1 1993 130 EPIGENETIC AND EPITRANSCRIPTOMIC MECHANISMS OF CHROMIUM CARCINOGENESIS. HEXAVALENT CHROMIUM [CR(VI)], A GROUP I CARCINOGEN CLASSIFIED BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC), REPRESENTS ONE OF THE MOST COMMON OCCUPATIONAL AND ENVIRONMENTAL POLLUTANTS. THE FINDINGS FROM HUMAN EPIDEMIOLOGICAL AND LABORATORY ANIMAL STUDIES SHOW THAT LONG-TERM EXPOSURE TO CR(VI) CAUSES LUNG CANCER AND OTHER CANCER. ALTHOUGH CR(VI) IS A WELL-RECOGNIZED CARCINOGEN, THE MECHANISM OF CR(VI) CARCINOGENESIS HAS NOT BEEN WELL UNDERSTOOD. DUE TO THE FACT THAT CR(VI) UNDERGOES A SERIES OF METABOLIC REDUCTIONS ONCE ENTERING CELLS TO GENERATE REACTIVE CR METABOLITES AND REACTIVE OXYGEN SPECIES (ROS) CAUSING GENOTOXICITY, CR(VI) IS GENERALLY CONSIDERED AS A GENOTOXIC CARCINOGEN. HOWEVER, MORE AND MORE STUDIES HAVE DEMONSTRATED THAT ACUTE OR CHRONIC CR(VI) EXPOSURE ALSO CAUSES EPIGENETIC DYSREGULATIONS INCLUDING CHANGING DNA METHYLATION, HISTONE POSTTRANSLATIONAL MODIFICATIONS AND REGULATORY NON-CODING RNA (MICRORNA AND LONG NON-CODING RNA) EXPRESSIONS. MOREOVER, EMERGING EVIDENCE SHOWS THAT CR(VI) EXPOSURE IS ALSO CAPABLE OF ALTERING CELLULAR EPITRANSCRIPTOME. GIVEN THE INCREASINGLY RECOGNIZED IMPORTANCE OF EPIGENETIC AND EPITRANSCRIPTOMIC DYSREGULATIONS IN CANCER INITIATION AND PROGRESSION, IT IS BELIEVED THAT CR(VI) EXPOSURE-CAUSED EPIGENETIC AND EPITRANSCRIPTOMIC CHANGES COULD PLAY IMPORTANT ROLES IN CR(VI) CARCINOGENESIS. THE GOAL OF THIS CHAPTER IS TO REVIEW THE EPIGENETIC AND EPITRANSCRIPTOMIC EFFECTS OF CR(VI) EXPOSURE AND DISCUSS THEIR ROLES IN CR(VI) CARCINOGENESIS. BETTER UNDERSTANDING THE MECHANISM OF CR(VI) CARCINOGENESIS MAY IDENTIFY NEW MOLECULAR TARGETS FOR MORE EFFICIENT PREVENTION AND TREATMENT OF CANCER RESULTING FROM CR(VI) EXPOSURE. 2023 2 4208 48 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 3 2961 44 GENETIC AND EPIGENETIC MECHANISMS IN METAL CARCINOGENESIS AND COCARCINOGENESIS: NICKEL, ARSENIC, AND CHROMIUM. CHRONIC EXPOSURE TO NICKEL(II), CHROMIUM(VI), OR INORGANIC ARSENIC (IAS) HAS LONG BEEN KNOWN TO INCREASE CANCER INCIDENCE AMONG AFFECTED INDIVIDUALS. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND THAT CARCINOGENIC RISKS ASSOCIATED WITH CHROMATE AND IAS EXPOSURES WERE SUBSTANTIALLY HIGHER THAN PREVIOUSLY THOUGHT, WHICH LED TO MAJOR REVISIONS OF THE FEDERAL STANDARDS REGULATING AMBIENT AND DRINKING WATER LEVELS. GENOTOXIC EFFECTS OF CR(VI) AND IAS ARE STRONGLY INFLUENCED BY THEIR INTRACELLULAR METABOLISM, WHICH CREATES SEVERAL REACTIVE INTERMEDIATES AND BYPRODUCTS. TOXIC METALS ARE CAPABLE OF POTENT AND SURPRISINGLY SELECTIVE ACTIVATION OF STRESS-SIGNALING PATHWAYS, WHICH ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF HUMAN CANCERS. DEPENDING ON THE METAL, ASCORBATE (VITAMIN C) HAS BEEN FOUND TO ACT EITHER AS A STRONG ENHANCER OR SUPPRESSOR OF TOXIC RESPONSES IN HUMAN CELLS. IN ADDITION TO GENETIC DAMAGE VIA BOTH OXIDATIVE AND NONOXIDATIVE (DNA ADDUCTS) MECHANISMS, METALS CAN ALSO CAUSE SIGNIFICANT CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS, LEADING TO EPIGENETIC SILENCING OR REACTIVATION OF GENE EXPRESSION. IN VITRO GENOTOXICITY EXPERIMENTS AND RECENT ANIMAL CARCINOGENICITY STUDIES PROVIDED STRONG SUPPORT FOR THE IDEA THAT METALS CAN ACT AS COCARCINOGENS IN COMBINATION WITH NONMETAL CARCINOGENS. COCARCINOGENIC AND COMUTAGENIC EFFECTS OF METALS ARE LIKELY TO STEM FROM THEIR ABILITY TO INTERFERE WITH DNA REPAIR PROCESSES. OVERALL, METAL CARCINOGENESIS APPEARS TO REQUIRE THE FORMATION OF SPECIFIC METAL COMPLEXES, CHROMOSOMAL DAMAGE, AND ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS PROMOTING SURVIVAL AND EXPANSION OF GENETICALLY/EPIGENETICALLY ALTERED CELLS. 2008 4 6370 42 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 5 1122 42 COMPARISON OF GENE EXPRESSION PROFILES IN CHROMATE TRANSFORMED BEAS-2B CELLS. BACKGROUND: HEXAVALENT CHROMIUM [CR(VI)] IS A POTENT HUMAN CARCINOGEN. OCCUPATIONAL EXPOSURE HAS BEEN ASSOCIATED WITH INCREASED RISK OF RESPIRATORY CANCER. MULTIPLE MECHANISMS HAVE BEEN SHOWN TO CONTRIBUTE TO CR(VI) INDUCED CARCINOGENESIS, INCLUDING DNA DAMAGE, GENOMIC INSTABILITY, AND EPIGENETIC MODULATION, HOWEVER, THE MOLECULAR MECHANISM AND DOWNSTREAM GENES MEDIATING CHROMIUM'S CARCINOGENICITY REMAIN TO BE ELUCIDATED. METHODS/RESULTS: WE ESTABLISHED CHROMATE TRANSFORMED CELL LINES BY CHRONIC EXPOSURE OF NORMAL HUMAN BRONCHIAL EPITHELIAL BEAS-2B CELLS TO LOW DOSES OF CR(VI) FOLLOWED BY ANCHORAGE-INDEPENDENT GROWTH. THESE TRANSFORMED CELL LINES NOT ONLY EXHIBITED CONSISTENT MORPHOLOGICAL CHANGES BUT ALSO ACQUIRED ALTERED AND DISTINCT GENE EXPRESSION PATTERNS COMPARED WITH NORMAL BEAS-2B CELLS AND CONTROL CELL LINES (UNTREATED) THAT AROSE SPONTANEOUSLY IN SOFT AGAR. INTERESTINGLY, THE GENE EXPRESSION PROFILES OF SIX CR(VI) TRANSFORMED CELL LINES WERE REMARKABLY SIMILAR TO EACH OTHER YET DIFFERED SIGNIFICANTLY FROM THAT OF EITHER CONTROL CELL LINES OR NORMAL BEAS-2B CELLS. A TOTAL OF 409 DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED IN CR(VI) TRANSFORMED CELLS COMPARED TO CONTROL CELLS. GENES RELATED TO CELL-TO-CELL JUNCTION WERE UPREGULATED IN ALL CR(VI) TRANSFORMED CELLS, WHILE GENES ASSOCIATED WITH THE INTERACTION BETWEEN CELLS AND THEIR EXTRACELLULAR MATRICES WERE DOWN-REGULATED. ADDITIONALLY, EXPRESSION OF GENES INVOLVED IN CELL PROLIFERATION AND APOPTOSIS