reduced, causing fetal hypotension and oligohydramnios (reduced volume of amniotic fluid). Those primary mechanisms lead to fetal death and stillbirth, middle- to late-trimester onset of oligohydramnios, and intrauterine growth restriction followed by delivery of infants with hypotension and renal failure (Barr 1997).

Other chemicals block protein polymerization, such as colchicine and colcimid blocking tubulin polymerization to microtubules or cytochalasins blocking actin aggregation to microfilaments. Those drugs bind to protein-protein association sites. There are examples of chemicals also binding at other kinds of sites. All fit the geometry and weak bonding properties of the site and competitively interfere with the binding of the normal cell component (substrate or ligand). Chelators of essential elements may interfere with protein function by limiting the availability of metal co-factors. Examples of proteins that require metals to function are metalloproteinases and several other enzymes, and zinc-finger transcription factors.

Maternally Mediated Effects

All the mechanisms discussed above occur within the embryo. However, there are examples in which developmental toxicity is the consequence of toxicity in the mother. Effects on the embryo occur secondarily, as a result of some effect on the pregnant mother. Effects include chemically induced maternal hypoxia or secondary nutritional deficiencies. An example of the former is the case of diflunisal (5-(2,4-difluorophenyl) salicylic acid, a nonsteroidal anti-inflammatory drug), which causes hemolytic anemia in pregnant rabbits. The anemia leads to adverse developmental effects (Clark et al. 1984). An example of secondary nutritional deficiencies is the functional zinc deficiency brought about by substantial induction of metallothionein in maternal liver as part of a systemic acute-phase response to a wide array of chemicals that have little in common other than their capacity to induce an acute-phase response, including de novo expression of metallothionein in the liver (Daston and Lehman-McKeeman 1996). The events that take place within the embryo after toxicant-induced zinc deficiency are equivalent to those occurring during dietary deficiency, but the salient point for developmental toxicology and risk assessment is the recognition that maternal factors might contribute substantially to embryonic response.

Other Mechanistic Considerations

There are other mechanisms that might be found to affect development. These might include such events as DNA intercalation, interaction with as yet unidentified targets, or complicated interactions that involve multiple changes, each of which is necessary—but not by itself sufficient—to initiate a pathogenetic cascade.



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