1 6370 98 THE ROLE OF MICRORNAS IN METAL CARCINOGEN-INDUCED CELL MALIGNANT TRANSFORMATION AND TUMORIGENESIS. MICRORNAS (MIRNAS), AN IMPORTANT COMPONENT OF EPIGENETIC MECHANISMS OF CARCINOGENESIS, HAVE BEEN SHOWN TO PLAY CRUCIAL ROLES IN CANCER INITIATION, METASTASIS, PROGNOSIS AND RESPONSES TO DRUG TREATMENT AND MAY SERVE AS BIOMARKERS FOR EARLY DIAGNOSIS OF CANCER AND TOOLS FOR CANCER THERAPY. METAL CARCINOGENS, SUCH AS ARSENIC, CADMIUM, HEXAVALENT CHROMIUM AND NICKEL, ARE WELL-ESTABLISHED HUMAN CARCINOGENS CAUSING VARIOUS CANCERS UPON LONG TERM EXPOSURE. HOWEVER, THE MECHANISM OF METAL CARCINOGENESIS HAS NOT BEEN WELL UNDERSTOOD, WHICH LIMITS OUR CAPABILITY TO EFFECTIVELY DIAGNOSE AND TREAT HUMAN CANCERS RESULTING FROM CHRONIC METAL CARCINOGEN EXPOSURE. OVER RECENT YEARS, THE ROLE OF MIRNAS IN METAL CARCINOGENESIS HAS BEEN ACTIVELY EXPLORED AND A GROWING BODY OF EVIDENCE INDICATES THE CRITICAL INVOLVEMENT OF MIRNAS IN METAL CARCINOGENESIS. THIS REVIEW AIMS TO DISCUSS RECENT STUDIES SHOWING THAT MIRNAS PLAY IMPORTANT ROLES IN METAL CARCINOGEN-INDUCED CELL MALIGNANT TRANSFORMATION AND TUMORIGENESIS. SOME THOUGHTS FOR FUTURE FURTHER STUDIES IN THIS FIELD ARE ALSO PRESENTED. 2016 2 1925 32 ENVIRONMENTAL EPIGENETICS IN METAL EXPOSURE. ALTHOUGH IT IS WIDELY ACCEPTED THAT CHRONIC EXPOSURE TO ARSENITE, NICKEL, CHROMIUM AND CADMIUM INCREASES CANCER INCIDENCE IN INDIVIDUALS, THE MOLECULAR MECHANISMS UNDERLYING THEIR ABILITY TO TRANSFORM CELLS REMAIN LARGELY UNKNOWN. CARCINOGENIC METALS ARE TYPICALLY WEAK MUTAGENS, SUGGESTING THAT GENETIC-BASED MECHANISMS MAY NOT BE PRIMARILY RESPONSIBLE FOR METAL-INDUCED CARCINOGENESIS. GROWING EVIDENCE SHOWS THAT ENVIRONMENTAL METAL EXPOSURE INVOLVES CHANGES IN EPIGENETIC MARKS, WHICH MAY LEAD TO A POSSIBLE LINK BETWEEN HERITABLE CHANGES IN GENE EXPRESSION AND DISEASE SUSCEPTIBILITY AND DEVELOPMENT. HERE, WE REVIEW RECENT ADVANCES IN THE UNDERSTANDING OF METAL EXPOSURE AFFECTING EPIGENETIC MARKS AND DISCUSS ESTABLISHMENT OF HERITABLE GENE EXPRESSION IN METAL-INDUCED CARCINOGENESIS. 2011 3 480 34 ARSENIC-INDUCED CARCINOGENESIS: THE IMPACT OF MIRNA DYSREGULATION. ARSENIC IS A TOXIC METALLOID WIDELY PRESENT IN THE EARTH'S CRUST, AND IS A PROVEN HUMAN CARCINOGEN. CHRONIC ARSENIC EXPOSURE MAINLY THROUGH DRINKING WATER CAUSES SKIN, LUNG, AND URINARY BLADDER CANCERS, AND IS ASSOCIATED WITH LIVER, PROSTATE, AND KIDNEY CANCERS, CARDIOVASCULAR AND NEUROLOGICAL DISORDERS, AND DIABETES. SEVERAL MODES OF ACTION HAVE BEEN SUGGESTED IN ARSENIC CARCINOGENESIS. HOWEVER, THE MOLECULAR ETIOLOGY OF ARSENIC-INDUCED CANCER REMAINS UNCLEAR. RECENT EVIDENCE CLEARLY INDICATES THAT GENE EXPRESSION MODIFICATIONS INDUCED BY ARSENIC MAY INVOLVE EPIGENETIC ALTERATIONS, INCLUDING MIRNA DYSREGULATION. MANY MIRNAS HAVE BEEN IMPLICATED IN DIFFERENT HUMAN CANCERS AS A CONSEQUENCE OF LOSSES AND OR GAINS OF MIRNA FUNCTION THAT CONTRIBUTE TO CANCER DEVELOPMENT. PROGRESS IN IDENTIFYING MIRNA DYSREGULATION INDUCED BY ARSENIC HAS BEEN MADE USING DIFFERENT APPROACHES AND MODELS. THE PRESENT REVIEW DISCUSSES THE RECENT DATA REGARDING DYSREGULATED EXPRESSION OF MIRNA IN ARSENIC-INDUCED MALIGNANT TRANSFORMATION IN VITRO, GAPS IN CURRENT UNDERSTANDING AND DEFICIENCIES IN CURRENT MODELS FOR ARSENIC-INDUCED CARCINOGENESIS, AND FUTURE DIRECTIONS OF RESEARCH THAT WOULD IMPROVE OUR KNOWLEDGE REGARDING THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS. 2018 4 4840 26 ONCOGENOMIC DISRUPTIONS IN ARSENIC-INDUCED