1 1517 152 DNA METHYLATION AS A MEDIATOR OF ASSOCIATIONS BETWEEN THE ENVIRONMENT AND CHRONIC DISEASES: A SCOPING REVIEW ON APPLICATION OF MEDIATION ANALYSIS. DNA METHYLATION (DNAM) IS ONE OF THE MOST STUDIED EPIGENETIC MODIFICATIONS. DNAM HAS EMERGED AS A KEY BIOLOGICAL MECHANISM AND BIOMARKERS TO TEST ASSOCIATIONS BETWEEN ENVIRONMENTAL EXPOSURE AND OUTCOMES IN EPIDEMIOLOGICAL STUDIES. ALTHOUGH PREVIOUS STUDIES HAVE FOCUSED ON ASSOCIATIONS BETWEEN DNAM AND EITHER EXPOSURE/OUTCOMES, IT IS USEFUL TO TEST FOR MEDIATION OF THE ASSOCIATION BETWEEN EXPOSURE AND OUTCOME BY DNAM. THE PURPOSE OF THIS SCOPING REVIEW IS TO INTRODUCE THE METHODOLOGICAL ESSENCE OF STATISTICAL MEDIATION ANALYSIS AND TO EXAMINE EMERGING EPIDEMIOLOGICAL RESEARCH APPLYING MEDIATION ANALYSES. WE CONDUCTED THIS SCOPING REVIEW FOR PUBLISHED PEER-REVIEWED JOURNALS ON THIS TOPIC USING ONLINE DATABASES (PUBMED, SCOPUS, COCHRANE, AND CINAHL) ENDING IN DECEMBER 2020. WE EXTRACTED A TOTAL OF 219 ARTICLES BY INITIAL SCREENING. AFTER REVIEWING TITLES, ABSTRACTS, AND FULL TEXTS, A TOTAL OF 69 ARTICLES WERE ELIGIBLE FOR THIS REVIEW. THE BREAKDOWN OF STUDIES ASSIGNED TO EACH CATEGORY WAS 13 FOR SMOKING (18.8%), 8 FOR DIETARY INTAKE AND FAMINE (11.6%), 6 FOR OTHER LIFESTYLE FACTORS (8.7%), 8 FOR CLINICAL ENDPOINTS (11.6%), 22 FOR ENVIRONMENTAL CHEMICAL EXPOSURES (31.9%), 2 FOR SOCIOECONOMIC STATUS (SES) (2.9%), AND 10 FOR GENETIC FACTORS AND RACE (14.5%). IN THIS REVIEW, WE PROVIDE AN EXPOSURE-WIDE SUMMARY FOR THE MEDIATION ANALYSIS USING DNAM LEVELS. HOWEVER, WE FOUND HETEROGENOUS METHODS AND INTERPRETATIONS IN MEDIATION ANALYSIS WITH TYPICAL ISSUES SUCH AS DIFFERENT CELL COMPOSITIONS AND TISSUE-SPECIFICITY. FURTHER ACCUMULATION OF EVIDENCE WITH DIVERSE EXPOSURES, POPULATIONS AND WITH RIGOROUS METHODOLOGY WILL BE EXPECTED TO PROVIDE FURTHER INSIGHT IN THE ROLE OF DNAM IN DISEASE SUSCEPTIBILITY. 2022 2 2093 42 EPIGENETIC EFFECTS FOLLOWING ACUTE AND CHRONIC EXERCISE IN CARDIOVASCULAR DISEASE: A SYSTEMATIC REVIEW. INTRODUCTION: ACUTE EXERCISE AND EXERCISE TRAINING MAY CONFER EPIGENETIC MODIFICATIONS IN HEALTHY SUBJECTS. EPIGENETIC EFFECTS AFTER EXERCISE HAVE BEEN SHOWED IN PATIENTS WITH CARDIOVASCULAR DISEASE. THE AIM OF THIS SYSTEMATIC REVIEW WAS TO SUMMARIZE THE EVIDENCE FROM AVAILABLE CLINICAL TRIALS THAT STUDY EPIGENETIC ADAPTATIONS AFTER EXERCISE IN PATIENTS WITH CARDIOVASCULAR DISEASE. METHODS: THE SEARCH STRATEGY WAS PERFORMED IN PUBMED AND CENTRAL DATABASES ON ARTICLES PUBLISHED UNTIL SEPTEMBER 2020. STUDIES WITH TITLES AND ABSTRACTS RELEVANT TO EXERCISE EPIGENETIC MODIFICATION APPLIED TO CARDIOVASCULAR PATIENTS WERE FULLY EXAMINED. INCLUSION AND EXCLUSION CRITERIA WERE UTILIZED FOR STUDIES SCREENING. QUALITY ASSESSMENT WITH PEDRO SCALE AND EVALUATION BY TWO INDEPENDENT REVIEWERS WAS PERFORMED. RESULTS: OF THE 1714 ARTICLES RETRIEVED, 88 ARTICLES WERE ASSESSED FOR ELIGIBILITY CRITERIA AND 8 ARTICLES MATCHED OUR SEARCH CRITERIA AND FINALLY INCLUDED IN THE SYSTEMATIC ANALYSIS. THE ACUTE EXERCISE EPIGENETIC (MIRNAS) EFFECTS WERE ASSESSED IN THREE STUDIES AND THE CHRONIC EXERCISE TRAINING EFFECTS (MIRNAS AND DNA METHYLATION) IN SIX STUDIES. THE RESULTS HAVE SHOWN THAT THERE IS POSSIBLY AN ACUTE SIGNIFICANT EXERCISE EFFECT ON EPIGENETIC TARGETS WHICH IS MORE EVIDENT AFTER CHRONIC EXERCISE TRAINING. CONCLUSIONS: BY THE PRESENT SYSTEMATIC REVIEW, WE PROVIDE PRELIMINARY EVIDENCE OF BENEFICIAL EPIGENETIC ADAPTATIONS FOLLOWING ACUTE AND CHRONIC EXERCISE IN PATIENTS WITH CARDIOVASCULAR DISEASE. MORE CONTROLLED STUDIES ARE NEEDED TO CONFIRM SUCH EVIDENCE. 