1 6663 121 UPREGULATION OF HISTONE-LYSINE METHYLTRANSFERASES PLAYS A CAUSAL ROLE IN HEXAVALENT CHROMIUM-INDUCED CANCER STEM CELL-LIKE PROPERTY AND CELL TRANSFORMATION. WHILE HEXAVALENT CHROMIUM [CR(VI)] IS GENERALLY CONSIDERED AS A GENOTOXIC ENVIRONMENTAL CARCINOGEN, STUDIES SHOWED THAT CR(VI) EXPOSURE ALSO CAUSES EPIGENETIC CHANGES. HOWEVER, WHETHER CR(VI)-CAUSED EPIGENETIC DYSREGULATIONS PLAYS AN IMPORTANT ROLE IN CR(VI) CARCINOGENICITY REMAIN LARGELY UNKNOWN. THE AIM OF THIS STUDY WAS TO DETERMINE IF CHRONIC LOW DOSE CR(VI) EXPOSURE CAUSES EPIGENETIC CHANGES, THE UNDERLYING MECHANISM AND WHETHER CHRONIC LOW DOSE CR(VI) EXPOSURE-CAUSED EPIGENETIC DYSREGULATION CONTRIBUTES CAUSALLY TO CR(VI)-INDUCED CANCER STEM CELL (CSC)-LIKE PROPERTY AND CELL TRANSFORMATION. TWO IMMORTALIZED HUMAN BRONCHIAL EPITHELIAL CELL LINES (BEAS-2B AND 16HBE) WERE EXPOSED TO 0.25 MUM OF K(2)CR(2)O(7) FOR 20 AND 40 WEEKS TO INDUCE CELL TRANSFORMATION, RESPECTIVELY. CR(VI)-INDUCED EPIGENETIC CHANGES WERE EXAMINED IN CR(VI)-TRANSFORMED CELLS AND CR(VI) EXPOSURE-CAUSED HUMAN LUNG CANCER TISSUES. PHARMACOLOGICAL INHIBITORS AND GENE KNOCKDOWN EXPERIMENTS WERE USED TO DETERMINE THE ROLE OF EPIGENETIC DYSREGULATION IN CR(VI) CARCINOGENICITY. WE FOUND THAT CHRONIC CR(VI) EXPOSURE CAUSES EPIGENETIC DYSREGULATION AS EVIDENCED BY THE INCREASED LEVELS OF HISTONE H3 REPRESSIVE METHYLATION MARKS (H3K9ME2 AND H3K27ME3) AND THE RELATED HISTONE-LYSING METHYLTRANSFERASES (HMTASES). PHARMACOLOGICAL INHIBITION OR KNOCKDOWN OF HMTASES REDUCES H3 REPRESSIVE METHYLATION MARKS AND MALIGNANT PHENOTYPES OF CR(VI)-TRANSFORMED CELLS. MOREOVER, KNOCKDOWN OF HMTASES IN PARENTAL CELLS SIGNIFICANTLY REDUCES CHRONIC CR(VI) EXPOSURE-INDUCED CSC-LIKE PROPERTY AND CELL TRANSFORMATION. FURTHER MECHANISTIC STUDY REVEALED THAT KNOCKDOWN OF HMTASES DECREASES CR(VI) EXPOSURE-CAUSED DNA DAMAGE. OUR FINDINGS INDICATE THAT CHRONIC CR(VI) EXPOSURE INCREASES H3 REPRESSIVE METHYLATION MARKS BY INCREASING THE RELATED HMTASES EXPRESSION; AND THAT INCREASED EXPRESSION OF HMTASES PLAYS A CAUSAL ROLE IN CR(VI)-INDUCED CSC-LIKE PROPERTY AND CELL TRANSFORMATION. 2018 2 1993 44 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 3 1557 29 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 4 1987 46 EPIGENETIC ALTERATIONS OF CXCL5 IN CR(VI)-INDUCED CARCINOGENESIS. CHRONIC EXPOSURE TO HEXAVALENT CHROMIUM COMPOUNDS [CR(VI)] IS ASSOCIATED WITH AN INCREASED RISK OF CANCERS, BUT THE MOLECULAR MECHANISMS REMAIN TO BE ELUCIDATED. IN THIS