CARCINOGENESIS. CHRONIC EXPOSURE TO ARSENIC AFFECTS MORE THAN 200 MILLION PEOPLE WORLDWIDE, AND HAS BEEN ASSOCIATED WITH MANY ADVERSE HEALTH EFFECTS, INCLUDING CANCER IN SEVERAL ORGANS. THERE IS ACCUMULATING EVIDENCE THAT ARSENIC BIOTRANSFORMATION, A STEP IN THE ELIMINATION OF ARSENIC FROM THE HUMAN BODY, CAN INDUCE CHANGES AT A GENETIC AND EPIGENETIC LEVEL, LEADING TO CARCINOGENESIS. AT THE GENETIC LEVEL, ARSENIC INTERFERES WITH KEY CELLULAR PROCESSES SUCH AS DNA DAMAGE-REPAIR AND CHROMOSOMAL STRUCTURE, LEADING TO GENOMIC INSTABILITY. AT THE EPIGENETIC LEVEL, ARSENIC PLACES A HIGH DEMAND ON THE CELLULAR METHYL POOL, LEADING TO GLOBAL HYPOMETHYLATION AND HYPERMETHYLATION OF SPECIFIC GENE PROMOTERS. THESE ARSENIC-ASSOCIATED DNA ALTERATIONS RESULT IN THE DEREGULATION OF BOTH ONCOGENIC AND TUMOUR-SUPPRESSIVE GENES. FURTHERMORE, RECENT REPORTS HAVE IMPLICATED ABERRANT EXPRESSION OF NON-CODING RNAS AND THE CONSEQUENTIAL DISRUPTION OF SIGNALING PATHWAYS IN THE CONTEXT OF ARSENIC-INDUCED CARCINOGENESIS. THIS ARTICLE PROVIDES AN OVERVIEW OF THE ONCOGENOMIC ANOMALIES ASSOCIATED WITH ARSENIC EXPOSURE AND CONVEYS THE IMPORTANCE OF NON-CODING RNAS IN THE ARSENIC-INDUCED CARCINOGENIC PROCESS. 2017 5 5557 27 ROLE OF GENOMIC INSTABILITY IN ARSENIC-INDUCED CARCINOGENICITY. A REVIEW. EXPOSURE TO CHRONIC ARSENIC TOXICITY IS ASSOCIATED WITH CANCER. ALTHOUGH UNSTABLE GENOME IS A CHARACTERISTIC FEATURE OF CANCER CELLS, THE MECHANISMS LEADING TO GENOMIC INSTABILITY IN ARSENIC-INDUCED CARCINOGENESIS ARE POORLY UNDERSTOOD. WHILE THERE ARE EXCELLENT REVIEWS RELATING TO GENOMIC INSTABILITY IN GENERAL, THERE IS NO COMPREHENSIVE REVIEW PRESENTING THE MECHANISMS INVOLVED IN ARSENIC-INDUCED GENOMIC INSTABILITY. THIS REVIEW WAS UNDERTAKEN TO PRESENT THE CURRENT STATE OF RESEARCH IN THIS AREA AND TO HIGHLIGHT THE MAJOR MECHANISMS THAT MAY INVOLVED IN ARSENIC-INDUCED GENOMIC INSTABILITY LEADING TO CANCER. GENOMIC INSTABILITY IS BROADLY CLASSIFIED INTO CHROMOSOMAL INSTABILITY (CIN), PRIMARILY ASSOCIATED WITH MITOTIC ERRORS; AND MICROSATELLITE INSTABILITY (MIN), ASSOCIATED WITH DNA LEVEL INSTABILITY. ARSENIC-INDUCED GENOMIC INSTABILITY IS ESSENTIALLY MULTI-FACTORIAL IN NATURE AND INVOLVES MOLECULAR CROSS-TALK ACROSS SEVERAL CELLULAR PATHWAYS, AND IS MODULATED BY A NUMBER OF ENDOGENOUS AND EXOGENOUS FACTORS. ARSENIC AND ITS METABOLITES GENERATE OXIDATIVE STRESS, WHICH IN TURN INDUCES GENOMIC INSTABILITY THROUGH DNA DAMAGE, IRREVERSIBLE DNA REPAIR, TELOMERE DYSFUNCTION, MITOTIC ARREST AND APOPTOSIS. IN ADDITION TO GENETIC ALTERATION; EPIGENETIC REGULATION THROUGH PROMOTER METHYLATION AND MIRNA EXPRESSION ALTERS GENE EXPRESSION PROFILING LEADING TO GENOME MORE VULNERABLE AND UNSTABLE TOWARDS CANCER RISK. MOREOVER, MUTATIONS OR SILENCING OF PRO-APOPTOTIC GENES CAN LEAD TO GENOMIC INSTABILITY BY ALLOWING SURVIVAL OF DAMAGED CELLS THAT WOULD OTHERWISE DIE. ALTHOUGH A LARGE BODY OF INFORMATION IS NOW GENERATED REGARDING ARSENIC-INDUCED CARCINOGENESIS; FURTHER STUDIES EXPLORING GENOME-WIDE ASSOCIATION, ROLE OF ENVIRONMENT AND DIET ARE NEEDED FOR A BETTER UNDERSTANDING OF THE ARSENIC-INDUCED GENOMIC INSTABILITY. 