Brendan Le Daré
email: brendan.le.dare@chu-rennes.fr

Vincent Lagente

Thomas Gicquel

Ethanol and its metabolites: update on toxicity, benefits and focus on immunomodulatory effects Running head : Toxicity, benefits and immunomodulatory effects of ethanol

Keywords: Ethanol, alcohol, acetaldehyde, metabolism, toxicity, immunomodulation

This article summarizes recent experimental and epidemiological data on the toxic and beneficial effects of ethanol and its metabolites (acetaldehyde), and focuses on their immunomodulatory effects. The section dealing with the toxic effects of alcohol focuses on its chronic toxicity (liver disorders, carcinogenic effects, cardiovascular disorders, neuropsychic disorders, addiction and withdrawal syndrome, hematologic disorders, reprotoxicity, osteoporosis) although acute toxicity is considered. The role of oxidative metabolism of ethanol by alcohol dehydrogenase, cytochrome P450 2E1, and aldehyde dehydrogenase, as well as the impact of genetic polymorphism in its physiopathology are also highlighted. The section dealing with the beneficial effects of low to moderate alcohol consumption (on cardiovascular system, diabetes, the nervous system and sensory organs, autoimmune diseases, and rheumatology) highlights the importance of anti-inflammatory and immunomodulatory effects in these observations. This knowledge, enriched by a focus on the immunomodulatory effects of ethanol and its metabolites, in particular on the NLRP3 inflammasome pathway, might facilitate the development of treatments that can reduce ethanol's harmful effects or accentuate its beneficial effects.

The origin of alcoholic beverages

It is not known when humans discovered alcohol and its effects. One can nevertheless assume that as is often the case for the evolution of lifestyle factors, this was not a chance discovery.

Given that ethanol can be produced by the fermentation of sugars contained in fruits, our ancestors may have consumed alcohol involuntarily by eating rotten (and thus fermented) fruits. In Neolithic times, the simultaneous appearance of agriculture and pottery may have markedly facilitated the exploitation of this natural phenomenon. Thus, the first traces of fermented beverages based on rice, honey and fruits (discovered in Henan Province, China) date back to the seventh millennium BC [START_REF] Mcgovern | Fermented beverages of pre-and proto-historic China[END_REF]).

In the 18 th century, the development of new agricultural and distillation techniques led to the wide availability of spirits as consumer products. During the industrial revolution, the poor increasingly resorted to alcohol as a means of enduring their harsh working or living conditions. It was not until the end of the 18 th century that alcohol addiction and alcohol abuse began to be perceived as physical and mental health problems. In his 1849 book Alcoholismus Chronicus, the Swedish physician Magnus Huss introduced the term "alcoholism" and described a number of alcohol-related visceral or mental illnesses. The first temperance societies were founded in the following decades, on the basis of scientific publications and literary depictions of alcoholism (such as those by the novelists Zola in France and Dickens in the UK). The first centers for treating and recovering from alcoholism were also founded at around this time (Porter 1987).

Specialist in-hospital care of alcoholic patients appeared in the 1920s; for example, Sainte-Anne psychiatric hospital (Paris, France) opened a ward in 1922. The first pharmacologic A c c e p t e d m a n u s c r i p t treatment (apomorphine, with its emetic effects) was introduced in the 1930s. Disulfiram (discovered in 1948) is still prescribed today in out-patient treatment (Porter 1987). A large body of scientific research has now shed light on the pathophysiological mechanisms underlying acute and chronic alcoholism. However, there is also a growing body of evidences in favor of ethanol's beneficial effects in general and its anti-inflammatory and immunomodulatory effects in particular. These diverging characteristics mean that ethanol has a "Jekyll and Hyde" profile. Here, we review the current state of knowledge about ethanol and its harmful and beneficial effects (notably its immunomodulatory properties).

Search strategy

MEDLINE and PubMed databases were searched for relevant papers published in English in peer-reviewed journals between 1979 and 2019. Studies providing information about association between drinking and selected diseases or benefits, or mechanic explanation for the association were included for review.

The metabolism of ethanol

Given that ethanol's biological effects are closely related to its metabolism, knowledge of the latter is essential for understanding the associated pathophysiological mechanisms (Figure 1).

In the first part of this section, we consider the metabolism of ethanol to acetaldehyde. In the second part, we look at the production of acetate from acetaldehyde.

Cytosolic alcohol dehydrogenase (ADH) is the major enzyme responsible for the phase I oxidative metabolism of ethanol, producing acetaldehyde and reduced nicotinamide adenine A c c e p t e d m a n u s c r i p t dinucleotide (NADH) [START_REF] Cederbaum | Alcohol Metabolism[END_REF]). The enzyme is predominantly expressed by hepatocytes but is also found in the gastrointestinal tract, lung and kidneys [START_REF] Crabb | Ethanol oxidizing enzymes: roles in alcohol metabolism and alcoholic liver disease[END_REF][START_REF] Edenberg | Regulation of the mammalian alcohol dehydrogenase genes[END_REF]. In humans, seven genes (ADH1 to ADH7) code respectively for ADH's different subunits (α, β1, β2, β3, γ1, γ2, π, χ, σ, and μ) [START_REF] Cederbaum | Alcohol Metabolism[END_REF]. These subunits bind together in pairs to form isoenzymes classified into five classes (ADH class I to ADH class V), depending on their enzymatic proprieties [START_REF] Crabb | Ethanol oxidizing enzymes: roles in alcohol metabolism and alcoholic liver disease[END_REF]. Class I ADH (formed from subunits encoded by ADH1, ADH2 and ADH3) has a crucial role in alcohol metabolism. Even though polymorphisms in ADH isoenzyme have been described, they do not appear to be linked to a particular alcohol-related disease or change in alcohol metabolism. However, some researchers have reported that alcohol is eliminated more slowly in the fasted state than in the fed state because of decreased ADH levels [START_REF] Cederbaum | Alcohol Metabolism[END_REF].

The microsomal pathway (involving the cytochrome P450 (CYP) family) is responsible for about 10% of the body's ethanol metabolism [START_REF] Hamitouche | Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: Role of CYP2C isoforms in human liver microsomes[END_REF]. Even though CYP1A2 and CYP3A4 are known to be involved, CYP2E1 is considered to be the main CYP in the first phase of ethanol metabolism [START_REF] Kunitoh | Metabolism of acetaldehyde to acetate by rat hepatic P-450s: presence of different metabolic pathway from acetaldehyde dehydrogenase system[END_REF][START_REF] Cederbaum | Alcohol Metabolism[END_REF]. This oxidative metabolic pathway takes place in the endoplasmic reticulum of hepatocytes. Using NADPH and oxygen, CYP2E1 converts ethanol into acetaldehyde and then acetaldehyde into acetate.

The conversion of ethanol into acetaldehyde produces reactive oxygen species (ROS), which notably contribute to alcohol's toxicity [START_REF] Ekström | Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1)[END_REF]. Furthermore, ethanol upregulates its own metabolism by protecting CYP2E1 from ubiquitination and degradation by the proteasome complex (Zhukov and Ingelman-Sundberg 1999; [START_REF] Lu | CYP2E1 and oxidative liver injury by alcohol[END_REF]. This mechanism results in an elevated levels of CYP2E1 in hepatocytes, and is considered to have a major role in the ethanol tolerance seen in chronic alcohol users [START_REF] Cederbaum | Alcohol Metabolism[END_REF].

A c c e p t e d m a n u s c r i p t

Catalase (an enzyme found in peroxisomes) is also known to metabolize alcohol. However, hepatic catalase does not have a significant role in ethanol metabolism. In contrast, brain catalase appears to be involved in alcohol tolerance and positive reinforcement [START_REF] Cederbaum | Alcohol Metabolism[END_REF].

