1 6823 97 [GENERAL CONCEPTS OF EPIGENETICS: PROJECTIONS IN PAEDIATRICS]. CURRENT EVIDENCE SUPPORTS THE NOTION THAT ALTERATIONS IN INTRAUTERINE GROWTH AND DURING THE FIRST YEARS OF LIFE HAVE A SUBSTANTIAL EFFECT ON THE RISK FOR THE DEVELOPMENT OF CHRONIC DISEASE, WHICH IN SOME CASES IS EVEN HIGHER THAN THOSE DUE TO GENETIC FACTORS. THE PERSISTENCE AND REPRODUCIBILITY OF THE PHENOTYPES ASSOCIATED WITH ALTERED EARLY DEVELOPMENT SUGGEST THE PARTICIPATION OF MECHANISMS THAT WOULD RECORD ENVIRONMENTAL CUES, GENERATING A CELLULAR REPROGRAMMING (I.E., EPIGENETIC MECHANISMS). THIS REVIEW IS AN INTRODUCTION TO A SERIES OF FIVE ARTICLES FOCUSED ON THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF HIGHLY PREVALENT CHRONIC DISEASES (I.E., CARDIOVASCULAR, METABOLIC, ASTHMA/ALLERGIES AND CANCER) AND THEIR ORIGINS IN THE FOETAL AND NEONATAL PERIOD. THIS SERIES OF ARTICLES AIMS TO SHOW THE STATE OF THE ART IN THIS RESEARCH AREA AND PRESENT THE UPCOMING CLUES AND CHALLENGES, IN WHICH PAEDIATRICIANS HAVE A PROMINENT ROLE, DEVELOPING STRATEGIES FOR THE PREVENTION, EARLY DETECTION AND FOLLOW-UP. 2016 2 6905 26 [THE ROLE OF EPIGENETIC REGULATIONS IN EARLY CHILDHOOD DISEASES]. WITH THE ACCEPTANCE OF "THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" CONCEPT IN THE 1990S, IT BECAME CLEAR THAT EPIGENETIC INHERITANCE, WHICH DO NOT INVOLVE CHANGES IN THE DNA SEQUENCE HAS IMPORTANT ROLE IN THE PATHOGENESIS OF DISEASES. EPIGENETIC REGULATION SERVES THE ADAPTATION TO THE CHANGING ENVIRONMENT AND MAINTAINS THE REPRODUCTIVE FITNESS EVEN ON THE DRAWBACK OF INCREASED RISK OF DISEASES IN LATER LIFE. THE ROLE OF EPIGENETIC MECHANISMS IN CHRONIC NON-COMMUNICABLE DISEASES HAS BEEN WELL ESTABLISHED. RECENT STUDIES HAVE REVEALED THAT EPIGENETIC CHANGES HAVE ALSO CAUSAL ROLE IN CERTAIN PEDIATRIC DISEASES. THE REVIEW EVALUATES THE RECENT EPIGENETIC FINDINGS IN THE PATHOMECHANISM OF COMMON PEDIATRIC DISEASES. THE WIDE RANGE AND LONG-LASTING DURATION OF EPIGENETIC REGULATIONS GIVE IMPORTANCE TO THE SUBJECT. METHODS ARE ALREADY AVAILABLE TO EVALUATE A PART OF THE EPIGENETIC CHANGES IN THE CLINICAL PRACTICE, PRESENTLY AIMING PRIMARILY THE ESTIMATION OF THE DISEASE RISK OR DEFINITION OF DIAGNOSIS. FURTHERMORE, THERE ARE ALREADY AVAILABLE LIMITED MEANS TO INFLUENCE THE EPIGENETIC REGULATION. 2019 3 6844 25 [METABOLIC PROGRAMMING: THEORETICAL CONCEPTS AND EXPERIMENTAL EVIDENCE]. IT IS KNOWN THAT THE POOR NUTRITION DURING A FETAL DEVELOPMENT MAY CONTRIBUTE TO AN INCREASED RISK OF CHRONIC DISEASES IN ADULTHOOD. IN A MODERN LITERATURE, THIS PHENOMENON IS CALLED <>. IT IS ASSUMED THAT THE QUALITATIVE OR QUANTITATIVE DEFICIENCY OF CERTAIN NUTRITIONAL COMPONENTS DURING AN EARLY DEVELOPMENT MAY LEAD TO THE ADAPTATIONS THAT CONTRIBUTE TO IMPROVED SURVIVAL DURING THE PRENATAL AND EARLY POSTNATAL PERIODS OF AN ONTOGENESIS. HOWEVER, THE CONSEQUENCE OF SUCH ADAPTIVE CHANGES MAY ALSO BE THE DEVELOPMENT OF VARIOUS PATHOLOGICAL PROCESSES AT THE LATER STAGES OF LIFE. RECENT STUDIES HAVE SHOWN THAT ONE OF THE MAJOR MECHANISMS INVOLVED IN THESE ADAPTATIONS IS THE EPIGENETIC