1 3572 113 IMPACT OF MATERNAL DIABETES ON EPIGENETIC MODIFICATIONS LEADING TO DISEASES IN THE OFFSPRING. GESTATIONAL DIABETES, OCCURRING DURING THE HYPERGLYCEMIC PERIOD OF PREGNANCY IN MATERNAL LIFE, IS A PATHOLOGIC STATE THAT INCREASES THE INCIDENCE OF COMPLICATIONS IN BOTH MOTHER AND FETUS. OFFSPRING THUS EXPOSED TO AN ADVERSE FETAL AND EARLY POSTNATAL ENVIRONMENT MAY MANIFEST INCREASED SUSCEPTIBILITY TO A NUMBER OF CHRONIC DISEASES LATER IN LIFE. COMPELLING EVIDENCE FOR THE ROLE OF EPIGENETIC TRANSMISSION IN THESE COMPLICATIONS HAS COME FROM COMPARISON OF SIBLINGS BORN BEFORE AND AFTER THE DEVELOPMENT OF MATERNAL DIABETES, EXPOSURE TO THIS INTRAUTERINE DIABETIC ENVIRONMENT BEING SHOWN TO CAUSE ALTERATIONS IN FETAL GROWTH PATTERNS WHICH PREDISPOSE THESE INFANTS TO DEVELOPING OVERWEIGHT AND OBESITY LATER IN LIFE. DIABETES OF THE OFFSPRING IS ALSO MAINLY THE CONSEQUENCE OF EXPOSURE TO THE DIABETIC INTRAUTERINE ENVIRONMENT, IN ADDITION TO GENETIC SUSCEPTIBILITY. SINCE OBESITY AND DIABETES ARE KNOWN TO INCREASE THE RISK OF CARDIOVASCULAR DISEASE, CARDIOVASCULAR SEQUELAE IN THE OFFSPRING OF DIABETIC MOTHERS ARE VIRTUALLY INEVITABLE. RESEARCH DATA ALSO SUGGEST THAT EXPOSURE TO A DIABETIC INTRAUTERINE ENVIRONMENT DURING PREGNANCY IS ASSOCIATED WITH AN INCREASE IN DYSLIPIDEMIA, SUBCLINICAL VASCULAR INFLAMMATION, AND ENDOTHELIAL DYSFUNCTION PROCESSES IN THE OFFSPRING, ALL OF WHICH ARE LINKED WITH DEVELOPMENT OF CARDIOVASCULAR DISEASE LATER IN LIFE. THE MAIN UNDERLYING MECHANISMS INVOLVE PERSISTENT HYPERGLYCEMIA HYPERINSULINEMIA AND LEPTIN RESISTANCE. 2012 2 2267 36 EPIGENETIC PROGRAMMING OF OBESITY AND DIABETES BY IN UTERO EXPOSURE TO GESTATIONAL DIABETES MELLITUS. IT IS NOW WELL ACCEPTED THAT OFFSPRING EXPOSED TO MATERNAL UNDERNUTRITION, OBESITY, OR GESTATIONAL DIABETES MELLITUS HAVE AN INCREASED RISK FOR CHRONIC DISEASES LATER IN LIFE, SUPPORTING THE THEORY OF THE EARLY ORIGINS OF CHRONIC DISEASES. HOWEVER, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXPOSURE TO AN ALTERED IN UTERO ENVIRONMENT TRANSLATES INTO THE DEVELOPMENT OF CHRONIC DISEASES ARE NOT YET WELL UNDERSTOOD. RECENTLY REPORTED PROMISING RESULTS HELP TO RESOLVE THIS ISSUE. THEY SUGGEST THAT EPIGENETIC MODIFICATIONS ARE A POTENTIAL MECHANISM FOR FETAL METABOLIC PROGRAMMING. THIS REVIEW PROVIDES AN OVERVIEW OF THE RELATIONSHIP BETWEEN THE EXPOSURE TO AN ALTERED INTRAUTERINE ENVIRONMENT AND FETAL METABOLIC PROGRAMMING, FOCUSING ON GESTATIONAL DIABETES MELLITUS AND EPIGENETIC VARIATIONS AT ADIPOKINE CANDIDATE GENES. 2013 3 3707 36 INFLUENCE OF MATERNAL OVERNUTRITION AND GESTATIONAL DIABETES ON THE PROGRAMMING OF METABOLIC HEALTH OUTCOMES IN THE OFFSPRING: EXPERIMENTAL EVIDENCE. THE INCIDENCE OF OBESITY AND TYPE 2 DIABETES MELLITUS HAVE RISEN ACROSS THE WORLD DURING THE PAST FEW DECADES AND HAS ALSO REACHED AN ALARMING LEVEL AMONG CHILDREN. IN ADDITION, WOMEN ARE CURRENTLY MORE LIKELY THAN EVER TO ENTER PREGNANCY OBESE. AS A RESULT, THE INCIDENCE OF GESTATIONAL DIABETES MELLITUS IS ALSO ON THE RISE. WHILE DIET AND LIFESTYLE CONTRIBUTE TO THESE TRENDS, POPULATION HEALTH DATA SHOW THAT MATERNAL OBESITY AND DIABETES DURING PREGNANCY DURING CRITICAL STAGES OF DEVELOPMENT ARE MAJOR FACTORS THAT CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC