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

6 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONB. Wilson’s Principles 151. Susceptibility to Teratogenesis Depends on the Genotype of the Conceptusand the Manner in Which This Interacts with Adverse Environmental Factors 15It must also be kept in mind that in some cases there is a purely genetic cause, e.g., Down syndromein humans, and there can be purely environmental causes, such as x-rays at high doses. In stillother cases, however, a combination of environmental insult(s) and a susceptible genome in theconceptus is required for adverse effects to appear, a scenario that Fraser termed multifactorialcausation. 16It is now well established that the genetic makeup of the conceptus can significantly influencethe outcome of exposures to developmental toxicants, especially if the level of exposure is nearthe threshold for causing a particular adverse effect. This has been readily observed in studiesinvolving treatment of inbred mouse strains and crosses between them. However, one must beaware of the caveat that the developmental outcome may also be influenced by the genotype of thedam as a determinant of, for example, the rate or preferred pathway of biotransformation of thetoxicant in question and its peak level in the maternal blood or its area under the curve (AUC, thearea under the plasma [or serum or blood] concentration versus time curve). The outcome here canbe influenced by whether it is the parent compound or a metabolite that is developmentally toxic,and of course in some cases both can be toxic. Fetal alcohol syndrome may be a case where thematernal and/or fetal genotype can interact with the toxic agent (and probably with other environmentalinfluences, such as the maternal diet) to produce damage in some instances and few or noobvious effects in others. 17Recently, confirmation of the significant influence of specific genes has come from experimentsin which knockout mice lacking a specific gene have been found to be either enhanced or diminishedin susceptibility to exposure to a developmentally toxic agent. 18 Further, recent human studies haveprobed the potential influence of combinations of specific gene polymorphisms and dietary deficiencies,especially folate deficiency, on the incidence of neural tube defects. 19 And deficiency inthe activity of a detoxifying enzyme, epoxide hydroxylase, may be an important determinant ofthe manifestation of fetal hydantoin effects. 20Species differences in response to developmental toxicants may be due to differences in inherentsusceptibility of the conceptus to differences in maternal pharmacokinetics — including biotransformation— and maternal physiology, or to a combination of these. The same is true of strain andlitter differences in response to toxic insult, and the basis for strain differences can be determinedby use of reciprocal crosses and by embryo transfer. Typically, there are also individual differenceswithin litters. This is probably most commonly due, at least in part, to genotypic differences amongthe individual fetuses, though this should be less often true when inbred strains are involved.Differences in developmental stage at the time of exposure to toxic insults — those of shortduration or those that begin during organogenesis — may explain some of the differences inindividual response among fetuses within the same litter. In some cases, there are sex differencesin the response, i.e., males and females may be affected differently. Differences in the intrauterineenvironment of each conceptus may also contribute to nonuniformity of response within litters.For example, placental blood supply varies somewhat according to location in the uterus 21,22 andmay bring or remove greater or lesser amounts of a toxic substance or of nutrients, waste products,or respiratory gases. Female rodent fetuses that are found next to one male or (especially) betweentwo male fetuses can be altered in certain attributes, such as sexual attractiveness and estrous cyclelength, compared with those of females not found next to males. 23 Such effects are presumablycaused by the transfer of androgen from the male to the adjacent female fetuses.Even differences in fetal drug metabolizing capability may be influential, at least in fetuses inwhich enhanced levels of xenobiotic biotransforming enzymes had been induced. Nebert found© 2006 by Taylor & Francis Group, LLC