REGULATION OF A GENE ACTIVITY. IN THIS REVIEW, THE EXPERIMENTAL EVIDENCE IS PROVIDED THAT PROCESSES ARISING FROM A QUANTITATIVELY OR QUALITATIVELY RESTRICTED DIET DURING THE EARLY STAGES OF DEVELOPMENT PLAY AN IMPORTANT ROLE IN THE FURTHER LIFE AND CAN GREATLY INFLUENCE RISK OF VARIOUS AGE-RELATED DISEASES AND LIFE SPAN. 2013 4 4125 29 MECHANISMS OF DISEASE: IN UTERO PROGRAMMING IN THE PATHOGENESIS OF HYPERTENSION. NUTRITIONAL AND OTHER ENVIRONMENTAL CUES DURING DEVELOPMENT CAN PERMANENTLY ALTER THE STRUCTURE, HOMEOSTATIC SYSTEMS, AND FUNCTIONS OF THE BODY. THIS PHENOMENON HAS BEEN REFERRED TO AS 'PROGRAMMING'. EPIDEMIOLOGICAL AND ANIMAL STUDIES SHOW THAT PROGRAMMED EFFECTS OPERATE WITHIN THE NORMAL RANGE OF GROWTH AND DEVELOPMENT, AND INFLUENCE THE RISK OF CHRONIC DISEASE IN ADULT LIFE. WE REVIEW THE EVIDENCE THAT THESE EFFECTS INCLUDE REDUCED NEPHRON NUMBER AND COMPENSATORY ADAPTATIONS, WHICH MIGHT LEAD TO HYPERTENSION, AND PERHAPS ACCELERATE THE DECLINE IN RENAL FUNCTION THAT ACCOMPANIES AGING. THESE PROCESSES MIGHT BE EXACERBATED BY PROGRAMMED CHANGES IN VASCULAR STRUCTURE AND FUNCTION, AND ALTERATIONS IN ENDOCRINE AND METABOLIC HOMEOSTASIS. PROGRAMMED EFFECTS MIGHT BE INITIATED AS EARLY AS THE PERICONCEPTUAL PHASE OF DEVELOPMENT, AND COULD INVOLVE EPIGENETIC CHANGES IN GENE EXPRESSION OR ALTERED STEM CELL ALLOCATION. BETTER UNDERSTANDING OF THESE PROCESSES COULD LEAD TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND PREVENTIVE MEASURES, AND TO EARLY DETECTION OF AT-RISK INDIVIDUALS. BY MONITORING BLOOD PRESSURE, WEIGHT, AND RENAL FUNCTION IN CHILDREN, IT MIGHT BE POSSIBLE TO REDUCE THE RISK OF CARDIOVASCULAR AND RENAL DISEASE IN LATER LIFE. 2006 5 2007 32 EPIGENETIC BASIS FOR FETAL ORIGINS OF AGE-RELATED DISEASE. THE CURRENT CONCEPT OF FETAL ORIGINS OF ADULT DISEASES DESCRIBES IN UTERO PROGRAMMING, OR ADAPTATION TO A SPECTRUM OF ADVERSE ENVIRONMENTAL CONDITIONS THAT ULTIMATELY LEADS TO INCREASED SUSCEPTIBILITY TO AGE-RELATED DISEASES (E.G., TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE) LATER IN LIFE. ALTHOUGH THE PRECISE MECHANISM OF THIS BIOLOGICAL MEMORY REMAINS UNCLEAR, MOUNTING EVIDENCE SUGGESTS AN EPIGENETIC BASIS. THE INCREASED SUSCEPTIBILITY TO CHRONIC DISEASE AND INVOLVEMENT OF MULTIPLE ORGAN SYSTEMS THAT IS OBSERVED IS ANALOGOUS TO THE DECLINE IN RESISTANCE TO DISEASE THAT IS TYPICAL OF NORMAL AGING. ALTHOUGH THE CUMULATIVE ENVIRONMENT OVER THE COURSE OF A LIFETIME CAN INDUCE INCREASING EPIGENETIC DYSREGULATION, WE PROPOSE THAT ADVERSE EVENTS THAT OCCUR DURING EARLY DEVELOPMENT CAN INDUCE SIGNIFICANT ADDITIONAL DYSREGULATION OF THE EPIGENOME. HERE, WE DESCRIBE THE CURRENT EVIDENCE FOR FETAL ORIGINS OF ADULT DISEASE AND THE ASSOCIATED ROLE OF EPIGENETIC DYSREGULATION. IN ADDITION, WE PRESENT A NEW PERSPECTIVE ON THE INDUCTION OF EPIGENETIC ALTERATIONS IN UTERO, WHICH SUBSEQUENTLY LEAD TO AN AGING PHENOTYPE MARKED BY INCREASED SUSCEPTIBILITY TO AGE-RELATED DISEASES. 