1 2638 82 EPIGENOME: BIOSENSOR OF CUMULATIVE EXPOSURE TO CHEMICAL AND NONCHEMICAL STRESSORS RELATED TO ENVIRONMENTAL JUSTICE. UNDERSTANDING DIFFERENTIAL DISEASE SUSCEPTIBILITY REQUIRES NEW TOOLS TO QUANTIFY THE CUMULATIVE EFFECTS OF ENVIRONMENTAL STRESS. EVIDENCE SUGGESTS THAT SOCIAL, PHYSICAL, AND CHEMICAL STRESSORS CAN INFLUENCE DISEASE THROUGH THE ACCUMULATION OF EPIGENETIC MODIFICATIONS. GEOGRAPHICALLY STABLE EPIGENETIC ALTERATIONS COULD IDENTIFY PLAUSIBLE MECHANISMS FOR HEALTH DISPARITIES AMONG THE DISADVANTAGED AND POOR. RELATIONS BETWEEN NEIGHBORHOOD-SPECIFIC EPIGENETIC MARKERS AND DISEASE WOULD IDENTIFY THE MOST APPROPRIATE TARGETS FOR MEDICAL AND ENVIRONMENTAL INTERVENTION. COMPLEX INTERACTIONS AMONG GENES, THE ENVIRONMENT, AND DISEASE REQUIRE THE EXAMINATION OF HOW EPIGENETIC CHANGES REGULATE SUSCEPTIBILITY TO ENVIRONMENTAL STRESSORS. PROGRESS IN UNDERSTANDING DISPARITIES IN DISEASE SUSCEPTIBILITY MAY DEPEND ON ASSESSING THE CUMULATIVE EFFECT OF ENVIRONMENTAL STRESSORS ON GENETIC SUBSTRATES. WE HIGHLIGHT KEY CONCEPTS REGARDING THE INTERFACE BETWEEN ENVIRONMENTAL STRESS, EPIGENETICS, AND CHRONIC DISEASE. 2014 2 1453 28 DISCOVERING HOW ENVIRONMENTAL EXPOSURES ALTER GENES COULD LEAD TO NEW TREATMENTS FOR CHRONIC ILLNESSES. EMERGING RESEARCH DEMONSTRATES THAT DIET, POLLUTION, AND OTHER ENVIRONMENTAL TRIGGERS CAN ALTER BOTH THE FUNCTION AND EXPRESSION OF HUMAN GENES AND LEAD TO A HEIGHTENED DISEASE RISK. THESE ENVIRONMENT-GENE INTERACTIONS CAN CAUSE SO-CALLED EPIGENETIC CHANGES IN GENE EXPRESSION-PATTERNS OF WHICH GENES ARE SWITCHED "ON" OR "OFF"-THAT MAY ACCOUNT FOR THE RISING MORTALITY FROM CHRONIC DISEASES IN INDUSTRIALIZED NATIONS. IN THIS PAPER, WE CALL FOR A NEW TRANSDISCIPLINARY APPROACH TO PUBLIC HEALTH THAT WOULD EXAMINE HOW ENVIRONMENTAL EXPOSURES, BOTH PHYSICAL AND SOCIAL, INFLUENCE GENE EXPRESSION AND A PERSON'S SUSCEPTIBILITY TO CHRONIC DISEASE. THIS INITIATIVE COULD LEAD TO NEW WAYS TO PREVENT AND TREAT SUCH ILLNESSES. 2011 3 1938 27 EPIDEMIOLOGIC EVIDENCE FOR ASSOCIATION BETWEEN ADVERSE ENVIRONMENTAL EXPOSURES IN EARLY LIFE AND EPIGENETIC VARIATION: A POTENTIAL LINK TO DISEASE SUSCEPTIBILITY? A GROWING BODY OF EVIDENCE SUGGESTS THAT THE RISK OF DEVELOPMENT AND PROGRESSION OF A VARIETY OF HUMAN CHRONIC DISEASES DEPENDS ON EPIGENETIC MODIFICATIONS TRIGGERED BY ENVIRONMENTAL CUES DURING EARLY LIFE SENSITIVE STAGES. EXPOSURES TO ENVIRONMENTAL FACTORS SUCH AS ADVERSE NUTRITIONAL, PSYCHOLOGICAL, AND SOCIAL CONDITIONS, AS WELL AS POLLUTANTS AND SUBSTANCE ABUSE IN EARLY LIFE, HAVE BEEN SHOWN TO BE IMPORTANT DETERMINANTS OF EPIGENETIC PROGRAMMING OF CHRONIC PATHOLOGICAL CONDITIONS IN HUMAN POPULATIONS. OVER THE PAST YEARS, IT HAS BECOME INCREASINGLY CLEAR DUE TO THE EPIGENOME-WIDE ASSOCIATION STUDIES (EWASS) THAT EARLY LIFE ADVERSE ENVIRONMENTAL EVENTS MAY TRIGGER WIDESPREAD AND PERSISTENT ALTERATIONS IN TRANSCRIPTIONAL PROFILING. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED UNDERLYING THESE ASSOCIATIONS. IN THIS CONTEXT, DNA METHYLATION IS THE MOST INTENSIVELY STUDIED EPIGENETIC PHENOMENON. IN THIS REVIEW, THE CLINICAL AND EPIDEMIOLOGICAL EVIDENCE FOR THE ROLE OF EPIGENETIC FACTORS IN MEDIATING THE LINK BETWEEN EARLY LIFE EXPERIENCES AND LONG-TERM HEALTH OUTCOMES ARE SUMMARIZED. 