2021 3 6112 51 THE EPIGENETIC CLOCK AS A PREDICTOR OF DISEASE AND MORTALITY RISK: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND: AGEING IS ONE OF THE PRINCIPAL RISK FACTORS FOR MANY CHRONIC DISEASES. HOWEVER, THERE IS CONSIDERABLE BETWEEN-PERSON VARIATION IN THE RATE OF AGEING AND INDIVIDUAL DIFFERENCES IN THEIR SUSCEPTIBILITY TO DISEASE AND DEATH. EPIGENETIC MECHANISMS MAY PLAY A ROLE IN HUMAN AGEING, AND DNA METHYLATION AGE BIOMARKERS MAY BE GOOD PREDICTORS OF AGE-RELATED DISEASES AND MORTALITY RISK. THE AIMS OF THIS SYSTEMATIC REVIEW WERE TO IDENTIFY AND SYNTHESISE THE EVIDENCE FOR AN ASSOCIATION BETWEEN PERIPHERALLY MEASURED DNA METHYLATION AGE AND LONGEVITY, AGE-RELATED DISEASE, AND MORTALITY RISK. METHODS: A SYSTEMATIC SEARCH WAS CONDUCTED IN LINE WITH THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. USING RELEVANT SEARCH TERMS, MEDLINE, EMBASE, COCHRANE CENTRAL REGISTER OF CONTROLLED TRIALS, AND PSYCHINFO DATABASES WERE SEARCHED TO IDENTIFY ARTICLES MEETING THE INCLUSION CRITERIA. STUDIES WERE ASSESSED FOR BIAS USING JOANNA BRIGGS INSTITUTE CRITICAL APPRAISAL CHECKLISTS. DATA WAS EXTRACTED FROM STUDIES MEASURING AGE ACCELERATION AS A PREDICTOR OF AGE-RELATED DISEASES, MORTALITY OR LONGEVITY, AND THE FINDINGS FOR SIMILAR OUTCOMES COMPARED. USING REVIEW MANAGER 5.3 SOFTWARE, TWO META-ANALYSES (ONE PER EPIGENETIC CLOCK) WERE CONDUCTED ON STUDIES MEASURING ALL-CAUSE MORTALITY. RESULTS: TWENTY-THREE RELEVANT ARTICLES WERE IDENTIFIED, INCLUDING A TOTAL OF 41,607 PARTICIPANTS. FOUR STUDIES FOCUSED ON AGEING AND LONGEVITY, 11 ON AGE-RELATED DISEASE (CANCER, CARDIOVASCULAR DISEASE, AND DEMENTIA), AND 11 ON MORTALITY. THERE WAS SOME, ALTHOUGH INCONSISTENT, EVIDENCE FOR AN ASSOCIATION BETWEEN INCREASED DNA METHYLATION AGE AND RISK OF DISEASE. META-ANALYSES INDICATED THAT EACH 5-YEAR INCREASE IN DNA METHYLATION AGE WAS ASSOCIATED AN 8 TO 15% INCREASED RISK OF MORTALITY. CONCLUSION: DUE TO THE SMALL NUMBER OF STUDIES AND HETEROGENEITY IN STUDY DESIGN AND OUTCOMES, THE ASSOCIATION BETWEEN DNA METHYLATION AGE AND AGE-RELATED DISEASE AND LONGEVITY IS INCONCLUSIVE. INCREASED EPIGENETIC AGE WAS ASSOCIATED WITH MORTALITY RISK, BUT POSITIVE PUBLICATION BIAS NEEDS TO BE CONSIDERED. FURTHER RESEARCH IS NEEDED TO DETERMINE THE EXTENT TO WHICH DNA METHYLATION AGE CAN BE USED AS A CLINICAL BIOMARKER. 2019 4 6127 35 THE EPIGENETIC OVERLAP BETWEEN OBESITY AND MOOD DISORDERS: A SYSTEMATIC REVIEW. (1) BACKGROUND: OBESITY AND MOOD DISORDERS ARE CONSIDERED AS THE MOST PREVALENT MORBIDITIES IN MANY COUNTRIES. WE SUPPOSE THAT EPIGENETIC MECHANISMS MAY INDUCE HIGHER RATES OF OBESITY IN SUBJECTS WHO SUFFER FROM MOOD DISORDERS. IN THIS SYSTEMATIC REVIEW, WE FOCUSED ON THE POTENTIAL ROLES OF DNA METHYLATION ON MOOD DISORDERS AND OBESITY DEVELOPMENT. (2) METHODS: THIS SYSTEMATIC REVIEW WAS CONDUCTED IN ACCORDANCE