Figure 1 near here Other minor phase II non-oxidative metabolic pathways for ethanol include glucuronidation (giving rise to ethylglucuronide) and sulfation (giving rise to ethylsulfate).

Phosphatidylethanol and fatty acid ethyl esters (respectively produced by phospholipase D and fatty acid ethyl ester synthase) also contribute to the non-oxidative metabolism of ethanol [START_REF] Pichini | Ethylglucuronide and ethylsulfate in meconium to assess gestational ethanol exposure: preliminary results in two Mediterranean cohorts[END_REF][START_REF] Cederbaum | Alcohol Metabolism[END_REF][START_REF] Schröck | Determination of the formation rate of phosphatidylethanol by phospholipase D (PLD) in blood and test of two selective PLD inhibitors[END_REF]).

The acetaldehyde generated by these metabolic pathways is then oxidized by aldehyde dehydrogenase (ALDH) to form acetate. In humans, the ALDH superfamily of NAD+dependent enzymes is encoded by 16 genes. The cytosolic ALDH1 and mitochondrial ALDH2 isoenzymes are those primarily involved in ethanol metabolism [START_REF] Vasiliou | Polymorphisms of Human Aldehyde Dehydrogenases[END_REF]. In contrast to ADH, polymorphisms appears to have a greater influence on ALDH activity. The ALDH2*1 allele (known to code for a highly active variant) is considered to protect against liver disease in alcoholism, whereas the enzyme encoded by ALDH2*2 allele is an inactive enzyme [START_REF] Cederbaum | Alcohol Metabolism[END_REF]. Furthermore, chronic ethanol consumption lowers ALDH and increases the acetaldehyde level [START_REF] Lin | Erythrocyte aldehyde dehydrogenase activity in alcoholism[END_REF]. Acetate is not the final metabolite in this pathway because it be converted into CO2, fatty acids, ketones, cholesterol or steroids [START_REF] Cederbaum | Alcohol Metabolism[END_REF].

A c c e p t e d m a n u s c r i p t

The activity of the various isoforms of ADH and ALDH regulates acetaldehyde concentrations, and constitutes a risk factor in the development of alcoholism (Agarwal and Goedde 1989). Indeed, the effects of ethanol intolerance (such as nausea, dysphagia, headache, and the vasodilation responsible for facial flush in particular) have been attributed

to the concentration of acetaldehyde. The accumulation of this metabolite in individuals with inactive or poorly active ALDH isoenzymes may explain the cultural barriers to drinking large amounts of alcohol seen in some societies, which thus protect against alcoholism. This is particularly the case in eastern Asia, where 15-40% of the population have inactive ALDH2

isoenzymes and thus acetaldehyde levels that are 5 to 20 times higher than in individuals with active isoenzyme [START_REF] Cederbaum | Alcohol Metabolism[END_REF].

The toxicity of ethanol

According to the World Health Organization, alcohol consumption is a causal factor in more than 60 major types of diseases and injuries, and results in approximately 2.5 million deaths each year (World Health Organization 2011). Thus, approximately 4.5% of the global burden of disease and injury is attributable to alcohol. Furthermore, this morbidity and mortality caused by alcohol consumption has socioeconomic impacts, including the medical costs borne by governments, and the financial and psychological burden to families (World Health Organization 2011). By convention, ethanol's toxicity is subdivided into acute toxicity and chronic toxicity. Here, we review the main acute and chronic outcomes of ethanol consumption, and describe the relationship between dose and overall mortality.

A c c e p t e d m a n u s c r i p t

Overall mortality as a function of dose

Many researchers have reported that low levels of alcohol intake are associated with a lower risk of mortality [START_REF] Keller | Benefits of Moderate Alcohol Consumption Not Disproven[END_REF]. Jayasekara et al.'s (2014) meta-analysis of 62,950 study participants found that ethanol's protective effect is observed for intakes of 1 to 29 g/day (corresponding to zero to three standard units of alcohol per day), with a relative risk (RR) [START_REF] Jayasekara | Alcohol Consumption Over Time and Risk of Death: A Systematic Review and Meta-Analysis[END_REF]. In a study of 380,395 people, [START_REF] Bergmann | The association of pattern of lifetime alcohol use and cause of death in the European Prospective Investigation into Cancer and Nutrition (EPIC) study[END_REF] found that limiting alcohol consumption to below five alcoholic units per day was associated with a lower risk of death (mainly due to less cardiovascular disease), whereas the consumption of five or more alcoholic drinks per day was associated with a 2-to 5-fold greater risk of death (mainly due to alcohol-related cancer) [START_REF] Bergmann | The association of pattern of lifetime alcohol use and cause of death in the European Prospective Investigation into Cancer and Nutrition (EPIC) study[END_REF]. A meta-analysis linking moderate ethanol consumption to lower allcause mortality was consistent with these results [START_REF] Gmel | How stable is the risk curve between alcohol and all-cause mortality and what factors influence the shape? A precision-weighted hierarchical meta-analysis[END_REF][START_REF] Castelnuovo | Alcohol Dosing and Total Mortality in Men and Women: An Updated Meta-analysis of 34 Prospective Studies[END_REF].

Despite the growing body of evidence for a protective effect of low to moderate alcohol consumption, the results are subject to debate. For example, Goulden et al.'s (2016) study of 24,029 individuals over the age of 50 years did not reveal an association between all-cause mortality and moderate alcohol consumption [START_REF] Goulden | Moderate Alcohol Consumption Is Not Associated with Reduced All-cause Mortality[END_REF]. Likewise, a recent study of 28 million individuals found that all-cause mortality rose with increasing levels of consumption;

the researchers concluded that the level of alcohol consumption minimizing health loss is zero [START_REF] Griswold | Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016[END_REF].

A c c e p t e d m a n u s c r i p t

Thus, the evidence is inconclusive as to whether moderate alcohol consumption has a protective effect. However, all researchers agree that excessive alcohol consumption increases all-cause mortality. The dose at which excess mortality is observed varies from one study to another but ranges from 30 to 40 g/day -corresponding to three to four standard units of alcohol [START_REF] Bergmann | The association of pattern of lifetime alcohol use and cause of death in the European Prospective Investigation into Cancer and Nutrition (EPIC) study[END_REF][START_REF] Jayasekara | Alcohol Consumption Over Time and Risk of Death: A Systematic Review and Meta-Analysis[END_REF].

Acute toxicity

The clinical manifestations of acute alcohol intoxication are well known, and are closely related to those of alcoholism. The initial neuropsychic symptoms (intellectual and psychic excitation) are followed by a cerebellar syndrome accompanying marked drunkenness, and then by a variably deep coma that may be life-threatening (through paralysis of the respiratory centers) [START_REF] Wimer | Alcohols toxicology[END_REF][START_REF] Girre | Toxicité de l'éthanol[END_REF].

In humans, the first symptoms (decreased motor coordination, longer reaction time, and impaired judgment) can be observed at a blood alcohol concentration of 0.2 g/L. These effects disappear quickly after the end of the exposure [START_REF] Bismuth | Toxicologie clinique[END_REF]. Curiously, the acute intoxicant effects of a given blood alcohol concentration are more intense when the level is rising than when it is falling (the so-called "Mellanby effect"). By extension, this term is used to refer to the phenomenon of rapid ethanol tolerance because the neuropsychic effects are less intense when the concentration is falling [START_REF] Wang | Proprioceptive Responses under Rising and Falling BACs: A Test of the Mellanby Effect[END_REF][START_REF] Holland | A systematic review of the evidence for acute tolerance to alcoholthe "Mellanby effect[END_REF]).

Ethanol's depressant neuropsychic effects have been well documented, and are related to the compound's interaction with gamma-aminobutyric acid (GABA)-A receptors [START_REF] Davies | The role of GABAA receptors in mediating the effects of alcohol in the central nervous system[END_REF].