2015 4 6119 22 THE EPIGENETIC IMPACTS OF SOCIAL STRESS: HOW DOES SOCIAL ADVERSITY BECOME BIOLOGICALLY EMBEDDED? EPIGENETIC MECHANISMS ARE IMPLICATED IN THE PROCESSES THROUGH WHICH SOCIAL STRESSORS ERODE HEALTH IN HUMANS AND OTHER ANIMALS. HERE I REVIEW PROGRESS IN ELUCIDATING THE BIOLOGICAL PATHWAYS UNDERLYING THE SOCIAL GRADIENT IN HEALTH, WITH PARTICULAR EMPHASIS ON HOW BEHAVIORAL STRESSES INFLUENCE EPIGENOMIC VARIATION LINKED TO HEALTH. THE EVIDENCE THAT EPIGENETIC CHANGES ARE INVOLVED IN EMBEDDING OF SOCIAL STATUS-LINKED CHRONIC STRESS IS REVIEWED IN THE CONTEXT OF CURRENT KNOWLEDGE ABOUT BEHAVIOR WITHIN ANIMAL DOMINANCE HIERARCHIES AND THE IMPACTS OF SOCIAL POSITION ON BEHAVIORS THAT AFFECT HEALTH. THE ROLES OF EPIGENETIC MECHANISMS IN RESPONSES TO TRAUMA AND THE EVIDENCE FOR THEIR INVOLVEMENT IN INTERGENERATIONAL TRANSMISSION OF THE BIOLOGICAL IMPACTS OF TRAUMATIC STRESS ARE ALSO CONSIDERED. TAKEN TOGETHER, THE EMERGING INSIGHTS HAVE IMPORTANT IMPLICATIONS FOR DEVELOPMENT OF STRATEGIES TO IMPROVE SOCIETAL HEALTH AND WELL-BEING. 2016 5 5813 23 STRESS AND ASTHMA: NOVEL INSIGHTS ON GENETIC, EPIGENETIC, AND IMMUNOLOGIC MECHANISMS. IN THE UNITED STATES THE ECONOMICALLY DISADVANTAGED AND SOME ETHNIC MINORITIES ARE OFTEN EXPOSED TO CHRONIC PSYCHOSOCIAL STRESSORS AND DISPROPORTIONATELY AFFECTED BY ASTHMA. CURRENT EVIDENCE SUGGESTS A CAUSAL ASSOCIATION BETWEEN CHRONIC PSYCHOSOCIAL STRESS AND ASTHMA OR ASTHMA MORBIDITY. RECENT FINDINGS SUGGEST POTENTIAL MECHANISMS UNDERLYING THIS ASSOCIATION, INCLUDING CHANGES IN THE METHYLATION AND EXPRESSION OF GENES THAT REGULATE BEHAVIORAL, AUTONOMIC, NEUROENDOCRINE, AND IMMUNOLOGIC RESPONSES TO STRESS. THERE IS ALSO EVIDENCE SUGGESTING THE EXISTENCE OF SUSCEPTIBILITY GENES THAT PREDISPOSE CHRONICALLY STRESSED YOUTH TO BOTH POST-TRAUMATIC STRESS DISORDER AND ASTHMA. IN THIS REVIEW WE CRITICALLY EXAMINE PUBLISHED EVIDENCE AND SUGGEST FUTURE DIRECTIONS FOR RESEARCH IN THIS FIELD. 2014 6 6630 22 UNDERSTANDING THE INTERPLAY BETWEEN HEALTH DISPARITIES AND EPIGENOMICS. SOCIAL EPIGENOMICS HAS EMERGED AS AN INTEGRATIVE FIELD OF RESEARCH FOCUSED ON IDENTIFICATION OF SOCIO-ENVIRONMENTAL FACTORS, THEIR INFLUENCE ON HUMAN BIOLOGY THROUGH EPIGENOMIC MODIFICATIONS, AND HOW THEY CONTRIBUTE TO CURRENT HEALTH DISPARITIES. SEVERAL HEALTH DISPARITIES STUDIES HAVE BEEN PUBLISHED USING GENETIC-BASED APPROACHES; HOWEVER, INCREASING ACCESSIBILITY AND AFFORDABILITY OF MOLECULAR TECHNOLOGIES HAVE ALLOWED FOR AN IN-DEPTH INVESTIGATION OF THE INFLUENCE OF EXTERNAL FACTORS ON EPIGENETIC MODIFICATIONS (E.G., DNA METHYLATION, MICRO-RNA EXPRESSION). CURRENTLY, RESEARCH IS FOCUSED ON EPIGENETIC CHANGES IN RESPONSE TO ENVIRONMENT, AS WELL AS TARGETED EPIGENETIC THERAPIES AND ENVIRONMENTAL/SOCIAL STRATEGIES FOR POTENTIALLY MINIMIZING CERTAIN HEALTH DISPARITIES. HERE, WE WILL REVIEW RECENT FINDINGS IN THIS FIELD PERTAINING TO CONDITIONS AND DISEASES OVER LIFE SPAN ENCOMPASSING PRENATAL TO ADULT STAGES. 