DISEASE IN ADOLESCENT AND ADULT OFFSPRING. FETAL PROGRAMMING OF METABOLIC FUNCTION, THROUGH PHYSIOLOGICAL AND (OR) EPIGENETIC MECHANISMS, MAY ALSO HAVE AN INTERGENERATIONAL EFFECT, AND AS A RESULT MAY PERPETUATE METABOLIC DISORDERS IN THE NEXT GENERATION. IN THIS REVIEW, WE SUMMARIZE THE EXISTING LITERATURE THAT CHARACTERIZES HOW MATERNAL OBESITY AND GESTATIONAL DIABETES MELLITUS CONTRIBUTE TO METABOLIC AND CARDIOVASCULAR DISORDERS IN THE OFFSPRING. IN PARTICULAR, WE FOCUS ON ANIMAL STUDIES THAT INVESTIGATE THE MOLECULAR MECHANISMS THAT ARE PROGRAMMED BY THE GESTATIONAL ENVIRONMENT AND LEAD TO DISEASE PHENOTYPES IN THE OFFSPRING. WE ALSO REVIEW INTERVENTIONAL STUDIES THAT PREVENT DISEASE WITH A DEVELOPMENTAL ORIGIN IN THE OFFSPRING. 2015 4 3573 45 IMPACT OF MATERNAL UNDERNUTRITION ON DIABETES AND CARDIOVASCULAR DISEASE RISK IN ADULT OFFSPRING. EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL OBSERVATIONS HAVE LED TO THE HYPOTHESIS THAT THE RISK OF DEVELOPING CHRONIC DISEASES IN ADULTHOOD IS INFLUENCED NOT ONLY BY GENETIC AND ADULT LIFESTYLE FACTORS, BUT ALSO BY ENVIRONMENTAL FACTORS DURING EARLY LIFE. LOW BIRTH WEIGHT, A MARKER OF INTRAUTERINE STRESS, HAS BEEN LINKED TO PREDISPOSITION TO CARDIOVASCULAR DISEASE (CVD) AND DIABETES. THE COMPELLING ANIMAL EVIDENCE AND SIGNIFICANT HUMAN DATA TO SUPPORT THIS CONCLUSION ARE REVIEWED. SPECIFICALLY, THE REVIEW DISCUSSES THE ROLE OF MATERNAL NUTRITION BEFORE AND DURING PREGNANCY, PLACENTAL INSUFFICIENCIES AND EPIGENETIC CHANGES IN THE INCREASED PREDISPOSITION TO DIABETES AND CVD IN ADULT LIFE. THE IMPACT OF LOW BIRTH WEIGHT AND CATCH-UP GROWTH AS THEY PERTAIN TO RISK OF DISEASE IN ADULT LIFE IS ALSO DISCUSSED. IN ADDITION, ADULT DISEASE RISK IN THE OVERNOURISHED FETUS IS ALSO MENTIONED. REFERENCE IS MADE TO SOME OF THE MECHANISMS OF THE INDUCTION OF DIABETES AND CVD PHENOTYPE. IT IS PROPOSED THAT FETAL NUTRITION, GROWTH AND DEVELOPMENT THROUGH EFFICIENT MATERNAL NUTRITION BEFORE AND DURING PREGNANCY COULD CONSTITUTE THE BASIS FOR NUTRITIONAL STRATEGIES FOR THE PRIMARY PREVENTION OF DIABETES AND CVD. 2009 5 6819 44 [FETAL PROGRAMMING OF METABOLIC DISORDERS]. OUR KNOWLEDGE OF FETAL PROGRAMMING HAS DEVELOPED NOTABLY OVER THE YEARS AND RECENT DATA SUGGEST THAT AN UNBALANCED DIET PRIOR AND DURING PREGNANCY CAN HAVE EARLY-ONSET AND LONG-LASTING CONSEQUENCES ON THE HEALTH OF THE OFFSPRING. SPECIFIC NEGATIVE INFLUENCES OF HIGH DIETARY GLUCOSE AND LIPID CONSUMPTION, AS WELL AS UNDERNUTRITION, ARE ASSOCIATED WITH DEVELOPMENT OF METABOLIC SYNDROME, INSULIN RESISTANCE AND DIABETES IN THE OFFSPRING. THE MECHANISMS UNDERLYING THE EFFECTS OF MATERNAL HYPERGLYCEMIA ON THE FETUS MAY INVOLVE STRUCTURAL, METABOLIC AND EPIGENETIC CHANGES. THE AIM OF THIS REVIEW IS TO ILLUSTRATE HOW ADVERSE INTRAUTERINE ENVIRONMENT MAY INFLUENCE MOLECULAR MODIFICATIONS IN THE FETUS AND CAUSE EPIGENETIC ALTERATIONS IN PARTICULAR. IT HAS BEEN DEMONSTRATED THAT PRENATAL EPIGENETIC MODIFICATIONS MAY BE LINKED TO THE PATHOGENESIS AND PROGRESSION OF THE ADULT CHRONIC DISORDERS. STUDIES ON EPIGENETIC ALTERATIONS WILL CONTRIBUTE TO A BETTER UNDERSTANDING OF THE LONG-TERM EFFECTS OF IN UTERO EXPOSURE AND MAY OPEN NEW PERSPECTIVES FOR DISEASE PREVENTION AND TREATMENT. 