1 4208 112 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 2 1157 31 CONTAMINANT METALS AS CARDIOVASCULAR RISK FACTORS: A SCIENTIFIC STATEMENT FROM THE AMERICAN HEART ASSOCIATION. EXPOSURE TO ENVIRONMENTAL POLLUTANTS IS LINKED TO INCREASED RISK OF CARDIOVASCULAR DISEASE. BEYOND THE EXTENSIVE EVIDENCE FOR PARTICULATE AIR POLLUTION, ACCUMULATING EVIDENCE SUPPORTS THAT EXPOSURE TO NONESSENTIAL METALS SUCH AS LEAD, CADMIUM, AND ARSENIC IS A SIGNIFICANT CONTRIBUTOR TO CARDIOVASCULAR DISEASE WORLDWIDE. HUMANS ARE EXPOSED TO METALS THROUGH AIR, WATER, SOIL, AND FOOD AND EXTENSIVE INDUSTRIAL AND PUBLIC USE. CONTAMINANT METALS INTERFERE WITH CRITICAL INTRACELLULAR REACTIONS AND FUNCTIONS LEADING TO OXIDATIVE STRESS AND CHRONIC INFLAMMATION THAT RESULT IN ENDOTHELIAL DYSFUNCTION, HYPERTENSION, EPIGENETIC DYSREGULATION, DYSLIPIDEMIA, AND CHANGES IN MYOCARDIAL EXCITATION AND CONTRACTILE FUNCTION. LEAD, CADMIUM, AND ARSENIC HAVE BEEN LINKED TO SUBCLINICAL ATHEROSCLEROSIS, CORONARY ARTERY STENOSIS, AND CALCIFICATION AS WELL AS TO INCREASED RISK OF ISCHEMIC HEART DISEASE AND STROKE, LEFT VENTRICULAR HYPERTROPHY AND HEART FAILURE, AND PERIPHERAL ARTERY DISEASE. EPIDEMIOLOGICAL STUDIES SHOW THAT EXPOSURE TO LEAD, CADMIUM, OR ARSENIC IS ASSOCIATED WITH CARDIOVASCULAR DEATH MOSTLY ATTRIBUTABLE TO ISCHEMIC HEART DISEASE. PUBLIC HEALTH MEASURES REDUCING METAL EXPOSURE ARE ASSOCIATED WITH REDUCTIONS IN CARDIOVASCULAR DISEASE DEATH. POPULATIONS OF COLOR AND LOW SOCIOECONOMIC MEANS ARE MORE COMMONLY EXPOSED TO METALS AND THEREFORE AT GREATER RISK OF METAL-INDUCED CARDIOVASCULAR DISEASE. TOGETHER WITH STRENGTHENING PUBLIC HEALTH MEASURES TO PREVENT METAL EXPOSURES, DEVELOPMENT OF MORE SENSITIVE AND SELECTIVE MEASUREMENT MODALITIES, CLINICAL MONITORING OF METAL EXPOSURES, AND THE DEVELOPMENT OF METAL CHELATION THERAPIES COULD FURTHER DIMINISH THE BURDEN OF CARDIOVASCULAR DISEASE ATTRIBUTABLE TO METAL EXPOSURE. 2023 3 1925 34 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 4 3739 32 INS AND OUTS OF CADMIUM-INDUCED CARCINOGENESIS: MECHANISM AND PREVENTION. CADMIUM (CD) IS A HEAVY METAL AND A HIGHLY TOXIC POLLUTANT THAT IS RELEASED INTO THE ENVIRONMENT AS A BYPRODUCT OF MOST MODERN FACTORIES AND INDUSTRIES. CD ENTERS OUR BODY IN SIGNIFICANT QUANTITIES FROM CONTAMINATED WATER, CIGARETTE SMOKE, OR FOOD PRODUCT TO MANY DETRIMENTAL HEALTH HAZARDS. BASED ON CAUSAL ASSOCIATION ALL THE CD-RELATED OR DERIVED COMPOUNDS HAVE BEEN CLASSIFIED AS CARCINOGENS. IN THIS STUDY, WE PRESENT AN OVERVIEW OF THE PUBLISHED LITERATURE TO UNDERSTAND THE MOLECULAR MECHANISMS FOR CD-INDUCED CARCINOGENESIS AND ITS PREVENTION. IN