Maternal Ethanol Consumption Alters the Epigenotype and the Phenotype of Offspring in a Mouse Model

Recent studies have shown that exposure to some nutritional supplements and chemicals in utero can affect the epigenome of the developing mouse embryo, resulting in adult disease.

Our hypothesis is that epigenetics is also involved in the gestational programming of adult phenotype by alcohol.

We have developed a model of gestational ethanol exposure in the mouse based on maternal ad libitum ingestion of 10% (v/v) ethanol between gestational days 0.5–8.5 and observed changes in the expression of an epigenetically-sensitive allele, Agouti viable yellow (A^vy), in the offspring.

We found that exposure to ethanol increases the probability of transcriptional silencing at this locus, resulting in more mice with an agouti-colored coat. As expected, transcriptional silencing correlated with hypermethylation at A^vy.

This demonstrates, for the first time, that ethanol can affect adult phenotype by altering the epigenotype of the early embryo. Interestingly, we also detected postnatal growth restriction and craniofacial dysmorphology reminiscent of fetal alcohol syndrome, in congenic a/a siblings of the A^vy mice.

These findings suggest that moderate ethanol exposure in utero is capable of inducing changes in the expression of genes other than A^vy, a conclusion supported by our genome-wide analysis of gene expression in these mice. In addition, offspring of female mice given free access to 10% (v/v) ethanol for four days per week for ten weeks prior to conception also showed increased transcriptional silencing of the A^vy allele.

Our work raises the possibility of a role for epigenetics in the etiology of fetal alcohol spectrum disorders, and it provides a mouse model that will be a useful resource in the continued efforts to understand the consequences of gestational alcohol exposure at the molecular level.

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Neural Substrates of Alcohol-Induced Smoking Urge in Heavy Drinking Nondaily Smokers

A strong link exists between cigarette smoking and alcohol use, which may be explained by the experimental observation that alcohol ingestion promotes cigarette craving and precipitates smoking.

At the neuroanatomic level, it is unclear where and how alcohol exerts these effects, although the process likely involves the ventral striatum given its function in motivational salience and appetitive reinforcement.

In a double-blinded, placebo-controlled, crossover study, heavy drinking nondaily social smokers (ie, light smokers or ‘chippers’) were examined using functional magnetic resonance imaging after they ingested an acute dose of alcohol or placebo. We probed reactivity in the ventral striatum and other brain regions during exposure to visual smoking vs nonsmoking control cues.

We found that alcohol enhanced self-reported ratings of desire to smoke, and in this context, significantly increased ventral striatum responses to smoking compared with control cues.

In exploratory analyses, we observed that alcohol dampened orbitofrontal activity across both cue types, whereas dorsolateral prefrontal and anterior cingulate cortex activation to smoking cues was not affected by alcohol.

This study bridges a pharmacological challenge approach to the study of brain reactivity to smoking cues, extends prior cigarette cue imaging studies to nondependent smokers, and elucidates a potential neurobiological mechanism to explain the co-consumption of alcohol and cigarettes in nondependent users.

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Separable Roles of the Nucleus Accumbens Core and Shell in Context- and Cue-Induced Alcohol-Seeking

Conditioned responding to drug-predictive discrete cues can be strongly modulated by drug-associated contexts.

We tested the hypothesis that differential recruitment of the nucleus accumbens (NAc) core and shell mediates responding to drug cues in a drug vs non-drug context.

Rats were trained to discriminate between two 10-s auditory stimuli: one stimulus (CS+) was paired with ethanol (10% v/v; 0.2 ml; oral) whereas the other (CS−) was not. Training occurred in operant conditioning chambers distinguished by contextual stimuli, and resulted in increased entries into the ethanol delivery port during the CS+ when compared with the CS−. In experiment 1, port entries were then extinguished in a second context by withholding ethanol, after which context-induced renewal of ethanol-seeking was tested by presenting both stimuli without ethanol in the previous training context. This manipulation stimulated strong responding to the CS+ in rats pretreated with saline in the core (n=9) or shell (n=10), which was attenuated by pharmacologically inactivating (muscimol/baclofen; 0.1/1.0 mM; 0.3 μl/side) either subregion pretest. In experiment 2, after discrimination, training rats were habituated to a different context in which ethanol and both stimuli were withheld. Cue-induced ethanol-seeking was then elicited by presenting the CS+ and CS− without ethanol in the different context. Saline-pretreated rats responded more to the CS+ than the CS− (core n=8; shell n=9), and inactivating the core but not shell attenuated this effect.

