1 1970 81 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 2 588 32 BENZENE EXPOSURE IS ASSOCIATED WITH EPIGENETIC CHANGES (REVIEW). BENZENE IS A VOLATILE AROMATIC HYDROCARBON SOLVENT AND IS KNOWN AS ONE OF THE PREDOMINANT AIR POLLUTANTS IN THE ENVIRONMENT. CHRONIC EXPOSURE TO BENZENE IS KNOWN TO CAUSE APLASTIC ANEMIA AND INCREASED RISK OF ACUTE MYELOGENOUS LEUKEMIA IN HUMANS. ALTHOUGH THE MECHANISMS BY WHICH BENZENE CAUSES TOXICITY REMAIN TO BE FULLY ELUCIDATED, IT IS WIDELY ACCEPTED THAT ITS METABOLISM IS CRUCIAL TO ITS TOXICITY, WITH INVOLVEMENT OF ONE OR MORE REACTIVE METABOLITES. NOVEL APPROACHES AIMED AT EVALUATING DIFFERENT MECHANISMS BY WHICH BENZENE CAN IMPACT ON HUMAN HEALTH BY ALTERING GENE REGULATION HAVE BEEN DEVELOPED. AMONG THESE NOVEL APPROACHES, EPIGENETICS APPEARS TO BE PROMISING. THE PRESENT REVIEW ARTICLE SUMMARIZES THE MOST IMPORTANT FINDINGS, REPORTED FROM THE LITERATURE, ON EPIGENETIC MODIFICATIONS CORRELATED TO BENZENE EXPOSURE. A COMPUTERIZED SEARCH IN PUBMED WAS PERFORMED IN NOVEMBER 2014, USING SEARCH TERMS, INCLUDING 'BENZENE', 'EPIGENETIC', 'HISTONE MODIFICATIONS', 'DNA METHYLATION' AND 'MICRORNA'. EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES HAVE DEMONSTRATED THE POTENTIAL EPIGENETIC EFFECTS OF BENZENE EXPOSURE. SEVERAL OF THE EPIGENOMIC CHANGES OBSERVED IN RESPONSE TO ENVIRONMENTAL EXPOSURES MAY BE MECHANISTICALLY ASSOCIATED WITH SUSCEPTIBILITY TO DISEASES. HOWEVER, FURTHER ELUCIDATION OF THE MECHANISMS BY WHICH BENZENE ALTERS GENE EXPRESSION MAY IMPROVE PREDICTION OF THE TOXIC POTENTIAL OF NOVEL COMPOUNDS INTRODUCED INTO THE ENVIRONMENT, AND ALLOW FOR MORE TARGETED AND APPROPRIATE DISEASE PREVENTION STRATEGIES. 2016 3 3210 30 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 4 3710 40 INFLUENCES OF POLYCYCLIC AROMATIC HYDROCARBON ON THE EPIGENOME TOXICITY AND ITS APPLICABILITY IN HUMAN HEALTH RISK ASSESSMENT. THE EXISTENCE OF POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) IN AMBIENT AIR IS AN ESCALATING CONCERN WORLDWIDE BECAUSE OF THEIR ABILITY TO CAUSE CANCER AND INDUCE PERMANENT CHANGES IN THE GENETIC MATERIAL. GROWING EVIDENCE IMPLIES THAT DURING EARLY LIFE-SENSITIVE STAGES, THE RISK OF PROGRESSION OF ACUTE AND CHRONIC DISEASES DEPENDS ON EPIGENETIC CHANGES INITIATED BY THE INFLUENCE OF ENVIRONMENTAL CUES. SEVERAL REPORTS DECIPHERED THE RELATIONSHIP BETWEEN EXPOSURE TO ENVIRONMENTAL CHEMICALS AND EPIGENETICS, AND HAVE KNOWN TOXICANTS THAT ALTER THE EPIGENETIC STATES. AMONGST PAHS, BENZO[A]PYRENE (B[A]P) IS ACCEPTED AS A GROUP 1 CANCER-CAUSING AGENT BY THE INTERNATIONAL AGENCY FOR THE RESEARCH ON CANCER (IARC). B[A]P IS A