1 6063 77 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 2 1938 40 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 3 6378 44 THE ROLE OF NUTRITION ON EPIGENETIC MODIFICATIONS AND THEIR IMPLICATIONS ON HEALTH. NUTRITION PLAYS A KEY ROLE IN MANY ASPECTS OF HEALTH AND DIETARY IMBALANCES ARE MAJOR DETERMINANTS OF CHRONIC DISEASES INCLUDING CARDIOVASCULAR DISEASE, OBESITY, DIABETES AND CANCER. ADEQUATE NUTRITION IS PARTICULARLY ESSENTIAL DURING CRITICAL PERIODS IN EARLY LIFE (BOTH PRE- AND POSTNATAL). IN THIS REGARD, THERE IS EXTENSIVE EPIDEMIOLOGIC AND EXPERIMENTAL DATA SHOWING THAT EARLY SUB-OPTIMAL NUTRITION CAN HAVE HEALTH CONSEQUENCES SEVERAL DECADES LATER. THE HYPOTHESIS THAT EPIGENETIC MECHANISMS MAY LINK SUCH NUTRITIONAL IMBALANCES WITH ALTERED DISEASE RISK HAS BEEN GAINING ACCEPTANCE OVER RECENT YEARS. EPIGENETICS CAN BE DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION THAT DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE. EPIGENETIC MARKS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND A VARIETY OF NON-CODING RNAS. STRIKINGLY, THEY ARE PLASTIC AND RESPOND TO ENVIRONMENTAL SIGNALS, INCLUDING DIET. HERE WE WILL REVIEW HOW DIETARY FACTORS MODULATE THE ESTABLISHMENT AND MAINTENANCE OF EPIGENETIC MARKS, THEREBY INFLUENCING GENE EXPRESSION AND, HENCE, DISEASE RISK AND HEALTH. 2012 4 4126 33 MECHANISMS OF DISEASE: THE DEVELOPMENTAL ORIGINS OF DISEASE AND THE ROLE OF THE EPIGENOTYPE. THERE IS ACCUMULATING EVIDENCE THAT MANY CHRONIC DISEASES SUCH AS TYPE 2 DIABETES AND CORONARY HEART DISEASE MIGHT ORIGINATE DURING EARLY LIFE. THIS EVIDENCE GIVES RISE TO THE DEVELOPMENTAL ORIGINS OF DISEASE HYPOTHESIS, AND IS SUPPORTED BY EPIDEMIOLOGICAL DATA IN HUMANS AND EXPERIMENTAL ANIMAL MODELS. A PERTURBED ENVIRONMENT IN EARLY LIFE IS THOUGHT TO ELICIT A RANGE OF PHYSIOLOGICAL AND CELLULAR ADAPTIVE RESPONSES IN KEY ORGAN SYSTEMS. THESE ADAPTIVE CHANGES RESULT IN PERMANENT ALTERATIONS AND MIGHT LEAD TO PATHOLOGY IN LATER LIFE. AGING ORGANS AND CELLS SEEM THEREFORE TO RETAIN A 'MEMORY' OF THEIR FETAL HISTORY AND ADAPTIVE RESPONSES. THE MECHANISMS UNDERLYING THE DEVELOPMENTAL ORIGINS OF DISEASE REMAIN POORLY DEFINED. EPIGENETIC TAGGING OF GENES, SUCH AS DNA METHYLATION AND HISTONE MODIFICATION, CONTROLS THE FUNCTION OF THE GENOME AT DIFFERENT LEVELS AND MAINTAINS CELLULAR MEMORY AFTER MANY CELLULAR DIVISIONS; IMPORTANTLY, TAGGING CAN BE MODULATED BY THE ENVIRONMENT AND IS INVOLVED IN ONSET OF DISEASES SUCH AS CANCER. HERE WE REVIEW THE EVIDENCE FOR THE DEVELOPMENTAL ORIGINS OF DISEASE AND DISCUSS THE ROLE OF THE EPIGENOTYPE AS A CONTRIBUTING MECHANISM. ENVIRONMENTALLY INDUCED CHANGES IN THE EPIGENOTYPE MIGHT BE KEY PRIMARY EVENTS IN THE DEVELOPMENTAL ORIGINS OF DISEASE, WITH IMPORTANT CLINICAL IMPLICATIONS. 