1 495 207 ASSESSMENT OF THE HEALTH EFFECTS OF TRICHLOROETHYLENE. THE EPIDEMIOLOGICAL STUDIES PERFORMED THUS FAR HAVE PRESENTED ONLY LIMITED EVIDENCE FOR THE CARCINOGENICITY OF TRICHLOROETHYLENE (TRI) TO HUMANS. HOWEVER, THESE STUDIES HAD DRAWBACKS SUCH AS INSUFFICIENT SIZE OF COHORT, SHORT OBSERVATION PERIOD, AND INADEQUATE TRI EXPOSURE ASSESSMENT; THEREFORE, NO CONCRETE CONCLUSION HAS BEEN REACHED CONCERNING TRI CARCINOGENICITY TO HUMANS. DESPITE THE LIMITED EPIDEMIOLOGICAL EVIDENCE AS TO THE CARCINOGENICITY OF TRI, THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) HAS CHANGED THE CARCINOGENICITY CLASSIFICATION OF TRI FROM GROUP 3 (NOT CLASSIFIABLE AS TO CARCINOGENICITY TO HUMANS) TO GROUP 2A (PROBABLY CARCINOGENIC TO HUMANS). IN REGARD TO THE NEW CLASSIFICATION BY THE IARC, THE COMMITTEE FOR OCCUPATIONAL EXPOSURE LIMITS OF THE JAPAN SOCIETY FOR OCCUPATIONAL HEALTH HAS MADE A PROPOSAL THAT IT IS TOO EARLY TO CLASSIFY THE CARCINOGENICITY OF TRI AS GROUP 2A AND THAT IT IS PROPER TO PROMOTE EXPOSURE CONTROL WITH THE CARCINOGENICITY BEING CLASSIFIED AS 2B FOR THE MOMENT. THERE ARE SPECIES DIFFERENCES IN TRI CARCINOGENICITY, PARTICULARLY BETWEEN RATS AND MICE. ALTHOUGH EXPERIMENTAL STUDIES HAVE FOUND NO EVIDENCE THAT TRI INDUCES LIVER CANCER IN RATS, THERE IS AMPLE EVIDENCE THAT TRI PROMOTES THE DEVELOPMENT OF LIVER CANCER IN MICE, PARTICULARLY IN B6C3F1 MICE. THE CARCINOGENICITY OF TRI IN THIS STRAIN OF MICE MAY BE BASED ON AN EPIGENETIC MECHANISM RATHER ON A GENOTOXIC MECHANISM AND THE LIVER CANCER MAY BE INDUCED ONLY AFTER TRI HAS BEEN INHALED FOR A LONG PERIOD OF TIME AT CONCENTRATIONS HIGH ENOUGH TO CAUSE CYTOTOXICITY. CONVERSELY, WITH NO REPORTS SHOWING TRI-INDUCED RENAL TUMORS IN MICE, THE POSSIBILITY HAS BEEN SUGGESTED THAT THIS CHEMICAL INDUCES SUCH TUMORS IN MALE RATS. THE SPECIES DIFFERENCES ARE MAINLY ACCOUNTED FOR BY DIFFERENCES IN THE METABOLISM OF TRI BETWEEN RATS AND MICE. FROM A GENERAL SURVEY OF THE LITERATURE, IT CAN BE CONCLUDED THAT TRI ITSELF IS NOT MUTAGENIC. HOWEVER, THE CONJUGATION OF TRI WITH GLUTATHIONE (GSH), A MINOR PATHWAY OF TRI METABOLISM, RESULTS IN MUTAGENIC METABOLITES IN THE KIDNEY OF RATS. THE ACUTE TOXICITY OF TRI IS NEUROTOXICITY BASED ON ITS ANESTHETIC ACTION. AN EXPOSURE TO EXTREMELY HIGH LEVELS OF TRI MAY CAUSE THE LIVER AND KIDNEY DISORDERS. REPEATED EXPOSURES TO HIGH LEVELS OF TRI MAY RESULT IN NEURO-, HEPATO-, AND/OR NEPHROTOXICITY. THE MAIN SYMPTOMS APPEARING AFTER CHRONIC EXPOSURE AT LOW LEVELS ARE NEUROLOGICAL CHANGES REPRESENTED BY SUBJECTIVE SYMPTOMS RELATING TO CENTRAL AND AUTONOMIC NERVOUS SYSTEMS, OR BY A LOWERED CONDUCTION VELOCITY OF THE NERVES OR A PROLONGED LATENCY OF THE NERVE RESPONSES. FOR THE PRESENT, IT IS REASONABLE TO USE THE NEUROLOGICAL FINDINGS FOR ESTABLISHING THE REFERENCE VALUES OF TRI FOR BOTH WORK AND GENERAL ENVIRONMENTS. A VALUE OF 25 PPM (135 MG/M3) IS PROPOSED AS A REFERENCE VALUE FOR WORK ENVIRONMENTS, AND 25-50 PPB (135-270 MICROGRAMS/M3) FOR THE GENERAL ENVIRONMENT (1/1,000 OF THE VALUE FOR WORK ENVIRONMENT). 