Consuming alcohol leads to epigenetic changes in brain memory centers

October 23, 2019

Science Daily/University of Pennsylvania School of Medicine

New research revealed a surprising pathway that shows alcohol byproducts travel to the brain to promote addiction memory. They show how acetate travels to the brain's learning system and directly alters proteins the regulate DNA function, impacting how some genes are expressed and ultimately affecting how mice behave when given environmental cues to consume alcohol.

Triggers in everyday life such as running into a former drinking buddy, walking by a once-familiar bar, and attending social gatherings can all cause recovering alcoholics to "fall off the wagon." About 40 to 60 percent of people who have gone through treatment for substance abuse will experience some kind of relapse, according to the National Institute on Drug Abuse. But what drives the biology behind these cravings has remained largely unknown.

Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania, have shown, in mouse models, how acetate -- a byproduct of the alcohol breakdown produced mostly in the liver -- travels to the brain's learning system and directly alters proteins that regulate DNA function. This impacts how some genes are expressed and ultimately affects how mice behave when given environmental cues to consume alcohol. Their findings were published today in Nature.

"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," said the study's senior author Shelley Berger, PhD, the Daniel S. Och University Professor in the departments Cell and Developmental Biology and Biology, and director of the Penn Epigenetics Institute. "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."

It has been known that a major source of acetate in the body comes from the breakdown of alcohol in the liver, which leads to rapidly increased blood acetate. In this study, the team, co-led by Philipp Mews, PhD, a former graduate student in the Berger lab who is now a postdoctoral fellow at Mount Sinai, and Gabor Egervari, MD, PhD, a postdoctoral fellow in Berger's lab, sought to determine whether acetate from alcohol breakdown contributes to rapid histone acetylation in the brain. They did so by using stable-isotope labeling of alcohol to show that alcohol metabolism does, in fact, contribute to this process by directly depositing acetyl groups onto histones via an enzyme called ACSS2.

Authors said that "ACSS2, 'fuels' a whole machinery of gene regulators 'on site' in the nucleus of nerve cells to turn on key memory genes that are important for learning. In fact, Berger and colleagues published findings on ACSS2 in a 2017 Nature paper. In that paper and previous work, the researchers found that ACSS2 is needed to form spatial memories.

In the current study, to better understand how the alcohol-induced changes in gene expression ultimately effect behavior, Berger and her team employed a behavioral test. Mice were exposed to "neutral" stimuli and alcohol reward in distinct compartments, distinguished by environmental cues. After this conditioning period, the researchers measured the preference of the mice by allowing them free access to either compartment, and recording the time spent in both the neutral and alcohol-paired chamber. They found that, as expected, mice with normal ACSS2 activity spent more time in the alcohol compartment following the training period.

To test the importance of ACSS2 in this behavior, researchers reduced the protein level of ACSS2 in a brain region important for learning and memory, and observed that, with lowered ACSS2, there was no preference shown for the alcohol-paired compartment.

"This indicates to us that that alcohol-related memory formation requires ACSS2," Egervari said. "Our molecular and behavioral data, when taken together, establish ACSS2 as a possible intervention target in alcohol use disorder -- in which memory of alcohol-associated environmental cues is a primary driver of craving and relapse even after protracted periods of abstinence."

Importantly, these findings suggest that other external or peripheral sources of physiological acetate -- primarily the gut microbiome -- may similarly affect central histone acetylation and brain function, which may either control or foster other metabolic syndromes.

In addition to investigating the impact of alcohol consumption on brain changes in adults, the team also looked into the effects of consumption in pregnant mice and thus the impact of alcohol on brain cells in developing mice. In utero, alcohol causes impaired neurodevelopmental gene expression and can elicit numerous alcohol-associated postnatal disease symptoms such as small head size, low body weight, and hyperactivity. And while the number of those affected by fetal alcohol spectrum disorders (FASDs) -- which includes fetal alcohol syndrome -- is unknown, the Centers for Disease Control and Prevention suggests that the full range of FASDs in the United States and some Western European countries could be as high as one to five percent of the population.

In this arm of the study, researchers found that, upon consumption of alcohol, acetate is delivered through the placenta and into the developing fetus. The fetal brains of these mice showed that alcohol exposure on the level of "binge drinking" in the pregnant female resulted in deposition of alcohol-derived acetyl-groups onto histones in fetal brains in early neural development in the mice.

Much like the primary results of the study being useful for the potential treatment of alcohol-use disorder, these results could have implications for understanding and combating fetal alcohol syndrome.

https://www.sciencedaily.com/releases/2019/10/191023132254.htm

Fathers-to-be should avoid alcohol six months before conception

Parental alcohol consumption linked to raised risk of congenital heart disease

October 3, 2019

Science Daily/European Society of Cardiology

Aspiring parents should both avoid drinking alcohol prior to conception to protect against congenital heart defects, according to research published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).

Drinking alcohol three months before pregnancy or during the first trimester was associated with a 44% raised risk of congenital heart disease for fathers and 16% for mothers, compared to not drinking. Binge drinking, defined as five or more drinks per sitting, was related to a 52% higher likelihood of these birth defects for men and 16% for women.

