1 6818 116 [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 2 5202 39 PRENATAL ORIGINS OF ADULT DISEASE. PURPOSE OF REVIEW: HUMAN EPIDEMIOLOGICAL AND ANIMAL STUDIES SHOW THAT MANY CHRONIC ADULT CONDITIONS HAVE THEIR ANTECEDENTS IN COMPROMISED FETAL AND EARLY POSTNATAL DEVELOPMENT. DEVELOPMENTAL PROGRAMMING IS DEFINED AS THE RESPONSE BY THE DEVELOPING MAMMALIAN ORGANISM TO A SPECIFIC CHALLENGE DURING A CRITICAL TIME WINDOW THAT ALTERS THE TRAJECTORY OF DEVELOPMENT WITH RESULTING PERSISTENT EFFECTS ON PHENOTYPE. MAMMALS PASS MORE BIOLOGICAL MILESTONES BEFORE BIRTH THAN ANY OTHER TIME IN THEIR LIVES. EACH INDIVIDUAL'S PHENOTYPE IS INFLUENCED BY THE DEVELOPMENTAL ENVIRONMENT AS MUCH AS THEIR GENES. A BETTER UNDERSTANDING IS REQUIRED OF GENE-ENVIRONMENT INTERACTIONS LEADING TO ADULT DISEASE. RECENT FINDINGS: DURING DEVELOPMENT, THERE ARE CRITICAL PERIODS OF VULNERABILITY TO SUBOPTIMAL CONDITIONS WHEN PROGRAMMING MAY PERMANENTLY MODIFY DISEASE SUSCEPTIBILITY. PROGRAMMING INVOLVES STRUCTURAL CHANGES IN IMPORTANT ORGANS; ALTERED CELL NUMBER, IMBALANCE IN DISTRIBUTION OF DIFFERENT CELL TYPES WITHIN THE ORGAN, AND ALTERED BLOOD SUPPLY OR RECEPTOR NUMBERS. COMPENSATORY EFFORTS BY THE FETUS MAY CARRY A PRICE. EFFECTS OF PROGRAMMING MAY PASS ACROSS GENERATIONS BY MECHANISMS THAT DO NOT NECESSARILY INVOLVE STRUCTURAL GENE CHANGES. PROGRAMMING OFTEN HAS DIFFERENT EFFECTS IN MALES AND FEMALES. SUMMARY: DEVELOPMENTAL PROGRAMMING SHOWS THAT EPIGENETIC FACTORS PLAY MAJOR ROLES IN DEVELOPMENT OF PHENOTYPE AND PREDISPOSITION TO DISEASE IN LATER LIFE. 2008 3 4798 33 NUTRITIONALLY MEDIATED PROGRAMMING OF THE DEVELOPING IMMUNE SYSTEM. A GROWING BODY OF EVIDENCE HIGHLIGHTS THE IMPORTANCE OF A MOTHER'S NUTRITION FROM PRECONCEPTION THROUGH LACTATION IN PROGRAMMING THE EMERGING ORGAN SYSTEMS AND HOMEOSTATIC PATHWAYS OF HER OFFSPRING. THE DEVELOPING IMMUNE SYSTEM MAY BE PARTICULARLY VULNERABLE. INDEED, EXAMPLES OF NUTRITION-MEDIATED IMMUNE PROGRAMMING CAN BE FOUND IN THE LITERATURE ON INTRA-UTERINE GROWTH RETARDATION, MATERNAL MICRONUTRIENT DEFICIENCIES, AND INFANT FEEDING. CURRENT MODELS OF IMMUNE ONTOGENY DEPICT A "LAYERED" EXPANSION OF INCREASINGLY COMPLEX DEFENSES, WHICH MAY BE PERMANENTLY ALTERED BY MATERNAL MALNUTRITION. ONE PROGRAMMING MECHANISM INVOLVES ACTIVATION OF THE MATERNAL HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN RESPONSE TO NUTRITIONAL STRESS. FETAL OR NEONATAL EXPOSURE TO ELEVATED STRESS HORMONES IS LINKED IN ANIMAL STUDIES TO PERMANENT CHANGES IN NEUROENDOCRINE-IMMUNE INTERACTIONS, WITH DIVERSE MANIFESTATIONS SUCH AS AN ATTENUATED INFLAMMATORY RESPONSE OR REDUCED RESISTANCE TO TUMOR COLONIZATION. MATERNAL MALNUTRITION MAY ALSO HAVE A DIRECT