WERE ALSO CHANGED. CONCLUSION: THIS STUDY IS THE FIRST TO REPORT GENE EXPRESSION PROFILING OF CR(VI) TRANSFORMED CELLS. THE GENE EXPRESSION CHANGES ACROSS INDIVIDUAL CHROMATE EXPOSED CLONES WERE REMARKABLY SIMILAR TO EACH OTHER BUT DIFFERED SIGNIFICANTLY FROM THE GENE EXPRESSION FOUND IN ANCHORAGE-INDEPENDENT CLONES THAT AROSE SPONTANEOUSLY. OUR ANALYSIS IDENTIFIED MANY NOVEL GENE EXPRESSION CHANGES THAT MAY CONTRIBUTE TO CHROMATE INDUCED CELL TRANSFORMATION, AND COLLECTIVELY THIS TYPE OF INFORMATION WILL PROVIDE A BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING CHROMATE CARCINOGENICITY. 2011 6 1557 31 DNA METHYLATION MODIFICATIONS INDUCED BY HEXAVALENT CHROMIUM. HEXAVALENT CHROMIUM [CR (VI)] CONTRIBUTES A SIGNIFICANT HEALTH RISK AND CAUSES A NUMBER OF CHRONIC DISEASES AND CANCERS. WHILE THE GENOTOXIC AND CARCINOGENIC EFFECTS OF HEXAVALENT CHROMIUM EXPOSURE ARE EXPLICIT AND BETTER-CHARACTERIZED, THE EXACT MECHANISM UNDERLYING THE CARCINOGENIC PROCESS OF CR (VI) IS STILL A MATTER OF DEBATE. IN RECENT YEARS, STUDIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS, ESPECIALLY DNA METHYLATION, MAY PLAY A SIGNIFICANT ROLE IN CR (VI)-INDUCED CARCINOGENESIS. THE AIM OF THIS REVIEW IS TO SUMMARIZE OUR UNDERSTANDING REGARDING THE EFFECTS OF CR (VI) ON GLOBAL AND GENE-SPECIFIC DNA METHYLATION. 2019 7 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 8 4840 31 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 9 480 36 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 10 1970 35 EPIGENETIC ALTERATIONS AND OCCUPATIONAL EXPOSURE TO BENZENE, FIBERS, AND HEAVY METALS ASSOCIATED WITH TUMOR DEVELOPMENT (REVIEW). THE CHRONIC OCCUPATIONAL EXPOSURE TO CONTAMINANTS AND CARCINOGENS LEADS TO THE DEVELOPMENT OF CANCER. OVER THE PAST DECADES, MANY CARCINOGENS HAVE BEEN FOUND IN THE OCCUPATIONAL ENVIRONMENT AND THEIR PRESENCE IS OFTEN ASSOCIATED WITH AN INCREASED INCIDENCE OF CANCER. ACCORDING TO THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC), THE MAJORITY OF CARCINOGENS ARE CLASSIFIED AS 'PROBABLE' AND 'POSSIBLE' HUMAN CARCINOGENS, WHILE, DIRECT EVIDENCE OF CARCINOGENICITY IS PROVIDED IN EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES. ADDITIONALLY, ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS MAY BE EARLY INDICATORS OF GENOTOXIC AND NON-GENOTOXIC CARCINOGEN EXPOSURE. IN THE PRESENT REVIEW, THE RELATIONSHIP BETWEEN EXPOSURES TO BENZENE, MINERAL FIBERS, METALS AND EPIGENETIC ALTERATIONS ARE DISCUSSED AS THE MOST IMPORTANT CANCER RISK FACTORS DURING WORK ACTIVITIES. 