1 2741 121 EXPOSURE TO IONIZING RADIATION DISRUPTS NORMAL EPIGENETIC AGING IN JAPANESE MEDAKA. ALTERATIONS TO THE EPIGENOME ARE A HALLMARK OF BIOLOGICAL AGING AND AGE-DEPENDENT PATTERNING OF THE DNA METHYLOME ("EPIGENETIC AGING") CAN BE MODELED TO PRODUCE EPIGENETIC AGE PREDICTORS. RATES OF EPIGENETIC AGING VARY AMONGST INDIVIDUALS AND CORRELATE TO THE ONSET OF AGE-RELATED DISEASE AND ALL-CAUSE MORTALITY. YET, THE ORIGINS OF EPIGENETIC-TO-CHRONOLOGICAL AGE DISCORDANCE ARE NOT EMPIRICALLY RESOLVED. HERE, WE INVESTIGATE THE RELATIONSHIP BETWEEN AGING, DNA METHYLATION, AND ENVIRONMENTAL EXPOSURES IN JAPANESE MEDAKA (ORYZIAS LATIPES). WE FIND AGE-ASSOCIATED DNA METHYLATION PATTERNING ENRICHED IN GENOMIC REGIONS OF LOW CPG DENSITY AND THAT, SIMILAR TO MAMMALS, MOST AGE-RELATED CHANGES OCCUR DURING EARLY LIFE. WE CONSTRUCT AN EPIGENETIC CLOCK CAPABLE OF PREDICTING CHRONOLOGICAL AGE WITH A MEAN ERROR OF 61.1 DAYS (~8.4% OF AVERAGE LIFESPAN). TO TEST THE ROLE OF ENVIRONMENTAL FACTORS IN DRIVING EPIGENETIC AGE VARIATION, WE EXPOSED MEDAKA TO CHRONIC, ENVIRONMENTALLY RELEVANT DOSES OF IONIZING RADIATION. BECAUSE MOST ORGANISMS SHARE AN EVOLUTIONARY HISTORY WITH IONIZING RADIATION, WE HYPOTHESIZED THAT EXPOSURE WOULD REVEAL FUNDAMENTAL INSIGHTS INTO ENVIRONMENT-BY-EPIGENETIC AGING INTERACTIONS. RADIATION EXPOSURE DISRUPTED EPIGENETIC AGING BY ACCELERATING AND DECELERATING NORMAL AGE-ASSOCIATED PATTERNING AND WAS MOST PRONOUNCED IN CYTOSINES THAT WERE MODERATELY ASSOCIATED WITH AGE. THESE FINDINGS EMPIRICALLY DEMONSTRATE THE ROLE OF DNA METHYLATION IN INTEGRATING ENVIRONMENTAL FACTORS INTO AGING TRAJECTORIES. 2021 2 934 35 CHRONIC LOW DOSE IRRADIATION ALTERS HEPATIC TRANSCRIPTIONAL PROFILES, BUT NOT GLOBAL DNA METHYLATION IN MEDAKA (ORYZIAS LATIPES). IONIZING RADIATION (IR) RESULTING FROM BOTH NATURAL AND ANTHROPOGENIC SOURCES IS UBIQUITOUS THROUGHOUT THE ENVIRONMENT. HISTORICALLY, STUDIES ON THE BIOLOGICAL IMPACTS OF RADIATION PRIMARILY FOCUSED ON RESPONSES TO ACUTE DOSES OF RADIATION, WITH LITTLE ADVANCEMENT IN OUR UNDERSTANDING OF ENVIRONMENTALLY RELEVANT EXPOSURES. EPIGENETIC MECHANISMS ARE CAPABLE OF MEDIATING ORGANISMAL RESPONSES TO ENVIRONMENTAL STRESSORS AND DNA METHYLATION PLAYS IMPORTANT ROLES IN GENE REGULATION AND PROMOTING CHROMOSOMAL STABILITY. HERE, WE ASSESS BROAD-SCALE TRANSCRIPTIONAL AND EPIGENETIC VARIATION RESULTING FROM CHRONIC EXPOSURE TO LOW DOSES OF IONIZING RADIATION (LDIR; 5.78, 53.76, OR 520.23 MGY/DAY) USING JAPANESE MEDAKA FISH (ORYZIAS LATIPES) IN A REPLICATED MESOCOSM DESIGN. WE OBSERVED SIGNIFICANT CHANGES TO THE HEPATIC TRANSCRIPTOME INDUCED BY A 3-MONTH CHRONIC EXPOSURE TO IR, WHEREAS GLOBAL DNA METHYLATION APPEARED LARGELY UNAFFECTED. OUR FINDINGS REVEAL A SET OF GENES, INCLUDING THOSE INVOLVED IN IMMUNE FUNCTION, RESPONDING TO ENVIRONMENTALLY RELEVANT IR EXPOSURES, WHICH DO NOT APPEAR TO BE MEDIATED BY A SYSTEMIC GLOBAL SHIFT IN DNA METHYLATION. 