1 4574 128 MYOCARDIN-RELATED TRANSCRIPTION FACTOR A EPIGENETICALLY REGULATES RENAL FIBROSIS IN DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY (DN) IS ONE OF THE MOST COMMON COMPLICATIONS ASSOCIATED WITH DIABETES AND CHARACTERIZED BY RENAL MICROVASCULAR INJURY ALONG WITH ACCELERATED SYNTHESIS OF EXTRACELLULAR MATRIX PROTEINS CAUSING TUBULOINTERSTITIAL FIBROSIS. PRODUCTION OF TYPE I COLLAGEN, THE MAJOR COMPONENT OF EXTRACELLULAR MATRIX, IS AUGMENTED DURING RENAL FIBROSIS AFTER CHRONIC EXPOSURE TO HYPERGLYCEMIA. HOWEVER, THE TRANSCRIPTIONAL MODULATOR RESPONSIBLE FOR THE EPIGENETIC MANIPULATION LEADING TO INDUCTION OF TYPE I COLLAGEN GENES IS NOT CLEARLY DEFINED. WE SHOW HERE THAT TUBULOINTERSTITIAL FIBROSIS AS A RESULT OF DN WAS DIMINISHED IN MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A) -DEFICIENT MICE. IN CULTURED RENAL TUBULAR EPITHELIAL CELLS AND THE KIDNEYS OF MICE WITH DN, MRTF-A WAS INDUCED BY GLUCOSE AND SYNERGIZED WITH GLUCOSE TO ACTIVATE COLLAGEN TRANSCRIPTION. NOTABLY, MRTF-A SILENCING LED TO THE DISAPPEARANCE OF PROMINENT HISTONE MODIFICATIONS INDICATIVE OF TRANSCRIPTIONAL ACTIVATION, INCLUDING ACETYLATED HISTONE H3K18/K27 AND TRIMETHYLATED HISTONE H3K4. DETAILED ANALYSIS REVEALED THAT MRTF-A RECRUITED P300, A HISTONE ACETYLTRANSFERASE, AND WD REPEAT-CONTAINING PROTEIN 5 (WDR5), A KEY COMPONENT OF THE HISTONE H3K4 METHYLTRANSFERASE COMPLEX, TO THE COLLAGEN PROMOTERS AND ENGAGED THESE PROTEINS IN TRANSCRIPTIONAL ACTIVATION. ESTRADIOL SUPPRESSED COLLAGEN PRODUCTION BY DAMPENING THE EXPRESSION AND BINDING ACTIVITY OF MRTF-A AND INTERFERING WITH THE INTERACTION BETWEEN P300 AND WDR5 IN RENAL EPITHELIAL CELLS. THEREFORE, TARGETING THE MRTF-A-ASSOCIATED EPIGENETIC MACHINERY MIGHT YIELD INTERVENTIONAL STRATEGIES AGAINST DN-ASSOCIATED RENAL FIBROSIS. 2015 2 4506 37 MRTF-A MEDIATES LPS-INDUCED PRO-INFLAMMATORY TRANSCRIPTION BY INTERACTING WITH THE COMPASS COMPLEX. CHRONIC INFLAMMATION UNDERSCORES THE PATHOGENESIS OF A RANGE OF HUMAN DISEASES. LIPOPOLYSACCHARIDE (LPS) ELICITS STRONG PRO-INFLAMMATORY RESPONSES IN MACROPHAGES THROUGH THE TRANSCRIPTION FACTOR NF-KAPPAB. THE EPIGENETIC MECHANISM UNDERLYING LPS-INDUCED PRO-INFLAMMATORY TRANSCRIPTION IS NOT FULLY UNDERSTOOD. HEREIN, WE DESCRIBE A ROLE FOR MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A, ALSO KNOWN AS MKL1) IN THIS PROCESS. MRTF-A OVEREXPRESSION ENHANCED NF-KAPPAB-DEPENDENT PRO-INFLAMMATORY TRANSCRIPTION, WHEREAS MRTF-A SILENCING INHIBITED THIS PROCESS. MRTF-A DEFICIENCY ALSO REDUCED THE SYNTHESIS OF PRO-INFLAMMATORY MEDIATORS IN A MOUSE MODEL OF COLITIS. LPS PROMOTED THE RECRUITMENT OF MRTF-A TO THE PROMOTERS OF PRO-INFLAMMATORY GENES IN AN NF-KAPPAB-DEPENDENT MANNER. RECIPROCALLY, MRTF-A INFLUENCED THE NUCLEAR ENRICHMENT AND TARGET BINDING OF NF-KAPPAB. MECHANISTICALLY, MRTF-A WAS NECESSARY FOR THE ACCUMULATION OF ACTIVE HISTONE MODIFICATIONS ON NF-KAPPAB TARGET PROMOTERS BY COMMUNICATING WITH THE HISTONE H3K4 METHYLTRANSFERASE COMPLEX (COMPASS). SILENCING OF INDIVIDUAL MEMBERS OF COMPASS, INCLUDING ASH2, WDR5 AND SET1 (ALSO KNOWN AS SETD1A), DOWNREGULATED THE PRODUCTION OF PRO-INFLAMMATORY MEDIATORS AND IMPAIRED THE NF-KAPPAB KINETICS. IN SUMMARY, OUR WORK HAS UNCOVERED A PREVIOUSLY UNKNOWN FUNCTION FOR MRTF-A AND PROVIDED INSIGHTS INTO THE RATIONALIZED DEVELOPMENT OF ANTI-INFLAMMATORY THERAPEUTIC STRATEGIES. 2014 3 333 19 ALTERATION OF PTGS2 PROMOTER METHYLATION IN CHRONIC PERIODONTITIS. LEVELS OF PROSTAGLANDIN E(2) AND THE PROSTAGLANDIN-ENDOPEROXIDE SYNTHASE-2 (PTGS2, OR COX-2) INCREASE IN ACTIVELY PROGRESSING PERIODONTAL LESIONS, BUT DECREASE IN CHRONIC DISEASE. WE HYPOTHESIZED THAT CHRONIC INFLAMMATION IS ASSOCIATED WITH ALTERED DNA METHYLATION LEVELS WITHIN THE PTGS2 PROMOTER, WITH EFFECTS ON COX-2 MRNA EXPRESSION. PTGS2 PROMOTER METHYLATION LEVELS FROM PERIODONTALLY INFLAMED GINGIVAL BIOPSIES SHOWED A 5.06-FOLD INCREASE AS COMPARED WITH NON-INFLAMED SAMPLES (P = 0.03), AND THE ODDS OF METHYLATION IN A CPG SITE IN THE INFLAMED GINGIVAL GROUP IS 4.46 TIMES HIGHER THAN IN THE SAME SITE IN THE NON-INFLAMED GROUP (P = 0.016). THE LEVEL OF METHYLATION AT -458 BP WAS INVERSELY ASSOCIATED WITH TRANSCRIPTIONAL LEVELS OF PTGS2 (RT-PCR) (P = 0.01). ANALYSIS OF THE DATA SUGGESTS THAT, IN CHRONICALLY INFLAMED TISSUES, THERE IS A HYPERMETHYLATION PATTERN OF THE PTGS2 PROMOTER IN ASSOCIATION WITH A LOWER LEVEL OF PTGS2 TRANSCRIPTION, CONSISTENT WITH A DAMPENING OF COX-2 EXPRESSION IN CHRONIC PERIODONTITIS. THESE FINDINGS SUGGEST THAT THE CHRONIC PERSISTENCE OF THE BIOFILM AND INFLAMMATION MAY BE ASSOCIATED WITH EPIGENETIC CHANGES IN LOCAL TISSUES AT THE BIOFILM-GINGIVAL INTERFACE. 