2015 6 140 35 ABERRANT DNA METHYLATION MEDIATES THE TRANSGENERATIONAL RISK OF METABOLIC AND CHRONIC DISEASE DUE TO MATERNAL OBESITY AND OVERNUTRITION. MATERNAL OBESITY IS A RAPIDLY EVOLVING UNIVERSAL EPIDEMIC LEADING TO ACUTE AND LONG-TERM MEDICAL AND OBSTETRIC HEALTH ISSUES, INCLUDING INCREASED MATERNAL RISKS OF GESTATIONAL DIABETES, HYPERTENSION AND PRE-ECLAMPSIA, AND THE FUTURE RISKS FOR OFFSPRING'S PREDISPOSITION TO METABOLIC DISEASES. EPIGENETIC MODIFICATION, IN PARTICULAR DNA METHYLATION, REPRESENTS A MECHANISM WHEREBY ENVIRONMENTAL EFFECTS IMPACT ON THE PHENOTYPIC EXPRESSION OF HUMAN DISEASE. MATERNAL OBESITY OR OVERNUTRITION CONTRIBUTES TO THE ALTERATIONS IN DNA METHYLATION DURING EARLY LIFE WHICH, THROUGH FETAL PROGRAMMING, CAN PREDISPOSE THE OFFSPRING TO MANY METABOLIC AND CHRONIC DISEASES, SUCH AS NON-ALCOHOLIC FATTY LIVER DISEASE, OBESITY, DIABETES, AND CHRONIC KIDNEY DISEASE. THIS REVIEW AIMS TO SUMMARIZE FINDINGS FROM HUMAN AND ANIMAL STUDIES, WHICH SUPPORT THE ROLE OF MATERNAL OBESITY IN FETAL PROGRAMING AND THE POTENTIAL BENEFIT OF ALTERING DNA METHYLATION TO LIMIT MATERNAL OBESITY RELATED DISEASE IN THE OFFSPRING. 2021 7 4078 39 MATERNAL INFLAMMATION, GROWTH RETARDATION, AND PRETERM BIRTH: INSIGHTS INTO ADULT CARDIOVASCULAR DISEASE. THE "FETAL ORIGIN OF ADULT DISEASE HYPOTHESIS" ORIGINALLY DESCRIBED BY BARKER ET AL. IDENTIFIED THE RELATIONSHIP BETWEEN IMPAIRED IN UTERO GROWTH AND ADULT CARDIOVASCULAR DISEASE RISK AND DEATH. SINCE THEN, NUMEROUS CLINICAL AND EXPERIMENTAL STUDIES HAVE CONFIRMED THAT EARLY DEVELOPMENTAL INFLUENCES CAN LEAD TO CARDIOVASCULAR, PULMONARY, METABOLIC, AND PSYCHOLOGICAL DISEASES DURING ADULTHOOD WITH AND WITHOUT ALTERATIONS IN BIRTH WEIGHT. THIS SO CALLED "FETAL PROGRAMMING" INCLUDES DEVELOPMENTAL DISRUPTION, IMMEDIATE ADAPTATION, OR PREDICTIVE ADAPTATION AND CAN LEAD TO EPIGENETIC CHANGES AFFECTING A SPECIFIC ORGAN OR OVERALL HEALTH. THE INTRAUTERINE ENVIRONMENT IS DRAMATICALLY IMPACTED BY THE OVERALL MATERNAL HEALTH. BOTH PREMATURE BIRTH OR LOW BIRTH WEIGHT CAN RESULT FROM A VARIETY OF MATERNAL CONDITIONS INCLUDING UNDERNUTRITION OR DYSNUTRITION, METABOLIC DISEASES, CHRONIC MATERNAL STRESSES INDUCED BY INFECTIONS AND INFLAMMATION, AS WELL AS HYPERCHOLESTEROLEMIA AND SMOKING. NUMEROUS ANIMAL STUDIES HAVE SUPPORTED THE IMPORTANCE OF BOTH MATERNAL HEALTH AND MATERNAL ENVIRONMENT ON THE LONG TERM OUTCOMES OF THE OFFSPRING. WITH INCREASING RATES OF OBESITY AND DIABETES AND SURVIVAL OF PRETERM INFANTS BORN AT EARLY GESTATIONAL AGES, THE NEED TO ELUCIDATE MECHANISMS RESPONSIBLE FOR PROGRAMMING OF ADULT CARDIOVASCULAR DISEASE IS ESSENTIAL FOR THE TREATMENT OF UPCOMING GENERATIONS. 2011 8 5203 33 PRENATAL PROGRAMMING AND EPIGENETICS IN THE GENESIS OF THE CARDIORENAL SYNDROME. THE PRESENCE OF A GROUP OF INTERACTING MALADAPTIVE FACTORS, INCLUDING HYPERTENSION, INSULIN RESISTANCE, METABOLIC DYSLIPIDEMIA, OBESITY, AND MICROALBUMINURIA AND/OR REDUCED RENAL FUNCTION, COLLECTIVELY CONSTITUTES THE CARDIORENAL METABOLIC SYNDROME (CRS). NUTRITIONAL AND OTHER ENVIRONMENTAL CUES DURING FETAL DEVELOPMENT CAN PERMANENTLY AFFECT THE COMPOSITION, HOMEOSTATIC SYSTEMS, AND FUNCTIONS OF MULTIPLE ORGANS AND SYSTEMS; THIS PROCESS HAS BEEN REFERRED TO AS 'PROGRAMMING'. SINCE THE ORIGINAL FORMULATION OF THE NOTION THAT LOW BIRTH WEIGHT IS