2013 6 4208 44 METAL CARCINOGEN EXPOSURE INDUCES CANCER STEM CELL-LIKE PROPERTY THROUGH EPIGENETIC REPROGRAMING: A NOVEL MECHANISM OF METAL CARCINOGENESIS. ARSENIC, CADMIUM, NICKEL AND HEXAVALENT CHROMIUM ARE AMONG THE MOST COMMON ENVIRONMENTAL POLLUTANTS AND POTENT CARCINOGENS. CHRONIC EXPOSURE TO THESE METALS CAUSES VARIOUS TYPES OF CANCER IN HUMANS, REPRESENTING A SIGNIFICANT ENVIRONMENTAL HEALTH ISSUE. ALTHOUGH UNDER ACTIVE INVESTIGATION, THE MECHANISMS OF METAL CARCINOGENESIS HAVE NOT BEEN CLEARLY DEFINED. ONE COMMON FEATURE OF THESE METAL CARCINOGENS IS THAT THEY ARE ALL ABLE TO CAUSE VARIOUS EPIGENETIC DYSREGULATIONS, WHICH ARE BELIEVED TO PLAY IMPORTANT ROLES IN THEIR CARCINOGENICITY. HOWEVER, HOW METAL CARCINOGEN-CAUSED EPIGENETIC DYSREGULATION CONTRIBUTES TO METAL CARCINOGENESIS REMAINS LARGELY UNKNOWN. THE EVOLUTION OF CANCER STEM CELL (CSC) THEORY HAS OPENED EXCITING NEW AVENUES FOR STUDYING THE MECHANISM OF METAL CARCINOGENESIS. INCREASING EVIDENCE INDICATES THAT CHRONIC METAL CARCINOGEN EXPOSURE PRODUCES CSC-LIKE CELLS THROUGH DYSREGULATED EPIGENETIC MECHANISMS. THIS REVIEW WILL FIRST PROVIDE SOME BRIEF INTRODUCTIONS ABOUT CSC, EPIGENETICS AND EPIGENETIC REGULATION OF CSCS; THEN SUMMARIZE PROGRESSES IN RECENT STUDIES ON METAL CARCINOGEN-INDUCED CSC-LIKE PROPERTY THROUGH EPIGENETIC REPROGRAMING AS A NOVEL MECHANISM OF METAL CARCINOGENESIS. SOME PERSPECTIVES FOR FUTURE STUDIES IN THIS FIELD ARE ALSO PRESENTED. 2019 7 1889 26 ENDOMETRIOSIS MALIGNANT TRANSFORMATION: EPIGENETICS AS A PROBABLE MECHANISM IN OVARIAN TUMORIGENESIS. ENDOMETRIOSIS, DEFINED AS THE PRESENCE OF ECTOPIC ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY, IS A CHRONIC, HORMONE-DEPENDENT GYNECOLOGIC DISEASE AFFECTING MILLIONS OF WOMEN ACROSS THE WORLD, WITH SYMPTOMS INCLUDING CHRONIC PELVIC PAIN, DYSMENORRHEA, DYSPAREUNIA, DYSURIA, AND SUBFERTILITY. IN ADDITION, THERE IS WELL-ESTABLISHED EVIDENCE THAT, ALTHOUGH ENDOMETRIOSIS IS CONSIDERED BENIGN, IT IS ASSOCIATED WITH AN INCREASED RISK OF MALIGNANT TRANSFORMATION, WITH THE INVOLVEMENT OF VARIOUS MECHANISMS OF DEVELOPMENT. MORE AND MORE EVIDENCE REVEALS AN IMPORTANT CONTRIBUTION OF EPIGENETIC MODIFICATION NOT ONLY IN ENDOMETRIOSIS BUT ALSO IN MECHANISMS OF ENDOMETRIOSIS MALIGNANT TRANSFORMATION, INCLUDING DNA METHYLATION AND DEMETHYLATION, HISTONE MODIFICATIONS, AND MIRNA ABERRANT EXPRESSIONS. IN THIS PRESENT REVIEW, WE MAINLY SUMMARIZE THE RESEARCH PROGRESS ABOUT THE CURRENT KNOWLEDGE REGARDING THE EPIGENETIC MODIFICATIONS OF THE RELATIONS BETWEEN ENDOMETRIOSIS MALIGNANT TRANSFORMATION AND OVARIAN CANCER IN AN EFFORT TO IDENTIFY SOME RISK FACTORS PROBABLY ASSOCIATED WITH ECTOPIC ENDOMETRIUM TRANSFORMATION. 2018 8 3210 26 HEALTH EFFECTS ASSOCIATED WITH PRE- AND PERINATAL EXPOSURE TO ARSENIC. INORGANIC ARSENIC IS A WELL-ESTABLISHED HUMAN CARCINOGEN, ABLE TO INDUCE GENETIC AND EPIGENETIC ALTERATIONS. MORE THAN 200 MILLION PEOPLE WORLDWIDE ARE EXPOSED TO ARSENIC CONCENTRATIONS IN DRINKING WATER EXCEEDING THE RECOMMENDED WHO THRESHOLD (10MUG/L). ADDITIONALLY, CHRONIC EXPOSURE TO LEVELS BELOW THIS THRESHOLD IS KNOWN TO RESULT IN LONG-TERM HEALTH EFFECTS IN HUMANS. THE ARSENIC-RELATED HEALTH EFFECTS IN HUMANS ARE ASSOCIATED WITH ITS BIOTRANSFORMATION PROCESS, WHEREBY THE RESULTING METABOLITES CAN INDUCE MOLECULAR DAMAGE THAT ACCUMULATES OVER TIME. THE EFFECTS DERIVED FROM THESE ALTERATIONS INCLUDE GENOMIC INSTABILITY ASSOCIATED WITH OXIDATIVE DAMAGE, ALTERATION OF GENE EXPRESSION (INCLUDING CODING AND NON-CODING RNAS), GLOBAL AND LOCALIZED EPIGENETIC REPROGRAMMING, AND HISTONE POSTTRANSLATIONAL MODIFICATIONS. THESE ALTERATIONS DIRECTLY AFFECT MOLECULAR PATHWAYS INVOLVED IN THE ONSET AND PROGRESSION OF MANY CONDITIONS THAT CAN ARISE EVEN DECADES AFTER THE EXPOSURE OCCURS. IMPORTANTLY, ARSENIC METABOLITES