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Fetal hydantoin syndrome in rats: dose-effect relationships of prenatal phenytoin on postnatal development and
Insights
Phenytoin exposure during gestation in rats caused significant behavioral abnormalities in offspring, including increased activity and impaired learning. These effects occurred at doses below those causing physical birth defects, highlighting phenytoin
Area of Science:
- Neuroscience
- Developmental Toxicology
- Pharmacology
Background:
- Phenytoin is an anticonvulsant medication used to treat epilepsy.
- Previous studies suggest potential developmental risks associated with phenytoin exposure.
Purpose of the Study:
- To investigate the behavioral teratogenicity of phenytoin in Sprague-Dawley rats.
- To determine dose-response relationships for phenytoin-induced behavioral effects in offspring.
Main Methods:
- Pregnant Sprague-Dawley rats were administered phenytoin (100, 150, or 200 mg/kg) daily from gestation days 7-18.
- Offspring were assessed for various behavioral parameters including activity, motor development, learning, and startle responses.
- Maternal weight, offspring mortality, postnatal growth, and adult brain parameters were also evaluated.
Main Results:
- The highest phenytoin dose reduced maternal weight and increased offspring mortality.
- Offspring exposed to the highest dose exhibited increased activity, delayed motor development, impaired learning in mazes, and reduced tactile startle responses.
- Lower doses showed dose-dependent effects on several behavioral measures, with significant dose-effect relationships observed for early activity, motor development, and maze learning.
Conclusions:
- Phenytoin is a potent behavioral teratogen, inducing significant neurodevelopmental and behavioral abnormalities in offspring at doses below those causing overt physical toxicity.
- The findings underscore the importance of considering behavioral endpoints in teratogenicity studies of medications with central nervous system effects.
Abstract:
Sprague-Dawley rats were gavaged once daily on days 7-18 of gestation with, 100, 150, or 200 mg/kg of phenytoin. Only the highest dose of phenytoin decreased maternal weight during gestation or increased offspring mortality up to weaning. Offspring were evaluated for activity prior to weaning (pivoting and photocell) and afterwards (figure 8, open-field, and hole-board), dynamic righting development, maze learning (Biel maze), and visual discrimination (Y maze), and for startle reaction to both auditory and tactile stimuli. The highest dose of phenytoin produced increased activity on all tests of activity, delayed dynamic righting development, impaired Biel maze and Y-maze learning, and inhibited tactile startle responses. The two lower doses of phenytoin generally showed a dose-effect relationship with values on most measures intermediate between values for controls and for the highest-dose group. Dose-effect relationships were most evident on measures of early activity (both tests), dynamic righting, and Biel maze learning, whereas only trends were evident on measures of later activity, Y maze, and startle. A dose-related rotational defect was found in a minority of phenytoin offspring, and although these individuals contributed to the behavioral abnormalities observed, they in no instance accounted for the overall pattern of effects seen in the phenytoin offspring. Maternal plasma phenytoin levels at the end of treatment were dose-related. Offspring showed no effects on postnatal growth, total brain weight, or brain protein content as adults. The data support the view that phenytoin is a potent behavioral teratogen at doses well below those causing any evidence of gross teratogenicity or embryotoxicity.