1 2840 149 FRAMEWORK ANALYSIS FOR THE CARCINOGENIC MODE OF ACTION OF NITROBENZENE. NITROBENZENE (CASRN: 98-95-3) HAS BEEN SHOWN TO INDUCE CANCERS IN MANY TISSUES INCLUDING KIDNEY, LIVER, AND THYROID, FOLLOWING CHRONIC INHALATION IN ANIMALS. HOWEVER, WITH A FEW EXCEPTIONS, GENOTOXICITY ASSAYS USING NITROBENZENE HAVE GIVEN NEGATIVE RESULTS. SOME DNA BINDING/ADDUCT STUDIES HAVE BROUGHT FORTH QUESTIONABLE RESULTS AND, CONSIDERING THE AVAILABLE WEIGHT OF EVIDENCE, IT DOES NOT APPEAR THAT NITROBENZENE CAUSES CANCER VIA A GENOTOXIC MODE OF ACTION. NITROBENZENE PRODUCES A NUMBER OF FREE RADICALS DURING ITS REDUCTIVE METABOLISM, IN THE GUT AS WELL AS AT THE CELLULAR LEVEL, AND GENERATES SUPEROXIDE ANION AS A BY-PRODUCT DURING OXIDATIVE MELABOLISM. THE REACTIVE SPECIES GENERATED DURING NITROBENZENE METABOLISM ARE CONSIDERED CANDIDATES FOR CARCINOGENICITY. FURTHERMORE, SEVERAL LINES OF EVIDENCE SUGGEST THAT NITROBENZENE EXERTS ITS CARCINOGENICITY THROUGH A NON-DNA REACTIVE (EPIGENETIC) FASHION, SUCH AS A STRONG TEMPORAL RELATIONSHIP BETWEEN NON-, PRE-, AND NEOPLASTIC LESIONS LEADING TO CARCINOGENESIS. IN THIS REPORT, WE FIRST DESCRIBE THE ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION OF NITROBENZENE FOLLOWED BY A SUMMARY OF THE AVAILABLE GENOTOXICITY STUDIES AND THE ONLY AVAILABLE CANCER BIOASSAY. WE SUBSEQUENTLY REFER TO THE MODE OF ACTION FRAMEWORK OF THE U.S. ENVIRONMENTAL PROTECTION AGENCY'S 2005 GUIDELINES FOR CARCINOGEN RISK ASSESSMENT AS A BASIS FOR PRESENTING POSSIBLE MODES OF ACTION FOR NITROBENZENE-INDUCED CANCERS OF THE LIVER, THYROID, AND KIDNEY, AS SUPPORTED BY THE AVAILABLE EXPERIMENTAL DATA. THE RATIONALE(S) REGARDING HUMAN RELEVANCE OF EACH MODE OF ACTION IS ALSO PRESENTED. FINALLY, WE HYPOTHESIZE THAT THE CARCINOGENIC MODE OF ACTION FOR NITROBENZENE IS MULTIFACTORIAL IN NATURE AND REFLECTIVE OF FREE RADICALS, INFLAMMATION, AND/OR ALTERED METHYLATION. 2007 2 266 51 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 3 5493 18 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 4 5119 36 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 5 1970 29 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 6 1918 46 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 4119 42 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 8 301 41 AIR POLLUTION ASSOCIATED EPIGENETIC MODIFICATIONS: TRANSGENERATIONAL INHERITANCE AND UNDERLYING MOLECULAR MECHANISMS. AIR POLLUTION IS ONE OF THE LEADING CAUSES OF DEATHS IN SOUTHEAST ASIAN COUNTRIES INCLUDING INDIA. EXPOSURE TO AIR POLLUTANTS AFFECTS VITAL CELLULAR MECHANISMS AND IS INTIMATELY LINKED