WELL-STUDIED PRO-CARCINOGEN THAT IS METABOLICALLY ACTIVATED BY THE ARYL HYDROCARBON RECEPTOR (AHR)/CYTOCHROME P450 PATHWAY. CYTOCHROME P450 PLAYS A PIVOTAL ROLE IN THE STIMULATION STEP, WHICH IS ESSENTIAL FOR DNA ADDUCT FORMATION. ACCRUING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS ASSUME A FUNDAMENTAL PART IN PAH-PROMOTED CARCINOGENESIS. THIS INTERACTION BETWEEN PAHS AND EPIGENETIC FACTORS RESULTS IN AN ALTERED PROFILE OF THESE MARKS, GLOBALLY AND LOCUS-SPECIFIC. SOME OF THE EPIGENETIC CHANGES DUE TO EXPOSURE TO PAHS LEAD TO INCREASED DISEASE SUSCEPTIBILITY AND PROGRESSION. IT IS WELL UNDERSTOOD THAT EXPOSURE TO ENVIRONMENTAL CARCINOGENS, SUCH AS PAH TRIGGERS DISEASE PATHWAYS THROUGH CHANGES IN THE GENOME. SEVERAL EVIDENCE REPORTED DUE TO THE EPIGENOME-WIDE ASSOCIATION STUDIES, THAT EARLY LIFE ADVERSE ENVIRONMENTAL EVENTS MAY TRIGGER WIDESPREAD AND PERSISTENT VARIATIONS IN TRANSCRIPTIONAL PROFILING. MOREOVER, THESE VARIATIONS RESPOND TO DNA DAMAGE AND/OR A CONSEQUENCE OF EPIGENETIC MODIFICATIONS THAT NEED FURTHER INVESTIGATION. GROWING EVIDENCE HAS ASSOCIATED PAHS WITH EPIGENETIC VARIATIONS INVOLVING ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION, AND MICRO RNA (MIRNA) REGULATION. EPIGENETIC ALTERATIONS TO PAH EXPOSURE WERE RELATED TO CHRONIC DISEASES, SUCH AS PULMONARY DISEASE, CARDIOVASCULAR DISEASE, ENDOCRINE DISRUPTOR, NERVOUS SYSTEM DISORDER, AND CANCER. THIS HORMETIC RESPONSE GIVES A NOVEL PERCEPTION CONCERNING THE TOXICITY OF PAHS AND THE BIOLOGICAL REACTION THAT MAY BE A DISTINCT RELIANCE ON EXPOSURE. THIS REVIEW SHEDS LIGHT ON UNDERSTANDING THE LATEST EVIDENCE ABOUT HOW PAHS CAN ALTER EPIGENETIC PATTERNS AND HUMAN HEALTH. IN CONCLUSION, AS SEVERAL EPIGENETIC CHANGE MECHANISMS REMAIN UNCLEAR YET, FURTHER ANALYSES DERIVED FROM PAHS EXPOSURE MUST BE PERFORMED TO FIND NEW TARGETS AND DISEASE BIOMARKERS. IN SPITE OF THE CURRENT LIMITATIONS, NUMEROUS EVIDENCE SUPPORTS THE PERCEPTION THAT EPIGENETICS GRIPS SUBSTANTIAL POTENTIAL FOR ADVANCING OUR KNOWLEDGE ABOUT THE MOLECULAR MECHANISMS OF ENVIRONMENTAL TOXICANTS, ALSO FOR PREDICTING HEALTH-ASSOCIATED RISKS DUE TO ENVIRONMENTAL CIRCUMSTANCES EXPOSURE AND INDIVIDUAL SUSCEPTIBILITY. 2022 5 1928 38 ENVIRONMENTAL EXPOSURE MEASUREMENT IN CANCER EPIDEMIOLOGY. ENVIRONMENTAL EXPOSURES, USED IN THE BROADEST SENSE OF LIFESTYLE, INFECTIONS, RADIATION, NATURAL AND MAN-MADE CHEMICALS AND OCCUPATION, ARE A MAJOR CAUSE OF HUMAN CANCER. HOWEVER, THE PRECISE CONTRIBUTION OF SPECIFIC RISK FACTORS AND THEIR INTERACTION, BOTH WITH EACH OTHER AND WITH GENOTYPE, CONTINUES TO BE DIFFICULT TO ELUCIDATE. THIS IS PARTIALLY DUE TO LIMITATIONS IN