STUDY, WE FOUND THAT CXCL5 LEVELS IN PERIPHERAL BLOOD MONOCYTES (PBMCS) AND PLASMA FROM WORKERS WITH OCCUPATIONAL EXPOSURE TO CR(VI) WERE DRAMATICALLY UPREGULATED COMPARED TO NON-EXPOSURE HEALTHY SUBJECTS, AND PLASMA C-X-C MOTIF CHEMOKINE LIGAND 5 (CXCL5) CXCL5 LEVELS WERE POSITIVELY CORRELATED WITH CR CONCENTRATIONS IN SUBJECTS' TOENAILS. ZINC CHROMATE EXPOSED MICE SHOWED HIGHER LEVELS OF CXCL5 AND ITS RECEPTOR CXCR2 IN LUNG TISSUES, AND IN PBMCS. SIMILAR CXCL5 UPREGULATION WAS EVIDENT IN CR(VI)-INDUCED TRANSFORMED (CR-T) CELLS WITH LONG-TERM CR(VI) TREATMENT. MECHANISTIC STUDIES SHOWED THAT ELEVATED CXCL5 EXPRESSION LEVELS WERE REGULATED BY CR(VI)-INDUCED HISTONE MODIFICATIONS AND DNA HYPOMETHYLATION, AND THAT THE C-MYC/P300 COMPLEX WAS A KEY UPSTREAM REGULATOR OF HISTONE H3 ACETYLATION. CXCL5 OVEREXPRESSION PROMOTED CR(VI)-INDUCED THE EPITHELIAL TO MESENCHYME TRANSITION (EMT) BY UPREGULATING ZINC FINGER E-BOX BINDING HOMEOBOX 1 (ZEB1) TO PROMOTE TUMOR DEVELOPMENT. OUR FINDINGS IDENTIFY A NOVEL MECHANISM BY WHICH CXCL5 IS UPREGULATED AND PROMOTES EMT AND CARCINOGENESIS UPON CHRONIC CR(VI) EXPOSURE. OUR WORK ALSO IMPLIES THAT CXCL5 MRNA AND PROTEIN LEVELS WILL ELEVATE IN PBMCS AND SERUM AFTER OCCUPATIONAL CR(VI) EXPOSURE, WHICH MAY BE A POTENTIAL TARGET AND BIOMARKER FOR CANCER PREVENTION AND HEALTH SURVEILLANCE AMONG POPULATIONS EXPOSED TO CR(VI). 2022 5 4208 38 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 6 1122 50 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 7 2961 38 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 8 1925 30 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 9 6370 31 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 10 481 43 ARSENIC-INDUCED SUMOYLATION OF MUS81 IS INVOLVED IN REGULATING GENOMIC STABILITY. CHRONIC ENVIRONMENTAL EXPOSURE TO METAL TOXICANTS SUCH AS CHROMIUM AND ARSENIC IS CLOSELY RELATED TO THE DEVELOPMENT OF SEVERAL TYPES OF COMMON CANCERS. GENETIC AND EPIGENETIC STUDIES IN THE PAST DECADE REVEAL THAT POST-TRANSLATIONAL MODIFICATIONS OF HISTONES PLAY A ROLE IN METAL CARCINOGENESIS. HOWEVER, EXACT MOLECULAR MECHANISMS OF METAL CARCINOGENESIS REMAIN TO BE ELUCIDATED. IN THIS STUDY WE FOUND THAT AS(2)O(3), AN ENVIRONMENTAL METAL TOXICANT, UPREGULATED OVERALL MODIFICATIONS OF MANY CELLULAR PROTEINS BY SUMO2/3. SUMOYLATED PROTEINS FROM ARSENIC-TREATED CELLS CONSTITUTIVELY EXPRESSING HIS(6)-SUMO2 WERE PULLED DOWN BY NI-IDA RESIN UNDER DENATURING CONDITIONS. MASS SPECTROMETRIC ANALYSIS REVEALED OVER 