1 483 155 ART AND HEALTH: CLINICAL OUTCOMES AND INSIGHTS ON MOLECULAR MECHANISMS FROM RODENT STUDIES. SINCE THE BIRTH OF THE FIRST IVF-CONCEIVED CHILD IN 1978, THE USE OF ASSISTED REPRODUCTIVE TECHNOLOGIES (ART) HAS GROWN DRAMATICALLY, CONTRIBUTING TO THE SUCCESSFUL BIRTH OF 5 MILLION INDIVIDUALS WORLDWIDE. HOWEVER, THERE ARE SEVERAL REPORTED ASSOCIATIONS OF ART WITH PREGNANCY COMPLICATIONS, SUCH AS LOW BIRTHWEIGHT (LBW), PRETERM BIRTH, BIRTH DEFECTS, EPIGENETIC DISORDERS, CANCER AND POOR METABOLIC HEALTH. WHETHER THIS IS ATTRIBUTED TO ART PROCEDURES OR TO THE SUBSET OF THE POPULATION SEEKING ART REMAINS A CONTROVERSY, BUT THE MOST RELEVANT QUESTION TODAY CONCERNS THE POTENTIAL LONG-TERM IMPLICATIONS OF ASSISTED CONCEPTION. RECENT EVIDENCE HAS EMERGED SUGGESTING THAT ART-CONCEIVED CHILDREN HAVE DISTINCT METABOLIC PROFILES THAT MAY PREDISPOSE TO CARDIOVASCULAR PATHOLOGIES IN ADULTHOOD. BECAUSE THE ELDEST IVF INDIVIDUALS ARE STILL TOO YOUNG TO EXHIBIT COMPONENTS OF CHRONIC MIDDLE-AGED SYNDROMES, THE USE OF ANIMAL MODELS HAS BECOME PARTICULARLY USEFUL IN DESCRIBING THE EFFECTS OF UNUSUAL OR STRESSFUL PREIMPLANTATION EXPERIENCES ON ADULT FITNESS. ELUCIDATING THE MOLECULAR MECHANISMS BY WHICH EMBRYOS INTEGRATE ENVIRONMENTAL SIGNALS INTO DEVELOPMENT AND METABOLIC GENE EXPRESSION PROGRAMS WILL BE ESSENTIAL FOR OPTIMIZING ART PROCEDURES SUCH AS IN VITRO CULTURE CONDITIONS, EMBRYO SELECTION AND TRANSFER. IN THE FUTURE, ADDITIONAL ANIMAL STUDIES TO IDENTIFY MECHANISMS UNDERLYING UNFAVORABLE ART OUTCOMES, AS WELL AS MORE EPIDEMIOLOGICAL REVIEWS TO MONITOR THE LONG-TERM HEALTH OF ART CHILDREN ARE REQUIRED, GIVEN THAT ART PROCEDURES HAVE BECOME ROUTINE MEDICAL PRACTICE. 2013 2 6173 55 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 3 721 40 CAN ASSISTED REPRODUCTIVE TECHNOLOGIES CAUSE ADULT-ONSET DISEASE? EVIDENCE FROM HUMAN AND MOUSE. MILLIONS OF CHILDREN HAVE BEEN BORN WORLDWIDE THOUGH ASSISTED REPRODUCTIVE TECHNOLOGIES (ART). CONSISTENT WITH THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS, THERE IS CONCERN THAT ART CAN INDUCE ADVERSE EFFECTS, ESPECIALLY BECAUSE PROCEDURES COINCIDE WITH EPIGENETIC REPROGRAMMING EVENTS. ALTHOUGH THE MAJORITY OF STUDIES INVESTIGATING THE EFFECTS OF ART HAVE FOCUSED ON PERINATAL OUTCOMES, MORE RECENT STUDIES DEMONSTRATE THAT ART-CONCEIVED CHILDREN MAY BE AT INCREASED RISK FOR POSTNATAL EFFECTS. HERE, WE PRESENT THE CURRENT EPIDEMIOLOGICAL