Neoplastic Transformation of Fetal Rat Brain Cells in Culture After Exposure to Ethylnitrosourea In Vivo23

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Abstract
A single, transplacental pulse of N-ethyl-N-nitrosourea (ENU; 75 µg body wt) to the fetal (18th day of gestation) BD IX rat led to death with malignant tumors of the central and peripheral nervous system after a median time of ≈195 days. In contrast to untreated control cells, dissociated brain cells transferred to long-term cell culture 20–90 hours after the ENU pulse became tumorigenic after ≈200 days, as assayed byreimplantation into baby BD IX rats. This was preceded by a characteristic sequence of phenotypic alterations (termed “stages I-IV”). During early primary culture (stage I), both ENU and control cultures exhibited stationary glia-like cells on a growing layer of epithelioid (possibly glia precursors) and few fibroblast-like cells. Stage II (≈10th-40th day) was characterized by a constant proportion of glia-like cells in the ENU cultures and by their disappearance in the controls. During stage III (≈40th-100th day), slowly proliferating glia-like cells in the ENU cultures formed “piled-up” foci. They could then be removed from the underlying cell layer and cultured separately. Transition to stage IV (≈100th–200th day) was marked by proliferation of morphologically altered cells, which subsequently acquired the capacity to form colonies in semisolid agar and finally became tumorigenic (stage V). This system may represent a model for the study of malignant transformation.

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