1 4197 136 METABOLIC PROFILES IN OVINE CAROTID ARTERIES WITH DEVELOPMENTAL MATURATION AND LONG-TERM HYPOXIA. BACKGROUND: LONG-TERM HYPOXIA (LTH) IS AN IMPORTANT STRESSOR RELATED TO HEALTH AND DISEASE DURING DEVELOPMENT. AT DIFFERENT TIME POINTS FROM FETUS TO ADULT, WE ARE EXPOSED TO HYPOXIC STRESS BECAUSE OF PLACENTAL INSUFFICIENCY, HIGH-ALTITUDE RESIDENCE, SMOKING, CHRONIC ANEMIA, PULMONARY, AND HEART DISORDERS, AS WELL AS CANCERS. INTRAUTERINE HYPOXIA CAN LEAD TO FETAL GROWTH RESTRICTION AND LONG-TERM SEQUELAE SUCH AS COGNITIVE IMPAIRMENTS, HYPERTENSION, CARDIOVASCULAR DISORDERS, DIABETES, AND SCHIZOPHRENIA. SIMILARLY, PROLONGED HYPOXIC EXPOSURE DURING ADULT LIFE CAN LEAD TO ACUTE MOUNTAIN SICKNESS, CHRONIC FATIGUE, CHRONIC HEADACHE, COGNITIVE IMPAIRMENT, ACUTE CEREBRAL AND/OR PULMONARY EDEMA, AND DEATH. AIM: LTH ALSO CAN LEAD TO ALTERATION IN METABOLITES SUCH AS FUMARATE, 2-OXOGLUTARATE, MALATE, AND LACTATE, WHICH ARE LINKED TO EPIGENETIC REGULATION OF GENE EXPRESSION. IMPORTANTLY, DURING THE INTRAUTERINE LIFE, A FETUS IS UNDER A RELATIVE HYPOXIC ENVIRONMENT, AS COMPARED TO NEWBORN OR ADULT. THUS, THE CHANGES IN GENE EXPRESSION WITH DEVELOPMENT FROM FETUS TO NEWBORN TO ADULT MAY BE AS A CONSEQUENCE OF UNDERLYING CHANGES IN THE METABOLIC PROFILE BECAUSE OF THE HYPOXIC ENVIRONMENT ALONG WITH DEVELOPMENTAL MATURATION. TO EXAMINE THIS POSSIBILITY, WE EXAMINED THE METABOLIC PROFILE IN CAROTID ARTERIES FROM NEAR-TERM FETUS, NEWBORN, AND ADULT SHEEP IN BOTH NORMOXIC AND LONG-TERM HYPOXIC ACCLIMATIZED GROUPS. RESULTS: OUR RESULTS DEMONSTRATE THAT LTH DIFFERENTIALLY REGULATED GLUCOSE METABOLISM, MITOCHONDRIAL METABOLISM, NICOTINAMIDE COFACTOR METABOLISM, OXIDATIVE STRESS AND ANTIOXIDANTS, MEMBRANE LIPID HYDROLYSIS, AND FREE FATTY ACID METABOLISM, EACH OF WHICH MAY PLAY A ROLE IN GENETIC-EPIGENETIC REGULATION. 2015 2 6133 36 THE EPIGENETIC ROLE OF VITAMIN C IN NEURODEVELOPMENT. THE MATERNAL DIET DURING PREGNANCY IS A KEY DETERMINANT OF OFFSPRING HEALTH. EARLY STUDIES HAVE LINKED POOR MATERNAL NUTRITION DURING GESTATION WITH A PROPENSITY FOR THE DEVELOPMENT OF CHRONIC CONDITIONS IN OFFSPRING. THESE CONDITIONS INCLUDE CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND EVEN COMPROMISED MENTAL HEALTH. WHILE MULTIPLE FACTORS MAY CONTRIBUTE TO THESE OUTCOMES, DISTURBED EPIGENETIC PROGRAMMING DURING EARLY DEVELOPMENT IS ONE POTENTIAL BIOLOGICAL MECHANISM. THE EPIGENOME IS PROGRAMMED PRIMARILY IN UTERO, AND DURING THIS TIME, THE DEVELOPING FETUS IS HIGHLY SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS NUTRITIONAL INSULTS. DURING NEURODEVELOPMENT, EPIGENETIC PROGRAMMING COORDINATES THE FORMATION OF PRIMITIVE CENTRAL NERVOUS SYSTEM STRUCTURES, NEUROGENESIS, AND NEUROPLASTICITY. DYSREGULATED EPIGENETIC PROGRAMMING HAS BEEN IMPLICATED IN THE AETIOLOGY OF SEVERAL NEURODEVELOPMENTAL DISORDERS SUCH AS TATTON-BROWN-RAHMAN SYNDROME. ACCORDINGLY, THERE IS GREAT INTEREST IN DETERMINING HOW MATERNAL NUTRIENT AVAILABILITY IN PREGNANCY MIGHT AFFECT THE EPIGENETIC