Abstract
Adverse effect of alcohol on neural function has been well documented. Especially, the teratogenic effect of alcohol on neurodevelopment during embryogenesis has been demonstrated in various models, which could be a pathologic basis for fetal alcohol spectrum disorders (FASDs). While the developmental defects from alcohol abuse during gestation have been described, the specific mechanisms by which alcohol mediates these injuries have yet to be determined. Recent studies have shown that alcohol has significant effect on molecular and cellular regulatory mechanisms in embryonic stem cell (ESC) differentiation including genes involved in neural development. To test our hypothesis that alcohol induces molecular alterations during neural differentiation we have derived neural precursor cells from pluripotent human ESCs in the presence or absence of ethanol treatment. Genome-wide transcriptomic profiling identified molecular alterations induced by ethanol exposure during neural differentiation of hESCs into neural rosettes and neural precursor cell populations. The Database for Annotation, Visualization and Integrated Discovery (DAVID) functional analysis on significantly altered genes showed potential ethanol’s effect on JAK-STAT signaling pathway, neuroactive ligand-receptor interaction, Toll-like receptor (TLR) signaling pathway, cytokine-cytokine receptor interaction and regulation of autophagy. We have further quantitatively verified ethanol-induced alterations of selected candidate genes. Among verified genes we further examined the expression of P2RX3, which is associated with nociception, a peripheral pain response. We found ethanol significantly reduced the level of P2RX3 in undifferentiated hESCs, but induced the level of P2RX3 mRNA and protein in hESC-derived NPCs. Our result suggests ethanol-induced dysregulation of P2RX3 along with alterations in molecules involved in neural activity such as neuroactive ligand-receptor interaction may be a molecular event associated with alcohol-related peripheral neuropathy of an enhanced nociceptive response.
Highlights
Alcohol consumption is recognized as the leading preventable cause of birth defects and mental retardation
The teratogenic effect of alcohol on neurodevelopment during embryogenesis has been demonstrated in various models, which could be a pathologic basis for fetal alcohol spectrum disorders (FASDs)
We found ethanol significantly reduced the level of P2RX3 in undifferentiated human embryonic stem cells (hESCs), but induced the level of P2RX3 mRNA and protein in hESC-derived neural precursor cells (NPC)
Summary
Alcohol consumption is recognized as the leading preventable cause of birth defects and mental retardation. Gastrulation period is considered to be the most sensitive to teratogenic insult, suggesting that differentiating cells might be especially vulnerable to the teratogenic effects of alcohol [7] It is not clearly established what causes FASDs. Recently, epigenetic regulations have emerged as potential mechanisms associated with alcohol teratogenesis. An established in vitro neural stem cell model will be useful for the evaluation of developmental regulatory mechanisms and the significance of their alterations in pathological conditions such as developmental disorders or exposure to neuroteratogens [19]. It was found that alcohol exposure of neural precursor cells resulted in significant alterations of molecular signatures that may have functional role in neural stem cell maintenance and development and may be further involved in deleterious cellular effect of alcohol exposure
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