ACCURATELY MEASURING EXPOSURE WITH THE SUBSEQUENT RISK OF MISCLASSIFICATION. ONE OF THE PRIMARY CHALLENGES OF MOLECULAR CANCER EPIDEMIOLOGY THEREFORE IS TO IMPROVE EXPOSURE ASSESSMENT. PROGRESS HAS BEEN MADE WITH BIOMARKERS SUCH AS CARCINOGENS AND THEIR METABOLITES, DNA AND PROTEIN ADDUCTS AND MUTATIONS MEASURED IN VARIOUS TISSUES AND BODY FLUIDS. NEVERTHELESS, MUCH REMAINS TO BE ACCOMPLISHED IN ORDER TO ESTABLISH AETIOLOGY AND PROVIDE THE EVIDENCE BASE FOR PUBLIC HEALTH DECISIONS. THIS REVIEW CONSIDERS SOME OF THE PRINCIPLES BEHIND THE APPLICATION OF EXPOSURE BIOMARKERS IN CANCER EPIDEMIOLOGY. IT ALSO DEMONSTRATES HOW THE SAME BIOMARKERS CAN CONTRIBUTE BOTH TO ESTABLISHING THE BIOLOGICAL PLAUSIBILITY OF ASSOCIATIONS BETWEEN EXPOSURE AND DISEASE AND BE VALUABLE ENDPOINTS IN INTERVENTION STUDIES. THE POTENTIAL OF NEW TECHNOLOGIES SUCH AS TRANSCRIPTOMICS, PROTEOMICS AND METABONOMICS TO PROVIDE A STEP CHANGE IN ENVIRONMENTAL EXPOSURE ASSESSMENT IS DISCUSSED. AN INCREASING RECOGNITION OF THE ROLE OF EPIGENETIC CHANGES IN CARCINOGENESIS PRESENTS A FRESH CHALLENGE AS ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA IN RESPONSE TO ENVIRONMENTAL EXPOSURES DEMAND A NEW GENERATION OF EXPOSURE BIOMARKER. THE OVERALL IMPORTANCE OF THIS AREA OF RESEARCH IS BROUGHT INTO SHARP RELIEF BY THE LARGE PROSPECTIVE COHORT STUDIES (E.G. UK BIOBANK) WHICH NEED ACCURATE EXPOSURE MEASUREMENT IN ORDER TO SHED LIGHT ON THE COMPLEX GENE:ENVIRONMENT INTERACTIONS UNDERLYING COMMON CHRONIC DISORDERS INCLUDING CANCER. IT IS SUGGESTED THAT A CONCERTED EFFORT IS NOW REQUIRED, WITH APPROPRIATE FUNDING, TO DEVELOP AND VALIDATE THE REQUIRED EXPOSURE ASSESSMENT METHODOLOGY BEFORE THESE COHORTS COME TO MATURITY. 2009 6 1918 40 ENVIRONMENTAL CARCINOGENESIS AND TRANSGENERATIONAL TRANSMISSION OF CARCINOGENIC RISK: FROM GENETICS TO EPIGENETICS. THE DOMINANT PATHOGENIC MODEL, SOMATIC MUTATION THEORY (SMT), CONSIDERS CARCINOGENESIS AS A 'GENETIC ACCIDENT' DUE TO THE ACCUMULATION OF 'STOCHASTIC' DNA MUTATIONS. THIS MODEL WAS PROPOSED AND ACCEPTED BY THE SCIENTIFIC COMMUNITY WHEN CANCER MAINLY AFFECTED THE ELDERLY, BUT IT DOES NOT EXPLAIN THE EPIDEMIOLOGICAL OBSERVATION OF THE CONTINUOUS INCREASE IN CANCER INCIDENCE AMONG CHILDREN AND YOUNG ADULTS. SOMATIC MUTATION THEORY HAS BEEN PROPOSED FOR A REVISION BASED ON THE EMERGING EXPERIMENTAL EVIDENCE, AS IT DOES NOT FULLY ADDRESS SOME ISSUES THAT HAVE PROVEN TO BE CRUCIAL FOR CARCINOGENESIS, NAMELY: THE INFLAMMATORY CONTEXT OF CANCER; THE KEY ROLE PLAYED BY THE STROMA, MICROENVIRONMENT, ENDOTHELIAL CELLS, ACTIVATED MACROPHAGES, AND SURROUNDING TISSUES; AND THE DISTORTED DEVELOPMENTAL COURSE