ACUTE CD POISONING PRODUCTION OF REACTIVE OXYGEN SPECIES IS A KEY FACTOR. HOWEVER, CHRONIC CD EXPOSURE CAN TRANSFORM CELLS TO BECOME MORE RESISTANT TO OXIDATIVE STRESS. ALSO, AS AN EPIGENETIC MECHANISM CD ACTS INDIRECTLY ON DNA REPAIR MECHANISMS VIA ALTERATION OF REACTIONS UPSTREAM. THOSE TRANSFORMED CELLS ACQUIRE RESISTANCE TO APOPTOSIS AND DEREGULATION OF CALCIUM HOMEOSTASIS. LEADING TO UNCONTROLLED CARCINOGENIC CELL PROLIFERATION AND INHERENT DNA LESIONS. FLAVONOIDS COMMONLY FOUND IN PLANT FOODS HAVE BEEN SHOWN TO HAVE A PROTECTIVE EFFECT AGAINST CD-INDUCED CARCINOGENICITY. A WIDE VARIETY OF TUMORIGENIC MECHANISMS INVOLVED IN CHRONIC CD EXPOSURE AND THE BENEFICIAL EFFECTS OF FLAVONOIDS AGAINST CD-INDUCED CARCINOGENICITY NECESSITATE FURTHER INVESTIGATIONS. 2021 5 5295 33 PROTECTIVE POTENTIAL OF THYMOQUINONE AGAINST CADMIUM, ARSENIC, AND LEAD TOXICITY: A SHORT REVIEW WITH EMPHASIS ON OXIDATIVE PATHWAYS. HEAVY METALS ARE AMONG THE MOST IMPORTANT ENVIRONMENTAL POLLUTIONS USED IN VARIOUS INDUSTRIES. THEIR EXTENSIVE USE HAS INCREASED HUMAN SUSCEPTIBILITY TO DIFFERENT CHRONIC DISEASES. TOXIC METAL EXPOSURE, ESPECIALLY CADMIUM, ARSENIC, AND LEAD, CAUSES OXIDATIVE DAMAGES, MITOCHONDRIAL DYSFUNCTION, AND GENETIC AND EPIGENETIC MODIFICATIONS. MEANWHILE, THYMOQUINONE (TQ) IS AN EFFECTIVE COMPONENT OF NIGELLA SATIVA OIL THAT PLAYS AN IMPORTANT ROLE IN PREVENTING THE DESTRUCTIVE EFFECTS OF HEAVY METALS. THE PRESENT REVIEW DISCUSSES HOW TQ CAN PROTECT VARIOUS TISSUES AGAINST OXIDATIVE DAMAGE OF HEAVY METALS. THIS REVIEW IS BASED ON THE RESEARCH REPORTED ABOUT THE PROTECTIVE EFFECTS OF TQ IN THE TOXICITY OF HEAVY METALS, APPROXIMATELY THE LAST 10 YEARS (2010-2021). SCIENTIFIC DATABASES, INCLUDING SCOPUS, WEB OF SCIENCE, AND PUBMED, WERE SEARCHED USING THE FOLLOWING KEYWORDS EITHER ALONE OR IN COMBINATION: CADMIUM, ARSENIC, LEAD, TQ, AND OXIDATIVE STRESS. TQ, AS A POTENT ANTIOXIDANT, CAN DISTRIBUTE TO CELLULAR COMPARTMENTS AND PREVENT OXIDATIVE DAMAGE OF TOXIC METALS. HOWEVER, DEPENDING ON THE TYPE OF TOXIC METAL AND THE CARRIER SYSTEM USED TO RELEASE TQ IN BIOLOGICAL SYSTEMS, ITS THERAPEUTIC DOSAGE RANGE MAY BE VARIED. 2023 6 904 32 CHRONIC EXPOSURE TO CADMIUM INDUCES DIFFERENTIAL METHYLATION IN MICE SPERMATOZOA. CADMIUM EXPOSURE IS UBIQUITOUS AND HAS BEEN LINKED TO DISEASES INCLUDING CANCERS AND REPRODUCTIVE DEFECTS. SINCE CADMIUM IS NONMUTAGENIC, IT IS THOUGHT TO EXERT ITS GENE DYSREGULATORY EFFECTS THROUGH EPIGENETIC REPROGRAMMING. SEVERAL STUDIES HAVE IMPLICATED GERMLINE EXPOSURE TO CADMIUM IN DEVELOPMENTAL REPROGRAMMING. HOWEVER, MOST OF THESE STUDIES HAVE FOCUSED ON MATERNAL