GENERATED DURING ITS BIOTRANSFORMATION CAN ALSO PASS THROUGH THE PLACENTAL BARRIER, RESULTING IN FETAL EXPOSURE TO THIS CARCINOGEN AT SIMILAR LEVELS TO THOSE OF THE MOTHER. AS SUCH, MORE IMMEDIATE EFFECTS OF THE ARSENIC-INDUCED MOLECULAR DAMAGE CAN BE OBSERVED AS DETRIMENTAL EFFECTS ON FETAL DEVELOPMENT, PREGNANCY, AND BIRTH OUTCOMES. IN THIS REVIEW, WE FOCUS ON THE GENETIC AND EPIGENETIC DAMAGE ASSOCIATED WITH EXPOSURE TO LOW LEVELS OF ARSENIC, PARTICULARLY THOSE AFFECTING EARLY DEVELOPMENTAL STAGES. WE ALSO PRESENT HOW THESE ALTERATIONS OCCURRING DURING EARLY LIFE CAN IMPACT THE DEVELOPMENT OF CERTAIN DISEASES IN ADULT LIFE. 2021 9 1917 34 ENVIRONMENTAL ARSENIC EXPOSURE: FROM GENETIC SUSCEPTIBILITY TO PATHOGENESIS. MORE THAN 200 MILLION PEOPLE IN 70 COUNTRIES ARE EXPOSED TO ARSENIC THROUGH DRINKING WATER. CHRONIC EXPOSURE TO THIS METALLOID HAS BEEN ASSOCIATED WITH THE ONSET OF MANY DISEASES, INCLUDING CANCER. EPIDEMIOLOGICAL EVIDENCE SUPPORTS ITS CARCINOGENIC POTENTIAL, HOWEVER, DETAILED MOLECULAR MECHANISMS REMAIN TO BE ELUCIDATED. DESPITE THE GLOBAL MAGNITUDE OF THIS PROBLEM, NOT ALL INDIVIDUALS FACE THE SAME RISK. SUSCEPTIBILITY TO THE TOXIC EFFECTS OF ARSENIC IS INFLUENCED BY ALTERATIONS IN GENES INVOLVED IN ARSENIC METABOLISM, AS WELL AS BIOLOGICAL FACTORS, SUCH AS AGE, GENDER AND NUTRITION. MOREOVER, CHRONIC ARSENIC EXPOSURE RESULTS IN SEVERAL GENOTOXIC AND EPIGENETIC ALTERATIONS TIGHTLY ASSOCIATED WITH THE ARSENIC BIOTRANSFORMATION PROCESS, RESULTING IN AN INCREASED CANCER RISK. IN THIS REVIEW, WE: 1) REVIEW THE ROLES OF INTER-INDIVIDUAL DNA-LEVEL VARIATIONS INFLUENCING THE SUSCEPTIBILITY TO ARSENIC-INDUCED CARCINOGENESIS; 2) DISCUSS THE CONTRIBUTION OF ARSENIC BIOTRANSFORMATION TO CANCER INITIATION; 3) PROVIDE INSIGHTS INTO EMERGING RESEARCH AREAS AND THE CHALLENGES IN THE FIELD; AND 4) COMPILE A RESOURCE OF PUBLICLY AVAILABLE ARSENIC-RELATED DNA-LEVEL VARIATIONS, TRANSCRIPTOME AND METHYLATION DATA. UNDERSTANDING THE MOLECULAR MECHANISMS OF ARSENIC EXPOSURE AND ITS SUBSEQUENT HEALTH EFFECTS WILL SUPPORT EFFORTS TO REDUCE THE WORLDWIDE HEALTH BURDEN AND ENCOURAGE THE DEVELOPMENT OF STRATEGIES FOR MANAGING ARSENIC-RELATED DISEASES IN THE ERA OF PERSONALIZED MEDICINE. 2018 10 3003 31 GENETIC, EPIGENETIC AND STEM CELL ALTERATIONS IN ENDOMETRIOSIS: NEW INSIGHTS AND POTENTIAL THERAPEUTIC PERSPECTIVES. HUMAN ENDOMETRIUM IS A HIGHLY DYNAMIC TISSUE, UNDERGOING PERIODIC GROWTH AND REGRESSION AT EACH MENSTRUAL CYCLE. ENDOMETRIOSIS IS A FREQUENT CHRONIC PATHOLOGICAL STATUS CHARACTERIZED BY ENDOMETRIAL TISSUE WITH AN ECTOPIC LOCALIZATION, CAUSING PELVIC PAIN AND INFERTILITY AND A VARIABLE CLINICAL PRESENTATION. IN ADDITION, THERE IS WELL-ESTABLISHED EVIDENCE THAT, ALTHOUGH ENDOMETRIOSIS IS CONSIDERED BENIGN, IT IS ASSOCIATED WITH AN INCREASED RISK OF MALIGNANT TRANSFORMATION IN APPROXIMATELY 1.0% OF AFFECTED WOMEN, WITH THE INVOLVEMENT OF MULTIPLE PATHWAYS OF DEVELOPMENT. INCREASING EVIDENCE SUPPORTS A KEY CONTRIBUTION OF DIFFERENT STEM/PROGENITOR CELL POPULATIONS NOT ONLY IN THE CYCLIC REGENERATION OF EUTOPIC ENDOMETRIUM, BUT ALSO IN THE PATHOGENESIS OF AT LEAST SOME TYPES OF ENDOMETRIOSIS. EVIDENCE HAS ARISEN FROM EXPERIMENTS IN ANIMAL MODELS OF DISEASE THROUGH DIFFERENT KINDS OF ASSAYS (INCLUDING CLONOGENICITY, THE LABEL-RETAINING CELL APPROACH, THE ANALYSIS OF UNDIFFERENTIATION MARKERS), AS WELL AS FROM DESCRIPTIVE STUDIES ON ECTOPIC AND EUTOPIC TISSUE SAMPLES HARVESTED FROM AFFECTED WOMEN. CHANGES