2010 6 1938 33 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 7 3582 23 IMPACT OF PRENATAL AND EARLY LIFE ENVIRONMENTAL EXPOSURES ON NORMAL HUMAN DEVELOPMENT. THE GLOBAL BURDEN AND PATTERN OF DISEASE HAS CHANGED IN RECENT DECADES, WITH FEWER EARLY CHILDHOOD DEATHS AND LONGER LIVES COMPLICATED BY CHRONIC DISEASE. DISRUPTION OF NORMAL HUMAN GROWTH AND DEVELOPMENT BY ADVERSE ENVIRONMENTAL EXPOSURES, ESPECIALLY DURING FOETAL DEVELOPMENT AND EARLY POSTNATAL LIFE INCREASE LIFE-LONG RISK OF CHRONIC DISEASE. THE DEVELOPMENTAL TIMING AND METHOD OF ADVERSE EXPOSURE DETERMINES THE LIKELY IMPACT ON HEALTH AND DEVELOPMENT. WHILE MANY ORGAN SYSTEMS ARE STRUCTURALLY AND FUNCTIONALLY MATURE AT BIRTH, THE CNS, RESPIRATORY AND IMMUNE SYSTEMS ARE NOT AND UNDERGO PROLONGED PERIODS OF POSTNATAL GROWTH AND DEVELOPMENT. AS SUCH, THESE ORGAN SYSTEMS ARE VULNERABLE TO ADVERSE EFFECTS OF BOTH PRENATAL AND POSTNATAL ENVIRONMENTAL EXPOSURES. WHILE THE PRECISE MECHANISMS UNDERLYING CHRONIC DISEASE ARE UNKNOWN, EPIGENETIC MECHANISMS AND THE INDUCTION OF OXIDATIVE STRESS ARE LIKELY TO BE INVOLVED. AN UNDERSTANDING OF THESE PROCESSES IS NECESSARY TO DEVELOP MITIGATION STRATEGIES AIMED AT REDUCING CHRONIC DISEASE PREVALENCE. 2021 8 3771 32 INTER- AND TRANSGENERATIONAL EPIGENETIC INHERITANCE: EVIDENCE IN ASTHMA AND COPD? EVIDENCE IS NOW EMERGING THAT EARLY LIFE ENVIRONMENT CAN HAVE LIFELONG EFFECTS ON METABOLIC, CARDIOVASCULAR, AND PULMONARY FUNCTION IN OFFSPRING, A CONCEPT ALSO KNOWN AS FETAL OR DEVELOPMENTAL PROGRAMMING. IN MAMMALS, DEVELOPMENTAL PROGRAMMING IS THOUGHT TO OCCUR MAINLY VIA EPIGENETIC MECHANISMS, WHICH INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND EXPRESSION OF NON-CODING RNAS. THE EFFECTS OF DEVELOPMENTAL PROGRAMMING CAN BE INDUCED BY THE INTRAUTERINE ENVIRONMENT, LEADING TO INTERGENERATIONAL EPIGENETIC EFFECTS FROM ONE GENERATION TO THE NEXT. TRANSGENERATIONAL EPIGENETIC INHERITANCE MAY BE CONSIDERED WHEN DEVELOPMENTAL PROGRAMMING IS TRANSMITTED ACROSS GENERATIONS THAT WERE NOT EXPOSED TO THE INITIAL ENVIRONMENT WHICH TRIGGERED THE CHANGE. SO FAR, INTER- AND TRANSGENERATIONAL PROGRAMMING HAS BEEN MAINLY DESCRIBED FOR CARDIOVASCULAR AND METABOLIC DISEASE RISK. IN THIS REVIEW, WE DISCUSS AVAILABLE EVIDENCE THAT EPIGENETIC INHERITANCE ALSO OCCURS IN RESPIRATORY DISEASES, USING ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AS EXAMPLES. WHILE MULTIPLE EPIDEMIOLOGICAL AS WELL AS ANIMAL STUDIES DEMONSTRATE EFFECTS OF 'TOXIC' INTRAUTERINE EXPOSURE ON VARIOUS ASTHMA-RELATED PHENOTYPES IN THE OFFSPRING, ONLY FEW STUDIES LINK EPIGENETIC MARKS TO THE OBSERVED PHENOTYPES. AS EPIGENETIC MARKS MAY DISTINGUISH INDIVIDUALS MOST AT RISK OF LATER DISEASE AT EARLY AGE, IT WILL ENABLE EARLY INTERVENTION STRATEGIES TO REDUCE SUCH RISKS. TO ACHIEVE THIS GOAL FURTHER, WELL DESIGNED EXPERIMENTAL AND HUMAN STUDIES ARE NEEDED. 