2020 3 1516 36 DNA METHYLATION AS A BIOMARKER OF AGING IN EPIDEMIOLOGIC STUDIES. CANCER IS LARGELY AN AGING DISEASE. ACCELERATED BIOLOGICAL AGING MAY BE THE STRONGEST PREDICTOR OF CANCER AND OTHER CHRONIC DISEASE RISKS. IN THE ABSENCE OF RELIABLE AND QUANTIFIABLE BIOMARKERS OF AGING TO DATE, IT HAS LONG BEEN OBSERVED THAT TUMORIGENESIS SHARES DISTINCT EPIGENETIC ALTERATIONS WITH THE AGING PROCESS. RECENTLY, EPIGENETIC AGE ESTIMATES HAVE BEEN DEVELOPED BASED ON THE AVAILABILITY OF GENOME-WIDE DNA METHYLATION PROFILES, BY APPLYING IN THE PREDICTION FORMULA THE METHYLATION LEVEL AT A SUBSET OF HIGHLY PREDICTIVE METHYLATION SITES, CALLED EPIGENETIC CLOCK. THESE DNA METHYLATION AGE ESTIMATES HAVE PRODUCED REMARKABLY STRONG CORRELATIONS WITH CHRONOLOGICAL AGE, WITH A SMALL DEVIATION AND HIGH REPRODUCIBILITY ACROSS DIFFERENT AGE GROUPS AND STUDY POPULATIONS. MOREOVER, AN INCREASING NUMBER OF EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED AN INDEPENDENT ASSOCIATION OF DNA METHYLATION AGE OR THE EXTENT OF ACCELERATION WITH MORTALITY AND VARIOUS AGING-RELATED CONDITIONS, EVEN AFTER ACCOUNTING FOR DIFFERENCES IN CHRONOLOGICAL AGE AND OTHER RISK FACTORS. ALTHOUGH EPIGENETIC PROFILES ARE KNOWN TO BE TISSUE-SPECIFIC, BOTH TARGET TISSUE- AND MULTIPLE TISSUE-DERIVED ESTIMATES APPEAR TO PERFORM WELL TO CAPTURE WHAT IS THOUGHT TO BE THE CUMULATIVE EPIGENETIC DRIFT THAT REPRESENTS A MULTIFACTORIAL DEGENERATIVE PROCESS ACROSS TISSUES AND ORGANISMS. FURTHER REFINEMENT OF THE EPIGENETIC AGE ESTIMATES IS ANTICIPATED OVER TIME TO ACCOMMODATE A BETTER TECHNOLOGICAL COVERAGE OF THE METHYLOME AND A BETTER UNDERSTANDING OF THE BIOLOGY UNDERLYING PREDICTIVE REGIONS. EPIDEMIOLOGIC PRINCIPLES WILL REMAIN CRITICAL FOR THE EVALUATION OF RESEARCH FINDINGS INVOLVING, FOR EXAMPLE, DIFFERENT STUDY POPULATIONS, DESIGN, FOLLOW-UP TIME, AND QUALITY OF COVARIATE DATA. OVERALL, THE EPIGENETIC AGE ESTIMATES ARE AN EXCITING DEVELOPMENT WITH USEFUL IMPLICATIONS FOR BIOMEDICAL RESEARCH OF HEALTHY AGING AND DISEASE PREVENTION AND CONTROL. 