INFLUENCE, AS EVIDENCED BY NUTRIENT-DRIVEN EPIGENETIC CHANGES TO DEVELOPING T REGULATORY CELLS AND SUBSEQUENT RISK OF ALLERGY OR ASTHMA. A 3RD PROGRAMMING PATHWAY INVOLVES PLACENTAL OR BREAST MILK TRANSFER OF MATERNAL IMMUNE FACTORS WITH IMMUNOMODULATORY FUNCTIONS (E.G. CYTOKINES). MATERNAL MALNUTRITION CAN DIRECTLY AFFECT TRANSFER MECHANISMS OR INFLUENCE THE QUALITY OR QUANTITY OF TRANSFERRED FACTORS. THE PUBLIC HEALTH IMPLICATIONS OF NUTRITION-MEDIATED IMMUNE PROGRAMMING ARE OF PARTICULAR IMPORTANCE IN THE DEVELOPING WORLD, WHERE PREVALENT MATERNAL UNDERNUTRITION IS COUPLED WITH PERSISTENT INFECTIOUS CHALLENGES. HOWEVER, EARLY ALTERATIONS TO THE IMMUNE SYSTEM, RESULTING FROM EITHER NUTRITIONAL DEFICIENCIES OR EXCESSES, HAVE BROAD RELEVANCE FOR IMMUNE-MEDIATED DISEASES, SUCH AS ASTHMA, AND CHRONIC INFLAMMATORY CONDITIONS LIKE CARDIOVASCULAR DISEASE. 2011 4 6844 34 [METABOLIC PROGRAMMING: THEORETICAL CONCEPTS AND EXPERIMENTAL EVIDENCE]. IT IS KNOWN THAT THE POOR NUTRITION DURING A FETAL DEVELOPMENT MAY CONTRIBUTE TO AN INCREASED RISK OF CHRONIC DISEASES IN ADULTHOOD. IN A MODERN LITERATURE, THIS PHENOMENON IS CALLED <>. IT IS ASSUMED THAT THE QUALITATIVE OR QUANTITATIVE DEFICIENCY OF CERTAIN NUTRITIONAL COMPONENTS DURING AN EARLY DEVELOPMENT MAY LEAD TO THE ADAPTATIONS THAT CONTRIBUTE TO IMPROVED SURVIVAL DURING THE PRENATAL AND EARLY POSTNATAL PERIODS OF AN ONTOGENESIS. HOWEVER, THE CONSEQUENCE OF SUCH ADAPTIVE CHANGES MAY ALSO BE THE DEVELOPMENT OF VARIOUS PATHOLOGICAL PROCESSES AT THE LATER STAGES OF LIFE. RECENT STUDIES HAVE SHOWN THAT ONE OF THE MAJOR MECHANISMS INVOLVED IN THESE ADAPTATIONS IS THE EPIGENETIC REGULATION OF A GENE ACTIVITY. IN THIS REVIEW, THE EXPERIMENTAL EVIDENCE IS PROVIDED THAT PROCESSES ARISING FROM A QUANTITATIVELY OR QUALITATIVELY RESTRICTED DIET DURING THE EARLY STAGES OF DEVELOPMENT PLAY AN IMPORTANT ROLE IN THE FURTHER LIFE AND CAN GREATLY INFLUENCE RISK OF VARIOUS AGE-RELATED DISEASES AND LIFE SPAN. 2013 5 3594 43 IMPLICATIONS OF EARLY LIFE STRESS ON FETAL METABOLIC PROGRAMMING OF SCHIZOPHRENIA: A FOCUS ON EPIPHENOMENA UNDERLYING MORBIDITY AND EARLY MORTALITY. THE FETAL ORIGIN OF ADULT DISEASE HYPOTHESIS POSTULATES THAT A STRESSFUL IN UTERO ENVIRONMENT CAN HAVE DELETERIOUS CONSEQUENCES ON FETAL PROGRAMMING, POTENTIALLY LEADING TO CHRONIC DISEASE IN LATER LIFE. FACTORS KNOWN TO IMPACT FETAL PROGRAMMING INCLUDE THE TIMING, INTENSITY, DURATION AND NATURE OF THE EXTERNAL STRESSOR DURING PREGNANCY. AS SUCH, DYNAMIC MODULATION OF FETAL PROGRAMMING IS HEAVILY INVOLVED IN SHAPING HEALTH THROUGHOUT THE LIFE COURSE, POSSIBLY BY INFLUENCING METABOLIC PARAMETERS INCLUDING INSULIN ACTION, HYPOTHALAMIC-PITUITARY-ADRENAL ACTIVITY AND IMMUNE