2015 9 2495 34 EPIGENETICS AND DOHAD: FROM BASICS TO BIRTH AND BEYOND. DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) IS THE STUDY OF HOW THE EARLY LIFE ENVIRONMENT CAN IMPACT THE RISK OF CHRONIC DISEASES FROM CHILDHOOD TO ADULTHOOD AND THE MECHANISMS INVOLVED. EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS ARE INVOLVED IN MEDIATING HOW EARLY LIFE ENVIRONMENT IMPACTS LATER HEALTH. THIS REVIEW IS A SUMMARY OF THE EPIGENETICS AND DOHAD WORKSHOP HELD AT THE 2016 DOHAD SOCIETY OF AUSTRALIA AND NEW ZEALAND CONFERENCE. OUR EXTENSIVE KNOWLEDGE OF HOW THE EARLY LIFE ENVIRONMENT IMPACTS LATER RISK FOR CHRONIC DISEASE WOULD NOT HAVE BEEN POSSIBLE WITHOUT ANIMAL MODELS. IN THIS REVIEW WE HIGHLIGHT SOME ANIMAL MODEL EXAMPLES THAT DEMONSTRATE HOW AN ADVERSE EARLY LIFE EXPOSURE RESULTS IN EPIGENETIC AND GENE EXPRESSION CHANGES THAT MAY CONTRIBUTE TO INCREASED RISK OF CHRONIC DISEASE LATER IN LIFE. TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE ARE CHRONIC DISEASES WITH AN INCREASING INCIDENCE DUE TO THE INCREASED NUMBER OF CHILDREN AND ADULTS THAT ARE OBESE. EPIGENETIC CHANGES SUCH AS DNA METHYLATION HAVE BEEN SHOWN TO BE ASSOCIATED WITH METABOLIC HEALTH MEASURES AND POTENTIALLY PREDICT FUTURE METABOLIC HEALTH STATUS. ALTHOUGH MORE DIFFICULT TO ELUCIDATE IN HUMANS, RECENT STUDIES SUGGEST THAT DNA METHYLATION MAY BE ONE OF THE EPIGENETIC MECHANISMS THAT MEDIATES THE EFFECTS OF EARLY LIFE EXPOSURES ON LATER LIFE RISK OF OBESITY AND OBESITY RELATED DISEASES. FINALLY, WE DISCUSS THE ROLE OF THE MICROBIOME AND HOW IT IS A NEW PLAYER IN DEVELOPMENTAL PROGRAMMING AND MEDIATING EARLY LIFE EXPOSURES ON LATER RISK OF CHRONIC DISEASE. 2017 10 3848 25 IS EPIGENETICS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE? BACKGROUND: EPIGENETIC MECHANISMS PROVIDE ONE POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL INFLUENCES IN EARLY LIFE CAUSE LONG-TERM CHANGES IN CHRONIC DISEASE SUSCEPTIBILITY. WHEREAS EPIGENETIC DYSREGULATION IS INCREASINGLY IMPLICATED IN VARIOUS RARE DEVELOPMENTAL SYNDROMES AND CANCER, THE ROLE OF EPIGENETICS IN COMPLEX CHRONIC DISEASES, SUCH AS CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND OBESITY, REMAINS LARGELY UNCHARACTERIZED. EXTENSIVE WORK IN ANIMAL MODELS IS REQUIRED TO DEVELOP SPECIFIC HYPOTHESES THAT CAN BE PRACTICABLY TESTED IN HUMANS. ANIMAL MODELS: WE HAVE DEVELOPED A MOUSE MODEL SHOWING THAT METHYL DONOR SUPPLEMENTATION PREVENTS TRANSGENERATIONAL AMPLIFICATION OF OBESITY, SUGGESTING A ROLE FOR DNA METHYLATION IN THE DEVELOPMENTAL ESTABLISHMENT OF BODY WEIGHT REGULATION. CONCLUSIONS: COUPLING SUCH MODELS WITH RECENTLY DEVELOPED EPIGENOMIC TECHNOLOGIES SHOULD ULTIMATELY ENABLE US TO DETERMINE IF EPIGENETICS IS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE. 2009 11 4802 28 OBESITY AND LIFESPAN HEALTH--IMPORTANCE OF THE FETAL ENVIRONMENT. A MARKED INCREASE IN THE FREQUENCY OF OBESITY AT THE POPULATION LEVEL HAS RESULTED IN AN INCREASING NUMBER OF OBESE WOMEN ENTERING PREGNANCY. THE INCREASING REALIZATION OF THE IMPORTANCE OF THE FETAL ENVIRONMENT IN RELATION TO CHRONIC DISEASE ACROSS THE LIFESPAN HAS FOCUSED ATTENTION ON THE ROLE OF MATERNAL OBESITY IN FETAL DEVELOPMENT. PREVIOUS STUDIES HAVE DEMONSTRATED THAT OBESITY DURING ADOLESCENCE AND ADULTHOOD CAN BE TRACED BACK TO FETAL AND EARLY CHILDHOOD EXPOSURES. THIS REVIEW FOCUSES ON FACTORS THAT CONTRIBUTE TO EARLY DEVELOPMENTAL EVENTS, SUCH AS EPIGENETIC