How can progress be made in the analysis of mechanisms of toxicity? What variety of mechanisms is there? Are there certain molecular components and processes of development that seem to be frequent targets of toxicants? The recent advances in developmental biology, cell biology, and genomics provide information about components, functions, and processes for the first time and for a wide range of animals, including mammals. Fortunately, many of the components and processes are conserved across phyla, making it possible to study them initially in experimentally convenient organisms, such as C. elegans and Drosophila, or even yeast and bacteria in some cases, and then carry the information across species to the studies of mammalian development, with great success. Many aspects of mammalian development resemble arthropod and nematode development.
The committee’s recommendation for future studies on mechanisms of developmental toxicity is that greater use be made of model organisms, taking advantage of the shared features of development with mammals. Fruit flies, nematodes, and mice have different organs and body organization, and yet they use many of the same molecular components and basic molecular interactions, although in different combinations and sequences. The analysis of toxicity mechanisms would have to bear the similarities and dissimilarities in mind.
Mechanisms of toxicity can now be understood more fully at the level of affected molecular components and the consequences of the altered activity of this component for developmental processes. Previously, toxicity analysis often ended with defining the time window of sensitivity of the conceptus to the toxicant and the profile of affected organs. This information is still important to have. Because toxicants affect the activity of molecular components, the recommended emphasis would be to identify components with which toxicants interact, determine the toxicant’s effect on the component’s function (the functions of many components are now understood), and fit the altered function into the effects on a developmental process, the abnormal operation of which leads to a structural or functional defect. The committee recommends that model organisms be used extensively to access this level of analysis so that researchers can benefit from genetic tractability, experimental convenience, and a background of information about molecular components and developmental processes.
1.1. In searching for mechanisms of developmental toxicity, the committee recommends research on how toxicants perturb evolutionarily conserved molecular targets and pathways of development.
To learn about mechanisms of developmental toxicity, special attention should be given to research in the areas of (1) signaling pathways and their associated genetic regulatory circuits (a group of key developmental targets); (2) molecular-stress and checkpoint pathways (a group of key cellular targets); and (3) the DMEs (a group of key toxicokinetic components).