1 3569 148 IMPACT OF INTRA-UTERINE LIFE ON FUTURE HEALTH. SINCE THE EMERGENCE OF THE CONCEPT OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD), SUGGESTED BY BARKER IN THE 1980S, NUMEROUS EPIDEMIOLOGICAL STUDIES IN HUMANS HAVE CONFIRMED THE RELATIONSHIP BETWEEN MATERNAL OBESITY DURING PREGNANCY AND THE RISK OF OFFSPRING DEVELOPING VARIOUS CHRONIC ADULT ILLNESSES. THESE EFFECTS OF INTRAUTERINE LIFE ARE INDEPENDENT OF INHERITANCE OF DISEASE SUSCEPTIBILITY GENES AND/OR SOCIO-ECONOMIC FACTORS. REGARDING POTENTIAL MECHANISMS, RECENT DATA FROM ANIMAL MODELS SUGGESTS A ROLE OF INSULIN RESISTANCE EARLY IN DEVELOPMENT. ANOTHER POTENTIAL MECHANISM, IN THE CASE OF MATERNAL OBESITY, IS INCREASED PLACENTAL NUTRIENT TRANSFER. THE DOHAD CONCEPT ALSO INCLUDES FETAL EXPOSURE TO ENVIRONMENTAL ENDOCRINE DISRUPTORS (EEDS). A DANISH GROUP FOR THE FIRST TIME RECENTLY ANALYZED EED PASSAGE ACROSS THE PLACENTA IN HUMANS THROUGHOUT PREGNANCY. THIS STUDY SHOWED DIFFERENT LEVELS OF BIOACCUMULATION DEPENDING ON THE FETAL ORGAN, WITH GREATER VULNERABILITY IN MALE THAN FEMALE FETUSES. RECENT CLINICAL STUDIES SUGGESTED AN ASSOCIATION BETWEEN FETAL EXPOSURE TO PARTICULAR EEDS AND PRECOCIOUS PUBERTY, INCREASED INCIDENCE OF CRYPTORCHIDISM AND IMPAIRED SPERM QUALITY IN ADULTHOOD. THESE MODIFICATIONS OF THE IN-UTERO ENVIRONMENT ALSO APPEAR TO BE RESPONSIBLE FOR EPIGENETIC CHANGES THAT ARE TRANSMITTABLE OVER SEVERAL GENERATIONS. A RECENT EXAMPLE OF THIS IS THE DEMONSTRATION OF THE TRANSMISSION OF POLYCYSTIC OVARY SYNDROME (PCOS) IN MICE. IN SUMMARY, AN INCREASING NUMBER OF EXAMPLES OF THE IMPACT OF INTRAUTERINE LIFE ON THE HEALTH OF OFFSPRING HAVE APPEARED IN RECENT YEARS, ILLUSTRATING THE IMPORTANT ROLE THAT ENDOCRINOLOGISTS CAN PLAY IN PREVENTING PARTICULAR PATHOLOGIES IN FUTURE GENERATIONS. 2022 2 4189 43 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 3 4078 51 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 4 4802 48 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 2802 41 FETAL AND INFANT ORIGINS OF ASTHMA. PREVIOUS STUDIES HAVE SUGGESTED THAT ASTHMA, LIKE OTHER COMMON DISEASES, HAS AT LEAST PART OF ITS ORIGIN EARLY IN LIFE. LOW BIRTH WEIGHT HAS BEEN SHOWN TO BE ASSOCIATED WITH INCREASED RISKS OF ASTHMA, CHRONIC OBSTRUCTIVE AIRWAY DISEASE, AND IMPAIRED LUNG FUNCTION IN ADULTS, AND INCREASED RISKS OF RESPIRATORY SYMPTOMS IN EARLY CHILDHOOD. THE DEVELOPMENTAL PLASTICITY HYPOTHESIS SUGGESTS THAT THE ASSOCIATIONS BETWEEN LOW BIRTH WEIGHT AND DISEASES IN LATER LIFE ARE EXPLAINED BY ADAPTATION MECHANISMS IN FETAL LIFE AND INFANCY IN RESPONSE TO VARIOUS ADVERSE EXPOSURES. VARIOUS PATHWAYS LEADING FROM ADVERSE FETAL AND INFANT EXPOSURES TO GROWTH ADAPTATIONS AND RESPIRATORY HEALTH OUTCOMES HAVE BEEN STUDIED, INCLUDING FETAL AND EARLY INFANT GROWTH PATTERNS, MATERNAL SMOKING AND DIET, CHILDREN'S DIET, RESPIRATORY TRACT INFECTIONS AND ACETAMINOPHEN USE, AND GENETIC SUSCEPTIBILITY. STILL, THE SPECIFIC ADVERSE EXPOSURES IN FETAL AND EARLY POSTNATAL LIFE