A PROXY FOR 'PRENATAL PROGRAMMING' OF ADULT HYPERTENSION AND CARDIOVASCULAR DISEASE, EVIDENCE HAS ALSO EMERGED FOR PROGRAMMING OF KIDNEY DISEASE, INSULIN RESISTANCE, OBESITY, METABOLIC DYSLIPIDEMIA, AND OTHER CHRONIC DISEASES. THE PROGRAMMING CONCEPT WAS INITIALLY PREDICATED ON THE NOTION THAT IN UTERO GROWTH RESTRICTION DUE TO FAMINE WAS RESPONSIBLE FOR INCREASED HYPERTENSION, AND CARDIOVASCULAR AND RENAL DISEASES. ON THE OTHER HAND, WE ARE NOW MORE COMMONLY EXPOSED TO INCREASING RATES OF MATERNAL OBESITY. THE CURRENT REVIEW WILL DISCUSS THE OVERARCHING ROLE OF MATERNAL OVERNUTRITION, AS WELL AS FETAL UNDERNUTRITION, IN EPIGENETIC PROGRAMMING IN RELATION TO THE PATHOGENESIS OF THE CRS IN CHILDREN AND ADULTS. 2011 9 4782 42 NUTRIGENETICS, EPIGENETICS AND GESTATIONAL DIABETES: CONSEQUENCES IN MOTHER AND CHILD. GESTATIONAL DIABETES MELLITUS (GDM) IS THE MOST COMMON METABOLIC CONDITION DURING PREGNANCY AND MAY RESULT IN SHORT- AND LONG-TERM COMPLICATIONS FOR BOTH MOTHER AND OFFSPRING. THE COMPLEXITY OF PHENOTYPIC OUTCOMES SEEMS INFLUENCED BY GENETIC SUSCEPTIBILITY, NUTRIENT-GENE INTERACTIONS AND LIFESTYLE INTERACTING WITH CLINICAL FACTORS. THERE IS STRONG EVIDENCE THAT NOT ONLY THE ADVERSE GENETIC BACKGROUND BUT ALSO THE EPIGENETIC MODIFICATIONS IN RESPONSE TO NUTRITIONAL AND ENVIRONMENTAL FACTORS COULD INFLUENCE THE MATERNAL HYPERGLYCEMIA IN PREGNANCY AND THE FOETAL METABOLIC PROGRAMMING. IN THIS VIEW, THE CORRELATION BETWEEN EPIGENETIC MODIFICATIONS AND THEIR TRANSGENERATIONAL EFFECTS REPRESENTS A VERY INTERESTING FIELD OF STUDY. THE PRESENT REVIEW GIVES INSIGHT INTO THE ROLE OF GENE VARIANTS AND THEIR INTERACTIONS WITH NUTRIENTS IN GDM. IN ADDITION, WE PROVIDE AN OVERVIEW OF THE EPIGENETIC CHANGES AND THEIR ROLE IN THE MATERNAL-FOETAL TRANSMISSION OF CHRONIC DISEASES. OVERALL, THE KNOWLEDGE OF EPIGENETIC MODIFICATIONS INDUCED BY AN ADVERSE INTRAUTERINE AND PERINATAL ENVIRONMENT COULD SHED LIGHT ON THE POTENTIAL PATHOPHYSIOLOGICAL MECHANISMS OF LONG-TERM DISEASE DEVELOPMENT IN THE OFFSPRING AND PROVIDE USEFUL TOOLS FOR THEIR PREVENTION. 2019 10 1376 36 DEVELOPMENTAL PROGRAMMING OF BODY COMPOSITION: UPDATE ON EVIDENCE AND MECHANISMS. PURPOSE OF REVIEW: A GROWING BODY OF EPIDEMIOLOGICAL AND EXPERIMENTAL DATA INDICATE THAT NUTRITIONAL OR ENVIRONMENTAL STRESSORS DURING EARLY DEVELOPMENT CAN INDUCE LONG-TERM ADAPTATIONS THAT INCREASE RISK OF OBESITY, DIABETES, CARDIOVASCULAR DISEASE, AND OTHER CHRONIC CONDITIONS-A PHENOMENON TERMED "DEVELOPMENTAL PROGRAMMING." A COMMON PHENOTYPE IN HUMANS AND ANIMAL MODELS IS ALTERED BODY COMPOSITION, WITH REDUCED MUSCLE AND BONE MASS, AND INCREASED FAT MASS. IN THIS REVIEW, WE SUMMARIZE THE RECENT LITERATURE LINKING PRENATAL FACTORS TO FUTURE BODY COMPOSITION AND EXPLORE CONTRIBUTING MECHANISMS. RECENT FINDINGS: MANY PRENATAL EXPOSURES, INCLUDING INTRAUTERINE GROWTH RESTRICTION, EXTREMES OF BIRTH WEIGHT, MATERNAL OBESITY, AND MATERNAL DIABETES, ARE ASSOCIATED WITH INCREASED FAT MASS, REDUCED MUSCLE MASS, AND DECREASED BONE DENSITY, WITH EFFECTS REPORTED THROUGHOUT INFANCY AND CHILDHOOD, AND PERSISTING INTO MIDDLE AGE. MECHANISMS AND MEDIATORS INCLUDE MATERNAL DIET, BREASTMILK COMPOSITION, METABOLITES, APPETITE REGULATION, GENETIC AND EPIGENETIC INFLUENCES, STEM CELL COMMITMENT AND