These receptors belong to a family of ligand-dependent transmembrane ion channels that A c c e p t e d m a n u s c r i p t enable rapid neuronal responses within the mammalian central nervous system. Most GABA-A receptors are postsynaptic, although some subtypes are located outside the synapses [START_REF] Davies | The role of GABAA receptors in mediating the effects of alcohol in the central nervous system[END_REF].

In addition to these effects on GABA-A receptors, ethanol antagonizes N-methyl-D-aspartate receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and kainate receptors [START_REF] Valenzuela | Acute effects of ethanol on pharmacologically isolated kainate receptors in cerebellar granule neurons: comparison with NMDA and AMPA receptors[END_REF][START_REF] Läck | Ethanol inhibition of kainate receptor-mediated excitatory neurotransmission in the rat basolateral nucleus of the amygdala[END_REF]. Since glutamate is an excitatory neurotransmitter, blockade of these receptors heightens ethanol's depressant action on the central nervous system [START_REF] Hoffman | N-methyl-D-aspartate receptors and ethanol: inhibition of calcium flux and cyclic GMP production[END_REF]). Lastly, ethanol has also been shown to interact with glycine receptors, neuronal nicotinic receptors, and serotonin type 3 receptors [START_REF] Davies | The role of GABAA receptors in mediating the effects of alcohol in the central nervous system[END_REF][START_REF] Ding | The reinforcing effects of ethanol within the nucleus accumbens shell involve activation of local GABA and serotonin receptors[END_REF].

Chronic toxicity

Chronic ethanol exposure is toxic for many different organs, and notably affects the digestive tract (steatosis, hepatic cirrhosis, chronic gastritis, and pancreatitis), the nervous system (polyneuritis, cerebellar atrophy, and memory disorders) and the cardiovascular system.

Ethanol also has chronic hematologic, carcinogenic and reprotoxic effects. In the following section, we review the pathophysiological effects of ethanol and its metabolites on these various organ systems.

Liver disorders

In the early stages of ethanol-related liver disease, the ROS generated by ethanol metabolism are responsible for a rapid increase in the fluidity of the hepatocyte cell membrane. In turn,

A c c e p t e d m a n u s c r i p t this leads to elevated cytoplasmic levels of low-molecular-weight iron and thus even greater ROS production. This phenomenon can then induce lipid peroxidation and apoptosis [START_REF] Sergent | Role for Membrane Fluidity in Ethanol-Induced Oxidative Stress of Primary Rat Hepatocytes[END_REF].

Liver injury due to ethanol can be divided into three phases. The first phase (hepatic steatosis)

involves the accumulation of lipids in hepatocytes. It is relatively benign, and usually reversible. The pathophysiology of steatosis is closely related to the oxidative metabolism of ethanol. By inducing lipolysis in adipocytes, chronic alcohol consumption increases the fraction of free fatty acids captured by the liver [START_REF] Wei | Chronic Alcohol Exposure Disturbs Lipid Homeostasis at the Adipose Tissue-Liver Axis in Mice: Analysis of Triacylglycerols Using High-Resolution Mass Spectrometry in Combination with In Vivo Metabolite Deuterium Labeling[END_REF][START_REF] Osna | Alcoholic Liver Disease: Pathogenesis and Current Management[END_REF].

Furthermore, acetaldehyde increases the expression of sterol regulatory element-binding protein transcription factor which upregulates lipogenesis genes [START_REF] Osna | Alcoholic Liver Disease: Pathogenesis and Current Management[END_REF]).

In the second phase, steatohepatitis follows steatosis. The lipids accumulated in the hepatocytes undergo peroxidation and oxidative damage. Complex interactions involving the effects of acetaldehyde, ROS, intestinal lipopolysaccharide-mediated lesions and endoplasmic reticulum stress are responsible for infiltration of the liver by immune system cells (such as neutrophils) and activation of Kupffer cells (the liver's resident macrophages) [START_REF] Osna | Alcoholic Liver Disease: Pathogenesis and Current Management[END_REF]. The resulting massive release of pro-inflammatory cytokines is directly responsible for hepatocyte death and the maintenance of alcoholic hepatitis [START_REF] Duddempudi | Immunology in Alcoholic Liver Disease[END_REF].

The third phase reflects the fibrotic progression of inflammatory steatohepatitis. The regeneration of hepatocytes is severely compromised, and hepatic lesions lead to the activation of hepatic stellate cells -the main sources of extracellular matrix deposition that characterizes fibrosis. The progression of fibrosis during ethanol-induced chronic inflammation leads to the progressive replacement of the hepatic parenchyma by scar tissue,

A c c e p t e d m a n u s c r i p t which compromises the liver's metabolic and homeostatic functions [START_REF] Osna | Alcoholic Liver Disease: Pathogenesis and Current Management[END_REF].

Ultimately, severe complications develop, such as hepatocellular carcinoma -the second leading cause of cancer deathand portal hypertension [START_REF] Grewal | Liver Cancer and Alcohol[END_REF]Zhou et al. 2016).

Carcinogenic effects

According to Seits and Stickel (2007), 3.6% of cancers worldwide are due to chronic alcohol consumption. This causal relationship is particularly strong for tumors of the upper digestive tract (such as cancers of the mouth, pharynx, larynx and esophagus), liver tumors, colonic tumors, and breast tumors [START_REF] Seitz | Molecular mechanisms of alcohol-mediated carcinogenesis[END_REF]Zhou et al. 2016).

Once again, acetaldehyde has been incriminated in the pathophysiology of these cancers.

Indeed, this initial metabolite of ethanol can bind to proteins and alter their structures and functions -particularly for enzymes involved in DNA repair and glutathione [START_REF] Garro | The effects of chronic ethanol consumption on carcinogen metabolism and on O6-methylguanine transferase-mediated repair of alkylated DNA[END_REF]). Furthermore, acetaldehyde can bind to DNA and form adducts [START_REF] Wang | Identification of DNA adducts of acetaldehyde[END_REF].

Lastly, carriers of an allele coding for inactive ALDH2 * 2 have an increased risk of esophageal cancer, due to overexposure to this metabolite [START_REF] Seitz | Molecular mechanisms of alcohol-mediated carcinogenesis[END_REF].

Thus, the mechanisms of ethanol-induced hepatocarcinogenesis are closely related to ethanol's metabolic pathways; they involve the induction of hepatic cirrhosis, increased oxidative stress, and alterations in methylation. Lastly, retinoic acid (which is essential for proliferation and cell differentiation) is metabolized abnormally after CYP2E1 expression has been upregulated by ethanol [START_REF] Seitz | Molecular mechanisms of alcohol-mediated carcinogenesis[END_REF].

A c c e p t e d m a n u s c r i p t

In chronic alcohol users, a meta-analysis found that the risk of breast cancer increase with a dose-response relation giving a relative risk of 1.11 (CI = 1.07-1.16), 1.24 (CI = 1.15-1.34), and 1.38 (CI = 1.23-1.55) with the consumption of one, two or three drinks a day respectively [START_REF] Longnecker | Alcoholic beverage consumption in relation to risk of breast cancer: metaanalysis and review[END_REF]). This risk is linked to the ethanol-induced increase in estradiol levels.

Since steroid hormones, including estrogens are metabolized by ADH (McEvily et al. 1988), the effect might be due to competition between estrogen and ethanol, resulting in impaired metabolism of estrogens [START_REF] Seitz | Molecular mechanisms of alcohol-mediated carcinogenesis[END_REF]Al-Sader et al. 2009). These data are supported by [START_REF] Hines | A prospective study of the effect of alcohol consumption and ADH3 genotype on plasma steroid hormone levels and breast cancer risk[END_REF] findings, showing a positive correlation between alcohol consumption and bioavailable estradiol in a prospective study involving 1086 individuals [START_REF] Hines | A prospective study of the effect of alcohol consumption and ADH3 genotype on plasma steroid hormone levels and breast cancer risk[END_REF]. In addition, ethanol can stimulate the transcriptional activity of estrogen receptor in human breast cancer cells which is related to increased breast cancer risk [START_REF] Fan | Alcohol stimulates estrogen receptor signaling in human breast cancer cell lines[END_REF].