These data highlight an important role for the core in cue-induced ethanol-seeking, and suggest that the shell is required to mediate the influence of contexts on conditioned ethanol-seeking.

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ICAP Periodic Review on Drinking and Culture

Alcohol consumption is an integral part of the social fabric in many countries. Yet the role occupied by drinking is quite different across countries and cultures, and is reflected in local customs, patterns, and attitudes. Despite this wide diversity, the lingua franca of the alcohol field is English, as are the publications that provide the evidence base most commonly used in international policy discussions. As a result, much of the research published in other languages and reflecting different cultural contexts and approaches escapes broader notice.

The ICAP Periodic Review on Drinking and Culture is an electronic publication that seeks to help remedy this disparity. Its key objectives are to:

1. give greater exposure to research not currently published or widely available in English;
2. broaden the range of cultural perspectives and the evidence base used in the crafting of policy and prevention.

Each issue of the Periodic Review presents English translations of abstracts of publications appearing in language areas currently underrepresented in major English-language research databases. Coverage of the Periodic Review is limited to psychosocial and socio-cultural research, to focus on drinking culture, behavior, patterns, and psychosocial outcomes.

Identification and selection of key research to be featured and all editorial decisions are carried out by an Editorial Group, consisting of experts from diverse geographic, linguistic, and disciplinary areas

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A grandparent-influenced locus for alcohol preference on mouse chromosome 2.

Loci on mouse chromosome 2 have previously been associated with ethanol consumption. Here, we used a limited access choice paradigm in which mice consume large quantities of ethanol (2–3 g/kg/2 h) with a high preference (>80%). In addition, mouse chromosome substitution strains were used to further evaluate the contribution of chromosome 2 to ethanol consumption.

Using a limited access choice paradigm, we found that mouse chromosome 2 carries an allelic variant of a locus for ethanol intake and a distinct locus selective for ethanol preference. The heritability of alcoholism has been suggested to be parent-specific, perhaps resulting from genetic imprinting. Our findings suggest that grandparent-influenced vulnerability for ethanol consumption is conferred by genes on chromosome 2, providing important new leads to enhance our understanding of the heritability of alcoholism.

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Request Reprint E-Mail: h.m.b.lesscher@umcutrecht.nl

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The association between time perspective and alcohol consumption in university students: cross-sectional study

Heavy alcohol consumption is associated with significant morbidity and mortality. Levels of alcohol consumption among students and young people are particularly high. Time perspective describes the varying value individuals place on outcomes in the present and future. In general, it has been found that individuals prefer to receive a gain today rather than in the future. There is evidence that time perspective is associated with addictive health behaviours, including alcoholism and cigarette smoking, but less evidence of its association with non-addictive, but hazardous, levels of alcohol consumption.

The objective was to determine if there is an association between time perspective and hazardous alcohol consumption. Hazardous alcohol consumption was reported by 264 (82%) respondents. After controlling for potential confounding by socio-demographic variables, greater consideration of future consequences was associated with lower odds of reporting hazardous drinking ,

Interventions aimed at increasing future orientated time perspective may be effective in decreasing hazardous alcohol consumption in students.

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The Effectiveness of Tax Policy Interventions for Reducing Excessive Alcohol Consumption and Related Harms

A systematic review of the literature to assess the effectiveness of alcohol tax policy interventions for reducing excessive alcohol consumption and related harms was conducted for the Guide to Community Preventive Services (Community Guide).

Seventy-two papers or technical reports, which were published prior to July 2005, met specified quality criteria, and included evaluation outcomes relevant to public health (e.g., binge drinking, alcohol-related crash fatalities), were included in the final review.

Nearly all studies, including those with different study designs, found that there was an inverse relationship between the tax or price of alcohol and indices of excessive drinking or alcohol-related health outcomes.

Among studies restricted to underage populations, most found that increased taxes were also significantly associated with reduced consumption and alcohol-related harms.

According to Community Guide rules of evidence, these results constitute strong evidence that raising alcohol excise taxes is an effective strategy for reducing excessive alcohol consumption and related harms.

The impact of a potential tax increase is expected to be proportional to its magnitude and to be modified by such factors as disposable income and the demand elasticity for alcohol among various population groups.