EVIDENCE THAT ART-CONCEIVED CHILDREN HAVE DETECTABLE DIFFERENCES IN BLOOD PRESSURE, BODY COMPOSITION, AND GLUCOSE HOMEOSTASIS. SIMILAR EFFECTS ARE OBSERVED IN THE ART MOUSE MODEL, WHICH HAVE NO UNDERLYING INFERTILITY, SUGGESTING THAT CARDIOMETABOLIC EFFECTS ARE LIKELY CAUSED BY ART PROCEDURES AND NOT DUE TO REASONS RELATED TO INFERTILITY. WE PROPOSE THAT THE MOUSE SYSTEM CAN, CONSEQUENTLY, BE USED TO ADEQUATELY STUDY, MODIFY, AND IMPROVE OUTCOMES FOR ART CHILDREN. 2017 4 6088 57 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 5 6867 37 [PARENTAL AGEING AND ASSISTED REPRODUCTION TECHNOLOGIES: ANALYSIS OF RISK OF CHRONIC DISEASES IN THE PROGENY]. CONCEPTION OF A CHILD AT ADVANCED PARENTAL AGE (> 35 YEARS) HAS BEEN STEADILY INCREASING IN RECENT DECADES, ESPECIALLY IN DEVELOPED COUNTRIES. SOCIO-ECONOMIC FACTORS, EFFECTIVE CONTRACEPTIVES, AND THE AVAILABILITY OF ASSISTED REPRODUCTION TECHNOLOGIES (ART) HAVE A DIRECT IMPACT ON POSTPONING THE DECISION TO HAVE A BABY. ART ENABLES REPRODUCTIVE SUCCESS FOR PEOPLE DIAGNOSED AS INFERTILE OR WITH REDUCED POSSIBILITIES OF BECOMING PREGNANT DUE TO CONCOMITANT PATHOLOGIES. EPIDEMIOLOGICAL STUDIES INDICATE THAT BOTH ADVANCED PARENTAL AGE AND ART ARE ASSOCIATED WITH PATHOLOGIES OF PREGNANCY, SUCH AS GESTATIONAL DIABETES, RISK OF PRE-ECLAMPSIA, MISCARRIAGE, PLACENTAL ABRUPTION, PRETERM LABOR, STILLBIRTH, NEURODEVELOPMENTAL DISORDERS AND CHRONIC DISEASE OF THE OFFSPRING. IN OUR WORK, WE WILL FOCUS ON THE AVAILABLE INFORMATION ON METABOLIC CHANGES THAT INCREASE THE RISK OF DEVELOPING CARDIOVASCULAR DISEASES IN THE OFFSPRING OF PARENTS AT AN ADVANCED AGE AND CONCEIVED THROUGH ART. FINALLY, WE WILL ADDRESS THE SOURCES OF THE OBSERVED DISTURBANCES AT THE GAMETE AND EMBRYO LEVEL, RELATED TO OXYGEN STRESS, EPIGENETIC MODIFICATIONS AND DNA DAMAGE, CONSIDERING POSSIBLE RESCUE ACTIONS. 2022 6 1911 41 ENVIRONMENT IN CHILDREN'S HEALTH: A NEW CHALLENGE FOR RISK ASSESSMENT. IN THE LAST FEW YEARS, MANY STUDIES HAVE FOCUSED ON THE EFFECTS OF ENVIRONMENTAL CONTAMINANT EXPOSURE DURING THE PRENATAL PERIOD OR INFANCY AS PREDICTORS OF HEALTH OUTCOMES IN THE FUTURE. IN THESE TIME WINDOWS, DUE TO THEIR RAPID GROWTH, AND PHYSIOLOGIC AND METABOLIC DEVELOPMENT, WE CAN OBSERVE A HIGHER VULNERABILITY TO THE EFFECTS OF ENVIRONMENT, WITH RESPECT TO ADULTHOOD. THE EVIDENCE OF POSSIBLE INFLUENCES, PARTLY MEDIATED BY EPIGENETIC MECHANISMS, INVOLVE NEUROBEHAVIORAL RESPONSES