More studies are required to explore how ethanol exposure regulates gene expression in human microglial cultures and how AUD PRS influences the gene expression and functionality of microglial cells. Alcohol can also directly activate microglial cells to increase the production of proinflammatory chemokines and cytokines, which may regulate gene expression in microglial cells (80). Neurons can metabolize ethanol into acetate (54), but whether microglial cells can produce acetate and highly reactive acetaldehyde from ethanol remains to be investigated. Nevertheless, human microglial cells produced from iPSCs express multiple ADH and ALDH genes necessary to participate in the metabolic process for ethanol (table S2). The ethanol metabolite acetate can be a crucial source of acetyl-CoA produced by chromatin-bound acetyl-CoA synthetase, essential for histone acetylation and epigenetic regulation for gene expression (81). It is also possible that the excessive alcohol consumption in the AUD high-PRS subjects that the high-PRS iPSCs were derived from carried certain epigenetic changes that confer the differences between gene expression and functional differences between the high-PRS versus low-PRS microglial cells. How AUD and PRS may interact with histone acetylation,