IN STEM CELL POPULATIONS IN ENDOMETRIOTIC LESIONS ARE ASSOCIATED WITH GENETIC AND EPIGENETIC ALTERATIONS, INCLUDING IMBALANCE OF MIRNA EXPRESSION, HISTONE AND DNA MODIFICATIONS AND CHROMOSOMAL ABERRATIONS. THE PRESENT SHORT REVIEW MAINLY SUMMARIZES THE LATEST OBSERVATIONS CONTRIBUTING TO THE CURRENT KNOWLEDGE REGARDING THE PRESENCE AND THE POTENTIAL CONTRIBUTION OF STEM/PROGENITOR CELLS IN EUTOPIC ENDOMETRIUM AND THE AETIOLOGY OF ENDOMETRIOSIS, TOGETHER WITH A REPORT OF THE MOST RECENTLY IDENTIFIED GENETIC AND EPIGENETIC ALTERATIONS IN ENDOMETRIOSIS. WE ALSO DESCRIBE THE POTENTIAL ADVANTAGES OF SINGLE CELL MOLECULAR PROFILING IN ENDOMETRIUM AND IN ENDOMETRIOTIC LESIONS. ALL THESE DATA CAN HAVE CLINICAL IMPLICATIONS AND PROVIDE A BASIS FOR NEW POTENTIAL THERAPEUTIC APPLICATIONS. 2014 11 712 34 CADMIUM AND ITS EPIGENETIC EFFECTS. CADMIUM (CD) IS A TOXIC, NONESSENTIAL TRANSITION METAL AND CONTRIBUTES A HEALTH RISK TO HUMANS, INCLUDING VARIOUS CANCERS AND CARDIOVASCULAR DISEASES; HOWEVER, UNDERLYING MOLECULAR MECHANISMS REMAIN LARGELY UNKNOWN. CELLS TRANSMIT INFORMATION TO THE NEXT GENERATION VIA TWO DISTINCT WAYS: GENETIC AND EPIGENETIC. CHEMICAL MODIFICATIONS TO DNA OR HISTONE THAT ALTERS THE STRUCTURE OF CHROMATIN WITHOUT CHANGE OF DNA NUCLEOTIDE SEQUENCE ARE KNOWN AS EPIGENETICS. THESE HERITABLE EPIGENETIC CHANGES INCLUDE DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF HISTONE TAILS (ACETYLATION, METHYLATION, PHOSPHORYLATION, ETC), AND HIGHER ORDER PACKAGING OF DNA AROUND NUCLEOSOMES. APART FROM DNA METHYLTRANSFERASES, HISTONE MODIFICATION ENZYMES SUCH AS HISTONE ACETYLTRANSFERASE, HISTONE DEACETYLASE, AND METHYLTRANSFERASE, AND MICRORNAS (MIRNAS) ALL INVOLVE IN THESE EPIGENETIC CHANGES. RECENT STUDIES INDICATE THAT CD IS ABLE TO INDUCE VARIOUS EPIGENETIC CHANGES IN PLANT AND MAMMALIAN CELLS IN VITRO AND IN VIVO. SINCE ABERRANT EPIGENETICS PLAYS A CRITICAL ROLE IN THE DEVELOPMENT OF VARIOUS CANCERS AND CHRONIC DISEASES, CD MAY CAUSE THE ABOVE-MENTIONED PATHOGENIC RISKS VIA EPIGENETIC MECHANISMS. HERE WE REVIEW THE IN VITRO AND IN VIVO EVIDENCE OF EPIGENETIC EFFECTS OF CD. THE AVAILABLE FINDINGS INDICATE THAT EPIGENETICS OCCURRED IN ASSOCIATION WITH CD INDUCTION OF MALIGNANT TRANSFORMATION OF CELLS AND PATHOLOGICAL PROLIFERATION OF TISSUES, SUGGESTING THAT EPIGENETIC EFFECTS MAY PLAY A ROLE IN CD TOXIC, PARTICULARLY CARCINOGENIC EFFECTS. THE FUTURE OF ENVIRONMENTAL EPIGENOMIC RESEARCH ON CD SHOULD INCLUDE THE ROLE OF EPIGENETICS IN DETERMINING LONG-TERM AND LATE-ONSET HEALTH EFFECTS FOLLOWING CD EXPOSURE. 2012 12 3673 31 INFLAMMATION AND DE-DIFFERENTIATION IN PANCREATIC CARCINOGENESIS. PANCREATIC CANCER IS A MALIGNANCY WITH AN EXTREMELY POOR PROGNOSIS. CHRONIC PANCREATITIS IS A WELL-KNOWN RISK FACTOR FOR PANCREATIC CANCER. INFLAMMATION IS THOUGHT TO INFLUENCE CARCINOGENESIS THROUGH DNA DAMAGE AND ACTIVATION OF INTRACELLULAR SIGNALING PATHWAYS. MANY TRANSCRIPTION FACTORS AND SIGNALING PATHWAYS CO-OPERATE TO DETERMINE AND MAINTAIN CELL IDENTITY AT EACH PHASE OF PANCREATIC ORGANOGENESIS AND CELL DIFFERENTIATION. RECENT STUDIES HAVE SHOWN THAT CARCINOGENESIS IS PROMOTED THROUGH THE SUPPRESSION OF TRANSCRIPTION FACTORS RELATED TO DIFFERENTIATION. PANCREATITIS ALSO DEMONSTRATES TRANSCRIPTIONAL CHANGES, SUGGESTING THAT MULTIFACTORIAL EPIGENETIC CHANGES LEAD TO IMPAIRED DIFFERENTIATION. TAKEN TOGETHER, THESE FACTORS MAY CONSTITUTE AN IMPORTANT FRAMEWORK FOR PANCREATIC CARCINOGENESIS. IN THIS REVIEW, WE DISCUSS THE ROLE OF INFLAMMATION AND DE-DIFFERENTIATION IN THE DEVELOPMENT OF PANCREATIC CANCER, AS WELL AS THE FUTURE OF NOVEL THERAPEUTIC APPLICATIONS. 