1 544 144 ATTAINMENT OF THERMOREGULATION AS AFFECTED BY ENVIRONMENTAL FACTORS. THE REVIEW ADDRESSES THE DEVELOPMENT OF THERMOREGULATION IN POULTRY EMBRYOS AS WELL AS THE EFFECT OF ACUTE AND CHRONIC CHANGES OF ENVIRONMENTAL FACTORS ON THIS PROCESS AND THE INCUBATION TEMPERATURE BEING THE FOREMOST. IN POULTRY, THE EARLY DEVELOPMENT OF ADAPTIVE BODY FUNCTIONS, LIKE THE THERMOREGULATORY SYSTEM, IS CHARACTERIZED BY THE FOLLOWING PECULIARITIES. FIRST, THE DEVELOPMENT OF PERIPHERAL AS WELL AS CENTRAL NERVOUS THERMOREGULATORY MECHANISMS START DURING THE PRENATAL ONTOGENY. HOWEVER, THEIR MATURITY IS ATTAINED DURING EARLY POSTNATAL DEVELOPMENT. IN THE PERINATAL PERIOD, ENVIRONMENTAL FACTORS HAVE A HIGH EFFECT ON DEVELOPMENT OF TEMPERATURE REGULATION. SECOND, ACUTE CHANGES IN THE ENVIRONMENTAL CONDITIONS INDUCE AS A RULE FIRST UNCOORDINATED AND IMMEDIATELY NONADAPTIVE REACTIONS. LATER, THE UNCOORDINATED NONADAPTIVE REACTIONS CHANGE INTO COORDINATED (ADAPTIVE) REACTIONS. PRENATAL ENVIRONMENTAL INFLUENCES MAY HAVE A TRAINING EFFECT ON THE POSTNATAL EFFICIENCY OF THE THERMO-REGULATORY SYSTEM. THIRD, FUNCTIONAL SYSTEMS OF THE ORGANISM DEVELOP FROM AN OPEN LOOP SYSTEM WITHOUT FEEDBACK CONTROL INTO A CLOSED SYSTEM CONTROLLED BY A FEEDBACK MECHANISM. DURING THIS CRITICAL PERIOD, THE ACTUAL ENVIRONMENT MODULATES THE DEVELOPMENT OF THE RESPECTIVE PHYSIOLOGICAL CONTROL SYSTEMS FOR THE ENTIRE LIFE PERIOD, ESPECIALLY BY CHANGES IN NEUROORGANIZATION AND EXPRESSION OF RELATED EFFECTOR GENES. KNOWLEDGE ON THESE MECHANISMS MIGHT BE SPECIFICALLY USED TO GENERATE LONG-TERM ADAPTATION OF THE ORGANISM TO THE POSTNATAL CLIMATIC CONDITIONS (PERINATAL EPIGENETIC TEMPERATURE ADAPTATION). IN POULTRY, PERINATAL EPIGENETIC TEMPERATURE ADAPTATION WAS DEVELOPED BY CHANGES IN THE INCUBATION TEMPERATURE. WHEN A COMPARISON IS MADE IN BIRDS, WHICH WERE INCUBATED AT 37.5 DEGREES C, A LOW INCUBATION TEMPERATURE INDUCED POSTNATAL COLD ADAPTATION, AND WARM INCUBATION TEMPERATURE INDUCED POSTNATAL HEAT ADAPTATION. PERINATAL EPIGENETIC TEMPERATURE ADAPTATION EXHIBITED CHANGES IN THE NEURONAL THERMOSENSITIVITY IN THE HYPOTHALAMUS AS WELL AS IN THE PERIPHERAL THERMOREGULATORY MECHANISMS. THESE ALTERATIONS COULD BE ALREADY FOUND AT THE END OF INCUBATION. FURTHER, TEMPERATURE-EXPERIENCED EMBRYOS HAVE A LOWER C-FOS EXPRESSION THAN IN THE CONTROL AFTER ACUTE HEAT STRESS. 