EXPOSURE, WHILE THE IMPACT ON SPERM FERTILITY AND DISEASE SUSCEPTIBILITY HAS RECEIVED LESS ATTENTION. IN THIS STUDY, WE USED REDUCED REPRESENTATION BISULFITE SEQUENCING TO COMPREHENSIVELY INVESTIGATE THE IMPACT OF CHRONIC CADMIUM EXPOSURE ON MOUSE SPERMATOZOA DNA METHYLATION. ADULT MALE C57BL/J6 MICE WERE PROVIDED WATER WITH OR WITHOUT CADMIUM CHLORIDE FOR 9 WEEKS. SPERM, TESTES, LIVER, AND KIDNEY TISSUES WERE COLLECTED AT THE END OF THE TREATMENT PERIOD. CADMIUM EXPOSURE WAS CONFIRMED THROUGH GENE EXPRESSION ANALYSIS OF METALLOTHIONEIN-1 AND 2, 2 WELL-KNOWN CADMIUM-INDUCED GENES. ANALYSIS OF SPERM DNA METHYLATION CHANGES REVEALED 1788 DIFFERENTIALLY METHYLATED SITES PRESENT AT REGULATORY REGIONS IN SPERM OF MICE EXPOSED TO CADMIUM COMPARED WITH VEHICLE (CONTROL) MICE. FURTHERMORE, MOST OF THESE DIFFERENTIAL METHYLATION CHANGES POSITIVELY CORRELATED WITH CHANGES IN GENE EXPRESSION AT BOTH THE TRANSCRIPTION INITIATION STAGE AS WELL AS THE SPLICING LEVELS. INTERESTINGLY, THE GENES TARGETED BY CADMIUM EXPOSURE ARE INVOLVED IN SEVERAL CRITICAL DEVELOPMENTAL PROCESSES. OUR RESULTS PRESENT A COMPREHENSIVE ANALYSIS OF THE SPERM METHYLOME IN RESPONSE TO CHRONIC CADMIUM EXPOSURE. THESE DATA, THEREFORE, HIGHLIGHT A FOUNDATIONAL FRAMEWORK TO STUDY GENE EXPRESSION PATTERNS THAT MAY AFFECT FERTILITY IN THE EXPOSED INDIVIDUAL AS WELL AS THEIR OFFSPRING, THROUGH PATERNAL INHERITANCE. 2021 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 1915 33 ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE OF METALS AND FEMALE REPRODUCTIVE HEALTH. UNTAINTED ENVIRONMENT PROMOTES HEALTH, BUT THE LAST FEW DECADES EXPERIENCED STEEP UPSURGE IN ENVIRONMENTAL CONTAMINANTS POSING DETRIMENTAL PHYSIOLOGICAL IMPACT. THE RESPONSIBLE FACTORS MAINLY INCLUDE THE EXPONENTIAL GROWTH OF HUMAN POPULATION, HAVOC RISE IN INDUSTRIALIZATION, POORLY PLANNED URBANIZATION, AND SLAPDASH ENVIRONMENT MANAGEMENT. ENVIRONMENTAL DEGRADATION CAN INCREASE THE LIKELIHOOD OF HUMAN EXPOSURE TO HEAVY METALS, RESULTING IN HEALTH CONSEQUENCES SUCH AS REPRODUCTIVE PROBLEMS. AS A RESULT, RESEARCH INTO METAL-INDUCED CAUSES OF REPRODUCTIVE IMPAIRMENT AT THE GENETIC, EPIGENETIC, AND BIOCHEMICAL LEVELS MUST BE STRENGTHENED FURTHER. THESE METALS IMPACT UPON THE FEMALE REPRODUCTION AT ALL STRATA OF ITS REGULATION AND FUNCTIONS, BE IT DEVELOPMENT, MATURATION, OR ENDOCRINE FUNCTIONS, AND ARE LINKED TO AN INCREASE IN THE CAUSES OF INFERTILITY IN WOMEN. CHRONIC EXPOSURES TO THE HEAVY METALS MAY LEAD TO BREAST CANCER, ENDOMETRIOSIS, ENDOMETRIAL CANCER, MENSTRUAL DISORDERS, AND SPONTANEOUS ABORTIONS, AS WELL AS PRE-TERM DELIVERIES, STILLBIRTHS. FOR