1 5493 55 REVIEW OF IN VITRO TEST SYSTEMS USING DNA DAMAGE AND REPAIR FOR SCREENING OF CHEMICAL CARCINOGENS. CHEMICAL CARCINOGENS ARE MECHANISTICALLY CLASSIFIED AS GENOTOXIC WHICH INTERACT DIRECTLY WITH DNA, AND EPIGENETIC WHICH CAUSE CHRONIC TISSUE INJURY, HORMONAL IMBALANCE, AND PROMOTIONAL EFFECTS. THIS REVIEW EVALUATES IN VITRO TESTS FOR THEIR CONTRIBUTION TO A BATTERY FOR IDENTIFYING GENOTOXIC CHEMICAL CARCINOGENS. IN ADDITION TO BACTERIAL MUTAGENIC ASSAYS, NONSPECIFIC DNA DAMAGE/REPAIR TESTS ARE RECOMMENDED FOR SCREENING CHEMICALS, IN PARTICULAR THE HEPATOCYTE PRIMARY CULTURE/DNA REPAIR TEST. 1979 2 5282 18 PROMOTION OF HEPATOCARCINOGENESIS IN HUMANS AND ANIMAL MODELS. RISK ASSESSMENT BASED ON RODENT CARCINOGENICITY DATA DEPENDS ON THE ASSUMPTION OF SIMILARITY BETWEEN RODENTS AND HUMANS. WHILE THIS ASSUMPTION IS CONCEIVABLE IN THE CASE OF GENOTOXIC INITIATING CARCINOGENS, CONSIDERABLE SPECIES DIFFERENCES HAVE BEEN OBSERVED WITH NONGENOTOXIC TUMOR PROMOTERS. THIS HETEROGENEOUS GROUP OF AGENTS INCREASES THE PROBABILITY OF CANCER BY STIMULATING SELECTION AND CLONAL EXPANSION OF CELLS TRANSFORMED DURING TUMOR INITIATION. SINCE TUMOR PROMOTERS DIFFERENTIALLY AFFECT NORMAL TISSUE AND PRENEOPLASTIC CELL CLONES, THEIR ACTION CANNOT BE DISCUSSED WITHOUT KNOWLEDGE OF PERSISTENT GENOMIC AND EPIGENETIC ALTERATIONS OCCURRING DURING INITIATION AND FORMATION OF PRENEOPLASTIC CELLS. CHEMICAL CARCINOGENESIS, AND IN PARTICULAR, TUMOR PROMOTION, IS KNOWN TO BE TISSUE SPECIFIC. WE FOCUS ON HEPATOCARCINOGENESIS IN HUMANS AND IN ANIMAL MODELS AND EMPHASIZE TWO DIFFERENT MODES OF ACTION: (1) CHRONIC CYTOTOXICITY LEADING TO PROMOTION OF LIVER CARCINOGENESIS IN BOTH HUMANS AND ANIMAL MODELS; (2) SUSTAINED ACTIVATION OF ORPHAN RECEPTORS SUCH AS CAR, PPARALPHA AND AH RECEPTOR LEADING TO PROMOTION OF RODENT BUT PROBABLY NOT HUMAN HEPATOCARCINOGENESIS. FURTHER STUDIES ON THE DIFFERENT MODES OF ACTION MAY HELP TO AVOID OVERESTIMATION OF THE RISK OF LIVER TUMOR PROMOTION. 2008 3 6842 20 [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 4 4119 20 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 5 266 31 ADVERSE OUTCOME PATHWAYS FOR IONIZING RADIATION AND BREAST CANCER INVOLVE DIRECT AND INDIRECT DNA DAMAGE, OXIDATIVE STRESS, INFLAMMATION, GENOMIC INSTABILITY, AND INTERACTION WITH HORMONAL REGULATION OF THE BREAST. KNOWLEDGE ABOUT ESTABLISHED BREAST CARCINOGENS CAN SUPPORT IMPROVED AND MODERNIZED TOXICOLOGICAL TESTING METHODS BY IDENTIFYING KEY MECHANISTIC EVENTS. IONIZING RADIATION (IR) INCREASES THE RISK OF BREAST CANCER, ESPECIALLY FOR WOMEN AND FOR EXPOSURE AT YOUNGER AGES, AND EVIDENCE OVERALL SUPPORTS A LINEAR DOSE-RESPONSE RELATIONSHIP. WE USED THE ADVERSE OUTCOME PATHWAY (AOP) FRAMEWORK TO OUTLINE AND EVALUATE THE EVIDENCE LINKING IONIZING RADIATION WITH BREAST CANCER FROM MOLECULAR INITIATING EVENTS TO THE ADVERSE OUTCOME THROUGH INTERMEDIATE KEY EVENTS, CREATING A QUALITATIVE AOP. WE IDENTIFIED KEY