Late-onset cerebellar degeneration in mice induced transplacentally by methylnitrosourea.

Abstract

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 methylnitrosourea (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.