2010 4 5654 21 SEX, NUTRITION, AND NAFLD: RELEVANCE OF ENVIRONMENTAL POLLUTION. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON FORM OF CHRONIC LIVER DISEASE AND REPRESENTS AN INCREASING PUBLIC HEALTH ISSUE GIVEN THE LIMITED TREATMENT OPTIONS AND ITS ASSOCIATION WITH SEVERAL OTHER METABOLIC AND INFLAMMATORY DISORDERS. THE EPIDEMIC, STILL GROWING PREVALENCE OF NAFLD WORLDWIDE CANNOT BE MERELY EXPLAINED BY CHANGES IN DIET AND LIFESTYLE THAT OCCURRED IN THE LAST FEW DECADES, NOR FROM THEIR ASSOCIATION WITH GENETIC AND EPIGENETIC RISK FACTORS. IT IS CONCEIVABLE THAT ENVIRONMENTAL POLLUTANTS, WHICH ACT AS ENDOCRINE AND METABOLIC DISRUPTORS, MAY CONTRIBUTE TO THE SPREADING OF THIS PATHOLOGY DUE TO THEIR ABILITY TO ENTER THE FOOD CHAIN AND BE INGESTED THROUGH CONTAMINATED FOOD AND WATER. GIVEN THE STRICT INTERPLAY BETWEEN NUTRIENTS AND THE REGULATION OF HEPATIC METABOLISM AND REPRODUCTIVE FUNCTIONS IN FEMALES, POLLUTANT-INDUCED METABOLIC DYSFUNCTIONS MAY BE OF PARTICULAR RELEVANCE FOR THE FEMALE LIVER, DAMPENING SEX DIFFERENCES IN NAFLD PREVALENCE. DIETARY INTAKE OF ENVIRONMENTAL POLLUTANTS CAN BE PARTICULARLY DETRIMENTAL DURING GESTATION, WHEN ENDOCRINE-DISRUPTING CHEMICALS MAY INTERFERE WITH THE PROGRAMMING OF LIVER METABOLISM, ACCOUNTING FOR THE DEVELOPMENTAL ORIGIN OF NAFLD IN OFFSPRING. THIS REVIEW SUMMARIZES CAUSE-EFFECT EVIDENCE BETWEEN ENVIRONMENTAL POLLUTANTS AND INCREASED INCIDENCE OF NAFLD AND EMPHASIZES THE NEED FOR FURTHER STUDIES IN THIS FIELD. 2023 5 6520 27 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF MONOCYTE AND MACROPHAGE DYSFUNCTION BY CHRONIC ALCOHOL CONSUMPTION. DRINKING ALCOHOL, EVEN IN MODERATION, CAN AFFECT THE IMMUNE SYSTEM. STUDIES HAVE SHOWN DISPROPORTIONATE EFFECTS OF ALCOHOL ON CIRCULATING AND TISSUE-RESIDENT MYELOID CELLS (GRANULOCYTES, MONOCYTES, MACROPHAGES, DENDRITIC CELLS). THESE CELLS ORCHESTRATE THE BODY'S FIRST LINE OF DEFENSE AGAINST MICROBIAL CHALLENGES AS WELL AS MAINTAIN TISSUE HOMEOSTASIS AND REPAIR. ALCOHOL'S EFFECTS ON THESE CELLS ARE DEPENDENT ON EXPOSURE PATTERN, WITH ACUTE DRINKING DAMPENING BUT CHRONIC DRINKING ENHANCING PRODUCTION OF INFLAMMATORY MEDIATORS. ALTHOUGH CHRONIC DRINKING IS ASSOCIATED WITH HEIGHTENED SYSTEMIC INFLAMMATION, STUDIES ON TISSUE RESIDENT MACROPHAGE POPULATIONS IN SEVERAL ORGANS INCLUDING THE SPLEEN, LIVER, BRAIN, AND LUNG HAVE ALSO SHOWN COMPROMISED FUNCTIONAL AND METABOLIC CAPACITIES OF THESE CELLS. MANY OF THESE EFFECTS ARE THOUGHT TO BE MEDIATED BY OXIDATIVE STRESS CAUSED BY ALCOHOL AND ITS METABOLITES WHICH CAN DIRECTLY IMPACT THE CELLULAR EPIGENETIC LANDSCAPES. IN ADDITION, SINCE MYELOID CELLS ARE RELATIVELY SHORT-LIVED IN CIRCULATION AND ARE UNDER CONSTANT REPOPULATION FROM THE BONE MARROW COMPARTMENT, ALCOHOL'S EFFECTS ON BONE MARROW PROGENITORS AND HEMATOPOIESIS ARE IMPORTANT FOR UNDERSTANDING THE IMPACT OF ALCOHOL SYSTEMICALLY ON THESE MYELOID POPULATIONS. ALCOHOL-INDUCED DISRUPTION OF PROGENITOR, CIRCULATING, AND TISSUE RESIDENT MYELOID POPULATIONS CONTRIBUTE TO THE INCREASED SUSCEPTIBILITY OF PATIENTS WITH ALCOHOL USE DISORDERS TO VIRAL AND BACTERIAL INFECTIONS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE IMPACT OF CHRONIC ALCOHOL CONSUMPTION ON THE FUNCTION OF MONOCYTES AND MACROPHAGES IN HOST DEFENSE, TISSUE REPAIR AND INFLAMMATION. WE THEN SUMMARIZE OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING ALCOHOL-INDUCED DISRUPTION AND EXAMINE CHANGES IN TRANSCRIPTOME AND EPIGENOME OF MONOCYTES AND MCROPHAGES. OVERALL, CHRONIC ALCOHOL CONSUMPTION LEADS TO HYPER-INFLAMMATION CONCOMITANT WITH DECREASED MICROBIAL AND WOUND HEALING RESPONSES BY MONOCYTES/MACROPHAGES DUE TO A REWIRING OF THE EPIGENTIC AND TRANSCRIPTIONAL LANDSCAPE. HOWEVER, IN ADVANCED ALCOHOLIC LIVER DISEASE, MYELOID CELLS BECOME IMMUNOSUPPRESSED AS A RESPONSE TO THE SURROUNDING HYPER-INFLAMMATORY MILIEU. THEREFORE, THE EFFECT OF CHRONIC ALCOHOL ON THE INFLAMMATORY RESPONSE DEPENDS ON DISEASE STATE AND THE IMMUNE CELL POPULATION. 