1997 2 3214 39 HEAT STRESS-INDUCED LIFE SPAN EXTENSION IN YEAST. THE YEAST SACCHAROMYCES CEREVISIAE HAS A LIMITED LIFE SPAN THAT CAN BE MEASURED BY THE NUMBER OF TIMES INDIVIDUAL CELLS DIVIDE. SEVERAL GENETIC MANIPULATIONS HAVE BEEN SHOWN TO PROLONG THE YEAST LIFE SPAN. HOWEVER, ENVIRONMENTAL EFFECTS THAT EXTEND LONGEVITY HAVE BEEN LARGELY IGNORED. WE HAVE FOUND THAT MILD, NONLETHAL HEAT STRESS EXTENDED YEAST LIFE SPAN WHEN IT WAS ADMINISTERED TRANSIENTLY EARLY IN LIFE. THE INCREASED LONGEVITY WAS DUE TO A REDUCTION IN THE MORTALITY RATE THAT PERSISTED OVER MANY CELL DIVISIONS (GENERATIONS) BUT WAS NOT PERMANENT. THE GENES RAS1 AND RAS2 WERE NECESSARY TO OBSERVE THIS EFFECT OF HEAT STRESS. THE RAS2 GENE IS CONSISTENTLY REQUIRED FOR MAINTENANCE OF LIFE SPAN WHEN HEAT STRESS IS CHRONIC OR IN ITS EXTENSION WHEN HEAT STRESS IS TRANSIENT OR ABSENT ALTOGETHER. RAS1, ON THE OTHER HAND, APPEARS TO HAVE A ROLE IN SIGNALING LIFE EXTENSION INDUCED BY TRANSIENT, MILD HEAT STRESS, WHICH IS DISTINCT FROM ITS LIFE-SPAN-CURTAILING EFFECT IN THE ABSENCE OF STRESS AND ITS LACK OF INVOLVEMENT IN THE RESPONSE TO CHRONIC HEAT STRESS. THIS DISTINCTION BETWEEN THE RAS GENES MAY BE PARTIALLY RELATED TO THEIR DIFFERENT EFFECTS ON GROWTH-PROMOTING GENES AND STRESS-RESPONSIVE GENES. THE RAS2 MUTATION CLEARLY HINDERED RESUMPTION OF GROWTH AND RECOVERY FROM STRESS, WHILE THE RAS1 MUTATION DID NOT. THE HSP104 GENE, WHICH IS LARGELY RESPONSIBLE FOR INDUCED THERMOTOLERANCE IN YEAST, WAS NECESSARY FOR LIFE EXTENSION INDUCED BY TRANSIENT HEAT STRESS. AN INTERACTION BETWEEN MITOCHONDRIAL PETITE MUTATIONS AND HEAT STRESS WAS FOUND, SUGGESTING THAT MITOCHONDRIA MAY BE NECESSARY FOR LIFE EXTENSION BY TRANSIENT HEAT STRESS. THE RESULTS RAISE THE POSSIBILITY THAT THE RAS GENES AND MITOCHONDRIA MAY PLAY A ROLE IN THE EPIGENETIC INHERITANCE OF REDUCED MORTALITY RATE AFFORDED BY TRANSIENT, MILD HEAT STRESS. 1998 3 6296 58 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 4 1970 42 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 5 818 33 CHARACTERISTICS OF THE SPECTRUM OF PROLIFERATIVE LESIONS OBSERVED IN THE KIDNEY AND URINARY BLADDER OF FISCHER 344 RATS AND B6C3F1 MICE. MANY RODENT RENAL AND BLADDER CARCINOGENS RELY UPON EPIGENETIC MECHANISMS OF CARCINOGENESIS; SUCH MECHANISMS ARE LIKELY TO INFLUENCE THE SPECTRUM OF URINARY TRACT TUMORS OBSERVED IN CONTROL AND TREATED ANIMALS. THIS IS REFLECTED IN SEVERAL FEATURES OF CHEMICALLY INDUCED RODENT URINARY TRACT NEOPLASMS, INCLUDING A LOW OVERALL TUMOR INCIDENCE, AN INCREASED PREVALENCE OF URINARY TRACT TUMORS IN RATS COMPARED TO MICE AND MALES COMPARED TO FEMALES, THE TENDENCY FOR EPITHELIAL TUMORS TO PREDOMINATE OVER NONEPITHELIAL TYPES, AND DEMONSTRATED LINKS TO CHRONIC PROGRESSIVE NEPHROPATHY AND UROLITHIASIS. SUCH TENDENCIES ARE ALSO CHARACTERISTIC OF SPONTANEOUS URINARY TRACT TUMORS IN RODENTS. DATA TO SUPPORT THESE OBSERVATIONS CAN BE DERIVED FROM LARGE HISTORICAL DATABASES SUCH AS THE TOXICOLOGY DATA MANAGEMENT SYSTEM, MAINTAINED BY NATIONAL TOXICOLOGY PROGRAM. 