2020 7 6063 24 THE DEVELOPMENTAL ENVIRONMENT, EPIGENETIC BIOMARKERS AND LONG-TERM HEALTH. EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES HAS SHOWN THAT THE PRENATAL AND EARLY POSTNATAL ENVIRONMENTS INFLUENCE SUSCEPTIBILITY TO CHRONIC DISEASE IN LATER LIFE AND SUGGESTS THAT EPIGENETIC PROCESSES ARE AN IMPORTANT MECHANISM BY WHICH THE ENVIRONMENT ALTERS LONG-TERM DISEASE RISK. EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNAS, PLAY A CENTRAL ROLE IN REGULATING GENE EXPRESSION. THE EPIGENOME IS HIGHLY SENSITIVE TO ENVIRONMENTAL FACTORS IN EARLY LIFE, SUCH AS NUTRITION, STRESS, ENDOCRINE DISRUPTION AND POLLUTION, AND CHANGES IN THE EPIGENOME CAN INDUCE LONG-TERM CHANGES IN GENE EXPRESSION AND PHENOTYPE. IN THIS REVIEW WE FOCUS ON HOW THE EARLY LIFE NUTRITIONAL ENVIRONMENT CAN ALTER THE EPIGENOME LEADING TO AN ALTERED SUSCEPTIBILITY TO DISEASE IN LATER LIFE. 2015 8 2651 24 EPIGENOMICS AND TRANSCRIPTOMICS IN THE PREDICTION AND DIAGNOSIS OF CHILDHOOD ASTHMA: ARE WE THERE YET? ASTHMA IS THE MOST COMMON NON-COMMUNICABLE CHRONIC DISEASE OF CHILDHOOD. DESPITE ITS HIGH PREVALENCE, TO DATE WE LACK METHODS THAT ARE BOTH EFFICIENT AND ACCURATE IN DIAGNOSING ASTHMA. MOST TRADITIONAL APPROACHES HAVE BEEN BASED ON GARNERING CLINICAL EVIDENCE, SUCH AS RISK FACTORS AND EXPOSURES. GIVEN THE HIGH HERITABILITY OF ASTHMA, MORE RECENT APPROACHES HAVE LOOKED AT GENETIC POLYMORPHISMS AS POTENTIAL "RISK FACTORS." HOWEVER, GENETIC VARIANTS EXPLAIN ONLY A SMALL PROPORTION OF ASTHMA RISK, AND HAVE BEEN LESS THAN OPTIMAL AT PREDICTING RISK FOR INDIVIDUAL SUBJECTS. EPIGENOMIC STUDIES OFFER SIGNIFICANT ADVANTAGES OVER PREVIOUS APPROACHES. EPIGENETIC REGULATION IS HIGHLY TISSUE-SPECIFIC, AND CAN INDUCE BOTH SHORT- AND LONG-TERM CHANGES IN GENE EXPRESSION. SUCH CHANGES CAN START IN UTERO, CAN VARY THROUGHOUT THE LIFE SPAN, AND IN SOME INSTANCES CAN BE PASSED ON FROM ONE GENERATION TO ANOTHER. MOST IMPORTANTLY, THE EPIGENOME CAN BE MODIFIED BY ENVIRONMENTAL FACTORS AND EXPOSURES, AND THUS EPIGENETIC AND TRANSCRIPTOMIC PROFILING MAY YIELD THE MOST ACCURATE RISK ESTIMATES FOR A GIVEN PATIENT BY INCORPORATING ENVIRONMENTAL (AND TREATMENT) EFFECTS THROUGHOUT THE LIFESPAN. HERE WE WILL REVIEW THE MOST RECENT ADVANCES IN THE USE OF EPIGENETIC AND TRANSCRIPTOMIC ANALYSIS FOR THE EARLY DIAGNOSIS OF ASTHMA AND ATOPY, AS WELL AS CHALLENGES AND FUTURE DIRECTIONS IN THE FIELD AS IT MOVES FORWARD. WE WILL PARTICULARLY FOCUS ON DNA METHYLATION, THE MOST STUDIED MECHANISM OF EPIGENETIC REGULATION. 2019 9 5164 31 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017 10 1936 25 ENVIRONMENTAL RISK FACTORS OF TYPE 2 DIABETES-AN EXPOSOME APPROACH. TYPE 2 DIABETES IS ONE OF THE MAJOR CHRONIC DISEASES ACCOUNTING FOR A SUBSTANTIAL PROPORTION OF DISEASE BURDEN IN WESTERN COUNTRIES. THE MAJORITY OF THE BURDEN OF TYPE 2 DIABETES IS ATTRIBUTED TO ENVIRONMENTAL RISKS AND MODIFIABLE RISK FACTORS SUCH AS LIFESTYLE. THE ENVIRONMENT WE LIVE IN, AND CHANGES TO IT, CAN THUS CONTRIBUTE SUBSTANTIALLY TO THE PREVENTION OF TYPE 2 DIABETES AT A POPULATION LEVEL. THE 'EXPOSOME' REPRESENTS THE (MEASURABLE) TOTALITY OF ENVIRONMENTAL, I.E. NONGENETIC, DRIVERS OF HEALTH AND DISEASE. THE EXTERNAL EXPOSOME COMPRISES ASPECTS OF THE BUILT ENVIRONMENT, THE SOCIAL ENVIRONMENT, THE PHYSICO-CHEMICAL ENVIRONMENT AND THE LIFESTYLE/FOOD ENVIRONMENT. THE INTERNAL EXPOSOME