EVENTS BASED ON REVIEW ARTICLES, SEARCHED PUBMED FOR RECENT LITERATURE ON KEY EVENTS AND IR, AND IDENTIFIED ADDITIONAL PAPERS USING REFERENCES. WE MANUALLY CURATED PUBLICATIONS AND EVALUATED DATA QUALITY. IONIZING RADIATION DIRECTLY AND INDIRECTLY CAUSES DNA DAMAGE AND INCREASES PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES (RONS). RONS LEAD TO DNA DAMAGE AND EPIGENETIC CHANGES LEADING TO MUTATIONS AND GENOMIC INSTABILITY (GI). PROLIFERATION AMPLIFIES THE EFFECTS OF DNA DAMAGE AND MUTATIONS LEADING TO THE AO OF BREAST CANCER. SEPARATELY, RONS AND DNA DAMAGE ALSO INCREASE INFLAMMATION. INFLAMMATION CONTRIBUTES TO DIRECT AND INDIRECT EFFECTS (EFFECTS IN CELLS NOT DIRECTLY REACHED BY IR) VIA POSITIVE FEEDBACK TO RONS AND DNA DAMAGE, AND SEPARATELY INCREASES PROLIFERATION AND BREAST CANCER THROUGH PRO-CARCINOGENIC EFFECTS ON CELLS AND TISSUE. FOR EXAMPLE, GENE EXPRESSION CHANGES ALTER INFLAMMATORY MEDIATORS, RESULTING IN IMPROVED SURVIVAL AND GROWTH OF CANCER CELLS AND A MORE HOSPITABLE TISSUE ENVIRONMENT. ALL OF THESE EVENTS OVERLAP AT MULTIPLE POINTS WITH EVENTS CHARACTERISTIC OF "BACKGROUND" INDUCTION OF BREAST CARCINOGENESIS, INCLUDING HORMONE-RESPONSIVE PROLIFERATION, OXIDATIVE ACTIVITY, AND DNA DAMAGE. THESE OVERLAPS MAKE THE BREAST PARTICULARLY SUSCEPTIBLE TO IONIZING RADIATION AND REINFORCE THAT THESE BIOLOGICAL ACTIVITIES ARE IMPORTANT CHARACTERISTICS OF CARCINOGENS. AGENTS THAT INCREASE THESE BIOLOGICAL PROCESSES SHOULD BE CONSIDERED POTENTIAL BREAST CARCINOGENS, AND PREDICTIVE METHODS ARE NEEDED TO IDENTIFY CHEMICALS THAT INCREASE THESE PROCESSES. TECHNIQUES ARE AVAILABLE TO MEASURE RONS, DNA DAMAGE AND MUTATION, CELL PROLIFERATION, AND SOME INFLAMMATORY PROTEINS OR PROCESSES. IMPROVED ASSAYS ARE NEEDED TO MEASURE GI AND CHRONIC INFLAMMATION, AS WELL AS THE INTERACTION WITH HORMONALLY DRIVEN DEVELOPMENT AND PROLIFERATION. SEVERAL METHODS MEASURE DIVERSE EPIGENETIC CHANGES, BUT IT IS NOT CLEAR WHICH CHANGES ARE RELEVANT TO BREAST CANCER. IN ADDITION, MOST TOXICOLOGICAL ASSAYS ARE NOT CONDUCTED IN MAMMARY TISSUE, AND SO IT IS A PRIORITY TO EVALUATE IF RESULTS FROM OTHER TISSUES ARE GENERALIZABLE TO BREAST, OR TO CONDUCT ASSAYS IN BREAST TISSUE. DEVELOPING AND APPLYING THESE ASSAYS TO IDENTIFY EXPOSURES OF CONCERN WILL FACILITATE EFFORTS TO REDUCE SUBSEQUENT BREAST CANCER RISK. 2020 6 1010 19 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 7 3697 16 INFLAMMATORY MARKERS IN CANCER: POTENTIAL RESOURCES. CANCER IS A LEADING CAUSE OF DEATH WORLDWIDE AND A MAJOR BURDEN ON DEVELOPING AND LESS DEVELOPED COUNTRIES OF THE WORLD WITH LIMITED RESOURCES FOR PREVENTION AND EFFECTIVE TREATMENT OF CANCER. ALTHOUGH CANCER IS MULTIFACTORIAL IN ORIGIN, VARIOUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST THAT CHRONIC INFLAMMATION HAS AN IMPORTANT ROLE IN ALL STAGES OF CANCER, FROM INITIATION TO PROGRESSION AND EVEN SURVIVAL OF THE PATIENT. INFLAMMATORY PRODUCTS LIKE