AND IMMUNE, ENDOCRINE, AND RESPIRATORY SYSTEMS, ACTING DIRECTLY ON THE CHILD OR INDIRECTLY WHEN MEDIATED BY PLACENTAL TRANSFER OR BREAST FEEDING. IN PARTICULAR, DUE TO A GREATER INTAKE OF AIR, FOOD, AND FLUIDS RELATIVE TO BODY WEIGHT, CRAWLING BEHAVIORS AND SHORT STATURE, THE RISK OF EXCESSIVE EXPOSURE IS GREATER IN CHILDREN. HOWEVER, DATA ON THE LONG-TERM IMPLICATIONS OF EARLY EXPOSURES ARE SCARCE. ADDITIONALLY, SO THAT PHYSICIANS AND INSTITUTIONS FOR CHILD CARE AND ASSISTANCE OF PREGNANT WOMEN CAN TAKE ACTIONS TO COUNTERACT THE EFFECTS OF CHEMICAL POLLUTION (I.E., BY EDUCATIONAL OPPORTUNITIES), A RISK ASSESSMENT PERSPECTIVE THAT RESPONDS TO THE BIOCOMPLEXITY OF THE HUMAN BEING IS NEEDED. THE PRESENT PAPER PROVIDES AN OVERVIEW OF PHYSIOLOGIC AND BEHAVIORAL CHARACTERISTICS DURING THE PERINATAL PERIOD AND IN CHILDHOOD, SUGGESTING IN A MORE INTEGRATED WAY, THE NEED OF A NEW RISK-ASSESSMENT APPROACH TO MANAGING CHRONIC DISEASE IN PEDIATRIC PATIENTS. 2021 7 1755 43 EARLY NUTRITION AND LATER OUTCOMES IN PRETERM INFANTS. THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE IS AN EMERGING AREA OF INTEREST THAT AMALGAMATES MANY AREAS OF SCIENTIFIC STUDIES AND ENCOMPASSES A WIDE RANGE OF DIVERSE DISCIPLINES FROM EPIDEMIOLOGY TO MOLECULAR BIOLOGY. EVIDENCE HAS ACCUMULATED TO SHOW THAT EARLY LIFE EXPERIENCES, BOTH IN UTERO AND IN INFANCY HAVE LONG-TERM EFFECTS ON MANY BODY SYSTEMS. THERE ARE NOW GOOD DATA TO SHOW THAT SUBOPTIMAL IN UTERO GROWTH, ESPECIALLY WHEN COMBINED WITH RAPID GROWTH ACCELERATION IN EARLY POSTNATAL LIFE MAY INCREASE THE RISK OF LATER LIFE METABOLIC DISEASE. THE MECHANISMS ARE COMPLEX BUT LIKELY TO INVOLVE EPIGENETIC MARKS SUCH AS DNA METHYLATION. PRETERM INFANTS FREQUENTLY EXPERIENCE SUBOPTIMAL NUTRIENT INTAKES IN EARLY POSTNATAL LIFE AND EXHIBIT GROWTH FAILURE WITHIN THE NICU. THEY ALSO RECEIVE PRODUCTS THAT MAY NOT PROVIDE EITHER AN OPTIMAL QUANTITY OR QUALITY OF NUTRIENTS. FOLLOW-UP STUDIES HAVE NOW SHOWN MUCH HIGHER RISKS FOR LONG-TERM CHRONIC DISEASE IN CHILDREN AND ADULTS WHO WERE BORN PRETERM. THERE ARE HIGHER LEVELS OF INSULIN RESISTANCE AND ABNORMAL PARTITIONING OF FAT DEPOSITION. THE ONSET OF PUBERTY SEEMS EARLIER, AVERAGE HEIGHT IS LESS AND BLOOD PRESSURE, MEASURES OF VASCULAR HEALTH AND LIPID PROFILES SUGGEST CARDIOVASCULAR HEALTH IS LIKELY TO DIFFER FROM HEALTHY TERM BORN CONTROLS. DESPITE THIS, THERE ARE NO DATA TO SUGGEST AN OVERALL BENEFIT OF LIMITING