mammalian embryos the need to coordinate and integrate the many temporally and spatially distinct cell regulatory networks operating during development. A fully developed, functional fly wing, fish fin, or human arm are all products of comparable hierarchically organized processes.

1.1.2. Molecular-stress and checkpoint pathways as potential targets of toxicants.

There is evidence that some toxicants primarily damage basic cell functions, such as those of cellular reproduction, and that the damaged cells subsequently fail to participate in development. Such toxicants can act indirectly on development, although the failing of basic cell functions can soon enough impede development. Molecular-stress and checkpoint pathways are the cell’s defenses for counteracting such damage. At least 10 of these pathways are known. They respond to different kinds of damage and decisions to make different counteractions. Apoptosis is the ultimate pathway, by which the cell is self-destroyed. This is thought to happen when the other counteractions are not sufficient to restore the cell to a minimal state of basic function.

Especially with regard to environmental toxicants, these pathways might deserve special attention, because some toxicants react widely with cellular components. As mentioned in Chapter 6, many environmental toxicants set off an enlarged domain of apoptosis in the embryo. The particular spectrum of activated pathways would give an indication of the impacted cellular processes and components. Also, low- and high-dose effects could be discriminated. At low doses, cells might recover or a fraction might die and be replaced by the proliferation of others, in which case, development might continue normally. At high doses, recovery might be exceeded by impaired proliferation or apoptosis and defects occur.

The investigation of toxicant targets in these pathways can exploit C. elegans, Drosophila, zebrafish, and mouse. The molecular-stress and checkpoint pathways have been well analyzed in these organisms (in fact, discovered in them in some cases). The pathways are nearly identical in all those organisms, although mammals have a greater variety of closely related components. In general, there has been less study of these pathways in embryos than in adults, so there might be some unexpected differences.

1.1.3. Toxicokinetic components, especially drug-metabolizing enzymes.

As noted above, there are many steps in absorption, distribution, metabolism, and excretion that determine whether the conceptus will be exposed to a toxicant. The molecular components of absorption, distribution, and excretion are not well known, but those of metabolism, the DMEs, have been extensively elucidated in recent years. There might be a few hundred kinds of DMEs, with different substrate specificities and time and place of expression in the mother and conceptus. Studies are well under way to analyze the roles of DMEs to



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