FUNCTION, AND MITOCHONDRIAL METABOLISM. DIFFERENCES IN BODY COMPOSITION ARE A COMMON PHENOTYPE FOLLOWING DISRUPTIONS TO THE PRENATAL ENVIRONMENT, AND MAY CONTRIBUTE TO DEVELOPMENTAL PROGRAMMING OF OBESITY AND DIABETES RISK. 2019 11 6873 45 [PREVENTION OF OBESITY FROM PERINATAL STAGE]. OBESITY IS ONE OF THE MAJOR HEALTH PROBLEMS AND A DETERMINING FACTOR IN THE PREVALENCE OF DISEASES SUCH AS METABOLIC SYNDROME, ASTHMA, SLEEP APNEA, INFERTILITY AND VARIOUS TYPES OF CANCER. ITS ORIGIN IS MULTIFACTORIAL, INVOLVING GENETIC, SOCIOECONOMIC AND ENVIRONMENTAL FACTORS. THESE LAST ONES CONTRIBUTE MOSTLY TO EXPLAIN THE CURRENT EPIDEMIC GROWTH OF THIS DISEASE. THE SEDENTARY LIFESTYLE, INADEQUATE DIET, LACK OF SLEEP, ALTERATIONS IN INTESTINAL MICROBIOTA AND STRESS ARE FACTORS RELATED TO ITS DEVELOPMENT. SINCE BARKER PRESENTED HIS HYPOTHESIS ABOUT THE "FETAL ORIGIN OF ADULT DISEASES", THERE ARE INCREASING NUMBER OF STUDIES THAT SHOW THE INFLUENCE OF AN INADEQUATE NUTRITIONAL STATUS AND MATERNAL WEIGHT IN THE DEVELOPMENT OF CHRONIC DISEASES, AS OBESITY IN OFFSPRING. THE NUTRITIONAL DEFICIENCIES OF THE PREGNANT MOTHER CAUSE EPIGENETIC MODIFICATIONS AND ABNORMAL PROGRAMMING OF THE DEVELOPMENT OFORGANS AND DEVICES, ADAPTING THE FETUS TO THIS SITUATION OF DEFICIENCY AND BEING ABLE TO ADAPT TO AN OBESOGENIC ENVIRONMENT AFTER BIRTH, INCREASING ITS PROPENSITY TO OBESITY. ALSO, POOR MATERNAL NUTRITIONAL STATUS IS RELATED TO INTRAUTERINE GROWTH RETARDATION AND LOW BIRTH WEIGHT INFANTS, WITH A HIGHER RISK OF CHILDHOOD AND ADULT CENTRAL OBESITY. CURRENTLY, DEFICIENT INTAKE OF MICRONUTRIENTS AND OVERWEIGHT OR MATERNAL OBESITY TEND TO OVERLAP, AND THIS COMBINATION MAY EXACERBATE THE INCREASE IN OBESITY IN THE OFFSPRING. IT IS IMPORTANT TO IDENTIFY PREGNANT MOTHERS AT RISK OF SUFFERING NUTRITIONAL ALTERATIONS AND ESTABLISH THEIR IMPROVEMENT AS A PRIMARY PREVENTION STRATEGY FOR OVERWEIGHT AND OBESITY. 2017 12 2806 45 FETAL PROGRAMMING AND THE RISK OF NONCOMMUNICABLE DISEASE. THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) HYPOTHESIS PROPOSES THAT ENVIRONMENTAL CONDITIONS DURING FETAL AND EARLY POST-NATAL DEVELOPMENT INFLUENCE LIFELONG HEALTH AND CAPACITY THROUGH PERMANENT EFFECTS ON GROWTH, STRUCTURE AND METABOLISM. THIS HAS BEEN CALLED 'PROGRAMMING'. THE HYPOTHESIS IS SUPPORTED BY EPIDEMIOLOGICAL EVIDENCE IN HUMANS LINKING NEWBORN SIZE, AND INFANT GROWTH AND NUTRITION, TO ADULT HEALTH OUTCOMES, AND BY EXPERIMENTS IN ANIMALS SHOWING THAT MATERNAL UNDER- AND OVER-NUTRITION AND OTHER INTERVENTIONS (E.G., GLUCOCORTICOID EXPOSURE) DURING PREGNANCY LEAD TO ABNORMAL METABOLISM AND BODY COMPOSITION IN THE ADULT OFFSPRING. EARLY LIFE PROGRAMMING IS NOW THOUGHT TO BE IMPORTANT IN THE ETIOLOGY OF OBESITY, TYPE 2 DIABETES, AND CARDIOVASCULAR DISEASE, OPENING UP THE POSSIBILITY THAT THESE COMMON DISEASES COULD BE PREVENTED BY ACHIEVING OPTIMAL FETAL AND INFANT DEVELOPMENT. THIS IS LIKELY TO HAVE ADDITIONAL BENEFITS FOR INFANT SURVIVAL AND HUMAN CAPITAL (E.G., IMPROVED COGNITIVE PERFORMANCE AND PHYSICAL WORK CAPACITY). FETAL NUTRITION IS INFLUENCED BY THE MOTHER'S DIET AND BODY SIZE AND COMPOSITION, BUT HARD EVIDENCE THAT THE NUTRITION OF THE HUMAN MOTHER PROGRAMMES CHRONIC DISEASE RISK IN HER OFFSPRING IS CURRENTLY LIMITED. RECENT FINDINGS FROM FOLLOW-UP OF CHILDREN BORN AFTER RANDOMISED NUTRITIONAL INTERVENTIONS IN PREGNANCY ARE MIXED, BUT SHOW SOME EVIDENCE OF BENEFICIAL EFFECTS ON VASCULAR FUNCTION, LIPID CONCENTRATIONS, GLUCOSE TOLERANCE AND INSULIN RESISTANCE. WORK IN EXPERIMENTAL ANIMALS SUGGESTS THAT EPIGENETIC PHENOMENA, WHEREBY GENE EXPRESSION IS MODIFIED BY DNA METHYLATION, AND WHICH ARE SENSITIVE TO THE NUTRITIONAL ENVIRONMENT IN EARLY LIFE, MAY BE ONE MECHANISM UNDERLYING PROGRAMMING. 