2018 4 1014 31 CIGARETTE SMOKING AND DNA METHYLATION. DNA METHYLATION IS THE MOST STUDIED EPIGENETIC MODIFICATION, CAPABLE OF CONTROLLING GENE EXPRESSION IN THE CONTEXTS OF NORMAL TRAITS OR DISEASES. IT IS HIGHLY DYNAMIC DURING EARLY EMBRYOGENESIS AND REMAINS RELATIVELY STABLE THROUGHOUT LIFE, AND SUCH PATTERNS ARE INTRICATELY RELATED TO HUMAN DEVELOPMENT. DNA METHYLATION IS A QUANTITATIVE TRAIT DETERMINED BY A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL FACTORS. GENETIC VARIANTS AT A SPECIFIC LOCUS CAN INFLUENCE BOTH REGIONAL AND DISTANT DNA METHYLATION. THE ENVIRONMENT CAN HAVE VARYING EFFECTS ON DNA METHYLATION DEPENDING ON WHEN THE EXPOSURE OCCURS, SUCH AS DURING PRENATAL LIFE OR DURING ADULTHOOD. IN PARTICULAR, CIGARETTE SMOKING IN THE CONTEXT OF BOTH CURRENT SMOKING AND PRENATAL EXPOSURE IS A STRONG MODIFIER OF DNA METHYLATION. EPIGENOME-WIDE ASSOCIATION STUDIES HAVE UNCOVERED CANDIDATE GENES ASSOCIATED WITH CIGARETTE SMOKING THAT HAVE BIOLOGICALLY RELEVANT FUNCTIONS IN THE ETIOLOGY OF SMOKING-RELATED DISEASES. AS SUCH, DNA METHYLATION IS A POTENTIAL MECHANISTIC LINK BETWEEN CURRENT SMOKING AND CANCER, AS WELL AS PRENATAL CIGARETTE-SMOKE EXPOSURE AND THE DEVELOPMENT OF ADULT CHRONIC DISEASES. 2013 5 5748 31 SOCIAL AND PHYSICAL ENVIRONMENTS EARLY IN DEVELOPMENT PREDICT DNA METHYLATION OF INFLAMMATORY GENES IN YOUNG ADULTHOOD. CHRONIC INFLAMMATION CONTRIBUTES TO A WIDE RANGE OF HUMAN DISEASES, AND ENVIRONMENTS IN INFANCY AND CHILDHOOD ARE IMPORTANT DETERMINANTS OF INFLAMMATORY PHENOTYPES. THE UNDERLYING BIOLOGICAL MECHANISMS CONNECTING EARLY ENVIRONMENTS WITH THE REGULATION OF INFLAMMATION IN ADULTHOOD ARE NOT KNOWN, BUT EPIGENETIC PROCESSES ARE PLAUSIBLE CANDIDATES. WE TESTED THE HYPOTHESIS THAT PATTERNS OF DNA METHYLATION (DNAM) IN INFLAMMATORY GENES IN YOUNG ADULTHOOD WOULD BE PREDICTED BY EARLY LIFE NUTRITIONAL, MICROBIAL, AND PSYCHOSOCIAL EXPOSURES PREVIOUSLY ASSOCIATED WITH LEVELS OF INFLAMMATION. DATA COME FROM A POPULATION-BASED LONGITUDINAL BIRTH COHORT STUDY IN METROPOLITAN CEBU, THE PHILIPPINES, AND DNAM WAS CHARACTERIZED IN WHOLE BLOOD SAMPLES FROM 494 PARTICIPANTS (AGE 20-22 Y). ANALYSES FOCUSED ON PROBES IN 114 TARGET GENES INVOLVED IN THE REGULATION OF INFLAMMATION, AND WE IDENTIFIED 10 SITES ACROSS NINE GENES WHERE THE LEVEL OF DNAM WAS SIGNIFICANTLY PREDICTED BY THE FOLLOWING VARIABLES: HOUSEHOLD SOCIOECONOMIC STATUS IN CHILDHOOD, EXTENDED ABSENCE OF A PARENT IN CHILDHOOD, EXPOSURE TO ANIMAL FECES IN INFANCY, BIRTH IN THE DRY SEASON, OR DURATION OF EXCLUSIVE BREASTFEEDING. TO EVALUATE THE BIOLOGICAL SIGNIFICANCE OF THESE SITES, WE TESTED FOR ASSOCIATIONS WITH A PANEL OF INFLAMMATORY BIOMARKERS MEASURED IN PLASMA OBTAINED AT THE SAME AGE AS DNAM ASSESSMENT. THREE SITES PREDICTED ELEVATED INFLAMMATION, AND ONE SITE PREDICTED LOWER INFLAMMATION, CONSISTENT WITH THE INTERPRETATION THAT LEVELS OF DNAM AT THESE SITES ARE FUNCTIONALLY RELEVANT. THIS PATTERN OF RESULTS POINTS TOWARD DNAM AS A POTENTIALLY IMPORTANT BIOLOGICAL MECHANISM THROUGH WHICH DEVELOPMENTAL ENVIRONMENTS SHAPE INFLAMMATORY PHENOTYPES ACROSS THE LIFE COURSE. 