Ethanol neurotoxicity. 2. Direct effects on differentiating astrocytes.

In a previous investigation, we demonstrated altered patterns of growth, as indicated by RNA, DNA and protein contents, in rapidly growing astrocytes exposed to ethanol in primary culture. The present experiments were conducted to investigate the direct effects of ethanol on the differentiation of astrocytes as reflected in the activity of the astrocyte-specific enzyme, glutamine synthetase (Glu-S). Astroblasts obtained from the newborn mouse neopallium were continuously exposed to ethanol (0.0, 11.0, 22.3 or 44.5 mM) in primary cultures for 4, 11 or 18 days during the peak period of cell growth and differentiation. As seen previously, the lowest ethanol concentration (0.06 g/dl) had a "growth-promoting" effect on astroglia, reflected in an increase in protein content in ethanol-exposed cultures compared to controls. At higher concentrations (0.12 and 0.24 g/dl), there was a progressive "growth-impairing" effect. In contrast, the specific activity of Glu-S was reduced at all ethanol concentrations compared to controls in a concentration-dependent manner. By increasing the duration of exposure to ethanol, the effects on both protein content and Glu-S activity became more pronounced. It appears, however, that the timing of exposure relative to critical events in astrogliogenesis is a more important determinant of ethanol's toxicity than is duration of exposure. Derangements in astrocyte growth and differentiation may be major contributors to the pathogenesis of brain abnormalities in the fetal alcohol syndrome.