2013 13 2038 30 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 14 6818 34 [FETAL PROGRAMMING AS A CAUSE OF CHRONIC DISEASES IN ADULT LIFE]. LONG-TERM ADAPTIVE CHANGES OCCURRING IN A DEVELOPING FETUS IN RESPONSE TO UNSTABLE IN UTERO ENVIRONMENTAL CONDITIONS, WHICH APPEAR AT A PARTICULAR TIME (CRITICAL WINDOW), ARE CALLED INTRAUTERINE OR FETAL PROGRAMMING. THESE ADAPTIVE CHANGES ARE BENEFICIAL DURING THE INTRAUTERINE PERIOD BECAUSE THEY ADAPT THE FETUS TO CURRENT NEEDS, BUT MAY TURN OUT TO BE HARMFUL IN THE END AND LEAD TO DEVELOPMENT OF CHRONIC DISEASES IN ADULT LIFE. FETAL PROGRAMMING MEANS THE STRUCTURAL AND FUNCTIONAL CHANGING OF AN ORGANISM, METABOLISM AND FUNCTION OF SOME CELLS, TISSUES AND SYSTEMS, THAT OCCUR EVEN DESPITE INTRAUTERINE LIMITATIONS. EVENTS OF FETAL LIFE INFLUENCE THE DETERMINATION OF PHYSIOLOGICAL PATTERNS WHICH MAY MANIFEST AS DISEASE PROCESSES IN THE ADULTHOOD (BARKER'S HYPOTHESIS). GENETIC AND ENVIRONMENTAL FACTORS (POOR DIET IN PREGNANCY CHRONIC INTRAUTERINE FETAL HYPOXIA, THE EFFECTS OF XENOBIOTICS AND DRUGS, AS WELL AS HORMONAL DISORDERS) INFLUENCE THE PHENOTYPE OF A NEWBORN AND ARE INVOLVED IN THE INTRAUTERINE PROGRAMMING PROCESS. THE EFFECTS OF FETAL PROGRAMMING MAY BE PASSED ALONG TO THE NEXT GENERATIONS VIA NOT FULLY UNDERSTOOD PATHWAYS, WHICH PROBABLY INCLUDE EPIGENETIC MECHANISMS. MOST OF THE MECHANISMS UNDERLYING THIS PROCESS REMAIN UNCLEAR AND NEED TO BE ELUCIDATED. 2014 15 3311 51 HIGHLIGHTING THE TRAJECTORY FROM INTRAUTERINE GROWTH RESTRICTION TO FUTURE OBESITY. DURING THE LAST DECADES SEVERAL LINES OF EVIDENCE REPORTED THE ASSOCIATION OF AN ADVERSE INTRAUTERINE ENVIRONMENT, LEADING TO INTRAUTERINE RESTRICTION, WITH FUTURE DISEASE, SUCH AS OBESITY AND METABOLIC SYNDROME, BOTH LEADING TO INCREASED CARDIOVASCULAR AND CANCER RISK. THE UNDERLYING EXPLANATION FOR THIS ASSOCIATION HAS FIRSTLY BEEN EXPRESSED BY THE BARKER'S HYPOTHESIS, THE "THRIFTY PHENOTYPE HYPOTHESIS". ACCORDING TO THIS HYPOTHESIS, A FETUS FACING AN ADVERSE INTRAUTERINE ENVIRONMENT ADAPTS TO THIS ENVIRONMENT THROUGH A REPROGRAMMING OF ITS ENDOCRINE-METABOLIC STATUS, DURING THE CRUCIAL WINDOW OF DEVELOPMENTAL PLASTICITY TO SAVE ENERGY FOR SURVIVAL, PROVIDING LESS ENERGY AND NUTRIENTS TO THE ORGANS THAT ARE NOT ESSENTIAL FOR SURVIVAL. THIS THEORY EVOLVED TO THE CONCEPT OF THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE (DOHAD). THUS, IN THE SETTING OF AN ADVERSE, F. EX. PROTEIN RESTRICTED INTRAUTERINE ENVIRONMENT, WHILE THE ENERGY IS MAINLY DIRECTED TO THE BRAIN, THE PERIPHERAL ORGANS, F.EX. THE MUSCLES AND THE LIVER UNDERGO AN ADAPTATION THAT IS EXPRESSED THROUGH INSULIN RESISTANCE. THE ADAPTATION AT THE HEPATIC LEVEL PREDISPOSES TO FUTURE DYSLIPIDEMIA, THE MODIFICATIONS AT THE VASCULAR LEVEL TO ENDOTHELIAL DAMAGE AND FUTURE HYPERTENSION