1 6086 140 THE EFFECTS OF ACETALDEHYDE EXPOSURE ON HISTONE MODIFICATIONS AND CHROMATIN STRUCTURE IN HUMAN LUNG BRONCHIAL EPITHELIAL CELLS. AS THE PRIMARY METABOLITE OF ALCOHOL AND THE MOST ABUNDANT CARCINOGEN IN TOBACCO SMOKE, ACETALDEHYDE IS LINKED TO A NUMBER OF HUMAN DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION AND SMOKING INCLUDING CANCERS. IN ADDITION TO DIRECT DNA DAMAGE AS A RESULT OF THE FORMATION OF ACETALDEHYDE-DNA ADDUCTS, ACETALDEHYDE MAY ALSO INDIRECTLY IMPACT PROPER GENOME FUNCTION THROUGH THE FORMATION OF PROTEIN ADDUCTS. HISTONE PROTEINS ARE THE MAJOR COMPONENT OF THE CHROMATIN. POST-TRANSLATIONAL HISTONE MODIFICATIONS (PTMS) ARE CRITICALLY IMPORTANT FOR THE MAINTENANCE OF GENETIC AND EPIGENETIC STABILITY. HOWEVER, LITTLE IS KNOWN ABOUT HOW ACETALDEHYDE-HISTONE ADDUCTS AFFECT HISTONE MODIFICATIONS AND CHROMATIN STRUCTURE. THE RESULTS OF PROTEIN CARBONYL ASSAYS SUGGEST THAT ACETALDEHYDE FORMS ADDUCTS WITH HISTONE PROTEINS IN HUMAN BRONCHIAL EPITHELIAL BEAS-2B CELLS. THE LEVEL OF ACETYLATION FOR N-TERMINAL TAILS OF CYTOSOLIC HISTONES H3 AND H4, AN IMPORTANT MODIFICATION FOR HISTONE NUCLEAR IMPORT AND CHROMATIN ASSEMBLY, IS SIGNIFICANTLY DOWNREGULATED FOLLOWING ACETALDEHYDE EXPOSURE IN BEAS-2B CELLS, POSSIBLY DUE TO THE FORMATION OF HISTONE ADDUCTS AND/OR THE DECREASE IN THE EXPRESSION OF HISTONE ACETYLTRANSFERASES. NOTABLY, THE LEVEL OF NUCLEOSOMAL HISTONES IN THE CHROMATIN FRACTION AND AT MOST OF THE GENOMIC LOCI WE TESTED ARE LOW IN ACETALDEHYDE-TREATED CELLS AS COMPARED WITH THE CONTROL CELLS, WHICH IS SUGGESTIVE OF INHIBITION OF CHROMATIN ASSEMBLY. MOREOVER, ACETALDEHYDE EXPOSURE PERTURBS CHROMATIN STRUCTURE AS EVIDENCED BY THE INCREASE IN GENERAL CHROMATIN ACCESSIBILITY AND THE DECREASE IN NUCLEOSOME OCCUPANCY AT GENOMIC LOCI FOLLOWING ACETALDEHYDE TREATMENT. OUR RESULTS INDICATE THAT REGULATION OF HISTONE MODIFICATIONS AND CHROMATIN ACCESSIBILITY MAY PLAY IMPORTANT ROLES IN ACETALDEHYDE-INDUCED PATHOGENESIS. ENVIRON. MOL. MUTAGEN. 59:375-385, 2018. (C) 2018 WILEY PERIODICALS, INC. 2018 2 1787 39 EFFECT OF CHRONIC ALCOHOL EXPOSURE ON GUT VITAMIN B7 UPTAKE: INVOLVEMENT OF EPIGENETIC MECHANISMS AND EFFECT OF ALCOHOL METABOLITES. VITAMIN B7 (BIOTIN) IS ESSENTIAL FOR NORMAL HEALTH AND ITS DEFICIENCY/SUBOPTIMAL LEVELS OCCUR IN A VARIETY OF CONDITIONS INCLUDING CHRONIC ALCOHOLISM. MAMMALS, INCLUDING HUMANS, OBTAIN BIOTIN FROM DIET AND GUT-MICROBIOTA VIA ABSORPTION ALONG THE INTESTINAL TRACT. THE ABSORPTION PROCESS IS CARRIER MEDIATED AND INVOLVES THE SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER (SMVT; SLC5A6). WE HAVE PREVIOUSLY SHOWN THAT CHRONIC ALCOHOL EXPOSURE SIGNIFICANTLY INHIBITS INTESTINAL/COLONIC BIOTIN UPTAKE VIA SUPPRESSION OF SLC5A6 TRANSCRIPTION IN ANIMAL AND CELL LINE MODELS. HOWEVER, LITTLE IS KNOWN ABOUT THE TRANSCRIPTIONAL/EPIGENETIC FACTORS THAT MEDIATE THIS SUPPRESSION. IN ADDITION, THE EFFECT OF ALCOHOL METABOLITES (GENERATED VIA ALCOHOL METABOLISM BY GUT MICROBIOTA AND HOST TISSUES) ON BIOTIN UPTAKE IS STILL UNKNOWN. TO ADDRESS THESE QUESTIONS, WE FIRST DEMONSTRATED THAT CHRONIC ALCOHOL EXPOSURE INHIBITS SMALL INTESTINAL AND COLONIC BIOTIN UPTAKE AND SMVT EXPRESSION IN HUMAN DIFFERENTIATED ENTEROID AND COLONOID MONOLAYERS. WE THEN SHOWED THAT CHRONIC ALCOHOL EXPOSURES OF BOTH, CACO-2 CELLS AND MICE, ARE ASSOCIATED WITH A SIGNIFICANT SUPPRESSION IN EXPRESSION OF THE NUCLEAR FACTOR KLF-4 (NEEDED FOR SLC5A6 PROMOTER ACTIVITY), AS WELL AS WITH EPIGENETIC ALTERATIONS (HISTONE MODIFICATIONS). WE ALSO FOUND THAT CHRONIC EXPOSURE OF NCM460 HUMAN COLONIC EPITHELIAL CELLS AS WELL AS HUMAN DIFFERENTIATED COLONOID MONOLAYERS, TO ALCOHOL METABOLITES (ACETALDEHYDE, ETHYL PALMITATE, ETHYL OLEATE) SIGNIFICANTLY INHIBITED BIOTIN UPTAKE AND SMVT EXPRESSION. THESE FINDINGS SHED LIGHT ONTO THE MOLECULAR/EPIGENETIC MECHANISMS THAT MEDIATE THE INHIBITORY EFFECT OF CHRONIC ALCOHOL EXPOSURE ON INTESTINAL BIOTIN UPTAKE. THEY FURTHER SHOW THAT ALCOHOL METABOLITES ARE ALSO CAPABLE OF INHIBITING BIOTIN UPTAKE IN THE GUT.NEW & NOTEWORTHY USING COMPLEMENTARY MODELS, INCLUDING HUMAN DIFFERENTIATED ENTEROID AND COLONOID MONOLAYERS, THIS STUDY SHOWS THE INVOLVEMENT OF MOLECULAR AND EPIGENETIC MECHANISMS IN MEDIATING THE INHIBITORY EFFECT OF CHRONIC ALCOHOL EXPOSURE ON BIOTIN UPTAKE ALONG THE INTESTINAL TRACT. THE STUDY ALSO SHOWS THAT ALCOHOL METABOLITES (GENERATED BY GUT MICROBIOTA AND HOST TISSUES) CAUSE INHIBITION IN GUT BIOTIN UPTAKE. 