LEADING TO RESPIRATORY DISEASE IN ADULT LIFE ARE NOT YET FULLY UNDERSTOOD. CURRENT STUDIES SUGGEST THAT BOTH ENVIRONMENTAL AND GENETIC FACTORS IN VARIOUS PERIODS OF LIFE, AND THEIR EPIGENETIC MECHANISMS MAY UNDERLIE THE COMPLEX ASSOCIATIONS OF LOW BIRTH WEIGHT WITH RESPIRATORY DISEASE IN LATER LIFE. NEW WELL-DESIGNED EPIDEMIOLOGICAL STUDIES ARE NEEDED TO IDENTIFY THE SPECIFIC UNDERLYING MECHANISMS. THIS REVIEW IS FOCUSED ON SPECIFIC ADVERSE FETAL AND INFANT GROWTH PATTERNS AND EXPOSURES, GENETIC SUSCEPTIBILITY, POSSIBLE RESPIRATORY ADAPTATIONS AND PERSPECTIVES FOR NEW STUDIES. 2012 6 317 50 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 7 6814 41 [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 8 6819 48 [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 9 1766 45 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 10 1992 40 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 11 2274 39 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 12 4083 39 MATERNAL NUTRITION AND FETAL DEVELOPMENT. NUTRITION IS THE MAJOR INTRAUTERINE ENVIRONMENTAL FACTOR THAT ALTERS EXPRESSION OF THE FETAL GENOME AND MAY HAVE LIFELONG CONSEQUENCES. THIS PHENOMENON, TERMED "FETAL PROGRAMMING," HAS LED TO THE RECENT THEORY OF "FETAL ORIGINS OF ADULT DISEASE." NAMELY, ALTERATIONS IN FETAL NUTRITION AND ENDOCRINE STATUS MAY RESULT IN DEVELOPMENTAL ADAPTATIONS THAT PERMANENTLY CHANGE THE STRUCTURE, PHYSIOLOGY, AND METABOLISM OF THE OFFSPRING, THEREBY PREDISPOSING INDIVIDUALS TO METABOLIC, ENDOCRINE, AND CARDIOVASCULAR DISEASES IN ADULT LIFE. ANIMAL STUDIES SHOW THAT BOTH MATERNAL UNDERNUTRITION AND OVERNUTRITION REDUCE PLACENTAL-FETAL BLOOD FLOWS AND STUNT FETAL GROWTH. IMPAIRED PLACENTAL SYNTHESES OF NITRIC OXIDE (A MAJOR VASODILATOR AND ANGIOGENESIS FACTOR) AND POLYAMINES (KEY REGULATORS OF DNA AND PROTEIN SYNTHESIS) MAY PROVIDE A UNIFIED EXPLANATION FOR INTRAUTERINE GROWTH RETARDATION IN RESPONSE TO THE 2 EXTREMES OF NUTRITIONAL PROBLEMS WITH THE SAME PREGNANCY OUTCOME. THERE IS GROWING EVIDENCE THAT MATERNAL NUTRITIONAL STATUS CAN ALTER THE EPIGENETIC STATE (STABLE ALTERATIONS OF GENE EXPRESSION THROUGH DNA METHYLATION AND HISTONE MODIFICATIONS) OF THE FETAL GENOME. THIS MAY PROVIDE A MOLECULAR MECHANISM FOR THE IMPACT OF MATERNAL NUTRITION ON BOTH FETAL PROGRAMMING AND GENOMIC IMPRINTING. PROMOTING OPTIMAL NUTRITION WILL NOT ONLY ENSURE OPTIMAL FETAL DEVELOPMENT, BUT WILL ALSO REDUCE THE RISK OF CHRONIC DISEASES IN ADULTS. 2004 13 2803 40 FETAL DEVELOPMENTAL PROGRAMING: INSIGHTS FROM HUMAN STUDIES AND EXPERIMENTAL MODELS. BACKGROUND: ENVIRONMENTAL FACTORS, PARTICULARLY NUTRITION DURING PREGNANCY AND EARLY LIFE CAN INFLUENCE THE RISK OF CHRONIC DISEASES IN LATER LIFE. THE UNDERLYING MECHANISM, TERMED "PROGRAMING", POSTULATES THAT AN ENVIRONMENTAL STIMULUS DURING A CRITICAL WINDOW OF TIME, EARLY IN LIFE, HAS A PERMANENT EFFECT ON SUBSEQUENT STRUCTURE AND FUNCTION OF THE ORGANISM. OBJECTIVE: IN THIS STUDY WE REVIEW THE CONCEPT OF FETAL PROGRAMING ON CHRONIC DISEASES AND THE PROPOSED HYPOTHESES FOR THE ASSOCIATION BETWEEN EARLY DEVELOPMENT AND LATER DISEASE, INCLUDING EPIGENETIC VARIATION. WE CONCENTRATE ON SPECIFIC ASPECTS OF MATERNAL NUTRITION, PARTICULARLY UNDER-NUTRITION AND OVER-NUTRITION, IN HUMANS AND ANIMAL MODELS. CONCLUSION: AN ADEQUATE MATERNAL NUTRITION DURING PREGNANCY IS CRUCIAL FOR THE HEALTH OUTCOME OF THE OFFSPRING AT ADULTHOOD. 