FUNCTION. THE ABILITY OF PRENATAL INSULTS TO PROGRAM ADULT DISEASE IS LIKELY TO OCCUR AS A RESULT OF REDUCED FUNCTIONAL CAPACITY IN KEY ORGANS-A "THRIFTY" PHENOTYPE-WHERE MORE RESOURCES ARE RE-ALLOCATED TO PRESERVE CRITICAL ORGANS SUCH AS THE BRAIN. NOTABLY, IT HAS BEEN POSTULATED THAT THE MANIFESTATION OF NEUROPSYCHIATRIC DISORDERS IN INDIVIDUALS PRIORLY EXPOSED TO PRENATAL STRESS MAY ARISE FROM THE INTERACTION BETWEEN HEREDITARY FACTORS AND THE INTRAUTERINE ENVIRONMENT, WHICH TOGETHER PRECIPITATE DISEASE ONSET BY DISRUPTING THE TRAJECTORY OF NORMAL BRAIN DEVELOPMENT. IN THIS REVIEW WE DISCUSS THE EVIDENCE LINKING PRENATAL PROGRAMMING TO NEUROPSYCHIATRIC DISORDERS, MAINLY SCHIZOPHRENIA, VIA A "THRIFTY PSYCHIATRIC PHENOTYPE" CONCEPT. WE START BY OUTLINING THE CONCEPTION OF THE THRIFTY PSYCHIATRIC PHENOTYPE. NEXT, WE DISCUSS THE CONVERGENCE OF POTENTIAL MECHANISTIC PATHWAYS THROUGH WHICH PRENATAL INSULTS MAY TRIGGER EPIGENETIC CHANGES THAT CONTRIBUTE TO THE INCREASED MORBIDITY AND EARLY MORTALITY OBSERVED IN NEUROPSYCHIATRIC DISORDERS. FINALLY, WE TOUCH ON THE PUBLIC HEALTH IMPORTANCE OF FETAL PROGRAMMING FOR THESE DISORDERS. WE CONCLUDE BY PROVIDING A BRIEF OUTLOOK ON THE FUTURE OF THIS EVOLVING FIELD OF RESEARCH. 2020 6 2958 39 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 7 2274 34 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 8 2184 39 EPIGENETIC MECHANISMS THAT UNDERPIN METABOLIC AND CARDIOVASCULAR DISEASES. CELLULAR COMMITMENT TO A SPECIFIC LINEAGE IS CONTROLLED BY DIFFERENTIAL SILENCING OF GENES, WHICH IN TURN DEPENDS ON EPIGENETIC PROCESSES SUCH AS DNA METHYLATION AND HISTONE MODIFICATION. DURING EARLY EMBRYOGENESIS, THE MAMMALIAN GENOME IS 'WIPED CLEAN' OF MOST EPIGENETIC MODIFICATIONS, WHICH ARE PROGRESSIVELY RE-ESTABLISHED DURING EMBRYONIC DEVELOPMENT. THUS, THE EPIGENOME OF EACH MATURE CELLULAR LINEAGE CARRIES THE RECORD OF ITS DEVELOPMENTAL HISTORY. THE SUBSEQUENT TRAJECTORY AND PATTERN OF DEVELOPMENT ARE ALSO RESPONSIVE TO ENVIRONMENTAL INFLUENCES, AND SUCH PLASTICITY IS LIKELY TO HAVE AN EPIGENETIC BASIS. EPIGENETIC MARKS MAY BE TRANSMITTED ACROSS GENERATIONS, EITHER DIRECTLY BY PERSISTING THROUGH MEIOSIS OR INDIRECTLY THROUGH REPLICATION IN THE NEXT GENERATION OF THE CONDITIONS IN WHICH THE EPIGENETIC CHANGE OCCURRED. DEVELOPMENTAL PLASTICITY EVOLVED TO MATCH AN ORGANISM TO ITS ENVIRONMENT, AND A MISMATCH BETWEEN THE PHENOTYPIC OUTCOME OF ADAPTIVE PLASTICITY AND THE CURRENT ENVIRONMENT INCREASES THE RISK OF METABOLIC AND CARDIOVASCULAR DISEASE. THESE CONSIDERATIONS POINT TO EPIGENETIC PROCESSES AS A KEY MECHANISM THAT UNDERPINS THE DEVELOPMENTAL ORIGINS OF CHRONIC NONCOMMUNICABLE DISEASE. HERE, WE REVIEW THE EVIDENCE THAT ENVIRONMENTAL INFLUENCES DURING MAMMALIAN DEVELOPMENT LEAD TO STABLE CHANGES IN THE EPIGENOME THAT ALTER THE INDIVIDUAL'S SUSCEPTIBILITY TO CHRONIC METABOLIC AND CARDIOVASCULAR DISEASE, AND DISCUSS THE CLINICAL IMPLICATIONS. 