NUTRIENT INTAKE, OR RESTRICTING GROWTH IN PRETERM INFANTS. THERE ARE STRONG DATA TO SHOW THAT THE PRETERM BRAIN IS EXQUISITELY VULNERABLE TO UNDERNUTRITION, AND THAT SUBOPTIMAL NUTRIENT INTAKES MAY PERMANENTLY AFFECT LATER COGNITIVE ATTAINMENT. A CLINICAL FOCUS ON EARLY NUTRIENT INTAKES AND BREAST MILK PROVISION IS KEY TO OPTIMISING LONG-TERM HEALTH OUTCOMES. 2013 8 6554 30 TRANSGENERATIONAL EFFECTS OF EARLY ENVIRONMENTAL INSULTS ON AGING AND DISEASE INCIDENCE. ADVERSE EARLY LIFE EXPERIENCES ARE MAJOR INFLUENCES ON DEVELOPMENTAL TRAJECTORIES WITH POTENTIALLY LIFE-LONG CONSEQUENCES. PRENATAL OR EARLY POSTNATAL EXPOSURE TO STRESS, UNDERNUTRITION OR ENVIRONMENTAL TOXICANTS MAY REPROGRAM BRAIN DEVELOPMENT AND INCREASE RISK OF BEHAVIOURAL AND NEUROLOGICAL DISORDERS LATER IN LIFE. NOT ONLY EXPERIENCE WITHIN A SINGLE LIFETIME, BUT ALSO ANCESTRAL EXPERIENCE AFFECTS HEALTH TRAJECTORIES AND CHANCES OF SUCCESSFUL AGING. THE CENTRAL MECHANISM IN TRANSGENERATIONAL PROGRAMMING OF A DISEASE MAY BE THE FORMATION OF EPIGENETIC MEMORY. THIS REVIEW EXPLORES TRANSGENERATIONAL EFFECTS OF EARLY ADVERSE EXPERIENCE ON HEALTH AND DISEASE INCIDENCE IN OLDER AGE. FIRST, WE ADDRESS MECHANISMS OF DEVELOPMENTAL AND TRANSGENERATIONAL PROGRAMMING OF DISEASE AND INHERITANCE. SECOND, WE DISCUSS EXPERIMENTAL AND CLINICAL FINDINGS LINKING EARLY ENVIRONMENTAL DETERMINANTS TO ADVERSE AGING TRAJECTORIES IN ASSOCIATION WITH POSSIBLE PARENTAL CONTRIBUTIONS AND SEX-SPECIFIC EFFECTS. THIRD, WE OUTLINE THE MAIN MECHANISMS OF AGE-RELATED FUNCTIONAL DECLINE AND SUGGEST POTENTIAL INTERVENTIONS TO REVERSE NEGATIVE EFFECTS OF TRANSGENERATIONAL PROGRAMMING. THUS, STRATEGIES THAT SUPPORT HEALTHY DEVELOPMENT AND SUCCESSFUL AGING SHOULD TAKE INTO ACCOUNT THE POTENTIAL INFLUENCES OF TRANSGENERATIONAL INHERITANCE. 2020 9 3582 25 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 10 5216 41 PRETERM BIRTH: LONG TERM CARDIOVASCULAR AND RENAL CONSEQUENCES. BACKGROUND: CARDIOVASCULAR AND CHRONIC KIDNEY DISEASES ARE A PART OF NONCOMMUNICABLE CHRONIC DISEASES, THE LEADING CAUSES OF PREMATURE DEATH WORLDWIDE. THEY ARE RECOGNIZED AS HAVING EARLY ORIGINS THROUGH ALTERED DEVELOPMENTAL PROGRAMMING, DUE TO ADVERSE ENVIRONMENTAL CONDITIONS DURING DEVELOPMENT. PRETERM BIRTH IS SUCH AN ADVERSE FACTOR. RATES OF PRETERM BIRTH INCREASED IN THE LAST DECADES, HOWEVER, WITH THE IMPROVEMENT IN PERINATAL AND NEONATAL CARE, A GROWING NUMBER OF