STATUS OF OFFSPRING, AND HOW SUCH INFLUENCES MAY PRESENT PHENOTYPICALLY. IN RECENT YEARS, A NUMBER OF EPIGENETIC ENZYMES THAT ARE ACTIVE DURING EMBRYONIC DEVELOPMENT HAVE BEEN FOUND TO REQUIRE VITAMIN C AS A COFACTOR. THESE ENZYMES INCLUDE THE TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASES (TETS) AND THE JUMONJI C DOMAIN-CONTAINING HISTONE LYSINE DEMETHYLASES THAT CATALYSE THE OXIDATIVE REMOVAL OF METHYL GROUPS ON CYTOSINES AND HISTONE LYSINE RESIDUES, RESPECTIVELY. THESE ENZYMES ARE INTEGRAL TO EPIGENETIC REGULATION AND HAVE FUNDAMENTAL ROLES IN CELLULAR DIFFERENTIATION, THE MAINTENANCE OF PLURIPOTENCY AND DEVELOPMENT. THE DEPENDENCE OF THESE ENZYMES ON VITAMIN C FOR OPTIMAL CATALYTIC ACTIVITY ILLUSTRATES A POTENTIALLY CRITICAL CONTRIBUTION OF THE NUTRIENT DURING MAMMALIAN DEVELOPMENT. THESE INSIGHTS ALSO HIGHLIGHT A POTENTIAL RISK ASSOCIATED WITH VITAMIN C INSUFFICIENCY DURING PREGNANCY. THE LINK BETWEEN VITAMIN C INSUFFICIENCY AND DEVELOPMENT IS PARTICULARLY APPARENT IN THE CONTEXT OF NEURODEVELOPMENT AND HIGH VITAMIN C CONCENTRATIONS IN THE BRAIN ARE INDICATIVE OF IMPORTANT FUNCTIONAL REQUIREMENTS IN THIS ORGAN. ACCORDINGLY, THIS REVIEW CONSIDERS THE EVIDENCE FOR THE POTENTIAL IMPACT OF MATERNAL VITAMIN C STATUS ON NEURODEVELOPMENTAL EPIGENETICS. 2022 3 4767 34 NUCLEAR AND MITOCHONDRIAL DNA ALTERATIONS IN NEWBORNS WITH PRENATAL EXPOSURE TO CIGARETTE SMOKE. NEWBORNS EXPOSED TO MATERNAL CIGARETTE SMOKE (CS) IN UTERO HAVE AN INCREASED RISK OF DEVELOPING CHRONIC DISEASES, CANCER, AND ACQUIRING DECREASED COGNITIVE FUNCTION IN ADULTHOOD. ALTHOUGH THE LITERATURE REPORTS MANY DELETERIOUS EFFECTS ASSOCIATED WITH MATERNAL CIGARETTE SMOKING ON THE FETUS, THE MOLECULAR ALTERATIONS AND MECHANISMS OF ACTION ARE NOT YET CLEAR. SMOKING MAY ACT DIRECTLY ON NUCLEAR DNA BY INDUCING MUTATIONS OR EPIGENETIC MODIFICATIONS. RECENT STUDIES ALSO INDICATE THAT SMOKING MAY ACT ON MITOCHONDRIAL DNA BY INDUCING A CHANGE IN THE NUMBER OF COPIES TO MAKE UP FOR THE DAMAGE CAUSED BY SMOKING ON THE RESPIRATORY CHAIN AND LACK OF ENERGY. IN ADDITION, INDIVIDUAL GENETIC SUSCEPTIBILITY PLAYS A SIGNIFICANT ROLE IN DETERMINING THE EFFECTS OF SMOKING DURING DEVELOPMENT. FURTHERMORE, PRIOR EXPOSURE OF PATERNAL AND MATERNAL GAMETES TO CIGARETTE SMOKE MAY AFFECT THE HEALTH OF THE DEVELOPING INDIVIDUAL, NOT ONLY THE IN UTERO EXPOSURE. THIS REVIEW EXAMINES THE GENETIC AND EPIGENETIC ALTERATIONS IN NUCLEAR AND MITOCHONDRIAL DNA ASSOCIATED WITH SMOKE EXPOSURE DURING THE MOST SENSITIVE PERIODS OF DEVELOPMENT (PRIOR TO CONCEPTION, PRENATAL AND EARLY POSTNATAL) AND ASSESSES HOW SUCH CHANGES MAY HAVE CONSEQUENCES FOR BOTH FETAL GROWTH AND DEVELOPMENT. 