2022 6 6384 27 THE ROLE OF POLYCARBONATE MONOMER BISPHENOL-A IN INSULIN RESISTANCE. BISPHENOL A (BPA) IS A SYNTHETIC UNIT OF POLYCARBONATE POLYMERS AND EPOXY RESINS, THE TYPES OF PLASTICS THAT COULD BE FOUND IN ESSENTIALLY EVERY HUMAN POPULATION AND INCORPORATED INTO ALMOST EVERY ASPECT OF THE MODERN HUMAN SOCIETY. BPA POLYMERS APPEAR IN A WIDE RANGE OF PRODUCTS, FROM LIQUID STORAGES (PLASTIC BOTTLES, CAN AND GLASS LININGS, WATER PIPES AND TANKS) AND FOOD STORAGES (PLASTICS WRAPS AND CONTAINERS), TO MEDICAL AND DENTAL DEVICES. BPA POLYMERS COULD BE HYDROLYZED SPONTANEOUSLY OR IN A PHOTO- OR TEMPERATURE-CATALYZED PROCESS, PROVIDING WIDESPREAD ENVIRONMENTAL DISTRIBUTION AND CHRONIC EXPOSURE TO THE BPA MONOMER IN CONTEMPORARY HUMAN POPULATIONS. BISPHENOL A IS ALSO A XENOESTROGEN, AN ENDOCRINE-DISRUPTING CHEMICAL (EDC) THAT INTERFERES WITH THE ENDOCRINE SYSTEM MIMICKING THE EFFECTS OF AN ESTROGEN AND COULD POTENTIALLY KEEP OUR ENDOCRINE SYSTEM IN A CONSTANT PERTURBATION THAT PARALLELS ENDOCRINE DISRUPTION ARISING DURING PREGNANCY, SUCH AS INSULIN RESISTANCE (IR). GESTATIONAL INSULIN RESISTANCE REPRESENTS A NATURAL BIOLOGICAL PHENOMENON OF HIGHER INSULIN RESISTANCE IN PERIPHERAL TISSUES OF THE PREGNANT FEMALES, WHEN NUTRIENTS ARE INCREASINGLY BEING DIRECTED TO THE EMBRYO INSTEAD OF BEING STORED IN PERIPHERAL TISSUES. GESTATIONAL DIABETES MELLITUS MAY APPEAR IN HEALTHY NON-DIABETIC FEMALES, DUE TO GESTATIONAL INSULIN RESISTANCE THAT LEADS TO INCREASED BLOOD SUGAR LEVELS AND HYPERINSULINEMIA (INCREASED INSULIN PRODUCTION FROM THE PANCREATIC BETA CELLS). THE HYPOTHESIS STATES THAT UNNOTICED AND CONSTANT EXPOSURE TO THIS ENVIRONMENTAL CHEMICAL MIGHT POTENTIALLY LEAD TO THE FORMATION OF CHRONIC LOW-LEVEL ENDOCRINE DISRUPTIVE STATE THAT RESEMBLES GESTATIONAL INSULIN RESISTANCE, WHICH MIGHT CONTRIBUTE TO THE DEVELOPMENT OF DIABETES. THE INCREASING BODY OF EVIDENCE SUPPORTS THE MAJOR PREMISES OF THIS HYPOTHESIS, AS EXEMPLIFIED BY THE NUMEROUS PUBLICATIONS EXAMINING THE ASSOCIATION OF BPA AND INSULIN RESISTANCE, BOTH EPIDEMIOLOGICAL AND MECHANISTIC. HOWEVER, TO WHAT EXTENT BPA MIGHT CONTRIBUTE TO THE DEVELOPMENT OF DIABETES IN THE MODERN SOCIETIES STILL REMAINS UNKNOWN. IN THIS REVIEW, I DISCUSS THE CHEMICAL PROPERTIES OF BPA AND THE SOURCES OF BPA CONTAMINATION FOUND IN THE ENVIRONMENT AND IN HUMAN TISSUES. I PROVIDE AN OVERVIEW OF MECHANISMS FOR THE PROPOSED ROLE OF BISPHENOL A IN INSULIN RESISTANCE AND DIABETES, AS WELL AS OTHER RELATED DISEASES, SUCH AS CARDIOVASCULAR DISEASES. I DESCRIBE THE TRANSMISSION OF BPA EFFECTS TO THE OFFSPRING AND POSTULATE THAT GENDER RELATED DIFFERENCES MIGHT ORIGINATE FROM DIFFERENCES IN LIVER ENZYME LEVELS, SUCH AS UDP-GLUCURONOSYLTRANSFERASE, WHICH IS INVOLVED IN BPA PROCESSING AND ITS ELIMINATION FROM THE ORGANISM. I DISCUSS THE MOLECULAR MECHANISMS OF BPA ACTION THROUGH NUCLEAR AND MEMBRANE-BOUND ER RECEPTORS, NON-MONOTONIC DOSE RESPONSE, EPIGENETIC MODIFICATIONS OF THE DNA AND PROPOSE THAT CHRONIC EXPOSURE TO WEAK BINDERS, SUCH AS BPA, MAY MIMIC THE EFFECTS OF STRONG BINDERS, SUCH AS ESTROGENS. 2017 7 3760 22 INTEGRATED SINGLE CELL ANALYSIS SHOWS CHRONIC ALCOHOL DRINKING DISRUPTS MONOCYTE DIFFERENTIATION IN THE BONE MARROW. CHRONIC HEAVY ALCOHOL DRINKING (CHD) REWIRES MONOCYTES AND MACROPHAGES TOWARD HEIGHTENED INFLAMMATORY STATES WITH COMPROMISED ANTIMICROBIAL DEFENSES THAT PERSIST AFTER 1-MONTH ABSTINENCE. TO DETERMINE WHETHER THESE CHANGES ARE MEDIATED THROUGH ALTERATIONS IN THE BONE MARROW NICHE, WE PROFILED MONOCYTES AND HEMATOPOIETIC STEM CELL PROGENITORS (HSCPS) FROM CHD RHESUS MACAQUES USING A COMBINATION OF FUNCTIONAL ASSAYS AND SINGLE CELL GENOMICS. CHD RESULTED IN TRANSCRIPTIONAL PROFILES CONSISTENT WITH INCREASED ACTIVATION AND INFLAMMATION