WITH THE PRISMA STATEMENT AND REGISTERED IN PROSPERO. A SYSTEMATIC SEARCH WAS CONDUCTED IN MEDLINE, SCOPUS, WEB OF SCIENCE, COCHRANE CENTRAL DATABASE, EMBASE, AND CINHAL. WE ALSO CONDUCTED A GREY LITERATURE SEARCH, SUCH AS GOOGLE SCHOLAR. (3) RESULTS: AFTER DEDUPLICATION, WE IDENTIFIED 198 POTENTIALLY RELATED CITATIONS. FINALLY, TEN UNIQUE STUDIES MET OUR INCLUSION CRITERIA. WE HAVE FOUND THREE OVERLAP GENES THAT SHOW SIGNIFICANT DNA METHYLATION CHANGES, BOTH IN OBESITY AND DEPRESSION. PATHWAY ANALYSIS INTERACTION FOR TAPBP, BDNF, AND SORBS2 CONFIRMED THE RELATION OF THESE GENES IN BOTH OBESITY AND MOOD DISORDERS. (4) CONCLUSIONS: WHILE MECHANISMS LINKING BOTH OBESITY AND MOOD DISORDERS TO EPIGENETIC RESPONSE ARE STILL UNKNOWN, WE HAVE ALREADY KNOWN CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM. AS THE RESULTS OF GENE ENRICHMENT, PATHWAYS ANALYSIS SHOWED THAT TAPBP, BDNF, AND SORBS2 LINKED TOGETHER BY INFLAMMATORY PATHWAYS. HYPERMETHYLATION IN THESE GENES MIGHT PLAY A CRUCIAL RULE IN THE CO-OCCURRENCE OF OBESITY AND MOOD DISORDERS. 2020 5 247 40 ADULTHOOD ASTHMA AS A CONSEQUENCE OF CHILDHOOD ADVERSITY: A SYSTEMATIC REVIEW OF EPIGENETICALLY AFFECTED GENES. THERE IS AN ACCUMULATING DATA THAT SHOWS RELATION BETWEEN CHILDHOOD ADVERSITY AND VULNERABILITY TO CHRONIC DISEASES AS WELL AS EPIGENETIC INFLUENCES THAT IN TURN GIVE RISE TO THESE DISEASES. ASTHMA IS ONE OF THE CHRONIC DISEASES THAT IS INFLUENCED FROM GENETIC REGULATION OF THE INFLAMMATORY BIOMOLECULES AND THEREFORE THE HYPOTHESIS IN THIS RESEARCH WAS CHILDHOOD ADVERSITY MIGHT HAVE CAUSED EPIGENETIC DIFFERENTIATION IN THE ASTHMA-RELATED GENES IN THE POPULATION WHO HAD CHILDHOOD TRAUMA. TO TEST THIS HYPOTHESIS, THE LITERATURE WAS SYSTEMATICALLY REVIEWED TO EXTRACT EPIGENETICALLY MODIFIED GENE DATA OF THE ADULTS WHO HAD CHILDHOOD ADVERSITY, AND AFFECTED GENES WERE FURTHER EVALUATED FOR THEIR ASSOCIATION WITH ASTHMA. PRISMA GUIDELINES WERE ADOPTED AND PUBMED AND GOOGLE SCHOLAR WERE INCLUDED IN THE SEARCHED DATABASES, TO EVALUATE EPIGENETIC MODIFICATIONS IN ASTHMA-RELATED GENES OF PHYSICALLY, EMOTIONALLY OR SEXUALLY ABUSED CHILDREN. AFTER RETRIEVING A TOTAL OF 5245 ARTICLES, 36 OF THEM WERE INCLUDED IN THE STUDY. SEVERAL GENES AND PATHWAYS THAT MAY CONTRIBUTE TO PATHOGENESIS OF ASTHMA DEVELOPMENT, INCREASED INFLAMMATION, OR RESPONSE TO ASTHMA TREATMENT WERE FOUND EPIGENETICALLY AFFECTED BY CHILDHOOD TRAUMAS. CHILDHOOD ADVERSITY, CAUSING EPIGENETIC CHANGES IN DNA, MAY LEAD TO ASTHMA DEVELOPMENT OR INFLUENCE THE COURSE OF THE DISEASE AND THEREFORE SHOULD BE TAKEN INTO ACCOUNT FOR THE PROLONGED HEALTH CONSEQUENCES. 2022 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 5194 43 PRENATAL EXPOSURE TO POTENTIALLY TOXIC METALS AND THEIR EFFECTS ON GENETIC MATERIAL IN OFFSPRING: A SYSTEMATIC REVIEW. IN RECENT YEARS, THE BACKGROUND LEVEL OF ENVIRONMENTAL POLLUTANTS, INCLUDING METALS, HAS INCREASED. POLLUTANT EXPOSURE DURING THE EARLIEST STAGES OF LIFE MAY DETERMINE CHRONIC DISEASE SUSCEPTIBILITY IN ADULTHOOD BECAUSE OF GENETIC OR EPIGENETIC CHANGES. THE OBJECTIVE OF THIS REVIEW WAS TO IDENTIFY THE ASSOCIATION BETWEEN PRENATAL AND EARLY POSTNATAL EXPOSURE TO POTENTIALLY TOXIC METALS (PTMS) AND