Journal Article

Neural precursor cell apoptosis and glial tumorigenesis following transplacental ethyl-nitrosourea exposure

Klocke, Barbara J, Leonard, Jeffrey R, D'Sa, Cleta, Roth, Kevin A

2001

Overview

Neural precursor cells (NPCs) populate the embryonic ventricular zone and persist in the subependymal zone of the adult brain. We hypothesized that hereditary and/or acquired mutations in apoptosis-associated genes, such as p53 and caspases, may protect NPCs from DNA damage-induced death and predispose them to subsequent neoplastic transformation. To test this hypothesis, we exposed NPCs from wild-type and targeted gene-disrupted mouse embryos (p53, caspase-9, caspase-3, and bax mutants) to ethyl-nitrosourea (ENU), a known DNA mutagen and neural carcinogen, and measured NPC viability. We found that ENU produced caspase-3 activation and apoptotic NPC death 6-24 h after administration both in vivo and in vitro. This effect was critically dependent on p53 and caspase-9 expression. The long-term effect of intrauterine ENU exposure was examined in control and p53-deficient mice. High grade glial tumors were found in 60% of p53(-/-) young adult mice exposed to ENU on gestational day 12.5 but not in p53(+/-) or p53(+/+) littermates or in untreated p53-deficient mice. All the tumors were located supratentorially and possessed strong immunoreactivity for glial fibrillary acidic protein and the anti-apoptotic molecule Bcl-X(L). These results suggest that intrauterine exposure of NPCs to certain DNA damaging agents may synergistically interact with specific genetic abnormalities (e.g. p53 deficiency) to produce glial neoplasms in the adult brain.

• Publisher: Nature Publishing,Nature Publishing Group
• Subject: Animals / Apoptosis / BAX protein / bcl-2-Associated X Protein / Bcl-x protein / Biological and medical sciences / Brain cancer / Brain Neoplasms - chemically induced / Brain Neoplasms - etiology / Brain Neoplasms - pathology / Carcinogens / Caspase 3 / Caspase 9 / Caspases - genetics / Caspases - metabolism / Cell death / Deoxyribonucleic acid / DNA / DNA damage / Ethyl nitrosourea / Ethylnitrosourea / Female / Fundamental and applied biological sciences. Psychology / Gene Targeting / Genes, p53 / Genetic transformation / Gestational age / Glial fibrillary acidic protein / Glioma - chemically induced / Glioma - etiology / Glioma - pathology / Hypotheses / Immunology / Immunoreactivity / Intrauterine exposure / Maternal-Fetal Exchange / Mice / Mice, Inbred ICR / Mice, Knockout / Molecular and cellular biology / Mutation / Neoplasia / Nervous system / Neuronal-glial interactions / Neurons - cytology / Neurons - metabolism / Neuropathology / p53 Protein / Pathology / Placenta / Pregnancy / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins c-bcl-2 / Stem Cells - cytology / Stem Cells - metabolism / Subependymal zone / Tumorigenesis / Tumors / Ventricle / Ventricular zone