100 PROTEINS THAT WERE POTENTIALLY MODIFIED BY SUMOYLATION. MUS81, A DNA ENDONUCLEASE INVOLVED IN HOMOLOGOUS RECOMBINATION REPAIR, WAS AMONG THE IDENTIFIED PROTEINS WHOSE SUMOYLATION WAS INCREASED AFTER TREATMENT WITH AS(2)O(3.) WE FURTHER SHOWED THAT K10 AND K524 WERE 2 LYSINE RESIDUES ESSENTIAL FOR MUS81 SUMOYLATION. MOREOVER, WE DEMONSTRATED THAT MUS81 SUMOYLATION IS IMPORTANT FOR NORMAL MITOTIC CHROMOSOME CONGRESSION AND THAT CELLS EXPRESSING SUMO-RESISTANT MUS81 MUTANTS DISPLAYED COMPROMISED DNA DAMAGE RESPONSES AFTER EXPOSURE TO METAL TOXINS SUCH AS CR(VI) AND ARSENIC. 2017 11 3942 52 LNCRNA DUXAP10 UPREGULATION AND THE HEDGEHOG PATHWAY ACTIVATION ARE CRITICALLY INVOLVED IN CHRONIC CADMIUM EXPOSURE-INDUCED CANCER STEM CELL-LIKE PROPERTY. CADMIUM (CD) IS A WELL-KNOWN LUNG CARCINOGEN. HOWEVER, THE MECHANISM OF CD CARCINOGENESIS REMAINS TO BE CLEARLY DEFINED. CD HAS BEEN SHOWN TO ACT AS A WEAK MUTAGEN, SUGGESTING THAT IT MAY EXERT TUMORIGENIC EFFECT THROUGH NONGENOTOXIC WAYS, SUCH AS EPIGENETIC MECHANISMS. LONG NONCODING RNAS (LNCRNAS) REFER TO RNA MOLECULES THAT ARE LONGER THAN 200 NUCLEOTIDES IN LENGTH BUT LACK PROTEIN-CODING CAPACITIES. REGULATION OF GENE EXPRESSIONS BY LNCRNAS IS CONSIDERED AS ONE OF IMPORTANT EPIGENETIC MECHANISMS. THE GOAL OF THIS STUDY IS TO INVESTIGATE THE MECHANISM OF CD CARCINOGENESIS FOCUSING ON THE ROLE OF LNCRNA DYSREGULATIONS. CD-INDUCED MALIGNANT TRANSFORMATION OF HUMAN BRONCHIAL EPITHELIA BEAS-2B CELLS WAS ACCOMPLISHED BY A 9-MONTH LOW-DOSE CD (CDCL2, 2.5 MICROM) EXPOSURE. THE CD-EXPOSED CELLS FORMED SIGNIFICANTLY MORE COLONIES IN SOFT AGAR, DISPLAYED CANCER STEM CELL (CSC)-LIKE PROPERTY, AND FORMED TUMORS IN NUDE MICE. MECHANISTICALLY, CHRONIC LOW-DOSE CD EXPOSURE DID NOT CAUSE SIGNIFICANT GENOTOXIC EFFECTS BUT DYSREGULATED LNCRNA EXPRESSIONS. FURTHER Q-PCR ANALYSIS CONFIRMED THE SIGNIFICANT UPREGULATION OF THE ONCOGENIC LNCRNA DUXAP10 IN CD-TRANSFORMED CELLS. DUXAP10 KNOCKDOWN IN CD-TRANSFORMED CELLS SIGNIFICANTLY REDUCED THEIR CSC-LIKE PROPERTY. FURTHER MECHANISTIC STUDIES SHOWED THAT THE HEDGEHOG PATHWAY IS ACTIVATED IN CD-TRANSFORMED CELLS AND INHIBITION OF THIS PATHWAY REDUCES CD-INDUCED CSC-LIKE PROPERTY. DUXAP10 KNOCKDOWN CAUSED THE HEDGEHOG PATHWAY INACTIVATION IN CD-TRANSFORMED CELLS. FURTHERMORE, PAX6 EXPRESSION WAS UPREGULATED IN CD-TRANSFORMED CELLS AND PAX6 KNOCKDOWN SIGNIFICANTLY REDUCED THEIR DUXAP10 LEVELS AND CSC-LIKE PROPERTY. IN SUMMARY, THESE FINDINGS SUGGEST THAT THE LNCRNA DUXAP10 UPREGULATION MAY PLAY AN IMPORTANT ROLE IN CD CARCINOGENESIS. 