FOLLOWED BY THE NEOPLASTIC TISSUE. FURTHERMORE, SMT IS OFTEN NOT ABLE TO CONSIDER EITHER THE EXISTENCE OF SPECIFIC MUTATIONS RESULTING IN A WELL-DEFINED CANCER TYPE, OR A CLEAR RELATIONSHIP BETWEEN MUTATIONS AND TUMOR PROGRESSION. MOREOVER, IT DOES NOT EXPLAIN THE MECHANISM OF ACTION OF THE NON-MUTAGENIC AND ENVIRONMENTAL CARCINOGENS. IN THE LAST DECADE, CANCER RESEARCH HAS HIGHLIGHTED THE PROMINENT ROLE OF AN ALTERED REGULATION OF GENE EXPRESSION, SUGGESTING THAT CANCER SHOULD BE CONSIDERED AS A RESULT OF A POLYCLONAL EPIGENETIC DISRUPTION OF STEM/PROGENITOR CELLS, MEDIATED BY TUMOUR-INDUCING GENES. THE MATERNAL AND FETAL EXPOSURE TO A WIDE RANGE OF CHEMICALS AND ENVIRONMENTAL CONTAMINANTS IS RAISING THE ATTENTION OF THE SCIENTIFIC COMMUNITY. INDEED, THE MOST POWERFUL PROCARCINOGENIC MECHANISMS OF ENDOCRINE DISRUPTORS AND OTHER POLLUTANTS IS LINKED TO THEIR POTENTIAL TO INTERFERE EPIGENETICALLY WITH THE EMBRYO-FETAL PROGRAMMING OF TISSUES AND ORGANS, ALTERING THE REGULATION OF THE GENES INVOLVED IN THE CELL CYCLE, CELL PROLIFERATION, APOPTOSIS, AND OTHER KEY SIGNALING PATHWAYS. THE EMBRYO-FETAL EXPOSURE TO ENVIRONMENTAL, STRESSFUL, AND PROINFLAMMATORY TRIGGERS (FIRST HIT), SEEMS TO ACT AS A 'DISEASE PRIMER', MAKING FETAL CELLS AND TISSUES MORE SUSCEPTIBLE TO THE SUBSEQUENT ENVIRONMENTAL EXPOSURES (SECOND HIT), TRIGGERING THE CARCINOGENIC PATHWAYS. FURTHERMORE, EVEN AT THE MOLECULAR LEVEL, IN CARCINOGENESIS, 'EPIGENETICS PRECEDES GENETICS' AS GLOBAL DNA HYPOMETHYLATION, AND THE HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES ARE COMMON BOTH IN CANCEROUS AND IN PRECANCEROUS CELLS, AND GENERALLY PRECEDE MUTATIONS. THESE EPIGENETIC MODELS MAY BETTER EXPLAIN THE INCREASE OF CANCER AND CHRONIC/DEGENERATIVE DISEASES IN THE LAST DECADES AND COULD BE USEFUL TO ADOPT APPROPRIATE PRIMARY PREVENTION MEASURES, ESSENTIALLY BASED ON THE REDUCTION OF MATERNAL-FETAL AND CHILD EXPOSURE TO SEVERAL PROCARCINOGENIC AGENTS AND FACTORS DISPERSED IN THE ENVIRONMENT AND IN THE FOOD-CHAINS, AS RECENTLY SUGGESTED BY THE WORLD HEALTH ORGANIZATION. 2018 7 6842 21 [MECHANISTIC ISSUES AND PREVENTION STRATEGIES TARGETING OCCUPATIONAL CARCINOGENESIS]. CARCINOGENESIS CAN BE VISUALIZED EITHER AS A MULTISTEP PROCESS (INITIATION, PROMOTION, PROGRESSION, INVASION, AND METASTASIS) OR AS A CONTINUUM OF MUTAGENIC AND MITOGENIC EVENTS, WITH THE CONTRIBUTION OF EPIGENETIC MECHANISMS. THE EXPONENTIAL GROWTH OF THE NEOPLASTIC MASS EXPLAINS THE IMPORTANCE OF SECONDARY PREVENTION (EARLY DIAGNOSIS) AND OF TERTIARY PREVENTION. PRIMARY PREVENTION, WHICH WAS SUCCESSFUL IN CONTROLLING OCCUPATIONAL CANCERS, AIMS AT MINIMIZING EXPOSURES