Furthermore, ethanol alters methyl group transfers. Gene methylation is crucial in the regulation of gene expression: hypermethylation tends to decrease gene expression, whereas hypomethylation increases it. Thus, the induction of oncogenes or the repression of tumor suppressor genes appear to be key steps in ethanol-induced cancer. These mechanisms would be associated with frequent malnutrition of alcoholics, leading to vitamins deficiencies (folate, vitamin B6), which are co-factors of methyl group transfer. Conversely, an excess of vitamin A has been associated with an increased risk of alcohol-associated tumours [START_REF] Seitz | Molecular mechanisms of alcohol-mediated carcinogenesis[END_REF].

Lastly, the results of animal experiments have shown that a large amount of acetaldehyde is produced by colonic bacteria after alcohol consumption [START_REF] Jokelainen | High intracolonic acetaldehyde values produced by a bacteriocolonic pathway for ethanol oxidation in piglets[END_REF]. Furthermore, A c c e p t e d m a n u s c r i p t elevated colonic acetaldehyde concentrations (due to the inhibition of ALDH) have been linked to the induction of colonic carcinogenesis [START_REF] Seitz | Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat[END_REF]).

Cardiovascular disorders

High-dose ethanol consumption has been linked to various cardiovascular disorders, such as hypertension, atrial fibrillation, atherosclerosis, and alcoholic cardiomyopathies [START_REF] Girre | Toxicité de l'éthanol[END_REF][START_REF] Bismuth | Toxicologie clinique[END_REF]Zhou et al. 2016;[START_REF] Obad | Alcohol-Mediated Organ Damages: Heart and Brain[END_REF].

Although the mechanisms underlying this toxicity are not fully understood, the metabolites of ethanol seem to be intricately involved. Indeed, myocardial damage appears to be associated with acetaldehyde accumulation [START_REF] Guo | Facilitated ethanol metabolism promotes cardiomyocyte contractile dysfunction through autophagy in murine hearts[END_REF]). The stress imposed on myocytes by the increase in pro-inflammatory cytokines, ROS, mitochondrial dysfunctions and endoplasmic reticulum stress are known to be involved in myocyte hypertrophy, which in turn is responsible for altering the heart's contractile performance [START_REF] Machackova | Myofibrillar remodeling in cardiac hypertrophy, heart failure and cardiomyopathies[END_REF]). The cardiovascular events associated with excessive alcohol consumption can therefore lead to cardiac arrest [START_REF] Haddad | Fingerprint Profile of Alcohol-Associated Heart Failure in Human Hearts[END_REF]. The pathophysiological mechanisms potentially involved in cardiovascular disease are summarized in Table 1.

Table 1 near here

Neuropsychic disorders

The toxic effects of ethanol and its metabolites on brain tissue vary according to the region of the brain, age, the dose, and the duration of exposure. Both neurons and glial cells are In light of these effects, it is not surprising that chronic alcohol consumption is responsible for severe cognitive impairment, including dementia. The most common types of alcohol-related dementia are Wernicke-Korsakoff syndrome and Marchiafava-Bignami disease (Charness

Addiction and withdrawal syndrome

In the field of addiction, "conventional" products act on a specific target: opiate receptors for heroin, cannabinoid CB1 receptors for cannabis, nicotinic receptors for tobacco, and monoamine transporters for cocaine [START_REF] Hamon | Bases neurobiologiques des traitements de l'alcoolo-dépendance -Quelles perspectives ?[END_REF]. In contrast, ethanol acts on many levels.

As mentioned above, ethanol facilitates GABAergic transmission via GABA-A receptors and decreases glutaminergic neurotransmission [START_REF] Hoffman | N-methyl-D-aspartate receptors and ethanol: inhibition of calcium flux and cyclic GMP production[END_REF][START_REF] Valenzuela | Acute effects of ethanol on pharmacologically isolated kainate receptors in cerebellar granule neurons: comparison with NMDA and AMPA receptors[END_REF][START_REF] Läck | Ethanol inhibition of kainate receptor-mediated excitatory neurotransmission in the rat basolateral nucleus of the amygdala[END_REF]; Uusi-Oukari and Korpi 2010).

Like other addictogenic compounds, alcohol activates the reward circuit and thus the release of dopamine into the mesocorticolimbic system. This system consists of dopaminergic neurons whose cell bodies are located in the ventral tegmental area and whose axons project into the nucleus accumbens, amygdala, and frontal cortex (Inserm 2012). Although dopamine has a key role in the mechanism of dependence, other neurotransmitters (such as GABA, glutamate, serotonin, norepinephrine, and opioid peptides) are also involved (Inserm 2012).

The repeated intake of alcohol leads to tolerance and adaptive processes that decrease the effectiveness of GABAergic neurotransmission and facilitate glutaminergic neurotransmission. In turn, these processes lead to neuronal hyperexcitability -a characteristic of alcohol dependence [START_REF] Hamon | Bases neurobiologiques des traitements de l'alcoolo-dépendance -Quelles perspectives ?[END_REF].

A c c e p t e d m a n u s c r i p t

The respective roles of ethanol and its metabolites in the mechanism of alcohol addiction are still unclear but acetaldehyde has its own psychoactive effects and rewarding proprieties [START_REF] Brancato | Acetaldehyde, Motivation and Stress: Behavioral Evidence of an Addictive ménage à trois[END_REF].

Chronic exposure to ethanol results in higher membrane levels of saturated fatty acids and cholesterol, which decrease the membrane's fluidity (i.e. the opposite of the fluidifying effects of acute ethanol consumption on the hepatocyte membrane described above). As a result, a sharp decrease in alcohol consumption causes temporary membrane hyper-rigidity and disrupts cellular homeostasis [START_REF] Littleton | Neurochemical mechanisms underlying alcohol withdrawal[END_REF]. In cases of sudden alcohol withdrawal, clinical alcohol withdrawal syndrome is characterized by hypertension, tachycardia, hallucinations, agitation, fever, tremor, seizures, and hyperexcitation, and may progress to delirium tremens [START_REF] Tetrault | Substance Abuse and Withdrawal in the Critical Care Setting[END_REF].

Hematologic disorders

Several hematological disorders are promoted or accentuated by alcohol consumption: leukopenia, anemia, thrombocytopenia, myelodysplasia, and acute leukemia [START_REF] Girre | Toxicité de l'éthanol[END_REF][START_REF] Bismuth | Toxicologie clinique[END_REF]. Recently, [START_REF] Smith | The Effects of Alcohol and Aldehyde Dehydrogenases on Disorders of Hematopoiesis[END_REF] hypothesized that an ALDH polymorphism predisposes to these hematological disorders. Since the ALDH1A1 isoform protein is present in hematopoietic stem cells, overexposure to acetaldehyde may explain the increased risk of impaired hematopoiesis associated with the inhibition of DNA repair [START_REF] Smith | The Effects of Alcohol and Aldehyde Dehydrogenases on Disorders of Hematopoiesis[END_REF].

A c c e p t e d m a n u s c r i p t

Reprotoxicity

Ethanol consumption disrupts the menstrual cycle in women and decreases male fertility, including testicular atrophy, reduced libido, and decreased testosterone. Furthermore, a decrease in the likelihood of a clinical pregnancy per cycle was observed from five units per week upwards (Council of the Netherlands 2000; ANSES 2010).