EXAMPLE, ENDOMETRIOSIS, ENDOMETRIAL CANCER, AND SPONTANEOUS ABORTIONS ARE ALL CAUSED BY THE METALLOESTROGEN CADMIUM (CD); LEAD (PB) LEVELS OVER A CERTAIN THRESHOLD CAN CAUSE SPONTANEOUS ABORTION AND HAVE A TERATOGENIC IMPACT; TOXIC AMOUNTS OF MERCURY (HG) HAVE AN INFLUENCE ON THE MENSTRUAL CYCLE, WHICH CAN LEAD TO INFERTILITY. IMPACT OF ENVIRONMENTAL EXPOSURE TO HEAVY METALS ON FEMALE FERTILITY IS THEREFORE A WELL-KNOWN FACT. THUS, THE UNDERLYING MECHANISMS MUST BE EXPLAINED AND PERIODICALLY UPDATED, GIVEN THE GROWING EVIDENCE ON THE INFLUENCE OF INCREASING ENVIRONMENTAL HEAVY METAL LOAD ON FEMALE FERTILITY. THE PURPOSE OF THIS REVIEW IS TO GIVE A CONCISE OVERVIEW OF HOW HEAVY METAL AFFECTS FEMALE REPRODUCTIVE HEALTH. 2022 9 4009 27 LOW LEVELS OF CD INDUCE PERSISTING EPIGENETIC MODIFICATIONS AND ACCLIMATION MECHANISMS IN THE EARTHWORM LUMBRICUS TERRESTRIS. TOXIC EFFECTS OF CADMIUM (CD), A COMMON SOIL POLLUTANT, ARE STILL NOT VERY WELL UNDERSTOOD, PARTICULARLY IN REGARD TO ITS EPIGENETIC IMPACT. THEREFORE, THE AIM OF THIS STUDY WAS TO ASSESS DNA METHYLATION CHANGES AND THEIR PERSISTENCE IN THE EARTHWORM LUMBRICUS TERRESTRIS UPON CHRONIC LOW DOSE CD EXPOSURE USING METHYLATION SENSITIVE AMPLIFICATION POLYMORPHISM (MSAP). MOREOVER, THE BIOMARKER RESPONSE AND FITNESS OF THE EARTHWORMS, AS WELL AS THE EXPRESSION OF DETOXIFICATION-RELATED GENES (METALLOTHIONEIN (MT) AND PHYTOCHELATIN SYNTHASE (PCS)) WAS EVALUATED. LOW LEVELS OF CD CAUSED AN INCREASE IN GENOME-WIDE DNA METHYLATION, WHICH REMAINED PARTLY MODIFIED, EVEN AFTER SEVERAL MONTHS OF RECOVERY IN UNPOLLUTED SOIL. INCREASED CELLULAR STRESS SEEMED TO DECREASE AFTER TWO WEEKS OF EXPOSURE WHEREAS FITNESS PARAMETERS REMAINED UNAFFECTED BY CD, PROBABLY AS A RESULT FROM THE ACTIVATION OF DETOXIFICATION MECHANISMS LIKE THE EXPRESSION OF MTS. INTERESTINGLY, EVEN THOUGH THE LEVEL OF CD EXPOSURE WAS VERY LOW, MT EXPRESSION LEVELS INDICATE THE DEVELOPMENT OF ACCLIMATION MECHANISMS. TAKEN TOGETHER, THIS STUDY DEMONSTRATES THAT ACCLIMATION, AS WELL AS EPIGENETIC MODIFICATIONS CAN OCCUR ALREADY IN MODERATELY POLLUTED ENVIRONMENTS. IN ADDITION, THESE EFFECTS CAN HAVE LONG-LASTING IMPACTS ON KEY SPECIES OF SOIL INVERTEBRATES AND MIGHT PERSIST LONG AFTER THE ACTUAL HEAVY METAL CHALLENGE HAS PASSED. 