TO CARCINOGENS IN HEALTHY SUBJECTS AND AT FAVORING THE INTAKE OF CHEMOPREVENTIVE AGENTS WITH DIETARY AND PHARMACOLOGICAL AGENTS. BESIDES CHEMICAL CARCINOGENS, OFTEN IN THE FORM OF COMPLEX MIXTURES, THE WORKPLACE MAY INVOLVE EXPOSURES TO PHYSICAL AGENTS, SUCH AS SUNLIGHT AND ARTIFICIAL ILLUMINATION SYSTEMS DELIVERING UV RADIATION, OR TO BIOLOGICAL AGENTS, SUCH AS CHRONIC VIRAL INFECTIONS (HBV, HCV, AND HIV) ASSOCIATED WITH CANCERS. A CONTROVERSIAL ISSUE IS THE OCCURRENCE OF THRESHOLD DOSES FOR CARCINOGENS IN THE WORKPLACE AND THE ENVIRONMENT. 2011 8 1010 29 CHRONICALLY ELEVATED PROLIFERATION AS A RISK FACTOR FOR NEOPLASIA. CHRONIC DISEASE CONDITIONS THAT ARE ASSOCIATED WITH ELEVATED PROLIFERATION ARE WELL ESTABLISHED AS RISK FACTORS FOR CANCER DEVELOPMENT. THESE MAY BE DUE TO VIRUSES (FOR EXAMPLE, IN THE CASE OF HEPATITIS AND LIVER CANCER), BACTERIAL INFECTIONS, PARASITE INFESTATION OR PHYSICAL TRAUMA. IN ADDITION TO THESE EXOGENOUS AGENTS THERE ARE ALSO METABOLIC ABNORMALITIES THAT CAN CONTRIBUTE, CAUSED BY GENETIC OR EPIGENETIC INFLUENCE. IN THE LATTER CASE, AN INCREASE IN SERUM LEVELS OF THE HORMONES OESTROGEN, TESTOSTERONE AND INSULIN MAY BE OF SPECIAL IMPORTANCE. THE PRESENT REVIEW CONCENTRATES ATTENTION ON FACTORS THAT INDUCE ELEVATED CELL TURNOVER AND FOR WHICH THERE IS EPIDEMIOLOGICAL AND/OR EXPERIMENTAL EVIDENCE OF A LINK WITH NEOPLASIA, WITH PARTICULAR STRESS ON THE INDIVIDUAL ORGAN OR TISSUE LEVEL. 1998 9 396 25 AN UPDATE ON EPIGENETICS AND CHILDHOOD RESPIRATORY DISEASES. EPIGENETIC MECHANISMS, DEFINED AS CHANGES IN PHENOTYPE OR GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE, HAVE BEEN PROPOSED TO CONSTITUTE A LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THAT AFFECT COMPLEX DISEASES. RECENT STUDIES SHOW THAT DNA METHYLATION, ONE OF THE KEY EPIGENETIC MECHANISMS, IS ALTERED IN CHILDREN EXPOSED TO AIR POLLUTANTS AND ENVIRONMENTAL TOBACCO SMOKE EARLY IN LIFE. SEVERAL CANDIDATE GENE STUDIES ON EPIGENETICS HAVE BEEN PUBLISHED TO DATE, BUT IT IS ONLY RECENTLY THAT GLOBAL METHYLATION ANALYSES HAVE BEEN PERFORMED FOR RESPIRATORY DISORDERS SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, LARGE-SCALE STUDIES WITH ADEQUATE POWER ARE YET TO BE PRESENTED IN CHILDREN, AND IMPLICATIONS FOR CLINICAL USE REMAIN TO BE EVALUATED. IN THIS REVIEW, WE SUMMARIZE THE RECENT ADVANCES IN EPIGENETICS AND RESPIRATORY DISORDERS IN CHILDREN, WITH A MAIN FOCUS ON METHODOLOGICAL CHALLENGES AND ANALYSES RELATED TO PHENOTYPE AND EXPOSURE USING GLOBAL METHYLATION APPROACHES. 