WITHIN BONE MARROW RESIDENT MONOCYTES AND MACROPHAGES. FURTHERMORE, CHD RESULTED IN TRANSCRIPTIONAL SIGNATURES ASSOCIATED WITH INCREASED OXIDATIVE AND CELLULAR STRESS IN HSCP. DIFFERENTIATION OF HSCP IN VITRO REVEALED SKEWING TOWARD MONOCYTES EXPRESSING "NEUTROPHIL-LIKE" MARKERS WITH GREATER INFLAMMATORY RESPONSES TO BACTERIAL AGONISTS. FURTHER ANALYSES OF HSCPS SHOWED BROAD EPIGENETIC CHANGES THAT WERE IN LINE WITH EXACERBATED INFLAMMATORY RESPONSES WITHIN MONOCYTES AND THEIR PROGENITORS. IN SUMMARY, CHD ALTERS HSCPS IN THE BONE MARROW LEADING TO THE PRODUCTION OF MONOCYTES POISED TO GENERATE DYSREGULATED HYPER-INFLAMMATORY RESPONSES. 2023 8 2671 29 ETHANOL CONSUMPTION INDUCES NONSPECIFIC INFLAMMATION AND FUNCTIONAL DEFECTS IN ALVEOLAR MACROPHAGES. CHRONIC ALCOHOL DRINKING IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO VIRAL AND BACTERIAL RESPIRATORY PATHOGENS. IN THIS STUDY, WE USE A RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION TO STUDY THE EFFECTS OF LONG-TERM ALCOHOL DRINKING ON THE IMMUNOLOGICAL LANDSCAPE OF THE LUNG. WE REPORT A HEIGHTENED INFLAMMATORY STATE IN ALVEOLAR MACROPHAGES (AMS) OBTAINED FROM ETHANOL (ETOH)-DRINKING ANIMALS THAT IS ACCOMPANIED BY INCREASED CHROMATIN ACCESSIBILITY IN INTERGENIC REGIONS THAT REGULATE INFLAMMATORY GENES AND CONTAIN BINDING MOTIFS FOR TRANSCRIPTION FACTORS AP-1, IRF8, AND NFKB P-65. IN LINE WITH THESE TRANSCRIPTIONAL AND EPIGENETIC CHANGES AT THE BASAL STATE, AMS FROM ETOH-DRINKING ANIMALS GENERATE ELEVATED INFLAMMATORY MEDIATOR RESPONSES TO LIPOPOLYSACCHARIDES AND RESPIRATORY SYNCYTIAL VIRUS. HOWEVER, THE TRANSCRIPTIONAL ANALYSIS REVEALED AN INEFFICIENT INDUCTION OF INTERFERON-STIMULATED GENES WITH ETOH IN RESPONSE TO THE RESPIRATORY SYNCYTIAL VIRUS, SUGGESTING DISRUPTION OF ANTIMICROBIAL DEFENSES. CORRESPONDINGLY, AMS FROM ETOH-DRINKING ANIMALS EXHIBITED TRANSCRIPTIONAL SHIFTS INDICATIVE OF INCREASED OXIDATIVE STRESS AND OXIDATIVE PHOSPHORYLATION, WHICH WAS COUPLED WITH HIGHER CYTOSOLIC REACTIVE OXYGEN SPECIES AND MITOCHONDRIAL POTENTIAL. THIS HEIGHTENED OXIDATIVE STRESS STATE WAS ACCOMPANIED BY DECREASED ABILITY TO PHAGOCYTOSE BACTERIA. BULK RNA AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING DATA FURTHER REVEALED REDUCED EXPRESSION AND CHROMATIN ACCESSIBILITY OF LOCI ASSOCIATED WITH TISSUE REPAIR AND MAINTENANCE WITH CHRONIC ETOH DRINKING. SIMILARLY, ANALYSIS OF SINGLE-CELL RNA SEQUENCING DATA REVEALED SHIFTS IN CELL STATES FROM TISSUE MAINTENANCE TO INFLAMMATORY RESPONSES WITH ETOH. COLLECTIVELY, THESE DATA PROVIDE NOVEL INSIGHT INTO MECHANISMS BY WHICH CHRONIC ETOH DRINKING INCREASES SUSCEPTIBILITY TO INFECTION IN PATIENTS WITH ALCOHOL USE DISORDERS. 2022 9 651 32 BISPHENOL A AND PHTHALATES MODULATE PERITONEAL MACROPHAGE FUNCTION IN FEMALE MICE INVOLVING SYMD2-H3K36 DIMETHYLATION. AMPLE EVIDENCE SUGGESTS THAT ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO BISPHENOL A (BPA) AND PHTHALATE, TWO CHEMICALS WIDELY USED IN THE PLASTICS INDUSTRY, DISTURBS HOMEOSTASIS OF INNATE IMMUNITY AND CAUSES INFLAMMATORY DISEASES. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS OF THESE TOXICANTS IN THE REGULATION OF MACROPHAGE INFLAMMATORY FUNCTIONS REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE ADDRESSED THE EFFECT OF CHRONIC EXPOSURE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE, EITHER IN VITRO OR IN VIVO, ON THE INFLAMMATORY REPROGRAMING OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT BPA AND PHTHALATES ADVERSELY AFFECTED EXPRESSION LEVELS OF THE PROINFLAMMATORY CYTOKINES AND MEDIATORS IN RESPONSE TO LIPOPOLYSACCHARIDE STIMULATION. EXPOSURE TO THESE TOXICANTS ALSO AFFECTED GENE EXPRESSION OF SCAVENGER RECEPTORS AND PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT THE EPIGENETIC INHIBITORS DIFFERENTIALLY MODULATED TARGET GENE EXPRESSION IN THESE CELLS. FURTHER ANALYSIS REVEALED THAT CERTAIN HISTONE MODIFICATION ENZYMES WERE ABERRANTLY EXPRESSED IN RESPONSE TO BPA OR PHTHALATE EXPOSURE, LEADING TO ALTERATION IN THE LEVELS OF H3K36 ACETYLATION AND DIMETHYLATION, TWO CHROMATIN MODIFICATIONS THAT ARE CRITICAL FOR TRANSCRIPTIONAL