2009 9 3582 29 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 4790 42 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 11 2007 33 EPIGENETIC BASIS FOR FETAL ORIGINS OF AGE-RELATED DISEASE. THE CURRENT CONCEPT OF FETAL ORIGINS OF ADULT DISEASES DESCRIBES IN UTERO PROGRAMMING, OR ADAPTATION TO A SPECTRUM OF ADVERSE ENVIRONMENTAL CONDITIONS THAT ULTIMATELY LEADS TO INCREASED SUSCEPTIBILITY TO AGE-RELATED DISEASES (E.G., TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE) LATER IN LIFE. ALTHOUGH THE PRECISE MECHANISM OF THIS BIOLOGICAL MEMORY REMAINS UNCLEAR, MOUNTING EVIDENCE SUGGESTS AN EPIGENETIC BASIS. THE INCREASED SUSCEPTIBILITY TO CHRONIC DISEASE AND INVOLVEMENT OF MULTIPLE ORGAN SYSTEMS THAT IS OBSERVED IS ANALOGOUS TO THE DECLINE IN RESISTANCE TO DISEASE THAT IS TYPICAL OF NORMAL AGING. ALTHOUGH THE CUMULATIVE ENVIRONMENT OVER THE COURSE OF A LIFETIME CAN INDUCE INCREASING EPIGENETIC DYSREGULATION, WE PROPOSE THAT ADVERSE EVENTS THAT OCCUR DURING EARLY DEVELOPMENT CAN INDUCE SIGNIFICANT ADDITIONAL DYSREGULATION OF THE EPIGENOME. HERE, WE DESCRIBE THE CURRENT EVIDENCE FOR FETAL ORIGINS OF ADULT DISEASE AND THE ASSOCIATED ROLE OF EPIGENETIC DYSREGULATION. IN ADDITION, WE PRESENT A NEW PERSPECTIVE ON THE INDUCTION OF EPIGENETIC ALTERATIONS IN UTERO, WHICH SUBSEQUENTLY LEAD TO AN AGING PHENOTYPE MARKED BY INCREASED SUSCEPTIBILITY TO AGE-RELATED DISEASES. 2010 12 4125 35 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 13 6094 30 THE EFFECTS OF MATERNAL AND POSTNATAL DIETARY METHYL NUTRIENTS ON EPIGENETIC CHANGES THAT LEAD TO NON-COMMUNICABLE DISEASES IN ADULTHOOD. THE RISK FOR NON-COMMUNICABLE DISEASES IN ADULTHOOD CAN BE PROGRAMMED BY EARLY NUTRITION. THIS PROGRAMMING IS MEDIATED BY CHANGES IN EXPRESSION OF KEY GENES IN VARIOUS METABOLIC PATHWAYS DURING DEVELOPMENT, WHICH PERSIST INTO ADULTHOOD. THESE DEVELOPMENTAL MODIFICATIONS OF GENES ARE DUE TO EPIGENETIC ALTERATIONS IN DNA METHYLATION PATTERNS. RECENT STUDIES HAVE DEMONSTRATED THAT DNA METHYLATION CAN BE AFFECTED BY MATERNAL OR EARLY POSTNATAL DIETS. BECAUSE METHYL GROUPS FOR METHYLATION REACTIONS COME FROM METHIONINE CYCLE NUTRIENTS (I.E., METHIONINE, CHOLINE, BETAINE, FOLATE), DEFICIENCY OR SUPPLEMENTATION OF THESE METHYL NUTRIENTS CAN DIRECTLY CHANGE EPIGENETIC REGULATION OF GENES PERMANENTLY. ALTHOUGH MANY STUDIES HAVE DESCRIBED THE EARLY PROGRAMMING OF ADULT DISEASES BY MATERNAL AND INFANT NUTRITION, THIS REVIEW DISCUSSES STUDIES THAT HAVE ASSOCIATED