WITH THE ETIOLOGY OF A NUMBER OF CHRONIC DISEASES. EARLIER WORK FROM OUR LABORATORY HAS SHOWN THAT AIRBORNE PARTICULATE MATTER DISTURBS THE MITOCHONDRIAL MACHINERY AND CAUSES SIGNIFICANT DAMAGE TO THE EPIGENOME. MITOCHONDRIAL REACTIVE OXYGEN SPECIES POSSESS THE ABILITY TO TRIGGER REDOX-SENSITIVE SIGNALING MECHANISMS AND INDUCE IRREVERSIBLE EPIGENOMIC CHANGES. THE ELECTROPHILIC NATURE OF REACTIVE METABOLITES CAN DIRECTLY RESULT IN DEPROTONATION OF CYTOSINE AT C-5 POSITION OR INTERFERE WITH THE DNA METHYLTRANSFERASES ACTIVITY TO CAUSE ALTERATIONS IN DNA METHYLATION. IN ADDITION, IT ALSO PERTURBS LEVEL OF CELLULAR METABOLITES CRITICALLY INVOLVED IN DIFFERENT EPIGENETIC PROCESSES LIKE ACETYLATION AND METHYLATION OF HISTONE CODE AND DNA HYPO OR HYPERMETHYLATION. INTERESTINGLY, THESE MODIFICATIONS MAY PERSIST THROUGH DOWNSTREAM GENERATIONS AND RESULT IN THE TRANSGENERATIONAL EPIGENOMIC INHERITANCE. THIS PHENOMENON OF SUBSEQUENT TRANSFER OF EPIGENETIC MODIFICATIONS IS MAINLY ASSOCIATED WITH THE GERM CELLS AND RELIES ON THE GERMLINE STABILITY OF THE EPIGENETIC STATES. OVERALL, THE RECENT LITERATURE SUPPORTS, AND ARGUABLY STRENGTHENS, THE CONTENTION THAT AIR POLLUTION MIGHT CONTRIBUTE TO TRANSMISSION OF EPIMUTATIONS FROM GAMETES TO ZYGOTES BY INVOLVING MITOCHONDRIAL DNA, PARENTAL ALLELE IMPRINTING, HISTONE WITHHOLDING AND NON-CODING RNAS. HOWEVER, LARGER PROSPECTIVE STUDIES USING INNOVATIVE, INTEGRATED EPIGENOME-WIDE METABOLOMIC STRATEGY ARE HIGHLY WARRANTED TO ASSESS THE AIR POLLUTION INDUCED TRANSGENERATIONAL EPIGENETIC INHERITANCE AND ASSOCIATED HUMAN HEALTH EFFECTS. 2019 9 1844 35 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 10 1340 33 DESIGNING SAFER DRUGS: (Q)SAR-BASED IDENTIFICATION OF MUTAGENS AND CARCINOGENS. MUTAGENICITY AND CARCINOGENICITY ARE CHRONIC EFFECTS OF PRIMARY CONCERN FOR HUMAN HEALTH. A UNIFYING APPROACH TO THEIR MECHANISTIC UNDERSTANDING IS THE RECOGNITION THAT MANY CHEMICALS PROVOKE BOTH EFFECTS BY ELECTROPHILIC ATTACK TO THE BIOLOGICAL MACROMOLECULES, AS SUCH OR AFTER METABOLISM (GENOTOXIC CARCINOGENICITY). QSARS OF INDIVIDUAL CLASSES OF GENOTOXIC CARCINOGENS HAVE CONTRIBUTED TO THE ELUCIDATION OF THE CHEMICAL DETERMINANTS OF THIS ACTIVITY. LITTLE WORK HAS BEEN DONE ON THE EPIGENETIC CARCINOGENS, ACTING THROUGH NON-GENOTOXIC, VERY SPECIFIC MECHANISMS. HOWEVER, THE EXISTING QSARS FOR INDIVIDUAL CHEMICAL CLASSES ARE TOO FEW TO BE OF REAL USEFULNESS IN THE SCREENING OF MASSES OF CANDIDATE DRUGS. MODELS FOR PREDICTING THE CARCINOGENICITY OF "ANY TYPE" OF CHEMICALS HAVE BEEN PROPOSED: PROSPECTIVE PREDICTION EXERCISES POINTED TO