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

154 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONthat there exists a broad diversity of mechanisms for transporting molecules through the placenta.The transport mechanisms 8–10 include both simple diffusion for most molecules (e.g., urea, oxygen,carbon dioxide) and carrier-mediated transport. The carrier-mediated mechanisms include activetransport (e.g., for sodium/potassium, calcium, amino acids), facilitated diffusion (e.g., for D-glucose), and receptor-mediated endocytosis (e.g., for immunoglobulins, vitamin B-12). Thus, giventhe multiplicity of available transport mechanisms, when any substance is presented to the placenta,the question concerning entry into the embryo should not be whether placental transfer occurs, butrather by what mechanism and at what rate will transfer occur. The closest phenomenon to a barrierfunction is the expression in trophoblast cells of the multidrug resistance (mdr) gene family, whichencodes a p-glycoprotein on the surface of the trophoblast membrane of conceptuses 11–13 exposed tocertain xenobiotics. This phenomenon serves to limit the exposure of embryos to selected molecules.In addition to transferring nutritive molecules to the embryo, the placenta may metabolizesubstances, whether they are nutrients or xenobiotic compounds. 9,10,14 For example, in cattle andsheep, the placental trophoblast converts maternally delivered glucose to fructose, which is in turntransferred to the embryo. In those species, an intravenous dose of glucose to the pregnant femalecauses a dramatic rise in fetal plasma fructose concentrations, rather than a rise in fetal plasmaglucose. This illustrates the concept that placentas are not merely sieves but have the ability to altersome of the types of molecules that traverse them.Placentas also contain various enzymes that are capable of metabolizing xenobiotics. 15–17 Theseenzymes include reductases, epoxide hydrases, cytochrome P-450 monooxgenases, glucuronidases,and others. These enzymes are not present at all times during gestation but make their appearancesas the placenta (and embryo) mature. The presence (or absence) of these enzymes reflects thegenotype of the embryo rather than that of the mother. Placental enzymes can be induced byinducers of monooxygenases, such as phenobarbital, benzo(a)pyrene, and 3-methylcholanthrene.In addition, the formation of reactive intermediates from xenobiotic compounds by placental enzymepreparations has been demonstrated in vitro (e.g., see Chapter 12 of this volume).Placental toxicity, per se, is rarely cited as a primary mechanism for developmental toxicity.This does not mean that the importance of the placenta in development is not recognized, nor doesit mean that placental dysfunction can be discounted as playing a critical role in development.10,14,17–20 That the placenta plays a role in developmental toxicity is not in dispute; rather, ithas proved difficult to determine whether developmental toxicity arises as a result of direct placentaltoxicity or from combined effects on the materno-feto-placental unit. Examples of developmentaltoxicity that have been ascribed to some combination of mother, fetus, and placenta include reductionsin utero-placental blood flow subsequent to hydroxyurea, 21,22 altered transport of nutrients by azodyes, 23,24 immunotoxicants, 25,26 lectins, 71 and hemoglobin-based oxygen carriers, 72 as well as pathologicalchanges observed in the trophoblast after exposure to placental toxicants, such as cadmium. 27,28III. EMBRYOLOGICAL PROCESSESDevelopment from zygote to embryo to fetus to independent animal is a dynamic and carefullyorchestrated phenomenon that involves numerous simultaneous processes that occurs in specificsequences and at particular times during both gestation and the postnatal period. This is especiallytrue for rodents, wherein many of the organ systems of neonates have attained only the state ofmaturation found in late second or early third trimester human fetuses. 29 While it is imperative thatdevelopmental schedules be maintained, each embryo develops at its own rate, and there is someroom for adjustment to the schedules. That is, some developmental events may be delayed to acertain extent without adverse consequences. Thus, the gestational ages given for developmentalevents are merely averages of the observed events. Embryos within the same litter of polytocousspecies are frequently at different developmental stages, especially during early embryogenesis.This may have resulted from different times of fertilization as well as from differences in the rateat which each embryo progresses through its own developmental schedule.© 2006 by Taylor & Francis Group, LLC