2021 3 5538 26 ROLE OF CHRONIC ALCOHOLISM CAUSING CANCER IN OMNIVORES AND VEGETARIANS THROUGH EPIGENETIC MODIFICATIONS. ONE OF THE SIGNIFICANT CONSEQUENCES OF ALCOHOL CONSUMPTION IS CANCER FORMATION VIA SEVERAL CONTRIBUTING FACTORS SUCH AS ACTION OF ALCOHOL METABOLITES, VITAMIN DEFICIENCIES, AND OXIDATIVE STRESS. ALL THESE FACTORS HAVE BEEN SHOWN TO CAUSE EPIGENETIC MODIFICATIONS VIA DNA HYPOMETHYLATION, THUS FORMING A BASIS FOR CANCER DEVELOPMENT. SEVERAL PUBLISHED REVIEWS AND STUDIES WERE SYSTEMATICALLY REVIEWED. OMNIVORES AND VEGETARIANS DIFFER IN TERMS OF NUTRITIONAL INTAKE AND DEFICIENCIES. AS FOLATE DEFICIENCY WAS FOUND TO BE COMMON AMONG THE OMNIVORES, CHRONIC ALCOHOLISM COULD POSSIBLY CAUSE DAMAGE AND EVENTUALLY CANCER IN AN OMNIVOROUS INDIVIDUAL VIA DNA HYPOMETHYLATION DUE TO FOLATE DEFICIENCY. FURTHERMORE, AS NIACIN WAS FOUND TO BE DEFICIENT AMONG VEGETARIANS, DAMAGE IN VEGETARIAN CHRONIC ALCOHOLICS COULD BE DUE TO INCREASED NADH/NAD (+) RATIO, THUS SLOWING ALCOHOL METABOLISM IN LIVER LEADING TO INCREASED ALCOHOL AND ACETALDEHYDE WHICH INHIBIT METHYLTRANSFERASE ENZYMES, EVENTUALLY LEADING TO DNA HYPOMETHYLATION. HENCE CORRECTING THE CONCERNED DEFICIENCY AND SUPPLEMENTATION WITH S-ADENOSYL METHIONINE COULD PROVE TO BE PROTECTIVE IN CHRONIC ALCOHOL USE. 2020 4 558 34 B-VITAMIN DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. CONVINCING EVIDENCE LINKS ABERRANT B-VITAMIN DEPENDENT HEPATIC METHIONINE METABOLISM TO THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). THIS REVIEW FOCUSES ON THE ESSENTIAL ROLES OF FOLATE AND VITAMINS B6 AND B12 IN HEPATIC METHIONINE METABOLISM, THE CAUSES OF THEIR DEFICIENCIES AMONG CHRONIC ALCOHOLIC PERSONS, AND HOW THEIR DEFICIENCIES TOGETHER WITH CHRONIC ALCOHOL EXPOSURE IMPACT ON ABERRANT METHIONINE METABOLISM IN THE PATHOGENESIS OF ALD. FOLATE IS THE DIETARY TRANSMETHYLATION DONOR FOR THE PRODUCTION OF S-ADENOSYLMETHIONINE (SAM), WHICH IS THE SUBSTRATE FOR ALL METHYLTRANSFERASES THAT REGULATE GENE EXPRESSIONS IN PATHWAYS OF LIVER INJURY, AS WELL AS A REGULATOR OF THE TRANSSULFURATION PATHWAY THAT IS ESSENTIAL FOR PRODUCTION OF GLUTATHIONE (GSH), THE PRINCIPAL ANTIOXIDANT FOR DEFENSE AGAINST OXIDATIVE LIVER INJURY. VITAMIN B12 REGULATES TRANSMETHYLATION REACTIONS FOR SAM PRODUCTION AND VITAMIN B6 REGULATES TRANSSULFURATION REACTIONS FOR GSH PRODUCTION. FOLATE DEFICIENCY ACCELERATES THE EXPERIMENTAL DEVELOPMENT OF ALD IN ETHANOL-FED ANIMALS WHILE REDUCING LIVER SAM LEVELS WITH RESULTANT ABNORMAL GENE EXPRESSION AND DECREASED PRODUCTION OF ANTIOXIDANT GSH. THROUGH ITS EFFECTS ON FOLATE METABOLISM, REDUCED SAM ALSO IMPAIRS NUCLEOTIDE BALANCE WITH RESULTANT INCREASED DNA STRAND BREAKS, OXIDATION, HEPATOCELLULAR APOPTOSIS, AND RISK OF CARCINOGENESIS. THE REVIEW ENCOMPASSES REFERENCED STUDIES ON MECHANISMS FOR PERTURBATIONS OF METHIONINE METABOLISM IN ALD, EVIDENCE FOR ALTERED GENE EXPRESSIONS AND THEIR EPIGENETIC REGULATION IN THE PATHOGENESIS OF ALD, AND CLINICAL STUDIES ON POTENTIAL PREVENTION AND TREATMENT OF ALD BY CORRECTION OF METHIONINE METABOLISM WITH SAM. 2013 5 319 28 ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS THE MOST PREVALENT TYPE OF CHRONIC LIVER DISEASE WORLDWIDE. ALD CAN PROGRESS FROM ALCOHOLIC FATTY LIVER (AFL) TO ALCOHOLIC STEATOHEPATITIS (ASH), WHICH IS CHARACTERIZED BY HEPATIC INFLAMMATION. CHRONIC ASH CAN EVENTUALLY LEAD TO FIBROSIS AND CIRRHOSIS AND IN SOME CASES HEPATOCELLULAR CANCER (HCC). IN ADDITION, SEVERE ASH (WITH OR WITHOUT CIRRHOSIS) CAN LEAD TO ALCOHOLIC HEPATITIS, WHICH IS AN ACUTE CLINICAL PRESENTATION OF ALD THAT IS ASSOCIATED WITH LIVER FAILURE AND HIGH MORTALITY. MOST INDIVIDUALS CONSUMING >40 G OF ALCOHOL PER DAY DEVELOP AFL; HOWEVER, ONLY A SUBSET OF INDIVIDUALS WILL DEVELOP MORE ADVANCED DISEASE. GENETIC, EPIGENETIC AND NON-GENETIC FACTORS MIGHT EXPLAIN THE CONSIDERABLE INTERINDIVIDUAL VARIATION IN ALD PHENOTYPE. THE PATHOGENESIS OF ALD INCLUDES HEPATIC STEATOSIS, OXIDATIVE STRESS, ACETALDEHYDE-MEDIATED TOXICITY AND CYTOKINE AND CHEMOKINE-INDUCED INFLAMMATION. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. THE DEGREE OF AFL AND LIVER FIBROSIS CAN BE DETERMINED BY ULTRASONOGRAPHY, TRANSIENT ELASTOGRAPHY, MRI, MEASUREMENT OF SERUM BIOMARKERS AND LIVER BIOPSY HISTOLOGY. ALCOHOL ABSTINENCE ACHIEVED BY PSYCHOSOMATIC INTERVENTION IS THE BEST TREATMENT FOR ALL STAGES OF ALD. IN THE CASE OF ADVANCED DISEASE SUCH AS CIRRHOSIS OR HCC, LIVER TRANSPLANTATION MAY BE REQUIRED. THUS, NEW THERAPIES ARE URGENTLY NEEDED. 2018 6 5609 33 S-ADENOSYLMETHIONINE DECREASES THE PEAK BLOOD ALCOHOL LEVELS 3 H AFTER AN ACUTE BOLUS OF ETHANOL BY INDUCING ALCOHOL METABOLIZING ENZYMES IN THE LIVER. INTRODUCTION: AN ALCOHOL BOLUS CAUSES THE BLOOD ALCOHOL LEVEL (BAL) TO PEAK AT 1-2 H POST INGESTION. THE ETHANOL ELIMINATION RATE IS REGULATED BY ALCOHOL METABOLIZING ENZYMES, PRIMARILY ALCOHOL DEHYDROGENASE (ADH1), ACETALDEHYDE DEHYDROGENASE (ALDH), AND CYTOCHROME P450 (CYP2E1). RECENTLY, S-ADENOSYLMETHIONINE (SAME) WAS FOUND TO REDUCE ACUTE BALS 3 H AFTER AN ALCOHOL BOLUS. THE QUESTION, THEN, WAS: WHAT IS THE MECHANISM INVOLVED IN THIS REDUCTION OF BAL BY FEEDING SAME? TO ANSWER THIS QUESTION, WE INVESTIGATED THE CHANGES IN ETHANOL METABOLIZING ENZYMES AND THE EPIGENETIC CHANGES THAT REGULATE THE EXPRESSION OF THESE ENZYMES DURING ACUTE BINGE DRINKING AND CHRONIC DRINKING. METHODS: RATS WERE FED A BOLUS OF ETHANOL WITH OR WITHOUT SAME, AND WERE SACRIFICED AT 3 H OR 12 H AFTER THE BOLUS. RESULTS: RT-PCR AND WESTERN BLOT ANALYSES SHOWED THAT SAME SIGNIFICANTLY INDUCED ADH1 LEVELS IN THE 3 H LIVER SAMPLES. HOWEVER, SAME DID NOT AFFECT THE CHANGES IN ADH1 PROTEIN LEVELS 12 H POST BOLUS. SINCE SAME IS A METHYL DONOR, IT WAS POSTULATED THAT THE ADH1 GENE EXPRESSION UP REGULATION AT 3 H WAS DUE TO A HISTONE MODIFICATION INDUCED BY METHYLATION FROM METHYL TRANSFERASES. DIMETHYLATED HISTONE 3 LYSINE 4 (H3K4ME2), A MODIFICATION RESPONSIBLE FOR GENE EXPRESSION ACTIVATION, WAS FOUND TO BE SIGNIFICANTLY INCREASED BY SAME AT 3 H POST BOLUS. CONCLUSION: THESE RESULTS CORRELATED WITH THE LOW BAL FOUND AT 3 H POST BOLUS, AND SUPPORT THE CONCEPT THAT SAME INCREASED THE GENE EXPRESSION TO INCREASE THE ELIMINATION RATE OF ETHANOL IN BINGE DRINKING BY INCREASING H3K4ME2. 2010 7 1852 36 ELECTRONIC CIGARETTES: THEIR CONSTITUENTS AND POTENTIAL LINKS TO ASTHMA. PURPOSE OF REVIEW: VAPING IS GAINING POPULARITY IN THE USA, PARTICULARLY AMONG TEENS AND YOUNG ADULTS. WHILE E-CIGS ARE COMMONLY REPRESENTED AS SAFER ALTERNATIVES TO TOBACCO CIGARETTES, LITTLE IS KNOWN REGARDING THE HEALTH EFFECTS OF THEIR SHORT- OR LONG-TERM USE, ESPECIALLY IN INDIVIDUALS WITH PRE-EXISTING RESPIRATORY DISEASES SUCH AS ASTHMA. FLAVORED E-CIG LIQUIDS (E-LIQUIDS) AND E-CIG AEROSOLS CONTAIN AIRWAY IRRITANTS AND TOXICANTS THAT HAVE BEEN IMPLICATED IN THE PATHOGENESIS AND WORSENING OF LUNG DISEASES. IN THIS REVIEW, WE WILL SUMMARIZE EXISTING DATA ON POTENTIAL HEALTH EFFECTS OF COMPONENTS PRESENT IN E-CIG AEROSOLS, SUCH AS PROPYLENE GLYCOL, VEGETABLE GLYCERIN, NICOTINE, AND FLAVORINGS, AND DISCUSS THEIR RELEVANCE IN THE CONTEXT OF ASTHMA. RECENT FINDINGS: RECENT SURVEY DATA INDICATE THAT ADOLESCENTS WITH ASTHMA HAD A HIGHER PREVALENCE OF CURRENT E-CIG USE (12.4%) COMPARED TO THEIR NON-ASTHMATICS PEERS (10.2%) AND CONVEYED POSITIVE BELIEFS ABOUT TOBACCO PRODUCTS, ESPECIALLY E-CIGS. SIMILARLY, A STUDY CONDUCTED AMONG HIGH SCHOOL STUDENTS FROM ONTARIO, CANADA, INDICATED A GREATER LIKELIHOOD OF E-CIG USE IN ASTHMATICS AS COMPARED TO THEIR NON-ASTHMATIC PEERS. AVAILABILITY OF DIFFERENT FLAVORINGS IS OFTEN CITED AS THE MAIN REASON AMONG YOUTH/ADOLESCENTS FOR TRYING E-CIGS OR SWITCHING FROM CIGARETTES TO E-CIGS. OCCUPATIONAL INHALATION OF SOME COMMON FOOD-SAFE FLAVORING AGENTS IS REPORTED TO CAUSE OCCUPATIONAL ASTHMA AND WORSEN ASTHMATIC SYMPTOMS. MOREOVER, WORKPLACE INHALATION EXPOSURES TO THE FLAVORING AGENT DIACETYL HAVE CAUSED IRREVERSIBLE OBSTRUCTIVE AIRWAY DISEASE IN HEALTHY WORKERS. ADDITIONALLY, RECENT STUDIES REPORT THAT THERMAL DECOMPOSITION OF PROPYLENE GLYCOL (PG) AND VEGETABLE GLYCERIN (VG), THE BASE CONSTITUENTS OF E-LIQUIDS, PRODUCES REACTIVE CARBONYLS, INCLUDING ACROLEIN, FORMALDEHYDE, AND ACETALDEHYDE, WHICH HAVE KNOWN RESPIRATORY TOXICITIES. FURTHERMORE, RECENT NICOTINE STUDIES IN RODENTS REVEAL THAT PRENATAL NICOTINE EXPOSURES LEAD TO EPIGENETIC REPROGRAMMING IN THE OFFSPRING, ABNORMAL LUNG DEVELOPMENT, AND MULTIGENERATIONAL TRANSMISSION OF ASTHMATIC-LIKE SYMPTOMS. COMPARISONS OF THE TOXICITY AND HEALTH EFFECTS OF E-CIGS AND CONVENTIONAL CIGARETTES OFTEN FOCUS ON TOXICANTS KNOWN TO BE PRESENT IN CIGARETTE SMOKE (CS) (I.E., FORMALDEHYDE, NITROSAMINES, ETC.), AS WELL AS SMOKING-ASSOCIATED CLINICAL ENDPOINTS, SUCH AS CANCER, BRONCHITIS, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). HOWEVER, THIS APPROACH DISREGARDS POTENTIAL TOXICITY OF COMPONENTS UNIQUE TO FLAVORED E-CIGS, SUCH AS PG, VG, AND THE MANY DIFFERENT FLAVORING CHEMICALS, WHICH LIKELY INDUCE RESPIRATORY EFFECTS NOT USUALLY OBSERVED IN CIGARETTE SMOKERS. 