2002 6 2901 50 GENDER DIFFERENCES IN GERM-CELL MUTAGENESIS AND GENETIC RISK. CURRENT INTERNATIONAL CLASSIFICATION SYSTEMS FOR CHEMICAL MUTAGENS ARE HAZARD-BASED RATHER THAN AIMED AT ASSESSING RISKS QUANTITATIVELY. IN THE PAST, GERM-CELL TESTS HAVE BEEN MAINLY PERFORMED WITH A LIMITED NUMBER OF SOMATIC CELL MUTAGENS, AND RARELY UNDER CONDITIONS AIMED AT COMPARING GENDER-SPECIFIC DIFFERENCES IN SUSCEPTIBILITY TO MUTAGEN EXPOSURES. THERE ARE PROFOUND DIFFERENCES IN THE GENETIC CONSTITUTION, AND IN HORMONAL, STRUCTURAL, AND FUNCTIONAL ASPECTS OF DIFFERENTIATION AND CONTROL OF GAMETOGENESIS BETWEEN THE SEXES. A CRITICAL REVIEW OF THE LITERATURE SUGGESTS THAT THESE DIFFERENCES MAY HAVE A PROFOUND IMPACT ON THE RELATIVE SUSCEPTIBILITY, STAGE OF HIGHEST SENSITIVITY AND THE RELATIVE RISK FOR THE GENESIS OF GENE MUTATION, AS WELL AS STRUCTURAL AND NUMERICAL CHROMOSOMAL ABERRATIONS IN MALE AND FEMALE GERM CELLS. TRANSMISSION OF GERM-CELL MUTATIONS TO THE OFFSPRING MAY ALSO ENCOUNTER GENDER-SPECIFIC INFLUENCES. GENDER DIFFERENCES IN SUSCEPTIBILITY TO CHEMICALLY DERIVED ALTERATIONS IN IMPRINTING PATTERNS MAY POSE A THREAT FOR THE HEALTH OF THE OFFSPRING AND MAY ALSO BE TRANSMITTED TO FUTURE GENERATIONS. RECENT REPORTS ON DIFFERENT GENETIC EFFECTS FROM HIGH ACUTE AND FROM CHRONIC LOW-DOSE EXPOSURES CHALLENGE THE VALIDITY OF CONCLUSIONS DRAWN FROM STANDARD METHODS OF MUTAGENICITY TESTING. IN CONCLUSION, RESEARCH IS URGENTLY NEEDED TO IDENTIFY GENETIC HAZARDS FOR A LARGER RANGE OF CHEMICAL COMPOUNDS, INCLUDING THOSE SUSPECTED TO DISTURB PROPER CHROMOSOME SEGREGATION. ALTERATIONS IN EPIGENETIC PROGRAMMING AND THEIR HEALTH CONSEQUENCES WILL HAVE TO BE INVESTIGATED. MORE ATTENTION SHOULD BE PAID TO GENDER-SPECIFIC GENETIC EFFECTS. FINALLY, THE DATABASE FOR GERM-CELL MUTAGENS SHOULD BE ENLARGED USING MOLECULAR METHODOLOGIES, AND GENETIC EPIDEMIOLOGY STUDIES SHOULD BE PERFORMED WITH THESE TECHNIQUES TO VERIFY HUMAN GENETIC RISK. 2007 7 837 66 CHEMICALLY INDUCED RENAL TUBULE TUMORS IN THE LABORATORY RAT AND MOUSE: REVIEW OF THE NCI/NTP DATABASE AND CATEGORIZATION OF RENAL CARCINOGENS BASED ON MECHANISTIC INFORMATION. THE INCIDENCE OF RENAL TUBULE CARCINOGENESIS IN MALE AND FEMALE RATS OR MICE WITH 69 CHEMICALS FROM THE 513 BIOASSAYS CONDUCTED TO DATE BY THE NCI/NTP HAS BEEN COLLATED, THE CHEMICALS CATEGORIZED, AND THE RELATIONSHIP BETWEEN CARCINOGENESIS AND RENAL TUBULE HYPERPLASIA AND EXACERBATION OF THE SPONTANEOUS, AGE-RELATED RODENT DISEASE CHRONIC PROGRESSIVE NEPHROPATHY (CPN) EXAMINED. WHERE INFORMATION ON MECHANISM OR MODE OF ACTION EXISTS, THE CHEMICALS HAVE BEEN CATEGORIZED BASED ON THEIR ABILITY TO DIRECTLY OR INDIRECTLY INTERACT WITH RENAL DNA, OR ON THEIR ACTIVITY VIA EPIGENETIC PATHWAYS INVOLVING EITHER DIRECT OR INDIRECT CYTOTOXICITY WITH REGENERATIVE HYPERPLASIA, OR EXACERBATION OF CPN. NINE CHEMICALS WERE IDENTIFIED AS DIRECTLY INTERACTING