THE SERIOUS LIMITATIONS OF MOST OF THESE APPROACHES. THE BEST ALTERNATIVE IS PROVIDED BY PANELS OF HUMAN EXPERTS. THE ABOVE PREDICTION EXERCISES CONSIDERED SAMPLES OF GENERAL CHEMICALS, THUS WE SPECIFICALLY ADDRESSED IN THIS PAPER THE ISSUE OF PHARMACEUTICAL DRUGS. WE APPLIED OUR EXPERT KNOWLEDGE TO A DATABASE OF DRUGS WHOSE CARCINOGENICITY/NONCARCINOGENICITY STATUS WAS KNOWN. WHEREAS MOST OF THE NONCARCINOGENS WERE CORRECTLY IDENTIFIED, OUR PREDICTION OF CARCINOGENS WAS LESS SUCCESSFUL THAN WITH THE GENERAL CHEMICALS. SEVERAL CARCINOGENIC DRUGS DID NOT SHOW RECOGNIZED STRUCTURAL ALERTS, AND SUPPOSEDLY ACTED BY EPIGENETIC MECHANISMS. WHEREAS THE CONTRIBUTION OF HUMAN EXPERTS IS HIGHLY VALUABLE IN THIS PHASE (E.G. PRIORITY SETTING), MORE WORK IS NECESSARY ON: A) EPIGENETIC CARCINOGENS; B) EFFICIENT COMPUTERIZED MODELS. 2003 11 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 12 1010 27 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 13 4018 38 LOW-DOSE IONIZING RADIATION: INDUCTION OF DIFFERENTIAL INTRACELLULAR SIGNALLING POSSIBLY AFFECTING INTERCELLULAR COMMUNICATION. GIVEN THE COMPLEXITY OF THE CARCINOGENIC PROCESS AND THE LACK OF ANY MECHANISTIC UNDERSTANDING OF HOW IONIZING RADIATION AT LOW-LEVEL EXPOSURES AFFECTS THE MULTISTAGE, MULTIMECHANISM PROCESSES OF CARCINOGENESIS, IT IS IMPERATIVE THAT CONCEPTS AND PARADIGMS BE REEXAMINED WHEN EXTRAPOLATING FROM HIGH DOSE TO LOW DOSE. ANY HEALTH EFFECT DIRECTLY LINKED TO LOW-DOSE RADIATION EXPOSURE MUST HAVE MOLECULAR/BIOCHEMICAL AND BIOLOGICAL BASES. ON THE OTHER HAND, DEMONSTRATING SOME MOLECULAR/BIOCHEMICAL OR CELLULAR EFFECT, USING SURROGATE SYSTEMS FOR THE HUMAN BEING, DOES NOT NECESSARILY IMPLY A CORRESPONDING HEALTH EFFECT. GIVEN THE GENERAL ACCEPTANCE OF AN EXTRAPOLATED LNT MODEL, OUR CURRENT UNDERSTANDING OF CARCINOGENESIS CRIES OUT FOR A RESOLUTION OF A REAL PROBLEM. HOW CAN A LOW-LEVEL ACUTE, OR EVEN A CHRONIC, EXPOSURE OF IONIZING RADIATION BRING ABOUT ALL THE DIFFERENT MECHANISMS (MUTAGENIC, CYTOTOXIC, AND EPIGENETIC) AND GENOTYPIC/PHENOTYPIC CHANGES NEEDED TO CONVERT NORMAL CELLS TO AN INVASIVE, MALIGNANT CELL, GIVEN ALL THE PROTECTIVE, REPAIR, AND SUPPRESSIVE SYSTEMS KNOWN TO EXIST IN THE HUMAN BODY? UNTIL RECENTLY, THE PREVAILING PARADIGM THAT IONIZING RADIATION BRINGS ABOUT CANCER PRIMARILY BY DNA DAMAGE AND ITS CONVERSION TO GENE AND CHROMOSOMAL MUTATIONS, DROVE OUR INTERPRETATION OF RADIATION CARCINOGENESIS. TODAY, OUR KNOWLEDGE INCLUDES THE FACTS BOTH THAT EPIGENETIC EVENTS PLAY A MAJOR ROLE IN CARCINOGENESIS AND THAT LOW-DOSE RADIATION CAN ALSO INDUCE EPIGENETIC EVENTS IN AND