Effects of Chlorambucil on the Brain Development in Mice during Post‐neurulation Period

Abstract

Abstract The teratogenic effect of chlorambucil (CA), given during proliferation of matrix cells of the brain following the closure of the neural tube, on the development of central nervous system in mouse embryos was investigated histologically. CA (4, 8 or 15 mg/kg) was given orally to pregnant mice on day 9, 10, 11 or 12 of gestation by single shot, and the fetuses were examined on day 18 of gestation.Significant decrease in the brain size and microcephaly occurred in fetuses treated with CA regardless of the gestational age studied. The microcephalic brains were characterized by the severe reduction of the cerebral hemispheres in a rostrocaudal direction rather than in the lateral directions. The fetal brains from mice given a low dosage of 4 mg/kg CA maintained normal cerebral cortex, but higher dosages (8 or 15 mg/kg) showed severe dysplasia of all the cerebral histological structures. In the groups treated with 8 or 15 mg/kg CA on day 10 or 11 of gestation, severe cranial malformations, identified as cranioschisis or encephalocele, were often observed. The malformed brains with cranioschisis showed an extensive necrosis of the brain tissue around the lesions. The present study shows that the microcephaly induced by cytotoxic teratogens such as CA, given during the proliferative period of matrix cells after closure of the neural tube, is different from that induced during the migratory period of the neuroblasts, and suggests that the degeneration of the brain tissue by the cytotoxic agent may induce the partial anencephaly in mice.