AND, OVERALL, THROUGH THE INSULIN RESISTANCE TO THE DEVELOPMENT OF METABOLIC SYNDROME. ALL THESE ADAPTATIONS ARE SUGGESTED TO TAKE PLACE THROUGH EPIGENETIC MODIFICATIONS OF THE EXPRESSION OF GENES WITHOUT CHANGE OF THEIR AMINO-ACID SEQUENCE. THE EPIGENETIC MODIFICATIONS LEADING TO FUTURE OBESITY AND CARDIOVASCULAR RISK ARE THOUGHT TO INDUCE APPETITE DYSREGULATION, PROMOTING FOOD INTAKE AND ADIPOGENESIS, FACILITATING OBESITY DEVELOPMENT. THE EPIGENETIC MODIFICATIONS MAY EVEN PERSIST INTO THE NEXT GENERATION EVEN THOUGH THE SUBSEQUENT GENERATION HAS NOT BEEN EXPOSED TO AN ADVERSE INTRAUTERINE ENVIRONMENT, A NOTION DEFINED AS THE "TRANSGENERATIONAL TRANSFER OF ENVIRONMENTAL INFORMATION". AS A CONSEQUENCE, IF THE INCREASED PUBLIC HEALTH BURDEN AND COSTS OF NON-COMMUNICABLE CHRONIC DISEASES SUCH AS OBESITY, HYPERTENSION, METABOLIC SYNDROME AND TYPE 2 DIABETES HAVE TO BE MINIMIZED, SPECIAL ATTENTION SHOULD BE LAID TO THE HEALTHY LIFESTYLE HABITS OF WOMEN OF REPRODUCTIVE AGE, INCLUDING HEALTHY DIET AND PHYSICAL ACTIVITY TO BE ESTABLISHED LONG BEFORE ANY PREGNANCY TAKES PLACE IN ORDER TO PROVIDE THE BEST CONDITIONS FOR BOTH SOMATIC AND MENTAL HEALTH OF FUTURE GENERATIONS. 2022 16 1801 45 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 17 2274 35 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 18 6814 32 [EVIDENCE AND MECHANISMS OF FETAL ORIGINS OF ADULT DISEASES]. THIS REVIEW FOCUSES ON THE FETAL ORIGINS OF ADULT DISEASE HYPOTHESIS PUT FORWARD BY DAVID BARKER AND HIS COLLEAGUES, RECENT ADVANCES IN EPIDEMIOLOGICAL STUDIES AND EXPERIMENTAL RESEARCH IN THIS FIELD. BARKER HYPOTHESIS STATES THAT ENVIRONMENTAL FACTORS, PARTICULARLY INTRAUTERINE NUTRITION, AS INDICATED BY BIRTH WEIGHT, OPERATE IN EARLY LIFE TO PROGRAM THE RISKS FOR ADVERSE HEALTH OUTCOMES IN ADULT LIFE. A LARGE GROWING BODY OF REPORTS DESCRIBED THE ASSOCIATION BETWEEN THE EARLY DEVELOPMENT AND ADULT DISEASES, SUCH AS DIABETES, HYPERTENSION, CORONARY HEART DISEASE, ABNORMAL LIPIDS METABOLISM, OBESITY AND CANCER, ETC. EXPERIMENTAL STUDIES SHOW THAT THE CHANGES OF SOME KEY GENES' EXPRESSION, CAUSED BY EPIGENETIC MODIFICATIONS, LEAD TO A PERMANENT ALTERATION OF CELLULAR PROLIFERATION AND DIFFERENTIATION AND FINALLY THE GENESIS IN KEY TISSUES AND ORGANS. THESE RESULTS BRING ABOUT THE IMPAIRMENT IN STRUCTURES AND FUNCTIONS AND THE INCREASED SUSCEPTIBILITY TO CHRONIC DISEASES IN ADULT LIFE. THE HYPOTHESIS PROVIDES A NEW PERSPECTIVE FOR THE PREVENTION AND THERAPY OF CHRONIC DISEASES. 2007 19 4189 40 METABOLIC DISEASE PROGRAMMING: FROM MITOCHONDRIA TO EPIGENETICS, GLUCOCORTICOID SIGNALLING AND BEYOND. EMBRYONIC AND FOETAL DEVELOPMENT ARE CRITICAL PERIODS OF DEVELOPMENT IN WHICH SEVERAL ENVIRONMENTAL CUES DETERMINE HEALTH AND DISEASE IN ADULTHOOD. MATERNAL CONDITIONS AND AN UNFAVOURABLE INTRAUTERINE ENVIRONMENT IMPACT FOETAL DEVELOPMENT AND MAY PROGRAMME THE OFFSPRING FOR INCREASED PREDISPOSITION TO METABOLIC DISEASES AND OTHER CHRONIC PATHOLOGIC CONDITIONS THROUGHOUT ADULT LIFE. PREVIOUSLY, NON-COMMUNICABLE CHRONIC DISEASES WERE ONLY ASSOCIATED WITH GENETICS AND LIFESTYLE. NOW THE ORIGINS OF NON-COMMUNICABLE CHRONIC DISEASES ARE ASSOCIATED WITH EARLY-LIFE ADAPTATIONS THAT PRODUCE LONG-TERM DYSFUNCTION. EARLY-LIFE ENVIRONMENT SETS THE LONG-TERM HEALTH AND