and circuits. Examples of organs and structures include the development of the heart, gut, eyes, appendages, blood vessels and tracheae, somites and body segments, and several structures associated with neurogenesis. Thus, for some organs and structures, the human and fruit fly differences are not great.

Chemicals showing effects on development can be identified for additional testing if human exposure or use is anticipated. Presumably, some of the chemicals active at information level 1 would also be active at level 2. In fact, effects at level 1 should allow predictions of effects in assays at levels 2 and 3. For example, if particular signaling-pathway components are affected in biochemical and cell assays, it should be possible to predict which kinds of organogenesis will be affected in the fruit fly, nematode, and zebrafish. False positives and high sensitivity are still to be preferred over false negatives and low sensitivity for useful information at level 2. All the test information would be entered in a database linking chemical-structure information and toxicity.

As described for information level 1, assays in level 2 will provide

  • structure-activity information,

  • relative potency information for chemicals evaluated in the same assays,

  • information about the activity of chemical mixtures, and

  • some quantitative information across assay end points for estimating relative potency across chemical classes.

In addition, these assays will give information on affected organs and organ systems. Impacts on specific cell signaling pathways can be connected to defects in organogenesis and perhaps to functional deficits (e.g., see the behavioral assessments in model organisms discussed in Chapter 7).

It is expected that DNA microarray techniques will have an increasing role in level 1 and 2 assessments. At present, the methods are sensitive and reliable enough to detect manifold differences in mRNA profiles in cells and tissues exposed to different conditions (e.g., growth medium, ploidy, and temperature), however, interpreting the changes remains a problem. In the near future, there will undoubtedly be microarrays representing certain classes of genes and gene products, for example, those for signaling components, by which the changes in mRNA profiles can be related to particular developmental processes altered in the presence of toxicants. Also, as information accumulates, it will be possible to



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