2021 12 3842 28 IRON- AND 2-OXOGLUTARATE-DEPENDENT DIOXYGENASES: AN EMERGING GROUP OF MOLECULAR TARGETS FOR NICKEL TOXICITY AND CARCINOGENICITY. NICKEL COMPOUNDS ARE IMPORTANT OCCUPATIONAL AND ENVIRONMENTAL POLLUTANTS. CHRONIC EXPOSURE TO THESE POLLUTANTS HAS BEEN CONNECTED WITH INCREASED RISKS OF RESPIRATORY CANCERS AND CARDIOVASCULAR DISEASES. HOWEVER, IT IS STILL NOT CLEAR WHAT ARE THE SPECIFIC MOLECULAR TARGETS FOR NICKEL TOXICITY AND CARCINOGENICITY. HERE, WE PROPOSE THAT THE IRON- AND 2-OXOGLUTARATE-DEPENDENT DIOXYGENASE FAMILY ENZYMES ARE IMPORTANT INTRACELLULAR TARGETS THAT MEDIATE THE TOXICITY AND CARCINOGENICITY OF NICKEL. IN SUPPORT OF THIS HYPOTHESIS, OUR DATA SHOW THAT THREE DIFFERENT CLASSES OF ENZYMES IN THIS IRON- AND 2-OXOGLUTARATE-DEPENDENT DIOXYGENASE FAMILY, INCLUDING HIF-PROLYL HYDROXYLASE PHD2, HISTONE DEMETHYLASE JHDM2A/JMJD1A, AND DNA REPAIR ENZYME ABH3, ARE ALL HIGHLY SENSITIVE TO NICKEL INHIBITION. INACTIVATION OF THESE ENZYMES ACCOUNTS FOR A NUMBER OF DELETERIOUS EFFECTS CAUSED BY NICKEL IN CELLS, NAMELY HYPOXIA-MIMIC STRESS AND ABERRANT EPIGENETIC CHANGES. FUTURE STUDIES ON NICKEL'S EFFECTS ON THESE IRON- AND 2-OXOGLUTARATE-DEPENDENT DIOXYGENASES WOULD DEEPEN OUR UNDERSTANDING ON NICKEL TOXICITY AND CARCINOGENICITY. 2009 13 1530 38 DNA METHYLATION CHANGES INDUCED BY PRENATAL TOXIC METAL EXPOSURE: AN OVERVIEW OF EPIDEMIOLOGICAL EVIDENCE. ACCUMULATING EVIDENCE SUGGESTS THAT EXPOSURE TO UNFAVORABLE CONDITIONS EARLY IN LIFE CAN SUBSTANTIALLY CONTRIBUTE TO THE RISK OF CHRONIC DISORDERS LATER IN LIFE ('DEVELOPMENTAL PROGRAMMING' PHENOMENON). THE MECHANISTIC BASIS FOR THIS PHENOMENON REMAINS POORLY UNDERSTOOD SO FAR, ALTHOUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNA-MEDIATED GENE REGULATION APPARENTLY PLAY A CRUCIAL ROLE. THE KEY ROLE OF EPIGENETIC MODIFICATIONS TRIGGERED BY UNFAVORABLE ENVIRONMENTAL CUES DURING SENSITIVE DEVELOPMENTAL PERIODS IN LINKING ADVERSE EARLY-LIFE EVENTS TO LATER-LIFE HEALTH OUTCOMES IS EVIDENT FROM A LARGE BODY OF STUDIES, INCLUDING METHYLOME-WIDE ASSOCIATION STUDIES AND RESEARCH OF CANDIDATE GENES. TOXIC METALS (TMS), SUCH AS HEAVY METALS, INCLUDING LEAD, CHROMIUM, CADMIUM, ARSENIC, MERCURY, ETC., ARE AMONG ENVIRONMENTAL CONTAMINANTS CURRENTLY MOST SIGNIFICANTLY IMPACTING HUMAN HEALTH STATUS. SINCE TMS CAN CROSS THE PLACENTAL BARRIER AND ACCUMULATE IN FETAL TISSUES, EXPOSURE TO HIGH DOSES OF THESE XENOBIOTICS EARLY IN DEVELOPMENT IS CONSIDERED TO BE AMONG IMPORTANT FACTORS CONTRIBUTING TO THE DEVELOPMENTAL PROGRAMMING OF ADULT-LIFE DISEASES IN MODERN SOCIETIES. IN THIS MINI-REVIEW, WE SUMMARIZE EPIDEMIOLOGICAL FINDINGS INDICATING THAT PRENATAL TM EXPOSURE CAN INDUCE EPIGENETIC DYSREGULATION, THEREBY POTENTIALLY AFFECTING ADULT HEALTH OUTCOMES. 