Human Neural Stem Cells Are More Sensitive Than Astrocytes to Ethanol Exposure

Abstract

This study demonstrates the susceptibility of human NSCs, compared with astrocytes, to EtOH and indicates that alterations in PKC signal transduction in NSC may play a role in EtOH-induced neuropathological processes.

Computational models of ethanol‐induced neurodevelopmental toxicity across species: Implications for risk assessment

“…Furthermore, a similar doseresponse relationship was found in human fetal astrocytes (Guizzetti et al, 2003). LOAEL values from in vitro studies in the human are based on a study looking at effects of ethanol in cultured human undifferentiated neural stem cells (Hao et al, 2003). Human neural stem cells may be acutely sensitive to ethanol exposure in culture, as extremely low concentrations (0.1 mM or 0.46 mg/dl) decrease viability in these cells (Hao et al, 2003).…”

“…For comparison, stereologically determined long-term neocortical neuronal loss in the somatosensory region (down triangle) and the medial prefrontal region (diamond) are shown when exposure occurs during neocortical neurogenesis (Mihalick et al, 2001;Miller and Potempa, 1990). In vitro dose-response relationships are shown for inhibition of BrdU incorporation in primary neuroepithelial cells dissociated from the embryonic rat telencephalon (E13) (open square) (Ma et al, 2003) or cell viability in an undifferentiated human neural stem cell culture (open circle) (Hao et al, 2003). Error bars represent reported SEM.…”

“…The results of this study compare well with our rodent model predictions, with the Weibull function shown in Figure 2 predicting neuronal loss at the high dose level more accurately than the Weibull dose-squared function illustrated in Figure 3. We compare our primate model predictions to a doseresponse relationship from an undifferentiated human neural stem cell culture derived from fetal human brain tissue (11-21 weeks) treated with varying concentrations of ethanol for 12 h and monitored for viability using the MTT assay (Hao et al, 2003). Consistent with our model predictions, the human-derived primary culture system shows increased sensitivity to ethanol-induced damage when compared to findings in the rat primary culture system, showing a significant loss of viability at a very low concentration of ethanol (0.46 mg/dl).…”

“…LOAEL values from in vitro studies in the human are based on a study looking at effects of ethanol in cultured human undifferentiated neural stem cells (Hao et al, 2003). Human neural stem cells may be acutely sensitive to ethanol exposure in culture, as extremely low concentrations (0.1 mM or 0.46 mg/dl) decrease viability in these cells (Hao et al, 2003). This is an interesting finding considering ethanol is endogenously produced by human intestinal flora (as a metabolic by-product), and present in human blood at an average background level of 0.15 mg/dL (HSDB, 2002).…”

Embryonic Cerebral Cortical Progenitors Are Resistant to Apoptosis, but Increase Expression of Suicide Receptor DISC‐Complex Genes and Suppress Autophagy Following Ethanol Exposure

“…This cell loss has largely been attributed to the ability of ethanol to induce apoptosis (Bhave and Hoffman, 1997;Cartwright et al, 1998;Bhave et al, 1999;Cheema et al, 1999;McAlhany et al, 2000;Ramachandran et al, 2003;Young et al, 2003;Takadera and Ohyashiki, 2004;Dikranian et al, 2005). Although we know that ethanol can induce apoptosis of fetal cortical neurons in late gestation (Ramachandran et al, 2003), relatively few studies (Kentroti and Vernadakis, 1991;Hao et al, 2003;Santillano et al, 2005) have focused on the apoptotic effects of ethanol on embryonic neural progenitors during early neurogenesis. Paradoxically, the onset of neurogenesis is accompanied by a wave of apoptotic cell death, similar to the death observed later in development as neurons seek appropriate synaptic targets (Blaschke et al,1996;Thomaidou et al, 1997;Blaschke et al, 1998;Cheema et al, 1999;Bähr, 2000;De la Rosa and De Pablo, 2000).…”