1 6088 162 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 2 6173 63 THE HEALTH OUTCOMES OF HUMAN OFFSPRING CONCEIVED BY ASSISTED REPRODUCTIVE TECHNOLOGIES (ART). CONCERNS HAVE BEEN RAISED ABOUT THE HEALTH AND DEVELOPMENT OF CHILDREN CONCEIVED BY ASSISTED REPRODUCTIVE TECHNOLOGIES (ART) SINCE 1978. CONTROVERSIALLY, ART HAS BEEN LINKED WITH ADVERSE OBSTETRIC AND PERINATAL OUTCOMES, AN INCREASED RISK OF BIRTH DEFECTS, CANCERS, AND GROWTH AND DEVELOPMENT DISORDERS. EMERGING EVIDENCE SUGGESTS THAT ART TREATMENT MAY ALSO PREDISPOSE INDIVIDUALS TO AN INCREASED RISK OF CHRONIC AGEING RELATED DISEASES SUCH AS OBESITY, TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE. THIS REVIEW WILL SUMMARIZE THE AVAILABLE EVIDENCE ON THE SHORT-TERM AND LONG-TERM HEALTH OUTCOMES OF ART SINGLETONS, AS MULTIPLE PREGNANCIES AFTER MULTIPLE EMBRYOS TRANSFER, ARE ASSOCIATED WITH LOW BIRTH WEIGHT AND PRETERM DELIVERY, WHICH CAN SEPARATELY INCREASE RISK OF ADVERSE POSTNATAL OUTCOMES, AND IMPACT LONG-TERM HEALTH. WE WILL ALSO EXAMINE THE POTENTIAL FACTORS THAT MAY CONTRIBUTE TO THESE HEALTH RISKS, AND DISCUSS UNDERLYING MECHANISMS, INCLUDING EPIGENETIC CHANGES THAT MAY OCCUR DURING THE PREIMPLANTATION PERIOD AND REPROGRAM DEVELOPMENT IN UTERO, AND ADULT HEALTH, LATER IN LIFE. LASTLY, THIS REVIEW WILL CONSIDER THE FUTURE DIRECTIONS WITH THE VIEW TO OPTIMIZE THE LONG-TERM HEALTH OF ART CHILDREN. 2017 3 6234 48 THE LONG-TERM EFFECTS OF PRENATAL DEVELOPMENT ON GROWTH AND METABOLISM. PEOPLE WHO WERE SMALL AT BIRTH AND HAD POOR INFANT GROWTH HAVE AN INCREASED RISK OF ADULT CARDIOVASCULAR DISEASE, OSTEOPOROSIS, AND TYPE 2 DIABETES, PARTICULARLY IF THEIR RESTRICTED EARLY GROWTH WAS FOLLOWED BY INCREASED CHILDHOOD WEIGHT GAIN. THESE RELATIONS EXTEND ACROSS THE NORMAL RANGE OF BIRTH SIZE IN A GRADED MANNER, SO REDUCED SIZE IS NOT A PREREQUISITE. IN ADDITION, LARGER BIRTH SIZE IS ASSOCIATED WITH RISKS OF OBESITY AND TYPE 2 DIABETES. THE ASSOCIATIONS APPEAR TO REFLECT DEVELOPMENTAL PLASTIC RESPONSES MADE BY THE FETUS AND INFANT BASED ON CUES ABOUT THE ENVIRONMENT, INFLUENCED BY MATERNAL CHARACTERISTICS INCLUDING DIET, BODY COMPOSITION, STRESS, AND EXERCISE LEVELS. THESE RESPONSES INVOLVE EPIGENETIC PROCESSES THAT MODIFY THE OFFSPRING'S PHENOTYPE. VULNERABILITY TO ILL HEALTH RESULTS IF THE ENVIRONMENT IN INFANCY, CHILDHOOD, AND LATER LIFE IS MISMATCHED TO THE PHENOTYPE INDUCED IN DEVELOPMENT, INFORMED BY THE DEVELOPMENTAL CUES. THIS MISMATCH MAY ARISE THROUGH UNBALANCED DIET OR BODY COMPOSITION OF THE MOTHER OR A CHANGE IN LIFESTYLE FACTORS BETWEEN GENERATIONS. THESE INSIGHTS OFFER NEW POSSIBILITIES FOR THE EARLY DIAGNOSIS AND PREVENTION OF CHRONIC DISEASE. 