Effects of Hydroxyurea Exposure on the Rat Cerebellar Neuroepithelium: an Immunohistochemical and Electron Microscopic Study Along the Anteroposterior and Mediolateral Axes

We present a histological study of the cell death of cerebellar neuroepithelial neuroblasts following treatment with the cytotoxic agent hydroxyurea (HU) during the embryonic life. Pregnant rats were treated with a single dose of HU (300 mg/kg) at embryonic days 13, 14, or 15 of gestation, and their fetuses were studied from 5 to 35 h after treatment to elucidate the mechanisms of HU-induced fetotoxicity. Quantification of several parameters such as the density of pyknotic, mitotic, and PCNA-immunoreactive cells indicated that HU compromises the survival of the cerebellar neuroepithelium neuroblasts. On the other hand, our light and electron microscopic investigations during the course of prenatal development indicated that HU leads to two types of cell death: apoptosis and cells presenting cytoplasmic vacuolization, altered organelles, and a recognizable cell nucleus. Both modalities of cell death resulted in a substantial loss of cerebellar neuroepithelium cells. Current results suggest that HU exposure during gestation is toxic to the cerebellar neuroepithelium. Moreover, they allow to examine the mechanisms of HU-induced toxicity during the early development of the central nervous system. Our data also suggest that it is essential to avoid underestimating the adverse effects of HU when administered during early prenatal life.