THEIR ADVERSE EFFECTS ON THE GENETIC MATERIAL OF OFFSPRING. A SYSTEMATIC REVIEW WAS CARRIED OUT FOLLOWING THE COCHRANE METHODOLOGY IN FOUR DATABASES: PUBMED, SCOPUS, WEB OF SCIENCE, AND THE COCHRANE LIBRARY. ELIGIBLE PAPERS WERE THOSE CONDUCTED IN HUMANS AND PUBLISHED IN ENGLISH BETWEEN 2010/01/01 AND 2021/04/30. A TOTAL OF 57 ARTICLES WERE INCLUDED, MOST OF WHICH EVALUATED PRENATAL EXPOSURE. MOST COMMONLY EVALUATED PTMS WERE AS, CD, AND PB. MAIN ADVERSE EFFECTS ON THE GENETIC MATERIAL OF NEWBORNS ASSOCIATED WITH PTM PRENATAL EXPOSURE WERE ALTERATIONS IN TELOMERE LENGTH, GENE OR PROTEIN EXPRESSION, MITOCHONDRIAL DNA CONTENT, METABOLOMICS, DNA DAMAGE, AND EPIGENETIC MODIFICATIONS. MANY OF THESE EFFECTS WERE SEX-SPECIFIC, BEING PREDOMINANT IN BOYS. ONE ARTICLE REPORTED A SYNERGISTIC INTERACTION BETWEEN AS AND HG, AND TWO ARTICLES OBSERVED ANTAGONISTIC INTERACTIONS BETWEEN PTMS AND ESSENTIAL METALS, SUCH AS CU, SE, AND ZN. THE FINDINGS IN THIS REVIEW HIGHLIGHT THAT THE PROBLEM OF PTM EXPOSURE PERSISTS, AFFECTING THE MOST SUSCEPTIBLE POPULATIONS, SUCH AS NEWBORNS. SOME OF THESE ASSOCIATIONS WERE OBSERVED AT LOW CONCENTRATIONS OF PTMS. MOST OF THE STUDIES HAVE FOCUSED ON SINGLE EXPOSURES; HOWEVER, THREE INTERACTIONS BETWEEN ESSENTIAL AND NONESSENTIAL METALS WERE OBSERVED, HIGHLIGHTING THAT METAL MIXTURES NEED MORE ATTENTION. 2023 8 6678 38 USING GENETIC BURDEN SCORES FOR GENE-BY-METHYLATION INTERACTION ANALYSIS ON METABOLIC SYNDROME IN AFRICAN AMERICANS. WITH THE RAPID ADVANCEMENT OF OMICS-BASED RESEARCH, PARTICULARLY BIG DATA SUCH AS GENOME- AND EPIGENOME-WIDE ASSOCIATION STUDIES THAT INCLUDE EXTENSIVE ENVIRONMENTAL AND CLINICAL VARIABLES, DATA ANALYTICS HAVE BECOME INCREASINGLY COMPLEX. RESEARCHERS FACE SIGNIFICANT CHALLENGES REGARDING HOW TO ANALYZE MULTIFACTORIAL DATA AND MAKE USE OF THE FINDINGS FOR CLINICAL TRANSLATION. THE PURPOSE OF THIS ARTICLE IS TO PROVIDE A SCIENTIFIC EXEMPLAR FOR USE OF GENETIC BURDEN SCORES AS A DATA ANALYSIS METHOD FOR STUDIES WITH BOTH GENOTYPE AND DNA METHYLATION DATA IN WHICH THE GOAL IS TO EVALUATE ASSOCIATIONS WITH CHRONIC CONDITIONS SUCH AS METABOLIC SYNDROME (METS). THIS STUDY INCLUDED 739 AFRICAN AMERICAN MEN AND WOMEN FROM THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY STUDY WHO MET DIAGNOSTIC CRITERIA FOR METS AND HAD AVAILABLE GENETIC AND EPIGENETIC DATA. GENETIC BURDEN SCORES FOR EVALUATED GENES WERE NOT SIGNIFICANT AFTER MULTIPLE TESTING CORRECTIONS, BUT DNA METHYLATION AT 2 CPG SITES (DIHYDROOROTATE DEHYDROGENASE CG22381196 PFDR = .014; CTNNA3 CG00132141 PFDR = .043) WAS SIGNIFICANTLY ASSOCIATED WITH METS AFTER CONTROLLING FOR MULTIPLE COMPARISONS. INTERACTIONS BETWEEN THE MARGINALLY SIGNIFICANT CPG SITES AND BURDEN SCORES, HOWEVER, WERE NOT SIGNIFICANT. MORE WORK IS REQUIRED IN THIS AREA TO IDENTIFY INTERMEDIATE BIOLOGICAL PATHWAYS INFLUENCED BY ENVIRONMENTAL, GENETIC, AND EPIGENETIC VARIATION THAT MAY EXPLAIN THE HIGH PREVALENCE OF METS AMONG AFRICAN AMERICANS. THIS STUDY DOES SERVE, HOWEVER, AS AN EXAMPLE OF THE USE OF THE GENETIC BURDEN SCORE AS AN ALTERNATIVE DATA ANALYSIS APPROACH FOR COMPLEX STUDIES INVOLVING THE ANALYSIS OF GENETIC AND EPIGENETIC DATA SIMULTANEOUSLY. 