2017 14 1922 39 ENVIRONMENTAL EPIGENETIC INTERACTION OF GAMETES AND EARLY EMBRYOSDAGGER. IN RECENT YEARS, THE DEVELOPMENTAL ORIGINS OF DISEASES HAVE BEEN INCREASINGLY RECOGNIZED AND ACCEPTED. AS SUCH, IT HAS BEEN SUGGESTED THAT MOST ADULTHOOD CHRONIC DISEASES SUCH AS DIABETES, OBESITY, CARDIOVASCULAR DISEASE, AND EVEN TUMORS MAY DEVELOP AT A VERY EARLY STAGE. IN ADDITION TO INTRAUTERINE ENVIRONMENTAL EXPOSURE, GERM CELLS CARRY AN IMPORTANT INHERITANCE ROLE AS THE PRIMARY LINK BETWEEN THE TWO GENERATIONS. ADVERSE EXTERNAL INFLUENCES DURING DIFFERENTIATION AND DEVELOPMENT CAN CAUSE DAMAGE TO GERM CELLS, WHICH MAY THEN INCREASE THE RISK OF CHRONIC DISEASE DEVELOPMENT LATER IN LIFE. HERE, WE FURTHER ELUCIDATE AND CLARIFY THE CONCEPT OF GAMETE AND EMBRYO ORIGINS OF ADULT DISEASES BY FOCUSING ON THE ENVIRONMENTAL INSULTS ON GERM CELLS, FROM DIFFERENTIATION TO MATURATION AND FERTILIZATION. 2022 15 6803 30 [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 4998 42 PERINATAL ORIGINS OF ADULT DISEASE. EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES HAVE SHOWN THAT THE PERI-CONCEPTION PERIOD, PREGNANCY, AND INFANCY ARE WINDOWS OF PARTICULAR SENSIBILITY TO ENVIRONMENTAL CLUES WHICH INFLUENCE LIFELONG TRAJECTORIES ACROSS HEALTH AND DISEASE. NUTRITION, STRESS, AND TOXINS INDUCE EPIGENETIC MARKS THAT CONTROL LONG-TERM GENE EXPRESSION PATTERNS AND CAN BE TRANSMITTED TRANSGENERATIONALLY. CHRONIC DISEASES OF ADULTHOOD SUCH AS HYPERTENSION, DIABETES, AND OBESITY THUS HAVE EARLY, DEVELOPMENTAL ORIGINS IN THE PERINATAL PERIOD. THE EARLY EPIGENOME, IN INTERACTION WITH OTHER ACTORS SUCH AS THE MICROBIOME, ADD POWERFUL LAYERS OF DIVERSITY TO THE BIOLOGICAL PREDISPOSITION GENERATED BY THE GENOME. SUCH "PROGRAMMING" IS A NORMAL, ADAPTIVE COMPONENT OF DEVELOPMENT, INCLUDING IN NORMAL PREGNANCIES AND BIRTHS. HOWEVER, PERINATAL DISEASE, EITHER MATERNAL (SUCH AS PRE-ECLAMPSIA, GES-TATIONAL DIABETES, OR INFLAMMATORY DISEASE) OR FETAL, AND NEONATAL DISEASES (SUCH AS INTRAUTERINE GROWTH RESTRICTION AND PRETERM BIRTH) ARE MAJOR CONDITIONS OF ALTERED PROGRAMMING, TRANSLATED INTO AN INCREASED RISK FOR CHRONIC DISEASE IN THESE PATIENTS WHEN THEY REACH ADULTHOOD. EARLY PREVENTION, OPTIMAL PERINATAL NUTRITION, AND SPECIFIC FOLLOW-UP MEASURES ARE KEY FACTORS IN THE EARLY PRESERVATION OF LONG-TERM HEALTH. 2018 17 2267 37 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 18 1375 34 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 6873 40 [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 20 3572 47 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