MODIFICATIONS, THE POTENTIAL FOR AN INCREASE IN INFLAMMATORY BURDEN, EARLY DEVELOPMENTAL PROGRAMMING CHANGES SUCH AS THE VARIABLE DEVELOPMENT OF WHITE VERSUS BROWN ADIPOSE TISSUE, AND ALTERATIONS IN ORGAN ONTOGENY. WE HYPOTHESIZE THAT THESE MECHANISMS PROMOTE AN UNFAVORABLE FETAL ENVIRONMENT AND CAN HAVE A LONG-STANDING IMPACT, WITH EARLY MANIFESTATIONS OF CHRONIC DISEASE THAT CAN RESULT IN AN INCREASED DEMAND FOR FUTURE HEALTH CARE. IN ORDER TO IDENTIFY APPROPRIATE PREVENTIVE MEASURES, ATTENTION NEEDS TO BE PLACED BOTH ON REDUCING MATERNAL OBESITY AS WELL AS UNDERSTANDING THE MOLECULAR, CELLULAR, AND EPIGENETIC MECHANISMS THAT MAY BE RESPONSIBLE FOR THE PRENATAL ONSET OF CHRONIC DISEASE. 2014 12 1801 34 EFFECT OF MATERNAL DIET ON THE EPIGENOME: IMPLICATIONS FOR HUMAN METABOLIC DISEASE. THE RAPID INCREASE IN THE INCIDENCE OF CHRONIC NON-COMMUNICABLE DISEASES OVER THE PAST TWO DECADES CANNOT BE EXPLAINED SOLELY BY GENETIC AND ADULT LIFESTYLE FACTORS. THERE IS NOW CONSIDERABLE EVIDENCE THAT THE FETAL AND EARLY POSTNATAL ENVIRONMENT ALSO STRONGLY INFLUENCES THE RISK OF DEVELOPING SUCH DISEASES IN LATER LIFE. HUMAN STUDIES HAVE SHOWN THAT LOW BIRTH WEIGHT IS ASSOCIATED WITH AN INCREASED RISK OF CVD, TYPE II DIABETES, OBESITY AND HYPERTENSION, ALTHOUGH RECENT STUDIES HAVE SHOWN THAT OVER-NUTRITION IN EARLY LIFE CAN ALSO INCREASE SUSCEPTIBILITY TO FUTURE METABOLIC DISEASE. THESE FINDINGS HAVE BEEN REPLICATED IN A VARIETY OF ANIMAL MODELS, WHICH HAVE SHOWN THAT BOTH MATERNAL UNDER- AND OVER-NUTRITION CAN INDUCE PERSISTENT CHANGES IN GENE EXPRESSION AND METABOLISM WITHIN THE OFFSPRING. THE MECHANISM BY WHICH THE MATERNAL NUTRITIONAL ENVIRONMENT INDUCES SUCH CHANGES IS BEGINNING TO BE UNDERSTOOD AND INVOLVES THE ALTERED EPIGENETIC REGULATION OF SPECIFIC GENES. THE DEMONSTRATION OF A ROLE FOR ALTERED EPIGENETIC REGULATION OF GENES IN THE DEVELOPMENTAL INDUCTION OF CHRONIC DISEASES RAISES THE POSSIBILITY THAT NUTRITIONAL OR PHARMACEUTICAL INTERVENTIONS MAY BE USED TO MODIFY LONG-TERM CARDIO-METABOLIC DISEASE RISK AND COMBAT THIS RAPID RISE IN CHRONIC NON-COMMUNICABLE DISEASES. 2011 13 1371 27 DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE: NEW INSIGHTS. EPIDEMIOLOGICAL AND ANIMAL STUDIES SHOW THAT SMALL CHANGES IN THE DEVELOPMENTAL ENVIRONMENT CAN INDUCE PHENOTYPIC CHANGES AFFECTING AN INDIVIDUAL'S RESPONSES TO THEIR LATER ENVIRONMENT. THESE MAY ALTER THE RISK OF CHRONIC DISEASE SUCH AS METABOLIC SYNDROME OR CARDIOVASCULAR DISEASE. RECENT RESEARCH SHOWS THAT ANIMALS EXPOSED TO SUCH A MISMATCH BETWEEN PRENATAL AND POSTNATAL ENVIRONMENT DEVELOP OBESITY, REDUCED ACTIVITY, LEPTIN AND INSULIN RESISTANCE, ELEVATED BLOOD PRESSURE AND VASCULAR ENDOTHELIAL DYSFUNCTION. EPIGENETIC PROCESSES ARE INVOLVED IN SUCH EFFECTS, TARGETED TO PROMOTER REGIONS OF SPECIFIC GENES IN SPECIFIC TISSUES. SUCH FINE CONTROL OF GENE EXPRESSION SUGGESTS THAT THE MECHANISMS HAVE BEEN RETAINED THROUGH EVOLUTION THROUGH THEIR ADAPTIVE ADVANTAGE, RATHER THAN REPRESENTING EXTREME EFFECTS OF DEVELOPMENTAL DISRUPTION AKIN TO TERATOGENESIS. THERE MAY BE ADAPTIVE ADVANTAGE