COMPRISES MEASUREMENTS AT THE EPIGENETIC, TRANSCRIPT, PROTEOME, MICROBIOME OR METABOLOME LEVEL TO STUDY EITHER THE EXPOSURES DIRECTLY, THE IMPRINTS THESE EXPOSURES LEAVE IN THE BIOLOGICAL SYSTEM, THE POTENTIAL OF THE BODY TO COMBAT ENVIRONMENTAL INSULTS AND/OR THE BIOLOGY ITSELF. IN THIS REVIEW, WE DESCRIBE THE EVIDENCE FOR ENVIRONMENTAL RISK FACTORS OF TYPE 2 DIABETES, FOCUSING ON BOTH THE GENERAL EXTERNAL EXPOSOME AND IMPRINTS OF THIS ON THE INTERNAL EXPOSOME. STUDIES PROVIDED ESTABLISHED ASSOCIATIONS OF AIR POLLUTION, RESIDENTIAL NOISE AND AREA-LEVEL SOCIOECONOMIC DEPRIVATION WITH AN INCREASED RISK OF TYPE 2 DIABETES, WHILE NEIGHBOURHOOD WALKABILITY AND GREEN SPACE ARE CONSISTENTLY ASSOCIATED WITH A REDUCED RISK OF TYPE 2 DIABETES. THERE IS LITTLE OR INCONSISTENT EVIDENCE ON THE CONTRIBUTION OF THE FOOD ENVIRONMENT, OTHER ASPECTS OF THE SOCIAL ENVIRONMENT AND OUTDOOR TEMPERATURE. THESE ENVIRONMENTAL FACTORS ARE THOUGHT TO AFFECT TYPE 2 DIABETES RISK MAINLY THROUGH MECHANISMS INCORPORATING LIFESTYLE FACTORS SUCH AS PHYSICAL ACTIVITY OR DIET, THE MICROBIOME, INFLAMMATION OR CHRONIC STRESS. TO FURTHER ASSESS CAUSALITY OF THESE ASSOCIATIONS, FUTURE STUDIES SHOULD FOCUS ON INVESTIGATING THE LONGITUDINAL EFFECTS OF OUR ENVIRONMENT (AND CHANGES TO IT) IN RELATION TO TYPE 2 DIABETES RISK AND WHETHER THESE ASSOCIATIONS ARE EXPLAINED BY THESE PROPOSED MECHANISMS. 2022 11 2528 29 EPIGENETICS AS A KEY LINK BETWEEN PSYCHOSOCIAL STRESS AND AGING: CONCEPTS, EVIDENCE, MECHANISMS . PSYCHOSOCIAL STRESS-ESPECIALLY WHEN CHRONIC, EXCESSIVE, OR OCCURRING EARLY IN LIFE-HAS BEEN ASSOCIATED WITH ACCELERATED AGING AND INCREASED DISEASE RISK. WITH RAPID AGING OF THE WORLD POPULATION, THE NEED TO ELUCIDATE THE UNDERLYING MECHANISMS IS PRESSING, NOW MORE SO THAN EVER. AMONG MOLECULAR MECHANISMS LINKING STRESS AND AGING, THE PRESENT ARTICLE REVIEWS EVIDENCE ON THE ROLE OF EPIGENETICS, BIOCHEMICAL PROCESSES THAT CAN BE SET INTO MOTION BY STRESSORS AND IN TURN INFLUENCE GENOMIC FUNCTION AND COMPLEX PHENOTYPES, INCLUDING AGING-RELATED OUTCOMES. THE ARTICLE FURTHER PROVIDES A CONCEPTUAL MECHANISTIC FRAMEWORK ON HOW STRESS MAY DRIVE EPIGENETIC CHANGES AT SUSCEPTIBLE GENOMIC SITES, THEREBY EXERTING SYSTEMS-LEVEL EFFECTS ON THE AGING EPIGENOME WHILE ALSO REGULATING THE EXPRESSION OF MOLECULES IMPLICATED IN AGING-RELATED PROCESSES. THIS EMERGING EVIDENCE, TOGETHER WITH WORK EXAMINING RELATED BIOLOGICAL PROCESSES, BEGINS TO SHED LIGHT ON THE EPIGENETIC AND, MORE BROADLY, MOLECULAR UNDERPINNINGS OF THE LONG-HYPOTHESIZED CONNECTION BETWEEN STRESS AND AGING. . 2019 12 2517 21 EPIGENETICS AND THE BURDEN OF NONCOMMUNICABLE DISEASE: A PAUCITY OF RESEARCH IN AFRICA. EPIDEMIOLOGICAL EVIDENCE SUGGESTS THAT AN ADVERSE IN UTERO ENVIRONMENT IS ASSOCIATED WITH AN INCREASED RISK FOR DEVELOPING ADULT ONSET DISEASES. THE MOLECULAR MECHANISMS FOR SUSCEPTIBILITY TO CHRONIC NONCOMMUNICABLE DISEASES ARE NOT FULLY UNDERSTOOD, ALTHOUGH RECENT RESEARCH HAS PROPOSED THAT EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN FETAL PROGRAMMING. GENETIC AND ENVIRONMENTAL FACTORS CONTRIBUTE TO INTERINDIVIDUAL AND SPATIOTEMPORAL TISSUE-SPECIFIC METHYLATION PATTERNS. ALTHOUGH THE DIVERSE