During pregnancy, ethanol consumption is responsible in a dose-dependent manner for multiple congenital anomalies, such as growth restriction, central nervous system impairments, and malformations. These manifestations are referred to collectively as fetal alcohol syndrome (FAS), and give rise to a particular facies with narrow palpebral fissures, a flat mid-face, a short nose, a smooth philtrum, a thin upper lip, epicanthus, a flat nasal bridge, minor ear abnormalities, and micrognathia [START_REF] Wattendorf | Fetal alcohol spectrum disorders[END_REF].

The pathogenesis of FAS is related to the pharmacokinetics and metabolism of ethanol. It is well known that ethanol crosses the placenta, and distributes into the fetal compartment.

Furthermore, ethanol is eliminated slowly by the fetus, leading to greater exposure [START_REF] Heller | Review of ethanol dispersion, distribution, and elimination from the fetal compartment: Fetal Alcohol Exposure[END_REF]. Furthermore, several characteristics make the fetus more fragile to alterations in oxidative metabolism. CYP2E1 protein is produced earlier than ADH during gestation [START_REF] Hines | The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes[END_REF]Arfsten et al. 2004), and the induction of placental CYP2E1 by ethanol [START_REF] Rasheed | Variation in Induction of Human Placental CYP2E1: Possible Role in Susceptibility to Fetal Alcohol Syndrome?[END_REF]) means that CYP becomes the major metabolic pathway for ethanol.

Ethanol's teratogenic effects are thought to be due to ROS production (leading to mitochondrial damage, brain lipid peroxidation, and a decrease in endogenous antioxidant levels), apoptosis (leading to disrupted neuron-neuron adhesion), placenta vasoconstriction, and inhibition of cofactors required for fetal growth and development [START_REF] Gupta | An Update on Fetal Alcohol Syndrome-Pathogenesis, Risks, and Treatment[END_REF].

A c c e p t e d m a n u s c r i p t

Acetaldehyde is also directly involved in the induction of FAS. It is now known that retinoic acid regulates various embryonic and differentiation processes (Shabtai and Fainsod 2018).

However, retinoic acid is obtained from retinaldehyde, which itself is obtained from vitamin A. Through competition with retinaldehyde dehydrogenase, acetaldehyde inhibits the production of retinoic acid and leads to characteristics developmental malformations (Shabtai and Fainsod 2018;Shabtai et al. 2018). Furthermore, the administration of acetaldehyde to pregnant mice had teratogenic effectssuggesting that this metabolite of ethanol has a direct role (O 'Shea and Kaufman 1979).

Maternal consumption of 10 to 20 g of alcohol per day (corresponding to one to two standard units) has been shown to induce intellectual and behavioral delaysespecially if the infant is breastfed [START_REF] Bonnard | Ethanol -Fiche toxicologique n°48[END_REF].

Osteoporosis

It is well known that chronic high-level ethanol consumption is associated with osteoporosis and osteoporotic fractures [START_REF] Diamond | Ethanol reduces bone formation and may cause osteoporosis[END_REF][START_REF] Schapira | Alcohol abuse and osteoporosis[END_REF]). The underlying mechanism has been linked to elevated p21 expression, which suppresses osteoblast differentiation and mineralization and disturbs remodeling [START_REF] Maurel | Alcohol and bone: review of dose effects and mechanisms[END_REF][START_REF] Mikosch | Alcohol and bone[END_REF]. Furthermore, the observation that protein-disrupting ALDH2 polymorphisms accentuate this toxicity suggests that acetaldehyde has a direct role [START_REF] Shimizu | Reduced bone formation in alcohol-induced osteopenia is associated with elevated p21 expression in bone marrow cells in aldehyde dehydrogenase 2-disrupted mice[END_REF][START_REF] Tsuchiya | Disruption of aldehyde dehydrogenase 2 gene results in altered cortical bone structure and increased cortical bone mineral density in the femoral diaphysis of mice[END_REF].

Benefits of ethanol

Despite Burton et al.'s (2018) statement that "no level of alcohol consumption improves health" [START_REF] Burton | No level of alcohol consumption improves health[END_REF] and the many harmful effects of ethanol consumption, it nevertheless appears that light to moderate alcohol consumption does have beneficial effects.

The cardiovascular system

There is evidence of an inverse correlation between low to moderate alcohol consumption (corresponding to one to two units per day) and mortality from cardiovascular disease; this gives rise to the "French paradox" (Albert et al. 1999;[START_REF] Belleville | The French paradox: possible involvement of ethanol in the protective effect against cardiovascular diseases[END_REF][START_REF] Ronksley | Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis[END_REF]).

However, high alcohol consumption increases the risk of mortality from other causes and wipes out the beneficial effects -giving results in a "J" shaped curve for the relationship between mortality and alcohol consumption [START_REF] Klatsky | Alcohol and mortality[END_REF]. At present, there is no consensus on whether the protective cardiovascular effects of ethanol are restricted to one or more types of alcoholic beverage drink (i.e. wine, beer or spirits) [START_REF] Bau | Alcohol consumption, cardiovascular health, and endothelial function markers[END_REF]. However, many studies have found that wine had a greater beneficial effect on cardiovascular events.

Rodrigues et al. [START_REF] Rodrigues | Association Between Alcohol Intake and Cardiac Remodeling[END_REF] found that wine consumption was associated with less harmful findings in cardiac structure. Wine's particular protective effect is linked to the antiinflammatory, antioxidant and hypotensive properties of polyphenols [START_REF] Das | Experimental evidence for the cardioprotective effects of red wine[END_REF]; Arranz 2002). Moderate long-term alcohol consumption was also found to be associated with low blood triglyceride levels and elevated lipoprotein lipase activity [START_REF] Kovář | Moderate alcohol consumption and triglyceridemia[END_REF]. A review of wine's metabolic effects has been published [START_REF] Markoski | Molecular Properties of Red Wine Compounds and Cardiometabolic Benefits[END_REF].

Gil-Bernabe et al. [START_REF] Gil-Bernabe | Atherosclerosis amelioration by moderate alcohol consumption is associated with increased circulating levels of stromal cell-derived factor-1[END_REF] found that moderate alcohol consumption reduces atherosclerosis by regulating fibroblasts' production of CXCL12 (stromal cell-derived factor-1). Furthermore, Nurmi et al.'s (2013) work on the underlying pathophysiological mechanisms prompted the suggestion that the NLRP3 inflammasome is a key player in the protective cardiovascular effect of moderate alcohol consumption. Indeed, acute exposure to ethanol was found to inhibit the NLRP3 inflammasome in macrophages, leading to an antiinflammatory effect [START_REF] Nurmi | Ethanol Inhibits Activation of NLRP3 and AIM2 Inflammasomes in Human Macrophages-A Novel Anti-Inflammatory Action of Alcohol[END_REF]). These results were confirmed by Hoyt et al. ( 2016) [START_REF] Hoyt | Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation[END_REF].

The procyanidin compounds in wine have also been found to inhibit the NLRP3 inflammasome; this suggests that wine has a stronger anti-inflammatory effect than other beverages. Given the presence of many pharmacologically active compounds other than ethanol in alcoholic beverages, it is hard to predict the effects of these mixtures [START_REF] Liu | Grape seed-derived procyanidins alleviate gout pain via NLRP3 inflammasome suppression[END_REF].