IN A DEVELOPMENTAL CUE INDUCING A PHENOTYPIC CHANGE IN GENERATIONS BEYOND THE IMMEDIATE PREGNANCY, AND A RANGE OF DATA THAT SUPPORT THIS CONCEPT. IN ANIMALS, EPIGENETIC EFFECTS SUCH AS DNA METHYLATION CAN BE PASSED TO SUCCESSIVE GENERATIONS. ENVIRONMENTAL TOXINS, INCLUDING ENDOCRINE DISRUPTORS, MAY INDUCE GREATER RISK OF CHRONIC DISEASE, EVEN AT LOW EXPOSURE LEVELS, IF THEY AFFECT SUCH NORMAL DEVELOPMENTAL EPIGENETIC PROCESSES. APPROPRIATE INTERVENTIONS MAY HAVE LONG-TERM MULTIGENERATIONAL EFFECTS TO REDUCE THE RISK OF CHRONIC DISEASE. 2008 14 6892 24 [SIGNIFICANCE OF PREVENTING DEVELOPMENTAL ORIGINS OF DISEASES IN IMPROVING POPULATION QUALITY]. MORE STUDIES SHOW THAT VARIOUS DISEASES, ESPECIALLY CHRONIC NON-INFECTIOUS DISEASES, HAVE DEVELOPMENTAL ORIGIN. DEVELOPMENTAL ORIGINS OF DISEASES ARE MAINLY DUE TO GAMETES AND EARLY LIFE DEVELOPMENT STAGE BEING EXPOSED TO ADVERSE ENVIRONMENT, RESULTING IN ABNORMAL MODIFICATION OF EPIGENETIC AND STABLE INHERITANCE TO THE ADULT STAGE, WHICH COULD MAKE THE RISK OF VARIOUS LONG-TERM DISEASES OF INDIVIDUALS HIGH. THE THEORY OF DEVELOPMENTAL ORIGIN PROVIDES A NEW PERSPECTIVE FOR THE OCCURRENCE AND DEVELOPMENT OF DISEASES, AND ALSO PROVIDES A THEORETICAL BASIS FOR DISEASE PREVENTION. ATTACHING IMPORTANCE TO MATERNAL AND CHILD HEALTH CARE AND LIFE-CYCLE MANAGEMENT IS CONDUCIVE TO THE PREVENTION OF DEVELOPMENTAL DISEASES AND IS OF GREAT SIGNIFICANCE TO THE IMPROVEMENT OF POPULATION QUALITY. 2023 15 6812 27 [EPIGENETICS, INTERFACE BETWEEN ENVIRONMENT AND GENES: ROLE IN COMPLEX DISEASES]. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION OR CELLULAR PHENOTYPE CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. EPIGENETICS IS ONE OF THE MAJOR MECHANISMS EXPLAINING THE "DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASES" (DOHAD). BESIDES GENETIC BACKGROUND INHERITED FROM PARENTS, WHICH CONFERS SUSCEPTIBILITY TO CERTAIN PATHOLOGIES, EPIGENETIC CHANGES CONSTITUTE THE MEMORY OF PREVIOUS EVENTS, EITHER POSITIVE OR NEGATIVE, ALONG THE LIFE CYCLE, INCLUDING AT THE IN UTERO STAGE. THE LATER EXPOSITION TO HOSTILE ENVIRONMENT MAY REVEAL SUCH SUSCEPTIBILITY, WITH THE DEVELOPMENT OF VARIOUS PATHOLOGIES, AMONG THEM NUMEROUS CHRONIC COMPLEX DISEASES. THE DEMONSTRATION OF SUCH A SEQUENCE OF EVENTS HAS BEEN SHOWN FOR METABOLIC DISEASES AS OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES, CARDIOVASCULAR DISEASE AND CANCER. IN CONTRAST TO GENETIC PREDISPOSITION, WHICH IS IRREVERSIBLE, EPIGENETIC CHANGES ARE POTENTIALLY REVERSIBLE, THUS GIVING TARGETS NOT ONLY FOR PREVENTION, BUT POSSIBLY ALSO FOR THE TREATMENT OF CERTAIN COMPLEX DISEASES. 