1 1992 110 EPIGENETIC AND DEVELOPMENTAL INFLUENCES ON THE RISK OF OBESITY, DIABETES, AND METABOLIC SYNDROME. METABOLIC SYNDROME IS A GROWING CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. METABOLIC SYNDROME IS CHARACTERIZED BY THE PRESENCE OF A VARIETY OF METABOLIC DISTURBANCES INCLUDING OBESITY, HYPERLIPIDEMIA, HYPERTENSION, AND ELEVATED FASTING BLOOD SUGAR. ALTHOUGH THE RISK FOR METABOLIC SYNDROME HAS LARGELY BEEN ATTRIBUTED TO ADULT LIFESTYLE FACTORS SUCH AS POOR NUTRITION, LACK OF EXERCISE, AND SMOKING, THERE IS NOW STRONG EVIDENCE SUGGESTING THAT PREDISPOSITION TO THE DEVELOPMENT OF METABOLIC SYNDROME BEGINS IN UTERO. FIRST POSITED BY HALES AND BARKER IN 1992, THE "THRIFTY PHENOTYPE" HYPOTHESIS PROPOSES THAT SUSCEPTIBILITY TO ADULT CHRONIC DISEASES CAN OCCUR IN RESPONSE TO EXPOSURES IN THE PRENATAL AND PERINATAL PERIODS. THIS HYPOTHESIS HAS BEEN CONTINUALLY SUPPORTED BY EPIDEMIOLOGIC STUDIES AND STUDIES INVOLVING ANIMAL MODELS. IN THIS REVIEW, WE DESCRIBE THE STRUCTURAL, METABOLIC AND EPIGENETIC CHANGES THAT OCCUR IN RESPONSE TO ADVERSE INTRAUTERINE ENVIRONMENTS INCLUDING PRENATAL AND POSTNATAL DIET, MATERNAL OBESITY, AND PREGNANCY COMPLICATIONS. GIVEN THE INCREASING PREVALENCE OF METABOLIC SYNDROME IN BOTH THE DEVELOPED AND DEVELOPING WORLDS, A GREATER UNDERSTANDING AND APPRECIATION FOR THE ROLE OF THE INTRAUTERINE ENVIRONMENT IN ADULT CHRONIC DISEASE ETIOLOGY IS IMPERATIVE. 2015 2 6819 39 [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 3 6814 40 [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 4 4802 35 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 5 4189 35 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 6 2267 30 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 7 4280 30 MICRONUTRIENTS IN EARLY LIFE AND OFFSPRING METABOLIC HEALTH PROGRAMMING: A PROMISING TARGET FOR PREVENTING NON-COMMUNICABLE DISEASES. CHRONIC NON-COMMUNICABLE DISEASES ARE THE LEADING CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. DEVELOPING AND IMPLEMENTING EFFECTIVE PREVENTIVE STRATEGIES IS THE BEST WAY TO ENSURE THE OVERALL METABOLIC HEALTH STATUS OF THE POPULATION AND TO COUNTER THE GLOBAL BURDEN OF NON-COMMUNICABLE DISEASES. PREDISPOSITION TO OBESITY AND OTHER NON-COMMUNICABLE DISEASES IS DUE TO A COMBINATION OF GENETIC AND ENVIRONMENTAL FACTORS THROUGHOUT LIFE, BUT THE EARLY ENVIRONMENT, PARTICULARLY THE ENVIRONMENT DURING THE FETAL PERIOD AND THE EARLY YEARS OF LIFE, IS CRUCIAL IN DETERMINING METABOLIC HEALTH, HENCE THE CONCEPT