Alcohol-Induced Molecular Dysregulation in Human Embryonic Stem Cell-Derived Neural Precursor Cells.
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.
Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA, 90095, United States of America.
Yi Young
YY
Kim
Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA, 90095, United States of America.
Ivan
I
Roubal
Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA, 90095, United States of America.
Youn Soo
YS
Lee
Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA, 90095, United States of America.
Jin Seok
JS
Kim
Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA, 90095, United States of America.
Michael
M
Hoang
Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA, 90095, United States of America.
Nathan
N
Mathiyakom
Laboratory of Stem Cell & Cancer Epigenetic Research, School of Dentistry, University of California Los Angeles, 10833 Le Conte Avenue, 73-041 CHS, Los Angeles, CA, 90095, United States of America.|Center for Oral and Head/Neck Oncology Research Center, Division of Oral Biology & Medicine, UCLA School of Dentistry, 10833 Le Conte Avenue, 73-022 CHS, Los Angeles, CA, 90095, United States of America.|UCLA's Jonsson Comprehensive Cancer Center, 8-684 Factor Building, Box 951781, Los Angeles, CA, 90095, United States of America.|UCLA Broad Stem Cell Research Center, Box 957357, Los Angeles, CA, 90095, United States of America.
Yong
Y
Kim
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