ENVIRONMENTS AND HIGH GENETIC DIVERSITY OF AFRICAN POPULATIONS PROVIDE UNPARALLELED POTENTIAL TO INVESTIGATE THE EFFECTS OF ENVIRONMENTAL CHANGE ON THE EPIGENETIC PROFILE IN HUMANS, ONLY A SMALL PERCENTAGE OF GENOMIC AND EPIGENETIC STUDIES HAVE FOCUSED ON POPULATIONS FROM THIS CONTINENT. THIS EMPHASIZES THE NEED TO BUILD CAPACITY IN AFRICA FOR RESEARCH THAT LEADS TO AN UNDERSTANDING OF THE ASSOCIATION BETWEEN GENETIC, EPIGENETIC AND ENVIRONMENTAL RISK FACTORS FOR NONCOMMUNICABLE DISEASES ON THE CONTINENT. 2015 13 5650 20 SEX DIFFERENCES IN THE DEVELOPMENT OF PHYSICAL AGGRESSION: AN INTERGENERATIONAL PERSPECTIVE AND IMPLICATIONS FOR PREVENTIVE INTERVENTIONS. THIS ARTICLE REVIEWS THE STATE OF KNOWLEDGE ON THE DEVELOPMENT OF CHRONIC PHYSICAL AGGRESSION (CPA), WITH THE AIM OF IDENTIFYING THE MOST EFFECTIVE PREVENTION STRATEGIES. WE SPECIFICALLY FOCUS ON THE EARLY DEVELOPMENT OF PHYSICAL AGGRESSION, ON SEX DIFFERENCES IN THE USE OF PHYSICAL AGGRESSION, AND ON THE TRANSMISSION OF BEHAVIOR PROBLEMS FROM ONE GENERATION TO THE OTHER. THE BODY OF RESEARCH ON THE DEVELOPMENT OF CPA FROM THE PAST THREE DECADES THAT WE REVIEW SHOWS INCREASING EVIDENCE THAT ITS PREVENTION REQUIRES A LONG-TERM BIOPSYCHOSOCIAL DEVELOPMENTAL APPROACH WHICH ALSO MUST INCLUDE AN INTERGENERATIONAL PERSPECTIVE. RECENT GENETIC AND EPIGENETIC RESEARCH HAS INDICATED THAT THERE ARE BOTH IMPORTANT GENETIC AND ENVIRONMENTAL EFFECTS ON GENE EXPRESSION WHICH START AT CONCEPTION. WE CONCLUDE THAT ONE OF THE MOST EFFECTIVE STRATEGIES TO BREAK THE INTERGENERATIONAL TRANSMISSION OF CPA INVOLVES GIVING LONG-TERM SUPPORT TO PREGNANT WOMEN WITH A HISTORY OF BEHAVIOR PROBLEMS, THEIR SPOUSE, AND THEIR OFFSPRING. 2019 14 4342 28 MINIREVIEW: EPIGENETICS OF OBESITY AND DIABETES IN HUMANS. UNDERSTANDING THE DETERMINANTS OF HUMAN HEALTH AND DISEASE IS OVERWHELMINGLY COMPLEX, PARTICULARLY FOR COMMON, LATE-ONSET, CHRONIC DISORDERS, SUCH AS OBESITY AND DIABETES. ELUCIDATING THE GENETIC AND ENVIRONMENTAL FACTORS THAT INFLUENCE SUSCEPTIBILITY TO DISRUPTIONS IN ENERGY HOMEOSTASIS AND METABOLIC REGULATION REMAIN A CHALLENGE, AND PROGRESS WILL ENTAIL THE INTEGRATION OF MULTIPLE ASSESSMENTS OF TEMPORALLY DYNAMIC ENVIRONMENTAL EXPOSURES IN THE CONTEXT OF EACH INDIVIDUAL'S GENOTYPE. TO MEET THIS CHALLENGE, RESEARCHERS ARE INCREASINGLY EXPLORING THE EPIGENOME, WHICH IS THE MALLEABLE INTERFACE OF GENE-ENVIRONMENT INTERACTIONS. EPIGENETIC VARIATION, WHETHER INNATE OR INDUCED, CONTRIBUTES TO VARIATION IN GENE EXPRESSION, THE RANGE OF POTENTIAL INDIVIDUAL RESPONSES TO INTERNAL AND EXTERNAL CUES, AND RISK FOR METABOLIC DISEASE. ULTIMATELY, ADVANCEMENT IN OUR UNDERSTANDING OF CHRONIC DISEASE SUSCEPTIBILITY IN HUMANS WILL DEPEND ON REFINEMENT OF EXPOSURE ASSESSMENT TOOLS AND SYSTEMS BIOLOGY APPROACHES TO INTERPRETATION. IN THIS REVIEW, WE PRESENT RECENT PROGRESS IN EPIGENETICS OF HUMAN OBESITY AND DIABETES, EXISTING CHALLENGES, AND THE POTENTIAL FOR NEW APPROACHES TO UNRAVEL THE COMPLEX BIOLOGY OF METABOLIC DYSREGULATION. 