OF 'FETAL PROGRAMMING'. THE ORIGINS OF THIS CAUSAL LINK BETWEEN ENVIRONMENTAL FACTORS AND DISEASE LIE IN EPIGENETIC MECHANISMS. AMONG THE ENVIRONMENTAL FACTORS, DIET PLAYS A CRUCIAL ROLE IN THIS PROCESS. SUBSTANTIAL EVIDENCE DOCUMENTED THE KEY ROLE OF MACRONUTRIENTS IN THE PROGRAMMING OF METABOLIC DISEASES EARLY IN LIFE. RECENTLY, THE EFFECT OF MATERNAL MICRONUTRIENT INTAKE ON OFFSPRING METABOLIC HEALTH IN LATER LIFE EMERGED. THE PURPOSE OF THIS NARRATIVE REVIEW IS TO BRING TO LIGHT AVAILABLE EVIDENCE IN THE LITERATURE ON THE EFFECT OF MATERNAL MICRONUTRIENT STATUS ON OFFSPRING METABOLIC HEALTH AND UNDERLYING EPIGENETIC MECHANISMS THAT DRIVE THIS LINK TO HIGHLIGHT ITS POTENTIAL ROLE IN THE PREVENTION OF NON-COMMUNICABLE DISEASES. 2023 8 6873 41 [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 9 3707 35 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 10 3311 41 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 11 6557 40 TRANSGENERATIONAL EPIGENETIC INHERITANCE OF DIABETES RISK AS A CONSEQUENCE OF EARLY NUTRITIONAL IMBALANCES. IN TODAY'S WORLD, THERE IS AN UNPRECEDENTED RISE IN THE PREVALENCE OF CHRONIC METABOLIC DISEASES, INCLUDING OBESITY, INSULIN RESISTANCE AND TYPE 2 DIABETES (T2D). THE PATHOGENESIS OF T2D INCLUDES BOTH GENETIC AND ENVIRONMENTAL FACTORS, SUCH AS EXCESSIVE ENERGY INTAKE AND PHYSICAL INACTIVITY. IT HAS RECENTLY BEEN SUGGESTED THAT ENVIRONMENTAL FACTORS EXPERIENCED DURING EARLY STAGES OF DEVELOPMENT, INCLUDING THE INTRAUTERINE AND NEONATAL PERIODS, MIGHT PLAY A MAJOR ROLE IN PREDISPOSING INDIVIDUALS TO T2D. FURTHERMORE, SEVERAL STUDIES HAVE SHOWN THAT SUCH EARLY ENVIRONMENTAL CONDITIONS MIGHT EVEN CONTRIBUTE TO DISEASE RISK IN FURTHER GENERATIONS. IN THIS REVIEW, WE SUMMARISE RECENT DATA DESCRIBING HOW PARENTAL NUTRITION DURING DEVELOPMENT INCREASES THE RISK OF DIABETES IN THE OFFSPRING. WE ALSO DISCUSS THE POTENTIAL MECHANISMS UNDERLYING TRANSGENERATIONAL INHERITANCE OF METABOLIC DISEASE, WITH PARTICULAR EMPHASIS ON EPIGENETIC MECHANISMS. 2016 12 5203 40 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 13 4782 41 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 14 2038 31 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 15 6803 25 [EPIGENETIC MECHANISMS IN PHYSIOLOGIC AND PATHOLOGIC PREGNANCIES]. EPIGENETIC FACTORS ARE NOWADAYS IN THE FOCUS OF SCIENTIFIC INTEREST IN MEDICINE INCLUDING OBSTETRICS. THE ENVIRONMENT IN UTERO AND EARLY NEONATAL LIFE MAY INDUCE A PERMANENT RESPONSE IN THE FETUS AND THE NEWBORN LEADING