2011 4 2274 38 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 5 1801 50 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 6 6064 43 THE DEVELOPMENTAL ORIGINS OF ADULT DISEASE. EPIDEMIOLOGICAL AND CLINICAL OBSERVATIONS HAVE LED TO THE HYPOTHESIS THAT THE RISK OF DEVELOPING SOME CHRONIC DISEASES IN ADULTHOOD IS INFLUENCED NOT ONLY BY GENETIC AND ADULT LIFESTYLE FACTORS, BUT ALSO BY ENVIRONMENTAL FACTORS ACTING IN EARLY LIFE. THESE FACTORS ACT THROUGH THE PROCESSES OF DEVELOPMENTAL PLASTICITY AND POSSIBLY EPIGENETIC MODIFICATION, AND CAN BE DISTINGUISHED FROM DEVELOPMENTAL DISRUPTION. THE CONCEPT OF PREDICTIVE ADAPTATION HAS BEEN DEVELOPED TO EXPLAIN THE RELATIONSHIP BETWEEN EARLY LIFE EVENTS AND THE RISK OF LATER DISEASE. AT ITS BASE, THE MODEL SUGGESTS THAT A MISMATCH BETWEEN FETAL EXPECTATION OF ITS POSTNATAL ENVIRONMENT AND ACTUAL POSTNATAL ENVIRONMENT CONTRIBUTE TO LATER ADULT DISEASE RISK. THIS MISMATCH IS EXACERBATED, IN PART, BY THE PHENOMENON OF "MATERNAL CONSTRAINT" ON FETAL GROWTH, WHICH IMPLICITLY PROVIDES AN UPPER LIMIT OF POSTNATAL NUTRITIONAL ENVIRONMENT THAT HUMANS HAVE ADAPTED FOR AND IS NOW FREQUENTLY EXCEEDED. THESE EXPERIMENTAL, CLINICAL AND CONCEPTUAL CONSIDERATIONS HAVE IMPORTANT IMPLICATIONS FOR PREVENTION AND INTERVENTION IN THE CURRENT EPIDEMIC OF CHILDHOOD OBESITY AND ADULT METABOLIC AND CARDIOVASCULAR DISORDERS. 2005 7 3582 34 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 3707 44 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 9 4782 43 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 3311 64 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 1370 47 DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE THEORY IN CARDIOLOGY. NUMEROUS EPIDEMIOLOGICAL AND ANIMAL STUDIES DISCLOSED THAT BIRTH WEIGHT IS INVERSELY ASSOCIATED WITH THE INCIDENCE OF THE LIFESTYLE-RELATED DISORDERS IN ADULT LIFE, SUCH AS CARDIOVASCULAR DISEASE, DIABETES, AND /OR CHRONIC KIDNEY DISEASE. LOWER BIRTH WEIGHT OCCURS IN NUMEROUS UNDESIRED INTRAUTERINE ENVIRONMENTS INCLUDING MALNUTRITION, SMOKING, ALCOHOL CONSUMPTION, OR STRESS. THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE (DOHAD) THEORY IS BASED ON THE CONCEPT THAT THE ORIGINS OF LIFESTYLE-RELATED DISEASE IS FORMED AT THE TIME OF FERTILIZATION, EMBRYONIC, FETAL, AND NEONATAL STAGES BY THE INTERRELATION BETWEEN GENES AND THE ENVIRONMENTS (NUTRITION, STRESS, OR ENVIRONMENTAL CHEMICALS). ADULT DISEASE DEVELOPS AFTER DELIVERY FACING TO ABNORMAL ENVIRONMENTS SUCH AS OVER-NUTRITION, MUCH STRESS, OR LACK OF EXERCISE. DISEASE DEVELOPS THROUGH THESE TWO INSULTS. THIS CONCEPT WAS FIRST PROPOSED AS THE "BARKER HYPOTHESIS." DAVID BARKER HAD DISCOVERED THE RELATION BETWEEN THE LOWER BIRTH WEIGHT AND THE HIGHER PREVALENCE OF ISCHEMIC HEART DISEASE MORTALITY. PREVIOUS EPIDEMIOLOGIC STUDIES HAVE FOUND THE PEOPLE EXPOSED TO FAMINE DURING EARLY LIFE HAD HIGHER RISKS OF CARDIOVASCULAR DISEASES IN ADULTHOOD. YET, THE EXACT MECHANISMS THAT PERMANENTLY CHANGE THE STRUCTURE, PHYSIOLOGY, AND ENDOCRINE STATUS OF AN INDIVIDUAL ACROSS THEIR LIFESPAN FOLLOWING ALTERED GROWTH DURING FETAL LIFE ARE NOT ENTIRELY CLEAR. EPIDEMIOLOGICAL STUDIES INCLUDING PROSPECTIVE COHORT