DISEASE RISK AND CAN SPAN THROUGH MULTIPLE GENERATIONS. RECENT RESEARCH IN DEVELOPMENTAL PROGRAMMING AIMS AT IDENTIFYING THE MOLECULAR MECHANISMS RESPONSIBLE FOR DEVELOPMENTAL PROGRAMMING OUTCOMES THAT IMPACT CELLULAR PHYSIOLOGY AND TRIGGER ADULTHOOD DISEASE. THE IDENTIFICATION OF NEW THERAPEUTIC TARGETS CAN IMPROVE OFFSPRING'S HEALTH MANAGEMENT AND PREVENT OR OVERCOME ADVERSE CONSEQUENCES OF FOETAL PROGRAMMING. THIS REVIEW SUMMARIZES RECENT BIOMEDICAL DISCOVERIES IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) HYPOTHESIS AND HIGHLIGHT POSSIBLE DEVELOPMENTAL PROGRAMMING MECHANISMS, INCLUDING PRENATAL STRUCTURAL DEFECTS, METABOLIC (MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, PROTEIN MODIFICATION), EPIGENETIC AND GLUCOCORTICOID SIGNALLING-RELATED MECHANISMS SUGGESTING MOLECULAR CLUES FOR THE CAUSES AND CONSEQUENCES OF PROGRAMMING OF INCREASED SUSCEPTIBILITY OF OFFSPRING TO METABOLIC DISEASE AFTER BIRTH. IDENTIFYING MECHANISMS INVOLVED IN DOHAD CAN CONTRIBUTE TO EARLY INTERVENTIONS IN PREGNANCY OR EARLY CHILDHOOD, TO RE-SET THE METABOLIC HOMEOSTASIS AND BREAK THE CHAIN OF SUBSEQUENT EVENTS THAT COULD LEAD TO THE DEVELOPMENT OF DISEASE. 2021 20 6088 47 THE EFFECTS OF ASSISTED REPRODUCTION TECHNOLOGIES ON METABOLIC HEALTH AND DISEASEDAGGER. THE INCREASING PREVALENCE OF METABOLIC DISEASES PLACES A SUBSTANTIAL BURDEN ON HUMAN HEALTH THROUGHOUT THE WORLD. IT IS BELIEVED THAT PREDISPOSITION TO METABOLIC DISEASE STARTS EARLY IN LIFE, A PERIOD OF GREAT SUSCEPTIBILITY TO EPIGENETIC REPROGRAMMING DUE TO ENVIRONMENTAL INSULTS. ASSISTED REPRODUCTIVE TECHNOLOGIES (ART), I.E., TREATMENTS FOR INFERTILITY, MAY AFFECT EMBRYO DEVELOPMENT, RESULTING IN MULTIPLE ADVERSE HEALTH OUTCOMES IN POSTNATAL LIFE. THE MOST FREQUENTLY OBSERVED ALTERATION IN ART PREGNANCIES IS IMPAIRED PLACENTAL NUTRIENT TRANSFER. MOREOVER, CONSEQUENT INTRAUTERINE GROWTH RESTRICTION AND LOW BIRTH WEIGHT FOLLOWED BY CATCH-UP GROWTH CAN ALL PREDICT FUTURE OBESITY, INSULIN RESISTANCE, AND CHRONIC METABOLIC DISEASES. IN THIS REVIEW, WE HAVE FOCUSED ON EVIDENCE OF ADVERSE METABOLIC ALTERATIONS ASSOCIATED WITH ART, WHICH CAN CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC ADULT-ONSET DISEASES, SUCH AS METABOLIC SYNDROME, TYPE 2 DIABETES, AND CARDIOVASCULAR DISEASE. DUE TO HIGH PHENOTYPIC PLASTICITY, ART PREGNANCIES CAN PRODUCE BOTH OFFSPRING WITH ADVERSE HEALTH OUTCOMES, AS WELL AS HEALTHY INDIVIDUALS. WE FURTHER DISCUSS THE SEX-SPECIFIC AND AGE-DEPENDENT METABOLIC ALTERATIONS REFLECTED IN ART OFFSPRING, AND HOW THE DEGREE OF INTERFERENCE OF A GIVEN ART PROCEDURE (FROM MILD TO MORE SEVERE MANIPULATION OF THE EGG) AFFECTS THE OCCURRENCE AND DEGREE OF OFFSPRING ALTERATIONS. OVER THE LAST FEW YEARS, STUDIES HAVE REPORTED SIGNS OF CARDIOMETABOLIC ALTERATIONS IN ART OFFSPRING THAT ARE DETECTABLE AT A YOUNG AGE BUT THAT DO NOT APPEAR TO CONSTITUTE A HIGH RISK OF DISEASE AND MORBIDITY PER SE. THESE ABNORMAL PHENOTYPES COULD BE EARLY INDICATORS OF THE DEVELOPMENT OF CHRONIC DISEASES, INCLUDING METABOLIC SYNDROME, IN ADULTHOOD. THE EARLY DETECTION OF METABOLIC ALTERATIONS COULD CONTRIBUTE TO PREVENTING THE ONSET OF DISEASE IN ADULTHOOD. SUCH EARLY INTERVENTIONS MAY COUNTERACT THE RISK FACTORS AND IMPROVE THE LONG-TERM HEALTH OF THE INDIVIDUAL. 2021