ethylenethiourea and Necrosis

The monocell layers, containing a mixture of neuronal and non-neuronal (primarily glial) cells, were obtained by growing cells dissociated from trypsinized fetal brains of 19-day pregnant rats under optimum conditions. Ethylenethiourea (ETU), at greater than or equal to .5 mM concentrations, caused in monocell layers in vitro a necrosis of neuronal cells and a marked depression in the formation of neurites and fascicles without any noticeable change in the non-neuronal cells. In the in vivo study, ETU orally administered as a single 30 or 45 mg/kg dose to rats on day 19 of pregnancy was found to induce necrosis of neuroblasts in the fetal CNS after 18 and 24 hours of dosing and a high incidence of hydrocephalus in postnatal pups at both doses. In an in vivo/in vitro experiment, rat fetal brains from 19-day pregnant dams which had previously been dosed with 80 or 120 mg ETU/kg were trypsinized and then dissociated into a cell suspension in a nutrient medium. The total number of viable cells in the suspension was significantly reduced compared to the number in the control suspension. The test suspension with cell density adjusted to that in the control suspension grew into monocell layers manifesting a marked decreased population of neuronal cells with a concomitantly increased population of non-neuronal cells. It was concluded that the target of ETU action was most likely the neuronal cells rather than the organization of nervous tissue per se.

Topics: Animals; Brain; Cells, Cultured; Ethylenethiourea; Female; Hydrocephalus; Imidazoles; Maternal-Fetal Exchange; Necrosis; Nerve Degeneration; Neurons; Pregnancy; Rats; Rats, Inbred Strains; Teratogens

Ethylenethiourea (ETU)-induced early histologic changes in fetal CNS and their effect on postnatal survival was studied at 0, 15 or 30 mg/kg administered as single oral dose on day 13 of pregnancy. Fetuses, from 4-6 dams killed at post-treatment intervals of 12, 24, 48 and 72 h were fixed and studied for histopathological changes following routine methods. The remaining dams were allowed to litter and their progeny was studied for postnatal survival until 80 days of age. Histologic study revealed the presence of karyorrhexis in the germinal layer of basal lamina of CNS extending from the thoracic spinal cord to the telencephalon twelve hours after treatment with 30 mg of ETU/kg. At 48 h post-treatment, the spinal cord showed obliteration and duplication of the central canal and disorganization of germinal and mantle layers. In the brain, the ventricular lining was focally denuded, neuroepithelial cells were arranged in the form of rosettes and the nerve cell proliferation was disorganized. In the 15 mg of ETU/kg group, cellular necrosis was less severe and consisted of degeneration in a single or a small group of cells widely dispersed in the germinal layer of neuraxis. The initial degenerative changes were observed in a specific nerve cell type, identified as the undifferentiated migrating neuroblast. In the postnatal study, since survival was reduced to 50% at the 30 mg/kg and unaffected at the 15 mg/kg, it was concluded that necrosis of neuroblasts up to a certain degree was compatible with postnatal life until adulthood.

Topics: Animals; Brain; Ethylenethiourea; Female; Imidazoles; Necrosis; Nerve Degeneration; Pregnancy; Rats; Rats, Inbred Strains; Spinal Cord