2018 13 416 32 ANALYSIS OF THE DYNAMIC ABERRANT LANDSCAPE OF DNA METHYLATION AND GENE EXPRESSION DURING ARSENIC-INDUCED CELL TRANSFORMATION. INORGANIC ARSENIC IS A WELL-KNOWN CARCINOGEN ASSOCIATED WITH SEVERAL TYPES OF CANCER, BUT THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS ARE NOT FULLY UNDERSTOOD. RECENT EVIDENCE POINTS TO EPIGENETIC DYSREGULATION AS AN IMPORTANT MECHANISM IN THIS PROCESS; HOWEVER, THE EFFECTS OF EPIGENETIC ALTERATIONS IN GENE EXPRESSION HAVE NOT BEEN EXPLORED IN DEPTH. USING MICROARRAY DATA AND APPLYING A MULTIVARIATE CLUSTERING ANALYSIS IN A GAUSSIAN MIXTURE MODEL, WE DESCRIBE THE ALTERATIONS IN DNA METHYLATION AROUND THE PROMOTER REGION AND THE IMPACT ON GENE EXPRESSION IN HACAT CELLS DURING THE TRANSFORMATION PROCESS CAUSED BY CHRONIC EXPOSURE TO ARSENIC. USING THIS CLUSTERING APPROACH, THE GENES WERE GROUPED ACCORDING TO THEIR METHYLATION AND EXPRESSION STATUS IN THE EPIGENETIC LANDSCAPE, AND THE CHANGES THAT OCCURRED DURING THE CELLULAR TRANSFORMATION WERE IDENTIFIED ADEQUATELY. THUS, WE PRESENT A VALUABLE METHOD FOR IDENTIFYING EPIGENOMIC DYSREGULATION. 2019 14 1447 18 DIOXIN AND ENDOMETRIOSIS: A NEW POSSIBLE RELATION BASED ON EPIGENETIC THEORY. ENDOMETRIOSIS IS A CHRONIC DISEASE CHARACTERIZED BY THE GROWTH OF ENDOMETRIAL-LIKE GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY. NOWADAYS, THE EXACT ETIOLOGY OF ENDOMETRIOSIS IS UNCLEAR AND THE INTERACTION BETWEEN A VARIETY OF ENVIRONMENTAL PHYSICAL AND CHEMICAL COMPOUNDS MAY POTENTIALLY PROMOTE THE DISEASE IN WOMEN WITH AN INDIVIDUAL SUSCEPTIBILITY. THE FIRST DEMONSTRATION OF A RELATION BETWEEN AN ENVIRONMENTAL FACTOR AND ENDOMETRIOSIS WAS OBTAINED WITH THE CHRONIC DIETARY EXPOSURE OF A PRIMATE COLONY TO 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD). BESIDES THE WELL-KNOWN DIOXIN'S PATHWAY OF ACTION, SEVERAL PAPERS ARE FOCUSING ON THE ROLE OF EPIGENETIC MECHANISMS, A WAY THROUGH WHICH THE GENOME RESPONDS TO THE ENVIRONMENT AND CAN LEAD TO PERMANENT CHANGES IN GENE EXPRESSION UNTIL AFFECTING THE PHENOTYPES OR CAUSE DISEASE. IN THIS REVIEW, WE FOCUS ON THE POSSIBLE ROLE OF DIOXIN EPIGENETICS MODIFICATION IN ENDOMETRIOSIS. 2020 15 5492 29 REVIEW OF ARSENIC TOXICITY, SPECIATION AND POLYADENYLATION OF CANONICAL HISTONES. ARSENIC CONTAMINATION IMPACTS HUNDREDS OF MILLIONS OF PEOPLE IN THE WORLD. ARSENIC IS A WELL-ESTABLISHED HUMAN CARCINOGEN AND HAS BEEN SHOWN TO CAUSE SKIN, LUNG, BLADDER, LIVER, PROSTATE AND KIDNEY CANCERS, IN HUMANS. MECHANISMS THAT UNDERLIE ARSENIC-MEDIATED CARCINOGENESIS, INCLUDING EPIGENETIC ALTERATIONS, REMAIN LARGELY UNKNOWN. HUMAN EXPOSURE TO ARSENIC IS REVIEWED, AND THE MECHANISMS OF ITS ACUTE AND CHRONIC TOXICITY AND MECHANISMS OF ITS CARCINOGENESIS IN HUMANS ARE DISCUSSED. ARSENIC IS ONE OF THE FEW METALS THAT IS METABOLIZED IN VIVO, AND ARSENIC METHYLATION AND HOW THIS RESULTS IN A SHORTER HALF-LIFE IN VIVO ARE DISCUSSED. A REVIEW OF RECENT FINDINGS THAT ARSENIC CAUSES LOSS IN THE CELLULAR LEVELS OF STEM LOOP BINDING PROTEIN (SLBP) RESULTING IN POLYADENYLATION OF CANONICAL HISTONES (H3.1) AS A DEFAULT, INCREASING LEVELS OF H3.1 PROTEIN OUTSIDE OF S-PHASE. MALIGNANT CELL TRANSFORMATION IS INDUCED BY KNOCKDOWN OF SLBP AND BY OVEREXPRESSION OF POLYADENYLATED H3.1. ARSENIC INDUCED POLYADENYLATION OF H3.1 CAUSES ENHANCED LEVELS OF H3.1 PROTEIN DISPLACING H3.3 PROTEIN FROM ITS CELLULAR BINDING SITES, SINCE THE TWO PROTEINS DIFFER BY ONLY 5 AMINO ACIDS. KNOCKDOWN OF H3.3 ALONE CAN INDUCE CARCINOGENESIS, AND THEREFORE DISPLACEMENT OF FUNCTIONAL H3.3 PROTEIN BY INCREASED H3.1 PROTEIN, IS LIKELY A MECHANISM OF ARSENIC CARCINOGENESIS. 