2017 6 2047 30 EPIGENETIC CLOCKS MAY COME OUT OF RHYTHM-IMPLICATIONS FOR THE ESTIMATION OF CHRONOLOGICAL AGE IN FORENSIC CASEWORK. THERE IS A GROWING PERCEPTION THAT DNA METHYLATION MAY BE INFLUENCED BY EXOGENOUS AND ENDOGENOUS PARAMETERS. KNOWLEDGE OF THESE FACTORS IS OF GREAT RELEVANCE FOR THE INTERPRETATION OF DNA-METHYLATION DATA FOR THE ESTIMATION OF CHRONOLOGICAL AGE IN FORENSIC CASEWORK. WE PERFORMED A LITERATURE REVIEW TO IDENTIFY PARAMETERS, WHICH MIGHT BE OF RELEVANCE FOR THE PREDICTION OF CHRONOLOGICAL AGE BASED ON DNA METHYLATION. THE QUALITY OF AGE PREDICTIONS MIGHT PARTICULARLY BE INFLUENCED BY LIFETIME ADVERSITIES (CHRONIC STRESS, TRAUMA/POST-TRAUMATIC STRESS DISORDER (PTSD), VIOLENCE, LOW SOCIOECONOMIC STATUS/EDUCATION), CANCER, OBESITY AND RELATED DISEASES, INFECTIOUS DISEASES (ESPECIALLY HIV AND CYTOMEGALOVIRUS (CMV) INFECTIONS), SEX, ETHNICITY AND EXPOSURE TO TOXINS (ALCOHOL, SMOKING, AIR POLLUTION, PESTICIDES). SUCH FACTORS MAY ALTER THE DNA METHYLATION PATTERN AND MAY EXPLAIN THE PARTLY HIGH DEVIATIONS BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE IN SINGLE CASES (DESPITE OF LOW MEAN ABSOLUTE DEVIATIONS) THAT CAN ALSO BE OBSERVED WITH "EPIGENETIC CLOCKS" COMPRISING A HIGH NUMBER OF CPG SITES. SO FAR, ONLY FEW PUBLICATIONS DEALING WITH FORENSIC AGE ESTIMATION ADDRESS THESE CONFOUNDING FACTORS. FUTURE RESEARCH SHOULD FOCUS ON THE IDENTIFICATION OF FURTHER RELEVANT CONFOUNDING FACTORS AND THE DEVELOPMENT OF MODELS THAT ARE "ROBUST" AGAINST THE INFLUENCE OF SUCH BIOLOGICAL FACTORS BY SYSTEMATIC INVESTIGATIONS UNDER TARGETED INCLUSION OF DIVERSE AND DEFINED COHORTS. 2020 7 287 33 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING. 2010 8 1206 33 COUNTERACTING AGED DNA METHYLATION STATES TO COMBAT AGEING AND AGE-RELATED DISEASES. DNA METHYLATION (DNAM) OVERWRITES INFORMATION ABOUT MULTIPLE EXTRINSIC FACTORS ON THE GENOME. AGE IS ONE OF THESE FACTORS. AGE CAUSES CHARACTERISTIC DNAM CHANGES THAT ARE THOUGHT TO BE NOT ONLY MAJOR DRIVERS OF NORMAL AGEING BUT ALSO PRECURSORS TO DISEASES, CANCER BEING ONE OF THESE. ALTHOUGH THERE IS STILL MUCH TO LEARN ABOUT THE RELATIONSHIP BETWEEN AGEING, AGE-RELATED DISEASES AND DNAM, WE NOW KNOW HOW TO INTERPRET SOME OF THE EFFECTS CAUSED BY AGE IN THE FORM OF CHANGES IN METHYLATION MARKS AT SPECIFIC LOCI. IN FACT, THESE CHANGES FORM THE BASIS OF THE SO CALLED "EPIGENETIC CLOCKS", WHICH TRANSLATE THE GENOMIC METHYLATION PROFILE INTO AN "EPIGENETIC