regulator; Chapter 4), smoking and transforming growth factor (TGF) variants in humans (the receptor tyrosine kinase pathway; Chapter 5), and smoking and MSX/BMP variants in humans (the TGF pathway; Chapter 5).

The committee acknowledges that signaling and gene regulation have not been proved to be particularly vulnerable points of development. An argument can be made that, because these pathways are so essential for all aspects of development, evolutionary selection has made them particularly resistant to perturbation, including that by toxicants. However, data from experimentally constructed mutant animals contradict this argument. In invertebrates, such as Drosophila and C. elegans, null mutants are often lethal, and hypomorphic mutants (i.e., ones having partial activity) show specific developmental defects, probably reflecting the times and places where the inadequate component is required at highest activity. In vertebrates, including mammals, the picture is somewhat different. The genes encoding most components have undergone duplication and slight diversification, so there are functionally equivalent members for each kind of component. This is termed “redundancy”. The members are expressed at different times and places in development. In vertebrates, null mutants frequently show, not lethality, but specific local losses, reflecting the few times and places where a lost component’s function is not overlapped by a related component. Some of these null phenotypes in mice closely resemble human developmental defects (e.g., see Tables 6-4 and 6-5). Thus, the committee’s hypothesis, namely, that signaling pathways and the associated genetic regulatory circuits are critical molecular points of susceptibility of development to toxicants, has not been proved.

A final point should be made about the appropriate use of model organisms for studies of molecular mechanisms of toxicity. As mentioned above, although these organisms have different organs from mammals, the developmental processes involved in their organogenesis are similar to those of mammals. Organogenesis in various species represents different combinations and orderings of conserved processes, such as signaling pathways and the responses they engender (e.g., proliferation, locomotion, and secretion). Thus, for example, in the course of a study of toxicity mechanisms, Drosophila might be scored for the effects of a chemical on its wing development, but what is really being scored is the effect of the chemical on the kinds of signaling pathways and genetic regulatory circuits also used in human development of different organs. Wing development serves as a well understood set of conserved molecular components and interactions. Effects on the wing can be readily recognized, and because of the advanced understanding of its development, the targeted developmental processes can be surmised. From the fly results, predictions can be made of the effects of those chemicals on mammalian organogenesis, for organs in which these same components operate. Zebrafish, as a vertebrate test animal, are expected to share many developmental processes with mammals (e.g., more details of specific organogenesis) and can be used as an intermediate model. All these model systems share with

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