Late‐onset cerebellar degeneration in mice induced transplacentally by methylnitrosourea

A late‐onset degenerative disease in the cerebellum was produced in the offspring of mice exposed to 1 mg/kg of the direct‐acting DNA alkylating agent methylnirosourea (MNU) on day 16 of gestation. This intrauterine exposure to MNU also provoked a progressive retinal degeneration that was described elsewhere. Mild ataxia in the MNU‐exposed animals was expressed by 20 weeks of age. Although animals appeared normal in the immediate post‐natal period, quantitative histological evaluation of cerebellar coronal sections indicated that MNU‐exposed animals had a significantly greater number of pyknotic Purkinje cells than age‐matched controls. The number of pyknotic Purkinje cells declined with age in the drug exposed animals; however, the percentage of pyknotic Purkinje cells to total number of Purkinje cells still was greater in MNU‐induced animals at 36 weeks than in controls, suggesting that a slow degenerative process was ongoing in the MNU‐exposed animals. Furthermore, the folia were grossly disrupted in 90% of the older MNU‐exposed animals (ages greater than 12 weeks), suggesting permanent cerebellar disruption macroscopically. Such intrauterine exposure to low doses of alkylating agents may be potentially useful in modeling degenerative neuronal diseases.