WITH DNA, WITH SIX OF THESE PRODUCING RENAL TUBULE TUMORS AT HIGH INCIDENCE IN RATS OF BOTH SEXES, AND IN SOME CASES ALSO IN MICE. OCHRATOXIN A WAS THE MOST POTENT COMPOUND IN THIS GROUP, PRODUCING A HIGH TUMOR INCIDENCE AT VERY LOW DOSES, OFTEN WITH METASTASIS. THREE CHEMICALS WERE DISCUSSED IN THE CONTEXT OF INDIRECT DNA DAMAGE MEDIATED BY AN OXIDATIVE FREE RADICAL MECHANISM, ONE OF THESE BEING FROM THE NTP DATABASE. A THIRD CATEGORY INCLUDED FOUR CHEMICALS THAT HAD THE POTENTIAL TO CAUSE DNA DAMAGE FOLLOWING CONJUGATION WITH GLUTATHIONE AND SUBSEQUENT ENZYMATIC ACTIVATION TO A REACTIVE SPECIES, USUALLY A THIOL-CONTAINING ENTITY. TWO CHEMICALS WERE ALLOCATED INTO THE CATEGORY INVOLVING A DIRECT CYTOTOXIC ACTION ON THE RENAL TUBULE FOLLOWED BY SUSTAINED COMPENSATORY CELL PROLIFERATION, WHILE NINE WERE INCLUDED IN A GROUP WHERE THE CELL LOSS AND SUSTAINED INCREASE IN RENAL TUBULE CELL TURNOVER WERE DEPENDENT ON LYSOSOMAL ACCUMULATION OF THE MALE RAT-SPECIFIC PROTEIN, ALPHA2MU-GLOBULIN. IN A SIXTH CATEGORY, MORPHOLOGIC EVIDENCE ON TWO CHEMICALS INDICATED THAT THE RENAL TUMORS WERE A CONSEQUENCE OF EXACERBATED CPN. FOR THE REMAINING CHEMICALS, THERE WERE NO PERTINENT DATA ENABLING ASSIGNMENT TO A MECHANISTIC CATEGORY. ACCORDINGLY, THESE CHEMICALS, ACTING THROUGH AN AS YET UNKNOWN MECHANISM, WERE GROUPED AS EITHER BEING ASSOCIATED WITH AN ENHANCEMENT OF CPN (CATEGORY 7, 16 CHEMICALS), OR NOT ASSOCIATED WITH ENHANCED CPN (CATEGORY 8, 4 CHEMICALS). A NINTH CATEGORY DEALT WITH 11 CHEMICALS THAT WERE REGARDED AS PRODUCING INCREASES IN RENAL TUBULE TUMORS THAT DID NOT REACH STATISTICAL SIGNIFICANCE. A 10TH CATEGORY DISCUSSED 6 CHEMICALS THAT INDUCED RENAL TUMORS IN MICE BUT NOT IN RATS, PLUS 8 CHEMICALS THAT PRODUCED A LOW INCIDENCE OF RENAL TUBULE TUMORS IN MICE THAT DID NOT REACH STATISTICAL SIGNIFICANCE. AS MORE MECHANISTIC DATA ARE GENERATED, SOME CHEMICALS WILL INEVITABLY BE PLACED IN DIFFERENT GROUPS, PARTICULARLY THOSE FROM CATEGORIES 7 AND 8. A LARGE NUMBER OF CHEMICALS IN THE SERIES EXACERBATED CPN, BUT THOSE IN CATEGORY 7 ESPECIALLY MAY BE CANDIDATES FOR INCLUSION IN CATEGORY 6 WHEN FURTHER INFORMATION IS GLEANED FROM THE RELEVANT NTP STUDIES. ALSO, NEW DATA ON SPECIFIC CHEMICALS WILL PROBABLY EXPAND CATEGORY 5 AS CYTOTOXICITY AND CELL REGENERATION ARE IDENTIFIED AS OBLIGATORY STEPS IN RENAL CARCINOGENESIS IN MORE CASES. ADDITIONAL CONFIRMATORY OUTCOMES ARISING FROM THIS REVIEW ARE THAT METASTASES FROM RENAL TUBULE TUMORS, WHILE ENCOUNTERED WITH CHEMICALS CAUSING DNA DAMAGE, ARE RARE WITH THOSE ACTING THROUGH AN EPIGENETIC PATHWAY, WITH THE EXCEPTION BEING FUMONISIN B1; THAT MALE RATS AND MICE ARE GENERALLY MORE SUSCEPTIBLE THAN FEMALE RATS AND MICE TO CHEMICAL INDUCTION OF RENAL TUBULE TUMORS; AND THAT A BACKGROUND OF ATYPICAL TUBULE HYPERPLASIA IS A USEFUL INDICATOR REFLECTING A CHEMICALLY ASSOCIATED RENAL TUBULE TUMOR RESPONSE. WITH RESPECT TO RENAL TUBULE TUMORS AND HUMAN RISK ASSESSMENT, CHEMICALS IN CATEGORIES 1 AND 2, AND POSSIBLY 3, WOULD CURRENTLY BE JUDGED BY LINEAR DEFAULT METHODS; CHEMICALS IN CATEGORY 4 (AND PROBABLY SOME IN CATEGORY 3) AS EXHIBITING A THRESHOLD OF ACTIVITY WARRANTING THE BENCHMARK APPROACH; AND THOSE IN CATEGORIES 5 AND 6 AS REPRESENTING MECHANISMS THAT HAVE NO RELEVANCE FOR EXTRAPOLATION TO HUMANS. 