2012 16 6191 32 THE IMPACT OF MILK AND ITS COMPONENTS ON EPIGENETIC PROGRAMMING OF IMMUNE FUNCTION IN EARLY LIFE AND BEYOND: IMPLICATIONS FOR ALLERGY AND ASTHMA. SPECIFIC AND ADEQUATE NUTRITION DURING PREGNANCY AND EARLY LIFE IS AN IMPORTANT FACTOR IN AVOIDING NON-COMMUNICABLE DISEASES SUCH AS OBESITY, TYPE 2 DIABETES, CARDIOVASCULAR DISEASE, CANCERS, AND CHRONIC ALLERGIC DISEASES. ALTHOUGH EPIDEMIOLOGIC AND EXPERIMENTAL STUDIES HAVE SHOWN THAT NUTRITION IS IMPORTANT AT ALL STAGES OF LIFE, IT IS ESPECIALLY IMPORTANT IN PRENATAL AND THE FIRST FEW YEARS OF LIFE. DURING THE LAST DECADE, THERE HAS BEEN A GROWING INTEREST IN THE POTENTIAL ROLE OF EPIGENETIC MECHANISMS IN THE INCREASING HEALTH PROBLEMS ASSOCIATED WITH ALLERGIC DISEASE. EPIGENETICS INVOLVES SEVERAL MECHANISMS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS WHICH CAN MODIFY THE EXPRESSION OF GENES. IN THIS STUDY, WE FOCUS ON THE EFFECTS OF MATERNAL NUTRITION DURING PREGNANCY, THE EFFECTS OF THE BIOACTIVE COMPONENTS IN HUMAN AND BOVINE MILK, AND THE ENVIRONMENTAL FACTORS THAT CAN AFFECT EARLY LIFE (I.E., FARMING, MILK PROCESSING, AND BACTERIAL EXPOSURE), AND WHICH CONTRIBUTE TO THE EPIGENETIC MECHANISMS UNDERLYING THE PERSISTENT PROGRAMMING OF IMMUNE FUNCTIONS AND ALLERGIC DISEASES. THIS KNOWLEDGE WILL HELP TO IMPROVE APPROACHES TO NUTRITION IN EARLY LIFE AND HELP PREVENT ALLERGIES IN THE FUTURE. 2020 17 2103 28 EPIGENETIC EPIDEMIOLOGY OF THE DEVELOPMENTAL ORIGINS HYPOTHESIS. EXTENSIVE HUMAN EPIDEMIOLOGIC AND ANIMAL MODEL DATA INDICATE THAT DURING CRITICAL PERIODS OF PRENATAL AND POSTNATAL MAMMALIAN DEVELOPMENT, NUTRITION AND OTHER ENVIRONMENTAL STIMULI INFLUENCE DEVELOPMENTAL PATHWAYS AND THEREBY INDUCE PERMANENT CHANGES IN METABOLISM AND CHRONIC DISEASE SUSCEPTIBILITY. THE BIOLOGIC MECHANISMS UNDERLYING THIS "DEVELOPMENTAL ORIGINS HYPOTHESIS" ARE POORLY UNDERSTOOD. THIS REVIEW FOCUSES ON THE LIKELY INVOLVEMENT OF EPIGENETIC MECHANISMS IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD). WE DESCRIBE PERMANENT EFFECTS OF TRANSIENT ENVIRONMENTAL INFLUENCES ON THE DEVELOPMENTAL ESTABLISHMENT OF EPIGENETIC GENE REGULATION AND EVIDENCE LINKING EPIGENETIC DYSREGULATION WITH HUMAN DISEASE. WE PROPOSE A DEFINITION OF "EPIGENETIC EPIDEMIOLOGY" AND DELINEATE HOW THIS EMERGING FIELD PROVIDES A BASIS FROM WHICH TO EXPLORE THE ROLE OF EPIGENETIC MECHANISMS IN DOHAD. WE SUGGEST STRATEGIES FOR FUTURE HUMAN EPIDEMIOLOGIC STUDIES TO IDENTIFY CAUSAL ASSOCIATIONS BETWEEN EARLY EXPOSURES, LONG-TERM CHANGES IN EPIGENETIC REGULATION, AND DISEASE, WHICH MAY ULTIMATELY ENABLE SPECIFIC EARLY-LIFE INTERVENTIONS TO IMPROVE HUMAN HEALTH. 2007 18 2038 27 EPIGENETIC CHANGES PREDISPOSING TO TYPE 2 DIABETES IN INTRAUTERINE GROWTH RETARDATION. EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED AN ASSOCIATION BETWEEN INTRAUTERINE GROWTH RETARDATION AND A GREATER RISK OF CHRONIC DISEASE, INCLUDING CORONARY HEART DISEASE, HYPERTENSION, STROKE, AND TYPE 2 DIABETES IN ADULTHOOD. AN ADVERSE INTRAUTERINE ENVIRONMENT MAY AFFECT BOTH GROWTH AND DEVELOPMENT OF THE ORGANISM, PERMANENTLY PROGRAMMING ENDOCRINE AND METABOLIC FUNCTIONS. ONE OF THE MECHANISMS OF PROGRAMMING IS THE EPIGENETIC MODIFICATION OF GENE PROMOTERS INVOLVED IN THE CONTROL OF KEY METABOLIC PATHWAYS. THE AIM OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE EXPERIMENTAL EVIDENCE SHOWING THE EFFECTS OF EARLY EXPOSURE TO SUBOPTIMAL ENVIRONMENT ON EPIGENOME. THE KNOWLEDGE OF THE EPIGENETIC MARKERS OF PROGRAMMING MAY ALLOW THE IDENTIFICATION OF SUSCEPTIBLE INDIVIDUALS AND THE DESIGN OF TARGETED PREVENTION STRATEGIES. 