BETWEEN CELLS IN TISSUES. THIS CHALLENGES ANY SIMPLE EXTRAPOLATION OF THE LNT MODEL. ALTHOUGH A RECENT DELINEATION OF "HALLMARKS" OF THE CANCER PROCESS HAS HELPED TO FOCUS ON HOW IONIZING RADIATION MIGHT CONTRIBUTE TO THE INDUCTION OF CANCERS, SEVERAL OTHER HALLMARKS, PREVIOUSLY IGNORED--NAMELY, THE STEM CELLS IN TISSUES AS TARGETS FOR CARCINOGENESIS AND THE ROLE OF CELL-CELL COMMUNICATION PROCESSES IN MODULATING THE RADIATION EFFECTS ON THE TARGET CELL--MUST BE CONSIDERED, PARTICULARLY FOR THE ADAPTIVE RESPONSE, BYSTANDER EFFECTS, AND GENOMIC INSTABILITY PHENOMENA. 2005 14 1912 30 ENVIRONMENT, DIET AND CPG ISLAND METHYLATION: EPIGENETIC SIGNALS IN GASTROINTESTINAL NEOPLASIA. THE EPITHELIAL SURFACES OF THE MAMMALIAN ALIMENTARY TRACT ARE CHARACTERISED BY VERY HIGH RATES OF CELL PROLIFERATION AND DNA SYNTHESIS, AND IN HUMANS THEY ARE HIGHLY SUSCEPTIBLE TO CANCER. THE ROLE OF SOMATIC MUTATIONS AS DRIVERS OF CARCINOGENESIS IN THE ALIMENTARY TRACT IS WELL ESTABLISHED, BUT THE IMPORTANCE OF GENE SILENCING BY EPIGENETIC MECHANISMS IS INCREASINGLY RECOGNISED. METHYLATION OF CPG ISLANDS IS AN IMPORTANT COMPONENT OF THE EPIGENETIC CODE THAT REGULATES GENE EXPRESSION DURING DEVELOPMENT AND NORMAL CELLULAR DIFFERENTIATION, AND A NUMBER OF GENES ARE WELL KNOWN TO BECOME ABNORMALLY METHYLATED DURING THE DEVELOPMENT OF TUMOURS OF THE OESOPHAGUS, STOMACH AND COLORECTUM. ABERRANT PATTERNS OF DNA METHYLATION DEVELOP AS A RESULT OF PATHOLOGICAL PROCESSES SUCH AS CHRONIC INFLAMMATION, AND IN RESPONSE TO VARIOUS DIETARY FACTORS, INCLUDING IMBALANCES IN THE SUPPLY OF METHYL DONORS, PARTICULARLY FOLATES, AND EXPOSURE TO DNA METHYLTRANSFERASE INHIBITORS, WHICH INCLUDE POLYPHENOLS AND POSSIBLY ISOTHIOCYANATES FROM PLANT FOODS. HOWEVER THE IMPORTANCE OF THESE ENVIRONMENTAL INTERACTIONS IN HUMAN HEALTH AND DISEASE REMAINS TO BE ESTABLISHED. RECENT MOVES TO MODIFY THE EXPOSURE OF HUMAN POPULATIONS TO FOLATE, BY MANDATORY SUPPLEMENTATION OF CEREAL FOODS, EMPHASISE THE IMPORTANCE OF UNDERSTANDING THE SUSCEPTIBILITY OF THE HUMAN EPIGENOME TO DIETARY AND OTHER ENVIRONMENTAL EFFECTS. 2008 15 315 35 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS. 2013 16 106 32 A REVIEW OF MOLECULAR EVENTS OF CADMIUM-INDUCED CARCINOGENESIS. CADMIUM (CD) IS A TOXIC, HEAVY INDUSTRIAL METAL THAT POSES SERIOUS ENVIRONMENTAL HEALTH HAZARDS TO BOTH HUMANS AND WILDLIFE. RECENTLY, CD AND CD-CONTAINING COMPOUNDS HAVE BEEN CLASSIFIED AS KNOWN HUMAN CARCINOGENS, AND EPIDEMIOLOGICAL DATA SHOW CAUSAL ASSOCIATIONS WITH PROSTATE, BREAST, AND LUNG CANCER. THE MOLECULAR MECHANISMS INVOLVED IN CD-INDUCED