EFFICACY AND ACCURACY. OUR RESULTS FURTHER REVEALED THAT SILENCING OF H3K36-SPECIFIC METHYLTRANSFERASE SMYD2 EXPRESSION OR INHIBITION OF SMYD2 ENZYMATIC ACTIVITY ATTENUATED H3K36 DIMETHYLATION AND ENHANCED INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR-ALPHA EXPRESSION BUT DAMPENED THE PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. IN SUMMARY, OUR RESULTS INDICATE THAT PERITONEAL MACROPHAGES ARE VULNERABLE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE. THESE ENVIRONMENTAL TOXICANTS AFFECT PHENOTYPIC PROGRAMMING OF MACROPHAGES VIA EPIGENETIC MECHANISMS INVOLVING SMYD2-MEDIATED H3K36 MODIFICATION. 2018 10 1919 22 ENVIRONMENTAL ENDOCRINE DISRUPTORS: NEW DIABETOGENS? THE PREVALENCE OF TYPE-2 DIABETES HAS DRAMATICALLY INCREASED WORLDWIDE DURING THE LAST FEW DECADES. WHILE LIFESTYLE FACTORS (SEDENTARINESS, NOXIOUS FOOD), TOGETHER WITH GENETIC SUSCEPTIBILITY, ARE WELL-KNOWN ACTORS, THERE IS ACCUMULATING EVIDENCE SUGGESTING THAT ENDOCRINE DISRUPTING CHEMICALS (EDCS) MAY ALSO PLAY A PATHOPHYSIOLOGICAL ROLE IN THE OCCURRENCE OF METABOLIC DISEASES. BOTH EXPERIMENTAL AND EPIDEMIOLOGICAL EVIDENCE SUPPORT A ROLE FOR EARLY AND CHRONIC EXPOSURE TO LOW DOSES OF CHEMICAL POLLUTANTS WITH ENDOCRINE AND METABOLIC DISRUPTING EFFECTS. MOST ARE PRESENT IN THE FOOD CHAIN AND ACCUMULATE IN THE FAT MASS AFTER ABSORPTION. IN RODENTS, BISPHENOL A STIMULATES SYNTHESIS AND SECRETION OF PANCREATIC BETA CELLS AND DISTURBS INSULIN SIGNALING IN LIVER, MUSCLE AND ADIPOSE TISSUE THROUGH EPIGENETIC CHANGES LEADING TO INSULIN RESISTANCE AND BETA CELL IMPAIRMENT. IN HUMANS, EPIDEMIOLOGICAL REPORTS SHOW STATISTICAL LINK BETWEEN EXPOSURE TO PESTICIDES, POLYCHLORINATED BISPHENYLS, BISPHENOL A, PHTHALATES, DIOXINS OR AROMATIC POLYCYCLIC HYDROCARBIDES OR HEAVY METALS AND DT2 AFTER ACUTE ACCIDENTAL RELEASES OR EARLY IN LIFE AND/OR CHRONIC, LOW DOSES EXPOSURE. MORE PROSPECTIVE, LONGITUDINAL STUDIES ARE NEEDED TO DETERMINE THE IMPORTANCE OF SUCH ENVIRONMENTAL RISK FACTORS. 2017 11 5079 24 PHYSIOPATHOLOGY OF NONALCOHOLIC FATTY LIVER DISEASE: FROM DIET TO NUTRIGENOMICS. PURPOSE OF REVIEW: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE AND IS STRONGLY ASSOCIATED WITH METABOLIC DISORDERS, SUCH AS OBESITY, TYPE 2 DIABETES MELLITUS, AND METABOLIC SYNDROME, TO THE EXTENT THAT A NEW DEFINITION OF METABOLIC ASSOCIATED FATTY LIVER DISEASE HAS BEEN PROPOSED. RECENT FINDINGS: INSULIN RESISTANCE, WORSENED BY A HIGH-FAT AND HIGH-CARBOHYDRATE DIET, IS THE KEY TO THE PHYSIOPATHOLOGY OF HEPATIC STEATOSIS. THIS IS DRIVEN BY SEVERAL MECHANISMS THAT ARE MOSTLY ACTIVATED AT A GENETIC LEVEL, SUCH AS DE-NOVO LIPOGENESIS AND TRIGLYCERIDE SYNTHESIS. THEREFORE, MANY DIET REGIMENS HAVE BEEN STUDIED, ALTHOUGH SIGNIFICANT CONTROVERSIES REMAIN REGARDING THEIR METABOLIC EFFECTS AND LONG-TERM SUSTAINABILITY. SUMMARY: IN THIS REVIEW, WE SUMMARIZED THE ROLE AND EFFECTS OF THE MAIN MACRONUTRIENTS ON THE DEVELOPMENT OF NAFLD AND DISCUSSED THE MOLECULAR MECHANISMS INVOLVED. WE ALSO DISCUSSED THE IMPORTANCE OF GENETIC POLYMORPHISMS, EPIGENETIC ALTERATIONS, AND DYSBIOSIS TO DETERMINE IF LIFESTYLE MODIFICATION AND A SPECIFIC DIETARY REGIMEN COULD BE AN ESSENTIAL PART OF NAFLD TREATMENT. 2022 12 2862 27 FRUCTOSE-MEDIATED EFFECTS ON GENE EXPRESSION AND EPIGENETIC MECHANISMS ASSOCIATED WITH NAFLD PATHOGENESIS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A CHRONIC, FREQUENTLY PROGRESSIVE CONDITION THAT DEVELOPS IN RESPONSE TO EXCESSIVE HEPATOCYTE FAT ACCUMULATION (I.E., STEATOSIS) IN THE ABSENCE OF SIGNIFICANT ALCOHOL CONSUMPTION. LIVER STEATOSIS DEVELOPS AS A RESULT OF IMBALANCED LIPID METABOLISM, DRIVEN LARGELY BY INCREASED RATES OF DE NOVO LIPOGENESIS AND HEPATIC FATTY ACID UPTAKE AND REDUCED FATTY ACID OXIDATION AND/OR DISPOSAL TO THE CIRCULATION. FRUCTOSE IS A NATURALLY OCCURRING SIMPLE SUGAR, WHICH IS MOST COMMONLY CONSUMED IN MODERN DIETS IN THE FORM OF SUCROSE, A DISACCHARIDE COMPRISED OF ONE MOLECULE OF FRUCTOSE COVALENTLY BONDED WITH ONE MOLECULE OF GLUCOSE. A NUMBER OF OBSERVATIONAL AND EXPERIMENTAL STUDIES HAVE DEMONSTRATED DETRIMENTAL EFFECTS OF DIETARY FRUCTOSE CONSUMPTION NOT ONLY