2017 11 712 38 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 5557 38 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 13 6387 35 THE ROLE OF REACTIVE OXYGEN SPECIES IN ARSENIC TOXICITY. ARSENIC POISONING IS A GLOBAL HEALTH PROBLEM. CHRONIC EXPOSURE TO ARSENIC HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF A WIDE RANGE OF DISEASES AND HEALTH PROBLEMS IN HUMANS. ARSENIC EXPOSURE INDUCES THE GENERATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS), WHICH MEDIATE MULTIPLE CHANGES TO CELL BEHAVIOR BY ALTERING SIGNALING PATHWAYS AND EPIGENETIC MODIFICATIONS, OR CAUSE DIRECT OXIDATIVE DAMAGE TO MOLECULES. ANTIOXIDANTS WITH THE POTENTIAL TO REDUCE ROS LEVELS HAVE BEEN SHOWN TO AMELIORATE ARSENIC-INDUCED LESIONS. HOWEVER, EMERGING EVIDENCE SUGGESTS THAT CONSTRUCTIVE ACTIVATION OF ANTIOXIDATIVE PATHWAYS AND DECREASED ROS LEVELS CONTRIBUTE TO CHRONIC ARSENIC TOXICITY IN SOME CASES. THIS REVIEW DETAILS THE PATHWAYS INVOLVED IN ARSENIC-INDUCED REDOX IMBALANCE, AS WELL AS CURRENT STUDIES ON PROPHYLAXIS AND TREATMENT STRATEGIES USING ANTIOXIDANTS. 2020 14 474 27 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 15 860 38 CHROMATIN MODIFICATIONS DURING REPAIR OF ENVIRONMENTAL EXPOSURE-INDUCED DNA DAMAGE: A POTENTIAL MECHANISM FOR STABLE EPIGENETIC ALTERATIONS. EXPOSURES TO ENVIRONMENTAL TOXICANTS AND TOXINS CAUSE EPIGENETIC CHANGES THAT LIKELY PLAY A ROLE IN THE DEVELOPMENT OF DISEASES ASSOCIATED WITH EXPOSURE. THE MECHANISM BEHIND THESE EXPOSURE-INDUCED EPIGENETIC CHANGES IS CURRENTLY UNKNOWN. ONE COMMONALITY BETWEEN MOST ENVIRONMENTAL EXPOSURES IS THAT THEY CAUSE DNA DAMAGE EITHER DIRECTLY OR THROUGH CAUSING AN INCREASE IN REACTIVE OXYGEN SPECIES, WHICH CAN DAMAGE DNA. LIKE TRANSCRIPTION, DNA DAMAGE REPAIR MUST OCCUR IN THE CONTEXT OF CHROMATIN REQUIRING BOTH HISTONE MODIFICATIONS AND ATP-DEPENDENT CHROMATIN REMODELING. THESE CHROMATIN CHANGES AID IN DNA DAMAGE ACCESSIBILITY AND SIGNALING. SEVERAL PROTEINS AND COMPLEXES INVOLVED IN EPIGENETIC SILENCING DURING BOTH DEVELOPMENT AND CANCER HAVE BEEN FOUND TO BE LOCALIZED TO SITES OF DNA DAMAGE. THE CHROMATIN-BASED RESPONSE TO DNA DAMAGE IS CONSIDERED A TRANSIENT EVENT, WITH CHROMATIN BEING RESTORED TO NORMAL AS DNA DAMAGE REPAIR IS COMPLETED. HOWEVER, IN INDIVIDUALS CHRONICALLY EXPOSED TO ENVIRONMENTAL TOXICANTS OR WITH CHRONIC INFLAMMATORY DISEASE, REPEATED DNA DAMAGE-INDUCED CHROMATIN REARRANGEMENT MAY ULTIMATELY LEAD TO PERMANENT EPIGENETIC ALTERATIONS. UNDERSTANDING THE MECHANISM BEHIND EXPOSURE-INDUCED EPIGENETIC CHANGES WILL ALLOW US TO DEVELOP STRATEGIES TO PREVENT OR REVERSE THESE CHANGES. THIS REVIEW FOCUSES ON EPIGENETIC CHANGES AND DNA DAMAGE INDUCED BY ENVIRONMENTAL EXPOSURES, THE CHROMATIN CHANGES THAT OCCUR AROUND SITES OF DNA DAMAGE, AND HOW THESE TRANSIENT CHROMATIN CHANGES MAY LEAD TO HERITABLE EPIGENETIC ALTERATIONS AT SITES OF CHRONIC EXPOSURE. 