2004 8 3632 36 INCORPORATING TRANSGENERATIONAL EPIGENETIC INHERITANCE INTO ECOLOGICAL RISK ASSESSMENT FRAMEWORKS. CHRONIC EXPOSURE TO ENVIRONMENTAL CONTAMINANTS CAN INDUCE HERITABLE "TRANSGENERATIONAL" MODIFICATIONS TO ORGANISMS, POTENTIALLY AFFECTING FUTURE ECOSYSTEM HEALTH AND FUNCTIONALITY. INCORPORATING TRANSGENERATIONAL EPIGENETIC HERITABILITY INTO RISK ASSESSMENT PROCEDURES HAS BEEN PREVIOUSLY SUGGESTED. HOWEVER, A CRITICAL REVIEW OF EXISTING LITERATURE YIELDED NUMEROUS STUDIES CLAIMING TRANSGENERATIONAL IMPACTS, WITH LITTLE COMPELLING EVIDENCE. THEREFORE, CONTAMINANT-INDUCED EPIGENETIC INHERITANCE MAY BE LESS COMMON THAN IS REPORTED IN THE LITERATURE. WE IDENTIFIED A NEED FOR MULTIGENERATION EPIGENETIC STUDIES THAT EXTEND BEYOND WHAT COULD BE DEEMED "DIRECT EXPOSURE" TO F1 AND F2 GAMETES AND ALSO INCLUDE SUBSEQUENT MULTIPLE NONEXPOSED GENERATIONS TO ADEQUATELY EVALUATE TRANSGENERATIONAL RECOVERY TIMES. ALSO, INCREASED EXPERIMENTAL REPLICATION IS REQUIRED TO ACCOUNT FOR THE HIGHLY VARIABLE NATURE OF EPIGENETIC RESPONSES AND APPARENT IRREPRODUCIBILITY OF CURRENT STUDIES. FURTHER, EPIGENETIC END POINTS NEED TO BE CORRELATED WITH OBSERVABLE DETRIMENTAL ORGANISM CHANGES BEFORE A NEED FOR RISK MANAGEMENT CAN BE PROPERLY DETERMINED. WE SUGGEST THAT EPIGENETIC-BASED CONTAMINANT STUDIES INCLUDE CONCENTRATIONS LOWER THAN CURRENT "EC(10-20)" OR "LOWEST OBSERVABLE EFFECT CONCENTRATIONS" FOR THE ORGANISM'S MOST SENSITIVE PHENOTYPIC END POINT, AS HIGHER CONCENTRATIONS ARE LIKELY ALREADY REGULATED. FINALLY, WE PROPOSE A REGULATORY FRAMEWORK AND OPTIMAL EXPERIMENTAL DESIGN THAT ENABLES TRANSGENERATIONAL EPIGENETIC EFFECTS TO BE ASSESSED AND INCORPORATED INTO CONVENTIONAL ECOTOXICOLOGICAL TESTING. 2017 9 6790 38 [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 10 6078 44 THE EFFECT OF CHRONIC ARSENIC EXPOSURE IN ZEBRAFISH. ARSENIC IS A PREVALENT ENVIRONMENTAL TOXIN AND A GROUP ONE HUMAN CARCINOGENIC AGENT. CHRONIC ARSENIC EXPOSURE HAS BEEN ASSOCIATED WITH MANY HUMAN DISEASES. THE AIM OF THIS STUDY IS TO EVALUATE ZEBRAFISH AS AN ANIMAL MODEL TO ASSESS ARSENIC TOXICITY IN ELEVATED LONG-TERM ARSENIC EXPOSURE. WITH PROLONGED EXPOSURE (6 MONTHS) TO VARIOUS CONCENTRATIONS OF ARSENIC FROM 50 PPB TO 300 PPB, EFFECTS OF ARSENIC ACCUMULATION IN ZEBRAFISH TISSUES, AND PHENOTYPES WERE INVESTIGATED. RESULTS SHOWED THAT THERE ARE NO SIGNIFICANT CHANGES OF ARSENIC RETENTION IN ZEBRAFISH TISSUES, AND ZEBRAFISH DID NOT EXHIBIT ANY VISIBLE TUMOR FORMATION UNDER ARSENIC EXPOSURE CONDITIONS. HOWEVER, THE ZEBRAFISH DEMONSTRATE A DYSFUNCTION IN THEIR NEUROLOGICAL SYSTEM, WHICH IS REFLECTED BY A REDUCTION OF LOCOMOTIVE ACTIVITY. MOREOVER, ELEVATED LEVELS OF THE