2015 4 2274 33 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 6819 43 [FETAL PROGRAMMING OF METABOLIC DISORDERS]. OUR KNOWLEDGE OF FETAL PROGRAMMING HAS DEVELOPED NOTABLY OVER THE YEARS AND RECENT DATA SUGGEST THAT AN UNBALANCED DIET PRIOR AND DURING PREGNANCY CAN HAVE EARLY-ONSET AND LONG-LASTING CONSEQUENCES ON THE HEALTH OF THE OFFSPRING. SPECIFIC NEGATIVE INFLUENCES OF HIGH DIETARY GLUCOSE AND LIPID CONSUMPTION, AS WELL AS UNDERNUTRITION, ARE ASSOCIATED WITH DEVELOPMENT OF METABOLIC SYNDROME, INSULIN RESISTANCE AND DIABETES IN THE OFFSPRING. THE MECHANISMS UNDERLYING THE EFFECTS OF MATERNAL HYPERGLYCEMIA ON THE FETUS MAY INVOLVE STRUCTURAL, METABOLIC AND EPIGENETIC CHANGES. THE AIM OF THIS REVIEW IS TO ILLUSTRATE HOW ADVERSE INTRAUTERINE ENVIRONMENT MAY INFLUENCE MOLECULAR MODIFICATIONS IN THE FETUS AND CAUSE EPIGENETIC ALTERATIONS IN PARTICULAR. IT HAS BEEN DEMONSTRATED THAT PRENATAL EPIGENETIC MODIFICATIONS MAY BE LINKED TO THE PATHOGENESIS AND PROGRESSION OF THE ADULT CHRONIC DISORDERS. STUDIES ON EPIGENETIC ALTERATIONS WILL CONTRIBUTE TO A BETTER UNDERSTANDING OF THE LONG-TERM EFFECTS OF IN UTERO EXPOSURE AND MAY OPEN NEW PERSPECTIVES FOR DISEASE PREVENTION AND TREATMENT. 2015 6 4125 30 MECHANISMS OF DISEASE: IN UTERO PROGRAMMING IN THE PATHOGENESIS OF HYPERTENSION. NUTRITIONAL AND OTHER ENVIRONMENTAL CUES DURING DEVELOPMENT CAN PERMANENTLY ALTER THE STRUCTURE, HOMEOSTATIC SYSTEMS, AND FUNCTIONS OF THE BODY. THIS PHENOMENON HAS BEEN REFERRED TO AS 'PROGRAMMING'. EPIDEMIOLOGICAL AND ANIMAL STUDIES SHOW THAT PROGRAMMED EFFECTS OPERATE WITHIN THE NORMAL RANGE OF GROWTH AND DEVELOPMENT, AND INFLUENCE THE RISK OF CHRONIC DISEASE IN ADULT LIFE. WE REVIEW THE EVIDENCE THAT THESE EFFECTS INCLUDE REDUCED NEPHRON NUMBER AND COMPENSATORY ADAPTATIONS, WHICH MIGHT LEAD TO HYPERTENSION, AND PERHAPS ACCELERATE THE DECLINE IN RENAL FUNCTION THAT ACCOMPANIES AGING. THESE PROCESSES MIGHT BE EXACERBATED BY PROGRAMMED CHANGES IN VASCULAR STRUCTURE AND FUNCTION, AND ALTERATIONS IN ENDOCRINE AND METABOLIC HOMEOSTASIS. PROGRAMMED EFFECTS MIGHT BE INITIATED AS EARLY AS THE PERICONCEPTUAL PHASE OF DEVELOPMENT, AND COULD INVOLVE EPIGENETIC CHANGES IN GENE EXPRESSION OR ALTERED STEM CELL ALLOCATION. BETTER UNDERSTANDING OF THESE PROCESSES COULD LEAD TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND PREVENTIVE MEASURES, AND TO EARLY DETECTION OF AT-RISK INDIVIDUALS. BY MONITORING BLOOD PRESSURE, WEIGHT, AND RENAL FUNCTION IN CHILDREN, IT MIGHT BE POSSIBLE TO REDUCE THE RISK OF CARDIOVASCULAR AND RENAL DISEASE IN LATER LIFE. 2006 7 2567 42 EPIGENETICS MODIFIERS: POTENTIAL HUB FOR UNDERSTANDING AND TREATING NEURODEVELOPMENTAL DISORDERS FROM HYPOXIC INJURY. BACKGROUND: THE FETAL BRAIN IS ADAPTED TO THE HYPOXIC CONDITIONS PRESENT DURING NORMAL IN UTERO DEVELOPMENT. RELATIVELY MORE HYPOXIC STATES, EITHER CHRONIC OR ACUTE, ARE PATHOLOGIC AND CAN LEAD TO SIGNIFICANT LONG-TERM NEURODEVELOPMENTAL SEQUELAE. IN UTERO HYPOXIC INJURY IS ASSOCIATED WITH NEONATAL MORTALITY AND MILLIONS OF LIVES LIVED WITH VARYING DEGREES OF DISABILITY. MAIN BODY: GENETIC STUDIES OF CHILDREN WITH NEURODEVELOPMENTAL DISEASE INDICATE THAT EPIGENETIC MODIFIERS REGULATING DNA METHYLATION AND HISTONE REMODELING ARE CRITICAL FOR NORMAL BRAIN DEVELOPMENT. EPIGENETIC MODIFIERS ARE ALSO REGULATED BY ENVIRONMENTAL STIMULI, SUCH AS