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rfe3@cdc.gov

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The Intensity of Binge Alcohol Consumption Among U.S. Adults

Binge drinking (consuming five or more drinks during a drinking occasion) is responsible for more than half of the 79,000 annual deaths due to excessive drinking in the U.S. Although studies show a strong dose–response relationship between the intensity of binge drinking (i.e., the number of drinks consumed per binge episode) and adverse outcomes, there are no population-based studies assessing this measure,

Binge drinkers consumed an average of 8.0 drinks (median 6) during their most recent binge drinking episode; 70.0% of binge drinkers consumed six or more drinks, and 38.4% consumed eight or more drinks. Men consumed more drinks during their last binge episode than women (M=8.3 vs 7.0, median=7 vs 6), and those aged 18–34 years consumed more drinks than those aged >34 years for both men and women. Independent risk factors for consuming eight or more drinks included being male; being aged <35>

Most adult binge drinkers drink in excess of the five-drink threshold defining this risky behavior. The intensity of binge drinking should be monitored regularly by health agencies to improve surveillance and to better assess the impact of interventions designed to reduce binge drinking and its consequences.

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Request Reprint E-Mail tbn7@cdc.gov

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Excerpts from Transcript of Meeting on Measures to Reduce Alcohol Consumption in Russia

PRESIDENT OF RUSSIA DMITRY MEDVEDEV: Colleagues,

As was agreed a while ago, we are meeting today in expanded format to discuss measures for fighting alcoholism. At the State Council meeting on youth policy we agreed to address this subject separately, in detail, and make the necessary decisions.

You know just how serious a problem alcoholism has become for our country. Frankly speaking, it has taken on the proportions of a national disaster. According to the Healthcare and Social Development Ministry’s statistics, per capita alcohol consumption in Russia – taking the whole population, including babies – now stands at 18 litres of pure alcohol a year. You can calculate for yourselves how many bottles of vodka this means – quite simply alarming. This is more than twice the level that the World Health Organisation defines as dangerous for people’s health and lives. Such a high level is quite simply a real threat to our country’s and people’s normal life.

We have taken various measures over these last years of course. Tighter rules on production and sale of alcoholic beverages were introduced, and significant restrictions were imposed on their advertising. Tougher penalties were introduced for drunk driving. But so far, we have not seen any real change in the situation. To be really honest, all of these efforts have had no real effect at all. Let’s be up front about this. All they have done is brought some order to the situation. . . . . .

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Substance Use Disorders and Risk for Completed Suicide

Substance use disorders are among the most frequent psychiatric disorders found in suicides. In psychological autopsy studies between 19% and 63% of all suicides suffered from substance use disorders, mostly from alcohol use disorders.

Suicide risk is highly increased in substance use disorders, particularly in alcohol use disorders, and in co-morbid alcoholism and depression. So far, some risk factors for suicide have been identified in alcoholism. Nevertheless, various questions about the relationship between substance use disorders and suicide remain open, which indicate directions for future research.

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SCIENCE AND INDUSTRY: COMMENTS ON THE COMMENTARIES

We appreciate the thoughtful, diverse and engaging comments on our paper [1] by these distinguished alcohol academicians. We are even more grateful for the opportunity to respond.

First, we agree with Professor Heath's comments [2] that alcohol is known to have social as well as medical benefits, and that we could learn much by studying its benefits. However, given the increasing involvement of industry in alcohol science, studies of positive effects of drinking would be more trustworthy if they are not funded by the industry. We absolutely agree with Tanya Chikritzhs [3] and others that addiction journals have a crucial role to play as gatekeepers and that there is need for more research on conflict of interest declarations, as well as on all kinds of bias in alcohol research. . . . . .

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THE GOOD, THE BAD AND THE UGLY

Stenius & Babor [1] believe that there are three types of researchers: the good ones, who puristically almost wholly avoid any communication with the beverage alcohol industry; the bad ones, who naively and simple-mindedly see potential partnerships with the industry as acceptable; and the ugly ones, who think that collaboration with the industry (under strong regimentation) might be possible. Those who cannot be wholly good are threatened ('well advised') about damaging their futures (loss of reputation in a world going towards stringent 'ethical' standards). . . . . .

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WANTED: A BROADER VIEW OF ALCOHOL STUDIES

Rather than address in detail the specific findings and recommendations of this paper, I would like to voice my reservations about a simple premise upon which it is based.

It seems unfortunate that, in the opening paragraph, the authors include in 'the alcohol research community . . . [only] . . . individuals and organizations responsible for the production and interpretation of scientific information about the nature, causes and control of alcohol-related problems' ([1]. p. 191; emphasis added).