2017 10 3566 34 IMPACT OF HEAVY METALS ON THE FEMALE REPRODUCTIVE SYSTEM. INTRODUCTION: IT HAS BEEN RECOGNIZED THAT ENVIRONMENTAL POLLUTION CAN AFFECT THE QUALITY OF HEALTH OF THE HUMAN POPULATION. HEAVY METALS ARE AMONG THE GROUP OF HIGHLY EMITTED CONTAMINANTS AND THEIR ADVERSE EFFECT OF LIVING ORGANISMS HAS BEEN WIDELY STUDIED IN RECENT DECADES. LIFESTYLE AND QUALITY OF THE AMBIENT ENVIRONMENT ARE AMONG THESE FACTORS WHICH CAN MAINLY CONTRIBUTE TO THE HEAVY METALS EXPOSURE IN HUMANS. OBJECTIVE: A REVIEW OF LITERATURE LINKING HEAVY METALS AND THE FEMALE REPRODUCTIVE SYSTEM AND DESCRIPTION OF THE POSSIBLE ASSOCIATIONS WITH EMISSION AND EXPOSURE OF HEAVY METALS AND IMPAIRMENTS OF FEMALE REPRODUCTIVE SYSTEM ACCORDING TO CURRENT KNOWLEDGE. RESULTS: THE POTENTIAL HEALTH DISORDERS CAUSED BY CHRONIC OR ACUTE HEAVY METALS TOXICITY INCLUDE IMMUNODEFICIENCY, OSTEOPOROSIS, NEURODEGENERATION AND ORGAN FAILURES. POTENTIAL LINKAGES OF HEAVY METALS CONCENTRATION FOUND IN DIFFERENT HUMAN ORGANS AND BLOOD WITH OESTROGEN-DEPENDENT DISEASES SUCH AS BREAST CANCER, ENDOMETRIAL CANCER, ENDOMETRIOSIS AND SPONTANEOUS ABORTIONS, AS WELL AS PRE-TERM DELIVERIES, STILLBIRTHS AND HYPOTROPHY, HAVE ALSO BEEN REPORTED. CONCLUSIONS: ENVIRONMENTAL DETERIORATION CAN LEAD TO THE ELEVATED RISK OF HUMAN EXPOSURE TO HEAVY METALS, AND CONSEQUENTLY, HEALTH IMPLICATIONS INCLUDING DISTURBANCES IN REPRODUCTION. IT IS THEREFORE IMPORTANT TO CONTINUE THE INVESTIGATIONS ON METAL-INDUCED MECHANISMS OF FERTILITY IMPAIRMENT ON THE GENETIC, EPIGENETIC AND BIOCHEMICAL LEVEL. 2015 11 106 35 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 12 4119 35 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 13 6370 44 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 14 4881 32 OVERVIEW OF THE CARDIOVASCULAR EFFECTS OF ENVIRONMENTAL METALS: NEW PRECLINICAL AND CLINICAL INSIGHTS. ENVIRONMENTAL CAUSES OF CARDIOVASCULAR DISEASES (CVDS) ARE GLOBAL HEALTH ISSUES. IN PARTICULAR, AN ASSOCIATION BETWEEN METAL EXPOSURE AND CVDS HAS BECOME EVIDENT BUT CAUSAL EVIDENCE STILL LACKS. THEREFORE, THIS SYMPOSIUM AT THE SOCIETY OF TOXICOLOGY 2022 ANNUAL MEETING ADDRESSED EPIDEMIOLOGICAL, CLINICAL, PRE-CLINICAL ANIMAL MODEL-DERIVED AND MECHANISM-BASED EVIDENCE BY FIVE PRESENTATIONS: 1) AN EPIDEMIOLOGIC STUDY ON POTENTIAL CVD RISKS OF INDIVIDUALS EXPOSED OCCUPATIONALLY AND ENVIRONMENTALLY TO HEAVY METALS; 2) BOTH PRESENTATIONS OF THE SECOND AND THIRD WERE CLINICAL STUDIES FOCUSING ON THE POTENTIAL LINK BETWEEN HEAVY METALS AND PULMONARY ARTERIAL HYPERTENSION (PAH), BY PRESENTING ALTERED BLOOD METAL CONCENTRATIONS OF BOTH NON-ESSENTIAL AND ESSENTIAL METALS IN THE PATIENTS WITH PAH AND POTENTIAL THERAPEUTIC APPROACHES; 3) ARSENIC-INDUCED ATHEROSCLEROSIS VIA INFLAMMATORY CELLS IN MOUSE MODEL; 4) PATHOGENIC EFFECTS ON THE HEART BY ADULT CHRONIC EXPOSURE TO VERY LOW-DOSE CADMIUM VIA EPIGENETIC MECHANISMS AND WHOLE LIFE EXPOSURE TO LOW DOSE CADMIUM VIA EXACERBATING HIGH-FAT-DIET-LIPOTOXICITY. THIS SYMPOSIUM HAS