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Long-term effects of prenatal phenytoin exposure on offspring behavior in rats
1Institute for Developmental Research, Children's Hospital Research Foundation, Cincinnati, OH 45229-2899.
Insights
Phenytoin exposure during pregnancy caused significant postnatal dysfunction in rat offspring, including increased mortality and behavioral deficits. These effects, particularly circling behavior, highlight the drug
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Phenytoin is an anticonvulsant medication with known teratogenic potential.
- Prenatal exposure to certain drugs can lead to long-term neurodevelopmental deficits in offspring.
- Understanding the specific effects of phenytoin on offspring development is crucial for risk assessment.
Purpose of the Study:
- To investigate the postnatal functional deficits in Sprague-Dawley CD rat offspring following prenatal phenytoin exposure.
- To determine the duration, replicability, and generality of these dysfunctions.
- To analyze the contribution of circling behavior to the observed neurodevelopmental effects.
Main Methods:
- Pregnant rats were administered phenytoin (200 mg/kg) or vehicle on gestational days 7-18.
- Offspring were assessed at various ages using a battery of neurobehavioral tests.
- Data were analyzed comparing phenytoin-exposed offspring (categorized as circlers and non-circlers) to controls.
Main Results:
- Phenytoin offspring exhibited increased mortality and reduced body weight during the preweaning and early postnatal periods.
- Significant behavioral alterations were observed, including hyperactivity, impaired swimming, and deficits in learning and memory tasks.
- A subset of phenytoin offspring displayed circling behavior, which was associated with specific neurobehavioral deficits, but phenytoin also induced effects beyond vestibular dysfunction.
Conclusions:
- Prenatal phenytoin exposure induces significant and lasting neurodevelopmental and behavioral abnormalities in rat offspring.
- Circling behavior is a prominent feature linked to specific deficits, but phenytoin's teratogenic effects are broader than initially suggested.
- These findings underscore the importance of careful monitoring and risk-benefit assessment for phenytoin use during pregnancy.
Abstract:
Pregnant Sprague-Dawley CD rats were administered phenytoin by gavage on days 7-18 of gestation in doses of 0 or 200 mg/kg. The offspring were tested at various ages to determine the duration of postnatal dysfunction and its replicability and generality compared to previous experiments. Phenytoin offspring had increased newborn (5.2%) and preweaning (16.7%) mortality compared to controls (0% and 3.1%, respectively), and an 8.5% reduction in average body weight at 28-70 days. No weight differences were significant at other ages. Phenytoin offspring showed increased activity on multiple tests, swam slower in a straight channel, committed more errors and took more time in the Cincinnati water maze, startled less, and had longer latencies on the Morris hidden platform test. Among phenytoin offspring 42.3% exhibited the abnormal circling defect previously described (14,17). Consequently, data were reanalyzed in terms of circlers, noncirclers, and controls to determine the contribution of this effect to the dysfunctions observed. Circlers accounted for the differences in open-field activity, figure-8 ambulation, hole-board horizontal locomotion, straight channel swimming time, water maze retention errors, tactile prepulse startle inhibition, and some trials of the Morris test. Circlers and noncirclers differed from one another and from controls on measures of figure-8 rearing, water maze errors and times, and some trials of the Morris test, with circlers more affected than noncirclers. Circlers and noncirclers did not differ from one another, but both differed from controls, on measures of early locomotion, hole-board vertical activity, and unmodified startle amplitude. Circling was hypothesized to reflect an underlying vestibular defect, however, the data also support the view that phenytoin has effects beyond those accounted for by possible vestibular effects.