2021 14 323 39 ALKBH4 STABILIZATION IS REQUIRED FOR ARSENIC-INDUCED 6MA DNA METHYLATION INHIBITION, KERATINOCYTE MALIGNANT TRANSFORMATION, AND TUMORIGENICITY. INORGANIC ARSENIC IS ONE OF THE WELL-KNOWN HUMAN SKIN CARCINOGENS. HOWEVER, THE MOLECULAR MECHANISM BY WHICH ARSENIC PROMOTES CARCINOGENESIS REMAINS UNCLEAR. PREVIOUS STUDIES HAVE ESTABLISHED THAT EPIGENETIC CHANGES, INCLUDING CHANGES IN DNA METHYLATION, ARE AMONG THE CRITICAL MECHANISMS THAT DRIVE CARCINOGENESIS. N(6)-METHYLADENINE (6MA) METHYLATION ON DNA IS A WIDESPREAD EPIGENETIC MODIFICATION THAT WAS INITIALLY FOUND ON BACTERIAL AND PHAGE DNA. ONLY RECENTLY HAS 6MA BEEN IDENTIFIED IN MAMMALIAN GENOMES. HOWEVER, THE FUNCTION OF 6MA IN GENE EXPRESSION AND CANCER DEVELOPMENT IS NOT WELL UNDERSTOOD. HERE, WE SHOW THAT CHRONIC LOW DOSES OF ARSENIC INDUCE MALIGNANT TRANSFORMATION AND TUMORIGENESIS IN KERATINOCYTES AND LEAD TO THE UPREGULATION OF ALKBH4 AND DOWNREGULATION OF 6MA ON DNA. WE FOUND THAT REDUCED 6MA LEVELS IN RESPONSE TO LOW LEVELS OF ARSENIC WERE MEDIATED BY THE UPREGULATION OF THE 6MA DNA DEMETHYLASE ALKBH4. MOREOVER, WE FOUND THAT ARSENIC INCREASED ALKBH4 PROTEIN LEVELS AND THAT ALKBH4 DELETION IMPAIRED ARSENIC-INDUCED TUMORIGENICITY IN VITRO AND IN MICE. MECHANISTICALLY, WE FOUND THAT ARSENIC PROMOTED ALKBH4 PROTEIN STABILITY THROUGH REDUCED AUTOPHAGY. TOGETHER, OUR FINDINGS REVEAL THAT THE DNA 6MA DEMETHYLASEALKBH4 PROMOTES ARSENIC TUMORIGENICITY AND ESTABLISHES ALKBH4 AS A PROMISING TARGET FOR ARSENIC-INDUCED TUMORIGENESIS. 2022 15 1814 34 EFFECTS OF CHRONIC COBALT AND CHROMIUM EXPOSURE AFTER METAL-ON-METAL HIP RESURFACING: AN EPIGENOME-WIDE ASSOCIATION PILOT STUDY. METAL-ON-METAL (MOM) HIP RESURFACING HAS RECENTLY BEEN A POPULAR PROSTHESIS CHOICE FOR THE TREATMENT OF SYMPTOMATIC ARTHRITIS, BUT RESULTS IN THE RELEASE OF COBALT AND CHROMIUM IONS INTO THE CIRCULATION THAT CAN BE ASSOCIATED WITH ADVERSE CLINICAL EFFECTS. THE MECHANISM UNDERLYING THESE EFFECTS REMAINS UNCLEAR. WHILE CHROMOSOMAL ANEUPLOIDY AND TRANSLOCATIONS ARE ASSOCIATED WITH THIS EXPOSURE, THE PRESENCE OF SUBTLE STRUCTURAL EPIGENETIC MODIFICATIONS IN PATIENTS WITH MOM JOINT REPLACEMENTS REMAINS UNEXPLORED. CONSEQUENTLY, WE ANALYZED