TO ENHANCED SUSCEPTIBILITY TO LATER DISEASES. THERE IS NOW GROWING EVIDENCE THAT THE EFFECTS OF DEVELOPMENTAL PROGRAMMING MAY ALSO MANIFEST THEMSELVES IN THE NEXT GENERATIONS WITHOUT FURTHER SUBOPTIMAL EXPOSURE. THE SO-CALLED FETAL PROGRAMMING MAY ALSO HIGHLIGHT A TIGHT CONNECTION BETWEEN PATHOLOGICAL CONDITIONS IN PREGNANCY, ENVIRONMENTAL FACTORS AND THE DEVELOPMENT OF CHRONIC DISEASES IN ADULTHOOD. INVESTIGATION OF EPIGENETIC FACTORS MAY YIELD NEW POSSIBILITIES FOR THE PREVENTION OF CHRONIC DISEASES AFFECTING A SIGNIFICANT PART OF THE POPULATION. 2014 16 1372 39 DEVELOPMENTAL ORIGINS OF METABOLIC DISEASES. ALMOST 2 BILLION ADULTS IN THE WORLD ARE OVERWEIGHT, AND MORE THAN HALF OF THEM ARE CLASSIFIED AS OBESE, WHILE NEARLY ONE-THIRD OF CHILDREN GLOBALLY EXPERIENCE POOR GROWTH AND DEVELOPMENT. GIVEN THE VAST AMOUNT OF KNOWLEDGE THAT HAS BEEN GLEANED FROM DECADES OF RESEARCH ON GROWTH AND DEVELOPMENT, A NUMBER OF QUESTIONS REMAIN AS TO WHY THE WORLD IS NOW IN THE MIDST OF A GLOBAL EPIDEMIC OF OBESITY ACCOMPANIED BY THE "DOUBLE BURDEN OF MALNUTRITION," WHERE OVERWEIGHT COEXISTS WITH UNDERWEIGHT AND MICRONUTRIENT DEFICIENCIES. THIS CHALLENGE TO THE HUMAN CONDITION CAN BE ATTRIBUTED TO NUTRITIONAL AND ENVIRONMENTAL EXPOSURES DURING PREGNANCY THAT MAY PROGRAM A FETUS TO HAVE A HIGHER RISK OF CHRONIC DISEASES IN ADULTHOOD. TO EXPLORE THIS CONCEPT, FREQUENTLY CALLED THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD), THIS REVIEW CONSIDERS A HOST OF FACTORS AND PHYSIOLOGICAL MECHANISMS THAT DRIVE A FETUS OR CHILD TOWARD A HIGHER RISK OF OBESITY, FATTY LIVER DISEASE, HYPERTENSION, AND/OR TYPE 2 DIABETES (T2D). TO THAT END, THIS REVIEW EXPLORES THE EPIDEMIOLOGY OF DOHAD WITH DISCUSSIONS FOCUSED ON ADAPTATIONS TO HUMAN ENERGETICS, PLACENTAL DEVELOPMENT, DYSMETABOLISM, AND KEY ENVIRONMENTAL EXPOSURES THAT ACT TO PROMOTE CHRONIC DISEASES IN ADULTHOOD. THESE AREAS ARE COMPLEMENTARY AND ADDITIVE IN UNDERSTANDING HOW PROVIDING THE BEST CONDITIONS FOR OPTIMAL GROWTH CAN CREATE THE BEST POSSIBLE CONDITIONS FOR LIFELONG HEALTH. MOREOVER, UNDERSTANDING BOTH PHYSIOLOGICAL AS WELL AS EPIGENETIC AND MOLECULAR MECHANISMS FOR DOHAD IS VITAL TO MOST FULLY ADDRESS THE GLOBAL ISSUES OF OBESITY AND OTHER CHRONIC DISEASES. 