CARCINOGENESIS ARE POORLY UNDERSTOOD AND ARE ONLY NOW BEGINNING TO BE ELUCIDATED. THE EFFECTS OF CHRONIC EXPOSURE TO CD HAVE RECENTLY ATTRACTED GREAT INTEREST DUE TO THE DEVELOPMENT OF MALIGNANCIES IN CD-INDUCED TUMORIGENESIS IN ANIMALS MODELS. BRIEFLY, VARIOUS IN VITRO STUDIES DEMONSTRATE THAT CD CAN ACT AS A MITOGEN, CAN STIMULATE CELL PROLIFERATION AND INHIBIT APOPTOSIS AND DNA REPAIR, AND CAN INDUCE CARCINOGENESIS IN SEVERAL MAMMALIAN TISSUES AND ORGANS. THUS, THE VARIOUS MECHANISMS INVOLVED IN CHRONIC CD EXPOSURE AND MALIGNANT TRANSFORMATIONS WARRANT FURTHER INVESTIGATION. IN THIS REVIEW, WE FOCUS ON RECENT EVIDENCE OF VARIOUS LEADING GENERAL AND TISSUE-SPECIFIC MOLECULAR MECHANISMS THAT FOLLOW CHRONIC EXPOSURE TO CD IN PROSTATE-, BREAST-, AND LUNG-TRANSFORMED MALIGNANCIES. IN ADDITION, IN THIS REVIEW, WE CONSIDER LESS DEFINED MECHANISMS SUCH AS EPIGENETIC MODIFICATION AND AUTOPHAGY, WHICH ARE THOUGHT TO PLAY A ROLE IN THE DEVELOPMENT OF CD-INDUCED MALIGNANT TRANSFORMATION. 2014 17 6296 47 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 18 4121 35 MECHANISMS OF CHEMICALLY INDUCED RENAL CARCINOGENESIS IN THE LABORATORY RODENT. LABORATORY STUDIES WITH CLASSICAL RENAL CARCINOGENS IN THE RAT AND MOUSE, AS WELL AS RESEARCH INVESTIGATION WITH SOME OF THE CHEMICALS PROVING POSITIVE FOR THE KIDNEY IN NATIONAL TOXICOLOGY PROGRAM CARCINOGENICITY BIOASSAYS, HAVE DEMONSTRATED THE EXISTENCE OF A RANGE OF DIVERSE MECHANISMS UNDERLYING RODENT KIDNEY CARCINOGENESIS. THE CLASSICAL CARCINOGENS USED AS EXPERIMENTAL MODELS FOR STUDYING RENAL TUMOR PATHOGENESIS, SUCH AS THE NITROSAMINES, ARE GENOTOXIC AND INTERACT DIRECTLY WITH DNA, FORMING DNA ADDUCTS WITH MUTAGENIC POTENTIAL. IN CONTRAST, POTASSIUM BROMATE AND FERRIC NITRILOTRIACETATE (FE-NTA), ALSO EFFECTIVE RENAL CARCINOGENS, APPEAR TO CAUSE INDIRECT DAMAGE TO DNA MEDIATED BY OXIDATIVE STRESS. A NUMBER OF NONGENOTOXIC CHEMICALS ARE ASSOCIATED WITH EPIGENETIC RENAL TUMOR INDUCTION IN RODENTS, AND THE ACTIVITY OF THESE TENDS TO INVOLVE PROLONGED STIMULATION OF CELL PROLIFERATION THROUGHOUT THE DURATION OF EXPOSURE. THIS MODE OF ACTION REFLECTS A SUSTAINED REGENERATIVE RESPONSE, EITHER DUE TO DIRECT CHEMICAL TOXICITY TO THE TUBULE CELLS, AS WITH CHLOROFORM, OR TO INDIRECT CYTOTOXICITY ASSOCIATED WITH LYSOSOMAL OVERLOAD, AS IN ALPHA2U-GLOBULIN ACCUMULATION IN MALE RATS RESULTING FROM THE ADMINISTRATION OF SUCH CHEMICALS AS D-LIMONENE AND TETRACHLOROETHYLENE. THE HISTOPATHOLOGIC NATURE OF HYDROQUINONE RENAL CARCINOGENESIS SUGGESTS THAT AN ADDITIONAL EPIGENETIC PATHWAY TO RENAL TUBULE TUMOR FORMATION IN RATS MAY BE THROUGH CHEMICAL-MEDIATED EXACERBATION OF, AND INTERACTION WITH, THE AGE-RELATED SPONTANEOUS RENAL DISEASE, CHRONIC PROGRESSIVE NEPHROPATHY. THESE VARIOUS MECHANISTIC PATHWAYS HAVE IMPLICATIONS FOR THE NATURE OF THE INDUCED CANCER PROCESS WITH RESPECT TO TUMOR INCIDENCE, LATENCY, MALIGNANCY, AND SEX PREDISPOSITION. 