ON DIVERSE METABOLIC OUTCOMES SUCH AS INSULIN RESISTANCE AND OBESITY, BUT ALSO ON HEPATIC STEATOSIS AND NAFLD-RELATED FIBROSIS. DESPITE THE COMPELLING EVIDENCE THAT EXCESSIVE FRUCTOSE CONSUMPTION IS ASSOCIATED WITH THE PRESENCE OF NAFLD AND MAY EVEN PROMOTE THE DEVELOPMENT AND PROGRESSION OF NAFLD TO MORE CLINICALLY SEVERE PHENOTYPES, THE MOLECULAR MECHANISMS BY WHICH FRUCTOSE ELICITS EFFECTS ON DYSREGULATED LIVER METABOLISM REMAIN UNCLEAR. EMERGING DATA SUGGEST THAT DIETARY FRUCTOSE MAY DIRECTLY ALTER THE EXPRESSION OF GENES INVOLVED IN LIPID METABOLISM, INCLUDING THOSE THAT INCREASE HEPATIC FAT ACCUMULATION OR REDUCE HEPATIC FAT REMOVAL. THE AIM OF THIS REVIEW IS TO SUMMARIZE THE CURRENT RESEARCH SUPPORTING A ROLE FOR DIETARY FRUCTOSE INTAKE IN THE MODULATION OF TRANSCRIPTOMIC AND EPIGENETIC MECHANISMS UNDERLYING THE PATHOGENESIS OF NAFLD. 2020 13 4711 21 NON-ALCOHOLIC FATTY LIVER DISEASE IN OBESE CHILDREN AND ADOLESCENTS: A ROLE FOR NUTRITION? NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS BECOME THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE IN CHILDREN, PARALLELING THE INCREASING PREVALENCE OF OBESITY WORLDWIDE. THE PATHOGENESIS OF PAEDIATRIC NAFLD IS NOT FULLY UNDERSTOOD, BUT IT IS KNOWN THAT OBESITY, NUTRITION, LIFESTYLE VARIABLES, GENETIC AND EPIGENETIC FACTORS MAY BE CAUSALLY INVOLVED IN THE DEVELOPMENT OF THIS COMMON METABOLIC LIVER DISEASE. IN PARTICULAR, OBESITY AND NUTRITION ARE AMONG THE STRONGEST RISK FACTORS FOR PAEDIATRIC NAFLD, WHICH MAY EXERT THEIR ADVERSE HEPATIC EFFECTS ALREADY BEFORE BIRTH. EXCESS ENERGY INTAKE INDUCES HYPERTROPHY AND HYPERPLASIA OF ADIPOSE TISSUE WITH SUBSEQUENT DEVELOPMENT OF SYSTEMIC INSULIN RESISTANCE, WHICH IS ANOTHER IMPORTANT RISK FACTOR FOR NAFLD. DIET COMPOSITION AND IN PARTICULAR SIMPLE CARBOHYDRATE INTAKE (ESPECIALLY HIGH FRUCTOSE INTAKE) MAY PROMOTE THE DEVELOPMENT OF NAFLD, WHEREAS NON-DIGESTIBLE CARBOHYDRATES (DIETARY FIBER), BY AFFECTING GUT MICROBIOTA, MAY FAVOUR THE INTEGRITY OF GUT WALL AND REDUCE INFLAMMATION, OPPOSING THIS PROCESS. SATURATED FAT INTAKE MAY ALSO PROMOTE NAFLD DEVELOPMENT, WHEREAS UNSATURATED FAT INTAKE HAS SOME BENEFICIAL EFFECTS. PROTEIN INTAKE DOES NOT SEEM TO AFFECT THE DEVELOPMENT OF NAFLD, BUT FURTHER INVESTIGATION IS NEEDED. IN CONCLUSION, LIFESTYLE MODIFICATIONS TO INDUCE WEIGHT LOSS, THROUGH DIET AND PHYSICAL ACTIVITY, REMAIN THE MAINSTAY OF TREATMENT FOR PAEDIATRIC NAFLD. THE USE OF DIETARY SUPPLEMENTS, SUCH AS OMEGA-3 FATTY ACIDS AND PROBIOTICS, NEEDS FURTHER STUDY BEFORE RECOMMENDATION. 2022 14 987 30 CHRONIC SCHISTOSOMIASIS DURING PREGNANCY EPIGENETICALLY REPROGRAMS T-CELL DIFFERENTIATION IN OFFSPRING OF INFECTED MOTHERS. SCHISTOSOMIASIS IS A NONTRANSPLACENTAL HELMINTH INFECTION. CHRONIC INFECTION DURING PREGNANCY SUPPRESSES ALLERGIC AIRWAY RESPONSES IN OFFSPRING. WE ADDRESSED THE QUESTION WHETHER IN UTERO EXPOSURE TO CHRONIC SCHISTOSOME INFECTION (REG PHASE) IN MICE AFFECTS B-CELL AND T-CELL DEVELOPMENT. THEREFORE, WE FOCUSED OUR ANALYSES ON T-CELL DIFFERENTIATION CAPACITY INDUCED BY EPIGENETIC CHANGES IN PROMOTER REGIONS OF SIGNATURE CYTOKINES IN OFFSPRING. HERE, WE SHOW THAT NAIVE T CELLS FROM OFFSPRING OF SCHISTOSOME INFECTED FEMALE MICE HAD A STRONG CAPACITY TO DIFFERENTIATE INTO T(H) 1 CELLS, WHEREAS T(H) 2 DIFFERENTIATION WAS IMPAIRED. IN ACCORDANCE, REDUCED LEVELS OF HISTONE ACETYLATION OF THE IL-4 PROMOTER REGIONS WERE OBSERVED IN NAIVE T CELLS. TO CONCLUDE, OUR MOUSE MODEL REVEALED DISTINCT EPIGENETIC CHANGES WITHIN THE NAIVE T-CELL COMPARTMENT AFFECTING T(H) 2 AND T(H) 1 CELL DIFFERENTIATION IN OFFSPRING OF MOTHERS WITH CHRONIC HELMINTH INFECTION. THESE FINDINGS COULD EVENTUALLY HELP UNDERSTAND HOW HELMINTHS ALTER T-CELL DRIVEN IMMUNE RESPONSES INDUCED BY ALLERGENS, BACTERIAL OR VIRAL INFECTIONS, AS WELL AS VACCINES. 