2021 17 1801 48 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 18 1375 29 DEVELOPMENTAL PROGRAMMING OF ADULT HAEMATOPOIESIS SYSTEM. THE BARKER HYPOTHESIS OF 'FOETAL ORIGIN OF ADULT DISEASES' HAS LED TO EMPHASIZE THE CONCEPT OF 'DEVELOPMENTAL PROGRAMMING', BASED ON THE CRUCIAL ROLE OF EPIGENETIC FACTORS. ACCORDINGLY, IT HAS BEEN DEMONSTRATED THAT PARENTAL ADVERSITY (BEFORE CONCEPTION AND DURING PREGNANCY) AND FOETAL FACTORS (I.E., HYPOXIA, MALNUTRITION AND PLACENTAL INSUFFICIENCY) PERMANENTLY MODIFY THE PHYSIOLOGICAL SYSTEMS OF THE PROGENY, PREDISPOSING THEM TO PREMATURE AGEING AND CHRONIC DISEASE DURING ADULTHOOD. THUS, AN ALTERED FUNCTIONALITY OF THE ENDOCRINE, IMMUNE, NERVOUS AND CARDIOVASCULAR SYSTEMS IS OBSERVED IN THE PROGENY. HOWEVER, IT REMAINS TO BE UNDERSTOOD WHETHER THE HAEMATOPOIETIC SYSTEM ITSELF ALSO REPRESENTS A PORTRAIT OF FOETAL PROGRAMMING. HERE, WE PROVIDE EVIDENCE, REPORTING AND DISCUSSING RELATED THEORIES, AND RESULTS OF STUDIES DESCRIBED IN THE LITERATURE. IN ADDITION, WE HAVE OUTLINED OUR OPINIONS AND SUGGEST HOW IT IS POSSIBLE TO INTERVENE TO CORRECT FOETAL MAL-PROGRAMMING. SOME PRO-HEALTH INTERVENTIONS AND RECOMMENDATIONS ARE PROPOSED, WITH THE HOPE OF GUARANTEE THE HEALTH OF FUTURE GENERATIONS AND TRYING TO COMBAT THE CONTINUOUS INCREASE IN AGE-RELATED DISEASES IN HUMAN POPULATIONS. 2019 19 1766 40 EARLY-LIFE EXPERIENCES AND THE DEVELOPMENT OF ADULT DISEASES WITH A FOCUS ON MENTAL ILLNESS: THE HUMAN BIRTH THEORY. IN MAMMALS, EARLY ADVERSE EXPERIENCES, INCLUDING MOTHER-PUP INTERACTIONS, SHAPE THE RESPONSE OF AN INDIVIDUAL TO CHRONIC STRESS OR TO STRESS-RELATED DISEASES DURING ADULT LIFE. THIS HAS LED TO THE ELABORATION OF THE THEORY OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE, IN PARTICULAR ADULT DISEASES SUCH AS CARDIOVASCULAR AND METABOLIC DISORDERS. IN ADDITION, IN HUMANS, AS STATED BY MASSIMO FAGIOLI'S HUMAN BIRTH THEORY, BIRTH IS HEALTHY AND EQUAL FOR ALL INDIVIDUALS, SO THAT MENTAL ILLNESS DEVELOP EXCLUSIVELY IN THE POSTNATAL PERIOD BECAUSE OF THE QUALITY OF THE RELATIONSHIP IN THE FIRST YEAR OF LIFE. THUS, THIS REVIEW FOCUSES ON THE IMPORTANCE OF PROGRAMMING DURING THE EARLY DEVELOPMENTAL PERIOD ON THE MANIFESTATION OF ADULT DISEASES IN BOTH ANIMAL MODELS AND HUMANS. CONSIDERING THE OBVIOUS DIFFERENCES BETWEEN ANIMALS AND HUMANS WE CANNOT SYSTEMATICALLY MOVE FROM ANIMAL MODELS TO HUMANS. CONSEQUENTLY, IN THE FIRST PART OF THIS REVIEW, WE WILL DISCUSS HOW ANIMAL MODELS CAN BE USED TO DISSECT THE INFLUENCE OF ADVERSE EVENTS OCCURRING DURING THE PRENATAL AND POSTNATAL PERIODS ON THE DEVELOPMENTAL TRAJECTORIES OF THE OFFSPRING, AND IN THE SECOND PART, WE WILL DISCUSS THE ROLE OF POSTNATAL CRITICAL PERIODS ON THE DEVELOPMENT OF MENTAL DISEASES IN HUMANS. EPIGENETIC MECHANISMS