CYTOKINES, CHEMOKINES, LEUCOCYTES, PROSTAGLANDINS, CYCLOOXYGENASE, REACTIVE OXYGEN AND NITROGEN SPECIES, METALLOPROTEINASE INDUCE GENETIC AND EPIGENETIC CHANGES IN NORMAL CELLS DAMAGING ITS DNA, INHIBITING ITS REPAIR, ALTERING TRANSCRIPTION FACTORS, PREVENTING APOPTOSIS, AND STIMULATING ANGIOGENESIS, AND THUS RESULTING IN CARCINOGENESIS. THUS, THESE INFLAMMATORY MEDIATORS HAVE A POTENTIAL ROLE TO BECOME CANCER BIOMARKERS FOR ALL STAGES OF CANCER AS MANY OF THEM CAN BE MEASURED IN A COST-EFFECTIVE MANNER. HOWEVER, LARGE SCALE PROSPECTIVE TRIALS ARE REQUIRED TO VALIDATE THESE POTENTIAL CANCER BIOMARKERS. NONETHELESS, A TRANSITION FROM POTENTIAL TO PRACTICAL UTILIZATION OF THESE MARKERS WILL BE AN EFFECTIVE TOOL FOR THE AMELIORATION OF CANCER BURDEN AND MORTALITY IN A RESOURCE LIMITED SETTING. 2020 8 5557 21 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 9 835 24 CHEMICAL CARCINOGEN MECHANISMS OF ACTION AND IMPLICATIONS FOR TESTING METHODOLOGY. CHEMICAL CARCINOGENS ARE OF TWO DISTINCT TYPES, DNA-REACTIVE AND EPIGENETIC. TESTING METHODOLOGY CAN BE DIRECTED TOWARD DETECTING EFFECTS OF BOTH TYPES OF CARCINOGEN. CARCINOGENS OF THE DNA-REACTIVE TYPE ARE DEFINED BY THE FORMATION OF COVALENTLY BOUND DNA ADDUCTS. THESE CHEMICALS HAVE STRUCTURES THAT YIELD ELECTROPHILIC REACTANTS EITHER DIRECTLY OR AFTER BIOACTIVATION. THESE AGENTS CAUSE GENOMIC ALTERATION IN THE STRUCTURE OR FUNCTION OF DNA IN THE TARGET CELL. IN ADDITION, THESE COMPOUNDS CAN EXERT OTHER CELLULAR AND TISSUE EPIGENETIC EFFECTS, SUCH AS CELL PROLIFERATION AND GROWTH PROMOTION. CARCINOGENS OF THE EPIGENETIC (PARAGENETIC) TYPE, IN CONTRAST, DO NOT REACT WITH DNA, BUT RATHER DISPLAY CELLULAR EFFECTS SUCH AS NEOPLASM GROWTH PROMOTION, CYTOTOXICITY, INHIBITION OF TISSUE GROWTH REGULATION, PEROXISOME PROLIFERATION, ENDOCRINE MODIFICATION, IMMUNOSUPPRESSION AND/OR SUSTAINED TISSUE ISCHEMIA THAT CAN BE THE BASIS FOR INCREASES IN NEOPLASIA. THEIR CHEMICAL STRUCTURE IS SUCH THAT THEY DO NOT GIVE RISE TO A REACTIVE ELECTROPHILE. THE TESTING METHODOLOGIES TO IDENTIFY EITHER TYPE FOLLOW A DECISION POINT APPROACH DESIGNED TO IDENTIFY POTENTIAL CARCINOGENICITY AND YIELD MECHANISTIC INFORMATION ON THE PRODUCTION OF EFFECTS THAT UNDERLIE CARCINOGENICITY. IT HAS 5 STAGES FOCUSING ON THE CHEMICAL STRUCTURE, DNA-REACTIVITY, EPIGENETIC EFFECTS, LIMITED BIOASSAYS AND FINALLY THE APPLICATION OF THE ACCELERATED BIOASSAY (ABA). ABA REQUIRES 40 WEEKS AND APPLIES THE USE OF SENSITIVE MARKERS FOR INDUCTION OF NEOPLASIA IN COMPARISON TO POSITIVE CONTROL COMPOUNDS FOR IMPORTANT ORGANS IN HUMAN CARCINOGENESIS. IT ENABLES DATA ACQUISITION OF THE ENTIRE CARCINOGENIC PROCESS DIRECTED TOWARD DEVELOPING MECHANISTIC INFORMATION. THE ABA HAS THE POTENTIAL TO REPLACE THE CHRONIC BIOASSAY IN RODENTS IN SOME CIRCUMSTANCES AND CAN SERVE AS AN ALTERNATIVE TO A CHRONIC BIOASSAY IN A SECOND SPECIES. 