PRETERM BORN SUBJECTS HAS NOW ENTERED ADULTHOOD. CLINICAL AND EXPERIMENTAL EVIDENCE SUGGESTS THAT PRETERM BIRTH IS ASSOCIATED WITH IMPAIRED OR ARRESTED STRUCTURAL OR FUNCTIONAL DEVELOPMENT OF KEY ORGANS/SYSTEMS MAKING PRETERM INFANTS VULNERABLE TO CARDIOVASCULAR AND CHRONIC RENAL DISEASES AT ADULTHOOD. THIS REVIEW ANALYZES THE EVIDENCE OF SUCH CARDIOVASCULAR AND RENAL CHANGES, THE ROLE OF PERINATAL AND NEONATAL FACTORS SUCH AS ANTENATAL STEROIDS AND POTENTIAL PATHOGENIC MECHANISMS, INCLUDING DEVELOPMENTAL PROGRAMMING AND EPIGENETIC ALTERATIONS. CONCLUSION: PRETERM BORN SUBJECTS ARE EXPOSED TO A SIGNIFICANTLY INCREASED RISK FOR ALTERED CARDIOVASCULAR AND RENAL FUNCTIONS AT YOUNG ADULTHOOD. ADEQUATE, SPECIFIC FOLLOW-UP MEASURES REMAIN TO BE DETERMINED. WHILE ANTENATAL STEROIDS HAVE CONSIDERABLY IMPROVED PRETERM BIRTH OUTCOMES, REPEATED THERAPY SHOULD BE CONSIDERED WITH CAUTION, AS ANTENATAL STEROIDS INDUCE LONG-TERM CARDIOVASCULAR AND METABOLIC ALTERATIONS IN ANIMALS' MODELS AND THEIR INVOLVEMENT IN THE ACCELERATED CELLULAR SENESCENCE OBSERVED IN HUMAN STUDIES CANNOT BE EXCLUDED. 2018 11 1370 39 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 4803 32 OBESITY AND MALE INFERTILITY. THE WORLDWIDE PREVALENCE OF OBESITY IS INCREASING AMONG BOTH SEXES, WITH ASSOCIATED IMPACTS ON CHRONIC HEALTH AND MEDICAL COMORBIDITIES. SIMILARLY, THE EFFECTS OF OBESITY ON REPRODUCTIVE HEALTH ARE INCREASINGLY BEING RECOGNIZED. ADIPOSITY IS ASSOCIATED WITH REDUCED FERTILITY IN MEN, WITH A COMPLEX AND MULTIFACTORIAL ETIOLOGY. THE REPORTED EFFECTS OF OBESITY ON SEMEN PARAMETERS AND IMPAIRED FERTILITY ARE CONTRASTING, WITH SOME STUDIES SHOWING A CLEAR REDUCTION IN REPRODUCTIVE OUTCOMES ASSOCIATED WITH INCREASED BODY MASS INDEX, WHILE OTHERS DO NOT SHOW SUCH IMPACTS. THESE CONTROVERSIES MAY BE DUE TO THE COMPLEX PATHOPHYSIOLOGY AND INTERPLAY BETWEEN GONADOTROPINS AND END ORGANS, AS WELL AS GENETIC AND EPIGENETIC CHANGES AND OXIDATIVE STRESS ON MALE FERTILITY AND FUNCTION. THESE DIFFERENT ASPECTS HAVE LED TO HETEROGENEOUS PARTICIPANTS IN STUDIES AND VARYING IMPLICATIONS FOR ASSISTED REPRODUCTIVE OUTCOMES AS WELL AS OFFSPRING HEALTH. TREATMENT MODALITIES TO MANAGE OBESITY INCLUDE LIFESTYLE, MEDICAL, AND SURGICAL OPTIONS, WITH EMERGING AND EFFECTIVE MEDICAL TREATMENTS SHOWING PROMISE IN REPRODUCTIVE OUTCOMES. 