Correlations between the degree and type of forebrain malformations and the simultaneous neuro-oncogenic properties of ethylnitrosourea after diaplacental exposure in rats, alone and in combination with X-irradiation.

Single and combined treatments were performed in rats on day 13 of gestation with either ENU or ENU subsequent to various X-irradiation doses between 0.5 and 1.5 Gy. At this time of gestation, developmental anomalies of the brain are still inducible by any of these treatments, in addition to neurocarcinogenic effects after ENU alone or in combination with X-irradiation. We looked for correlations between the degree of brain malformations still detectable in the adult animals and the simultaneous occurrence of brain tumors. These evaluations were based on a histopathological analysis regarding the type and degree of malformation residues, as well as the type and distribution pattern of the tumors (especially regarding gliomas) within the forebrain. Both after ENU and X-irradiation plus ENU-treatment, the occurrence of glioma in the offspring was positively correlated with the degree of brain dysplasia. This effect was not only restricted to the total glioma incidence but also confirmed by the higher glioma multiplicity in major dysplastic brains. Additionally, gliomas were preferentially located within the subependymal layer, which simultaneously was most severely affected by the teratogenic effects after prenatal treatment. Although forebrain dysplasia generally presents a significant predisposition for glioma inducibility, this oncogenic event is apparently strictly inversely related to a certain type of forebrain malformation, namely the occurrence of heterotopic neuronal nodules within the telencephalic roof. They emerge from "rosettes," which are typical radiation lesions occurring only after doses above 1.0 Gy. In none of the forebrains which still revealed rosette-residues in later life could a simultaneous occurrence of gliomas be observed. This explains not only the substantial decrease of glioma incidence after combined treatment with 1.0 and 1.5 Gy X-irradiation doses, but also the consistent glioma multiplicity despite the decrease of frequency.