2017 15 3759 23 INTEGRATED SINGLE CELL ANALYSIS SHOWS CHRONIC ALCOHOL DRINKING DISRUPTS MONOCYTE DIFFERENTIATION IN THE BONE MARROW NICHE. CHRONIC ALCOHOL DRINKING REWIRES CIRCULATING MONOCYTES AND TISSUE-RESIDENT MACROPHAGES TOWARDS HEIGHTENED INFLAMMATORY STATES WITH COMPROMISED ANTI-MICROBIAL DEFENSES. AS THESE EFFECTS REMAIN CONSISTENT IN SHORT-LIVED MONOCYTES AFTER A 1-MONTH ABSTINENCE PERIOD IT IS UNCLEAR WHETHER THESE CHANGES ARE RESTRICTED TO THE PERIPHERY OR MEDIATED THROUGH ALTERATIONS IN THE PROGENITOR NICHE. TO TEST THIS HYPOTHESIS, WE PROFILED MONOCYTES/MACROPHAGES AND HEMATOPOIETIC STEM CELL PROGENITORS (HSCP) OF THE BONE MARROW COMPARTMENT FROM RHESUS MACAQUES AFTER 12 MONTHS OF ETHANOL CONSUMPTION USING A COMBINATION OF FUNCTIONAL ASSAYS AND SINGLE CELL GENOMICS. BONE MARROW-RESIDENT MONOCYTES/MACROPHAGES FROM ETHANOL-CONSUMING ANIMALS EXHIBITED HEIGHTENED INFLAMMATION. DIFFERENTIATION OF HSCP IN VITRO REVEALED SKEWING TOWARDS MONOCYTES EXPRESSING NEUTROPHIL-LIKE MARKERS WITH HEIGHTENED INFLAMMATORY RESPONSES TO BACTERIAL AGONISTS. SINGLE CELL TRANSCRIPTIONAL ANALYSIS OF HSCPS SHOWED REDUCED PROLIFERATION BUT INCREASED INFLAMMATORY MARKERS IN MATURE MYELOID PROGENITORS. WE OBSERVED TRANSCRIPTIONAL SIGNATURES ASSOCIATED WITH INCREASED OXIDATIVE AND CELLULAR STRESS AS WELL AS OXIDATIVE PHOSPHORYLATION IN IMMATURE AND MATURE MYELOID PROGENITORS. SINGLE CELL ANALYSIS OF THE CHROMATIN LANDSCAPE SHOWED ALTERED DRIVERS OF DIFFERENTIATION IN MONOCYTES AND PROGENITORS. COLLECTIVELY, THESE DATA INDICATE THAT CHRONIC ETHANOL DRINKING RESULTS IN REMODELING OF THE TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPES OF THE BONE MARROW COMPARTMENT LEADING TO ALTERED FUNCTIONS IN THE PERIPHERY. 2023 16 4455 27 MOLECULAR MECHANISMS FOR THE VICIOUS CYCLE BETWEEN INSULIN RESISTANCE AND THE INFLAMMATORY RESPONSE IN OBESITY. THE COMPREHENSIVE ANABOLIC EFFECTS OF INSULIN THROUGHOUT THE BODY, IN ADDITION TO THE CONTROL OF GLYCEMIA, INCLUDE ENSURING LIPID HOMEOSTASIS AND ANTI-INFLAMMATORY MODULATION, ESPECIALLY IN ADIPOSE TISSUE (AT). THE PREVALENCE OF OBESITY, DEFINED AS A BODY MASS INDEX (BMI) >/= 30 KG/M(2), HAS BEEN INCREASING WORLDWIDE ON A PANDEMIC SCALE WITH ACCOMPANYING SYNDEMIC HEALTH PROBLEMS, INCLUDING GLUCOSE INTOLERANCE, INSULIN RESISTANCE (IR), AND DIABETES. IMPAIRED TISSUE SENSITIVITY TO INSULIN OR IR PARADOXICALLY LEADS TO DISEASES WITH AN INFLAMMATORY COMPONENT DESPITE HYPERINSULINEMIA. THEREFORE, AN EXCESS OF VISCERAL AT IN OBESITY INITIATES CHRONIC LOW-GRADE INFLAMMATORY CONDITIONS THAT INTERFERE WITH INSULIN SIGNALING VIA INSULIN RECEPTORS (INSRS). MOREOVER, IN RESPONSE TO IR, HYPERGLYCEMIA ITSELF STIMULATES A PRIMARILY DEFENSIVE INFLAMMATORY RESPONSE ASSOCIATED WITH THE SUBSEQUENT RELEASE OF NUMEROUS INFLAMMATORY CYTOKINES AND A REAL THREAT OF ORGAN FUNCTION DETERIORATION. IN THIS REVIEW, ALL COMPONENTS OF THIS VICIOUS CYCLE ARE CHARACTERIZED WITH PARTICULAR EMPHASIS ON THE INTERPLAY BETWEEN INSULIN SIGNALING AND BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSES RELATED TO OBESITY. INCREASED VISCERAL AT ACCUMULATION IN OBESITY SHOULD BE CONSIDERED THE MAIN ENVIRONMENTAL FACTOR RESPONSIBLE FOR THE DISRUPTION IN THE EPIGENETIC REGULATORY MECHANISMS IN THE IMMUNE SYSTEM, RESULTING IN AUTOIMMUNITY AND INFLAMMATION. 2023 17 1721 21 DYSREGULATION OF AUTOPHAGY ACTS AS A PATHOGENIC MECHANISM OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) INDUCED BY COMMON ENVIRONMENTAL POLLUTANTS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS BEEN THE MOST COMMON CHRONIC LIVER DISEASE IN THE WORLD, INCLUDING THE DEVELOPING COUNTRIES. NAFLD IS METABOLIC DISEASE WITH SIGNIFICANT LIPID DEPOSITION IN THE HEPATOCYTES OF THE LIVER, WHICH IS USUALLY ASSOCIATED WITH OXIDATIVE STRESS, INFLAMMATION AND FIBROGENESIS, AND INSULIN RESISTANCE. PROGRESSIVE NAFLD CAN DEVELOP INTO NON-ALCOHOLIC STEATOHEPATITIS (NASH) OR HEPATOCELLULAR CARCINOMA. THE CURRENT EVIDENCE PROPOSES THAT ENVIRONMENTAL POLLUTANTS PROMOTE DEVELOPMENT AND PROGRESSION OF NAFLD, AND AUTOPHAGY PLAYS A VITAL ROLE BUT IS MULTIFACTORIAL AFFECTED IN NAFLD. IN THIS REVIEW, WE ANALYZED ON THE REGULATIONS OF COMMON ENVIRONMENTAL POLLUTANTS ON AUTOPHAGY IN NAFLD. TO CLARIFY THE INVOLVED ROLES OF AUTOPHAGY, WE DISCUSSED THE DYSREGULATION OF AUTOPHAGY BY ENVIRONMENTAL POLLUTANTS IN ADIPOSE TISSUE AND GUT, AND THEIR INTERACTIONS WITH LIVER, AS WELL AS EPIGENETIC REGULATION ON AUTOPHAGY BY ENVIRONMENTAL POLLUTANTS. FURTHERMORE, PROTECTIVE ROLES OF POTENTIAL THERAPEUTIC TREATMENTS ON THE MULTIPLE-HITS OF AUTOPHAGY IN NAFLD WERE DESCRIPTED. 