A Practical Approach, Second Edition=Ronald D. Ho.pdf

64 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONdose. The developmental period at which exposure occurs will determine which structures are mostsusceptible to the deleterious effects of the agent and to what extent the embryo can repair thedamage. The period of sensitivity may be narrow or broad, depending on the environmental agentand the malformation in question. Limb defects produced by thalidomide have a very short periodof susceptibility. Moreover, the type of limb defect that can be induced changes rapidly as embryonicage increases from 22 to 36 days postconception. 15,16 The mechanism of thalidomide’s action onthe cells, while still undetermined, very likely remains the same. Thus, the differing sensitivitiespresumably result from changes in the target cell population itself over time. Such changes couldinclude alterations in proliferation rate, stage in cell cycle, commitment to differentiation, orexpression of specific receptors. Other teratogens, and particularly those that cause a more nonspecificcytotoxicity, may have much longer periods of susceptibility. Radiation-induced microcephaly,which can be induced far into the fetal period, is an example. 17,18Numerous studies and observations have shown us that during the first period of embryonicdevelopment, from fertilization through the early postimplantation stage, the embryo is mostsensitive to the embryolethal effects of drugs and chemicals. Surviving embryos have malformationrates similar to the controls, not because malformations cannot be produced at this stage, but becausesignificant cell loss or chromosome abnormalities at these stages have a high likelihood of killingthe embryo. Because of the omnipotentiality of early embryonic cells, surviving embryos have amuch greater ability to have normal developmental potential. This trend of marked resistance tothe malforming consequences of teratogens has been termed the “all-or-none phenomenon.” Utilizingx-irradiation as the experimental teratogen, Wilson and Brent demonstrated that the all-ornonephenomenon disappears over a period of a few hours in the rat during early organogenesis. 19The term “all-or-none phenomenon” has been misinterpreted by some investigators to indicatethat malformations cannot be produced at this stage. On the contrary, it is likely that certain drugs,chemicals, and other insults during this stage of development can result in malformed offspring. 20,21But the nature of embryonic development at this stage will still reflect the basic characteristic ofthe all-or-none phenomenon, which is a propensity for embryolethality, rather than survivingmalformed embryos.The period of organogenesis encompasses rapid cell division, extensive patterning, and tissuedifferentiation. Thus, it is not surprising that this period represents the stage when the embryo ismost susceptible to dysmorphogenesis from developmental toxicants and that the majority ofcongenital malformations can be produced by alterations in developmental processes during thisperiod. Exceptions include malformations of the genitourinary system, palate, and brain, as wellas abnormalities produced by deformations and disruptions.During the fetal period, teratogenic agents may decrease the cell population by producing celldeath, inhibiting cell division, or interfering with cell differentiation. The resulting effects, such as celldepletion or functional abnormalities, may not be readily apparent at birth. Major structural anomaliescan be produced during the fetal period, and they usually result from disruptions or deformations dueto factors such as uterine constraint, hypoxia, or the action of vasoactive substances such as cocaine.Disruptions induced at this stage may involve limbs, major organs, including the brain, or other systems.Severe growth retardation in the whole embryo or fetus may also result in permanent deleterious effectson many organs or tissues, especially the brain and reproductive organs.B. Tissue SpecificityThe pathogenesis associated with a developmental toxicant depends not only on the nature of theteratogen itself but also on the susceptibility of the embryonic tissues. In general, rapidly dividingcell populations will be the most sensitive to developmental toxicants that result in cell death orreduced cell proliferation. This is not because other cell populations receive no exposure, butbecause depletion of the cell population in areas of rapid cell division is more likely to interfere© 2006 by Taylor & Francis Group, LLC