WHOLE BLOOD DNA METHYLATION IN 34 OA PATIENTS WITH MOM HIP RESURFACING (MOM HR) COMPARED TO 34 OA PATIENTS WITH NON-MOM TOTAL HIP REPLACEMENTS (NON-MOM THR), USING THE GENOME-WIDE ILLUMINA HUMANMETHYLATION 450K BEADCHIP. NO PROBES SHOWED DIFFERENTIAL METHYLATION SIGNIFICANT AT 5% FALSE-DISCOVERY RATE (FDR). WE ALSO TESTED ASSOCIATION OF PROBE METHYLATION LEVELS WITH BLOOD CHROMIUM AND COBALT LEVELS DIRECTLY; THERE WERE NO SIGNIFICANT ASSOCIATIONS AT 5% FDR. FINALLY, WE USED THE "EPIGENETIC CLOCK" TO COMPARE ESTIMATED TO ACTUAL AGE AT SAMPLE FOR ALL INDIVIDUALS. WE FOUND NO SIGNIFICANT DIFFERENCE BETWEEN MOM HR AND NON-MOM THR, AND NO CORRELATION OF AGE ACCELERATION WITH BLOOD METAL LEVELS. OUR RESULTS SUGGEST THE ABSENCE OF LARGE METHYLATION DIFFERENCES SYSTEMICALLY FOLLOWING METAL EXPOSURE, HOWEVER, LARGER SAMPLE SIZES WILL BE REQUIRED TO IDENTIFY POTENTIAL SMALL EFFECTS. ANY DNA METHYLATION CHANGES THAT MAY OCCUR IN THE LOCAL PERIPROSTHETIC TISSUES REMAIN TO BE ELUCIDATED. (C) 2017 THE AUTHORS. ORTHOPAEDIC RESEARCH SOCIETY. PUBLISHED BY WILEY PERIODICALS, INC. ON BEHALF OF ORTHOPAEDIC RESEARCH SOCIETY. J ORTHOP RES 35:2323-2328, 2017. 2017 16 4155 24 MECHANISTIC UNDERSTANDING OF THE TOXIC EFFECTS OF ARSENIC AND WARFARE ARSENICALS ON HUMAN HEALTH AND ENVIRONMENT. WORLDWIDE, MORE THAN 200 MILLION PEOPLE ARE ESTIMATED TO BE EXPOSED TO UNSAFE LEVELS OF ARSENIC. CHRONIC EXPOSURE TO UNSAFE LEVELS OF GROUNDWATER ARSENIC IS RESPONSIBLE FOR MULTIPLE HUMAN DISORDERS, INCLUDING DERMAL, CARDIOVASCULAR, NEUROLOGICAL, PULMONARY, RENAL, AND METABOLIC CONDITIONS. CONSUMPTION OF RICE AND SEAFOOD (WHERE HIGH LEVELS OF ARSENIC ARE ACCUMULATED) IS ALSO RESPONSIBLE FOR HUMAN EXPOSURE TO ARSENIC. THE TOXICITY OF ARSENIC COMPOUNDS VARIES GREATLY AND MAY DEPEND ON THEIR CHEMICAL FORM, SOLUBILITY, AND CONCENTRATION. SURPRISINGLY, SYNTHETIC ORGANOARSENICALS ARE EXTREMELY TOXIC MOLECULES WHICH CREATED INTEREST IN THEIR DEVELOPMENT AS CHEMICAL WARFARE AGENTS (CWAS) DURING WORLD WAR I (WWI). AMONG THESE CWAS, ADAMSITE, CLARK I, CLARK II, AND LEWISITE ARE OF CRITICAL IMPORTANCE, AS STOCKPILES OF THESE AGENTS STILL EXIST WORLDWIDE. IN ADDITION, UNUSED WWII WEAPONIZED ARSENICALS DISCARDED IN WATER BODIES OR BURIED IN MANY PARTS OF THE WORLD CONTINUE TO POSE A SERIOUS THREAT TO THE ENVIRONMENT AND HUMAN HEALTH. METABOLIC INHIBITION, OXIDATIVE STRESS, GENOTOXICITY, AND EPIGENETIC ALTERATIONS INCLUDING MICRO-RNA-DEPENDENT REGULATION ARE SOME OF THE UNDERLYING MECHANISMS OF ARSENIC TOXICITY. MECHANISTIC UNDERSTANDING OF THE TOXICITY OF ORGANOARSENICALS IS ALSO CRITICAL FOR THE DEVELOPMENT OF EFFECTIVE THERAPEUTIC INTERVENTIONS. THIS REVIEW PROVIDES COMPREHENSIVE DETAILS AND A CRITICAL ASSESSMENT OF RECENTLY PUBLISHED DATA ON VARIOUS CHEMICAL FORMS OF ARSENIC, THEIR EXPOSURE, AND IMPLICATIONS ON HUMAN AND ENVIRONMENTAL HEALTH. 