2012 15 6034 31 THE CHALLENGE BY MULTIPLE ENVIRONMENTAL AND BIOLOGICAL FACTORS INDUCE INFLAMMATION IN AGING: THEIR ROLE IN THE PROMOTION OF CHRONIC DISEASE. THE AGING PROCESS IS DRIVEN BY MULTIPLE MECHANISMS THAT LEAD TO CHANGES IN ENERGY PRODUCTION, OXIDATIVE STRESS, HOMEOSTATIC DYSREGULATION AND EVENTUALLY TO LOSS OF FUNCTIONALITY AND INCREASED DISEASE SUSCEPTIBILITY. MOST AGED INDIVIDUALS DEVELOP CHRONIC LOW-GRADE INFLAMMATION, WHICH IS AN IMPORTANT RISK FACTOR FOR MORBIDITY, PHYSICAL AND COGNITIVE IMPAIRMENT, FRAILTY, AND DEATH. AT ANY AGE, CHRONIC INFLAMMATORY DISEASES ARE MAJOR CAUSES OF MORBIMORTALITY, AFFECTING UP TO 5-8% OF THE POPULATION OF INDUSTRIALIZED COUNTRIES. SEVERAL ENVIRONMENTAL FACTORS CAN PLAY AN IMPORTANT ROLE FOR MODIFYING THE INFLAMMATORY STATE. GENETICS ACCOUNTS FOR ONLY A SMALL FRACTION OF CHRONIC-INFLAMMATORY DISEASES, WHEREAS ENVIRONMENTAL FACTORS APPEAR TO PARTICIPATE, EITHER WITH A CAUSATIVE OR A PROMOTIONAL ROLE IN 50% TO 75% OF PATIENTS. SEVERAL OF THOSE CHANGES DEPEND ON EPIGENETIC CHANGES THAT WILL FURTHER MODIFY THE INDIVIDUAL RESPONSE TO ADDITIONAL STIMULI. THE INTERACTION BETWEEN INFLAMMATION AND THE ENVIRONMENT OFFERS IMPORTANT INSIGHTS ON AGING AND HEALTH. THESE CONDITIONS, OFTEN DEPENDING ON THE INDIVIDUAL'S SEX, APPEAR TO LEAD TO DECREASED LONGEVITY AND PHYSICAL AND COGNITIVE DECLINE. IN ADDITION TO BIOLOGICAL FACTORS, THE ENVIRONMENT IS ALSO INVOLVED IN THE GENERATION OF PSYCHOLOGICAL AND SOCIAL CONTEXT LEADING TO STRESS. POOR PSYCHOLOGICAL ENVIRONMENTS AND OTHER SOURCES OF STRESS ALSO RESULT IN INCREASED INFLAMMATION. HOWEVER, THE MECHANISMS UNDERLYING THE ROLE OF ENVIRONMENTAL AND PSYCHOSOCIAL FACTORS AND NUTRITION ON THE REGULATION OF INFLAMMATION, AND HOW THE RESPONSE ELICITED FOR THOSE FACTORS INTERACT AMONG THEM, ARE POORLY UNDERSTOOD. WHEREAS CERTAIN DELETERIOUS ENVIRONMENTAL FACTORS RESULT IN THE GENERATION OF OXIDATIVE STRESS DRIVEN BY AN INCREASED PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES, ENDOPLASMIC RETICULUM STRESS, AND INFLAMMATION, OTHER FACTORS, INCLUDING NUTRITION (POLYUNSATURATED FATTY ACIDS) AND BEHAVIORAL FACTORS (EXERCISE) CONFER PROTECTION AGAINST INFLAMMATION, OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS, AND THUS AMELIORATE THEIR DELETERIOUS EFFECT. HERE, WE DISCUSS PROCESSES AND MECHANISMS OF INFLAMMATION ASSOCIATED WITH ENVIRONMENTAL FACTORS AND BEHAVIOR, THEIR LINKS TO SEX AND GENDER, AND THEIR OVERALL IMPACT ON AGING. 2020 16 396 21 AN UPDATE ON EPIGENETICS AND CHILDHOOD RESPIRATORY DISEASES. EPIGENETIC MECHANISMS, DEFINED AS CHANGES IN PHENOTYPE OR GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE, HAVE BEEN PROPOSED TO CONSTITUTE A LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THAT AFFECT COMPLEX DISEASES. RECENT STUDIES SHOW THAT DNA METHYLATION, ONE OF THE KEY EPIGENETIC MECHANISMS, IS ALTERED IN CHILDREN EXPOSED TO AIR POLLUTANTS AND ENVIRONMENTAL TOBACCO SMOKE EARLY IN LIFE. SEVERAL CANDIDATE GENE STUDIES ON EPIGENETICS HAVE BEEN PUBLISHED TO DATE, BUT IT IS ONLY RECENTLY THAT GLOBAL METHYLATION ANALYSES HAVE BEEN PERFORMED FOR RESPIRATORY DISORDERS SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, LARGE-SCALE STUDIES WITH ADEQUATE POWER ARE YET TO BE PRESENTED IN CHILDREN, AND IMPLICATIONS FOR CLINICAL USE REMAIN TO BE EVALUATED. IN THIS REVIEW, WE SUMMARIZE THE RECENT ADVANCES IN EPIGENETICS AND RESPIRATORY DISORDERS IN CHILDREN, WITH A MAIN FOCUS ON METHODOLOGICAL CHALLENGES AND ANALYSES RELATED TO PHENOTYPE AND EXPOSURE USING GLOBAL METHYLATION APPROACHES. 