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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.

Pregnant female Sprague-Dawley rats were treated from day 12 through day 15 of gestation with procarbazine, an antineoplastic drug, and their offspring were subjected to tests of locomotor development and behavior. Treatment levels ranged from 0.5 mg/kg/day, a dose that produced no abnormalities, to 10 mg/kg/day, a dose that caused a marked micrencephaly in the absence of other teratological changes. Despite marked morphological brain changes, preweaning locomotor development, as assessed by open-field swimming activity and vertical grid climbing, was normal in all offspring. Post-weaning passive avoidance learning and retention were also normal. Groups that had been treated prenatally with teratogenic doses (5.0 and 10.0 mg/kg/day) displayed less rearing behavior in the open field, while ambulation in the periphery of the open field arena was unaffected. Groups treated with subteratogenic doses (0.5 and 1.0 mg/kg/day) did not differ from control. In addition to the behavioral studies, sodium-dependent high-affinity choline uptake and choline acetyltransferase activity (CAT) were measured (per mg protein) in the cortex and hippocampus of animals that had been exposed prenatally to either teratogenic or subteratogenic doses of procarbazine. In spite of a substantial reduction in size of both brain structures in the group receiving a teratogenic dose, choline uptake and CAT did not differ from control.