2023 13 1372 42 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 14 2274 36 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 15 2802 37 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 16 6823 29 [GENERAL CONCEPTS OF EPIGENETICS: PROJECTIONS IN PAEDIATRICS]. CURRENT EVIDENCE SUPPORTS THE NOTION THAT ALTERATIONS IN INTRAUTERINE GROWTH AND DURING THE FIRST YEARS OF LIFE HAVE A SUBSTANTIAL EFFECT ON THE RISK FOR THE DEVELOPMENT OF CHRONIC DISEASE, WHICH IN SOME CASES IS EVEN HIGHER THAN THOSE DUE TO GENETIC FACTORS. THE PERSISTENCE AND REPRODUCIBILITY OF THE PHENOTYPES ASSOCIATED WITH ALTERED EARLY DEVELOPMENT SUGGEST THE PARTICIPATION OF MECHANISMS THAT WOULD RECORD ENVIRONMENTAL CUES, GENERATING A CELLULAR REPROGRAMMING (I.E., EPIGENETIC MECHANISMS). THIS REVIEW IS AN INTRODUCTION TO A SERIES OF FIVE ARTICLES FOCUSED ON THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF HIGHLY PREVALENT CHRONIC DISEASES (I.E., CARDIOVASCULAR, METABOLIC, ASTHMA/ALLERGIES AND CANCER) AND THEIR ORIGINS IN THE FOETAL AND NEONATAL PERIOD. THIS SERIES OF ARTICLES AIMS TO SHOW THE STATE OF THE ART IN THIS RESEARCH AREA AND PRESENT THE UPCOMING CLUES AND CHALLENGES, IN WHICH PAEDIATRICIANS HAVE A PROMINENT ROLE, DEVELOPING STRATEGIES FOR THE PREVENTION, EARLY DETECTION AND FOLLOW-UP. 2016 17 4863 42 ORIGINS OF LIFETIME HEALTH AROUND THE TIME OF CONCEPTION: CAUSES AND CONSEQUENCES. PARENTAL ENVIRONMENTAL FACTORS, INCLUDING DIET, BODY COMPOSITION, METABOLISM, AND STRESS, AFFECT THE HEALTH AND CHRONIC DISEASE RISK OF PEOPLE THROUGHOUT THEIR LIVES, AS CAPTURED IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT. RESEARCH ACROSS THE EPIDEMIOLOGICAL, CLINICAL, AND BASIC SCIENCE FIELDS HAS IDENTIFIED THE PERIOD AROUND CONCEPTION AS BEING CRUCIAL FOR THE PROCESSES MEDIATING PARENTAL INFLUENCES ON THE HEALTH OF THE NEXT GENERATION. DURING THIS TIME, FROM THE MATURATION OF GAMETES THROUGH TO EARLY EMBRYONIC DEVELOPMENT, PARENTAL LIFESTYLE CAN ADVERSELY INFLUENCE LONG-TERM RISKS OF OFFSPRING CARDIOVASCULAR, METABOLIC, IMMUNE, AND NEUROLOGICAL MORBIDITIES, OFTEN TERMED DEVELOPMENTAL PROGRAMMING. WE REVIEW PERICONCEPTIONAL INDUCTION OF DISEASE RISK FROM FOUR BROAD EXPOSURES: MATERNAL OVERNUTRITION AND OBESITY; MATERNAL UNDERNUTRITION; RELATED PATERNAL FACTORS; AND THE USE OF ASSISTED REPRODUCTIVE TREATMENT. STUDIES IN BOTH HUMANS AND ANIMAL MODELS HAVE DEMONSTRATED THE UNDERLYING BIOLOGICAL MECHANISMS, INCLUDING EPIGENETIC, CELLULAR, PHYSIOLOGICAL, AND METABOLIC PROCESSES. WE ALSO PRESENT