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

Neural precursor cells (NPCs) populate the embryonic ventricular zone and p ersist in the subependymal zone of the adult brain. We hypothesized that he reditary and/or acquired mutations in apoptosis-associated genes, such as p 53 and caspases, may protect NPCs from DNA damage-induced death and predisp ose them to subsequent neoplastic transformation. To test this hypothesis, we exposed NPCs from wild-type and targeted gene-disrupted mouse embryos (p 53, caspase-9, caspase-3, and bax mutants) to ethyl-nitrosourea (ENU), a kn own DNA mutagen and neural carcinogen, and measured NPC viability. We found that ENU produced caspase-3 activation and apoptotic NPC death 6-24 h afte r administration both in vivo and in vitro. This effect was critically depe ndent on p53 and caspase-9 expression. The long-term effect of intrauterine ENU exposure was examined in control and p53-deficient mice. High grade gl ial 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 unt reated 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 intrauterin e exposure of NPCs to certain DNA damaging agents may synergistically inter act with specific genetic abnormalities (e.g. p53 deficiency) to produce gl ial neoplasms in the adult brain.