2014 17 4996 21 PERINATAL EPIGENETIC DETERMINANTS OF COGNITIVE AND METABOLIC DISORDERS. MULTIPLE CUES FROM THE ENVIRONMENT OF OUR INDIRECT AND IMMEDIATE ANCESTORS, WHICH OFTEN PERSIST THROUGHOUT THE PRENATAL PERIOD AND ADULTHOOD, ARE SHAPING OUR PHENOTYPES THROUGH EITHER DIRECT, PARENT-TO-CHILD INFLUENCES, OR TRANSGENERATIONAL INHERITANCE. THESE EFFECTS ARE DUE TO GENE-ENVIRONMENT INTERACTIONS, WHICH ARE INTENDED TO BE A PREDICTIVE TOOL AND A MECHANISM OF QUICK ADAPTATION TO THE ENVIRONMENT, AS COMPARED WITH GENETIC VARIATIONS THAT ARE INHERITED OVER MANY GENERATIONS. IN CERTAIN CIRCUMSTANCES THE INFLUENCES INDUCED BY THE GENE-ENVIRONMENT INTERACTIONS CAN HAVE DELETERIOUS EFFECTS UPON THE HEALTH STATUS, IN THE CONTEXT OF A RADICAL CHANGE IN THE ENVIRONMENT THAT DOES NOT FIT WITH THE PREDICTED CONDITIONS, VIA EPIGENETIC ALTERATIONS. CONVERSELY THE BEST FIT TO THE EXPECTED ENVIRONMENT MIGHT HAVE A DELAYED AGING PROCESS AND A LONGER LIFE SPAN. THIS REVIEW WILL TOUCH UPON THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) CONCEPT, WHILE DISCUSSING RECENT ADVANCES IN THE UNDERSTANDING OF METABOLIC AND COGNITIVE DISRUPTIONS, WITH A FOCUS ON EPIGENETIC FACTORS, THEIR TRANSGENERATIONAL EFFECTS, AND THE CONSEQUENCES THEY MIGHT HAVE UPON THE ONSET OF CHRONIC DISEASE AND PREMATURE EXITUS. 2012 18 4460 28 MOLECULAR MECHANISMS OF ENVIRONMENTAL EXPOSURES AND HUMAN DISEASE. A SUBSTANTIAL PROPORTION OF DISEASE RISK FOR COMMON COMPLEX DISORDERS IS ATTRIBUTABLE TO ENVIRONMENTAL EXPOSURES AND POLLUTANTS. AN APPRECIATION OF HOW ENVIRONMENTAL POLLUTANTS ACT ON OUR CELLS TO PRODUCE DELETERIOUS HEALTH EFFECTS HAS LED TO ADVANCES IN OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THE PATHOGENESIS OF CHRONIC DISEASES, INCLUDING CANCER AND CARDIOVASCULAR, NEURODEGENERATIVE AND RESPIRATORY DISEASES. HERE, WE DISCUSS EMERGING RESEARCH ON THE INTERPLAY OF ENVIRONMENTAL POLLUTANTS WITH THE HUMAN GENOME AND EPIGENOME. WE REVIEW EVIDENCE SHOWING THE ENVIRONMENTAL IMPACT ON GENE EXPRESSION THROUGH EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNAS. WE ALSO HIGHLIGHT RECENT STUDIES THAT EVALUATE RECENTLY DISCOVERED MOLECULAR PROCESSES THROUGH WHICH THE ENVIRONMENT CAN EXERT ITS EFFECTS, INCLUDING EXTRACELLULAR VESICLES, THE EPITRANSCRIPTOME AND THE MITOCHONDRIAL GENOME. FINALLY, WE DISCUSS CURRENT CHALLENGES WHEN STUDYING THE EXPOSOME - THE CUMULATIVE MEASURE OF ENVIRONMENTAL INFLUENCES OVER THE LIFESPAN - AND ITS INTEGRATION INTO FUTURE ENVIRONMENTAL HEALTH RESEARCH. 2023 19 6251 31 THE MICROBIOLOGICAL MEMORY, AN EPIGENETIC REGULATOR GOVERNING THE BALANCE BETWEEN GOOD HEALTH AND METABOLIC DISORDERS. IF THE TRANSMISSION OF BIOLOGICAL INFORMATION FROM ONE GENERATION TO THE NEXT IS BASED ON DNA, MOST HERITABLE PHENOTYPIC TRAITS SUCH AS CHRONIC METABOLIC DISEASES, ARE NOT LINKED TO GENETIC VARIATION IN DNA SEQUENCES. NON-GENETIC HERITABILITY MIGHT HAVE SEVERAL CAUSES INCLUDING EPIGENETIC, PARENTAL EFFECT, ADAPTIVE SOCIAL LEARNING, AND INFLUENCE OF THE ECOLOGICAL ENVIRONMENT. DISTINGUISHING AMONG THESE