There is no doubt that 'heavy' or 'excessive' drinking of beverages containing alcohol is associated clearly with a broad range of social, psychological and biomedical problems. However, especially during the last decade, we have also seen a host of studies using various methods, based on large samples, over long periods of time, from around the world, with statistically significant evidence that 'light' or 'moderate' drinking is associated with a broad range of social, psychological and biomedical benefits or advantages. It hardly seems fair that the distinguished scientists who conduct such studies should be excluded from the 'alcohol research community' after having devoted years contributing to our understanding of ethanol and its relation to human beings. A brief summary of how this selective view came to be accepted widely is to be found in the paper by Heath [2]. . . . . .

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RESEARCH FUNDING—A COMPLEX BUSINESS

Having served as a scientist in the Finnish Alcohol Monopoly for 15 years, after receiving individual tax-free grants from the same source for several years, I feel perplexed to read the recommendation that '. . . it should be recognized from the information reviewed in this paper that under most circumstances collaboration [of researchers] with the alcoholic beverage industry is neither warranted nor advisable'. The Finnish monopoly, which capped not only retail but also wholesale, importation and production (of a wide range of goods) in its orb, had other constraints besides grinding money to the state; but it, too, had interests, not least of them getting rid of us. For the businessmen we were simply useless. Our research rarely troubled them enough to incite any attempts to interfere, even when we proposed and in fact convinced the alcohol policy circle for a short while that limiting the growth of the overall consumption, i.e. the business of our funding source, is a good idea [1].

Stenius & Babor have provided an important service to the research community by mapping out systematically the risks and hazards involved in receiving funding from private sources and in listing altogether 24 recommendations to all participants as how to avoid them [2]. Nevertheless, their perspective is very Nordic. If the alcohol industries were not to fund any research there would be practically none in France, Italy and probably many other countries. The original source of international alcohol consumption statistics was the Dutch distilling industry. Even in countries where alcohol research is funded formally from governments, the money is often raised from the drinks business. Their advice would stop most of the gambling research in the whole world. Applied to research on dangerous consumption or otherwise controversial social issues, the conclusion becomes even more confusing: think of the Volkswagen foundation, the Wellcome Foundation, the Guggenheim Foundation, the Rockefeller Foundation and thousands of other sources that fund research not only on alcohol and drug policy relevant topics, but also on other issues that involve conflicting interests. If anyone who makes money on a product would not be allowed to use it for research [3], the profits might be smaller but also many people would be less well and die earlier. . . . .

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PROTECTING THE INTEGRITY OF SHARED SCIENTIFIC KNOWLEDGE: IS THE CONFLICT OF INTEREST STATEMENT ENOUGH?

Stenius & Babor offer an erudite approach to the divisive problem of alcohol beverage industry research funding. They urge scientists strongly to abstain but recognize that not all will be able or willing [1].

Earlier this year, an extraordinary expression of support emerged for the 'hands-off' approach [2]. More than 50, mainly Australian, scientists (this author included) and health experts co-signed a letter to the editor of the Medical Journal of Australia highlighting the pro-industry function of social aspects/public relations organizations (SAPROs) [3] and pledging to reject funding from the Australian alcohol SAPRO, 'DrinkWise'[2]. A relative newcomer, DrinkWise has reportedly funded research by 'leading academics'[sic] from at least five Australian universities [4]. . . . .

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CONFLICTS OF INTEREST. A GOLDEN STANDARD TO GENERALIZE IN ADDICTION RESEARCH

It is difficult to disagree with Stenius & Babor [1]. The points they make are clear, consistent, logical and full of common sense. Also, anyone who has been in the field long enough to have some white hairs on his head (and I have plenty of those) has at some time experienced situations such as those described by the authors. As well, evidence on the hidden strategies of the alcohol industry against public health advocates continues to grow [2]. . . . .

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The dimensionality of alcohol use disorders and alcohol consumption in a cross-national perspective

To replicate the finding that there is a single dimension trait in alcohol use disorders and to test whether the usual 5+ drinks for men and 4+ drinks for women and other measures of alcohol consumption help to improve alcohol use disorder criteria in a series of diverse patients from emergency departments (EDs) in four countries.