HYPOXIA. INDEED, EPIGENETIC MODIFIERS THAT ARE MUTATED IN CHILDREN WITH GENETIC NEURODEVELOPMENTAL DISEASES ARE REGULATED BY HYPOXIA IN A NUMBER OF PRECLINICAL MODELS AND MAY BE PART OF THE MECHANISM FOR THE LONG-TERM NEURODEVELOPMENTAL SEQUELAE SEEM IN CHILDREN WITH HYPOXIC BRAIN INJURY. THUS, A COMPREHENSIVE UNDERSTANDING THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATIONS IN HYPOXIC INJURY IS CRITICAL FOR DEVELOPING NOVEL STRATEGIES TO TREAT CHILDREN WITH HYPOXIC INJURY. CONCLUSIONS: THIS REVIEW FOCUSES ON OUR CURRENT UNDERSTANDING OF THE INTERSECTION BETWEEN EPIGENETICS, BRAIN DEVELOPMENT, AND HYPOXIA. OPPORTUNITIES FOR THE USE OF EPIGENETICS AS BIOMARKERS OF NEURODEVELOPMENTAL DISEASE AFTER HYPOXIC INJURY AND POTENTIAL CLINICAL EPIGENETICS TARGETS TO IMPROVE OUTCOMES AFTER INJURY ARE ALSO DISCUSSED. WHILE THERE HAVE BEEN MANY PUBLISHED STUDIES ON THE EPIGENETICS OF HYPOXIA, MORE ARE NEEDED IN THE DEVELOPING BRAIN IN ORDER TO DETERMINE WHICH EPIGENETIC PATHWAYS MAY BE MOST IMPORTANT FOR MITIGATING THE LONG-TERM CONSEQUENCES OF HYPOXIC BRAIN INJURY. 2020 8 2038 27 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 9 1371 31 DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE: NEW INSIGHTS. EPIDEMIOLOGICAL AND ANIMAL STUDIES SHOW THAT SMALL CHANGES IN THE DEVELOPMENTAL ENVIRONMENT CAN INDUCE PHENOTYPIC CHANGES AFFECTING AN INDIVIDUAL'S RESPONSES TO THEIR LATER ENVIRONMENT. THESE MAY ALTER THE RISK OF CHRONIC DISEASE SUCH AS METABOLIC SYNDROME OR CARDIOVASCULAR DISEASE. RECENT RESEARCH SHOWS THAT ANIMALS EXPOSED TO SUCH A MISMATCH BETWEEN PRENATAL AND POSTNATAL ENVIRONMENT DEVELOP OBESITY, REDUCED ACTIVITY, LEPTIN AND INSULIN RESISTANCE, ELEVATED BLOOD PRESSURE AND VASCULAR ENDOTHELIAL DYSFUNCTION. EPIGENETIC PROCESSES ARE INVOLVED IN SUCH EFFECTS, TARGETED TO PROMOTER REGIONS OF SPECIFIC GENES IN SPECIFIC TISSUES. SUCH FINE CONTROL OF GENE EXPRESSION SUGGESTS THAT THE MECHANISMS HAVE BEEN RETAINED THROUGH EVOLUTION THROUGH THEIR ADAPTIVE ADVANTAGE, RATHER THAN REPRESENTING EXTREME EFFECTS OF DEVELOPMENTAL DISRUPTION AKIN TO TERATOGENESIS. THERE MAY BE ADAPTIVE ADVANTAGE IN A DEVELOPMENTAL CUE INDUCING A PHENOTYPIC CHANGE IN GENERATIONS BEYOND THE IMMEDIATE PREGNANCY, AND A RANGE OF DATA THAT SUPPORT THIS CONCEPT. IN ANIMALS, EPIGENETIC EFFECTS SUCH AS DNA METHYLATION CAN BE PASSED TO SUCCESSIVE GENERATIONS. ENVIRONMENTAL TOXINS, INCLUDING ENDOCRINE DISRUPTORS, MAY INDUCE GREATER RISK OF CHRONIC DISEASE, EVEN AT LOW EXPOSURE LEVELS, IF THEY AFFECT SUCH NORMAL DEVELOPMENTAL EPIGENETIC PROCESSES. APPROPRIATE INTERVENTIONS MAY HAVE LONG-TERM MULTIGENERATIONAL EFFECTS TO REDUCE THE RISK OF CHRONIC DISEASE. 