'Binge drinking by would-be parents is a high risk and dangerous behaviour that not only may increase the chance of their baby being born with a heart defect, but also greatly damages their own health,' said study author Dr Jiabi Qin, of Xiangya School of Public Health, Central South University, Changsha, China.

Dr Qin said the results suggest that when couples are trying for a baby, men should not consume alcohol for at least six months before fertilisation while women should stop alcohol one year before and avoid it while pregnant.

Congenital heart diseases are the most common birth defects, with approximately 1.35 million babies affected every year. These conditions can increase the likelihood of cardiovascular disease later life, even after surgical treatment, and are the main cause of perinatal death. Alcohol is a known teratogen and has been connected with fetal alcohol spectrum disorder (FASD). Around one in four children with FASD have congenital heart disease, indicating that alcohol might also be implicated in these disorders.

Previous studies investigating the link between alcohol and congenital heart disease have focused on prospective mothers, with inconclusive results. This is the first meta-analysis to examine the role of paternal alcohol drinking.

The researchers compiled the best data published between 1991 and 2019, which amounted to 55 studies including 41,747 babies with congenital heart disease and 297,587 without. The analysis showed a nonlinear dose-response relationship between parental alcohol drinking and congenital heart diseases.

Dr Qin said: 'We observed a gradually rising risk of congenital heart diseases as parental alcohol consumption increased. The relationship was not statistically significant at the lower quantities.'

Regarding specific defects, the study found that compared to abstinence, maternal drinking was correlated to a 20% greater risk of tetralogy of Fallot, a combination of four abnormalities in the heart's structure.

The authors noted that this was an observational study and does not prove a causal effect, nor does it prove that paternal drinking is more harmful to the fetal heart than maternal drinking. The data cannot be used to define a cut-off of alcohol consumption that might be considered safe.

Dr Qin said: 'The underlying mechanisms connecting parental alcohol and congenital heart diseases are uncertain and warrant further research. Although our analysis has limitations -- for example the type of alcohol was not recorded -- it does indicate that men and women planning a family should give up alcohol.'

https://www.sciencedaily.com/releases/2019/10/191003074846.htm

Binge drinking may be more damaging to women

August 19, 2019

Science Daily/University of Missouri-Columbia

Female rats more susceptible to liver injury after three binge drinking episodes

In a recently published study examining the effects of binge drinking on rats, researchers discovered that female rats who were of equal age and weight to male rats were more sensitive to alcohol and experienced alcoholic liver injury at a higher rate than male rats.

Alcohol consumption is a major cause of chronic liver disease in the United States, and binge drinking is emerging as a significant contributor to liver injury. According to the Centers for Disease Control and Prevention, one in six U.S. adults binge drink four times per month. In a recently published study examining the effects of binge drinking on rats, researchers from the University of Missouri School of Medicine discovered that female rats who were of equal age and weight to male rats were more sensitive to alcohol and experienced alcoholic liver injury at a higher rate than male rats.

"Some chronic drinkers can drink for several years and still live relatively healthy lives," said Shivendra Shukla, PhD, Margaret Proctor Mulligan Professor of medical pharmacology and physiology at the University of Missouri School of Medicine. "But many chronic drinkers are susceptible to liver damage when they binge drink. The liver is the metabolic powerhouse of the body and liver injury can compound damage to other organs. We studied the similarities and differences of gender-specific responses to repeat binge drinking. Our research showed just three binge drinking episodes triggered a response for more injury in the female rats."

Shukla found a statistically significant difference using just four male and four female rats, giving them the same amount of alcohol three times at 12-hour intervals. He collected and analyzed blood and liver tissues four hours after the last binge episode. Shukla discovered the blood alcohol concentration was twice that in the female rats, but not all damage in males and females reflected that ratio. He discovered the female rats had nearly 4 times as much fatty build-up in the liver, a trigger for additional inflammation and damage.

"There's a protein called diacylglycerol kinase-alpha (DGKa) that has been shown in other studies to promote tumor growth and cancer," Shukla said. "In our findings, this protein goes up 20% in male rats, but increases 95% in females. However, any role this protein plays in alcohol-induced breast cancer is unknown and remains to be investigated in the future."

Shukla says additional studies in humans will be needed to further understand the potential differences in how binge drinking affects males and females, and the metabolic causes for these differences.

"Unfortunately, alcohol has been glamorized," Shukla said. "It is dangerous. Don't binge drink. The research is very clear."

In addition to Shukla, the study authors include Ricardo Restrepo, PhD, Annayya Aroor, PhD, Robert Lim, PhD, Ronald Korthuis, PhD, and Xuanyou Liu, graduate student from the Department of Medical Pharmacology and Physiology at the University of Missouri School of Medicine; and David Ford, PhD, and Jacob Frank, graduate student, Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research at Saint Louis University.

The study, "Binge alcohol is more injurious to liver in female than male rats: histopathological, pharmacological, and epigenetic profiles," was recently published in the Journal of Pharmacology and Experimental Therapeutics. The authors of the study declare that they have no conflicts of interest.

https://www.sciencedaily.com/releases/2019/08/190819112725.htm