2019 16 2655 32 EPIMUTAGENESIS: A PROSPECTIVE MECHANISM TO REMEDIATE ARSENIC-INDUCED TOXICITY. ARSENIC TOXICITY IS A GLOBAL ISSUE, ADDRESSED BY THE WORLD HEALTH ORGANIZATION AS ONE OF THE MAJOR NATURAL CALAMITIES FACED BY HUMANS. MORE THAN 137 MILLION INDIVIDUALS IN 70 NATIONS ARE AFFECTED BY ARSENIC MAINLY THROUGH DRINKING WATER AND ALSO THROUGH DIET. CHRONIC ARSENIC EXPOSURE LEADS TO VARIOUS TYPES OF PATHO-PHYSIOLOGICAL END POINTS IN HUMANS INCLUDING CANCERS. ARSENIC, A XENOBIOTIC SUBSTANCE, IS BIOTRANSFORMED IN THE BODY TO ITS METHYLATED SPECIES BY USING THE PHYSIOLOGICAL S-ADENOSYL METHIONINE (SAM). SAM DICTATES METHYLATION STATUS OF THE GENOME AND ARSENIC METABOLISM LEADS TO DEPLETION OF SAM LEADING TO AN EPIGENETIC DISEQUILIBRIUM. SINCE EPIGENETICS IS ONE OF THE MAJOR PHENOMENON AT THE INTERFACE BETWEEN THE ENVIRONMENT AND HUMAN HEALTH IMPACT, ITS DISEQUILIBRIUM BY ARSENIC INFLICTS UPON THE CHROMATIN COMPACTION, GENE EXPRESSION, GENOMIC STABILITY AND A HOST OF BIOMOLECULAR INTERACTIONS, THE INTERACTOME WITHIN THE CELL. SINCE ARSENIC IS NOT MUTAGENIC BUT IS CARCINOGENIC IN NATURE, ARSENIC INDUCED EPIMUTAGENESIS HAS COME TO THE FOREFRONT SINCE IT DETERMINES THE TRANSCRIPTIONAL AND GENOMIC INTEGRITY OF THE CELL. ARSENIC TOXICITY BRINGS FORTH SEVERAL PATHOPHYSIOLOGICAL MANIFESTATIONS LIKE DERMATOLOGICAL NON-CANCEROUS, PRE-CANCEROUS AND CANCEROUS LESIONS, PERIPHERAL NEUROPATHY, DNA DAMAGE, RESPIRATORY DISORDERS AND CANCERS OF SEVERAL INTERNAL ORGANS. RECENTLY, SEVERAL DISEASES OF SIMILAR MANIFESTATIONS HAVE BEEN EXPLAINED WITH THE RELEVANT EPIGENETIC PERSPECTIVES REGARDING THE POSSIBLE MOLECULAR MECHANISM FOR THEIR ONSET. HENCE, IN THE CURRENT REVIEW, WE COMPREHENSIVELY TRY TO INTERCALATE THE INFORMATION ON ARSENIC-INDUCED EPIGENETIC ALTERATIONS OF DNA, HISTONES AND MICRORNA SO AS TO UNDERSTAND WHETHER THE ARSENIC-INDUCED TOXIC MANIFESTATIONS ARE BROUGHT ABOUT BY THE EPIGENETIC CHANGES. WE HIGHLIGHT THE NEED TO UNDERSTAND THE ASPECT OF EPIMUTAGENESIS AND SUBSEQUENT ALTERATIONS IN THE CELLULAR INTERACTOME DUE TO ARSENIC-INDUCED MOLECULAR CHANGES, WHICH MAY BE UTILIZED TO DEVELOP PUTATIVE THERAPEUTIC STRATEGIES TARGETING BOTH OXIDATIVE POTENTIAL AND EPIMUTAGENESIS IN HUMANS. 2015 17 2086 32 EPIGENETIC DYSREGULATION IN ENDOMETRIOSIS: IMPLICATIONS FOR PATHOPHYSIOLOGY AND THERAPEUTICS. ENDOMETRIOSIS IS A PREVALENT GYNECOLOGICAL CONDITION ASSOCIATED WITH PELVIC PAIN AND INFERTILITY. DESPITE MORE THAN A CENTURY OF RESEARCH, THE ETIOLOGY OF ENDOMETRIOSIS STILL ELUDES SCIENTIFIC CONSENSUS. THIS LACK OF CLARITY HAS RESULTED IN SUBOPTIMAL PREVENTION, DIAGNOSIS, AND TREATMENT OPTIONS. EVIDENCE OF GENETIC CONTRIBUTORS TO ENDOMETRIOSIS IS INTERESTING BUT LIMITED; HOWEVER, SIGNIFICANT PROGRESS HAS BEEN MADE IN RECENT YEARS IN IDENTIFYING EPIGENETIC ROLE IN THE PATHOGENESIS OF ENDOMETRIOSIS THROUGH CLINICAL STUDIES, IN VITRO CELL CULTURE EXPERIMENTS, AND IN VIVO ANIMAL MODELS. THE PREDOMINANT FINDINGS INCLUDE ENDOMETRIOSIS-RELATED DIFFERENTIAL EXPRESSION OF DNA METHYLTRANSFERASES AND DEMETHYLASES, HISTONE DEACETYLASES, METHYLTRANSFERASES, AND DEMETHYLASES, AND REGULATORS OF CHROMATIN ARCHITECTURE. THERE IS ALSO