2007 5 2103 37 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 6 3771 42 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 7 6844 35 [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 8 2007 30 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 9 2495 42 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 1155 37 CONSIDERING MATERNAL DIETARY MODULATORS FOR EPIGENETIC REGULATION AND PROGRAMMING OF THE FETAL EPIGENOME. FETAL LIFE IS CHARACTERIZED BY A TREMENDOUS PLASTICITY AND ABILITY TO RESPOND TO VARIOUS ENVIRONMENTAL AND LIFESTYLE FACTORS, INCLUDING MATERNAL NUTRITION. IDENTIFICATION OF THE ROLE OF DIETARY FACTORS THAT CAN MODULATE AND RESHAPE THE CELLULAR EPIGENOME DURING DEVELOPMENT, INCLUDING METHYL GROUP DONORS (E.G., FOLATE, CHOLINE) AND BIOACTIVE COMPOUNDS (E.G., POLYPHENOLS) IS OF GREAT IMPORTANCE; HOWEVER, THERE IS INSUFFICIENT KNOWLEDGE OF A PARTICULAR EFFECT OF EACH TYPE OF MODULATOR AND/OR THEIR COMBINATION ON FETAL LIFE. TO ENHANCE THE QUALITY AND SAFETY OF FOOD PRODUCTS FOR PROPER FETAL HEALTH AND DISEASE PREVENTION IN LATER LIFE, A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS OF DIETARY EPIGENETIC MODULATORS DURING THE CRITICAL PRENATAL PERIOD IS NECESSARY. THIS REVIEW FOCUSES ON THE INFLUENCE OF MATERNAL DIETARY COMPONENTS ON DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS, AND SUMMARIZES CURRENT KNOWLEDGE OF THE EFFECT AND IMPORTANCE OF DIETARY COMPONENTS ON EPIGENETIC MECHANISMS THAT CONTROL THE PROPER EXPRESSION OF GENETIC INFORMATION. EVIDENCE REVEALS THAT SOME COMPONENTS IN THE MATERNAL DIET CAN DIRECTLY OR INDIRECTLY AFFECT EPIGENETIC MECHANISMS. UNDERSTANDING THE UNDERLYING MECHANISMS OF HOW EARLY-LIFE NUTRITIONAL ENVIRONMENT AFFECTS THE EPIGENOME DURING DEVELOPMENT IS OF GREAT IMPORTANCE FOR THE SUCCESSFUL PREVENTION OF ADULT CHRONIC DISEASES THROUGH OPTIMAL MATERNAL NUTRITION. 2015 11 3848 33 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 12 2184 36 EPIGENETIC MECHANISMS THAT UNDERPIN METABOLIC AND CARDIOVASCULAR DISEASES. CELLULAR COMMITMENT TO A SPECIFIC LINEAGE IS CONTROLLED BY DIFFERENTIAL SILENCING OF GENES, WHICH IN TURN DEPENDS ON EPIGENETIC PROCESSES SUCH AS DNA METHYLATION AND HISTONE MODIFICATION. DURING EARLY EMBRYOGENESIS, THE MAMMALIAN GENOME IS 'WIPED CLEAN' OF MOST EPIGENETIC MODIFICATIONS, WHICH ARE PROGRESSIVELY RE-ESTABLISHED DURING EMBRYONIC DEVELOPMENT. THUS, THE EPIGENOME OF EACH MATURE CELLULAR LINEAGE CARRIES THE RECORD OF ITS DEVELOPMENTAL HISTORY. THE SUBSEQUENT TRAJECTORY AND PATTERN OF DEVELOPMENT ARE ALSO RESPONSIVE TO ENVIRONMENTAL INFLUENCES, AND SUCH PLASTICITY IS LIKELY TO HAVE AN EPIGENETIC BASIS. EPIGENETIC MARKS MAY BE TRANSMITTED ACROSS GENERATIONS, EITHER DIRECTLY BY PERSISTING THROUGH MEIOSIS OR INDIRECTLY THROUGH REPLICATION IN THE NEXT GENERATION OF THE CONDITIONS IN WHICH THE EPIGENETIC CHANGE OCCURRED. DEVELOPMENTAL PLASTICITY EVOLVED TO MATCH AN ORGANISM TO ITS ENVIRONMENT, AND A MISMATCH BETWEEN THE PHENOTYPIC OUTCOME OF ADAPTIVE PLASTICITY AND THE CURRENT ENVIRONMENT INCREASES THE RISK OF METABOLIC AND CARDIOVASCULAR DISEASE. THESE CONSIDERATIONS POINT TO EPIGENETIC PROCESSES AS A KEY MECHANISM THAT UNDERPINS THE DEVELOPMENTAL ORIGINS OF CHRONIC NONCOMMUNICABLE DISEASE. HERE, WE REVIEW THE EVIDENCE THAT ENVIRONMENTAL INFLUENCES DURING MAMMALIAN DEVELOPMENT LEAD TO STABLE CHANGES IN THE EPIGENOME THAT ALTER THE INDIVIDUAL'S SUSCEPTIBILITY TO CHRONIC METABOLIC AND CARDIOVASCULAR DISEASE, AND DISCUSS THE CLINICAL IMPLICATIONS. 