2014 16 106 36 A REVIEW OF MOLECULAR EVENTS OF CADMIUM-INDUCED CARCINOGENESIS. CADMIUM (CD) IS A TOXIC, HEAVY INDUSTRIAL METAL THAT POSES SERIOUS ENVIRONMENTAL HEALTH HAZARDS TO BOTH HUMANS AND WILDLIFE. RECENTLY, CD AND CD-CONTAINING COMPOUNDS HAVE BEEN CLASSIFIED AS KNOWN HUMAN CARCINOGENS, AND EPIDEMIOLOGICAL DATA SHOW CAUSAL ASSOCIATIONS WITH PROSTATE, BREAST, AND LUNG CANCER. THE MOLECULAR MECHANISMS INVOLVED IN CD-INDUCED CARCINOGENESIS ARE POORLY UNDERSTOOD AND ARE ONLY NOW BEGINNING TO BE ELUCIDATED. THE EFFECTS OF CHRONIC EXPOSURE TO CD HAVE RECENTLY ATTRACTED GREAT INTEREST DUE TO THE DEVELOPMENT OF MALIGNANCIES IN CD-INDUCED TUMORIGENESIS IN ANIMALS MODELS. BRIEFLY, VARIOUS IN VITRO STUDIES DEMONSTRATE THAT CD CAN ACT AS A MITOGEN, CAN STIMULATE CELL PROLIFERATION AND INHIBIT APOPTOSIS AND DNA REPAIR, AND CAN INDUCE CARCINOGENESIS IN SEVERAL MAMMALIAN TISSUES AND ORGANS. THUS, THE VARIOUS MECHANISMS INVOLVED IN CHRONIC CD EXPOSURE AND MALIGNANT TRANSFORMATIONS WARRANT FURTHER INVESTIGATION. IN THIS REVIEW, WE FOCUS ON RECENT EVIDENCE OF VARIOUS LEADING GENERAL AND TISSUE-SPECIFIC MOLECULAR MECHANISMS THAT FOLLOW CHRONIC EXPOSURE TO CD IN PROSTATE-, BREAST-, AND LUNG-TRANSFORMED MALIGNANCIES. IN ADDITION, IN THIS REVIEW, WE CONSIDER LESS DEFINED MECHANISMS SUCH AS EPIGENETIC MODIFICATION AND AUTOPHAGY, WHICH ARE THOUGHT TO PLAY A ROLE IN THE DEVELOPMENT OF CD-INDUCED MALIGNANT TRANSFORMATION. 2014 17 4119 41 MECHANISMS OF CADMIUM CARCINOGENICITY IN THE GASTROINTESTINAL TRACT. CANCER, A SERIOUS PUBLIC HEALTH PROBLEM IN WORLDWIDE, RESULTS FROM AN EXCESSIVE AND UNCONTROLLED PROLIFERATION OF THE BODY CELLS WITHOUT OBVIOUS PHYSIOLOGICAL DEMANDS OF ORGANS. THE GASTROINTESTINAL TRACT, INCLUDING THE ESOPHAGUS, STOMACH AND INTESTINE, IS A UNIQUE ORGAN SYSTEM. IT HAS THE HIGHEST CANCER INCIDENCE AND CANCER- RELATED MORTALITY IN THE BODY AND IS INFLUENCEED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. AMONG THE VARIOUS CHEMICAL ELEMENTS RECOGNIZED IN THE NATURE, SOME OF THEM INCLUDING ZINC, IRON, COBALT, AND COPPER HAVE ESSENTIAL ROLES IN THE VARIOUS BIOCHEMICAL AND PHYSIOLOGICAL PROCESSES, BUT ONLY AT LOW LEVELS AND OTHERS SUCH AS CADMIUM, LEAD, MERCURY, ARSENIC, AND NICKEL ARE CONSIDERED AS THREATS FOR HUMAN HEALTH ESPECIALLY WITH CHRONIC EXPOSURE AT HIGH LEVELS. CADMIUM, AN ENVIRONMENT CONTAMINANT, CANNOT BE DESTROYED IN NATURE. THROUGH IMPAIRMENT OF VITAMIN D METABOLISM IN THE KIDNEY IT CAUSES NEPHROTOXICITY AND SUBSEQUENTLY BONE METABOLISM IMPAIRMENT AND FRAGILITY. THE MAJOR MECHANISMS INVOLVED IN CADMIUM CARCINOGENESIS COULD