(epicanthal folds, hypertelorism, broad, flat bridge of the nose, upturned tip of nose, and prominent lips), distal digital hypoplasia, intrauterine growth retardation, and mental retardation. This cluster of defects has been termed the fetal hydantoin syndrome and occurs in about 11-17% of pregnancies in which the mother has taken the drug (Hanson et al. 1976; van Dyke et al. 1988).

It appears necessary for DPH to be metabolized by cytochrome P450 (CYP) enzymes to reactive intermediates that form adducts with DNA or protein within the embryo (for a review, see Wells et al. 1997). The most likely intermediate is an arene oxide. An alternative hypothesis suggests that DPH is metabolized by prostaglandin synthetase to a teratogenic intermediate. This hypothesis is supported by the observation that DPH teratogenicity in mice can be mitigated by cotreatment with aspirin, an inhibitor of prostaglandin synthetase (Wells et al. 1989). It has been observed that DPH treatment in rodents decreases the expression of the mRNAs for a number of important growth factors, including TGFβ, NT3 and WNT1 (Musselman et al. 1994). Whether the decrease is due to an effect on gene expression or a degradation of RNA by reactive intermediates of DPH is not known.


Methotrexate is a cancer chemotherapeutic drug. It is a competitive inhibitor of dihydrofolate reductase, which converts folate to tetrahydrofolate. Tetrahydrofolate is then metabolized to various coenzymes that play a role in the synthesis of purines and amino acids and conversion of deoxyuridylate to thymidylate. Exposure of rabbits to methotrexate during gestation causes craniofacial defects, limb deformities, and decreased fetal weight in the offspring (DeSesso and Goeringer 1991, 1992). Similar defects have been observed clinically in babies of mothers who had been given methotrexate between 35 and 50 days of gestation (Milunsky et al. 1968; Warkany 1978). Using a metabolic derivative of folinic acid, the authors (DeSesso and Goeringer 1991, 1992) demonstrated that methotrexate causes developmental toxicity by inhibition of dihydrofolate reductase. The metabolic derivative replaced the normal product of the inhibited enzyme and eradicated the developmental toxicity.


Methylmercury (MeHg) is an environmental toxicant that primarily affects the central nervous system (CNS) and, to a lesser extent, the liver and kidneys. To reach the brain, it must cross the blood-brain barrier by traversing the brain capillary endothelial cells. MeHg possesses a high affinity for thiol groups and will bind to endogenous sulfhydryl-containing ligands, such as proteins, and low-molecular-weight compounds, such as glutathione, found in blood and tissue (for a review, see Clarkson 1993). Hirayama (1980, 1985) reported that intravenous injection of MeHg chloride and cysteine in rats increased the rate of

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