2014 10 186 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 11 1917 31 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 12 1844 32 EFFECTS OF THE LIFESTYLE HABITS IN BREAST CANCER TRANSCRIPTIONAL REGULATION. THROUGH RESEARCH CARRIED OUT IN THE LAST 25 YEARS ABOUT THE BREAST CANCER ETIOLOGY, IT HAS BEEN POSSIBLE TO ESTIMATE THAT LESS THAN 10 % OF PATIENTS WHO ARE DIAGNOSED WITH THE CONDITION ARE CARRIERS OF SOME GERMLINE OR SOMATIC MUTATION. THE CLINICAL REPORTS OF BREAST CANCER PATIENTS WITH HEALTHY TWINS AND THE DEVELOPMENT OF DISEASE IN WOMEN WITHOUT HIGH PENETRANCE MUTATIONS DETECTED, WARN THE PARTICIPATION MORE FACTORS IN THE TRANSFORMATION PROCESS. THE HIGH INCIDENCE OF MAMMARY ADENOCARCINOMA IN THE MODERN WOMAN AND THE URGENT NEED FOR NEW METHODS OF PREVENTION AND EARLY DETECTION HAVE DEMANDED MORE INFORMATION ABOUT THE ROLE THAT ENVIRONMENT AND LIFESTYLE HAVE ON THE TRANSFORMATION OF MAMMARY GLAND EPITHELIAL CELLS. OBESITY, ALCOHOLISM AND SMOKING ARE FACTORS THAT HAVE SHOWN A CLOSE CORRELATION WITH THE RISK OF DEVELOPING BREAST CANCER. AND ALTHOUGH THESE CONDITIONS AFFECT DIFFERENT CELL REGULATION LEVELS, THE STUDY OF ITS EFFECTS IN THE MECHANISMS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION IS CONSIDERED CRITICAL FOR A BETTER UNDERSTANDING OF THE LOSS OF IDENTITY OF EPITHELIAL CELLS DURING CARCINOGENESIS OF THIS TISSUE. THE MAIN OBJECTIVE OF THIS REVIEW WAS TO ESTABLISH THE IMPORTANCE OF CHANGES OCCURRING TO TRANSCRIPTIONAL LEVEL IN THE MAMMARY GLAND AS A CONSEQUENCE OF ACUTE OR CHRONIC EXPOSURE TO HARMFUL PRODUCTS SUCH AS OBESITY-CAUSING FOODS, ETHANOL AND CIGARETTE SMOKE COMPONENTS. AT ANALYZE THE MAIN STUDIES RELATED TO TOPIC, IT HAS CONCLUDED THAT THE UNDERSTANDING OF EFFECTS CAUSED BY THE LIFESTYLE FACTORS IN PERFORMANCE OF THE TRANSCRIPTIONAL MECHANISMS THAT DETERMINE GENE EXPRESSION OF THE MAMMARY GLAND EPITHELIAL CELLS, MAY HELP EXPLAIN THE DEVELOPMENT OF THIS DISEASE IN WOMEN WITHOUT GENETIC PROPENSITY AND DIFFERENT PHENOTYPIC MANIFESTATIONS OF THIS CANCER TYPE. 2016 13 633 29 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 14 5557 28 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 15 6790 30 [DNA METHYLATION ANALYSIS IN ENVIRONMENTAL AND OCCUPATIONAL CANCER RESEARCH]. THE PRESENT PAPER REVIEWS RECENT LABORATORY METHODS AND EXPERIMENTAL EVIDENCE CONCERNING EPIGENETIC BIOMARKERS INVOLVED IN CARCINOGENESIS MECHANISMS. WE INTRODUCE DNA METHYLATION AND ITS ROLE IN GENE EXPRESSION CONTROL. DNA METHYLATION ANALYSIS MAY ALLOW TO IDENTIFY EARLY CHANGES LEADING TO CANCER AND OTHER CHRONIC DISEASES. WE DESCRIBE HERE STRATEGIES FOR LABORATORY ANALYSES AND THEIR POSSIBLE APPLICATIONS. WE EXAMINE RESULTS FROM RECENT EXPERIMENTAL STUDIES SUGGESTING THAT THE EFFECTS