EARLY DIETARY METHYL NUTRIENT MANIPULATION WITH DIRECT EFFECTS ON EPIGENETIC PATTERNS THAT COULD LEAD TO CHRONIC DISEASES IN ADULTHOOD. THE MATERNAL SUPPLY OF METHYL NUTRIENTS DURING GESTATION AND LACTATION CAN ALTER EPIGENETICS, BUT PROGRAMMING EFFECTS VARY DEPENDING ON THE TIMING OF DIETARY INTERVENTION, THE TYPE OF METHYL NUTRIENT MANIPULATED, AND THE TISSUE RESPONSIBLE FOR THE PHENOTYPE. MOREOVER, THE POSTNATAL MANIPULATION OF METHYL NUTRIENTS CAN PROGRAM EPIGENETICS, BUT MORE RESEARCH IS NEEDED ON WHETHER THIS APPROACH CAN RESCUE MATERNALLY PROGRAMMED OFFSPRING. 2020 14 4717 30 NON-GENOMIC TRANSGENERATIONAL INHERITANCE OF DISEASE RISK. THAT THERE IS A HERITABLE OR FAMILIAL COMPONENT OF SUSCEPTIBILITY TO CHRONIC NON-COMMUNICABLE DISEASES SUCH AS TYPE 2 DIABETES, OBESITY AND CARDIOVASCULAR DISEASE IS WELL ESTABLISHED, BUT THERE IS INCREASING EVIDENCE THAT SOME ELEMENTS OF SUCH HERITABILITY ARE TRANSMITTED NON-GENOMICALLY AND THAT THE PROCESSES WHEREBY ENVIRONMENTAL INFLUENCES ACT DURING EARLY DEVELOPMENT TO SHAPE DISEASE RISK IN LATER LIFE CAN HAVE EFFECTS BEYOND A SINGLE GENERATION. SUCH HERITABILITY MAY OPERATE THROUGH EPIGENETIC MECHANISMS INVOLVING REGULATION OF EITHER IMPRINTED OR NON-IMPRINTED GENES BUT ALSO THROUGH BROADER MECHANISMS RELATED TO PARENTAL PHYSIOLOGY OR BEHAVIOUR. WE REVIEW EVIDENCE AND POTENTIAL MECHANISMS FOR NON-GENOMIC TRANSGENERATIONAL INHERITANCE OF 'LIFESTYLE' DISEASE AND PROPOSE THAT THE 'DEVELOPMENTAL ORIGINS OF DISEASE' PHENOMENON IS A MALADAPTIVE CONSEQUENCE OF AN ANCESTRAL MECHANISM OF DEVELOPMENTAL PLASTICITY THAT MAY HAVE HAD ADAPTIVE VALUE IN THE EVOLUTION OF GENERALIST SPECIES SUCH AS HOMO SAPIENS. 2007 15 6064 35 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 16 1748 43 EARLY LIFE EVENTS AND THEIR CONSEQUENCES FOR LATER DISEASE: A LIFE HISTORY AND EVOLUTIONARY PERSPECTIVE. BIOMEDICAL SCIENCE HAS LITTLE CONSIDERED THE RELEVANCE OF LIFE HISTORY THEORY AND EVOLUTIONARY AND ECOLOGICAL DEVELOPMENTAL BIOLOGY TO CLINICAL MEDICINE. HOWEVER, THE OBSERVATIONS THAT EARLY LIFE INFLUENCES CAN ALTER LATER DISEASE RISK--THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) PARADIGM--HAVE LED TO A RECOGNITION THAT THESE PERSPECTIVES CAN INFORM OUR UNDERSTANDING OF HUMAN BIOLOGY. WE PROPOSE THAT THE DOHAD PHENOMENON CAN BE CONSIDERED AS A SUBSET OF THE BROADER PROCESSES OF DEVELOPMENTAL PLASTICITY BY WHICH ORGANISMS ADAPT TO THEIR ENVIRONMENT DURING THEIR LIFE COURSE. SUCH ADAPTIVE PROCESSES ALLOW GENOTYPIC VARIATION TO BE PRESERVED THROUGH TRANSIENT ENVIRONMENTAL CHANGES. CUES FOR PLASTICITY OPERATE PARTICULARLY DURING EARLY DEVELOPMENT; THEY MAY AFFECT A SINGLE ORGAN OR SYSTEM, BUT GENERALLY THEY INDUCE INTEGRATED