Diabetes

The positive impact of moderate alcohol consumption on the cardiovascular system appears to be coupled with beneficial effects on diabetes mellitus. In [START_REF] Knott | Alcohol Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of More Than 1.9 Million Individuals From 38 Observational Studies[END_REF] meta-analysis A c c e p t e d m a n u s c r i p t of 1,902,605 participants, consumption of less than 63 grams of alcohol per day in women and in non-Asian populations was associated with a decrease in the risk of developing type 2 diabetes mellitus [START_REF] Knott | Alcohol Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of More Than 1.9 Million Individuals From 38 Observational Studies[END_REF]. The risk of diabetes increased for alcohol consumption levels above this threshold. In mechanistic terms, some researchers have attributed these observations to a decrease in fasting insulin concentrations, an increase in the insulin sensitivity in moderate alcohol consumers [START_REF] Kawamoto | Alcohol Consumption Is Associated with Decreased Insulin Resistance Independent of Body Mass Index in Japanese Community-Dwelling Men[END_REF][START_REF] Schrieks | The effect of alcohol consumption on insulin sensitivity and glycemic status: a systematic review and metaanalysis of intervention studies[END_REF]Zhou et al. 2016) and an increase of estradiol in women [START_REF] Rohwer | Interrelationship Between Alcohol Intake and Endogenous Sex-Steroid Hormones on Diabetes Risk in Postmenopausal Women[END_REF]. Furthermore, alcohol consumption appears to have beneficial effects on lipid metabolism by raising levels of HDL and apolipoproteins A1 and A2 [START_REF] Fragopoulou | Wine and its metabolic effects. A comprehensive review of clinical trials[END_REF]). However, these findings must be considered with caution since detailed mechanisms are still poorly understood [START_REF] Polsky | Alcohol Consumption, Diabetes Risk, and Cardiovascular Disease Within Diabetes[END_REF]. Moreover, alcohol consumption, even moderate, is associated with impaired self-care behavior including glucose self-monitoring and exercise [START_REF] Howard | Effect of Alcohol Consumption on Diabetes Mellitus: A Systematic Review[END_REF][START_REF] Engler | Alcohol use of diabetes patients: the need for assessment and intervention[END_REF]. Lastly, interactions are well known between alcohol and diabetes medications such as sulphonylureas for which the risk of hypoglycemia is increased [START_REF] Shai | Moderate alcohol intake and markers of inflammation and endothelial dysfunction among diabetic men[END_REF]).

The nervous system and sensory organs

Neuroprotection and dementia

Interestingly, ethanol appears to have a neuroprotective effect. For example, Tizabi et al.'s (2017) studies in in vitro models of Parkinson's and Alzheimer disease evidenced a protective effect of low ethanol consumption [START_REF] Tizabi | Low Vs. High Alcohol: Central Benefits Vs. Detriments[END_REF]. The underlying mechanisms were related to low levels of pro-inflammatory cytokines (TNF-α and IL-1β) and elevated levels of brain-derived neurotrophic factor and the anti-inflammatory cytokine IL-10 -resulting in greater neuroplasticity and neuroprotection. Furthermore, preclinical studies in an animal In a broader context, a recent prospective study of 9,087 participants aged between 35 and 55 at baseline found that moderate alcohol consumption was associated with a lower risk of dementia. Over the 23-year study, teetotalers and those who consumed more than 14 units of alcohol per week had a higher risk of dementia (hazard ratio [95%CI] = 1. 47 [1.15; 1.89]).

People consuming between one and 14 units of alcohol per week were therefore protected against this risk (Yasar 2018). These results were supported by those of Perters et al. [START_REF] Peters | Alcohol, dementia and cognitive decline in the elderly: a systematic review[END_REF].

Consistently

Chronic pain

On the same lines, Scott et al.'s study (2018) of 2583 patients with chronic pain found that moderate alcohol consumption was associated with lower pain levels, fewer painful body areas, and less intense somatic and mood symptoms [START_REF] Scott | Moderate Alcohol Consumption Is Associated with Reduced Pain and Fibromyalgia Symptoms in Chronic Pain Patients[END_REF]. Physical function also appeared to be improved by moderate alcohol consumption [START_REF] Scott | Moderate Alcohol Consumption Is Associated with Reduced Pain and Fibromyalgia Symptoms in Chronic Pain Patients[END_REF].

Anxiolytic effects

As mentioned above, ethanol depresses the central nervous system by interacting with GABA and N-methyl-D-aspartate receptors. This depressant effect triggers an anxiolytic effect and A c c e p t e d m a n u s c r i p t behavioral disinhibition at ethanol blood concentrations between 5 to 10 mM, with an effect on the hippocampus and the amygdala in particular [START_REF] Harrison | Effects of acute alcohol on excitability in the CNS[END_REF]. Interestingly, ethanol's anxiolytic effects (i.e. making people more likely to start a conversation) have been linked to language abilities. Indeed, consumption of a small amount of ethanol was found to have beneficial effects on the pronunciation of a recently learned foreign language [START_REF] Renner | Dutch courage? Effects of acute alcohol consumption on self-ratings and observer ratings of foreign language skills[END_REF].

Autoimmune diseases

Of all ethanol's beneficial effects, those affecting the immune system are the least well understood, and there is no consensus on the pathophysiologic mechanisms. The following section summarizes the literature data in this field.

Rheumatoid arthritis

In Di Giuseppe et al.'s 2012 study of 34,141 women (197 of whom presented with rheumatoid arthritis), the consumption of at least three units of alcohol per week halved the incidence of the disease (relative to teetotalers) (Di [START_REF] Giuseppe | Long term alcohol intake and risk of rheumatoid arthritis in women: a population based cohort study[END_REF]. Consistently, a 2014 metaanalysis found that low to moderate alcohol consumption in women prevents the onset of rheumatoid arthritis in a time-, dose-and sex-dependent manner [START_REF] Jin | Alcohol consumption as a preventive factor for developing rheumatoid arthritis: a dose-response meta-analysis of prospective studies[END_REF]. Even after the development of rheumatoid arthritis, the effects of alcohol consumption should still be considered -especially for the avoidance of drug interactions. According to the results of a study published in 2008, alcohol consumption does not increase the hepatic toxicity of methotrexate and leflunomide -both of which are widely prescribed to patients with rheumatoid arthritis. Hence, the British Society for Rheumatology guidelines suggests that alcohol consumption well within national limits is appropriate [START_REF] Rajakulendran | Rheumatoid arthritis, alcohol, leflunomide and methotrexate. Can changes to the BSR guidelines for leflunomide and methotrexate on alcohol consumption be justified?[END_REF].

A c c e p t e d m a n u s c r i p t

Furthermore, the frequent consumption of low amounts of alcohol was found to interact with the innate immune response by delaying the onset and stopping the progression of collageninduced arthritis [START_REF] Jonsson | Ethanol prevents development of destructive arthritis[END_REF].

Systemic lupus erythematosus

Two studies have reported that alcohol has beneficial effects in patients with systemic lupus erythematosus; the consumption of no more than 30 units per week was inversely correlated with the development of this disease [START_REF] Nagata | Systemic lupus erythematosus: a case-control epidemiologic study in Japan[END_REF][START_REF] Hardy | Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study[END_REF].

Thyroid disorders

Alcohol consumption was found to protect against the development of autoimmune hypothyroidism, independently of sex or the type of alcoholic beverage [START_REF] Carle | Moderate alcohol consumption may protect against overt autoimmune hypothyroidism: a population-based case-control study[END_REF].

Interestingly, [START_REF] Carlé | Graves′ hyperthyroidism and moderate alcohol consumption: evidence for disease prevention[END_REF] also reported that moderate alcohol consumption is associated with a dose-dependent reduction in the risk of developing of Grave's hyperthyroidism [START_REF] Carlé | Graves′ hyperthyroidism and moderate alcohol consumption: evidence for disease prevention[END_REF]).