BROUGHT EPIDEMIOLOGISTS, THERAPEUTIC INDUSTRY, PHYSICIANS, AND TRANSLATIONAL SCIENTISTS TOGETHER TO DISCUSS THE HEALTH RISKS OF OCCUPATIONAL AND ENVIRONMENTAL EXPOSURE TO HEAVY METALS THROUGH DIRECT CARDIOTOXICITY AND INDIRECT DISRUPTION OF HOMEOSTATIC MECHANISMS REGULATING ESSENTIAL METALS, AS WELL AS LIPID LEVELS. THE DATA SUMMARIZED BY THE PRESENTERS INFERS A POTENTIAL CAUSAL LINK BETWEEN MULTIPLE METALS AND CVDS AND DEFINES DIFFERENCES AND COMMONALITIES. THEREFORE, SUMMARY OF THESE PRESENTATIONS MAY ACCELERATE THE DEVELOPMENT OF EFFICIENT PREVENTIVE AND THERAPEUTIC STRATEGIES BY FACILITATING COLLABORATIONS AMONG MULTIDISCIPLINARY INVESTIGATORS. 2022 15 1644 36 DOES THE ENVIRONMENT AFFECT MENOPAUSE? A REVIEW OF THE EFFECTS OF ENDOCRINE DISRUPTING CHEMICALS ON MENOPAUSE. ENDOCRINE DISRUPTING CHEMICALS ARE WIDELY DISTRIBUTED IN OUR ENVIRONMENT. HUMANS ARE EXPOSED TO THESE COMPOUNDS NOT ONLY THROUGH THEIR OCCUPATIONS, BUT ALSO THROUGH DIETARY CONSUMPTION AND EXPOSURE TO CONTAMINATED WATER, PERSONAL CARE PRODUCTS AND TEXTILES. CHEMICALS THAT ARE PERSISTENT IN THE BODY AND IN OUR ENVIRONMENT INCLUDE DIOXINS AND POLYCHLORINATED BIPHENYLS. NON-PERSISTENT CHEMICALS INCLUDING BISPHENOL A, PHTHALATES AND PARABENS ARE EQUALLY AS IMPORTANT BECAUSE THEY ARE UBIQUITOUS IN OUR ENVIRONMENT. HEAVY METALS, INCLUDING LEAD AND CADMIUM, CAN ALSO HAVE ENDOCRINE DISRUPTING PROPERTIES. ALTHOUGH DIFFICULT TO STUDY DUE TO THEIR VARIETY OF SOURCES OF EXPOSURES AND MECHANISMS OF ACTION, THESE CHEMICALS HAVE BEEN ASSOCIATED WITH EARLY MENOPAUSE, INCREASED FREQUENCY OF VASOMOTOR SYMPTOMS, ALTERED STEROID HORMONE LEVELS AND MARKERS OF DIMINISHED OVARIAN RESERVE. UNDERSTANDING THE IMPACTS OF THESE EXPOSURES IS IMPORTANT GIVEN THE POTENTIAL FOR EPIGENETIC MODIFICATION, WHICH CAN ALTER GENE FUNCTION AND RESULT IN MULTI-GENERATIONAL EFFECTS. THIS REVIEW SUMMARIZES FINDINGS IN HUMANS AND ANIMALS OR CELL-BASED MODELS FROM THE PAST DECADE OF RESEARCH. CONTINUED RESEARCH IS NEEDED TO ASSESS THE EFFECTS OF MIXTURES OF CHEMICALS, CHRONIC EXPOSURES AND NEW COMPOUNDS THAT ARE CONTINUOUSLY BEING DEVELOPED AS REPLACEMENTS FOR TOXIC CHEMICALS THAT ARE BEING PHASED OUT. 2023 16 1530 37 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 17 935 38 CHRONIC LOW-DOSE EXPOSURE TO XENOESTROGEN AMBIENT AIR POLLUTANTS AND BREAST CANCER RISK: XENAIR PROTOCOL FOR A CASE-CONTROL STUDY NESTED WITHIN THE FRENCH E3N COHORT. BACKGROUND: BREAST CANCER IS THE MOST FREQUENT CANCER IN WOMEN IN INDUSTRIALIZED COUNTRIES. LIFESTYLE AND ENVIRONMENTAL FACTORS, PARTICULARLY ENDOCRINE-DISRUPTING POLLUTANTS, HAVE BEEN SUGGESTED TO PLAY A ROLE IN