ADJUSTMENTS IN THE MATURE PHENOTYPE, A PROCESS UNDERPINNED BY EPIGENETIC MECHANISMS AND INFLUENCED BY PREDICTION OF THE MATURE ENVIRONMENT. IN MAMMALS, AN ADVERSE INTRAUTERINE ENVIRONMENT RESULTS IN AN INTEGRATED SUITE OF RESPONSES, SUGGESTING THE INVOLVEMENT OF A FEW KEY REGULATORY GENES, THAT RESETS THE DEVELOPMENTAL TRAJECTORY IN EXPECTATION OF POOR POSTNATAL CONDITIONS. MISMATCH BETWEEN THE ANTICIPATED AND THE ACTUAL MATURE ENVIRONMENT EXPOSES THE ORGANISM TO RISK OF ADVERSE CONSEQUENCES-THE GREATER THE MISMATCH, THE GREATER THE RISK. FOR HUMANS, PREDICTION IS INACCURATE FOR MANY INDIVIDUALS BECAUSE OF CHANGES IN THE POSTNATAL ENVIRONMENT TOWARD ENERGY-DENSE NUTRITION AND LOW ENERGY EXPENDITURE, CONTRIBUTING TO THE EPIDEMIC OF CHRONIC NONCOMMUNICABLE DISEASE. THIS VIEW OF HUMAN DISEASE FROM THE PERSPECTIVES OF LIFE HISTORY BIOLOGY AND EVOLUTIONARY THEORY OFFERS NEW APPROACHES TO PREVENTION, DIAGNOSIS AND INTERVENTION. 2007 17 1229 30 CRITICAL WINDOWS: EXPLORING THE ASSOCIATION BETWEEN PERINATAL TRAUMA, EPIGENETICS, AND CHRONIC PAIN. CHRONIC PAIN IS HIGHLY PREVALENT AND BURDENSOME, AFFECTING MILLIONS OF PEOPLE WORLDWIDE. ALTHOUGH IT EMERGES AT ANY POINT IN LIFE, IT OFTEN MANIFESTS IN ADOLESCENCE. GIVEN THAT ADOLESCENCE IS A UNIQUE DEVELOPMENTAL PERIOD, ADDITIONAL STRAINS ASSOCIATED WITH PERSISTENT AND OFTEN IDIOPATHIC PAIN LEAD TO SIGNIFICANT LONG-TERM CONSEQUENCES. WHILE THERE IS NO SINGULAR CAUSE FOR THE CHRONIFICATION OF PAIN, EPIGENETIC MODIFICATIONS THAT LEAD TO NEURAL REORGANIZATION MAY UNDERPIN CENTRAL SENSITIZATION AND SUBSEQUENT MANIFESTATION OF PAIN HYPERSENSITIVITY. EPIGENETIC PROCESSES ARE PARTICULARLY ACTIVE DURING THE PRENATAL AND EARLY POSTNATAL YEARS. WE DEMONSTRATE HOW EXPOSURE TO VARIOUS TRAUMAS, SUCH AS INTIMATE PARTNER VIOLENCE WHILE IN UTERO OR ADVERSE CHILDHOOD EXPERIENCES, CAN SIGNIFICANTLY INFLUENCE EPIGENETIC REGULATION WITHIN THE BRAIN AND IN TURN MODIFY PAIN-RELATED PROCESSES. WE PROVIDE COMPELLING EVIDENCE THAT THE BURDEN OF CHRONIC PAIN IS LIKELY INITIATED EARLY IN LIFE, OFTEN BEING TRANSMITTED FROM MOTHER TO OFFSPRING. WE ALSO HIGHLIGHT TWO PROMISING PROPHYLACTIC STRATEGIES, OXYTOCIN ADMINISTRATION AND PROBIOTIC USE, THAT HAVE THE POTENTIAL TO ATTENUATE THE EPIGENETIC CONSEQUENCES OF EARLY ADVERSITY. OVERALL, WE ADVANCE UNDERSTANDING OF THE CAUSAL RELATIONSHIP BETWEEN TRAUMA AND ADOLESCENT CHRONIC PAIN BY HIGHLIGHTING EPIGENETIC MECHANISMS THAT UNDERLIE THIS TRANSMISSION OF RISK, ULTIMATELY INFORMING HOW TO PREVENT THIS RISING EPIDEMIC. 