Ethanol's beneficial action on the symptoms of these autoimmune diseases highlights an interesting spectrum of immune effects. However, alcohol does not appears to be of value in all immune diseases, for example, [START_REF] Skaaby | Association of alcohol consumption with allergic disease and asthma: a multicenter Mendelian Randomization analysis[END_REF] did not observe a causal relationship between alcohol consumption and the prevalence of asthma or allergic disease [START_REF] Skaaby | Association of alcohol consumption with allergic disease and asthma: a multicenter Mendelian Randomization analysis[END_REF].

A c c e p t e d m a n u s c r i p t

Rheumatology

Over the last few decades, several studies have described beneficial effects of ethanol on bone mineral density in general and in the trochanteric region of the proximal femur in particular (Angus et al. 1988;[START_REF] Holbrook | A prospective study of alcohol consumption and bone mineral density[END_REF]. Furthermore, Felson et al. found that at least 7 oz/week (approximately 200 mL/week) of alcohol was associated with high bone density in postmenopausal women. The researchers concluded that these results might be related to the elevated endogenous estrogen levels induced by ethanol, and ruled out a direct effect of alcohol [START_REF] Felson | Alcohol intake and bone mineral density in elderly men and women. The Framingham Study[END_REF]. Consistent with these results, Ganry et al.'s analysis of the "Epidémiologie de l'Ostéoporose" (EPIDOS) study found that trochanteric bone mineral density was higher in elderly women with moderate alcohol consumption (one to three glasses of wine per day) than in teetotalers [START_REF] Ganry | Effect of alcohol intake on bone mineral density in elderly women: The EPIDOS Study. Epidémiologie de l'Ostéoporose[END_REF].

Cancer

Although alcohol is known to be a carcinogenic agent in humans (see above), moderate wine consumption may decrease the risk of several cancers (including colon, lung, ovarian and prostate cancer, basal cell carcinoma, and esophageal adenocarcinoma) [START_REF] Bianchini | Wine and resveratrol: mechanisms of cancer prevention?[END_REF][START_REF] Schoonen | Alcohol consumption and risk of prostate cancer in middle-aged men[END_REF]Anderson et al. 2009;[START_REF] Klarich | Moderate Alcohol Consumption and Colorectal Cancer Risk[END_REF]Zhou et al. 2016).

These proprieties are mostly related to resveratrol, an antioxidant agent that inhibits the metabolic activation of carcinogens, decreases cell proliferation, induces apoptosis and exerts anti-inflammatory effects. The mechanisms underlying the beneficial effects of ethanol are summarized in Table 2. In contrast, ethanol's harmful and beneficial effects on the cardiovascular system, nervous system, rheumatism and cancer do not appear to interact with the adaptive immune response.

One can therefore hypothesize that the duality of ethanol's effects (leading to antiinflammatory and pro-inflammatory responses) particularly involves the innate immune response. In the literature, a brief exposure to ethanol was found to modulate the function of innate immune cells (including monocytes) via the inhibition of NF-κB and then a reduction in TNF-α, IL-6 and IL-1β production [START_REF] Muralidharan | Moderate Alcohol Induces Stress Proteins HSF1 and hsp70 and Inhibits Proinflammatory Cytokines Resulting in Endotoxin Tolerance[END_REF]). Conversely, Sureshchandra et al. (2019) showed that chronic alcohol drinking, regardless of dose alters resting transcriptomes of peripherical blood mononuclear cells, with the largest impact seen in innate immune cells. Interestingly, the pro-inflammatory impact of drinking was significant only with chronic heavy alcohol drinking. These transcriptional changes are being claimed to be partially explained by alterations in microRNA profiles (Sureshchandra et al. 2019a).

Furthermore, expansion of granulocytic-myeloid-derived suppressor cells (one of the major components in the immune suppressive network in both innate and adaptive immune responses) in response to ethanol consumption has been highlighted to play a protective role in acute alcoholic liver damage [START_REF] Li | Expansion of Granulocytic, Myeloid-Derived Suppressor Cells in Response to Ethanol-Induced Acute Liver Damage[END_REF]. Conversely, prolonged exposure to alcohol in humans was associated with elevated blood levels of IL-6 and IL-1β [START_REF] Pang | Inhibition of TLR8-and TLR4-induced Type I IFN induction by alcohol is different from its effects on inflammatory cytokine production in monocytes[END_REF]).

Lastly, it has been reported that splenic macrophages from chronic heavy alcohol drinking animals generated a larger inflammatory response to lipopolysaccharide, both at protein and gene expression levels. By increasing levels of H3K4me3 (a histone mark of active promoters), as well as chromatin accessibility at promoters and intergenic regions that regulate inflammatory responses, alcohol is thought to alter the immune fitness of tissue- resident macrophages via epigenetic mechanisms (Sureshchandra et al. 2019b). Recent studies have highlighted the NRLP3 inflammasome (a cytosolic complex of the innate immune system mainly expressed by myeloid cells like monocytes and macrophages) as an important inhibitory target of ethanol [START_REF] Nurmi | Ethanol Inhibits Activation of NLRP3 and AIM2 Inflammasomes in Human Macrophages-A Novel Anti-Inflammatory Action of Alcohol[END_REF]). This inflammasome is a potent means of immune defense, and triggers the production of IL-1β and IL-18 in response to danger and pathogen signals. Activation of NRLP3 inflammasome requires the assembly of three effectors: (i) NLRP3, (ii) the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC, an adaptor protein), and (iii) procaspase 1 [START_REF] Keyel | How is inflammation initiated? Individual influences of IL-1, IL-18 and HMGB1[END_REF].

Interestingly, ethanol was found to interact with the NRLP3 inflammasome by activating the phosphorylation and thus inhibition of the ASC adaptor protein [START_REF] Hoyt | Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation[END_REF]. Hence, acute ethanol exposure has an anti-inflammatory effect.

As described above, high levels of alcohol consumption are responsible for many toxic effects. The oxidative metabolic production of acetaldehyde is the cornerstone of this toxicity.

Remarkably, oxidative stress and acetaldehyde were found to activate the NRLP3 inflammasome, which has a key role in the pro-inflammatory effect of chronic ethanol consumption [START_REF] Hoyt | Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome[END_REF]. This sterile inflammation mechanism may override ethanol's beneficial effects on the immune system and accentuate its toxicity. Furthermore, purinergic receptors (which are also able to activate the NLRP3 inflammasome [START_REF] Gicquel | Purinergic receptors: new targets for the treatment of gout and fibrosis[END_REF])) are affected by ethanol treatment. It was recently reported that 24 hours of ethanol exposure was enough to modulate purinergic receptor levels (including P2X7R upregulation in human macrophages) and thus interleukin production -highlighting a new target for ethanol [START_REF] Daré | Ethanol upregulates the P2X7 purinergic receptor in human macrophages[END_REF]. Taken as a whole, these results suggest that purinergic receptor and NLRP3 inflammasome antagonists may be of value in the treatment of ethanol-related disease.

A c c e p t e d m a n u s c r i p t

Conclusion

Alcohol consumption has both toxic and beneficial effects; ethanol can be likened to Doctor Jekyll, whereas acetaldehyde is Mister Hyde. The detrimental effects associated with high ethanol consumption are probably due to the high resulting concentrations of acetaldehyde.

Taken as a whole, the risk-benefit ratio of ethanol remains negative in terms of public health, particularly in view of the carcinogenic effects.

Although a variety of mechanisms underlie the pathologic and beneficial effects of alcohol consumption, it appears that most of ethanol's effects on the body relate to the immune system. Both innate and adaptive immune responses are affected by ethanol, leading to a spectrum of clinical presentations. Modulation of adaptive immunity might be associated with reductions in the incidence and severity of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, hyperthyroidism, and hypothyroidism. The inhibition of innate immunity by low to moderate alcohol consumption has been linked to beneficial effects, whereas high consumption is associated with detrimental effects (through pro-inflammatory activities). Although the specific mechanisms have yet to be characterized, the modulation of cytokine production via the NF-κB or NLRP3 pathways appears to be the cornerstone of ethanol's immunomodulatory effects.