2021 18 4464 24 MOLECULAR MECHANISMS OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)/NONALCOHOLIC STEATOHEPATITIS (NASH). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST COMMON CHRONIC LIVER DISEASES WORLDWIDE AND HAS GARNERED INCREASING ATTENTION IN RECENT DECADES. NAFLD IS CHARACTERIZED BY A WIDE RANGE OF LIVER CHANGES, FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH), CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE PATHOGENESIS OF NAFLD/NASH IS VERY COMPLICATED AND INVOLVES LIPID ACCUMULATION, INSULIN RESISTANCE, INFLAMMATION, AND FIBROGENESIS. IN ADDITION, NAFLD IS CLOSELY ASSOCIATED WITH COMPLICATIONS SUCH AS OBESITY, DYSLIPIDEMIA, AND TYPE 2 DIABETES. IN PARTICULAR, THE CLINICAL SPECTRUM, PATHOPHYSIOLOGY, AND THERAPEUTIC OPTIONS OF NAFLD SHARE MANY THINGS IN COMMON WITH DIABETES. INSULIN RESISTANCE IS AN UNDERLYING BASIS FOR THE PATHOGENESIS OF DIABETES AND NAFLD. THIS CHAPTER FOCUSES ON THE MOLECULAR MECHANISM INVOLVED IN THE PATHOGENESIS OF INSULIN RESISTANCE, DIABETES, AND NASH/NAFLD INCLUDING THOSE THAT DRIVE DISEASE PROGRESSION SUCH AS OXIDATIVE STRESS, GENETIC AND EPIGENETIC MECHANISMS, ADIPONECTIN, CYTOKINES, AND IMMUNE CELLS. 2021 19 1373 20 DEVELOPMENTAL ORIGINS OF NONALCOHOLIC FATTY LIVER DISEASE. OBESE PREGNANT WOMEN MAY TRANSMIT THEIR METABOLIC PHENOTYPE TO OFFSPRING, LEADING TO A CYCLE OF OBESITY AND DIABETES OVER GENERATIONS. EARLY CHILDHOOD OBESITY PREDICTS NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), THE MOST COMMON CHRONIC HUMAN LIVER DISEASE. THE FETUS MAY BE VULNERABLE TO STEATOSIS BECAUSE IMMATURE FETAL ADIPOSE DEPOTS ARE NOT AVAILABLE TO BUFFER THE EXCESS TRANSPLACENTAL LIPID DELIVERY IN MATERNAL OBESITY. IN ANIMAL MODELS, IN UTERO HIGH-FAT DIET EXPOSURE RESULTS IN AN INCREASE IN THE ACCUMULATION OF LIVER TRIGLYCERIDES IN OFFSPRING AND INCREASED HEPATIC OXIDATIVE STRESS AND APOPTOSIS, PERHAPS PRIMING THE LIVER FOR LATER DEVELOPMENT OF NAFLD. INNATE IMMUNE DYSFUNCTION AND NECROINFLAMMATORY CHANGES HAVE BEEN OBSERVED IN POSTNATAL OFFSPRING LIVER OF ANIMALS BORN TO HIGH-FAT-FED DAMS. POSTWEANING, LIVERS OF OFFSPRING EXPOSED TO MATERNAL HIGH-FAT FEEDING IN UTERO SHARE PATHOPHYSIOLOGIC FEATURES WITH HUMAN NAFLD, INCLUDING INCREASED DE NOVO LIPOGENESIS AND DECREASED FREE FATTY ACID OXIDATION. HUMAN STUDIES USING MAGNETIC RESONANCE IMAGING HAVE SHOWN THAT MATERNAL BMI PREDICTS INFANT INTRAHEPATOCELLULAR LIPID STORAGE, AS SEEN IN ANIMAL MODELS. THE GENERATIONAL TRANSFER OF NAFLD MAY OCCUR VIA EPIGENETIC CHANGES IN OFFSPRING LIVER. TRANSMISSION OF MICROBIOTA FROM MOTHER TO INFANT MAY IMPACT ENERGY RETENTION AND IMMUNE FUNCTION THAT CONTRIBUTE TO A PREDISPOSITION TO NAFLD. 2014 20 3610 19 IN UTERO EXPOSURE TO ENDOCRINE-DISRUPTING CHEMICALS, MATERNAL FACTORS AND ALTERATIONS IN THE EPIGENETIC LANDSCAPE UNDERLYING LATER-LIFE HEALTH EFFECTS. WIDESPREAD PERSISTENCE OF ENDOCRINE-DISRUPTING CHEMICALS (EDCS) IN THE ENVIRONMENT HAS MANDATED THE NEED TO STUDY THEIR POTENTIAL EFFECTS ON AN INDIVIDUAL'S LONG-TERM HEALTH AFTER BOTH ACUTE AND CHRONIC EXPOSURE PERIODS. IN THIS REVIEW ARTICLE A PARTICULAR FOCUS IS GIVEN ON IN UTERO EXPOSURE TO EDCS IN RODENT MODELS WHICH RESULTED IN ALTERED EPIGENETIC PROGRAMMING AND TRANSGENERATIONAL EFFECTS IN THE OFFSPRING CAUSING DISRUPTED REPRODUCTIVE AND METABOLIC PHENOTYPES. THE LITERATURE TO DATE ESTABLISHES THE IMPACT OF TRANSGENERATIONAL EFFECTS OF EDCS POTENTIALLY ASSOCIATED WITH EPIGENETIC MEDIATED MECHANISMS. THEREFORE, THIS REVIEW AIMS TO PROVIDE A COMPREHENSIVE OVERVIEW OF EPIGENETIC PROGRAMMING AND IT'S REGULATION IN MAMMALS, PRIMARILY FOCUSING ON THE EPIGENETIC PLASTICITY AND SUSCEPTIBILITY TO EXOGENOUS HORMONE ACTIVE CHEMICALS DURING THE EARLY DEVELOPMENTAL PERIOD. FURTHER, WE HAVE ALSO IN DEPTH DISCUSSED THE EPIGENETIC ALTERATIONS ASSOCIATED WITH THE EXPOSURE TO SELECTED EDCS SUCH AS BISPHENOL A (BPA), DI-2-ETHYLHEXYL PHTHALATE (DEHP) AND VINCLOZLIN UPON IN UTERO EXPOSURE ESPECIALLY IN RODENT MODELS. 2022