AGE". EPIGENETIC AGE DOES NOT ONLY ESTIMATE CHRONOLOGICAL AGE BUT CAN ALSO PREDICT THE RISK OF CHRONIC DISEASES AND MORTALITY. EPIGENETIC AGE IS BELIEVED TO BE ONE OF THE MOST ACCURATE METRICS OF BIOLOGICAL AGE. INITIAL EVIDENCE HAS RECENTLY BEEN GATHERED POINTING TO THE POSSIBILITY THAT THE RATE OF EPIGENETIC AGEING CAN BE SLOWED DOWN OR EVEN REVERSED. IN THIS REVIEW, WE DISCUSS SOME OF THE MOST RELEVANT ADVANCES IN THIS FIELD. EXPECTED OUTCOME IS THAT THIS APPROACH CAN PROVIDE INSIGHTS INTO HOW TO PRESERVE HEALTH AND REDUCE THE IMPACT OF AGEING DISEASES IN HUMANS. 2022 9 560 35 BACK TO THE FUTURE: EPIGENETIC CLOCK PLASTICITY TOWARDS HEALTHY AGING. AGING IS THE MOST IMPORTANT RISK FACTOR FOR MAJOR HUMAN LIFESTYLE DISEASES, INCLUDING CANCER, NEUROLOGICAL AND CARDIOMETABOLIC DISORDERS. DUE TO THE COMPLEX INTERPLAY BETWEEN GENETICS, LIFESTYLE AND ENVIRONMENTAL FACTORS, SOME INDIVIDUALS SEEM TO AGE FASTER THAN OTHERS, WHEREAS CENTENARIANS SEEM TO HAVE A SLOWER AGING PROCESS. THEREFORE, A BIOCHEMICAL BIOMARKER REFLECTING THE RELATIVE BIOLOGICAL AGE WOULD BE HELPFUL TO PREDICT AN INDIVIDUAL'S HEALTH STATUS AND AGING DISEASE RISK. ALTHOUGH IT IS ALREADY KNOWN FOR YEARS THAT CUMULATIVE EPIGENETIC CHANGES OCCUR UPON AGING, DNA METHYLATION PATTERNS WERE ONLY RECENTLY USED TO CONSTRUCT AN EPIGENETIC CLOCK PREDICTOR FOR BIOLOGICAL AGE, WHICH IS A MEASURE OF HOW WELL YOUR BODY FUNCTIONS COMPARED TO YOUR CHRONOLOGICAL AGE. MOREOVER, THE EPIGENETIC DNA METHYLATION CLOCK SIGNATURE IS INCREASINGLY APPLIED AS A BIOMARKER TO ESTIMATE AGING DISEASE SUSCEPTIBILITY AND MORTALITY RISK. FINALLY, THE EPIGENETIC CLOCK SIGNATURE COULD BE USED AS A LIFESTYLE MANAGEMENT TOOL TO MONITOR HEALTHY AGING, TO EVALUATE PREVENTIVE INTERVENTIONS AGAINST CHRONIC AGING DISORDERS AND TO EXTEND HEALTHY LIFESPAN. DISSECTING THE MECHANISM OF THE EPIGENETIC AGING CLOCK WILL YIELD VALUABLE INSIGHTS INTO THE AGING PROCESS AND HOW IT CAN BE MANIPULATED TO IMPROVE HEALTH SPAN. 2018 10 3914 39 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK. 2015 11 1655 26 DOSE-DEPENDENCE, SEX- AND TISSUE-SPECIFICITY, AND PERSISTENCE OF RADIATION-INDUCED GENOMIC DNA METHYLATION CHANGES. RADIATION IS A WELL-KNOWN GENOTOXIC AGENT AND HUMAN CARCINOGEN THAT GIVES RISE TO A VARIETY OF LONG-TERM EFFECTS. ITS DETRIMENTAL INFLUENCE ON CELLULAR FUNCTION IS ACTIVELY STUDIED NOWADAYS. ONE OF THE MOST ANALYZED, YET LEAST UNDERSTOOD LONG-TERM EFFECTS OF IONIZING RADIATION IS TRANSGENERATIONAL GENOMIC INSTABILITY. THE INHERITANCE OF GENOMIC INSTABILITY SUGGESTS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS, SUCH AS CHANGES OF THE METHYLATION OF CYTOSINE