2019 9 1045 37 CLINICAL CORRELATION AMONG MALE INFERTILITY AND OVERALL MALE HEALTH: A SYSTEMATIC REVIEW OF THE LITERATURE. PURPOSE: ONGOING EVIDENCE HAS SUGGESTED THE ROLE OF MALE FACTOR INFERTILITY AS A POTENTIAL PREDICTOR OF MORTALITY AND GENERAL HEALTH STATUS. THE AIM OF THE PRESENT REVIEW IS TO UPDATE THE CURRENT KNOWLEDGE BASE REGARDING THE ASSOCIATION BETWEEN MALE FACTOR INFERTILITY AND GENERAL HEALTH THROUGH A CRITICAL REVIEW OF THE LITERATURE. MATERIALS AND METHODS: A SYSTEMATIC REVIEW OF THE LITERATURE WAS CARRIED OUT FROM INCEPTION TO NOVEMBER 2019 IN ORDER TO EVALUATE SIGNIFICANT ASSOCIATIONS BETWEEN MALE INFERTILITY AND ADVERSE HEALTH OUTCOMES SUCH AS CARDIOVASCULAR, ONCOLOGIC, METABOLIC AND AUTOIMMUNE DISEASES AS WELL AS OVERALL MORTALITY. RESULTS: IN ALL, 27 STUDIES MET INCLUSION CRITERIA AND WERE CRITICALLY EXAMINED. FIVE STUDIES EXAMINED MALE INFERTILITY AND CARDIOVASCULAR DISEASE RISK, 11 EXAMINED ONCOLOGIC RISK (E.G., OVERALL CANCER RISK, TESTIS AND PROSTATE CANCER), 8 EXAMINED AGGREGATE CHRONIC MEDICAL DISEASES AND 5 INFERTILITY RELATED TO INCIDENCE OF MORTALITY, FOR A TOTAL OF 599,807 MEN DIAGNOSED WITH ANY MALE FACTOR INFERTILITY COVERING A PERIOD FROM 1916 TO 2016. CONCLUSIONS: A MAN'S FERTILITY AND OVERALL HEALTH APPEAR TO BE INTERCONNECTED. THEREFORE, A DIAGNOSIS OF MALE INFERTILITY MAY ALLOW A WINDOW INTO FUTURE COMORBIDITY AND/OR MORTALITY WHICH MAY HELP GUIDE CLINICAL DECISIONS AND COUNSELING. SEVERAL POSSIBLE ETIOLOGIES SUCH AS GENETIC, EPIGENETIC, DEVELOPMENTAL, AND LIFESTYLE-BASED FACTORS NEED TO BE FURTHER EVALUATED IN ORDER TO ESTABLISH THE UNDERLYING MECHANISMS BETWEEN MALE INFERTILITY AND HEALTH. 2020 10 4607 47 NEIGHBORHOOD ENVIRONMENT AND DNA METHYLATION: IMPLICATIONS FOR CARDIOVASCULAR DISEASE RISK. EXPOSURE TO CHRONIC STRESS SUCH AS LIVING IN DISADVANTAGED NEIGHBORHOODS HAS BEEN RELATED TO CARDIOVASCULAR DISEASE (CVD). CHRONIC STRESS MAY INCREASE THE RISK FOR CVD BY INCREASING LEVELS OF SYSTEMIC INFLAMMATION (E.G., HIGHER LEVELS OF PRO-INFLAMMATORY CYTOKINES). DIFFERENTIAL DNA METHYLATION OF INFLAMMATION-RELATED CANDIDATE GENES IS ALSO RELATED TO HIGHER RISK FOR CVD. THUS, THE PURPOSE OF THIS REVIEW WAS TO EXAMINE THE ASSOCIATION OF NEIGHBORHOOD DISADVANTAGE WITH DNA METHYLATION. A SEARCH OF LITERATURE WAS CONDUCTED USING SCOPUS, CINAHL, PUBMED, MEDLINE, AND EMBASE DATABASES. THE KEYWORDS NEIGHBORHOOD, NEIGHBORHOOD DISORDER, NEIGHBORHOOD CRIME, NEIGHBORHOOD VIOLENCE, NEIGHBORHOOD SAFETY, BUILT ENVIRONMENT, AND HOUSING VACANCY WERE COMBINED WITH THE KEYWORDS DNA METHYLATION AND EPIGENETICS. FIVE STUDIES WERE INCLUDED IN THIS REVIEW (N = 3 ADULT BLOOD SAMPLES AND N = 2 FETAL BLOOD SAMPLES). FOUR OF THE FIVE STUDIES REPORTED AN ASSOCIATION OF NEIGHBORHOOD SOCIOECONOMIC STATUS, SOCIAL ENVIRONMENT, AND CRIME WITH EITHER GLOBAL OR GENE-SPECIFIC DNA METHYLATION. ONLY TWO STUDIES EXAMINED THE ASSOCIATION OF NEIGHBORHOOD DISADVANTAGE WITH INFLAMMATION-RELATED CANDIDATE GENES. ONE OF THESE STUDIES FOUND A SIGNIFICANT ASSOCIATION OF NEIGHBORHOOD SOCIOECONOMIC DISADVANTAGE AND SOCIAL ENVIRONMENT WITH DNA METHYLATION IN INFLAMMATION-RELATED CANDIDATE GENES. THUS, DATA ARE LIMITED ON THE ASSOCIATION BETWEEN NEIGHBORHOOD DISADVANTAGE AND DNA METHYLATION