2017 8 873 38 CHRONIC ALCOHOL EXPOSURE INHIBITS BIOTIN UPTAKE BY PANCREATIC ACINAR CELLS: POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS. CHRONIC EXPOSURE TO ALCOHOL AFFECTS DIFFERENT PHYSIOLOGICAL ASPECTS OF PANCREATIC ACINAR CELLS (PAC), BUT ITS EFFECT ON THE UPTAKE PROCESS OF BIOTIN IS NOT KNOWN. WE ADDRESSED THIS ISSUE USING MOUSE-DERIVED PANCREATIC ACINAR 266-6 CELLS CHRONICALLY EXPOSED TO ALCOHOL AND WILD-TYPE AND TRANSGENIC MICE (CARRYING THE HUMAN SLC5A6 5'-PROMOTER) FED ALCOHOL CHRONICALLY. FIRST WE ESTABLISHED THAT BIOTIN UPTAKE BY PAC IS NA(+) DEPENDENT AND CARRIER MEDIATED AND INVOLVES SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER (SMVT). CHRONIC EXPOSURE OF 266-6 CELLS TO ALCOHOL LED TO A SIGNIFICANT INHIBITION IN BIOTIN UPTAKE, EXPRESSION OF SMVT PROTEIN, AND MRNA AS WELL AS IN THE ACTIVITY OF THE SLC5A6 PROMOTER. SIMILARLY, CHRONIC ALCOHOL FEEDING OF WILD-TYPE AND TRANSGENIC MICE CARRYING THE SLC5A6 PROMOTER LED TO A SIGNIFICANT INHIBITION IN BIOTIN UPTAKE BY PAC, AS WELL AS IN THE EXPRESSION OF SMVT PROTEIN AND MRNA AND THE ACTIVITY OF THE SLC5A6 PROMOTERS EXPRESSED IN THE TRANSGENIC MICE. WE ALSO FOUND THAT CHRONIC ALCOHOL FEEDING OF MICE IS ASSOCIATED WITH A SIGNIFICANT INCREASE IN THE METHYLATION STATUS OF CPG ISLANDS PREDICTED TO BE IN THE MOUSE SLC5A6 PROMOTERS AND A DECREASE IN THE LEVEL OF EXPRESSION OF TRANSCRIPTION FACTOR KLF-4, WHICH PLAYS AN IMPORTANT ROLE IN REGULATING SLC5A6 PROMOTER ACTIVITY. THESE RESULTS DEMONSTRATE, FOR THE FIRST TIME, THAT CHRONIC ALCOHOL EXPOSURE NEGATIVELY IMPACTS BIOTIN UPTAKE IN PAC AND THAT THIS EFFECT IS EXERTED (AT LEAST IN PART) AT THE LEVEL OF TRANSCRIPTION OF THE SLC5A6 GENE AND MAY INVOLVE EPIGENETIC/MOLECULAR MECHANISMS. 2014 9 3556 34 IMPACT OF ALCOHOL CONSUMPTION ON MALE FERTILITY POTENTIAL: A NARRATIVE REVIEW. ALCOHOL ABUSE DISORDER IS A SERIOUS CONDITION, IMPLICATING MORE THAN 15 MILLION PEOPLE AGED 12 YEARS AND OLDER IN 2019 IN THE UNITED STATES. ETHANOL (OR ETHYL ALCOHOL) IS MAINLY OXIDIZED IN THE LIVER, RESULTING IN THE SYNTHESIS OF ACETALDEHYDE AND ACETATE, WHICH ARE TOXIC AND CARCINOGENIC METABOLITES, AS WELL AS IN THE GENERATION OF A REDUCTIVE CELLULAR ENVIRONMENT. MOREOVER, ETHANOL CAN INTERACT WITH LIPIDS, GENERATING FATTY ACID ETHYL ESTERS AND PHOSPHATIDYLETHANOL, WHICH INTERFERE WITH PHYSIOLOGICAL CELLULAR PATHWAYS. THIS NARRATIVE REVIEW SUMMARIZES THE IMPACT OF EXCESSIVE ALCOHOL CONSUMPTION ON MALE FERTILITY BY DESCRIBING ITS METABOLISM AND HOW ETHANOL CONSUMPTION MAY INDUCE CELLULAR DAMAGE. FURTHERMORE, THE IMPACT OF ALCOHOL CONSUMPTION ON HORMONAL REGULATION, SEMEN QUALITY, AND GENETIC AND EPIGENETIC REGULATIONS IS DISCUSSED BASED ON EVIDENCE FROM ANIMAL AND HUMAN STUDIES, FOCUSING ON THE CONSEQUENCES ON THE OFFSPRING. FINALLY, THE LIMITATIONS OF THE CURRENT EVIDENCE ARE DISCUSSED. OUR REVIEW HIGHLIGHTS THE ASSOCIATION BETWEEN CHRONIC ALCOHOL CONSUMPTION AND POOR SEMEN QUALITY, MAINLY DUE TO THE DEVELOPMENT OF OXIDATIVE STRESS, AS WELL AS ITS GENOTOXIC IMPACT ON HORMONAL REGULATION AND DNA INTEGRITY, AFFECTING THE OFFSPRING'S HEALTH. NEW LANDSCAPES OF INVESTIGATION ARE PROPOSED FOR THE IDENTIFICATION OF MOLECULAR MARKERS FOR ALCOHOL-ASSOCIATED INFERTILITY, WITH A FOCUS ON ADVANCED OMICS-BASED APPROACHES APPLIED TO THE ANALYSIS OF SEMEN SAMPLES. 2021 10 3680 25 INFLAMMATION IN ALCOHOLIC LIVER DISEASE. FRANK BURR MALLORY'S LANDMARK OBSERVATION IN 1911 ON THE HISTOPATHOLOGY OF ALCOHOLIC LIVER DISEASE (ALD) WAS THE FIRST IDENTIFICATION OF A LINK BETWEEN INFLAMMATION AND ALD. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES REGARDING THE ORIGINS AND ROLES OF VARIOUS INFLAMMATORY COMPONENTS IN ALD. METABOLISM OF ETHANOL GENERATES A NUMBER OF METABOLITES, INCLUDING ACETATE, REACTIVE OXYGEN SPECIES, ACETALDEHYDE, AND EPIGENETIC CHANGES, THAT CAN INDUCE INFLAMMATORY RESPONSES. ALCOHOL AND ITS METABOLITES CAN ALSO INITIATE AND AGGRAVATE INFLAMMATORY CONDITIONS BY PROMOTING GUT LEAKINESS OF MICROBIAL PRODUCTS, BY SENSITIZING IMMUNE CELLS TO STIMULATION, AND BY ACTIVATING INNATE IMMUNE PATHWAYS, SUCH AS COMPLEMENT. CHRONIC ALCOHOL CONSUMPTION ALSO SENSITIZES NONIMMUNE CELLS, E.G., HEPATOCYTES, TO INFLAMMATORY SIGNALS AND IMPAIRS THEIR ABILITY TO RESPOND TO PROTECTIVE SIGNALS. BASED ON THESE ADVANCES, A NUMBER OF INFLAMMATORY TARGETS HAVE BEEN IDENTIFIED WITH POTENTIAL FOR THERAPEUTIC INTERVENTION IN ALD, PRESENTING NEW OPPORTUNITIES AND CHALLENGES FOR TRANSLATIONAL RESEARCH. 2012 11 6726 25 VITAMIN-DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. EMERGING EVIDENCE INDICATES THAT ETHANOL-INDUCED ALTERATIONS IN HEPATIC METHIONINE METABOLISM PLAY A CENTRAL ROLE IN THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). BECAUSE MALNUTRITION IS A UNIVERSAL CLINICAL FINDING IN THIS DISEASE AND HEPATIC METHIONINE METABOLISM IS DEPENDENT UPON DIETARY FOLATE AND VITAMINS B-6 AND B-12, ALD CAN BE CONSIDERED AN INDUCED NUTRITIONAL DISORDER THAT IS CONDITIONED BY ALCOHOL ABUSE. THE PRESENT REVIEW DESCRIBES THE ETIOLOGIES OF THESE 3 VITAMIN DEFICIENCIES IN ALD AND HOW THEY INTERACT WITH CHRONIC ETHANOL EXPOSURE TO ALTER HEPATIC METHIONINE METABOLISM. SUBSEQUENT SECTIONS FOCUS ON MOLECULAR MECHANISMS FOR THE INTERACTIONS OF ABERRANT METHIONINE METABOLISM WITH ETHANOL IN THE PATHOGENESIS OF ALD, IN PARTICULAR THE ROLE OF S-ADENOSYLMETHIONINE (SAM) IN REGULATING THE EPIGENETIC EXPRESSIONS OF GENES RELEVANT TO PATHWAYS OF LIVER INJURY. THE REVIEW WILL CONCLUDE WITH DESCRIPTIONS OF STUDIES ON THE EFFICACY OF SAM IN THE TREATMENT OF ALD AND WITH DISCUSSION OF POTENTIALLY FRUITFUL FUTURE AVENUES OF RESEARCH. 2011 12 4897 43 OXIDATIVE STRESS IN ALCOHOL-RELATED LIVER DISEASE. ALCOHOL CONSUMPTION IS ONE OF THE LEADING CAUSES OF THE GLOBAL BURDEN OF DISEASE AND RESULTS IN HIGH HEALTHCARE AND ECONOMIC COSTS. HEAVY ALCOHOL MISUSE LEADS TO ALCOHOL-RELATED LIVER DISEASE, WHICH IS RESPONSIBLE FOR A SIGNIFICANT PROPORTION OF ALCOHOL-ATTRIBUTABLE DEATHS GLOBALLY. OTHER THAN REDUCING ALCOHOL CONSUMPTION, THERE ARE CURRENTLY NO EFFECTIVE TREATMENTS FOR ALCOHOL-RELATED LIVER DISEASE. OXIDATIVE STRESS REFERS TO AN IMBALANCE IN THE PRODUCTION AND ELIMINATION OF REACTIVE OXYGEN SPECIES AND ANTIOXIDANTS. IT PLAYS IMPORTANT ROLES IN SEVERAL ASPECTS OF ALCOHOL-RELATED LIVER DISEASE PATHOGENESIS. HERE, WE REVIEW HOW CHRONIC ALCOHOL USE RESULTS IN OXIDATIVE STRESS THROUGH INCREASED METABOLISM VIA THE CYTOCHROME P450 2E1 SYSTEM PRODUCING REACTIVE OXYGEN SPECIES, ACETALDEHYDE AND PROTEIN AND DNA ADDUCTS. THESE TRIGGER INFLAMMATORY SIGNALING PATHWAYS WITHIN THE LIVER LEADING TO EXPRESSION OF PRO-INFLAMMATORY MEDIATORS CAUSING HEPATOCYTE APOPTOSIS AND NECROSIS. REACTIVE OXYGEN SPECIES EXPOSURE ALSO RESULTS IN MITOCHONDRIAL STRESS WITHIN HEPATOCYTES CAUSING STRUCTURAL AND FUNCTIONAL DYSREGULATION OF MITOCHONDRIA AND UPREGULATING APOPTOTIC SIGNALING. THERE IS ALSO EVIDENCE THAT OXIDATIVE STRESS AS WELL AS THE DIRECT EFFECT OF ALCOHOL INFLUENCES EPIGENETIC REGULATION. INCREASED GLOBAL HISTONE METHYLATION AND ACETYLATION AND SPECIFIC HISTONE ACETYLATION INHIBITS ANTIOXIDANT RESPONSES AND PROMOTES EXPRESSION OF KEY PRO-INFLAMMATORY GENES. THIS REVIEW HIGHLIGHTS ASPECTS OF THE ROLE OF OXIDATIVE STRESS IN DISEASE PATHOGENESIS THAT WARRANT FURTHER STUDY INCLUDING MITOCHONDRIAL STRESS AND EPIGENETIC REGULATION. IMPROVED UNDERSTANDING OF THESE PROCESSES MAY IDENTIFY NOVEL TARGETS FOR THERAPY. 2020 13 4659 34 NEW APPROACHES FOR STUDYING ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS MAJOR CAUSE OF CHRONIC LIVER INJURY WHICH RESULTS IN LIVER FIBROSIS AND CIRRHOSIS. ACCORDING TO THE SURVEILLANCE REPORT PUBLISHED BY THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM, LIVER CIRRHOSIS IS THE 12TH LEADING CAUSE OF DEATH IN THE UNITED STATES WITH 48 % OF THESE DEATHS BEING ATTRIBUTED TO EXCESSIVE ALCOHOL CONSUMPTION. ALD INCLUDES A SPECTRUM OF DISORDERS FROM SIMPLE STEATOSIS TO STEATOHEPATITIS, FIBROSIS, AND HEPATOCELLULAR CARCINOMA. SEVERAL MECHANISMS PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF ALD. THESE INCLUDE ETHANOL-INDUCED OXIDATIVE STRESS AND DEPLETION OF GLUTATHIONE, PATHOLOGICAL METHIONINE METABOLISM, INCREASED GUT PERMEABILITY AND RELEASE OF ENDOTOXINS INTO THE PORTAL BLOOD, RECRUITMENT AND ACTIVATION OF INFLAMMATORY CELLS INCLUDING BONE MARROW-DERIVED AND LIVER RESIDENT