SUPEROXIDE DISMUTASE (SOD2) PROTEIN WERE DETECTED IN THE EYE AND LIVER, SUGGESTING INCREASED OXIDATIVE STRESS. IN ADDITION, THE PROGENIES OF ARSENIC-TREATED PARENTS DISPLAYED A SMALLER BIOMASS (FOUR-FOLD REDUCTION IN BODY WEIGHT) COMPARED WITH THOSE FROM THEIR PARENTAL CONTROLS. THIS RESULT INDICATES THAT ARSENIC MAY INDUCE GENETIC OR EPIGENETIC CHANGES THAT ARE THEN PASSED ON TO THE NEXT GENERATION. OVERALL, THIS STUDY DEMONSTRATES THAT ZEBRAFISH IS A CONVENIENT VERTEBRATE MODEL WITH ADVANTAGES IN THE EVALUATION OF ARSENIC-ASSOCIATED NEUROLOGICAL DISORDERS AS WELL AS ITS INFLUENCES ON THE OFFSPRING. 2016 11 1340 41 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 12 1844 49 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 6257 33 THE MOLECULAR BASIS OF TOLERANCE. TOLERANCE IS DEFINED AS THE DIMINISHED RESPONSE TO ALCOHOL OR OTHER DRUGS OVER THE COURSE OF REPEATED OR PROLONGED EXPOSURE. THIS MECHANISM ALLOWS PHYSIOLOGICAL PROCESSES TO ACHIEVE STABILITY IN A CONSTANTLY CHANGING ENVIRONMENT. THE ONSET OF TOLERANCE MAY OCCUR WITHIN MINUTES, DURING A SINGLE EXPOSURE TO ALCOHOL (I.E., ACUTE TOLERANCE), OR OVER LONGER TIMEFRAMES AND WITH PROLONGED EXPOSURE TO ALCOHOL (I.E., RAPID OR CHRONIC TOLERANCE). CHANGES IN TOLERANCE INDUCED BY ALCOHOL MAY AFFECT SEVERAL PROCESSES AT THE MOLECULAR, CELLULAR, OR BEHAVIORAL LEVEL. THESE EFFECTS OFTEN ARE INTERRELATED AND MAY BE DIFFICULT TO SEPARATE. THIS ARTICLE DESCRIBES CHANGES AT THE MOLECULAR LEVEL THAT ARE RELATED TO THE ONSET OF ACUTE, RAPID, OR CHRONIC TOLERANCE. IT FOCUSES ON NEURONAL MEMBRANE-BOUND CHANNELS AND THE FACTORS THAT AFFECT THEIR FUNCTION AND PRODUCTION, SUCH AS MODIFICATION OF PROTEIN SYNTHESIS AND ACTIVITY, INTERACTION WITH THE MEMBRANE LIPID MICROENVIRONMENT, EPIGENETIC EFFECTS ON CYTOPLASMIC REGULATION, AND GENE TRANSCRIPTION. ALSO CONSIDERED IS THE GENETICS OF TOLERANCE. 2008 14 795 39 CELLULAR RESILIENCE. CELLULAR RESILIENCE DESCRIBES THE ABILITY OF A CELL TO COPE WITH ENVIRONMENTAL CHANGES SUCH AS TOXICANT EXPOSURE. IF CELLULAR METABOLISM DOES NOT COLLAPSE DIRECTLY AFTER THE HIT OR END IN PROGRAMMED CELL DEATH, THE ENSUING STRESS RESPONSES PROMOTE A NEW HOMEOSTASIS UNDER STRESS. THE PROCESSES OF REVERTING "BACK TO NORMAL" AND REVERSAL OF APOPTOSIS ("ANASTASIS") HAVE BEEN STUDIED LITTLE AT THE CELLULAR LEVEL. CELL TYPES SHOW ASTONISHINGLY SIMILAR VULNERABILITY TO MOST TOXICANTS, EXCEPT FOR THOSE THAT REQUIRE A VERY SPECIFIC TARGET, METABOLISM OR MECHANISM PRESENT ONLY IN SPECIFIC CELL TYPES. THE MAJORITY OF CHEMICALS TRIGGERS "GENERAL CYTOTOXICITY" IN ANY CELL AT SIMILAR CONCENTRATIONS. WE HYPOTHESIZE THAT CELLS DIFFER LESS IN THEIR VULNERABILITY TO A GIVEN TOXICANT THAN IN THEIR RESILIENCE (COPING WITH THE "HIT"). IN MANY CASES, CELLS DO NOT RETURN TO THE NAIVE STATE AFTER A TOXIC INSULT. THE PHENOMENA OF "PRE-CONDITIONING", "TOLERANCE" AND "HORMESIS" DESCRIBE THIS FOR LOW-DOSE EXPOSURES TO TOXICANTS THAT RENDER THE CELL MORE RESISTANT TO SUBSEQUENT HITS. THE DEFENSE