OF INFLAMMATION-RELATED CANDIDATE GENES, AS WELL AS GENES IN OTHER POTENTIAL MECHANISTIC PATHWAYS INCLUDING PSYCHOSOCIAL STRESS, TOXIN RESPONSE, AND ADIPOSITY. FUTURE STUDIES SHOULD EXAMINE THESE ASSOCIATIONS AND THE POTENTIAL EPIGENETIC MECHANISMS BY WHICH NEIGHBORHOOD DISADVANTAGE INCREASES THE RISK FOR CVD. 2019 11 2108 36 EPIGENETIC FACTORS RELATED TO LOW BACK PAIN: A SYSTEMATIC REVIEW OF THE CURRENT LITERATURE. LOW BACK PAIN (LBP) IS ONE OF THE MOST COMMON CAUSES OF PAIN AND DISABILITY. AT PRESENT, TREATMENT AND INTERVENTIONS FOR ACUTE AND CHRONIC LOW BACK PAIN OFTEN FAIL TO PROVIDE SUFFICIENT LEVELS OF PAIN RELIEF, AND FULL FUNCTIONAL RESTORATION CAN BE CHALLENGING. CONSIDERING THE SIGNIFICANT SOCIO-ECONOMIC BURDEN AND RISK-TO-BENEFIT RATIO OF MEDICAL AND SURGICAL INTERVENTION IN LOW BACK PAIN PATIENTS, THE IDENTIFICATION OF RELIABLE BIOMARKERS SUCH AS EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN COULD BE USEFUL IN CLINICAL PRACTICE. THE AIM OF THIS STUDY WAS TO REVIEW THE AVAILABLE LITERATURE REGARDING THE EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN. THIS REVIEW WAS CARRIED OUT IN ACCORDANCE WITH PREFERENTIAL REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. THE SEARCH WAS CARRIED OUT IN OCTOBER 2022. ONLY PEER-REVIEWED ARTICLES WERE CONSIDERED FOR INCLUSION. FOURTEEN STUDIES WERE INCLUDED AND SHOWED PROMISING RESULTS IN TERMS OF RELIABLE MARKERS. EPIGENETIC MARKERS FOR LBP HAVE THE POTENTIAL TO SIGNIFICANTLY MODIFY DISEASE MANAGEMENT. MOST RECENT EVIDENCE SUGGESTS THAT EPIGENETICS IS A MORE PROMISING FIELD FOR THE IDENTIFICATION OF FACTORS ASSOCIATED WITH LBP, OFFERING A RATIONALE FOR FURTHER INVESTIGATION IN THIS FIELD WITH THE LONG-TERM GOAL OF FINDING EPIGENETIC BIOMARKERS THAT COULD CONSTITUTE BIOLOGICAL TARGETS FOR DISEASE MANAGEMENT AND TREATMENT. 2023 12 5748 37 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 13 2510 36 EPIGENETICS AND POSTSURGICAL PAIN: A SCOPING REVIEW. OBJECTIVE: MULTIPLE FACTORS ARE INVOLVED IN THE PHYSIOLOGY AND VARIABILITY OF POSTSURGICAL PAIN, A GREAT PART OF WHICH CAN BE EXPLAINED BY GENETIC AND ENVIRONMENTAL FACTORS AND THEIR INTERACTION. EPIGENETICS REFERS TO THE MECHANISM BY WHICH THE ENVIRONMENT ALTERS THE STABILITY AND EXPRESSION OF GENES. WE CONDUCTED A SCOPING REVIEW TO EXAMINE THE AVAILABLE EVIDENCE IN BOTH ANIMAL MODELS AND CLINICAL STUDIES ON EPIGENETIC MECHANISMS INVOLVED IN THE REGULATION OF POSTSURGICAL AND CHRONIC POSTSURGICAL PAIN. METHODS: THE ARKSEY AND O'MALLEY FRAMEWORK AND THE PRISMA-SCR (PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEW AND META-ANALYSIS, SCOPING REVIEWS EXTENSION) GUIDELINES WERE USED. THE PUBMED, WEB OF SCIENCE, AND GOOGLE SCHOLAR DATABASES WERE SEARCHED, AND THE ORIGINAL ARTICLES CITED IN REVIEWS LOCATED THROUGH THE SEARCH WERE ALSO REVIEWED. ENGLISH-LANGUAGE ARTICLES WITHOUT TIME LIMITS WERE RETRIEVED. ARTICLES WERE SELECTED IF THE ABSTRACT ADDRESSED INFORMATION ON THE EPIGENETIC OR EPIGENOMIC MECHANISMS, HISTONE, OR DNA METHYLATION AND MICRORIBONUCLEIC ACIDS INVOLVED IN POSTSURGICAL AND CHRONIC POSTSURGICAL PAIN IN ANIMAL MODELS AND CLINICAL STUDIES. RESULTS: THE INITIAL SEARCH PROVIDED 174 ARTICLES, AND 95 WERE USED. THE