1996 10 860 21 CHROMATIN MODIFICATIONS DURING REPAIR OF ENVIRONMENTAL EXPOSURE-INDUCED DNA DAMAGE: A POTENTIAL MECHANISM FOR STABLE EPIGENETIC ALTERATIONS. EXPOSURES TO ENVIRONMENTAL TOXICANTS AND TOXINS CAUSE EPIGENETIC CHANGES THAT LIKELY PLAY A ROLE IN THE DEVELOPMENT OF DISEASES ASSOCIATED WITH EXPOSURE. THE MECHANISM BEHIND THESE EXPOSURE-INDUCED EPIGENETIC CHANGES IS CURRENTLY UNKNOWN. ONE COMMONALITY BETWEEN MOST ENVIRONMENTAL EXPOSURES IS THAT THEY CAUSE DNA DAMAGE EITHER DIRECTLY OR THROUGH CAUSING AN INCREASE IN REACTIVE OXYGEN SPECIES, WHICH CAN DAMAGE DNA. LIKE TRANSCRIPTION, DNA DAMAGE REPAIR MUST OCCUR IN THE CONTEXT OF CHROMATIN REQUIRING BOTH HISTONE MODIFICATIONS AND ATP-DEPENDENT CHROMATIN REMODELING. THESE CHROMATIN CHANGES AID IN DNA DAMAGE ACCESSIBILITY AND SIGNALING. SEVERAL PROTEINS AND COMPLEXES INVOLVED IN EPIGENETIC SILENCING DURING BOTH DEVELOPMENT AND CANCER HAVE BEEN FOUND TO BE LOCALIZED TO SITES OF DNA DAMAGE. THE CHROMATIN-BASED RESPONSE TO DNA DAMAGE IS CONSIDERED A TRANSIENT EVENT, WITH CHROMATIN BEING RESTORED TO NORMAL AS DNA DAMAGE REPAIR IS COMPLETED. HOWEVER, IN INDIVIDUALS CHRONICALLY EXPOSED TO ENVIRONMENTAL TOXICANTS OR WITH CHRONIC INFLAMMATORY DISEASE, REPEATED DNA DAMAGE-INDUCED CHROMATIN REARRANGEMENT MAY ULTIMATELY LEAD TO PERMANENT EPIGENETIC ALTERATIONS. UNDERSTANDING THE MECHANISM BEHIND EXPOSURE-INDUCED EPIGENETIC CHANGES WILL ALLOW US TO DEVELOP STRATEGIES TO PREVENT OR REVERSE THESE CHANGES. THIS REVIEW FOCUSES ON EPIGENETIC CHANGES AND DNA DAMAGE INDUCED BY ENVIRONMENTAL EXPOSURES, THE CHROMATIN CHANGES THAT OCCUR AROUND SITES OF DNA DAMAGE, AND HOW THESE TRANSIENT CHROMATIN CHANGES MAY LEAD TO HERITABLE EPIGENETIC ALTERATIONS AT SITES OF CHRONIC EXPOSURE. 2014 11 6865 17 [OXIDATIVE STRESS IN PROSTATE HYPERTROPHY AND CARCINOGENESIS]. AGING, SIGNIFICANT IMPAIRMENT OF THE OXIDATION/REDUCTION BALANCE, INFECTION, AND INFLAMMATION ARE RECOGNIZED RISK FACTORS OF BENIGN HYPERPLASIA AND PROSTATE CANCER. CHRONIC SYMPTOMATIC AND ASYMPTOMATIC PROSTATE INFLAMMATORY PROCESSES GENERATE SIGNIFICANTLY ELEVATED LEVELS OF REACTIVE OXYGEN AND NITROGEN SPECIES, AND HALOGENATED COMPOUNDS. PROSTATE CANCER PATIENTS SHOWED SIGNIFICANTLY HIGHER LIPID PEROXIDATION AND LOWER ANTIOXIDANT LEVELS IN PERIPHERAL BLOOD THAN HEALTHY CONTROLS, WHEREAS PATIENTS WITH PROSTATE HYPERPLASIA DID NOT SHOW SUCH SYMPTOMS. OXIDATIVE/NITROSATIVE/HALOGENATIVE STRESS CAUSES DNA MODIFICATIONS LEADING TO GENOME INSTABILITY THAT MAY INITIATE CARCINOGENESIS; HOWEVER, IT WAS SHOWN THAT OXIDATIVE DAMAGE ALONE IS NOT SUFFICIENT TO INITIATE THIS PROCESS. PEROXIDATION PRODUCTS INDUCED BY REACTIVE OXYGEN AND NITROGEN SPECIES SEEM TO TAKE PART IN EPIGENETIC MECHANISMS REGULATING GENOME ACTIVITY. ONE OF THE MOST COMMON CHANGES OCCURRING IN MORE THAN 90% OF ALL ANALYZED PROSTATE CANCERS IS THE SILENCING OF GSTP1 GENE ACTIVITY. THE GENE ENCODES GLUTATHIONE TRANSFERASE, AN ENZYME PARTICIPATING IN DETOXIFICATION PROCESSES. PROSTATE HYPERPLASIA IS OFTEN ACCOMPANIED BY CHRONIC INFLAMMATION