RESIDUES LOCATED WITHIN CPG DINUCLEOTIDES. IN THE CURRENT STUDY WE EVALUATED THE DOSE-DEPENDENCE OF THE RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION CHANGES. WE ALSO ANALYZED THE EFFECTS OF ACUTE AND CHRONIC HIGH DOSE (5GY) EXPOSURE ON DNA METHYLATION IN LIVER, SPLEEN, AND LUNG TISSUES OF MALE AND FEMALE MICE AND EVALUATED THE POSSIBLE PERSISTENCE OF THE RADIATION-INDUCED DNA METHYLATION CHANGES. HERE WE REPORT THAT RADIATION-INDUCED DNA METHYLATION CHANGES WERE SEX- AND TISSUE-SPECIFIC, DOSE-DEPENDENT, AND PERSISTENT. IN PARALLEL WE HAVE STUDIED THE LEVELS OF DNA DAMAGE IN THE EXPOSED TISSUES. BASED ON THE CORRELATION BETWEEN THE LEVELS OF DNA METHYLATION AND DNA DAMAGE WE PROPOSE THAT RADIATION-INDUCED GLOBAL GENOME DNA HYPOMETHYLATION IS DNA REPAIR-RELATED. 2004 12 2677 31 EVALUATING THE CHALLENGES AND REPRODUCIBILITY OF STUDIES INVESTIGATING DNA METHYLATION SIGNATURES OF PSYCHOLOGICAL STRESS. PSYCHOLOGICAL STRESS CAN INCREASE THE RISK OF A WIDE RANGE OF NEGATIVE HEALTH OUTCOMES. STUDIES HAVE BEEN COMPLETED TO DETERMINE IF DNA METHYLATION CHANGES OCCUR IN THE HUMAN BRAIN BECAUSE OF STRESS AND ARE ASSOCIATED WITH LONG-TERM EFFECTS AND DISEASE, BUT RESULTS HAVE BEEN INCONSISTENT. HUMAN CANDIDATE GENE STUDIES (150) AND EPIGENOME-WIDE ASSOCIATION STUDIES (67) WERE SYSTEMATICALLY EVALUATED TO ASSESS HOW DNA METHYLATION IS IMPACTED BY STRESS DURING THE PRENATAL PERIOD, EARLY CHILDHOOD AND ADULTHOOD. THE ASSOCIATION BETWEEN DNA METHYLATION OF NR3C1 EXON 1F AND CHILD MALTREATMENT AND EARLY LIFE ADVERSITY WAS WELL DEMONSTRATED, BUT OTHER GENES DID NOT EXHIBIT A CLEAR ASSOCIATION. THE REPRODUCIBILITY OF INDIVIDUAL CPG SITES IN EPIGENOME-WIDE ASSOCIATION STUDIES WAS ALSO POOR. HOWEVER, BIOLOGICAL PATHWAYS, INCLUDING STRESS RESPONSE, BRAIN DEVELOPMENT AND IMMUNITY, HAVE BEEN CONSISTENTLY IDENTIFIED ACROSS DIFFERENT STRESSORS THROUGHOUT THE LIFE SPAN. FUTURE STUDIES WOULD BENEFIT FROM THE INCREASED SAMPLE SIZE, LONGITUDINAL DESIGN, STANDARDIZED METHODOLOGY, OPTIMAL QUALITY CONTROL, AND IMPROVED STATISTICAL PROCEDURES. 2022 13 1503 29 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION. 2009 14 625 32 BIOLOGICAL AGE AND ENVIRONMENTAL RISK FACTORS FOR DEMENTIA AND STROKE: MOLECULAR MECHANISMS. SINCE THE DEVELOPMENT OF ANTIBIOTICS AND VACCINATION, AS WELL AS MAJOR IMPROVEMENTS IN PUBLIC HYGIENE, THE MAIN RISK FACTORS FOR MORBIDITY AND MORTALITY ARE AGE AND CHRONIC EXPOSURE TO ENVIRONMENTAL FACTORS, BOTH OF WHICH CAN INTERACT WITH GENETIC PREDISPOSITIONS. AS THE AVERAGE AGE OF THE POPULATION INCREASES, THE PREVALENCE AND COSTS OF CHRONIC DISEASES, ESPECIALLY NEUROLOGICAL