MACROPHAGES (KUPFFER CELLS). CHRONIC ALCOHOL CONSUMPTION RESULTS IN LIVER DAMAGE AND ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) AND MYOFIBROBLASTS, LEADING TO LIVER FIBROSIS. HERE WE DISCUSS THE CURRENT VIEW ON FACTORS THAT ARE SPECIFIC FOR DIFFERENT STAGES OF ALD AND THOSE THAT REGULATE ITS PROGRESSION, INCLUDING CYTOKINES AND CHEMOKINES, ALCOHOL-RESPONSIVE INTRACELLULAR SIGNALING PATHWAYS, AND TRANSCRIPTIONAL FACTORS. WE ALSO REVIEW RECENT STUDIES DEMONSTRATING THAT ALCOHOL-MEDIATED CHANGES CAN BE REGULATED ON AN EPIGENETIC LEVEL, INCLUDING MICRORNAS. FINALLY, WE DISCUSS THE REVERSIBILITY OF LIVER FIBROSIS AND INACTIVATION OF HSCS AS A POTENTIAL STRATEGY FOR TREATING ALCOHOL-INDUCED LIVER DAMAGE. 2014 14 3619 30 IN VIVO ACUTE ON CHRONIC ETHANOL EFFECTS IN LIVER: A MOUSE MODEL EXHIBITING EXACERBATED INJURY, ALTERED METABOLIC AND EPIGENETIC RESPONSES. CHRONIC ALCOHOLICS WHO ALSO BINGE DRINK (I.E., ACUTE ON CHRONIC) ARE PRONE TO AN EXACERBATED LIVER INJURY BUT ITS MECHANISM IS NOT UNDERSTOOD. WE THEREFORE INVESTIGATED THE IN VIVO EFFECTS OF CHRONIC AND BINGE ETHANOL INGESTION AND COMPARED TO CHRONIC ETHANOL FOLLOWED BY THREE REPEAT BINGE ETHANOL ON THE LIVER OF MALE C57/BL6 MICE FED ETHANOL IN LIQUID DIET (4%) FOR FOUR WEEKS FOLLOWED BY BINGE ETHANOL (INTRAGASTRIC ADMINISTRATION, 3.5 G/KG BODY WEIGHT, THREE DOSES, 12H APART). CHRONIC FOLLOWED BY BINGE ETHANOL EXACERBATED FAT ACCUMULATION, NECROSIS, DECREASE IN HEPATIC SAM AND SAM:SAH RATIO, INCREASE IN ADENOSINE LEVELS, AND ELEVATED CYP2E1 LEVELS. HISTONE H3 LYSINE ACETYLATION (H3ACK9), DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10), AND PHOSPHORYLATED H2AX INCREASED AFTER BINGE WHEREAS PHOSPHORYLATION OF HISTONE H3 SER 10 (H3S10) AND H3 SER 28 (H3S28) INCREASED AFTER CHRONIC ETHANOL-BINGE. HISTONE H3 LYSINE 4 AND 9 DIMETHYLATION INCREASED WITH A MARKED DIMETHYLATION IN H3K9 IN CHRONIC ETHANOL BINGE GROUP. TRIMETHYLATED HISTONE H3 LEVELS DID NOT CHANGE. NUCLEAR LEVELS OF HISTONE ACETYL TRANSFERASE GCN5 AND HISTONE DEACETYLASE HDAC3 WERE ELEVATED WHEREAS PHOSPHO-CREB DECREASED IN A DISTINCTIVE MANNER. TAKEN TOGETHER, ACUTE ON CHRONIC ETHANOL INGESTION CAUSED AMPLIFICATION OF LIVER INJURY AND ELICITED CHARACTERISTIC PROFILES OF HISTONE MODIFICATIONS, METABOLIC ALTERATIONS, AND CHANGES IN NUCLEAR PROTEIN LEVELS. THESE FINDINGS DEMONSTRATE THAT CHRONIC ETHANOL EXPOSURE RENDERS LIVER MORE SUSCEPTIBLE TO REPEAT ACUTE/BINGE ETHANOL INDUCED ACCELERATION OF ALCOHOLIC LIVER DISEASE. 2015 15 2120 31 EPIGENETIC HISTONE MODIFICATIONS IN A CLINICALLY RELEVANT RAT MODEL OF CHRONIC ETHANOL-BINGE-MEDIATED LIVER INJURY. PURPOSE: ETHANOL BINGE AUGMENTS LIVER INJURY AFTER CHRONIC ETHANOL CONSUMPTION IN HUMANS, BUT THE MECHANISM BEHIND THE ENHANCED LIVER INJURY BY ETHANOL BINGE IS NOT KNOWN. IN THIS STUDY WE USED A CLINICALLY RELEVANT RAT MODEL IN WHICH LIVER INJURY IS AMPLIFIED BY BINGE AFTER CHRONIC ETHANOL TREATMENT AND INVESTIGATED THE IMPORTANCE OF HISTONE MODIFICATIONS. METHODS: EIGHT-WEEK-OLD SPRAGUE-DAWLEY RATS WERE FED ETHANOL IN A LIQUID DIET FOR 4 WEEKS. CONTROL RATS WERE FED AN ISOCALORIC LIQUID DIET. THIS WAS FOLLOWED BY THREE BINGE ADMINISTRATIONS OF ETHANOL (INTRAGASTRIC 5 G/KG BODY WEIGHT, 12 H APART). IN THE CONTROL, ETHANOL WAS REPLACED BY WATER. FOUR HOURS AFTER THE LAST BINGE ADMINISTRATION, LIVER SAMPLES WERE ANALYZED FOR HISTONE MODIFICATIONS AND PARAMETERS OF LIVER INJURY. RESULTS: CHRONIC ETHANOL ADMINISTRATION ALONE CAUSED AN INCREASE IN HISTONE H3 SER10 AND SER28 (H3S10 OR S28) PHOSPHORYLATION, AND BINGE ETHANOL REDUCED THEIR LEVELS. LEVELS OF DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10) INCREASED AFTER ACUTE BINGE ETHANOL AND REMAINED SAME AFTER CHRONIC ETHANOL BINGE. IN CONTRAST, HISTONE H3 LYSINE-9 ACETYLATION (H3ACK9) WAS NOT INCREASED AFTER CHRONIC ETHANOL BUT INCREASED SIGNIFICANTLY AFTER ACUTE BINGE AND CHRONIC ETHANOL BINGE. INCREASE IN HISTONE ACETYLATION WAS ACCOMPANIED BY INCREASED PHOSPHO-ERK1/2 IN THE NUCLEAR EXTRACTS. INCREASED ACETYLATION AFTER CHRONIC ETHANOL BINGE WAS ALSO ACCOMPANIED BY INCREASED PROTEIN LEVELS OF GCN5 HISTONE ACETYL TRANSFERASE AND A MODEST INCREASE IN HDAC3 IN THE NUCLEUS. HISTONE LYSINE-9 DIMETHYLATION WAS SIGNIFICANTLY INCREASED AFTER CHRONIC ETHANOL BINGE. CHRONIC ETHANOL BINGE ALSO RESULTED IN A DECREASE IN THE SAM:SAH RATIO WITH A RELATIVE