ies of a variety of developmental toxicants, when developmental defects are scored at birth. The curve highlights the general conclusion that organ systems are most susceptible to pertubation by developmental toxicants, just prior to and during the overt phase of organ formation and differentiation, which occurs in mammals after the period of implantation, streak formation, and streak regression.

Several caveats need to be addressed, however. First, the pre-implantation period should not be viewed as a refractory period in terms of induced structural malformations (Rutledge 1997; Dwivedi and Iannaccone 1998). For example, ethylene oxide (EtO) can induce structural abnormalities in mice when administered during pre-implantation stages of embryogenesis (Generoso et al. 1987). Results from this study are particularly instructive because they show that agents can induce skeletal effects when administered to the pregnant dam at the zygote stage of development, long before skeletogenesis begins. Moreover, the spectrum of skeletal defects observed after exposure at the zygote stage differs from those observed after exposure during organogenesis. The mechanisms underlying that stage-specific effect of EtO on skeletal development are unknown.

The second caveat is that, although the susceptibility curve generally reflects the reality for structural defects, it is not a good generalization for developmental-toxicant-induced death, growth retardation, or functional deficits. For example, toxicant-induced death tends to occur most frequently at pre- and peri-implantation stages. As many as 30% of fertilized human oocytes are estimated to die during those early stages (see Chapter 2), and the role of developmental toxicants in that human loss is largely unknown.

The final point to be made is that development from fertilization to birth is a progressive process so that any adverse outcome (i.e., death, growth retardation, malformation, or functional deficits) after exposure to developmental toxicants will be dictated, in part, by the set of developmental processes active at the time of exposure.

5. “Teratogenic agents act through specific mechanisms on developing cells and tissues to initiate abnormal embryogenesis (pathogenesis).” Recent research focusing on how exogenous chemicals interact with endogenous molecular targets has increased our understanding of the mechanisms of action of toxicants. A detailed discussion on the mechanisms of action of toxicants follows this section.

6. “Susceptibility to teratogenesis depends on the genotype of the conceptus and the mother in which this interacts with environmental factors.” This principle was originally based on the knowledge that different species and strains of animals respond differently to a developmental toxicant. For example, it was already known in the 1970s that mouse embryos are unusually susceptible to the induction of cleft palate by glucocorticoids, and other mammalian species are resistant. Also, some mouse strains are sensitive to hyperthermia-induced neural



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