PRINCIPLES OF TOXICOLOGY - Biology East Borneo

11.3 DEVELOPMENTAL TOXICOLOGY 229risk for becoming pregnant from taking the drug, developmental deformities related to isotretinoinexposure continue to be reported.The defects associated with isotretinoin are wide ranging and include craniofacial deformities,including cleft palate, and cardiac and central nervous system abnormalities. This can be understoodon the basis of the role of the retinoids in normal development. Isotretinoin is a synthetic retinoid, orchemical relative of Vitamin A. Gradients of certain retinoids in tissues appear to play a major role inthe organization and orientation of tissue growth. The direction of cellular growth needed to extend alimb, for instance, is guided by retinoid signals. Disrupting this road map with exogenous retinoidscould clearly be a basis for inappropriate development. Exogenous exposure to most retinoids canproduce developmental defects, at least experimentally. Isotretinoin is a good example of a teratogenthat works by interfering with the chemical signaling used to guide development.Fetal Hydantoin Syndrome Another class of teratogenic drugs is still used by pregnant womenbecause the developmental risks are less than the risks of removing the drug. Diphenylhydantoin—phenytoin, valproic acid, and other anticonvulsants are used in epileptics to prevent seizures. They arealso teratogenic. In these cases, however, the therapeutic regimens are not associated with substantialnumbers of congenital defects, and the potential for injury to both the fetus and mother should a seizureoccur is more of a concern.A specific set of characteristic developmental features associated with anticonvulsant treatment hasbeen classified as Fetal Hydantoin Syndrome. There are craniofacial features, limb alterations, as wellas growth and learning deficits. While the structural effects may be mild, the growth and learningretardation are commonly permanent. The syndrome is not particularly common, however, and manystudies conclude that the risk is low, especially when the potential for epileptic seizures is considered.In experimental protocols, phenytoin produces more severe, specific craniofacial defects, includingcleft palate when given in the window of time associated with palatogenesis. Later exposures producethe limb effects.Valproic acid is clearly teratogenic in experimental protocols as well. The primary effects appearto be on the central nervous system, however, skeletal and craniofacial defects can also be produced.There are reports of neural tube defects and spina bifida in humans exposed to valproic acid throughmaternal treatment, and the occurrence appears to be higher than expected in some studies. However,most of these studies have selected cases to examine, and it is not clear what the actual incidence rateof valproic acid-related human defects is. Again, the concurrent epilepsy confounds the situation.DES: A Teratogen Associated with Cancer Endpoints Another type of teratogen is exemplified byanother human tragedy. Diethylstilbestrol (DES) is a synthetic steroid hormone that was used to helpprevent miscarriage in women with difficulty maintaining a pregnancy. In this case, rather than thehalf decade it took for thalidomide’s effects to become clear, around a quarter of a century passedbetween the mid-1940s and 1970 before the teratogenicity of DES became clear. An extremely rareform of reproductive tract cancers, clear cell adenocarcinomas, was detected in a series of womenwhose mothers had taken DES during the first trimester of pregnancy. Though the cancer risk was firstnoted in some early teenage girls, it peaked around age 19–22. This explains the delay in discoveringDES’s effects and illustrates an example where the congenital defect was not immediately obvious.DES is also an interesting example of a teratogen that produces cancer as its congenital defect. It iscurrently the only established human carcinogen that acts transplacentally.In addition to the cancer risk associated with DES, a variety of other reproductive disorders werenoted as the exposed children grew up. Among the female children, these included an increased riskof ectopic pregnancy, spontaneous abortion, menstrual irregularities and infertility. For the malechildren, abnormalities of the genitals, decreased sperm production, cryptorchidism, and a possibleincrease in testicular cancer were observed. All of these reproductive tract defects help point out thelikely actions of DES in the developing children. The development of the internal and external genitaliais coordinated by steroid hormone production, primarily by the fetal gonads. The hyperestrogenenvironment produced by DES is consistent with improper formation of the male internal and external