AND SUCH A RELATIONSHIP WAS NOT OBSERVED IN PROSTATE CANCER. THE PARTICIPATION OF INFECTION AND INFLAMMATION IN THE DEVELOPMENT OF HYPERPLASIA IS UNQUESTIONABLE AND THESE FACTORS PROBABLY ALSO TAKE PART IN INITIATING THE EARLY STAGES OF PROSTATE CARCINOGENESIS. THUS IT SEEMS THAT THERAPEUTIC STRATEGIES THAT PREVENT GENOME OXIDATIVE DAMAGE IN SITUATIONS INVOLVING OXIDATIVE/NITROSATIVE/HALOGENATIVE STRESS, I.E. USE OF ANTIOXIDANTS, PLANT STEROIDS, ANTIBIOTICS, AND NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, COULD HELP PREVENT CARCINOGENESIS. 2009 12 3287 24 HIERARCHICAL AND CYBERNETIC NATURE OF BIOLOGIC SYSTEMS AND THEIR RELEVANCE TO HOMEOSTATIC ADAPTATION TO LOW-LEVEL EXPOSURES TO OXIDATIVE STRESS-INDUCING AGENTS. DURING EVOLUTION IN AN AEROBIC ENVIRONMENT, MULTICELLULAR ORGANISMS SURVIVED BY ADAPTIVE RESPONSES TO BOTH THE ENDOGENOUS OXIDATIVE METABOLISM IN THE CELLS OF THE ORGANISM AND THE CHEMICALS AND LOW-LEVEL RADIATION TO WHICH THEY HAD BEEN EXPOSED. THE DEFENSE REPERTOIRE EXISTS AT ALL LEVELS OF THE BIOLOGICAL HIERARCHY--FROM THE MOLECULAR AND BIOCHEMICAL LEVEL TO THE CELLULAR AND TISSUE LEVEL TO THE ORGAN AND ORGAN SYSTEM LEVEL. CELLS CONTAIN PREVENTIVE ANTIOXIDANTS TO SUPPRESS OXIDATIVE DAMAGE TO MEMBRANES. CELLS ALSO CONTAIN PROTEINS AND DNA; BUILT-IN REDUNDANCIES FOR DAMAGED MOLECULES AND ORGANELLES; TIGHTLY COUPLED REDOX SYSTEMS; POOLS OF REDUCTANTS; ANTIOXIDANTS; DNA REPAIR MECHANISMS AND SENSITIVE SENSOR MOLECULES SUCH AS NUCLEAR FACTOR KAPPA BETA; AND SIGNAL TRANSDUCTION MECHANISMS AFFECTING BOTH TRANSCRIPTION AND POST-TRANSLATIONAL MODIFICATION OF PROTEINS NEEDED TO COPE WITH OXIDATIVE STRESS. THE BIOLOGIC CONSEQUENCES OF THE LOW-LEVEL RADIATION THAT EXCEEDS THE BACKGROUND LEVEL OF OXIDATIVE DAMAGE COULD BE NECROSIS OR APOPTOSIS, CELL PROLIFERATION, OR CELL DIFFERENTIATION. THESE EFFECTS ARE TRIGGERED BY OXIDATIVE STRESS-INDUCED SIGNAL TRANSDUCTION MECHANISMS--AN EPIGENETIC, NOT GENOTOXIC, PROCESS. IF THE END POINTS OF CELL PROLIFERATION, DIFFERENTIATION, OR CELL DEATH ARE NOT SEEN AT FREQUENCIES ABOVE BACKGROUND LEVELS IN AN ORGANISM, IT IS UNLIKELY THAT LOW-LEVEL RADIATION WOULD PLAY A ROLE IN THE MULTISTEP PROCESSES OF CHRONIC DISEASES SUCH AS CANCER. THE MECHANISM LINKED TO HOMEOSTATIC REGULATION OF PROLIFERATION AND ADAPTIVE FUNCTIONS IN A MULTICELLULAR ORGANISM COULD PROVIDE PROTECTION OF ANY ONE CELL RECEIVING DEPOSITED ENERGY BY THE RADIATION TRACT THROUGH THE SHARING OF REDUCTANTS AND BY TRIGGERING APOPTOSIS OF TARGET STEM CELLS. EXAMPLES OF THE ROLE OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION IN THE ADAPTIVE RESPONSE OF CELLS AND THE BYSTANDER EFFECT ILLUSTRATE HOW THE INTERACTION OF CELLS CAN MODULATE THE EFFECT OF RADIATION ON THE SINGLE CELL. 1998 13 1970 17 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 14 1407 21 DIETARY INFLUENCES ON MUTAGENESIS--WHERE IS THIS FIELD GOING? EARLY STUDIES ON DIETARY MUTAGENESIS WERE MOSTLY