THAT CAUSE REVERSIBLE MODIFICATIONS IN GENE EXPRESSION, DRIVING THE DEVELOPMENT OF A PATHOLOGICAL PHENOTYPE IN RESPONSE TO A NEGATIVE EARLY POSTNATAL ENVIRONMENT, MAY LIE AT THE CORE OF THIS PROGRAMMING, THEREBY PROVIDING POTENTIAL NEW THERAPEUTIC TARGETS. THE CONCEPT OF THE HUMAN BIRTH THEORY LEADS TO A COMPREHENSION OF THE MENTAL ILLNESS AS A PATHOLOGY OF THE HUMAN RELATIONSHIP IMMEDIATELY AFTER BIRTH AND DURING THE FIRST YEAR OF LIFE. 2017 20 317 35 ALCOHOL-INDUCED DEVELOPMENTAL ORIGINS OF ADULT-ONSET DISEASES. FETAL ALCOHOL EXPOSURE MAY IMPAIR GROWTH, DEVELOPMENT, AND FUNCTION OF MULTIPLE ORGAN SYSTEMS AND IS ENCOMPASSED BY THE TERM FETAL ALCOHOL SPECTRUM DISORDERS (FASD). RESEARCH HAS SO FAR FOCUSED ON THE MECHANISMS, PREVENTION, AND DIAGNOSIS OF FASD, WHILE THE RISK FOR ADULT-ONSET CHRONIC DISEASES IN INDIVIDUALS EXPOSED TO ALCOHOL IN UTERO IS NOT WELL EXPLORED. DAVID BARKER'S HYPOTHESIS ON DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) SUGGESTS THAT INSULTS TO THE MILIEU OF THE DEVELOPING FETUS PROGRAM IT FOR ADULT DEVELOPMENT OF CHRONIC DISEASES. IN THE 25 YEARS SINCE THE INTRODUCTION OF THIS HYPOTHESIS, EPIDEMIOLOGICAL AND ANIMAL MODEL STUDIES HAVE MADE SIGNIFICANT ADVANCEMENTS IN IDENTIFYING IN UTERO DEVELOPMENTAL ORIGINS OF CHRONIC ADULT-ONSET DISEASES AFFECTING CARDIOVASCULAR, ENDOCRINE, MUSCULOSKELETAL, AND PSYCHOBEHAVIORAL SYSTEMS. TERATOGEN EXPOSURE IS AN ESTABLISHED PROGRAMMING AGENT FOR ADULT DISEASES, AND RECENT STUDIES SUGGEST THAT PRENATAL ALCOHOL EXPOSURE CORRELATES WITH ADULT ONSET OF NEUROBEHAVIORAL DEFICITS, CARDIOVASCULAR DISEASE, ENDOCRINE DYSFUNCTION, AND NUTRIENT HOMEOSTASIS INSTABILITY, WARRANTING ADDITIONAL INVESTIGATION OF ALCOHOL-INDUCED DOHAD, AS WELL AS PATIENT FOLLOW-UP WELL INTO ADULTHOOD FOR AFFECTED INDIVIDUALS. IN UTERO EPIGENETIC ALTERATIONS DURING CRITICAL PERIODS OF METHYLATION ARE A KEY POTENTIAL MECHANISM FOR PROGRAMMING AND SUSCEPTIBILITY OF ADULT-ONSET CHRONIC DISEASES, WITH IMPRINTED GENES AFFECTING METABOLISM BEING CRITICAL TARGETS. ADDITIONAL STUDIES IN EPIDEMIOLOGY, PHENOTYPIC CHARACTERIZATION IN RESPONSE TO TIMING, DOSE, AND DURATION OF EXPOSURE, AS WELL AS ELUCIDATION OF MECHANISMS UNDERLYING FASD-DOHAD INTER RELATION, ARE THUS NEEDED TO CLINICALLY DEFINE CHRONIC DISEASE ASSOCIATED WITH PRENATAL ALCOHOL EXPOSURE. THESE STUDIES ARE CRITICAL TO ESTABLISH INTERVENTIONAL STRATEGIES THAT DECREASE INCIDENCE OF THESE ADULT-ONSET DISEASES AND PROMOTE HEALTHIER AGING AMONG INDIVIDUALS AFFECTED WITH FASD. 2016