The antioxidant butylated hydroxytoluene can retard cerebellar degeneration induced transplacentally by a single low dosage of N-methyl-N-nitrosourea.
Late-onset cerebellar degeneration can be induced transplacentally in mice by a single low-dose (1 mg/kg) injection of the direct-acting DNA alkylating agent N-methyl-N-nitrosourea (MNU) on day 16 of pregnancy. The offspring develop a mild ataxia that manifests by 12-16 weeks of age postnatally when the animals are challenged with a motor coordination task. Morphological evidence of degeneration includes pyknosis of Purkinje cells and abnormal foliation patterns. Additionally, these animals demonstrate a progressive retinopathy characterized by thinning of the nuclear and plexiform layers of the retina. Efforts to retard the cerebellar degeneration were undertaken in the present study. MNU-exposed and control animals were fed a standard mouse chow diet supplemented with 0.75% butylated hydroxytoluene (BHT), an antioxidant. This supplementation commenced 24 h following exposure to the teratogen and continued throughout the life of the offspring. A second group of MNU-exposed and control mice were fed a non-BHT-supplemented, standard Purina mouse chow diet. Quantitative histological evaluation of cerebellar coronal sections indicated that by 4 weeks of age BHT-fed, MNU-exposed mice had significantly fewer pyknotic Purkinje cells than non-BHT-fed, MNU-exposed animals. This was true for the vermal, paravermal, and lateral areas of the cerebellum. The findings suggest the usefulness of teratogenic models of degenerative diseases for the testing of potential intervention strategies.
Smith
S B
SB
National Eye Institute, National Institutes of Health, Bethesda, Maryland.
Cooke
C B
CB
Yielding
K L
KL
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002084:Butylated Hydroxytoluene / Q000627:therapeutic use*; D002526:Cerebellar Diseases / Q000151:congenital* / Q000188:drug therapy* / Q000196:embryology / Q000473:pathology; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D008770:Methylnitrosourea / Q000037:antagonists & inhibitors; D051379:Mice; D009410:Nerve Degeneration / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011689:Purkinje Cells / Q000187:drug effects / Q000473:pathology
D000975:Antioxidants; D002084:Butylated Hydroxytoluene; D008770:Methylnitrosourea