2008 10 4983 38 PATHOPHYSIOLOGY, CELLULAR AND MOLECULAR MECHANISMS OF FOETAL GROWTH RETARDATION. IN MAMMALS, SIZE AT BIRTH IS THE OUTCOME OF LENGTH OF GESTATION AND RATE OF FOETAL GROWTH. IN THE ABSENCE OF PREMATURE DELIVERY, FOETAL SIZE WITHIN SPECIES IS DETERMINED PRINCIPALLY BY FOETAL GROWTH RATE WHICH IS DEPENDENT ON BOTH GENETIC AND EPIGENETIC FACTORS. FAILURE OF EITHER OF THESE MECHANISMS LEADS TO FOETAL GROWTH RETARDATION. IN MAMMALS, INCLUDING HUMAN INFANTS, FOETAL GROWTH RETARDATION CAN OCCUR NATURALLY OR PATHOLOGICALLY. ONE MAJOR CAUSE FOR NATURAL FOETAL GROWTH RETARDATION OR RUNTING IS THE INCREASE IN LITTER SIZE. IN MANY CASES, HOWEVER, THE CAUSE OF RUNTING IS UNKNOWN. PARENTAL GENOTYPE OR ANTIGENIC DIFFERENCES BETWEEN THE MOTHER AND THE DEVELOPING CONCEPTUS MAY BE POTENTIAL CAUSES. PATHOLOGICAL FOETAL GROWTH RETARDATION OR INTRAUTERINE GROWTH RETARDATION (IUGR) IS DUE TO GENETIC CAUSES (CHROMOSOMAL ABNORMALITIES OR INHERITED SYNDROMES) OR EPIGENETIC CAUSES (INTRAUTERINE INFECTIONS, TOXINS AND CHEMICALS, MATERNAL DISEASES OF PREGNANCY AFFECTING THE PLACENTA). THE UNDERLYING PATHOPHYSIOLOGICAL PROCESSES THAT OCCUR AT THE CELLULAR AND MOLECULAR LEVEL IN IUGR ARE STILL UNKNOWN. REDUCTION IN THE SUPPLY OF SUBSTRATES THAT ARE NECESSARY FOR NORMAL CELLULAR FUNCTION, AND ALTERATION IN MEDIATOR MOLECULES THAT REGULATE CELLULAR GROWTH AND DIFFERENTIATION, ARE IMPORTANT MECHANISMS. A DECREASE IN GROWTH PROMOTING FACTORS OR AN INCREASE IN GROWTH INHIBITORY FACTORS MAY LEAD TO GROWTH FAILURE. GROWTH FACTORS AND THEIR RECEPTORS ARE EXPRESSED IN THE DEVELOPING EMBRYO (AS EARLY AS THE 1-2-CELL STAGE), PLACENTA AND MATERNAL UTERINE TISSUES, SUGGESTING THAT THESE MOLECULES MAY PLAY A ROLE IN REGULATING NORMAL GROWTH AND DIFFERENTIATION OF THE CONCEPTUS AS WELL AS MATERNAL REPRODUCTIVE TISSUES. THE LOCAL EXPRESSION WITHIN DEVELOPING TISSUES INDICATES THAT THESE FACTORS ACT IN EITHER AUTOCRINE OR PARACRINE MECHANISM. RECENT STUDIES USING GENE TARGETING TO KNOCK OUT ONE ALLELE OF INSULIN-LIKE GROWTH FACTOR II (IGF II) GENE IN MICE WHICH RESULTED IN GROWTH RETARDED PUPS AT BIRTH, STRONGLY SUPPORT THE IMPORTANCE OF LOCAL IGF II IN REGULATING TISSUE GROWTH. FOETAL GROWTH RETARDATION HAS ALSO BEEN INDUCED EXPERIMENTALLY IN SEVERAL SPECIES USING ONE OF THE FOLLOWING METHODS: (I) MATERNAL UNDERNUTRITION, (II) CHRONIC HYPOXIA, (III) PROLONGED REDUCTION IN UTERINE BLOOD FLOW, (IV) REDUCTION IN PLACENTAL SIZE, AND (V) ENDOCRINE ALTERATIONS. THESE MODELS PROVIDE USEFUL INFORMATION ON THE PHYSIOLOGICAL MECHANISMS UNDERLYING A SPECIFIC TYPE OF GROWTH RETARDATION. THESE IN-VIVO MODELS AND IN-VIVO TISSUE CULTURE MODELS CAN NOW BE ANALYSED BY BIOCHEMICAL AND MOLECULAR BIOLOGICAL TECHNIQUES TO UNRAVEL THE BASIC MECHANISMS THAT UNDERLIE FOETAL GROWTH RETARDATION. 1993 11 6192 28 THE IMPACT OF NUTRITIONAL INSULTS DURING FETAL LIFE ON BLOOD PRESSURE. NUMEROUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES PROVIDE COMPELLING EVIDENCE THAT NUTRITIONAL INSULTS THAT IMPACT FETAL GROWTH PROGRAM A MARKED INCREASE IN BLOOD PRESSURE IN LATER LIFE. SEX AND AGE ALSO INFLUENCE THE DEVELOPMENTAL PROGRAMMING OF HYPERTENSION; YET THE EXACT MECHANISMS THAT PERMANENTLY CHANGE THE STRUCTURE, PHYSIOLOGY, AND ENDOCRINE HEALTH OF AN INDIVIDUAL ACROSS THEIR LIFESPAN FOLLOWING EXPOSURE TO A NUTRITIONAL INSULT ARE NOT ENTIRELY CLEAR. FETAL