CONDITIONS, ARE RAPIDLY INCREASING. THE DELETERIOUS EFFECTS OF AGE AND ENVIRONMENTAL RISK FACTORS, DEVELOP CHRONICALLY OVER RELATIVELY LONG PERIODS OF TIME, IN CONTRAST TO THE RELATIVELY RAPID DELETERIOUS EFFECTS OF INFECTIOUS DISEASES OR ACCIDENTS. OF PARTICULAR INTEREST IS THE HYPOTHESIS THAT THE DELETERIOUS EFFECTS OF ENVIRONMENTAL FACTORS MAY BE MEDIATED BY ACCELERATION OF BIOLOGICAL AGE. THIS HYPOTHESIS IS SUPPORTED BY EVIDENCE THAT DIETARY RESTRICTION, WHICH UNIVERSALLY DELAYS AGE-RELATED DISEASES, ALSO AMELIORATES DELETERIOUS EFFECTS OF ENVIRONMENTAL FACTORS. CONVERSELY, BOTH AGE AND ENVIRONMENTAL RISK FACTORS ARE ASSOCIATED WITH THE ACCUMULATION OF SOMATIC MUTATIONS IN MITOTIC CELLS AND EPIGENETIC MODIFICATIONS THAT ARE A MEASURE OF "BIOLOGICAL AGE", A BETTER PREDICTOR OF AGE-RELATED MORBIDITY AND MORTALITY THAN CHRONOLOGICAL AGE. HERE WE REVIEW EVIDENCE THAT ENVIRONMENTAL RISK FACTORS SUCH AS SMOKING AND AIR POLLUTION MAY ALSO DRIVE NEUROLOGICAL CONDITIONS, INCLUDING ALZHEIMER'S DISEASE, BY THE ACCELERATION OF BIOLOGICAL AGE, MEDIATED BY CUMULATIVE AND PERSISTENT EPIGENETIC EFFECTS AS WELL AS SOMATIC MUTATIONS. ELUCIDATION OF SUCH MECHANISMS COULD PLAUSIBLY ALLOW THE DEVELOPMENT OF INTERVENTIONS WHICH DELAY DELETERIOUS EFFECTS OF BOTH AGING AND ENVIRONMENTAL RISK FACTORS. 2022 15 1772 33 EARLY-LIFE SOCIOECONOMIC DISADVANTAGE, NOT CURRENT, PREDICTS ACCELERATED EPIGENETIC AGING OF MONOCYTES. LOW SOCIOECONOMIC STATUS (SES) IN EARLY-LIFE AND ADULTHOOD INDEPENDENTLY CONTRIBUTE TO INCREASED RISK FOR AGING-RELATED CHRONIC DISEASES. ONE MECHANISTIC HYPOTHESIS FOR THESE ASSOCIATIONS INVOLVES FASTER CELLULAR AGING OF IMMUNE CELLS, WHICH COULD PLAUSIBLY CONTRIBUTE TO CHRONIC DISEASE PATHOGENESIS BY COMPROMISING HOST RESISTANCE AND/OR UP-REGULATING INFLAMMATION. HOWEVER, LITTLE IS KNOWN ABOUT THE ASSOCIATION BETWEEN LIFE-COURSE SES AND CELLULAR AGING. THE PRESENT STUDY EXAMINES THE ASSOCIATION OF EARLY-LIFE AND CURRENT SES WITH A NOVEL BIOMARKER OF CELLULAR AGING TERMED THE "EPIGENETIC CLOCK," IN MONOCYTES. ADDITIONALLY, WE EXAMINE HEALTH BEHAVIORS AND DEPRESSIVE SYMPTOMS AS POTENTIAL EXPLANATORY PATHWAYS. THE STUDY INVOLVED 335 PARTICIPANTS BETWEEN THE AGES OF 15 AND 55 FROM VANCOUVER, CANADA AND SURROUNDING AREAS. ENROLLED PARTICIPANTS HAD TO FIT INTO FOUR LIFE-COURSE SES TRAJECTORIES, CORRESPONDING TO LOW-LOW, LOW-HIGH, HIGH-LOW AND HIGH-HIGH COMBINATIONS OF EARLY-LIFE (AGES 0 TO 5) AND CURRENT SES RESPECTIVELY. CELLULAR AGING OF MONOCYTES WAS MEASURED USING HORVATH'S DNA METHYLATION DERIVED MEASURE OF EPIGENETIC AGE ACCELERATION. RESULTS INDICATED THAT SOCIOECONOMIC DISADVANTAGE DURING