OBSERVATIONAL, WITH LARGE NUMBERS OF POTENTIAL DIETARY MUTAGENS BEING IDENTIFIED FROM EVERY CONCEIVABLE DIETARY SOURCE. THESE INCLUDED KNOWN DIETARY CARCINOGENS SUCH AS AFLATOXIN B1 AND BENZO[A]PYRENE, AND HITHERTO UNRECOGNIZED DIETARY MUTAGENS, SUCH AS THE PYROLYSIS PRODUCTS FORMED DURING THE HEATING OF PROTEINACEOUS MATERIALS (HETEROCYCLIC AMINES). THE 1993 EVALUATION OF 2-AMINO-3-METHYL-3H-IMIDAZO(4,5-J)QUINOLINE AS A PROBABLE HUMAN CARCINOGEN BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER WAS A LANDMARK, AS THIS WAS DONE IN THE ABSENCE OF SPECIFIC HUMAN CARCINOGENICITY DATA, AND STRONGLY INFLUENCED BY MUTAGENICITY TEST DATA. IN THE 21ST CENTURY, THE FIELD HAS MOVED FROM THE IDENTIFICATION OF MORE AND MORE MUTAGENS, TO MOLECULAR EPIDEMIOLOGIC APPROACHES THAT NOT ONLY SHOW A MUTAGENIC EFFECT BUT ALSO SEEK TO LINK IT TO A DIETARY (OR ENVIRONMENTAL) CAUSE. EFFECTS OF DIET IN STIMULATING CHRONIC INFLAMMATION MAY LEAD TO REACTIVE SPECIES AND THEREBY MUTATION AS A SECONDARY CONSEQUENCE, WHILE DIETARY DEFICIENCIES AND NUTRIENT IMBALANCES MAY BE STRONG SOURCES OF MUTAGENESIS. RECOGNITION OF THE ROLES OF NUTRIENTS IN CELL SIGNALING PROCESSES AND CONTROL OF MICRORNAS SUGGEST MAJOR INFLUENCES ON GENE EXPRESSION, IN THE ABSENCE OF PERMANENT DNA CHANGES. GENOME-WIDE ASSOCIATION STUDIES HAVE HIGHLIGHTED NEW PATHWAYS SUCH AS JAK/STAT SIGNALING THAT PROFOUNDLY INFLUENCE GENOMIC INSTABILITY AND RESPONSES TO DIETARY MUTAGENS. WITH IMPROVED METHODOLOGIES FOR DNA SEQUENCING AND EPIGENETIC CHANGES, IT IS TIME TO APPLY MORE SOPHISTICATED APPROACHES TO RECOGNIZING AND PROVING THE ROLE OF DIET AS A PRIMARY MODULATOR OF MUTAGENESIS IN HUMANS. 2010 15 6296 26 THE PROSPECTS FOR A SIMPLIFIED AND INTERNATIONALLY HARMONIZED APPROACH TO THE DETECTION OF POSSIBLE HUMAN CARCINOGENS AND MUTAGENS. IT IS PROPOSED THAT THE MANY SETS OF REGULATORY GUIDELINES FOR THE ASSESSMENT OF CHEMICAL CARCINOGENICITY AND MUTAGENICITY SHOULD BE SIMPLIFIED AND HARMONIZED IN LIGHT OF CURRENT EXPERIMENTAL DATA. DATA ARE DISCUSSED WHICH ILLUSTRATE THAT AN ABSOLUTE DISTINCTION WOULD BE DRAWN BETWEEN ASSAYS CONDUCTED IN VITRO FROM THOSE IN VIVO, AND THAT THE GENOTOXICITY OF A CHEMICAL CAN BE ADEQUATELY DEFINED USING A COMBINATION OF THE SALMONELLA MUTATION ASSAY AND ONE FOR THE ASSESSMENT OF CHROMOSOME ABERRATIONS IN VITRO. IT IS SPECIFICALLY RECOMMENDED THAT ONCE A CHEMICAL HAS SHOWN A CLEAR POSITIVE RESPONSE IN VITRO, FURTHER SHORT-TERM ASSAYS SHOULD BE CONDUCTED IN VIVO; THIS AVOIDS CONSIDERING THE 'WEIGHT OF EVIDENCE' OF IN VITRO DATA, THE DANGERS OF WHICH ARE ILLUSTRATED. IT HAS NOW BEEN UNEQUIVOCALLY ESTABLISHED THAT NOT ALL IN VITRO GENOTOXINS PROVE CARCINOGENIC TO MAMMALS. IT IS THEREFORE RECOMMENDED THAT ALL NEW IN VITRO GENOTOXINS SHOULD BE ASSESSED IN VIVO USING THE MOUSE BONE MARROW MICRONUCLEUS ASSAY, AND IF A NEGATIVE RESPONSE IS OBSERVED, A LIVER GENOTOXICITY TEST. AT PRESENT AN ASSAY FOR THE INDUCTION OF UNSCHEDULED DNA SYNTHESIS (UDS) IN THE LIVER IS THE MOST WELL DEVELOPED FOR THIS PURPOSE. CURRENT DATA INDICATE THAT AN IN VITRO GENOTOXIN FOUND TO BE INACTIVE IN THESE TWO IN VIVO ASSAYS WILL BE NEITHER CARCINOGENIC NOR MUTAGENIC TO THE GERM CELLS OF MAMMALS. EQUALLY, GENOTOXICITY PRODUCED IN MAMMALS INDICATES A CARCINOGENIC AND MUTAGENIC POTENTIAL WHICH CAN USUALLY ONLY BE COUNTERED BY APPROPRIATE CHRONIC BIOASSAYS. THE USE OF SHORT-TERM IN VIVO ASSAYS IN THIS CRITICAL ROLE REQUIRES ATTENTION TO THE SELECTION OF APPROPRIATE DOSE-LEVELS AND ROUTES OF EXPOSURE - THESE ISSUES ARE DISCUSSED. THE ABOVE TESTING STRATEGY WILL NOT DETECT CERTAIN ANIMAL CARCINOGENS, SOME OF WHICH ARE SPECIFICALLY DISCUSSED. THESE CARCINOGENS HAVE BEEN VARIOUSLY REFERRED TO IN THE LITERATURE AS EPIGENETIC/NON-GENOTOXIC/HORMONAL/TOXIC/AMBIGUOUS OR AMBIVALENT CARCINOGENS. IT IS SUGGESTED THAT THEY PRESENT A MINOR POTENTIAL HAZARD TO MAN WHEN COMPARED WITH THAT OF GENOTOXIC CARCINOGENS AND THAT THEIR SHORT-TERM DETECTION CAN ONLY BE ACHIEVED BY THE DEVELOPMENT OF NEW WHOLE MAMMAL ASSAYS EMPLOYING NON-GENETIC ENDPOINTS. THIS IS IN CONTRAST TO THE PRESENT TENDENCY TO EMPLOY ADDITIONAL GENOTOXICITY ASSAYS FOR THEIR DETECTION IN THE UNJUSTIFIED BELIEF THAT THEY POSSESS AN EXQUISITE SPECIFICITY OF GENOTOXIC ACTION. THIS ARTICLE REPRESENTS A PERSONAL VIEW, BUT THE TESTING STRATEGY PROPOSED IS BASED TO A LARGE EXTENT ON THE ORIGINAL THREE-TIER APPROACH OF BRIDGES.(ABSTRACT TRUNCATED AT 400 WORDS) 1986 16 731 19 CANCER CHEMOPREVENTION: CLASSIC AND EPIGENETIC MECHANISMS INHIBITING TUMORIGENESIS. WHAT HAVE WE LEARNED SO FAR? CANCERS DERIVE FROM STEP BY STEP PROCESSES WHICH ARE DIFFERENTIATED BY THE PROGRESSIVELY ACCUMULATED MUTATIONS. FOR SOME TUMORS THERE IS A CLEAR PROGRESSIVE ADVANCEMENT FROM BENIGN LESIONS TO MALIGNANCY AND FOR THESE, PREVENTIVE SCREENING PROGRAMS EXIST. IN SUCH CASES HAVING THOSE BENIGN LESIONS ARE A CLEAR INDICATOR OF PREDISPOSITION WHILE FOR SOME OTHER CASES, FAMILIAL PATTERNS OF CANCER INCIDENCE AND THE IDENTIFICATION OF MUTATIONS ARE THE MAIN INDICATORS OF HIGHER RISK FOR HAVING THE DISEASE. FOR PATIENTS IDENTIFIED AS HAVING PREDISPOSITION, CHEMOPREVENTION IS A GOAL AND IN SOME CASES A POSSIBILITY. CHEMOPREVENTION IS THE USE OF ANY COMPOUND, EITHER NATURAL OR SYNTHETIC THAT ABROGATES CARCINOGENESIS OR TUMOR PROGRESSION, THROUGH DIFFERENT MECHANISMS, SOME OF WHICH HAVE ALREADY BEEN DESCRIBED. FOR EXAMPLE, THE CLASSIC MECHANISMS MAY INVOLVE ACTIVATION OF FREE RADICAL SCAVENGING ENZYMES, CONTROL OF CHRONIC INFLAMMATION, AND DOWNREGULATION OF SPECIFIC SIGNALING PATHWAYS. MORE RECENTLY, EPIGENETICS ALLOWED FURTHER UNDERSTANDING OF THE CHEMOPREVENTIVE POTENTIAL OF SEVERAL AGENTS, SUCH AS SULFORAPHANE, GREEN TEA DERIVED COMPOUNDS, RESVERATROL, ISOFLAVONES, AND OTHERS WHICH WE EXPLOIT IN THIS REVIEW ARTICLE. THROUGHOUT THE TEXT WE DISCUSS THE PROPERTIES COMPOUNDS SHOULD HAVE IN ORDER TO BE CLASSIFIED AS CHEMOPREVENTIVE ONES AND THE