AND RESILIENCE PROGRAMS INCLUDE EPIGENETIC CHANGES THAT LEAVE A "MEMORY/SCAR" - AN ALTERATION AS A CONSEQUENCE OF THE STRESS THE CELL HAS EXPERIENCED. THESE MEMORIES MIGHT HAVE LONG-TERM CONSEQUENCES, BOTH POSITIVE (RESISTANCE) AND NEGATIVE, THAT CONTRIBUTE TO CHRONIC AND DELAYED MANIFESTATIONS OF HAZARD AND, ULTIMATELY, DISEASE. THIS ARTICLE CALLS FOR MORE SYSTEMATIC ANALYSES OF HOW CELLS COPE WITH TOXIC PERTURBATIONS IN THE LONG-TERM AFTER STRESSOR WITHDRAWAL. A TECHNICAL PREREQUISITE FOR THESE ARE STABLE (ORGANOTYPIC) CULTURES AND A CHARACTERIZATION OF STRESS RESPONSE MOLECULAR NETWORKS. 2015 15 1407 49 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 16 266 43 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 17 2507 31 EPIGENETICS AND OBESITY: THE DEVIL IS IN THE DETAILS. OBESITY IS A COMPLEX DISEASE WITH MULTIPLE WELL-DEFINED RISK FACTORS. NEVERTHELESS, SUSCEPTIBILITY TO OBESITY AND ITS SEQUELAE WITHIN OBESOGENIC ENVIRONMENTS VARIES GREATLY FROM ONE PERSON TO THE NEXT, SUGGESTING A ROLE FOR GENE X ENVIRONMENT INTERACTIONS IN THE ETIOLOGY OF THE DISORDER. EPIGENETIC REGULATION OF THE HUMAN GENOME PROVIDES A PUTATIVE MECHANISM BY WHICH SPECIFIC ENVIRONMENTAL EXPOSURES CONVEY RISK FOR OBESITY AND OTHER HUMAN DISEASES AND IS ONE POSSIBLE MECHANISM THAT UNDERLIES THE GENE X ENVIRONMENT/TREATMENT INTERACTIONS OBSERVED IN EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS. A STUDY PUBLISHED IN BMC MEDICINE THIS MONTH BY WANG ET AL. REPORTS ON AN EXAMINATION OF DNA METHYLATION IN PERIPHERAL BLOOD LEUKOCYTES OF LEAN AND OBESE ADOLESCENTS, COMPARING METHYLATION PATTERNS BETWEEN THE TWO GROUPS. THE AUTHORS IDENTIFIED TWO GENES THAT WERE DIFFERENTIALLY METHYLATED, BOTH OF WHICH HAVE ROLES IN IMMUNE FUNCTION. HERE WE OVERVIEW THE FINDINGS FROM THIS STUDY IN THE CONTEXT OF THOSE EMERGING FROM OTHER RECENT GENETIC AND EPIGENETIC STUDIES, DISCUSS THE STRENGTHS AND WEAKNESSES OF THE STUDY AND SPECULATE ON THE FUTURE OF EPIGENETICS IN CHRONIC DISEASE RESEARCH. 2010 18 6065 42 THE DEVELOPMENTAL ORIGINS OF CHRONIC PHYSICAL AGGRESSION: BIOLOGICAL PATHWAYS TRIGGERED BY EARLY LIFE ADVERSITY. LONGITUDINAL EPIDEMIOLOGICAL STUDIES WITH BIRTH COHORTS HAVE SHOWN THAT PHYSICAL AGGRESSION IN HUMANS DOES NOT APPEAR SUDDENLY IN ADOLESCENCE AS COMMONLY THOUGHT. IN FACT, PHYSICALLY AGGRESSIVE BEHAVIOUR IS OBSERVED AS EARLY AS 12 MONTHS AFTER BIRTH, ITS FREQUENCY PEAKS AROUND 2-4 YEARS OF AGE AND DECREASES IN FREQUENCY UNTIL EARLY ADULTHOOD. HOWEVER, A MINORITY OF CHILDREN (3-7%) MAINTAIN A HIGH FREQUENCY OF PHYSICAL AGGRESSION FROM CHILDHOOD TO ADOLESCENCE AND DEVELOP SERIOUS SOCIAL ADJUSTMENT PROBLEMS DURING ADULTHOOD. GENETIC FACTORS AND EARLY SOCIAL EXPERIENCES, AS WELL AS THEIR INTERACTION, HAVE BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF CHRONIC AGGRESSIVE BEHAVIOUR. HOWEVER, THE BIOLOGICAL MECHANISMS UNDERLYING THESE ASSOCIATIONS ARE JUST BEGINNING TO BE UNCOVERED. RECENT EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS ARE RESPONSIVE TO ADVERSE ENVIRONMENTS AND COULD BE INVOLVED IN THE DEVELOPMENT OF CHRONIC AGGRESSION. USING BOTH GENE CANDIDATE AND GENOMIC APPROACHES, RECENT STUDIES HAVE IDENTIFIED EPIGENETIC MARKS, SUCH AS DNA METHYLATION ALTERATIONS IN GENES INVOLVED IN THE STRESS RESPONSE AND THE SEROTONIN AND IMMUNE SYSTEMS TO BE PARTLY RESPONSIBLE FOR THE LONG-LASTING EFFECTS OF EARLY ADVERSITY. FURTHER LONGITUDINAL STUDIES WITH BIOLOGICAL, ENVIRONMENTAL AND BEHAVIOURAL ASSESSMENTS FROM BIRTH ONWARDS ARE NEEDED TO ELUCIDATE THE SEQUENCE OF EVENTS THAT LEADS TO THESE LONG-LASTING EPIGENETIC MARKS ASSOCIATED WITH EARLY ADVERSITY AND AGGRESSION. 2015 19 3210 39 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 20 5193 42 PRENATAL EXPOSURE TO ENVIRONMENTAL PRO-OXIDANTS INDUCES MITOCHONDRIA-MEDIATED EPIGENETIC CHANGES: A CROSS-SECTIONAL PILOT STUDY. MITOCHONDRIA PLAY A CENTRAL ROLE IN MAINTAINING CELLULAR AND METABOLIC HOMEOSTASIS DURING VITAL DEVELOPMENT CYCLES OF FOETAL GROWTH. OPTIMAL MITOCHONDRIAL FUNCTIONS ARE IMPORTANT NOT ONLY TO SUSTAIN ADEQUATE ENERGY PRODUCTION BUT ALSO FOR REGULATED EPIGENETIC PROGRAMMING. HOWEVER, THESE ORGANELLES ARE SUBTLE TARGETS OF ENVIRONMENTAL EXPOSURES, AND ANY PERTURBANCE IN THE DEFINED MITOCHONDRIAL MACHINERY DURING THE DEVELOPMENTAL STAGE CAN LEAD TO THE RE-PROGRAMMING OF THE FOETAL EPIGENETIC LANDSCAPE. AS THESE MODIFICATIONS CAN BE TRANSFERRED TO SUBSEQUENT GENERATIONS, WE HEREIN PERFORMED A CROSS-SECTIONAL STUDY TO HAVE AN IN-DEPTH UNDERSTANDING OF THIS INTRICATE PHENOMENON. THE STUDY WAS CONDUCTED WITH TWO ARMS: WHEREAS THE FIRST GROUP CONSISTED OF IN UTERO PRO-OXIDANT EXPOSED INDIVIDUALS AND THE SECOND GROUP INCLUDED CONTROLS. OUR RESULTS SHOWED HIGHER LEVELS OF OXIDATIVE MTDNA DAMAGE AND ASSOCIATED INTEGRATED STRESS RESPONSE AMONG THE EXPOSED INDIVIDUALS. THESE DISTURBANCES WERE FOUND TO BE CLOSELY RELATED TO THE OBSERVED DISCREPANCIES IN MITOCHONDRIAL BIOGENESIS. THE EXPOSED GROUP SHOWED MTDNA HYPERMETHYLATION AND CHANGES IN ALLIED MITOCHONDRIAL FUNCTIONING. ALTERED EXPRESSION OF MITOMIRS AND THEIR RESPECTIVE TARGET GENES IN THE EXPOSED GROUP INDICATED THE POSSIBILITIES OF A DISTURBED MITOCHONDRIAL-NUCLEAR CROSS TALK. THIS WAS FURTHER CONFIRMED BY THE MODIFIED ACTIVITY OF THE MITOCHONDRIAL STRESS REGULATORS AND PRO-INFLAMMATORY MEDIATORS AMONG THE EXPOSED GROUP. IMPORTANTLY, THE DISTURBED DNMT FUNCTIONING, HYPERMETHYLATION OF NUCLEAR DNA, AND HIGHER DEGREE OF POST-TRANSLATIONAL HISTONE MODIFICATIONS ESTABLISHED THE EXISTENCE OF ABERRANT EPIGENETIC MODIFICATIONS IN THE EXPOSED INDIVIDUALS. OVERALL, OUR RESULTS DEMONSTRATE THE FIRST MOLECULAR INSIGHTS OF IN UTERO PRO-OXIDANT EXPOSURE ASSOCIATED CHANGES IN THE MITOCHONDRIAL-EPIGENETIC AXIS. ALTHOUGH, OUR STUDY MIGHT NOT CEMENT AN EXPOSURE-RESPONSE RELATIONSHIP FOR ANY PARTICULAR ENVIRONMENTAL PRO-OXIDANT, BUT SUFFICE TO ESTABLISH A DOGMA OF MITO-EPIGENETIC REPROGRAMMING AT INTRAUTERINE MILIEU WITH CHRONIC ILLNESS, A HITHERTO UNREPORTED INTERACTION. 2022