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The effect of prenatal procarbazine treatment on brain development in the rat
Insights
Procarbazine treatment during pregnancy caused dose-dependent brain development issues in rat offspring, leading to micrencephaly. The drug affected specific brain regions, with effects varying based on the timing of exposure during gestation.
Area of Science:
- Developmental toxicology
- Neuroscience
- Pharmacology
Background:
- Procarbazine is an antineoplastic drug used in cancer treatment.
- Understanding its effects on fetal development is crucial for risk assessment.
Purpose of the Study:
- To investigate the effects of procarbazine on prenatal brain development in Sprague-Dawley rats.
- To determine the dose-dependent and time-dependent neuroteratogenic effects of procarbazine.
Main Methods:
- Pregnant rats received oral procarbazine at various doses and gestational days.
- Offspring brains were weighed, and histological analyses were performed on embryos and fetuses.
Main Results:
- Procarbazine induced dose-dependent micrencephaly (reduced brain size) starting at 2.5 mg/kg/day.
- Exposure on gestation days 13-15 resulted in the most severe micrencephaly, particularly affecting the neocortex.
- Histological examination revealed cellular degeneration in various brain regions, with the neocortex showing thickened ventricular zones and reduced cellularity.
Conclusions:
- Procarbazine exhibits significant neuroteratogenic potential, causing dose- and time-dependent brain malformations in developing rats.
- The timing of exposure during gestation critically influences the severity and pattern of brain abnormalities.
Abstract:
Groups of pregnant Sprague-Dawley rats were treated orally with procarbazine, an antineoplastic drug, at dose levels of 0, 1.0, 2.5, 5.0, 7.5, and 10.0 mg/kg/day from days 12 through 15 of gestation. Following normal delivery, offspring were raised until day 21 and sacrificed, and their brains removed and weighed. A dose-dependent micrencephaly, characterized by hypoplasia of the cerebral hemispheres, was seen starting at 2.5 mg/kg/day. In a second study, groups of pregnant female rats were given a single dose of 10 mg/kg procarbazine on gestation day 12, 13, 14, or 15. Micrencephaly occurred in 21-day-old offspring from all groups, with the greatest effect induced on days 13, 14 and 15. Analysis of brain region weights revealed a maximum reduction in neocortex weight in offspring from groups treated on days 13 and 14. The hippocampus, cerebellum, and diencephalon-midbrain were also reduced in size, depending on the day of treatment, while the corpus striatum and pons-medulla were spared. In a final study, embryos from females treated on gestation days 12 through 15 were removed, fixed, and sectioned at 24-hour intervals starting on gestation days 13. Necrosis and cellular degeneration were observed with decreasing severity in the telencephalon, diencephalon, mesencephalon, and medulla. The neocortex of 20-day treated fetuses was characterized by a thickening of the ventricular zone and reduced cellularity of the cortical plate.