BREAST CANCER RISK. CURRENT EPIDEMIOLOGICAL STUDIES, ALTHOUGH NOT FULLY CONSISTENT, SUGGEST A POSITIVE ASSOCIATION OF BREAST CANCER RISK WITH EXPOSURE TO SEVERAL INTERNATIONAL AGENCY FOR RESEARCH ON CANCER GROUP 1 AIR-POLLUTANT CARCINOGENS, SUCH AS PARTICULATE MATTER, POLYCHLORINATED BIPHENYLS (PCB), DIOXINS, BENZO[A]PYRENE (BAP), AND CADMIUM. HOWEVER, EPIDEMIOLOGICAL STUDIES REMAIN SCARCE AND INCONSISTENT. IT HAS BEEN PROPOSED THAT THE MENOPAUSAL STATUS COULD MODIFY THE RELATIONSHIP BETWEEN POLLUTANTS AND BREAST CANCER AND THAT THE ASSOCIATION VARIES WITH HORMONE RECEPTOR STATUS. OBJECTIVE: THE XENAIR PROJECT WILL INVESTIGATE THE ASSOCIATION OF BREAST CANCER RISK (OVERALL AND BY HORMONE RECEPTOR STATUS) WITH CHRONIC EXPOSURE TO SELECTED AIR POLLUTANTS, INCLUDING PARTICULATE MATTER, NITROGEN DIOXIDE (NO2), OZONE (O3), BAP, DIOXINS, PCB-153, AND CADMIUM. METHODS: OUR RESEARCH IS BASED ON A CASE-CONTROL STUDY NESTED WITHIN THE FRENCH NATIONAL E3N COHORT OF 5222 INVASIVE BREAST CANCER CASES IDENTIFIED DURING FOLLOW-UP FROM 1990 TO 2011, AND 5222 MATCHED CONTROLS. A QUESTIONNAIRE WAS SENT TO ALL PARTICIPANTS TO COLLECT THEIR LIFETIME RESIDENTIAL ADDRESSES AND INFORMATION ON INDOOR POLLUTION. WE WILL ASSESS THESE EXPOSURES USING COMPLEMENTARY MODELS OF LAND-USE REGRESSION, ATMOSPHERIC DISPERSION, AND REGIONAL CHEMISTRY-TRANSPORT (CHIMERE) MODELS, VIA A GEOGRAPHIC INFORMATION SYSTEM. ASSOCIATIONS WITH BREAST CANCER RISK WILL BE MODELED USING CONDITIONAL LOGISTIC REGRESSION MODELS. WE WILL ALSO STUDY THE IMPACT OF EXPOSURE ON DNA METHYLATION AND INTERACTIONS WITH GENETIC POLYMORPHISMS. APPROPRIATE STATISTICAL METHODS, INCLUDING BAYESIAN MODELING, PRINCIPAL COMPONENT ANALYSIS, AND CLUSTER ANALYSIS, WILL BE USED TO ASSESS THE IMPACT OF MULTIPOLLUTANT EXPOSURE. THE FRACTION OF BREAST CANCER CASES ATTRIBUTABLE TO AIR POLLUTION WILL BE ESTIMATED. RESULTS: THE XENAIR PROJECT WILL CONTRIBUTE TO CURRENT KNOWLEDGE ON THE HEALTH EFFECTS OF AIR POLLUTION AND IDENTIFY AND UNDERSTAND ENVIRONMENTAL MODIFIABLE RISK FACTORS RELATED TO BREAST CANCER RISK. CONCLUSIONS: THE RESULTS WILL PROVIDE RELEVANT EVIDENCE TO GOVERNMENTS AND POLICY-MAKERS TO IMPROVE EFFECTIVE PUBLIC HEALTH PREVENTION STRATEGIES ON AIR POLLUTION. THE XENAIR DATASET CAN BE USED IN FUTURE EFFORTS TO STUDY THE EFFECTS OF EXPOSURE TO AIR POLLUTION ASSOCIATED WITH OTHER CHRONIC CONDITIONS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15167. 2020 18 1557 28 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 19 1993 48 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 20 1970 28 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