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Cardiovascular malformations induced by prenatal exposure to phenobarbital in rats
Hirokazu Okuda1, Tetsuji Nagao
1Japan Bioassay Research Center, Japan Industrial Safety and Health Association, Kanagawa, Japan. h-okuda@jisha.or.jp
Insights
Prenatal exposure to phenobarbital (PB) significantly increases cardiovascular malformations in rat fetuses during gestational days 8-11. While severe defects cause early death, minor defects like ventricular septal defects (VSD) persist but do not impact survival.
Area of Science:
- Developmental toxicology
- Cardiovascular embryology
- Teratology
Background:
- Phenobarbital (PB) is a widely used anticonvulsant and sedative.
- Prenatal exposure to certain medications can lead to developmental abnormalities.
- The specific effects of phenobarbital on fetal cardiovascular development require detailed investigation.
Purpose of the Study:
- To investigate the teratogenic effects of prenatal phenobarbital exposure on the developing cardiovascular system in Sprague Dawley rats.
- To identify the critical developmental window during which phenobarbital exposure induces cardiovascular malformations.
- To characterize the types and severity of cardiovascular defects resulting from prenatal phenobarbital exposure.
Main Methods:
- Sprague Dawley rats were administered phenobarbital (80 or 120 mg/kg/day) via gavage on specific consecutive gestational days (GD 7-8, 8-9, 9-10, 10-11).
- Fetal cardiovascular systems were examined on GD 20 for malformations.
- Postnatal pups were also assessed for phenobarbital-induced cardiovascular abnormalities.
- Statistical analysis was performed to determine significant increases in malformation incidences.
Main Results:
- Prenatal phenobarbital exposure, particularly at 120 mg/kg on GD 8-9, 9-10, or 10-11, significantly increased the incidence of major cardiovascular malformations.
- Key defects observed include ventricular septal defect (VSD), overriding aorta, double outlet right ventricle, and transposition of great arteries.
- Gestational days 8-11 were identified as the critical period for phenobarbital-induced cardiovascular teratogenicity in rats.
- While severe malformations led to early postnatal mortality, isolated VSDs persisted until weaning without affecting viability.
Conclusions:
- Prenatal phenobarbital exposure during a specific critical window (GD 8-11) is teratogenic to the developing cardiovascular system in rats.
- The dose and timing of exposure are crucial factors in the severity and type of cardiovascular malformations induced.
- Understanding these effects is vital for assessing the risks associated with phenobarbital use during pregnancy.
Abstract:
The effects of prenatal exposure to phenobarbital (PB) on the cardiovascular system were examined in rat fetuses and pups. PB was administered at a dose of 80 or 120 mg/kg/day by gavage to Sprague Dawley (SD) rats on two consecutive gestational days (GD): 7-8, 8-9, 9-10, or 10-11. Fetuses were examined for cardiovascular malformations on GD 20. In addition, pups were examined for PB-induced cardiovascular malformations. Incidences of ventricular septal defect (VSD), overriding aorta, double outlet right ventricle and transposition of great arteries were significantly increased in the fetuses whose dams were administered PB at 120 mg/kg on GD 8-9, 9-10 or 10-11. GD 8-11 was the critical period for the cardiovascular malformations associated with administration of PB in rats. Various types of cardiovascular malformations were detected in pups from the PB-administered dam. Severe cardiovascular malformations induced by PB caused deaths on early postnatal days. However, slight malformations such as isolated VSD persisted until weaning, and did not affect postnatal viability.