Using exploratory factor analyses alcohol use disorders can be described as a single, unidimensional continuum without any clear-cut distinction between the criteria for dependence and abuse in all sites. Results from item response theory analyses showed that the current DSM-IV criteria tap people in the middle–upper end of the alcohol use disorder continuum. Alcohol consumption (amount and frequency of use) can be used in all EDs with the current DSM-IV diagnostic criteria to help tap the middle–lower part of this continuum. Even though some specific diagnostic criteria and some alcohol consumption variables showed differential item function across sites, test response curves were invariant for ED sites and their inclusion would not impact the final (total) performance of the diagnostic system.

DSM-IV abuse and dependence form a unidimensional continuum in ED patients regardless of country of survey. Alcohol consumption variables, if added, would help to tap patients with more moderate severity. The DSM diagnostic system for alcohol use disorders showed invariance and performed extremely well in these samples.

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Alcohol Screening: Resources

CDC has developed Screening and Brief Intervention (SBI) for Unhealthy Alcohol Use: A Step-By-Step Implementation Guide for Trauma Centers to help Level I and II trauma centers plan, implement, and continually improve the new Committee on Trauma (COT) alcohol-screening and brief intervention requirements.

The guide includes steps and resources:

• Developing an SBI plan
• Choosing the team, including those providing the intervention
• Gaining long-term “buy-in”
• Implementing and Refining the SBI plan
• Worksheets to plan and track results
• Online resources
• Research articles on SBI

Download Screening and Brief Intervention (SBI) for Unhealthy Alcohol Use: A Step-by Step Implementation Guide for Trauma Centers
(PDF)
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Alcohol-Induced Blackout

For a long time, alcohol was thought to exert a general depressant effect on the central nervous system (CNS). However, currently the consensus is that specific regions of the brain are selectively vulnerable to the acute effects of alcohol.

An alcohol-induced blackout is the classic example; the subject is temporarily unable to form new long-term memories while relatively maintaining other skills such as talking or even driving.

A recent study showed that alcohol can cause retrograde memory impairment, that is, blackouts due to retrieval impairments as well as those due to deficits in encoding. Alcoholic blackouts may be complete (en bloc) or partial (fragmentary) depending on severity of memory impairment. In fragmentary blackouts, cueing often aids recall. Memory impairment during acute intoxication involves dysfunction of episodic memory, a type of memory encoded with spatial and social context.

Recent studies have shown that there are multiple memory systems supported by discrete brain regions, and the acute effects of alcohol on learning and memory may result from alteration of the hippocampus and related structures on a cellular level.

A rapid increase in blood alcohol concentration (BAC) is most consistently associated with the likelihood of a blackout. However, not all subjects experience blackouts, implying that genetic factors play a role in determining CNS vulnerability to the effects of alcohol. This factor may predispose an individual to alcoholism, as altered memory function during intoxication may affect an individual‟s alcohol expectancy; one may perceive positive aspects of intoxication while unintentionally ignoring the negative aspects.

Extensive research on memory and learning as well as findings related to the acute effects of alcohol on the brain may elucidate the mechanisms and impact associated with the alcohol- induced blackout.

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The myths of boozed-up Britain

Saloon bar oracles sit with their half-empty glasses and put the world to rights. The British pub has long hosted the debates which answer every question: what to do about yobs, immigrants, bankers, queues, TV repeats, noisy neighbours and the weather? On one subject, the drinker counts himself particularly expert, of course - booze.

So, if the conversation at your local tonight comes round to the latest ideas on what we should do about the problems of alcohol, I have culled a few key points from the parliamentary report on the subject published today. . . . . .

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Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant

In approximately one billion people, a point mutation inactivates a key detoxifying enzyme, aldehyde dehydrogenase (ALDH2).

This mitochondrial enzyme metabolizes toxic biogenic and environmental aldehydes, including the endogenously produced 4-hydroxynonenal (4HNE) and the environmental pollutant acrolein, and also bioactivates nitroglycerin.

ALDH2 is best known, however, for its role in ethanol metabolism. The accumulation of acetaldehyde following the consumption of even a single alcoholic beverage leads to the Asian alcohol-induced flushing syndrome in ALDH2*2 homozygotes. The ALDH2*2 allele is semidominant, and heterozygotic individuals show a similar but less severe phenotype.

We recently identified a small molecule, Alda-1, that activates wild-type ALDH2 and restores near-wild-type activity to ALDH2*2.

The structures of Alda-1 bound to ALDH2 and ALDH2*2 reveal how Alda-1 activates the wild-type enzyme and how it restores the activity of ALDH2*2 by acting as a structural chaperone.

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Request Reprint E-Mail: thurley@iupui.edu.
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