2023 18 5647 45 SEX DIFFERENCES IN FETAL KIDNEY REPROGRAMMING: THE CASE IN THE RENIN-ANGIOTENSIN SYSTEM. DURING THE EARLY STAGES OF THE DEVELOPMENT OF THE LIVING MULTIORGAN SYSTEMS, GENOME MODIFICATIONS OTHER THAN SEQUENCE VARIATION OCCUR THAT GUIDE CELL DIFFERENTIATION AND ORGANOGENESIS. THESE MODIFICATIONS ARE KNOWN TO OPERATE AS A FETAL PROGRAMMING CODE DURING THIS PERIOD, AND RECENT RESEARCH INDICATES THAT THERE ARE SOME TISSUE-SPECIFIC CODES IN ORGANOGENESIS WHOSE EFFECTS MAY PERSIST AFTER BIRTH UNTIL ADULTHOOD. CONSEQUENTLY, THE EVENTS THAT DISRUPT THE PRE-ESTABLISHED EPIGENETIC PATTERN COULD INDUCE SHIFTS IN ORGAN PHYSIOLOGY, WITH IMPLICATIONS ON HEALTH FROM BIRTH OR LATER IN ADULT LIFE. CHRONIC KIDNEY DISEASE (CKD) IS ONE OF THE MAIN CAUSES OF MORTALITY WORLDWIDE; ITS ETIOLOGY IS MULTIFACTORIAL, BUT DIABETES, OBESITY, AND HYPERTENSION ARE THE MAIN CAUSES OF CKD IN ADULTS, ALTHOUGH THERE ARE OTHER RISK FACTORS THAT ARE MAINLY ASSOCIATED WITH AN INDIVIDUAL'S LIFESTYLE. RECENT STUDIES SUGGEST THAT FETAL REPROGRAMMING IN THE DEVELOPING KIDNEY COULD BE IMPLICATED IN THE SUSCEPTIBILITY TO KIDNEY DISEASE IN BOTH CHILDHOOD AND ADULTHOOD. SOME EPIGENETIC MODIFICATIONS, SUCH AS GENOME METHYLATION STATUS, DYSREGULATION OF MIRNA, AND HISTONE CODING ALTERATIONS IN GENES RELATED TO THE REGULATION OF THE RENIN-ANGIOTENSIN AXIS, A COMMON DENOMINATOR IN CKD, MAY HAVE ORIGINATED DURING FETAL DEVELOPMENT. THIS REVIEW FOCUSES ON EPIGENETIC CHANGES DURING NEPHROGENESIS AND THEIR REPERCUSSIONS ON KIDNEY HEALTH AND DISEASE. IN ADDITION, THE FOCUS IS ON THE INFLUENCE OF ENVIRONMENTAL FACTORS DURING PREGNANCY, SUCH AS MATERNAL METABOLIC DISEASES AND DIETARY AND METABOLIC CONDITIONS, AS WELL AS SOME SEX DIFFERENCES IN FETAL KIDNEY REPROGRAMMING DURING WHICH DYSREGULATION OF THE RENIN-ANGIOTENSIN SYSTEM IS INVOLVED. 2023 19 1365 41 DEVELOPMENTAL ORIGIN OF CHRONIC DISEASES: TOXICOLOGICAL IMPLICATION. HUMAN EPIDEMIOLOGICAL AND EXPERIMENTAL ANIMAL STUDIES SHOW THAT SUBOPTIMAL ENVIRONMENTS IN FETAL AND NEONATAL LIFE EXERTS A PROFOUND INFLUENCE ON PHYSIOLOGICAL FUNCTION AND RISK OF DISEASE IN ADULT LIFE. THE MOLECULAR, CELLULAR, METABOLIC, ENDOCRINE AND PHYSIOLOGICAL ADAPTATIONS TO INTRAUTERINE NUTRITIONAL CONDITIONS RESULT IN PERMANENT ALTERATIONS OF CELLULAR PROLIFERATION AND DIFFERENTIATION OF TISSUES AND ORGAN SYSTEMS, WHICH IN TURN CAN MANIFEST BY PATHOLOGICAL CONSEQUENCES OR INCREASED VULNERABILITY TO CHRONIC DISEASES IN ADULTHOOD. INTRAUTERINE GROWTH RESTRICTION (IUGR) DUE TO INTRAUTERINE DEVELOPMENT DERANGEMENTS IS CONSIDERED THE IMPORTANT FACTOR IN DEVELOPMENT OF SUCH DISEASES AS ESSENTIAL HYPERTENSION, DIABETES MELLITUS, ISCHEMIC DISEASES OF THE HEART, OSTEOPOROSIS, RESPIRATORY, NEUROPSYCHIATRIC AND IMMUNE SYSTEM DISEASES.AN EARLY LIFE EXPOSURES TO DIETARY AND ENVIRONMENTAL EXPOSURES CAN HAVE A IMPORTANT EFFECT ON EPIGENETIC CODE, RESULTING IN DISEASES