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

1096 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONmust be factored into preclinical studies for potential impacts on the transplacental transfer of agiven chemical. As with the distinctions noted for the rat, although these differences should notobviate the selection of the dog as the test species, they must be considered in the interpretationof any results.Unfortunately, there was an insufficient number of studies characterizing the in utero developmentof the immune system in primates to make comparisons to the other species. Defining withmore precision the developmental landmarks in the various test species is essential to maximizingthe interpretation of preclinical studies, and ensuring that the parameters we extrapolate from animalmodels are physiologically and clinically relevant to the developing human. As emphasized above,the sequence of developmental landmarks described here has led some investigators to think interms of ‘windows’ of vulnerability (Holladay and Smialowicz, 2000). In fact, one of the cornerstonesof the evolution of developmental immunotoxicology is that it is assumed that some chemicalsmay have a greater effect during one or more of these ‘windows’ than another. Stated anotherway, the premise is that the developing immune system may be more or less sensitive to toxicinsult than the mature adult immune system. However, this premise should consider the physiologyof the immune system during the various stages of development. As noted above, both the developingimmune system and the mature immune system are characterized by a number of physiologicalprocesses, including cellular proliferation, cell migration, cell-to-cell interactions, expressionof surface markers (e.g., for activation, differentiation, adhesion, etc.). As such, a chemical with amode of action that targets one of these processes (e.g., such as an antiproliferative agent) wouldbe expected to affect all ‘windows’ where that process (e.g., proliferation) played an important role.One feature of the developing immune system that clearly distinguishes it from the matureimmune system, especially during gestation, is the role played by organogenesis. Defects in thedevelopment of the immune system due to heritable changes in the lymphoid elements have providedclinical and experimental examples of the devastating consequences of impaired immune development(Rosen et al., 1995). Therefore, the effects of chemicals on the genesis of critical componentsof the immune system in the developing fetus may be more important than effects on these tissuesafter they have been populated by hematopoietic and lymphoid cells. However, a chemical thatinduces the formation of this kind of developmental abnormality in the fetus would legitimatelybe classified as a ‘teratogen’. Interestingly, studies by Hendrickx et al. (2000) characterized theeffects of several well-known teratogenic pharmaceutical agents on the developing immune systemsin primates. Treatment with triamcinolone acetonide, 13-cis-retinoic acid and experimentallyinducedzinc deficiency all were shown to trigger an adverse effect on fetal thymus in macaquesand baboons. Moreover, one of the most widely studied environment contaminants, 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD or ‘dioxin’), that has been characterized by multiple laboratoriesas a developmental immunotoxicant (Barnett, 1996; Holladay and Smialowicz, 2000; Holladay andBlalock, 2002; Neubert et al., 1996; Neubert et al., 2002; and Smialowicz, 2002) is also a knownanimal teratogen (Couture et al., 1990). These results prompt the question as to how many knownteratogens would have an impact on the thymus or other critical immune organs and whether thesetypes of agents should be more appropriately classified as ‘immunoteratogens’, as opposed todevelopmental immunotoxicants.Results using clinical immunosuppressants, which are devoid of teratogenic effects, in pregnantwomen are relevant to this discussion. Recent advances in organ transplant success have resultedin increasing numbers of women becoming pregnant after an organ or tissue transplant procedure.These women require therapeutic immunosuppression throughout pregnancy to prevent allograftrejection. Studies of pregnant women receiving the required polytherapy (e.g., prednisone pluseither azathioprine or cyclosporine) following renal, heart or liver transplants indicate that the majorrisk is fetal growth restriction and that there is little evidence that exposure is associated with anincrease in congenital anomalies (Hou, 1999). In contrast, another study reported that a transientbut severe B-cell depletion was seen in neonates born to renal transplant mothers receiving cyclosporine,azathioprine and methylprednisolone (Takahashi et al., 1994). One report also showed an© 2006 by Taylor & Francis Group, LLC