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The fetal hydantoin syndrome : a mouse model Finnell, Richard H.

Abstract

The suspected teratogenicity of Diphenylhydantoin (DPH) in man is important, especially to the 0.3 to 0.5% of pregnant women who are epileptic and, therefore, candidates for anticonvulsant drug therapy. To separate the teratogenic effect of epilepsy from DPH treatment, an animal model closely approximating the human condition was developed to meet the following criteria: (i) the test animal must have spontaneous seizures (ii) the seizures must be controlled or eliminated by DPH treatment (iii) the drug must be administered orally (iv) serum DPH levels must fall within the optimal human therapeutic range between 5 and 20 micrograms per ml serum (v) treatment must begin prior to mating and continue throughout gestation (vi) the offspring of treated animals must exhibit the spectrum of malformations observed in the offspring of epileptic women The first criterion was met by mutant quaking (qk) mice. The seizure activity of these animals was reduced (from 2.1 to .34 seizures per mouse day) by DPH treatment. To separate the effect of this gene from that of the DPH in the etiology of the malformations, heterozygous (+/qk) and homozygous non- quaking (+/+) mice were also studied. Monitoring of DPH levels with the SYVA Emit spectrophotometry assay technique indicated serum concentrations within the human therapeutic range at 40 and 60 mg/kg body weight dosages. The incidence of fetuses born with skeletal or soft-tissue abnormalities increased with increasing DPH dosages. This was observed in all three genotypes. The ability of the untreated quaking (qk/qk) dams to -produce normal offspring implicates the drug rather than the mutant gene as the cause of malformations. A preliminary application of this animal model produced what can be considered the mouse equivalent of the fetal hydantion syndrome. The similarities between the human and mouse syndromes include prenatal growth deficiency, neural, cardiac, orofacial, ocular and genitourinary anomalies. Further large-scale application of the model should provide insight into the role of DPH in the etiology of the malformations observed amongst the offspring of epileptic women on hydantoin anticonvulsant drug therapy.

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