1998 19 2655 47 EPIMUTAGENESIS: A PROSPECTIVE MECHANISM TO REMEDIATE ARSENIC-INDUCED TOXICITY. ARSENIC TOXICITY IS A GLOBAL ISSUE, ADDRESSED BY THE WORLD HEALTH ORGANIZATION AS ONE OF THE MAJOR NATURAL CALAMITIES FACED BY HUMANS. MORE THAN 137 MILLION INDIVIDUALS IN 70 NATIONS ARE AFFECTED BY ARSENIC MAINLY THROUGH DRINKING WATER AND ALSO THROUGH DIET. CHRONIC ARSENIC EXPOSURE LEADS TO VARIOUS TYPES OF PATHO-PHYSIOLOGICAL END POINTS IN HUMANS INCLUDING CANCERS. ARSENIC, A XENOBIOTIC SUBSTANCE, IS BIOTRANSFORMED IN THE BODY TO ITS METHYLATED SPECIES BY USING THE PHYSIOLOGICAL S-ADENOSYL METHIONINE (SAM). SAM DICTATES METHYLATION STATUS OF THE GENOME AND ARSENIC METABOLISM LEADS TO DEPLETION OF SAM LEADING TO AN EPIGENETIC DISEQUILIBRIUM. SINCE EPIGENETICS IS ONE OF THE MAJOR PHENOMENON AT THE INTERFACE BETWEEN THE ENVIRONMENT AND HUMAN HEALTH IMPACT, ITS DISEQUILIBRIUM BY ARSENIC INFLICTS UPON THE CHROMATIN COMPACTION, GENE EXPRESSION, GENOMIC STABILITY AND A HOST OF BIOMOLECULAR INTERACTIONS, THE INTERACTOME WITHIN THE CELL. SINCE ARSENIC IS NOT MUTAGENIC BUT IS CARCINOGENIC IN NATURE, ARSENIC INDUCED EPIMUTAGENESIS HAS COME TO THE FOREFRONT SINCE IT DETERMINES THE TRANSCRIPTIONAL AND GENOMIC INTEGRITY OF THE CELL. ARSENIC TOXICITY BRINGS FORTH SEVERAL PATHOPHYSIOLOGICAL MANIFESTATIONS LIKE DERMATOLOGICAL NON-CANCEROUS, PRE-CANCEROUS AND CANCEROUS LESIONS, PERIPHERAL NEUROPATHY, DNA DAMAGE, RESPIRATORY DISORDERS AND CANCERS OF SEVERAL INTERNAL ORGANS. RECENTLY, SEVERAL DISEASES OF SIMILAR MANIFESTATIONS HAVE BEEN EXPLAINED WITH THE RELEVANT EPIGENETIC PERSPECTIVES REGARDING THE POSSIBLE MOLECULAR MECHANISM FOR THEIR ONSET. HENCE, IN THE CURRENT REVIEW, WE COMPREHENSIVELY TRY TO INTERCALATE THE INFORMATION ON ARSENIC-INDUCED EPIGENETIC ALTERATIONS OF DNA, HISTONES AND MICRORNA SO AS TO UNDERSTAND WHETHER THE ARSENIC-INDUCED TOXIC MANIFESTATIONS ARE BROUGHT ABOUT BY THE EPIGENETIC CHANGES. WE HIGHLIGHT THE NEED TO UNDERSTAND THE ASPECT OF EPIMUTAGENESIS AND SUBSEQUENT ALTERATIONS IN THE CELLULAR INTERACTOME DUE TO ARSENIC-INDUCED MOLECULAR CHANGES, WHICH MAY BE UTILIZED TO DEVELOP PUTATIVE THERAPEUTIC STRATEGIES TARGETING BOTH OXIDATIVE POTENTIAL AND EPIMUTAGENESIS IN HUMANS. 2015 20 5557 35 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