AVAILABLE STUDIES TO DATE, MOSTLY IN ANIMAL MODELS, HAVE SHOWN THAT EPIGENETICS CONTRIBUTES TO THE REGULATION OF GENE EXPRESSION IN THE PATHWAYS INVOLVED IN POSTSURGICAL PAIN AND IN MAINTAINING LONG-TERM PAIN. CONCLUSION: RESEARCH ON POSSIBLE EPIGENETIC MECHANISMS INVOLVED IN POSTSURGICAL PAIN AND CHRONIC POSTSURGICAL PAIN IN HUMANS IS SCARCE. IN VIEW OF THE EVIDENCE AVAILABLE IN ANIMAL MODELS, THERE IS A NEED TO EVALUATE EPIGENETIC PAIN MECHANISMS IN THE CONTEXT OF HUMAN AND CLINICAL STUDIES. 2022 14 4869 35 OSTEOARTHRITIS YEAR IN REVIEW: GENETICS, GENOMICS, EPIGENETICS. OBJECTIVE: IN THIS REVIEW, WE HAVE HIGHLIGHTED ADVANCES IN GENETICS, GENOMICS AND EPIGENETICS IN THE FIELD OF OSTEOARTHRITIS (OA) OVER THE PAST YEAR. METHODS: A LITERATURE SEARCH WAS PERFORMED USING PUBMED AND THE CRITERIA: "OSTEOARTHRITIS" AND ONE OF THE FOLLOWING TERMS "GENETIC(S), GENOMIC(S), EPIGENETIC(S), EPIGENOMIC(S), NONCODING RNA, MICRORNA, LONG NONCODING RNA, LNCRNA, CIRCULAR RNA, RNA SEQUENCING, SINGLE CELL SEQUENCING, OR DNA METHYLATION BETWEEN APRIL 1, 2019 AND APRIL 30, 2020. RESULTS: WE IDENTIFIED 653 UNIQUE PUBLICATIONS, MANY STUDIES SPANNED MULTIPLE SEARCH TERMS. WE SUMMARIZED ADVANCES RELATING TO EVOLUTIONARY GENETICS, PAIN, ETHNICITY SPECIFIC RISK FACTORS, FUNCTIONAL STUDIES OF GENE VARIANTS, AND INTERACTIONS BETWEEN CODING AND NON-CODING RNAS IN OA PATHOGENESIS. CONCLUSIONS: STUDIES HAVE IDENTIFIED VARIANTS CONTRIBUTING TO OA SUSCEPTIBILITY, CANDIDATE BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS, AS WELL AS PROMISING THERAPEUTIC CANDIDATES. VALIDATION IN MULTIPLE COHORTS, MULTI-OMICS STRATEGIES, AND MACHINE LEARNING AIDED COMPUTATIONAL ANALYSES HAVE ALL CONTRIBUTED TO THE STRENGTH OF PUBLISHED LITERATURE. OPEN ACCESS DATA-SETS, GREATER SAMPLE SIZES TO CAPTURE BROADER POPULATIONS AND UNDERSTANDING DISEASE MECHANISMS BY INVESTIGATING THE INTERACTIONS BETWEEN MULTIPLE TISSUE TYPES WILL FURTHER AID IN PROGRESS TOWARDS UNDERSTANDING AND CURING OA. 2021 15 381 30 AN EPIGENOME-WIDE ASSOCIATION STUDY OF EARLY-ONSET MAJOR DEPRESSION IN MONOZYGOTIC TWINS. MAJOR DEPRESSION (MD) IS A DEBILITATING MENTAL HEALTH CONDITION WITH PEAK PREVALENCE OCCURRING EARLY IN LIFE. GENOME-WIDE EXAMINATION OF DNA METHYLATION (DNAM) OFFERS AN ATTRACTIVE COMPLEMENT TO STUDIES OF ALLELIC RISK GIVEN IT CAN REFLECT THE COMBINED INFLUENCE OF GENES AND ENVIRONMENT. THE CURRENT STUDY USED MONOZYGOTIC TWINS TO IDENTIFY DIFFERENTIALLY AND VARIABLY METHYLATED REGIONS OF THE GENOME THAT DISTINGUISH TWINS WITH AND WITHOUT A LIFETIME HISTORY OF EARLY-ONSET MD. THE SAMPLE INCLUDED 150 CAUCASIAN MONOZYGOTIC TWINS BETWEEN THE AGES OF 15 AND 20 (73% FEMALE; MAGE = 17.52 SD = 1.28) WHO WERE ASSESSED DURING A DEVELOPMENTAL STAGE CHARACTERIZED BY RELATIVELY DISTINCT NEUROPHYSIOLOGICAL CHANGES. ALL TWINS WERE GENERALLY HEALTHY AND CURRENTLY FREE OF MEDICATIONS WITH PSYCHOTROPIC EFFECTS. DNAM WAS MEASURED IN PERIPHERAL BLOOD CELLS USING THE INFINIUM HUMAN BEADCHIP 450 K ARRAY. MD ASSOCIATIONS WITH EARLY-ONSET MD WERE DETECTED AT 760 DIFFERENTIALLY AND VARIABLY METHYLATED PROBES/REGIONS THAT MAPPED TO 428 GENES. GENES AND GENOMIC REGIONS INVOLVED NEURAL CIRCUITRY FORMATION, PROJECTION, FUNCTIONING, AND