CAUSES IS CRUCIAL TO RESOLVE MAJOR PHENOTYPIC ENIGMAS. STRONG EVIDENCE INDICATES THAT CHANGES IN DNA EXPRESSION THROUGH VARIOUS EPIGENETIC MECHANISMS CAN BE LINKED TO PARENT-OFFSPRING RESEMBLANCE IN TERMS OF SENSITIVITY TO METABOLIC DISEASES. AMONG NON-GENETIC HERITABLE TRAITS, EARLY NUTRITION COULD ACCOUNT FOR A LONG TERM DEVIANT PROGRAMMING OF GENES EXPRESSION RESPONSIBLE FOR METABOLIC DISEASES IN ADULTHOOD. NUTRITION COULD SHAPE AN INADEQUATE GUT MICROBIOTA (DYSBIOSIS), TRIGGERING EPIGENETIC DEREGULATION OF TRANSCRIPTION WHICH CAN BE OBSERVED IN CHRONIC METABOLIC DISEASES. WE REVIEW HEREIN THE EVIDENCE THAT DYSBIOSIS MIGHT BE A MAJOR CAUSE OF HERITABLE EPIGENETIC PATTERNS FOUND TO BE ASSOCIATED WITH METABOLIC DISEASES. BY TAKING INTO ACCOUNT THE RECENT ADVANCES ON THE GUT MICROBIOME, WE HAVE AGGREGATED TOGETHER DIFFERENT OBSERVATIONS SUPPORTING THE HYPOTHESIS THAT THE GUT MICROBIOTA COULD PROMOTE THE MOLECULAR CROSSTALK BETWEEN BACTERIA AND SURROUNDING HOST CELLS WHICH CONTROLS THE PATHOLOGICAL EPIGENETIC SIGNATURE. WE INTRODUCE FOR THE FIRST TIME THE CONCEPT OF "MICROBIOLOGICAL MEMORY" AS THE MAIN REGULATOR OF THE EPIGENETIC SIGNATURES, THEREBY INDICATING THAT DIFFERENT CAUSES OF NON-GENETIC HERITABILITY CAN INTERACT IN COMPLEX PATHWAYS TO PRODUCE INHERITANCE. 2018 20 2724 28 EXPERIENCE-SENSITIVE EPIGENETIC MECHANISMS, DEVELOPMENTAL PLASTICITY, AND THE BIOLOGICAL EMBEDDING OF CHRONIC DISEASE RISK. A WIDE RANGE OF DEVELOPMENTAL, NUTRITIONAL, ENVIRONMENTAL, AND SOCIAL FACTORS AFFECT THE BIOLOGICAL ACTIVITIES OF EPIGENETIC MECHANISMS. THESE FACTORS CHANGE SPATIOTEMPORAL PATTERNS OF GENE EXPRESSION IN A VARIETY OF DIFFERENT WAYS AND BRING SIGNIFICANT IMPACTS TO BEAR ON DEVELOPMENT, PHYSIOLOGY, AND DISEASE RISK THROUGHOUT THE LIFE COURSE. ABUNDANT EVIDENCE DEMONSTRATES THAT BEHAVIORAL STRESSORS AND ADVERSE NUTRITIONAL CONDITIONS ARE PARTICULARLY POTENT INDUCERS OF EPIGENETIC CHANGES AND ENHANCERS OF CHRONIC DISEASE RISKS. RECENT INSIGHTS FROM BOTH HUMAN CLINICAL STUDIES AND RESEARCH WITH MODEL ORGANISMS FURTHER INDICATE THAT SUCH EXPERIENCE-DEPENDENT CHANGES TO THE EPIGENOME CAN BE TRANSMITTED THROUGH THE GERMLINE ACROSS MULTIPLE GENERATIONS, WITH IMPORTANT CONSEQUENCES FOR THE HERITABILITY OF BOTH ADAPTIVE AND MALADAPTIVE PHENOTYPES. EPIGENETICS RESEARCH THUS OFFERS MANY POSSIBILITIES FOR DEVELOPING INFORMATIVE BIOMARKERS OF ACQUIRED CHRONIC DISEASE RISK AND DETERMINING THE EFFECTIVENESS OF PREVENTIVE AND THERAPEUTIC INTERVENTIONS. MOREOVER, THE EXPERIENCE-SENSITIVE NATURE OF THESE DISEASE RISKS RAISES IMPORTANT QUESTIONS ABOUT SOCIETAL AND INDIVIDUAL RESPONSIBILITIES FOR THE PREVENTION OF ILL-HEALTH AND THE PROMOTION OF WELL-BEING DURING DEVELOPMENT, ACROSS THE LIFE COURSE AND BETWEEN GENERATIONS. BETTER UNDERSTANDING OF HOW EPIGENETIC MECHANISMS REGULATE DEVELOPMENTAL PLASTICITY AND MEDIATE THE BIOLOGICAL EMBEDDING OF CHRONIC DISEASE RISKS IS THEREFORE LIKELY TO SHED IMPORTANT NEW LIGHT ON THE NATURE OF THE PATHOPHYSIOLOGICAL MECHANISMS LINKING SOCIAL AND HEALTH INEQUALITIES, AND WILL HELP TO INFORM PUBLIC POLICY INITIATIVES IN THIS AREA. CONFLICT OF INTEREST: THE AUTHOR HAS DECLARED NO CONFLICTS OF INTEREST FOR THIS ARTICLE. 2015