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Developmental effects of phenytoin may differ depending on sex of offspring
M A McCartney1, P L Scinto, S S Wang
1Department of Drug Safety Evaluation, R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA. mccartneysil@earthlink.net
Insights
Prenatal phenytoin exposure in rats caused developmental and behavioral deficits. These effects, including altered brain weights and impaired motor skills, varied between male and female offspring.
Area of Science:
- Neuroscience
- Developmental Toxicology
- Behavioral Science
Background:
- Phenytoin (sodium salt) is a known developmental neurotoxicant.
- Understanding its impact on offspring development and behavior is crucial.
Purpose of the Study:
- To investigate the developmental and behavioral effects of prenatal phenytoin exposure in rats.
- To determine if these effects differ based on offspring sex.
Main Methods:
- Pregnant rats were administered phenytoin (50-150 mg/kg) orally from gestation days 7-18.
- Developmental indices (body weight, brain weights) and behavioral tests (Morris water maze, reflexes, activity) were assessed in offspring.
- Offspring sex was analyzed for differential effects.
Main Results:
- Phenytoin exposure decreased maternal and pup body weight gains and various brain weights (hindbrain, forebrain, cerebellum).
- Behavioral deficits included impaired maze performance, altered reflexes (air righting, startle), increased locomotor activity, and accelerated developmental milestones (eye opening, incisor eruption).
- Female offspring showed more severe effects in some measures (incisor eruption, negative geotaxis, air righting, reactivity, maze activity), while males were more affected in others (eye opening, olfactory orientation, startle response).
Conclusions:
- Prenatal phenytoin exposure induces significant developmental and behavioral changes in offspring.
- The observed neurodevelopmental deficits and behavioral alterations exhibit sex-specific patterns.
- These findings highlight the potential risks of phenytoin exposure during critical developmental periods and underscore sex as a factor in its teratogenic effects.
Abstract:
Phenytoin (sodium salt), a developmental neurotoxicant, was administered orally by gavage (50-150 mg/kg) to pregnant rats on days 7-18 of gestation. Various developmental and behavioral indices were evaluated. Results indicated that phenytoin produced decreases in maternal and pup body weight gains, pup hindbrain, and F1 adult forebrain, whole brain, and cerebellar weights. Behavioral/developmental effects included performance deficits in a modified Morris water maze assay, in air righting and auditory startle responses, and increases in locomotor activity, accelerated eye opening, incisor eruption, negative geotaxis, and olfactory orientation. Female offspring appeared to be more severely affected when measuring incisor eruption, negative geotaxis, air righting, reactivity, and locomotor and maze activity. Males appeared to be more affected when measuring eye opening, olfactory orientation, and decreases in startle response. This study suggests that prenatal phenytoin exposure may result in developmental changes and behavioral deficits that may differ depending on the sex of the offspring.