Developmental-stage-dependent effects of X-ray exposure on the development of medulloblastomas in <I>Ptch1</I> heterozygous mice

It was reported that medulloblastomas (MBs), the most common childhood brain tumor, are induced frequently in Ptch1+/- mice after X-ray irradiation at postnatal day (PN) 1, and that the tumor incidence decreases with increasing age at irradiation during the postnatal short period. However, age-at-exposure dependency before birth has not yet been reported. We previously found that all spontaneous tumors in nonirradiated mice showed LOH in broad regions on chromosome 13, with losses at all consecutive markers distal to Ptch1 locus (S-type), while all tumors that developed after 3 Gy irradiation at PN1 exhibited interstitial losses around Ptch1 with distal markers retained (R-type). We here analyzed not only age-dependency of irradiation during embryonic and fetal development on MB incidence but also their mode of Ptch1 loss. We irradiated Ptch1+/- mice at 5 different stages with X-rays, and followed their survival until 250 days of age. The incidence of MB in mice irradiated with 0.5 Gy at early stages (E3.5, E8.5) was not significantly different from that obtained in unirradiated mice, and most of MBs (13/14,17/17) showed S-type LOH patterns, suggesting that these early stages, prior to neural tube formation, is refractory to the radiation-induction of MB. On the other hand, the incidence in mice irradiated at later stages (E13.5, E18.5) was significantly higher, and some MBs were R-type, suggesting the acquisition of susceptibility to radiation-induced MB during a period from E8.5 to E13.5. In contrast, the incidence was significantly decreased by 3Gy irradiation at PN10 (9.1%) compared with that in nonirradiated mice (34.7%). These data suggested that radiation not only induce but also suppress MB development in tightly associated with developmental stages.