2023 17 4267 32 MICROARRAY DATASET OF TRANSIENT AND PERMANENT DNA METHYLATION CHANGES IN HELA CELLS UNDERGOING INORGANIC ARSENIC-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION. THE NOVEL DATASET PRESENTED HERE REPRESENTS THE RESULTS OF THE CHANGING PATTERN OF DNA METHYLATION PROFILES IN HELA CELLS EXPOSED TO CHRONIC LOW DOSE (0.5 MICROM) SODIUM ARSENITE, RESULTING IN EPITHELIAL-TO-MESENCHYMAL TRANSITION, AS WELL AS DNA METHYLATION PATTERNS IN CELLS WHERE INORGANIC ARSENIC HAS BEEN REMOVED. INORGANIC ARSENIC IS A KNOWN CARCINOGEN, THOUGH NOT MUTAGENIC. SEVERAL MECHANISMS HAVE BEEN PROPOSED AS TO HOW INORGANIC ARSENIC DRIVES CARCINOGENESIS SUCH AS REGULATION OF THE CELL?S REDOX POTENTIAL AND/OR EPIGENETICS. IN FACT, THERE ARE GENE SPECIFIC STUDIES AND LIMITED GENOME-WIDE STUDIES THAT HAVE IMPLICATED EPIGENETIC FACTORS SUCH AS DNA METHYLATION IN INORGANIC ARSENIC-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT). HOWEVER, GENOME-WIDE STUDIES ABOUT THE IMPACT OF 1) CHRONIC, LOW-DOSE INORGANIC ARSENIC EXPOSURE ON DNA METHYLATION PATTERNS DURING INORGANIC ARSENIC-INDUCED EPITHELIAL-TO-MESENCHYMAL TRANSITION, AND 2) THE REMOVAL INORGANIC ARSENIC (REVERSAL) ON DNA METHYLATION PATTERNS, IS LACKING. FOR THIS DATASET, TWO REPLICATES WERE PERFORMED WITH EACH OF THE SAMPLES - NON-TREATED, INORGANIC ARSENIC-TREATED, AND REVERSE-TREATED CELLS. WE PROVIDE NORMALIZED AND PROCESSED DATA, AND LOG2 FOLD CHANGE IN DNA METHYLATION. THE RAW MICROARRAY DATA ARE AVAILABLE THROUGH NCBI GEO, ACCESSION NUMBER GSE95232 AND A RELATED RESEARCH PAPER HAS BEEN ACCEPTED FOR PUBLISHED IN TOXICOLOGY AND APPLIED PHARMACOLOGY (ECKSTEIN ET AL., 2017) [1]. 2017 18 6562 34 TRANSIENT AND PERMANENT CHANGES IN DNA METHYLATION PATTERNS IN INORGANIC ARSENIC-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION. CHRONIC LOW DOSE INORGANIC ARSENIC EXPOSURE CAUSES CELLS TO TAKE ON AN EPITHELIAL-TO-MESENCHYMAL PHENOTYPE, WHICH IS A CRUCIAL PROCESS IN CARCINOGENESIS. INORGANIC ARSENIC IS NOT A MUTAGEN AND THUS EPIGENETIC ALTERATIONS HAVE BEEN IMPLICATED IN THIS PROCESS. INDEED, DURING THE EPITHELIAL-TO-MESENCHYMAL TRANSITION, MORPHOLOGIC CHANGES TO CELLS