A META-ANALYSIS OF MOUSE PATERNAL AND MATERNAL PROTEIN UNDERNUTRITION THAT SUGGESTS DISTINCT PARENTAL PERICONCEPTIONAL CONTRIBUTIONS TO POSTNATAL OUTCOMES. WE PROPOSE THAT THE EVIDENCE FOR PERICONCEPTIONAL EFFECTS ON LIFETIME HEALTH IS NOW SO COMPELLING THAT IT CALLS FOR NEW GUIDANCE ON PARENTAL PREPARATION FOR PREGNANCY, BEGINNING BEFORE CONCEPTION, TO PROTECT THE HEALTH OF OFFSPRING. 2018 18 4790 37 NUTRITIONAL ADVERSITY, SEX AND REPRODUCTION: 30 YEARS OF DOHAD AND WHAT HAVE WE LEARNED? IT IS WELL ESTABLISHED THAT EARLY LIFE ENVIRONMENTAL SIGNALS, INCLUDING NUTRITION, SET THE STAGE FOR LONG-TERM HEALTH AND DISEASE RISK - EFFECTS THAT SPAN MULTIPLE GENERATIONS. THIS RELATIONSHIP BEGINS EARLY, IN THE PERICONCEPTIONAL PERIOD AND EXTENDS INTO EMBRYONIC, FETAL AND EARLY INFANT PHASES OF LIFE. NOW KNOWN AS THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD), THIS CONCEPT DESCRIBES THE ADAPTATIONS THAT A DEVELOPING ORGANISM MAKES IN RESPONSE TO EARLY LIFE CUES, RESULTING IN ADJUSTMENTS IN HOMEOSTATIC SYSTEMS THAT MAY PROVE MALADAPTIVE IN POSTNATAL LIFE, LEADING TO AN INCREASED RISK OF CHRONIC DISEASE AND/OR THE INHERITANCE OF RISK FACTORS ACROSS GENERATIONS. REPRODUCTIVE MATURATION AND FUNCTION IS SIMILARLY INFLUENCED BY EARLY LIFE EVENTS. THIS SHOULD NOT BE SURPRISING, SINCE PRIMORDIAL GERM CELLS ARE ESTABLISHED EARLY IN LIFE AND THUS VULNERABLE TO EARLY LIFE ADVERSITY. A MULTITUDE OF 'MODIFYING' CUES INDUCING DEVELOPMENTAL ADAPTATIONS HAVE BEEN IDENTIFIED THAT RESULT IN CHANGES IN REPRODUCTIVE DEVELOPMENT AND IMPAIRMENTS IN REPRODUCTIVE FUNCTION. MANY TYPES OF NUTRITIONAL CHALLENGES INCLUDING CALORIC RESTRICTION, MACRONUTRIENT EXCESS AND MICRONUTRIENT INSUFFICIENCIES HAVE BEEN SHOWN TO INDUCE EARLY LIFE ADAPTATIONS THAT PRODUCE LONG-TERM REPRODUCTIVE DYSFUNCTION. MANY PATHWAYS HAVE BEEN SUGGESTED TO UNDERPIN THESE ASSOCIATIONS, INCLUDING EPIGENETIC REPROGRAMMING OF GERM CELLS. WHILE THE MECHANISMS STILL REMAIN TO BE FULLY INVESTIGATED, IT IS CLEAR THAT A LIFECOURSE APPROACH TO UNDERSTANDING LIFETIME REPRODUCTIVE FUNCTION IS NECESSARY. FURTHERMORE, INVESTIGATIONS OF THE IMPACTS OF EARLY LIFE ADVERSITY MUST BE EXTENDED TO INCLUDE THE PATERNAL ENVIRONMENT, ESPECIALLY IN EPIDEMIOLOGICAL AND CLINICAL STUDIES OF OFFSPRING REPRODUCTIVE FUNCTION. 2019 19 6064 33 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 20 6234 32 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