DEVELOPED LATER IN LIFE. THE CONCEPT OF THE "DEVELOPMENTAL PROGRAMMING" AND DEVELOPMENTAL ORIGINS OF ADULT DISEASES (DOHAD) HAS BECOME WELL ACCEPTED BECAUSE OF THE COMPELLING ANIMAL STUDIES THAT HAVE PRECISELY DEFINED THE OUTCOMES OF SPECIFIC EXPOSURES.THE ENVIRONMENTAL POLLULLUTANTS AND OTHER CHEMICAL TOXICANTS MAY INFLUENCE CRUCIAL CELLULAR FUNCTIONS DURING CRITICAL PERIODS OF FETAL DEVELOPMENT AND PERMANENTLY ALTER THE STRUCTURE OR FUNCTION OF SPECIFIC ORGAN SYSTEMS. DEVELOPMENTAL EPIGENETICS IS BELIEVED TO ESTABLISH "ADAPTIVE" PHENOTYPES TO MEET THE DEMANDS OF THE LATER-LIFE ENVIRONMENT. RESULTING PHENOTYPES THAT MATCH PREDICTED LATER-LIFE DEMANDS WILL PROMOTE HEALTH, WHILE A HIGH DEGREE OF MISMATCH WILL IMPEDE ADAPTABILITY TO LATER-LIFE CHALLENGES AND ELEVATE DISEASE RISK. THE RAPID INTRODUCTION OF SYNTHETIC CHEMICALS, ENVIRONMENTAL POLLUTANTS AND MEDICAL INTERVENTIONS, MAY RESULT IN CONFLICT WITH THE PROGRAMMED ADAPTIVE CHANGES MADE DURING EARLY DEVELOPMENT, AND EXPLAIN THE ALARMING INCREASES IN SOME DISEASES. 2008 20 1361 32 DEVELOPMENTAL CONSEQUENCES OF TRACE MINERAL DEFICIENCIES IN RODENTS: ACUTE AND LONG-TERM EFFECTS. APPROXIMATELY 3% OF INFANTS BORN HAVE AT LEAST ONE SERIOUS CONGENITAL MALFORMATION. IN THE U.S., AN AVERAGE OF 10 INFANTS PER THOUSAND DIE BEFORE 1 Y OF LIFE; ABOUT HALF OF THESE DEATHS CAN BE ATTRIBUTED TO BIRTH DEFECTS, LOW BIRTH WEIGHT OR PREMATURITY. ALTHOUGH THE CAUSES OF DEVELOPMENTAL ABNORMALITIES ARE CLEARLY MULTIFACTORIAL IN NATURE, WE SUGGEST THAT A COMMON FACTOR CONTRIBUTING TO THE OCCURRENCE OF DEVELOPMENTAL ABNORMALITIES IS SUBOPTIMAL MINERAL NUTRITION DURING EMBRYONIC AND FETAL DEVELOPMENT. USING ZINC AND COPPER AS EXAMPLES, EVIDENCE IS PRESENTED THAT NUTRITIONAL DEFICIENCIES CAN RAPIDLY AFFECT THE DEVELOPING CONCEPTUS AND RESULT IN GROSS STRUCTURAL ABNORMALITIES. DEFICITS OF ZINC OR COPPER CAN RESULT IN RAPID CHANGES IN CELLULAR REDOX BALANCE, TISSUE OXIDATIVE STRESS, INAPPROPRIATE PATTERNS OF CELL DEATH, ALTERATIONS IN THE MIGRATION OF NEURAL CREST CELLS AND CHANGES IN THE EXPRESSION OF KEY PATTERNING GENES. IN ADDITION TO WELL-RECOGNIZED MALFORMATIONS, MINERAL DEFICIENCIES DURING PERINATAL DEVELOPMENT CAN RESULT IN BEHAVIORAL, IMMUNOLOGICAL AND BIOCHEMICAL ABNORMALITIES THAT PERSIST INTO ADULTHOOD. ALTHOUGH THESE PERSISTENT DEFECTS CAN IN PART BE ATTRIBUTED TO SUBTLE MORPHOLOGICAL ABNORMALITIES, IN OTHER CASES THEY MAY BE SECONDARY TO EPIGENETIC OR DEVELOPMENTAL CHANGES IN DNA METHYLATION PATTERNS. EPIGENETIC DEFECTS COMBINED WITH SUBTLE MORPHOLOGICAL ABNORMALITIES CAN INFLUENCE AN INDIVIDUAL'S RISK FOR CERTAIN CHRONIC DISEASES AND THUS INFLUENCE HIS OR HER RISK FOR MORBIDITY AND MORTALITY LATER IN LIFE. 2003