The principles of teratology have been articulated by Wilson (104). The first principle is that terato-gens act with specificity. A teratogen produces a specific abnormality or constellation of abnormalities. For example, thalidomide produces phocomelia, and valproic acid produces neural tube defects. This specificity also applies to species, because drug effects may be seen in one species and not in another. The best example is cortisol, which produces cleft palate in mice but not in humans.
The next principle is that teratogens demonstrate a dose-effect relationship. Given to the mother at a specific time during gestation, low doses can produce no effect, intermediate doses can produce the characteristic pattern of malformation, and higher doses will be lethal to the embryo. Dose-effect curves for most ter-atogens are steep, changing from minimal to maximal effect by dose doubling. Increasing the dose beyond that found to be lethal to the embryo will eventually lead to maternal death. This is used as an endpoint in animal teratogenicity studies.
The third principle is that teratogens must reach the developing conceptus in sufficient amounts to cause their effects. The extent of fetal exposure to drugs and other xenobiotics is determined not only by maternal dose, route of elimination, and placental transfer, but also by fetal elimination mechanisms. Because the fetal liver is interposed between the umbilical vein and systemic circulation, drugs transferred across the placenta are subject to fetal first-pass metabolism (77). This protective mechanism is compromised by ductus venosus shunting, which enables 30-70% of umbilical venous blood flow to bypass the liver. After drugs reach the fetal system circulation, hepatic metabolism constitutes the primary elimination mechanism and renal excretion is relatively ineffective because the fetal kidney is immature and fetal urine passing into the amniotic fluid is swallowed by the fetus. CYP3A7 is a fetal-specific enzyme that accounts for about one-third of fetal hepatic cytochrome P450. CYP1A1, CYP2C8, CYP2D6, and CYP3A3/4 have also been identified in fetal liver. These enzymes are not only protective, but their presence in fetal tissues other than liver is also capable of converting drugs into chemically reactive teratogenic intermediates such as phenytoin epoxide (see Scheme 11.11) (105).
The fourth principle is that the effect that a ter-atogenic agent has on a developing fetus depends upon the stage during development when the fetus is exposed. From conception to implantation there is an all-or-nothing effect, in that the embryo, if exposed to a teratogen, either survives unharmed or dies.
This concept developed from Brent's studies of the effects of radiation on the developing embryo and may or may not apply to fetal exposure to chemicals (106). After implantation, during the process of differentiation and embryogenesis, the embryo is very susceptible to teratogens. However, since terato-gens are capable of affecting many organ systems, the pattern of anomalies produced depends on which organ systems are differentiating at the time of ter-atogenic exposure. A difference of one or two days can result in a slightly different pattern of anomalies. After organogenesis, a teratogen can affect the growth of the embryo by producing growth retardation, or by changing the size or function of a specific organ. Of particular interest is the effect of psychoac-tive agents, such as cocaine, crack, or antidepressants, on the developing central nervous system during the second and third trimesters of pregnancy, as these drugs can potentially affect the function and behavior of the infant after delivery. Giving a teratogen after the fetus has developed normally has no effect on the development of organs already formed. For example, beginning lithium after cardiac development, or val-proic acid after the closure of the neural tube, will not produce either drug's characteristic anomalies.
The fifth principle is that susceptibility to terato-gens is influenced by the genotype of the mother and fetus. Animal studies have shown that certain animal strains are more susceptible to the production of malformations when exposed to a teratogen, compared to other animal strains. In humans, the fetus homozy-gous for the recessive allele associated with decreased epoxide hydrolase activity has an increased risk of developing the full fetal hydantoin syndrome (105). Maternal smoking increases the risk for the development of cleft lip and palate in a fetus carrying the atypical allele for transforming growth factor (107). Single mutant genes or polygenic inheritance may explain why certain fetuses are unusually susceptible to teratogens.
Mechanisms of teratogenesis include genetic interference, gene mutation, chromosomal breakage, interference with cellular function, enzyme inhibition, and altered membrane characteristics. The response of the developing embryo to these insults is failure of cell-cell interaction crucial for development, interference with cell migration, or mechanical cellular disruption. The common endpoint is cell death — teratogenesis causing fewer cells. Most mechanisms of teratogenesis are theoretical, not well understood, and imply a genetic component. One exception is the mechanism of thalidomide teratogenesis. In susceptible species, thalidomide causes oxidative DNA damage. Pretreatment with phenyl-N-tert-butylnitrone
(PBN), a free radical trapping agent, reduces the occurrence of thalidomide embryopathy, suggesting that the mechanism is free radical-mediated oxidative DNA damage (108).
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