2010 19 1360 28 DEVELOPMENTAL ASPECTS OF A LIFE COURSE APPROACH TO HEALTHY AGEING. WE EXAMINE THE MECHANISTIC BASIS AND WIDER IMPLICATIONS OF ADOPTING A DEVELOPMENTAL PERSPECTIVE ON HUMAN AGEING. PREVIOUS MODELS OF AGEING HAVE CONCENTRATED ON ITS GENETIC BASIS, OR THE DETRIMENTAL EFFECTS OF ACCUMULATED DAMAGE, BUT ALSO HAVE RAISED ISSUES ABOUT WHETHER AGEING CAN BE VIEWED AS ADAPTIVE ITSELF, OR IS A CONSEQUENCE OF OTHER ADAPTIVE PROCESSES, FOR EXAMPLE IF MAINTENANCE AND REPAIR PROCESSES IN THE PERIOD UP TO REPRODUCTION ARE TRADED OFF AGAINST LATER DECLINE IN FUNCTION. A LIFE COURSE MODEL PLACES AGEING IN THE CONTEXT OF THE ATTAINMENT OF PEAK CAPACITY FOR A BODY SYSTEM, STARTING IN EARLY DEVELOPMENT WHEN PLASTICITY PERMITS CHANGES IN STRUCTURE AND FUNCTION INDUCED BY A RANGE OF ENVIRONMENTAL STIMULI, FOLLOWED BY A PERIOD OF DECLINE, THE RATE OF WHICH DEPENDS ON THE PEAK ATTAINED AS WELL AS THE LATER LIFE CONDITIONS. SUCH PATH DEPENDENCY IN THE RATE OF AGEING MAY OFFER NEW INSIGHTS INTO ITS MODIFICATION. FOCUSING ON MUSCULOSKELETAL AND CARDIOVASCULAR FUNCTION, WE DISCUSS THIS MODEL AND THE POSSIBLE UNDERLYING MECHANISMS, INCLUDING ENDOTHELIAL FUNCTION, OXIDATIVE STRESS, STEM CELLS AND NUTRITIONAL FACTORS SUCH AS VITAMIN D STATUS. EPIGENETIC CHANGES INDUCED DURING DEVELOPMENTAL PLASTICITY, AND IMMUNE FUNCTION MAY PROVIDE A COMMON MECHANISTIC PROCESS UNDERLYING A LIFE COURSE MODEL OF AGEING. THE LIFE COURSE TRAJECTORY DIFFERS IN HIGH AND LOW RESOURCE SETTINGS. NEW INSIGHTS INTO THE DEVELOPMENTAL COMPONENTS OF THE LIFE COURSE MODEL OF AGEING MAY LEAD TO THE DESIGN OF BIOMARKERS OF LATER CHRONIC DISEASE RISK AND TO NEW INTERVENTIONS TO PROMOTE HEALTHY AGEING, WITH IMPORTANT IMPLICATIONS FOR PUBLIC HEALTH. 2016 20 2274 33 EPIGENETIC REGULATION AND FETAL PROGRAMMING. FETAL PROGRAMMING ENCOMPASSES THE ROLE OF DEVELOPMENTAL PLASTICITY IN RESPONSE TO ENVIRONMENTAL AND NUTRITIONAL SIGNALS DURING EARLY LIFE AND ITS POTENTIAL ADVERSE CONSEQUENCES (RISK OF CARDIOVASCULAR, METABOLIC AND BEHAVIOURAL DISEASES) IN LATER LIFE. THE FIRST STUDIES IN THIS FIELD HIGHLIGHTED AN ASSOCIATION BETWEEN POOR FETAL GROWTH AND CHRONIC ADULT DISEASES. HOWEVER, ENVIRONMENTAL SIGNALS DURING EARLY LIFE MAY LEAD TO ADVERSE LONG-TERM EFFECTS INDEPENDENTLY OF OBVIOUS EFFECTS ON FETAL GROWTH. ADVERSE LONG-TERM EFFECTS REFLECT A MISMATCH BETWEEN EARLY (FETAL AND NEONATAL) ENVIRONMENTAL CONDITIONS AND THE CONDITIONS THAT THE INDIVIDUAL WILL CONFRONT LATER IN LIFE. THE MECHANISMS UNDERLYING THIS RISK REMAIN UNCLEAR. HOWEVER, EXPERIMENTAL DATA IN RODENTS AND RECENT OBSERVATIONS IN HUMANS SUGGEST THAT EPIGENETIC CHANGES IN REGULATORY GENES AND GROWTH-RELATED GENES PLAY A SIGNIFICANT ROLE IN FETAL PROGRAMMING. IMPROVEMENTS IN OUR UNDERSTANDING OF THE BIOCHEMICAL AND MOLECULAR MECHANISMS AT PLAY IN FETAL PROGRAMMING WOULD MAKE IT POSSIBLE TO IDENTIFY BIOMARKERS FOR DETECTING INFANTS AT HIGH RISK OF ADULT-ONSET DISEASES. SUCH IMPROVEMENTS SHOULD ALSO LEAD TO THE DEVELOPMENT OF PREVENTIVE AND THERAPEUTIC STRATEGIES. 2008