2009 13 4125 35 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 14 1801 44 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 15 5247 25 PROGRAMMED ADULT KIDNEY DISEASE: IMPORTANCE OF FETAL ENVIRONMENT. THE BARKER HYPOTHESIS STRONGLY SUPPORTED THE INFLUENCE OF FETAL ENVIRONMENT ON THE DEVELOPMENT OF CHRONIC DISEASES IN LATER LIFE. MULTIPLE EXPERIMENTAL AND HUMAN STUDIES HAVE IDENTIFIED THAT THE DELETERIOUS EFFECT OF FETAL PROGRAMMING COMMONLY LEADS TO ALTERATIONS IN RENAL DEVELOPMENT. THE INTERPLAY BETWEEN ENVIRONMENTAL INSULTS AND FETAL GENOME CAN INDUCE EPIGENETIC CHANGES AND LEAD TO ALTERATIONS IN THE EXPRESSION OF RENAL PHENOTYPE. IN THIS REVIEW, WE HAVE EXPLORED THE RENAL DEVELOPMENT AND ITS FUNCTIONS, WHILE FOCUSING ON THE EPIGENETIC FINDINGS AND FUNCTIONAL ASPECTS OF THE RENIN-ANGIOTENSIN SYSTEM AND ITS COMPONENTS. 2020 16 3582 29 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 17 6812 31 [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 18 4460 37 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 34 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 4496 36 MORE THAN GENES: THE ADVANCED FETAL PROGRAMMING HYPOTHESIS. MANY LINES OF DATA, INITIAL EPIDEMIOLOGIC STUDIES AS WELL AS SUBSEQUENT EXTENSIVE EXPERIMENTAL STUDIES, INDICATE THAT EARLY-LIFE EVENTS PLAY A POWERFUL ROLE IN INFLUENCING LATER SUCEPTIBILITY TO CERTAIN CHRONIC DISEASES. SUCH EVENTS MIGHT BE OVER- OR UNDERNUTRITION, EXPOSURE TO ENVIRONMENTAL TOXINS, BUT ALSO CHANGES IN HORMONES, IN PARTICULAR STRESS HORMONES. TYPICALLY, THOSE EVENTS ARE TRIGGERED BY THE ENVIRONMENTAL CHALLENGES OF THE MOTHER. HOWEVER, RECENT STUDIES HAVE SHOWN THAT PATERNAL ENVIRONMENTAL OR NUTRITIONAL FACTORS AFFECT THE PHENOTYPE OF THE OFFSPRING AS WELL. THE MATERNAL AND PATERNAL ENVIRONMENTAL FACTORS ACT ON THE PHENOTYPE OF THE OFFSPRING VIA EPIGENETIC MODIFICATION OF ITS GENOME. THE ADVANCED FETAL PROGRAMMING HYPOTHESIS PROPOSES AN ADDITIONAL NON-ENVIRONMENTALLY DRIVEN MECHANISM: MATERNAL AND ALSO PATERNAL GENES MAY INFLUENCE THE MATURATING SPERM, THE OOCYTE, AND LATER THE EMBRYO/FETUS, LEADING TO THEIR EPIGENETIC ALTERATION. THUS, THE OBSERVED PHENOTYPE OF THE OFFSPRING MAY BE ALTERED BY MATERNAL/PATERNAL GENES INDEPENDENT OF THE FETAL GENOME. MEANWHILE, SEVERAL INDEPENDENT ASSOCIATION STUDIES IN HUMANS DEALING WITH METABOLIC AND NEUROLOGICAL TRAITS ALSO SUGGEST THAT MATERNAL GENES MIGHT AFFECT THE OFFSPRING PHENOTYPE INDEPENDENT OF THE TRANSMISSION OF THAT PARTICULAR GENE TO THE OFFSPRING. CONSIDERING THE IMPLICATIONS OF THIS HYPOTHESIS, SOME CONCLUSIONS DRAWN FROM TRANSGENIC OR KNOCKOUT ANIMAL MODELS AND BASED ON THE CAUSALITY BETWEEN A GENETIC ALTERATION AND A PHENOTYPE, NEED TO BE CHALLENGED. POSSIBLE IMPLICATIONS FOR THE DEVELOPMENT, DIAGNOSTIC AND THERAPY OF HUMAN GENETIC DISEASES HAVE TO BE INVESTIGATED. 2014