PLASTICITY. GENE ENRICHMENT ANALYSES IMPLICATED GENES RELATED TO NEURON STRUCTURES AND NEURODEVELOPMENTAL PROCESSES INCLUDING CELL-CELL ADHESION GENES (E.G., PCDHA GENES). GENES PREVIOUSLY IMPLICATED IN MOOD AND PSYCHIATRIC DISORDERS AS WELL AS CHRONIC STRESS (E.G., NRG3) ALSO WERE IDENTIFIED. DNAM REGIONS ASSOCIATED WITH EARLY-ONSET MD WERE FOUND TO OVERLAP GENETIC LOCI IDENTIFIED IN THE LATEST PSYCHIATRIC GENOMICS CONSORTIUM META-ANALYSIS OF DEPRESSION. UNDERSTANDING THE TIME COURSE OF EPIGENETIC INFLUENCES DURING EMERGING ADULTHOOD MAY CLARIFY DEVELOPMENTAL PHASES WHERE CHANGES IN THE DNA METHYLOME MAY MODULATE INDIVIDUAL DIFFERENCES IN MD RISK. 2020 16 6159 45 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010 17 2901 31 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 18 1519 28 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS. 2021 19 3652 35 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION. 2021 20 6633 38 UNHEALTHY SMOKERS: SCOPES FOR PROPHYLACTIC INTERVENTION AND CLINICAL TREATMENT. BACKGROUND: GLOBALLY, TOBACCO USE CAUSES APPROXIMATELY 6 MILLION DEATHS PER YEAR, AND PREDICTIONS REPORT THAT WITH CURRENT TRENDS; MORE THAN 8 MILLION DEATHS ARE EXPECTED ANNUALLY BY 2030. CIGARETTE SMOKINGS IS CURRENTLY ACCOUNTABLE FOR MORE THAN 480,000 DEATHS EACH YEAR IN UNITED STATES (US) AND IS THE LEADING CAUSE OF PREVENTABLE DEATH IN THE US. ON AVERAGE, SMOKERS DIE 10 YEARS EARLIER THAN NONSMOKERS AND IF SMOKING CONTINUES AT ITS CURRENT PROPORTION AMONG ADOLESCENTS, ONE IN EVERY 13 AMERICANS AGED 17 YEARS OR YOUNGER IS EXPECTED TO DIE PREMATURELY FROM A SMOKING-RELATED ILLNESS. EVEN THOUGH THERE HAS BEEN A MARGINAL SMOKING DECLINE OF AROUND 5% IN RECENT YEARS (2005 VS 2015), SMOKERS STILL ACCOUNT FOR 15% OF THE US ADULT POPULATION. WHAT IS ALSO CONCERNING IS THAT 41,000 OUT OF 480,000 DEATHS RESULTS FROM SECONDHAND SMOKE (SHS) EXPOSURE. HEREIN, WE PROVIDE A DETAILED REVIEW OF HEALTH COMPLICATIONS AND MAJOR PATHOLOGICAL MECHANISMS INCLUDING MUTATION, INFLAMMATION, OXIDATIVE STRESS, AND HEMODYNAMIC AND PLASMA PROTEIN CHANGES ASSOCIATED WITH CHRONIC SMOKING. FURTHER, WE DISCUSS PROPHYLACTIC INTERVENTIONS AND ASSOCIATED BENEFITS AND PROVIDE A RATIONALE FOR THE SCOPE OF CLINICAL TREATMENT. CONCLUSIONS: CONSIDERING THESE PREMISES, IT IS EVIDENT THAT MUCH DETAILED TRANSLATIONAL AND CLINICAL STUDIES ARE NEEDED. FACTORS SUCH AS THE LENGTH OF SMOKING CESSATION FOR EX-SMOKERS, THE LEVEL OF SMOKE EXPOSURE IN CASE OF SHS, PRE-ESTABLISHED HEALTH CONDITIONS, GENETICS (AND EPIGENETICS MODIFICATION CAUSED BY CHRONIC SMOKING) ARE FEW OF THE CRITERIA THAT NEED TO BE EVALUATED TO BEGIN ASSESSING THE PROPHYLACTIC AND/OR THERAPEUTIC IMPACT OF TREATMENTS AIMED AT CHRONIC AND FORMER SMOKERS (ESPECIALLY EARLY STAGE EX-SMOKERS) INCLUDING THOSE FREQUENTLY SUBJECTED TO SECOND HAND TOBACCO SMOKE EXPOSURE. HEREIN, WE PROVIDE A DETAILED REVIEW OF HEALTH COMPLICATIONS AND MAJOR PATHOLOGICAL MECHANISMS INCLUDING MUTATION, INFLAMMATION, OXIDATIVE STRESS, AND HEMODYNAMIC AND PLASMA PROTEIN CHANGES ASSOCIATED WITH CHRONIC SMOKING. FURTHER, WE DISCUSS ABOUT PROPHYLACTIC INTERVENTIONS AND ASSOCIATED BENEFITS AND PROVIDE A RATIONALE AND SCOPE FOR CLINICAL TREATMENT. 2017