AN EMERGING ROLE FOR MIRNAS IN THE CONTROL OF EPIGENETIC REGULATORS IN THE ENDOMETRIUM AND ENDOMETRIOSIS. CHANGES IN THESE EPIGENETIC REGULATORS RESULT IN DIFFERENTIAL CHROMATIN ORGANIZATION AND DNA METHYLATION WITH CONSEQUENCES FOR GENE EXPRESSION INDEPENDENT OF A GENETIC SEQUENCE. EPIGENETICALLY ALTERED EXPRESSION OF GENES RELATED TO STEROID HORMONE PRODUCTION AND SIGNALING, IMMUNE REGULATION, AND ENDOMETRIAL CELL IDENTITY AND FUNCTION HAVE ALL BEEN IDENTIFIED AND APPEAR TO PLAY INTO THE PATHOPHYSIOLOGICAL MECHANISMS OF ENDOMETRIOSIS AS WELL AS RESULTING INFERTILITY. THIS REVIEW SUMMARIZES AND CRITICALLY DISCUSSES EARLY SEMINAL FINDINGS, THE EVER-GROWING RECENT EVIDENCE OF EPIGENETIC CONTRIBUTIONS TO THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS, AND IMPLICATIONS FOR PROPOSED EPIGENETICALLY TARGETED THERAPEUTICS. 2023 18 474 16 ARSENIC BIOTRANSFORMATION AS A CANCER PROMOTING FACTOR BY INDUCING DNA DAMAGE AND DISRUPTION OF REPAIR MECHANISMS. CHRONIC EXPOSURE TO ARSENIC IN DRINKING WATER POSES A MAJOR GLOBAL HEALTH CONCERN. POPULATIONS EXPOSED TO HIGH CONCENTRATIONS OF ARSENIC-CONTAMINATED DRINKING WATER SUFFER SERIOUS HEALTH CONSEQUENCES, INCLUDING ALARMING CANCER INCIDENCE AND DEATH RATES. ARSENIC IS BIOTRANSFORMED THROUGH SEQUENTIAL ADDITION OF METHYL GROUPS, ACQUIRED FROM S-ADENOSYLMETHIONINE (SAM). METABOLISM OF ARSENIC GENERATES A VARIETY OF GENOTOXIC AND CYTOTOXIC SPECIES, DAMAGING DNA DIRECTLY AND INDIRECTLY, THROUGH THE GENERATION OF REACTIVE OXIDATIVE SPECIES AND INDUCTION OF DNA ADDUCTS, STRAND BREAKS AND CROSS LINKS, AND INHIBITION OF THE DNA REPAIR PROCESS ITSELF. SINCE SAM IS THE METHYL GROUP DONOR USED BY DNA METHYLTRANSFERASES TO MAINTAIN NORMAL EPIGENETIC PATTERNS IN ALL HUMAN CELLS, ARSENIC IS ALSO POSTULATED TO AFFECT MAINTENANCE OF NORMAL DNA METHYLATION PATTERNS, CHROMATIN STRUCTURE, AND GENOMIC STABILITY. THE BIOLOGICAL PROCESSES UNDERLYING THE CANCER PROMOTING FACTORS OF ARSENIC METABOLISM, RELATED TO DNA DAMAGE AND REPAIR, WILL BE DISCUSSED HERE. 2011 19 186 27 ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL CELLS AND CANCER RISK. CANCERS DEVELOP DUE TO THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. GENETIC ALTERATIONS ARE INDUCED BY AGING, MUTAGENIC CHEMICALS, ULTRAVIOLET LIGHT, AND OTHER FACTORS; WHEREAS, EPIGENETIC ALTERATIONS ARE MAINLY BY AGING AND CHRONIC INFLAMMATION. THE ACCUMULATION AND PATTERNS OF ALTERATIONS IN NORMAL CELLS REFLECT OUR PAST EXPOSURE LEVELS AND LIFE HISTORY. MOST ACCUMULATED ALTERATIONS ARE CONSIDERED AS PASSENGERS, BUT THEIR ACCUMULATION IS CORRELATED WITH CANCER DRIVERS. THIS HAS BEEN SHOWN FOR ABERRANT DNA METHYLATION BUT HAS ONLY BEEN SPECULATED FOR GENETIC ALTERATIONS. HOWEVER, RECENT TECHNOLOGICAL ADVANCEMENTS HAVE ENABLED MEASUREMENT OF RARE POINT MUTATIONS, AND STUDIES HAVE SHOWN THAT THEIR ACCUMULATION LEVELS ARE INDEED CORRELATED WITH CANCER RISK. WHEN THE ACCUMULATION LEVELS OF ABERRANT DNA METHYLATION AND POINT MUTATIONS ARE COMBINED, RISK PREDICTION BECOMES EVEN MORE ACCURATE. WHEN HIGH LEVELS OF ALTERATIONS ACCUMULATE, THE TISSUE HAS A HIGH RISK OF DEVELOPING CANCER OR EVEN MULTIPLE CANCERS AND IS CONSIDERED AS A "CANCERIZATION FIELD", WITH OR WITHOUT EXPANSION OF PHYSIOLOGICAL PATCHES OF CLONAL CELLS. IN THIS REVIEW, WE DESCRIBE THE FORMATION OF A CANCERIZATION FIELD AND HOW WE CAN APPLY ITS DETECTION IN PRECISION CANCER RISK DIAGNOSIS. 2019 20 315 23 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