CORRELATE WITH CHANGES IN CHROMATIN STRUCTURE AND GENE EXPRESSION, ULTIMATELY DRIVING THIS PROCESS. HOWEVER, STUDIES ON THE EFFECTS OF INORGANIC ARSENIC EXPOSURE/WITHDRAWAL ON THE EPITHELIAL-TO-MESENCHYMAL TRANSITION AND THE IMPACT OF EPIGENETIC ALTERATIONS IN THIS PROCESS ARE LIMITED. IN THIS STUDY WE USED HIGH-RESOLUTION MICROARRAY ANALYSIS TO MEASURE THE CHANGES IN DNA METHYLATION IN CELLS UNDERGOING INORGANIC ARSENIC-INDUCED EPITHELIAL-TO-MESENCHYMAL TRANSITION, AND ON THE REVERSAL OF THIS PROCESS, AFTER REMOVAL OF THE INORGANIC ARSENIC EXPOSURE. WE FOUND THAT CELLS EXPOSED TO CHRONIC, LOW-DOSE INORGANIC ARSENIC EXPOSURE SHOWED 30,530 SITES WERE DIFFERENTIALLY METHYLATED, AND WITH INORGANIC ARSENIC WITHDRAWAL SEVERAL DIFFERENTIAL METHYLATED SITES WERE REVERSED, ALBEIT NOT COMPLETELY. FURTHERMORE, THESE CHANGES IN DNA METHYLATION MAINLY CORRELATED WITH CHANGES IN GENE EXPRESSION AT MOST SITES TESTED BUT NOT AT ALL. THIS STUDY SUGGESTS THAT DNA METHYLATION CHANGES ON GENE EXPRESSION ARE NOT CLEAR-CUT AND PROVIDE A PLATFORM TO BEGIN TO UNCOVER THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION, SPECIFICALLY WITHIN THE CONTEXT OF INORGANIC ARSENIC TREATMENT. 2017 19 714 30 CADMIUM IS A MUTAGEN THAT ACTS BY INHIBITING MISMATCH REPAIR. MOST ERRORS THAT ARISE DURING DNA REPLICATION CAN BE CORRECTED BY DNA POLYMERASE PROOFREADING OR BY POST-REPLICATION MISMATCH REPAIR (MMR). INACTIVATION OF BOTH MUTATION-AVOIDANCE SYSTEMS RESULTS IN EXTREMELY HIGH MUTABILITY THAT CAN LEAD TO ERROR CATASTROPHE. HIGH MUTABILITY AND THE LIKELIHOOD OF CANCER CAN BE CAUSED BY MUTATIONS AND EPIGENETIC CHANGES THAT REDUCE MMR. HYPERMUTABILITY CAN ALSO BE CAUSED BY EXTERNAL FACTORS THAT DIRECTLY INHIBIT MMR. IDENTIFYING SUCH FACTORS HAS IMPORTANT IMPLICATIONS FOR UNDERSTANDING THE ROLE OF THE ENVIRONMENT IN GENOME STABILITY. WE FOUND THAT CHRONIC EXPOSURE OF YEAST TO ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF CADMIUM, A KNOWN HUMAN CARCINOGEN, CAN RESULT IN EXTREME HYPERMUTABILITY. THE MUTATION SPECIFICITY ALONG WITH RESPONSES IN PROOFREADING-DEFICIENT AND MMR-DEFICIENT MUTANTS INDICATE THAT CADMIUM REDUCES THE CAPACITY FOR MMR OF SMALL MISALIGNMENTS AND BASE-BASE MISMATCHES. IN EXTRACTS OF HUMAN CELLS, CADMIUM INHIBITED AT LEAST ONE STEP LEADING TO MISMATCH REMOVAL. TOGETHER, OUR DATA SHOW THAT A HIGH LEVEL OF GENETIC INSTABILITY CAN RESULT FROM ENVIRONMENTAL IMPEDIMENT OF A MUTATION-AVOIDANCE SYSTEM. 2003 20 1970 25 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