As the holiday season brings about more parties, people are more likely to drink beyond healthy limits. In this social minefield of alcoholic beverages being served liberally, addicts may find themselves more inclined to fall back into their habit, already facing an average rate of relapse somewhere between 40 and 60%.
We already know that alcohol can have several different effects on our epigenetics, all of which are negative. We’ve seen that binge drinking as a teenager can severely hinder healthy brain development, and it can also leave women more susceptible to developing liver disease. But new research on alcohol byproducts from the Perelman School of Medicine at the University of Pennsylvania shows that even in moderation, alcohol may be more harmful to the body’s epigenetic regulation process than previously thought, and in ways that destructively modify behavior around alcohol in a lasting way.
What was known going into this study is that the way alcohol is metabolized in the liver triggers a fast and large increase in acetate levels in the blood, which is then converted into acetyl-CoA via chromatin-bound acetyl-CoA synthetase 2 (ACSS2). But what effect does this acetyl-CoA then have on cells?
“It was a huge surprise to us that metabolized alcohol is directly used by the body to add chemicals called acetyl groups to the proteins that package DNA, called histones,” noted one of the lead authors on this study, Dr. Shelley Berger, director of the Penn Epigenetics Institute and the Daniel S. Och University Professor at the University of Pennsylvania’s Department of Cell and Developmental Biology and Biology. “To our knowledge, this data provides the first empirical evidence indicating that a portion of acetate derived from alcohol metabolism directly influences epigenetic regulation in the brain.”
Dr. Berger and her research team looked at mice that were administered alcohol that was molecularly labelled so that its metabolism and absorption into the body could be traced. They showed that histones were modified via the addition of acetyl groups, which is a form of epigenetic modification called histone acetylation. Even more striking was the detection of this modification in neurons; modifying these cells can affect behavior, potentially in lasting ways depending on the timing of the modification both in terms of development time point and in duration.
Although this same research group has previously shown ACSS2-dependent acetylation can drive spatial learning and memory formation, in this study they focused more specifically on the effects of alcohol—and its byproduct, acetate—on behavior. Behavioral testing involved exposing mice to compartments with either neutral stimuli or alcohol rewards. While mice with normal ACSS2 activity showed a distinct preference for the alcohol reward, mice with lowered ACSS2 activity showed no preference; they were not responsive to alcohol as a cue. While further study is needed to support this finding—including replication in humans—this could lead to a potential therapeutic target for intervention. One avenue might involve reducing ACSS2 activity in people with a history of alcohol addiction to try to stop them from relapsing.
The research team also looked at acetate’s effects in pregnant mice, where it was found to enter the developing fetus through the placenta; from there, and dependent on the extent of “binge drinking” (acetate exposure) in the mothers, acetyl groups derived from the ingested alcohol were placed onto histones. While it is already known that in utero alcohol exposure of developing fetuses leads to disrupted neural development and other disease symptoms, this acetate mechanism sheds light on downstream effects of alcohol exposure as well as a potential therapeutic target.
Alcohol metabolism does not exist and operate in a silo, independent of other bodily processes. Additional factors may affect its breakdown in the body and other sources of acetate may exacerbate the effects listed above. These factors and sources include the makeup of the gut microbiome, which is involved in complex ways with everything from metabolism through psychological health. Further study is needed to characterize the mechanisms behind the harmful effects of alcohol, how these vary over the course of human development, and how to intervene against them.
Source: Mews, P., Egervari, G., Nativio, R. et al. Alcohol metabolism contributes to brain histone acetylation. Nature 574, 717–721
Reference: Penn Medicine News Releases. Consuming alcohol leads to epigenetic changes in brain memory centers University of Pennsylvania Health System. 23 Oct. 2019. Web.