EXPOSURE TO MATERNAL GLUCOCORTICOIDS IS POSTULATED AS AN INITIATING EVENT. IN ADDITION, INAPPROPRIATE SUPPRESSION OR ACTIVATION OF THE RENIN ANGIOTENSIN SYSTEM (RAS) AND/OR ACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM (SNS) LEADING TO MARKED INCREASES IN OXIDATIVE STRESS AND ENDOTHELIN PRODUCTION ARE IMPLICATED IN THE ETIOLOGY OF HYPERTENSION THAT HAS ITS ORIGINS IN FETAL LIFE. THE RISK OF HYPERTENSION AND CHRONIC DISEASE IN ONE GENERATION IS TRANSMITTED TO THE NEXT IN THE ABSENCE OF AN ADDITIONAL PRENATAL INSULT IMPLICATING EPIGENETIC PROCESSES. YET, FURTHER STUDIES ARE NEEDED TO FULLY ELUCIDATE THE MECHANISMS THAT CONTRIBUTE TO HYPERTENSION PROGRAMMED IN RESPONSE TO NUTRITIONAL INSULTS DURING EARLY LIFE IN ORDER TO IMPROVE THE CARDIOVASCULAR HEALTH OF AN INDIVIDUAL ACROSS THEIR LIFESPAN. 2015 12 2958 37 GENETIC AND EPIGENETIC INSIGHTS INTO FETAL ALCOHOL SPECTRUM DISORDERS. THE MAGNITUDE OF THE DETRIMENTAL EFFECTS FOLLOWING IN UTERO ALCOHOL EXPOSURE, INCLUDING FETAL ALCOHOL SYNDROME AND OTHER FETAL ALCOHOL SPECTRUM DISORDERS (FASD), IS GLOBALLY UNDERESTIMATED. THE EFFECTS INCLUDE IRREVERSIBLE COGNITIVE AND BEHAVIORAL DISABILITIES AS A RESULT OF ABNORMAL BRAIN DEVELOPMENT, PRE- AND POSTNATAL GROWTH RETARDATION AND FACIAL DYSMORPHISM. PARENTAL ALCOHOL EXPOSURE AND ITS EFFECT ON OFFSPRING HAS BEEN RECOGNIZED FOR CENTURIES, BUT ONLY RECENTLY HAVE WE BEGUN TO GAIN MOLECULAR INSIGHT INTO THE MECHANISMS INVOLVED IN ALCOHOL TERATOGENESIS. GENETIC ATTRIBUTES (SUSCEPTIBILITY AND PROTECTIVE ALLELES) OF THE MOTHER AND THE FETUS CONTRIBUTE TO THE RISK OF DEVELOPING FASD AND SPECIFIC ADDITIONAL ENVIRONMENTAL CONDITIONS, INCLUDING MALNUTRITION, HAVE AN IMPORTANT ROLE. THE SEVERITY OF FASD DEPENDS ON THE LEVEL OF ALCOHOL EXPOSURE, THE DEVELOPMENTAL STAGE AT WHICH EXPOSURE OCCURS AND THE NATURE OF THE EXPOSURE (CHRONIC OR ACUTE), AND ALTHOUGH THE MOST VULNERABLE PERIOD IS DURING THE FIRST TRIMESTER, DAMAGE CAN OCCUR THROUGHOUT GESTATION. PRECONCEPTION ALCOHOL EXPOSURE CAN ALSO HAVE A DETRIMENTAL EFFECT ON THE OFFSPRING. SEVERAL DEVELOPMENTAL PATHWAYS ARE AFFECTED IN FASD, INCLUDING NERVOUS SYSTEM DEVELOPMENT, GROWTH AND REMODELING OF TISSUES, AS WELL AS METABOLIC PATHWAYS THAT REGULATE GLUCOCORTICOID SIGNALING AND BALANCED LEVELS OF RETINOL, INSULIN AND NITRIC OXIDE. A BODY OF KNOWLEDGE HAS ACCUMULATED TO SUPPORT THE ROLE OF ENVIRONMENTALLY INDUCED EPIGENETIC REMODELING DURING GAMETOGENESIS AND AFTER CONCEPTION AS A KEY MECHANISM FOR THE TERATOGENIC EFFECTS OF FASD THAT PERSIST INTO ADULTHOOD. TRANSGENERATIONAL EFFECTS ARE LIKELY TO CONTRIBUTE TO THE GLOBAL BURDEN OF ALCOHOL-RELATED DISEASE. FASD RESULTS IN LIFELONG DISABILITY AND PREVENTATIVE PROGRAMS SHOULD INCLUDE BOTH MATERNAL ALCOHOL ABSTENTION AND PRECONCEPTION ALCOHOL AVOIDANCE. 