CHALLENGES IN TRANSLATIONAL RESEARCH IN THIS AREA, AS LOTS OF THE SUCCESS ACHIEVED IN VITRO CANNOT BE TRANSLATED INTO THE CLINICAL SETTINGS, DUE TO SEVERAL DIFFERENT DRAWBACKS, WHICH INCLUDE TOXICITY, COST, DOSE DEFINITION, PATIENT ADHERENCE, AND REGIMEN OF USE. 2018 17 1828 18 EFFECTS OF INHALED TOBACCO SMOKE ON THE PULMONARY TUMOR MICROENVIRONMENT. TOBACCO SMOKE IS A MULTICOMPONENT MIXTURE OF CHEMICAL, ORGANIC, AND INORGANIC COMPOUNDS, AS WELL AS ADDITIVE SUBSTANCES AND RADIOACTIVE MATERIALS. MANY STUDIES HAVE PROVED THE CARCINOGENICITY OF VARIOUS OF THESE COMPOUNDS THROUGH THE INDUCTION OF DNA ADDUCTS, MUTATIONAL POTENTIAL, EPIGENETIC CHANGES, GENE FUSIONS, AND CHROMOSOMAL EVENTS. THE TUMOR MICROENVIRONMENT PLAYS AN IMPORTANT ROLE IN MALIGNANT TUMOR FORMATION AND PROGRESSION THROUGH THE REGULATION OF EXPRESSION OF KEY MOLECULES WHICH MEDIATE THE RECRUITMENT OF IMMUNE CELLS TO THE TUMOR SITE AND SUBSEQUENTLY REGULATE TUMOR GROWTH AND METASTASIS. IN THIS CHAPTER, WE DISCUSS THE EFFECTS OF INHALED TOBACCO SMOKE IN THE TUMOR MICROENVIRONMENT OF THE RESPIRATORY TRACT. THE MECHANISMS UNDERLYING THESE EFFECTS AS WELL AS THEIR LINK WITH TUMOR PROGRESSION ARE ANALYZED. 2020 18 1918 19 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 19 1844 19 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 20 5119 23 POSSIBLE CONTRIBUTION OF CHRONIC INFLAMMATION IN THE INDUCTION OF CANCER IN RHEUMATIC DISEASES. SEVERAL CHRONIC INFLAMMATORY CONDITIONS AND AUTOIMMUNE DISEASES INVOLVING DIFFERENT ORGANS AND TISSUES HAVE BEEN FOUND AT RISK OF PROGRESSION TO CANCER. A WIDE ARRAY OF PROINFLAMMATORY CYTOKINES, PROSTAGLANDINS, NITRIC OXIDE PRODUCTS, AND MATRICELLULAR PROTEINS ARE CLOSELY INVOLVED IN PREMALIGNANT AND MALIGNANT TRANSITION OF CELLS ALMOST ALWAYS IN A BACKGROUND OF CHRONIC INFLAMMATION. INTERESTINGLY, EPIGENETIC PERTURBATIONS (I.E. MIRNA ABERRATIONS, ALTERED DNA METHYLATION) TOGETHER WITH IMPORTANT STEROID HORMONE METABOLIC CHANGES (I.E. OESTROGENS), OR THE ALTERED VITAMIN D CONCENTRATIONS THAT MAY UNBALANCE THE IMMUNE / INFLAMMATORY RESPONSE, HAVE BEEN FOUND LINKED TO THE RISK AND SEVERITY IN SEVERAL CHRONIC INFLAMMATORY CONDITIONS, AS WELL AS IN CANCER. IN PARTICULAR, IT IS EVIDENT, THAT NOT ONLY THE PARENT OESTROGEN BUT ALSO OESTROGEN METABOLITES SHOULD BE TAKEN INTO ACCOUNT WHEN THIS PROCESS IS EVALUATED, SPECIALLY THE FORMATION OF CATECHOLOESTROGEN METABOLITES, THAT ARE CAPABLE OF FORMING EITHER STABLE OR DEPURINATING DNA ADDUCTS, WHICH CAN CAUSE EXTENSIVE DNA DAMAGE. IT IS INTERESTING THAT TODAY THE SUCCESSFUL TREATMENT OF SEVERAL CHRONIC IMMUNE/INFLAMMATORY RHEUMATIC DISEASES IS OBTAINED ALSO BY USING MEDICATIONS INITIALLY DEVELOPED FOR THEIR USE IN ONCOLOGY. THE CIRCADIAN INCREASE OF GROWTH FACTORS, SPECIALLY DURING THE LATE NIGHT, IN BOTH CHRONIC INFLAMMATION AND IN CANCER PATIENTS, AS WELL AS THE PRESENCE OF OESTROGEN-REGULATED CIRCADIAN MECHANISMS, SUGGESTS FURTHER IMPORTANT LINKS. 2014