BE RELATED TO THE SUPPRESSION OF GENE EXPRESSION, INHIBITION OF DNA DAMAGE REPAIR, INHIBITION OF APOPTOSIS, AND INDUCTION OF OXIDATIVE STRESS. IN ADDITION, CADMIUM MAY ACT THROUGH ABERRANT DNA METHYLATION. CADMIUM AFFECTS MULTIPLE CELLULAR PROCESSES, INCLUDING SIGNAL TRANSDUCTION PATHWAYS, CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. DOWN-REGULATION OF METHYLTRANSFERASES ENZYMES AND REDUCTION OF DNA METHYLATION HAVE BEEN STATED AS EPIGENETIC EFFECTS OF CADMIUM. FURTHERMORE, INCREASING INTRACELLULAR FREE CALCIUM ION LEVELS INDUCES NEURONAL APOPTOSIS IN ADDITION TO OTHER DELETERIOUS INFLUENCE ON THE STABILITY OF THE GENOME. 2015 18 633 35 BIOLOGICAL EFFECTS AND EPIDEMIOLOGICAL CONSEQUENCES OF ARSENIC EXPOSURE, AND REAGENTS THAT CAN AMELIORATE ARSENIC DAMAGE IN VIVO. THROUGH CONTAMINATED DIET, WATER, AND OTHER FORMS OF ENVIRONMENTAL EXPOSURE, ARSENIC AFFECTS HUMAN HEALTH. THERE ARE MANY U.S. AND WORLDWIDE "HOT SPOTS" WHERE THE ARSENIC LEVEL IN PUBLIC WATER EXCEEDS THE MAXIMUM EXPOSURE LIMIT. THE BIOLOGICAL EFFECTS OF CHRONIC ARSENIC EXPOSURE INCLUDE GENERATION OF REACTIVE OXYGEN SPECIES (ROS), LEADING TO OXIDATIVE STRESS AND DNA DAMAGE, EPIGENETIC DNA MODIFICATION, INDUCTION OF GENOMIC INSTABILITY, AND INFLAMMATION AND IMMUNOMODULATION, ALL OF WHICH CAN INITIATE CARCINOGENESIS. HIGH ARSENIC EXPOSURE IS EPIDEMIOLOGICALLY ASSOCIATED WITH SKIN, LUNG, BLADDER, LIVER, KIDNEY AND PANCREATIC CANCER, AND CARDIOVASCULAR, NEURONAL, AND OTHER DISEASES. THIS REVIEW BRIEFLY SUMMARIZES THE BIOLOGICAL EFFECTS OF ARSENIC EXPOSURE AND EPIDEMIOLOGICAL CANCER STUDIES WORLDWIDE, AND PROVIDES AN OVERVIEW FOR EMERGING RODENT-BASED STUDIES OF REAGENTS THAT CAN AMELIORATE THE EFFECTS OF ARSENIC EXPOSURE IN VIVO. THESE REAGENTS MAY BE TRANSLATED TO HUMAN POPULATIONS FOR DISEASE PREVENTION. WE PROPOSE THE IMPORTANCE OF DEVELOPING A BIOMARKER-BASED PRECISION PREVENTION APPROACH FOR THE HEALTH ISSUES ASSOCIATED WITH ARSENIC EXPOSURE THAT AFFECTS MILLIONS OF PEOPLE WORLDWIDE. 2017 19 5493 19 REVIEW OF IN VITRO TEST SYSTEMS USING DNA DAMAGE AND REPAIR FOR SCREENING OF CHEMICAL CARCINOGENS. CHEMICAL CARCINOGENS ARE MECHANISTICALLY CLASSIFIED AS GENOTOXIC WHICH INTERACT DIRECTLY WITH DNA, AND EPIGENETIC WHICH CAUSE CHRONIC TISSUE INJURY, HORMONAL IMBALANCE, AND PROMOTIONAL EFFECTS. THIS REVIEW EVALUATES IN VITRO TESTS FOR THEIR CONTRIBUTION TO A BATTERY FOR IDENTIFYING GENOTOXIC CHEMICAL CARCINOGENS. IN ADDITION TO BACTERIAL MUTAGENIC ASSAYS, NONSPECIFIC DNA DAMAGE/REPAIR TESTS ARE RECOMMENDED FOR SCREENING CHEMICALS, IN PARTICULAR THE HEPATOCYTE PRIMARY CULTURE/DNA REPAIR TEST. 1979 20 2655 41 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