Further investigations are thus required in order to clarify the biological effects attributable to ethanol and acetaldehyde, and thus characterize the complex interactions between alcohol and the immune system. This knowledge might facilitate the development of treatments that can reduce ethanol's harmful effects or accentuate its beneficial effects.

  major complications include alteration of astrocyte and oligodendrocyte functions, resulting in reduced synaptogenesis and cell survival.The diencephalon, cerebral cortex, hippocampus, and white matter corresponding to myelin, are also targets for the toxicity of ethanol and its metabolites. This toxicity results in atrophy of the brain, although the underlying mechanism is not yet fully understood (de la Monte 1988;[START_REF] Bühler | Alcohol and the Human Brain: A Systematic Review of Different Neuroimaging Methods: ALCOHOL AND THE HUMAN BRAIN[END_REF][START_REF] Konrad | Broad Disruption of Brain White Matter Microstructure and Relationship with Neuropsychological Performance in Male Patients with Severe Alcohol Dependence[END_REF]). These various neurotoxic consequences are aggravated by the thiamine (vitamin B1) deficiency caused by ethanol's inhibition of its absorption and physiological action[START_REF] Vetreno | Alcohol-related amnesia and dementia: Animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment[END_REF].Furthermore, there is growing evidence of a link between the alcohol-induced loss of liver function and neurotoxicity. Firstly, reduced ethanol metabolism in the liver is responsible for overexposure of the brain to this toxic compound. Secondly, liver damage leads to the production of metabolic and inflammatory mediators that damage the brain. This relationship is most notable in the context of hepatic encephalopathy (De la[START_REF] De La Monte | The Liver-Brain Axis of Alcohol-Mediated Neurodegeneration: Role of Toxic Lipids[END_REF][START_REF] Chen | Relationship Between Liver Function and Brain Shrinkage in Patients with Alcohol Dependence: RELATIONSHIP BETWEEN LIVER FUNCTION AND BRAIN SHRINKAGE[END_REF]. Lastly, by jeopardizing the tight junctions of the intestinal mucosa, ethanol allows lipopolysaccharide (a gram-negative bacterial endotoxin) to enter systemic circulation. As a result, lipopolysaccharide binds to TLR4 receptors on liver macrophages and promotes proinflammatory response via cytokines, chemokines, proteases and ROS production. These cytokines are known to cross the blood brain barrier and activate the brain's resident macrophages (microglia), increasing neurotoxicity[START_REF] Mayfield | Neuroimmune signaling: a key component of alcohol abuse[END_REF]).

  1994). Today, the frontal, cerebellar and/or temporal brain atrophy induced by ethanol consumption can be readily detected by medical imaging techniques[START_REF] Matsui | Clinical application of neuroimaging to alcohol-related dementia[END_REF]).

Figure 2

 2 Figure 2 near here

  It is now clear than acetaldehyde and oxidative stress generated by ethanol metabolism have key roles in the pathophysiology underlying alcohol's various toxic effects. The molecular and pathophysiological effects of acetaldehyde are summarized in Figure2. Thus, acetaldehyde appears to have only harmful effects, whereas ethanol's effects are both beneficial and harmful.

  s c r i p t et al. 2012). In parallel, ethanol per se has been linked to elevated high-density lipoprotein (HDL) cholesterol levels, reduced low-density lipoprotein (LDL) cholesterol levels, and reduced blood coagulation (Agarwal

  that a low blood ethanol concentration has an antidepressant effect[START_REF] Müller | Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis[END_REF]).

  , Paganini-Hill et al. (2016) found that moderate drinkers participating in the 90+ Study presented a decreased risk of dementia (Paganini-Hill et al. 2016).

FiguresFigure 1 :

 1 Figures

Figure 2 :

 2 Figure 2: Molecular and pathophysiological effects of acetaldehyde

Table 2

 2 Alcohol has contrasting effects on the body. Most of alcohol's toxic effects are linked to acetaldehyde (the first oxidative metabolite of ethanol), whereas most of its beneficial effects appear to be related to the properties of ethanol per se. Thus, ethanol can be likened to Robert Louis Stevenson's literary character Dr Jekyll, with acetaldehyde as Mister Hyde.Of all ethanol's effects on the body, those on the immune system are particularly contrasting: the adverse effects are associated with pro-inflammatory activities, whereas the beneficial effects are associated with anti-inflammatory activities (in cardiovascular disease, cancer, and neuroprotection) and immune system modulation (in rheumatoid arthritis, systemic lupus erythematosus, hyperthyroidism, and hypothyroidism).

	m a n u s c r i p t
	A c c e p t e d
	near here

with lower levels of immunoglobulins G, M and A

[START_REF] Gonzalez-Quintela | Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities: Serum immunoglobulin levels in adults[END_REF][START_REF] Romeo | Effects of moderate beer consumption on first-line immunity of healthy adults[END_REF]

). These findings may explain the above-mentioned beneficial effect of low to

Acknowledgments

We wish to thank Doctor David Fraser for the English revision; the kind support and enriching discussions provided by Professor Isabelle Morel are also acknowledged.

Bibliography

Agarwal DP. Cardioprotective effects of light-moderate consumption of alcohol: a review of putative mechanisms. Alcohol Alcohol. 2002 Oct;37(5):409-15. Agarwal DP, Goedde HW. Human aldehyde dehydrogenases: their role in alcoholism. Alcohol. 1989 Dec;6(6):517-23. Albert CM, Manson JE, Cook NR, Ajani UA, Gaziano JM, Hennekens CH. Moderate alcohol consumption and the risk of sudden cardiac death among US male physicians. Circulation. 1999 Aug 31;100(9):944-50. Al-Sader H, Abdul-Jabar H, Allawi Z, Haba Y. Alcohol and breast cancer: the mechanisms explained. J Clin Med Res. 2009 Aug;1(3):125-31. Anderson LA, Cantwell MM, Watson RGP, Johnston BT, Murphy SJ, Ferguson HR, et al. The Association Between Alcohol and Reflux Esophagitis, Barrett's Esophagus, and Esophageal Adenocarcinoma. Gastroenterology. 2009 Mar;136(3):799-805. Angus RM, Sambrook PN, Pocock NA, Eisman JA. Dietary intake and bone mineral density. Bone Miner. 1988 Jul;4(3):265-77. ANSES. L'éthanol en population professionnelle. Evaluation des risques de l'éthanol en population profes sionnelle ; avis et rapport d'expertise collective. 2010. Arfsten DP, Silbergeld EK, Loffredo CA. Fetal ADH2*3 , Maternal Alcohol Consumption, and Fetal Growth. International Journal of Toxicology. 2004 Jan;23(1):47-54. Arranz S, Chiva-Blanch G, Valderas-Martínez P, Medina-Remón A, Lamuela-Raventós RM, Estruch R. Wine, beer, alcohol and polyphenols on cardiovascular disease and cancer. Nutrients. 2012;4(7):759-81. Barr T, Helms C, Grant K, Messaoudi I. Opposing effects of alcohol on the immune system. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2016 Feb;65:242-51.

Declaration of interest

The authors declare that they have no conflict of interest.

Rheumatoid arthritis

Interaction with the innate immune response, delaying the onset of collagen-induced arthritis and stopping its progression [START_REF] Jonsson | Ethanol prevents development of destructive arthritis[END_REF][START_REF] Rajakulendran | Rheumatoid arthritis, alcohol, leflunomide and methotrexate. Can changes to the BSR guidelines for leflunomide and methotrexate on alcohol consumption be justified?[END_REF][START_REF] Giuseppe | Long term alcohol intake and risk of rheumatoid arthritis in women: a population based cohort study[END_REF]