DECREASE OF SAM LEVELS AND A CORRESPONDING INCREASE IN SAH LEVELS. CONCLUSIONS: ETHANOL BINGE AFTER CHRONIC ETHANOL ALTERED THE PROFILE OF SITE-SPECIFIC HISTONE MODIFICATIONS AND MAY UNDERLIE THE MECHANISM OF AUGMENTED LIVER INJURY BY CHRONIC-ETHANOL-BINGE-TREATED RATS. 2014 16 315 40 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS. 2013 17 6339 30 THE ROLE OF EPIGENETIC CHANGES IN THE PROGRESSION OF ALCOHOLIC STEATOHEPATITIS. ALCOHOLIC STEATOHEPATITIS (ASH) IS A PROGRESSION HEPATITIS WITH SEVERE FATTY LIVER AND ITS MORTALITY RATE FOR 30-DAYS IN PATIENTS ARE OVER 30%. ADDITIONALLY, ASH IS WELL KNOWN FOR ONE-FIFTH ALL ALCOHOLIC RELATED LIVER DISEASES IN THE WORLD. EXCESSIVE CHRONIC ALCOHOL CONSUMPTION IS ONE OF THE MOST COMMON CAUSES OF THE PROGRESSION OF ASH AND IS ASSOCIATED WITH POOR PROGNOSIS AND LIVER FAILURE. ALCOHOL ABUSE DYSREGULATES THE LIPID HOMEOSTASIS AND CAUSES OXIDATIVE STRESS AND INFLAMMATION IN THE LIVER. CONSEQUENTLY, METABOLIC PATHWAYS STIMULATING HEPATIC ACCUMULATION OF EXCESSIVE LIPID DROPLETS ARE INDUCED. RECENTLY, MANY STUDIES HAVE INDICATED A LINK BETWEEN ASH AND EPIGENETIC CHANGES, SHOWING DIFFERENTIAL EXPRESSION OF ALCOHOL-INDUCED EPIGENETIC GENES IN THE LIVER. HOWEVER, THE SPECIFIC MECHANISMS UNDERLYING THE PATHOGENESIS OF ASH REMAIN ELUSIVE. THUS, WE HERE SUMMARIZE THE CURRENT KNOWLEDGE ABOUT THE ROLES OF EPIGENETICS IN LIPOGENESIS, INFLAMMATION, AND APOPTOSIS IN THE CONTEXT OF ASH PATHOPHYSIOLOGY. ESPECIALLY, WE HIGHLIGHT THE LATEST FINDINGS ON THE ROLES OF SIRTUINS, A CONSERVED FAMILY OF CLASS-III HISTONE DEACETYLASES, IN ASH. ADDITIONALLY, WE DISCUSS THE INVOLVEMENT OF DNA METHYLATION, HISTONE MODIFICATIONS, AND MIRNAS IN ASH AS WELL AS THE ONGOING EFFORTS FOR THE CLINICAL TRANSLATION OF THE FINDINGS IN ASH-RELATED EPIGENETIC CHANGES. 2021 18 4683 39 NEW PERSPECTIVES ON FOLATE TRANSPORT IN RELATION TO ALCOHOLISM-INDUCED FOLATE MALABSORPTION--ASSOCIATION WITH EPIGENOME STABILITY AND CANCER DEVELOPMENT. FOLATES ARE MEMBERS OF THE B-CLASS OF VITAMINS, WHICH ARE REQUIRED FOR THE SYNTHESIS OF PURINES AND PYRIMIDINES, AND FOR THE METHYLATION OF ESSENTIAL BIOLOGICAL SUBSTANCES, INCLUDING PHOSPHOLIPIDS, DNA, AND NEUROTRANSMITTERS. FOLATES CANNOT BE SYNTHESIZED DE NOVO BY MAMMALS; HENCE, AN EFFICIENT INTESTINAL ABSORPTION PROCESS IS REQUIRED. INTESTINAL FOLATE TRANSPORT IS CARRIER-MEDIATED, PH-DEPENDENT AND ELECTRONEUTRAL, WITH SIMILAR AFFINITY FOR OXIDIZED AND REDUCED FOLIC ACID DERIVATIVES. THE VARIOUS TRANSPORTERS, I.E. REDUCED FOLATE CARRIER, PROTON-COUPLED FOLATE TRANSPORTER, FOLATE-BINDING PROTEIN, AND ORGANIC ANION TRANSPORTERS, ARE INVOLVED IN THE FOLATE TRANSPORT PROCESS IN VARIOUS TISSUES. ANY IMPAIRMENT IN UPTAKE OF FOLATE CAN LEAD TO A STATE OF FOLATE DEFICIENCY, THE MOST PREVALENT VITAMIN DEFICIENCY IN WORLD, AFFECTING 10% OF THE POPULATION IN THE USA. SUCH IMPAIRMENTS IN FOLATE TRANSPORT OCCUR IN A VARIETY OF CONDITIONS, INCLUDING CHRONIC USE OF ETHANOL, SOME INBORN HEREDITARY DISORDERS, AND CERTAIN DISEASES. AMONG THESE, ETHANOL INGESTION HAS BEEN THE MAJOR CONTRIBUTOR TO FOLATE DEFICIENCY. ETHANOL-ASSOCIATED FOLATE DEFICIENCY CAN DEVELOP BECAUSE OF DIETARY INADEQUACY, INTESTINAL MALABSORPTION, ALTERED HEPATOBILIARY METABOLISM, ENHANCED COLONIC METABOLISM, AND INCREASED RENAL EXCRETION. ETHANOL REDUCES THE INTESTINAL AND RENAL UPTAKE OF FOLATE BY ALTERING THE BINDING AND TRANSPORT KINETICS OF FOLATE TRANSPORT SYSTEMS. ALSO, ETHANOL REDUCES THE EXPRESSION OF FOLATE TRANSPORTERS IN BOTH INTESTINE AND KIDNEY, AND THIS MIGHT BE A CONTRIBUTING FACTOR FOR FOLATE MALABSORPTION, LEADING TO FOLATE DEFICIENCY. THE MAINTENANCE OF INTRACELLULAR FOLATE HOMEOSTASIS IS ESSENTIAL FOR THE ONE-CARBON TRANSFER REACTIONS NECESSARY FOR DNA SYNTHESIS AND BIOLOGICAL METHYLATION REACTIONS. DNA METHYLATION IS AN IMPORTANT EPIGENETIC DETERMINANT IN GENE EXPRESSION, IN THE MAINTENANCE OF DNA INTEGRITY AND STABILITY, IN CHROMOSOMAL MODIFICATIONS, AND IN THE DEVELOPMENT OF MUTATIONS. ETHANOL, A TOXIN THAT IS CONSUMED REGULARLY, HAS BEEN FOUND TO AFFECT THE METHYLATION OF DNA. IN ADDITION TO ITS EFFECT ON DNA METHYLATION DUE TO FOLATE DEFICIENCY, ETHANOL COULD DIRECTLY EXERT ITS EFFECT THROUGH ITS INTERACTION WITH ONE-CARBON METABOLISM, IMPAIRMENT OF METHYL GROUP SYNTHESIS, AND AFFECTING THE ENZYMES REGULATING THE SYNTHESIS OF S-ADENOSYLMETHIONINE, THE PRIMARY METHYL GROUP DONOR FOR MOST BIOLOGICAL METHYLATION REACTIONS. THUS, ETHANOL PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SEVERAL DISEASES THROUGH ITS POTENTIAL ABILITY TO MODULATE THE METHYLATION OF BIOLOGICAL MOLECULES. THIS REVIEW DISCUSSES THE UNDERLYING MECHANISM OF FOLATE MALABSORPTION IN ALCOHOLISM, THE MECHANISM OF METHYLATION-ASSOCIATED SILENCING OF GENES, AND HOW THE INTERACTION BETWEEN ETHANOL AND FOLATE DEFICIENCY AFFECTS THE METHYLATION OF GENES, THEREBY MODULATING EPIGENOME STABILITY AND THE RISK OF CANCER. 