OF CERTAIN OCCUPATIONAL AGENTS ARE MEDIATED BY ALTERATIONS IN DNA METHYLATION. PLANNING AND CONDUCTING INVESTIGATIONS ON EXPOSED HUMAN SUBJECTS WILL ALLOW TO VERIFY WHETHER DNA METHYLATION CHANGES IDENTIFIED IN ANIMAL AND IN-VITRO STUDIES MAY BE USED AS EARLY-EFFECT AND SUSCEPTIBILITY BIOMARKERS. DNA METHYLATION ANALYSIS HAS THE POTENTIAL FOR FUTURE APPLICATIONS IN RISK ASSESSMENT AND PREVENTION PROGRAMS CONDUCTED ON SUBJECTS EXPOSED TO HUMAN CARCINOGENS. 2005 16 1925 27 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 17 2282 26 EPIGENETIC REGULATION IN EXPOSOME-INDUCED TUMORIGENESIS: EMERGING ROLES OF NCRNAS. ENVIRONMENTAL FACTORS, INCLUDING POLLUTANTS AND LIFESTYLE, CONSTITUTE A SIGNIFICANT ROLE IN SEVERE, CHRONIC PATHOLOGIES WITH AN ESSENTIAL SOCIETAL, ECONOMIC BURDEN. THE MEASUREMENT OF ALL ENVIRONMENTAL EXPOSURES AND ASSESSING THEIR CORRELATION WITH EFFECTS ON INDIVIDUAL HEALTH IS DEFINED AS THE EXPOSOME, WHICH INTERACTS WITH OUR UNIQUE CHARACTERISTICS SUCH AS GENETICS, PHYSIOLOGY, AND EPIGENETICS. EPIGENETICS INVESTIGATES MODIFICATIONS IN THE EXPRESSION OF GENES THAT DO NOT DEPEND ON THE UNDERLYING DNA SEQUENCE. SOME STUDIES HAVE CONFIRMED THAT ENVIRONMENTAL FACTORS MAY PROMOTE DISEASE IN INDIVIDUALS OR SUBSEQUENT PROGENY THROUGH EPIGENETIC ALTERATIONS. VARIATIONS IN THE EPIGENETIC MACHINERY CAUSE A SPECTRUM OF DIFFERENT DISORDERS SINCE THESE MECHANISMS ARE MORE SENSITIVE TO THE ENVIRONMENT THAN THE GENOME, DUE TO THE INHERENT REVERSIBLE NATURE OF THE EPIGENETIC LANDSCAPE. SEVERAL EPIGENETIC MECHANISMS, INCLUDING MODIFICATIONS IN DNA (E.G., METHYLATION), HISTONES, AND NONCODING RNAS CAN CHANGE GENOME EXPRESSION UNDER THE EXOGENOUS INFLUENCE. NOTABLY, THE ROLE OF LONG NONCODING RNAS IN EPIGENETIC PROCESSES HAS NOT BEEN WELL EXPLORED IN THE CONTEXT OF EXPOSOME-INDUCED TUMORIGENESIS. IN THE PRESENT REVIEW, OUR SCOPE IS TO PROVIDE RELEVANT EVIDENCE INDICATING THAT EPIGENETIC ALTERATIONS MEDIATE THOSE DETRIMENTAL EFFECTS CAUSED BY EXPOSURE TO ENVIRONMENTAL TOXICANTS, FOCUSING MAINLY ON A MULTI-STEP REGULATION BY DIVERSE NONCODING RNAS SUBTYPES. 2022 18 480 30 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 19 838 34 CHEMISTRY MEETS BIOLOGY IN COLITIS-ASSOCIATED CARCINOGENESIS. THE INTESTINE COMPRISES AN EXCEPTIONAL VENUE FOR A DYNAMIC AND COMPLEX INTERPLAY OF NUMEROUS CHEMICAL AND BIOLOGICAL PROCESSES. HERE, MULTIPLE CHEMICAL AND BIOLOGICAL SYSTEMS, INCLUDING THE INTESTINAL TISSUE ITSELF, ITS ASSOCIATED IMMUNE SYSTEM, THE GUT MICROBIOTA, XENOBIOTICS, AND METABOLITES MEET AND INTERACT TO FORM A SOPHISTICATED AND TIGHTLY REGULATED STATE OF TISSUE HOMOEOSTASIS. DISTURBANCE OF THIS