AND OBSERVATIONAL ANALYSIS OF THE PEOPLE EXPOSED TO MALNUTRITION DURING FETAL OR INFANCY HAVE DISCLOSED THE STRONG RELATION BETWEEN THE LOWER BIRTH WEIGHT AND THE HIGHER CARDIOVASCULAR RISKS IN ADULTS. RECENT PROGRESS OF EPIGENETIC STUDIES UNVEILED STRONG GENETIC ASSOCIATION. HORMONAL REGULATION AND EPIGENETIC MODIFICATIONS HAVE AN IMPORTANT ROLE FOR PROPER ORGAN DEVELOPMENT AND PHYSIOLOGICAL FUNCTIONS. THE MOLECULAR MECHANISM OF PREDISPOSITION IS SUPPOSED TO BE THE EPIGENETICS MODIFICATIONS. THEIR DYSREGULATION IS RELATED TO THE ACQUISITION OF THE DISEASE-SUSCEPTIBLE TRAIT. IN THIS REVIEW, WE OVERVIEW THE CONCEPT OF DOHAD AND INTRODUCE RELATED CLINICAL AND BASIC RESEARCH. 2020 12 1376 45 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 13 3573 50 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 14 6819 49 [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 15 4802 44 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 16 4280 37 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 17 6873 46 [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 18 5089 43 PLACENTAL ADAPTATIONS TO MICRONUTRIENT DYSREGULATION IN THE PROGRAMMING OF CHRONIC DISEASE. POOR NUTRITION DURING PREGNANCY IS KNOWN TO IMPAIR FOETAL DEVELOPMENT AND INCREASE THE RISK OF CHRONIC DISEASE IN OFFSPRING. BOTH MACRONUTRIENTS AND MICRONUTRIENTS ARE REQUIRED FOR A HEALTHY PREGNANCY ALTHOUGH SIGNIFICANTLY LESS IS UNDERSTOOD ABOUT THE ROLE OF MICRONUTRIENTS IN THE PROGRAMMING OF CHRONIC DISEASE. THIS IS DESPITE THE FACT THAT MODERN CALORIE RICH DIETS ARE OFTEN ALSO DEFICIENT IN KEY MICRONUTRIENTS. THE IMPORTANCE OF MICRONUTRIENTS IN GESTATIONAL DISORDERS IS CLEARLY UNDERSTOOD BUT HOW THEY IMPACT LONG TERM DISEASE IN HUMANS REQUIRES FURTHER INVESTIGATION. IN CONTRAST, ANIMAL STUDIES HAVE DEMONSTRATED HOW DIETS HIGH OR LOW IN SPECIFIC MICRONUTRIENTS INFLUENCE OFFSPRING PHYSIOLOGY. MANY OF THESE STUDIES HIGHLIGHT THE IMPORTANCE OF THE PLACENTA IN DETERMINING DISEASE RISK. THIS REVIEW WILL EXPLORE THE EFFECTS OF INDIVIDUAL VITAMINS, MINERALS AND TRACE ELEMENTS ON OFFSPRING DISEASE OUTCOMES AND DISCUSS SEVERAL KEY PLACENTAL ADAPTATIONS THAT ARE AFFECTED BY MULTIPLE MICRONUTRIENTS. THESE PLACENTAL ADAPTATIONS INCLUDE MICRONUTRIENT INDUCED DYSREGULATION OF OXIDATIVE STRESS, ALTERED METHYL DONOR AVAILABILITY AND ITS IMPACT ON EPIGENETIC MECHANISMS AS WELL AS ENDOCRINE DYSFUNCTION. CRITICAL GAPS IN OUR CURRENT KNOWLEDGE AND THE RELATIVE IMPORTANCE OF DIFFERENT MICRONUTRIENTS AT DIFFERENT GESTATIONAL AGES WILL ALSO BE HIGHLIGHTED. FINALLY, THIS REVIEW WILL DISCUSS THE NEED FOR FURTHER STUDIES TO CHARACTERISE THE MICRONUTRIENT STATUS OF AUSTRALIAN WOMEN OF REPRODUCTIVE AGE AND CORRELATE MICRONUTRIENT STATUS TO PLACENTAL ADAPTATIONS, PREGNANCY COMPLICATIONS AND OFFSPRING DISEASE. 2018 19 1372 52 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 20 317 47 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