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

PRINCIPLES OF DEVELOPMENTAL TOXICOLOGY REVISITED 9Degree of ionization — less ionized substances pass more readily.Formation of complexes — complexed molecules are impeded in comparison with their “free” forms,especially if they are complexed with proteins.Existence of concentration gradients — substances present in high concentrations in the maternal bloodare likely to cross the placenta in larger amounts.Placental metabolism — the placenta can metabolize certain substances, but the influence of placentalmetabolism is thought to be minor for most compounds.From the foregoing, it can be seen that although the placenta only rarely acts as a completebarrier, it can greatly slow the passage of certain water soluble molecules, such as heparin andplasma proteins, that are large and/or highly charged. Also, certain physical agents, such as x-rays,gamma rays, ultrasound, and radiofrequency radiation, can readily reach the embryo or fetus, evenfrom outside the mother. And maternal metabolism and excretion may eliminate a portion of theabsorbed dose of a chemical agent or alter its nature prior to its reaching the conceptus. 29b. Relationship of the Placenta to TeratogenesisIt has been suggested that interference with the function of the yolk sac, particularly duringdevelopment of rodents and lagomorphs, may result in developmental defects because these speciesdepend for a considerable portion of gestation on an “inverted yolk sac placenta” 30 (see Chapter 6for more discussion and for comparisons with other species).c. Exposure of the ConceptusIf a potentially developmentally toxic agent reaches the embryo at a sufficiently high rate, it mayreach a sufficiently high concentration to cause an adverse effect; on the other hand, if the rate istoo low, it will not reach an effective concentration. This is because at very low exposure rates,cells may not be significantly affected, and at somewhat higher rates, damage that occurs may berepaired before irreparable harm is done. It should be noted that although mammalian embryosand fetuses can repair minor injuries, if they have developed past the blastocyst stage, they cannotregenerate lost parts. It is also of interest to note that in some cases a chemical may become moreconcentrated in the conceptus than in the mother, depending on the particular agent and exposureroute. 31-335. The Four Manifestations of Deviant Development Are Death, Malformation,Growth Retardation, and Functional Deficit 15In some cases, it is likely that malformation precedes and results in death. According to Kalter, 34as the dose is increased in such a scenario, an inverse relationship between malformation andprenatal mortality would be seen. This would occur as the severity of the induced defects increasedto the point of causing deaths among the offspring. A practical consequence is that an increasedincidence of prenatal deaths may obscure our ability to determine if an agent has caused malformationsbecause the most severely malformed offspring may not survive to be counted at cesarean sectionin a typical teratogenicity assay. However, malformation as the cause of prenatal demise can berevealed if examination of embryos or fetuses prior to birth reveals more malformations and fewerdeaths than would be expected at term. 15 In other cases, death and malformation may be due, atleast in part, to different causes, and thus it is sometimes possible to block or enhance one effectwithout blocking or enhancing the other. Independence of these two manifestations (malformationand death) would be suspected if their frequencies increased independently with increasing dose. 34The two additional possible consequences of developmental toxicity, growth retardation and functionaldeficit, may also be caused by malformations, or they may be induced independently by© 2006 by Taylor & Francis Group, LLC