2010 13 3311 39 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 14 2183 36 EPIGENETIC MECHANISMS RESPONSIBLE FOR THE TRANSGENERATIONAL INHERITANCE OF INTRAUTERINE GROWTH RESTRICTION PHENOTYPES. A POORLY FUNCTIONING PLACENTA RESULTS IN IMPAIRED EXCHANGES OF OXYGEN, NUTRITION, WASTES AND HORMONES BETWEEN THE MOTHER AND HER FETUS. THIS CAN LEAD TO RESTRICTION OF FETAL GROWTH. THESE GROWTH RESTRICTED BABIES ARE AT INCREASED RISK OF DEVELOPING CHRONIC DISEASES, SUCH AS TYPE-2 DIABETES, HYPERTENSION, AND KIDNEY DISEASE, LATER IN LIFE. ANIMAL STUDIES HAVE SHOWN THAT GROWTH RESTRICTED PHENOTYPES ARE SEX-DEPENDENT AND CAN BE TRANSMITTED TO SUBSEQUENT GENERATIONS THROUGH BOTH THE PATERNAL AND MATERNAL LINEAGES. ALTERED EPIGENETIC MECHANISMS, SPECIFICALLY CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS THAT REGULATE EXPRESSION OF GENES THAT ARE IMPORTANT FOR FETAL DEVELOPMENT HAVE BEEN SHOWN TO BE ASSOCIATED WITH THE TRANSMISSION PATTERN OF GROWTH RESTRICTED PHENOTYPES. THIS REVIEW WILL DISCUSS THE SUBSEQUENT HEALTH OUTCOMES IN THE OFFSPRING AFTER GROWTH RESTRICTION AND THE TRANSMISSION PATTERNS OF THESE DISEASES. EVIDENCE OF ALTERED EPIGENETIC MECHANISMS IN ASSOCIATION WITH FETAL GROWTH RESTRICTION WILL ALSO BE REVIEWED. 2022 15 6818 39 [FETAL PROGRAMMING AS A CAUSE OF CHRONIC DISEASES IN ADULT LIFE]. LONG-TERM ADAPTIVE CHANGES OCCURRING IN A DEVELOPING FETUS IN RESPONSE TO UNSTABLE IN UTERO ENVIRONMENTAL CONDITIONS, WHICH APPEAR AT A PARTICULAR TIME (CRITICAL WINDOW), ARE CALLED INTRAUTERINE OR FETAL PROGRAMMING. THESE ADAPTIVE CHANGES ARE BENEFICIAL DURING THE INTRAUTERINE PERIOD BECAUSE THEY ADAPT THE FETUS TO CURRENT NEEDS, BUT MAY TURN OUT TO BE HARMFUL IN THE END AND LEAD TO DEVELOPMENT OF CHRONIC DISEASES IN ADULT LIFE. FETAL PROGRAMMING MEANS THE STRUCTURAL AND FUNCTIONAL CHANGING OF AN ORGANISM, METABOLISM AND FUNCTION OF SOME CELLS, TISSUES AND SYSTEMS, THAT OCCUR EVEN DESPITE INTRAUTERINE LIMITATIONS. EVENTS OF FETAL LIFE INFLUENCE THE DETERMINATION OF PHYSIOLOGICAL PATTERNS WHICH MAY MANIFEST AS DISEASE PROCESSES IN THE ADULTHOOD (BARKER'S HYPOTHESIS). GENETIC AND ENVIRONMENTAL FACTORS (POOR DIET IN PREGNANCY CHRONIC INTRAUTERINE FETAL HYPOXIA, THE EFFECTS OF XENOBIOTICS AND DRUGS, AS WELL AS HORMONAL DISORDERS) INFLUENCE THE PHENOTYPE OF A NEWBORN AND ARE INVOLVED IN THE INTRAUTERINE PROGRAMMING PROCESS. THE EFFECTS OF FETAL PROGRAMMING MAY BE PASSED ALONG TO THE NEXT GENERATIONS VIA NOT FULLY UNDERSTOOD PATHWAYS, WHICH PROBABLY INCLUDE EPIGENETIC MECHANISMS. MOST OF THE MECHANISMS UNDERLYING THIS PROCESS REMAIN UNCLEAR AND NEED TO BE ELUCIDATED. 2014 16 1376 32 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 17 4496 34 MORE THAN GENES: THE ADVANCED FETAL PROGRAMMING HYPOTHESIS. MANY LINES OF DATA, INITIAL EPIDEMIOLOGIC STUDIES AS WELL AS SUBSEQUENT EXTENSIVE EXPERIMENTAL STUDIES, INDICATE THAT EARLY-LIFE EVENTS PLAY A POWERFUL ROLE IN INFLUENCING LATER SUCEPTIBILITY TO CERTAIN CHRONIC DISEASES. SUCH EVENTS MIGHT BE OVER- OR UNDERNUTRITION, EXPOSURE TO ENVIRONMENTAL TOXINS, BUT ALSO CHANGES IN HORMONES, IN PARTICULAR STRESS HORMONES. TYPICALLY, THOSE EVENTS ARE TRIGGERED BY THE ENVIRONMENTAL CHALLENGES OF THE MOTHER. HOWEVER, RECENT STUDIES HAVE