EARLY-LIFE, BUT NOT LATER IN LIFE, WAS ASSOCIATED WITH ACCELERATED EPIGENETIC AGING OF MONOCYTES. NO EARLY-LIFE SES BY CURRENT SES INTERACTION WAS DETECTED, SUGGESTING THAT SOCIOECONOMIC MOBILITY IS UNRELATED TO EPIGENETIC AGE ACCELERATION. IN PATH ANALYSES, NEITHER CURRENT HEALTH BEHAVIORS NOR CURRENT DEPRESSIVE SYMPTOMS EMERGED AS MEDIATORS OF THE EARLY-LIFE SES EFFECT. THESE FINDINGS SUGGEST SOCIOECONOMIC DISADVANTAGE IN EARLY-LIFE IS INDEPENDENTLY PREDICTIVE OF CELLULAR AGING OF IMMUNE CELLS, WITH POTENTIAL IMPLICATIONS FOR AGING-RELATED DISEASES LATER IN LIFE. 2018 16 2483 31 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002 17 1599 32 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES. 2014 18 1583 28 DNA METHYLATION PROFILES OF BLOOD CELLS ARE DISTINCT BETWEEN EARLY-ONSET OBESE AND CONTROL INDIVIDUALS. OBESITY IS A HIGHLY PREVALENT, CHRONIC DISORDER THAT HAS BEEN INCREASING IN INCIDENCE IN YOUNG PATIENTS. BOTH EPIGENETIC AND GENETIC ABERRATIONS MAY PLAY A ROLE IN THE PATHOGENESIS OF OBESITY. THEREFORE, IN-DEPTH EPIGENOMIC AND GENOMIC ANALYSES WILL ADVANCE OUR UNDERSTANDING OF THE DETAILED MOLECULAR MECHANISMS UNDERLYING OBESITY AND AID IN THE SELECTION OF POTENTIAL BIOMARKERS FOR OBESITY IN YOUTH. HERE, WE PERFORMED MICROARRAY-BASED DNA METHYLATION AND GENE EXPRESSION PROFILING OF PERIPHERAL WHITE BLOOD CELLS OBTAINED FROM SIX YOUNG, OBESE INDIVIDUALS AND SIX HEALTHY CONTROLS. WE OBSERVED THAT THE HIERARCHICAL CLUSTERING OF DNA METHYLATION, BUT NOT GENE EXPRESSION, CLEARLY SEGREGATES THE OBESE INDIVIDUALS FROM THE CONTROLS, SUGGESTING THAT THE METABOLIC DISTURBANCE THAT OCCURS AS A RESULT OF OBESITY AT A YOUNG AGE MAY AFFECT THE DNA METHYLATION OF PERIPHERAL BLOOD CELLS WITHOUT ACCOMPANYING TRANSCRIPTIONAL CHANGES. TO EXAMINE THE GENOME-WIDE DIFFERENCES IN THE DNA METHYLATION PROFILES OF YOUNG OBESE AND CONTROL INDIVIDUALS, WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES AND INVESTIGATED THEIR GENOMIC AND EPIGENOMIC CONTEXTS. THE ABERRANT DNA METHYLATION PATTERNS IN OBESE INDIVIDUALS CAN BE SUMMARIZED AS RELATIVE GAINS AND LOSSES OF DNA METHYLATION IN GENE PROMOTERS AND GENE BODIES, RESPECTIVELY. WE ALSO OBSERVED THAT THE CPG ISLANDS OF OBESE INDIVIDUALS ARE MORE SUSCEPTIBLE TO DNA METHYLATION COMPARED TO CONTROLS. OUR PILOT STUDY SUGGESTS THAT THE GENOME-WIDE ABERRANT DNA METHYLATION PATTERNS OF OBESE INDIVIDUALS MAY ADVANCE NOT ONLY OUR UNDERSTANDING OF THE EPIGENOMIC PATHOGENESIS BUT ALSO EARLY SCREENING OF OBESITY IN YOUTH. 2017 19 6065 31 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 20 6790 22 [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