2009 19 4709 31 NON-ALCOHOLIC FATTY LIVER DISEASE AND ALCOHOL-RELATED LIVER DISEASE: TWO INTERTWINED ENTITIES. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE, WITH A PREVALENCE OF 25-30%. SINCE ITS FIRST DESCRIPTION IN 1980, NAFLD HAS BEEN CONCEIVED AS A DIFFERENT ENTITY FROM ALCOHOL-RELATED FATTY LIVER DISEASE (ALD), DESPITE THAT, BOTH DISEASES HAVE AN OVERLAP IN THE PATHOPHYSIOLOGY, SHARE GENETIC-EPIGENETIC FACTORS, AND FREQUENTLY COEXIST. BOTH ENTITIES ARE CHARACTERIZED BY A BROAD SPECTRUM OF HISTOLOGICAL FEATURES RANGING FROM ISOLATED STEATOSIS TO STEATOHEPATITIS AND CIRRHOSIS. DISTINCTION BETWEEN NAFLD AND ALD IS BASED ON THE AMOUNT OF CONSUMED ALCOHOL, WHICH HAS BEEN ARBITRARILY ESTABLISHED. IN THIS CONTEXT, A PROPOSAL OF POSITIVE CRITERIA FOR NAFLD DIAGNOSIS NOT CONSIDERING EXCLUSION OF ALCOHOL CONSUMPTION AS A PREREQUISITE CRITERION FOR DIAGNOSIS HAD EMERGED, RECOGNIZING THE POSSIBILITY OF A DUAL ETIOLOGY OF FATTY LIVER IN SOME INDIVIDUALS. THE IMPACT OF MODERATE ALCOHOL USE ON THE SEVERITY OF NAFLD IS ILL-DEFINED. SOME STUDIES SUGGEST PROTECTIVE EFFECTS IN MODERATE DOSES, BUT CURRENT EVIDENCE SHOWS THAT THERE IS NO SAFE THRESHOLD FOR ALCOHOL CONSUMPTION FOR NAFLD. IN FACT, GIVEN THE SYNERGISTIC EFFECT BETWEEN ALCOHOL CONSUMPTION, OBESITY, AND METABOLIC DYSFUNCTION, IT IS LIKELY THAT ALCOHOL USE SERVES AS A SIGNIFICANT RISK FACTOR FOR THE PROGRESSION OF LIVER DISEASE IN NAFLD AND METABOLIC SYNDROME. THIS ALSO AFFECTS THE INCIDENCE OF HEPATOCELLULAR CARCINOMA. IN THIS REVIEW, WE SUMMARIZE THE OVERLAPPING PATHOPHYSIOLOGY OF NAFLD AND ALD, THE CURRENT DATA ON ALCOHOL CONSUMPTION IN PATIENTS WITH NAFLD, AND THE EFFECTS OF METABOLIC DYSFUNCTION AND OVERWEIGHT IN ALD. 2020 20 872 34 CHRONIC ALCOHOL EXPOSURE DIFFERENTIALLY ALTERS ONE-CARBON METABOLISM IN RAT LIVER AND BRAIN. BACKGROUND: EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION PLAY AN IMPORTANT ROLE IN REGULATING THE PATHOPHYSIOLOGY OF ALCOHOLISM. CHRONIC ALCOHOL EXPOSURE LEADS TO BEHAVIORAL CHANGES AS WELL AS DECREASED EXPRESSION OF GENES ASSOCIATED WITH SYNAPTIC PLASTICITY. IN THE LIVER, IT HAS BEEN DOCUMENTED THAT CHRONIC ALCOHOL EXPOSURE IMPAIRS METHIONINE SYNTHASE (MS) ACTIVITY LEADING TO A DECREASE IN S-ADENOSYL METHIONINE/S-ADENOSYL HOMOCYSTEINE (SAM/SAH) RATIO WHICH RESULTS IN DNA HYPOMETHYLATION; HOWEVER, IT IS NOT KNOWN WHETHER SIMILAR ALTERATIONS OF SAM AND SAH LEVELS ARE ALSO PRODUCED IN BRAIN. METHODS: MALE ADULT SPRAGUE DAWLEY RATS WERE FED CHRONICALLY WITH LIEBER-DECARLI ETHANOL (ETOH) (9% V/V) OR CONTROL DIET. THE ETOH-DIET-FED RATS WERE WITHDRAWN FOR 0 AND 24 HOURS. THE CEREBELLUM AND LIVER TISSUES WERE DISSECTED AND USED TO INVESTIGATE CHANGES IN ONE-CARBON METABOLISM, SAM, AND SAH LEVELS. RESULTS: WE FOUND THAT CHRONIC ETOH EXPOSURE DECREASED SAM LEVELS, SAM/SAH RATIO, MS, METHYLENE TETRAHYDROFOLATE REDUCTASE, AND BETAINE HOMOCYSTEINE METHYLTRANSFERASE (BHMT) EXPRESSION AND INCREASED METHIONINE ADENOSYLTRANSFERASE-2B (MAT2B) BUT NOT MAT2A EXPRESSION IN THE LIVER. IN CONTRAST, CHRONIC ETOH EXPOSURE DECREASED SAH LEVELS, INCREASED SAM/SAH RATIO AND THE EXPRESSION OF MAT2A AND S-ADENOSYL HOMOCYSTEINE HYDROLASE, WHILE THE LEVELS OF SAM OR BHMT EXPRESSION IN CEREBELLUM REMAINED UNALTERED. HOWEVER, IN BOTH LIVER AND CEREBELLUM, CHRONIC ETOH EXPOSURE DECREASED THE EXPRESSION OF MS AND INCREASED MAT2B EXPRESSION. ALL CHRONIC ETOH-INDUCED CHANGES OF ONE-CARBON METABOLISM IN CEREBELLUM, BUT NOT LIVER, RETURNED TO NEAR-NORMAL LEVELS DURING ETOH WITHDRAWAL. CONCLUSIONS: THESE RESULTS INDICATE A DECREASED "METHYLATION INDEX" IN LIVER AND AN INCREASED "METHYLATION INDEX" IN CEREBELLUM. THE OPPOSING CHANGES OF THE "METHYLATION INDEX" SUGGEST ALTERED DNA METHYLATION IN LIVER AND CEREBELLUM, THUS IMPLICATING ONE-CARBON METABOLISM IN THE PATHOPHYSIOLOGY OF ALCOHOLISM. 2017