SHOWN THAT PATERNAL ENVIRONMENTAL OR NUTRITIONAL FACTORS AFFECT THE PHENOTYPE OF THE OFFSPRING AS WELL. THE MATERNAL AND PATERNAL ENVIRONMENTAL FACTORS ACT ON THE PHENOTYPE OF THE OFFSPRING VIA EPIGENETIC MODIFICATION OF ITS GENOME. THE ADVANCED FETAL PROGRAMMING HYPOTHESIS PROPOSES AN ADDITIONAL NON-ENVIRONMENTALLY DRIVEN MECHANISM: MATERNAL AND ALSO PATERNAL GENES MAY INFLUENCE THE MATURATING SPERM, THE OOCYTE, AND LATER THE EMBRYO/FETUS, LEADING TO THEIR EPIGENETIC ALTERATION. THUS, THE OBSERVED PHENOTYPE OF THE OFFSPRING MAY BE ALTERED BY MATERNAL/PATERNAL GENES INDEPENDENT OF THE FETAL GENOME. MEANWHILE, SEVERAL INDEPENDENT ASSOCIATION STUDIES IN HUMANS DEALING WITH METABOLIC AND NEUROLOGICAL TRAITS ALSO SUGGEST THAT MATERNAL GENES MIGHT AFFECT THE OFFSPRING PHENOTYPE INDEPENDENT OF THE TRANSMISSION OF THAT PARTICULAR GENE TO THE OFFSPRING. CONSIDERING THE IMPLICATIONS OF THIS HYPOTHESIS, SOME CONCLUSIONS DRAWN FROM TRANSGENIC OR KNOCKOUT ANIMAL MODELS AND BASED ON THE CAUSALITY BETWEEN A GENETIC ALTERATION AND A PHENOTYPE, NEED TO BE CHALLENGED. POSSIBLE IMPLICATIONS FOR THE DEVELOPMENT, DIAGNOSTIC AND THERAPY OF HUMAN GENETIC DISEASES HAVE TO BE INVESTIGATED. 2014 18 3582 28 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 19 1520 37 DNA METHYLATION AT DIFFERENTIALLY METHYLATED REGIONS OF IMPRINTED GENES IS RESISTANT TO DEVELOPMENTAL PROGRAMMING BY MATERNAL NUTRITION. THE NUTRITIONAL ENVIRONMENT IN WHICH THE MAMMALIAN FETUS OR INFANT DEVELOP IS RECOGNIZED AS INFLUENCING THE RISK OF CHRONIC DISEASES, SUCH AS TYPE 2 DIABETES AND HYPERTENSION, IN A PHENOMENON THAT HAS BECOME KNOWN AS DEVELOPMENTAL PROGRAMMING. THE LATE ONSET OF SUCH DISEASES IN RESPONSE TO EARLIER TRANSIENT EXPERIENCES HAS LED TO THE SUGGESTION THAT DEVELOPMENTAL PROGRAMMING MAY HAVE AN EPIGENETIC COMPONENT, BECAUSE EPIGENETIC MARKS SUCH AS DNA METHYLATION OR HISTONE TAIL MODIFICATIONS COULD PROVIDE A PERSISTENT MEMORY OF EARLIER NUTRITIONAL STATES. ONE CLASS OF GENES THAT HAS BEEN CONSIDERED A POTENTIAL TARGET OR MEDIATOR OF PROGRAMMING EVENTS IS IMPRINTED GENES, BECAUSE THESE GENES CRITICALLY DEPEND UPON EPIGENETIC MODIFICATIONS FOR CORRECT EXPRESSION AND BECAUSE MANY IMPRINTED GENES HAVE ROLES IN CONTROLLING FETAL GROWTH AS WELL AS NEONATAL AND ADULT METABOLISM. IN THIS STUDY, WE HAVE USED AN ESTABLISHED MODEL OF DEVELOPMENTAL PROGRAMMING-ISOCALORIC PROTEIN RESTRICTION TO FEMALE MICE DURING GESTATION OR LACTATION-TO EXAMINE WHETHER THERE ARE EFFECTS ON EXPRESSION AND DNA METHYLATION OF IMPRINTED GENES IN THE OFFSPRING. WE FIND THAT ALTHOUGH EXPRESSION OF SOME IMPRINTED GENES IN LIVER OF OFFSPRING IS ROBUSTLY AND SUSTAINABLY CHANGED, METHYLATION OF THE DIFFERENTIALLY METHYLATED REGIONS (DMRS) THAT CONTROL THEIR MONOALLELIC EXPRESSION REMAINS LARGELY UNALTERED. WE CONCLUDE THAT DEREGULATION OF IMPRINTING THROUGH A GENERAL EFFECT ON DMR METHYLATION IS UNLIKELY TO BE A COMMON FACTOR IN DEVELOPMENTAL PROGRAMMING. 2012 20 4802 33 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