HOMEOSTASIS CAN CAUSE INFLAMMATORY BOWEL DISEASE (IBD)-A CHRONIC DISEASE OF MULTIFACTORIAL ETIOLOGY THAT IS STRONGLY ASSOCIATED WITH INCREASED RISK FOR CANCER DEVELOPMENT. THIS REVIEW ADDRESSES RECENT DEVELOPMENTS IN RESEARCH INTO CHEMICAL AND BIOLOGICAL MECHANISMS UNDERLYING THE ETIOLOGY OF INFLAMMATION-INDUCED COLON CANCER. BEGINNING WITH A GENERAL OVERVIEW OF REACTIVE CHEMICAL SPECIES GENERATED DURING COLONIC INFLAMMATION, THE MECHANISTIC INTERPLAY BETWEEN CHEMICAL AND BIOLOGICAL MEDIATORS OF INFLAMMATION, THE ROLE OF GENETIC TOXICOLOGY, AND MICROBIAL PATHOGENESIS IN DISEASE DEVELOPMENT ARE DISCUSSED. WHEN POSSIBLE, WE SYSTEMATICALLY COMPARE EVIDENCE FROM STUDIES UTILIZING HUMAN IBD PATIENTS WITH EXPERIMENTAL INVESTIGATIONS IN MICE. THE COMPARISON REVEALS THAT MANY STRONG PATHOLOGICAL AND MECHANISTIC CORRELATES EXIST BETWEEN MOUSE MODELS OF COLITIS-ASSOCIATED CANCER, AND THE CLINICALLY RELEVANT SITUATION IN HUMANS. WE ALSO SUMMARIZE SEVERAL EMERGING ISSUES IN THE FIELD, SUCH AS THE CARCINOGENIC POTENTIAL OF NOVEL INFLAMMATION-RELATED DNA ADDUCTS AND GENOTOXIC MICROBIAL FACTORS, THE SYSTEMIC DIMENSION OF INFLAMMATION-INDUCED GENOTOXICITY, AND THE COMPLEX ROLE OF GENOME MAINTENANCE MECHANISMS DURING THESE PROCESSES. TAKEN TOGETHER, CURRENT EVIDENCE POINTS TO THE INDUCTION OF GENETIC AND EPIGENETIC ALTERATIONS BY CHEMICAL AND BIOLOGICAL INFLAMMATORY STIMULI ULTIMATELY LEADING TO CANCER FORMATION. 2013 20 738 25 CANCER SUSCEPTIBILITY: EPIGENETIC MANIFESTATION OF ENVIRONMENTAL EXPOSURES. CANCER IS A DISEASE THAT RESULTS FROM BOTH GENETIC AND EPIGENETIC CHANGES. DISCORDANT PHENOTYPES AND VARYING INCIDENCES OF COMPLEX DISEASES SUCH AS CANCER IN MONOZYGOTIC TWINS AS WELL AS GENETICALLY IDENTICAL LABORATORY ANIMALS HAVE LONG BEEN ATTRIBUTED TO DIFFERENCES IN ENVIRONMENTAL EXPOSURES. ACCUMULATING EVIDENCE INDICATES, HOWEVER, THAT DISPARITIES IN GENE EXPRESSION RESULTING FROM VARIABLE MODIFICATIONS IN DNA METHYLATION AND CHROMATIN STRUCTURE IN RESPONSE TO THE ENVIRONMENT ALSO PLAY A ROLE IN DIFFERENTIAL SUSCEPTIBILITY TO DISEASE. DESPITE A GROWING CONSENSUS ON THE IMPORTANCE OF EPIGENETICS IN THE ETIOLOGY OF CHRONIC HUMAN DISEASES, THE GENES MOST PRONE TO EPIGENETIC DYSREGULATION ARE INCOMPLETELY DEFINED. MOREOVER, NEITHER THE ENVIRONMENTAL AGENTS MOST STRONGLY AFFECTING THE EPIGENOME NOR THE CRITICAL WINDOWS OF VULNERABILITY TO ENVIRONMENTALLY INDUCED EPIGENETIC ALTERATIONS ARE ADEQUATELY CHARACTERIZED. THESE MAJOR DEFICITS IN KNOWLEDGE MARKEDLY IMPAIR OUR ABILITY TO UNDERSTAND FULLY THE ETIOLOGY OF CANCER AND THE IMPORTANCE OF THE EPIGENOME IN DIAGNOSING AND PREVENTING THIS DEVASTATING DISEASE. 2007