2007 2 1263 50 CYCLIC VARIATIONS IN INCUBATION CONDITIONS INDUCE ADAPTIVE RESPONSES TO LATER HEAT EXPOSURE IN CHICKENS: A REVIEW. SELECTION PROGRAMS HAVE ENABLED BROILER CHICKENS TO GAIN MUSCLE MASS WITHOUT SIMILAR ENLARGEMENT OF THE CARDIOVASCULAR AND RESPIRATORY SYSTEMS THAT ARE ESSENTIAL FOR THERMOREGULATORY EFFICIENCY. MEAT-TYPE CHICKENS COPE WITH HIGH AMBIENT TEMPERATURE BY REDUCING FEED INTAKE AND GROWTH DURING CHRONIC AND MODERATE HEAT EXPOSURE. IN CASE OF ACUTE HEAT EXPOSURE, A DRAMATIC INCREASE IN MORBIDITY AND MORTALITY CAN OCCUR. IN ORDER TO ALLEVIATE HEAT STRESS IN THE LONG TERM, RESEARCH HAS RECENTLY FOCUSED ON EARLY THERMAL MANIPULATION. AIMED AT STIMULATION OF LONG-TERM THERMOTOLERANCE, THE THERMAL MANIPULATION OF EMBRYOS IS A METHOD BASED ON FINE TUNING OF INCUBATION CONDITIONS, TAKING INTO ACCOUNT THE LEVEL AND DURATION OF INCREASES IN TEMPERATURE AND RELATIVE HUMIDITY DURING A CRITICAL PERIOD OF EMBRYOGENESIS. THE CONSEQUENCES OF THERMAL MANIPULATION ON THE PERFORMANCE AND MEAT QUALITY OF BROILER CHICKENS HAVE BEEN EXPLORED TO ENSURE THE POTENTIAL APPLICATION OF THIS STRATEGY. THE PHYSIOLOGICAL BASIS OF THE METHOD IS THE INDUCTION OF EPIGENETIC AND METABOLIC MECHANISMS THAT CONTROL BODY TEMPERATURE IN THE LONG TERM. EARLY THERMAL MANIPULATION CAN ENHANCE POULTRY RESISTANCE TO ENVIRONMENTAL CHANGES WITHOUT MUCH EFFECT ON GROWTH PERFORMANCE. THIS REVIEW PRESENTS THE MAIN STRATEGIES OF EARLY HEAT EXPOSURE AND THE PHYSIOLOGICAL CONCEPTS ON WHICH THESE METHODS WERE BASED. THE CELLULAR MECHANISMS POTENTIALLY UNDERLYING THE ADAPTIVE RESPONSE ARE DISCUSSED AS WELL AS THE POTENTIAL INTEREST OF THERMAL MANIPULATION OF EMBRYOS FOR POULTRY PRODUCTION. 2015 3 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 4 1371 36 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 5 2159 29 EPIGENETIC MECHANISMS IMPACTED BY CHRONIC STRESS ACROSS THE RODENT LIFESPAN. EXPOSURES TO STRESS AT ALL STAGES OF DEVELOPMENT CAN LEAD TO LONG-TERM BEHAVIOURAL EFFECTS, IN PART THROUGH CHANGES IN THE EPIGENOME. THIS REVIEW DESCRIBES RODENT RESEARCH SUGGESTING THAT STRESS IN PRENATAL, POSTNATAL, ADOLESCENT AND ADULT STAGES LEADS TO LONG-TERM CHANGES IN EPIGENETIC REGULATION IN THE BRAIN WHICH HAVE CAUSAL IMPACTS ON RODENT BEHAVIOUR. WE FOCUS ON STRESS-INDUCED EPIGENETIC CHANGES THAT HAVE BEEN LINKED TO BEHAVIOURAL DEFICITS INCLUDING POOR LEARNING AND MEMORY, AND INCREASED ANXIETY-LIKE AND DEPRESSIVE-LIKE BEHAVIOURS. INTERESTINGLY, ASPECTS OF THESE STRESS-INDUCED BEHAVIOURAL CHANGES CAN BE TRANSMITTED TO OFFSPRING ACROSS SEVERAL GENERATIONS, A PHENOMENON THAT HAS BEEN PROPOSED TO RESULT VIA EPIGENETIC MECHANISMS IN THE GERMLINE. HERE, WE ALSO DISCUSS EVIDENCE FOR THE DIFFERENTIAL IMPACT OF STRESS ON THE EPIGENOME IN MALES AND FEMALES, CONSCIOUS OF THE FACT THAT THE MAJORITY OF PUBLISHED STUDIES HAVE ONLY INVESTIGATED MALES. THIS HAS LED TO A LIMITED PICTURE OF THE EPIGENETIC IMPACT OF STRESS, HIGHLIGHTING THE NEED FOR FUTURE STUDIES TO INVESTIGATE FEMALES AS WELL AS MALES. 2022 6 1765 33 EARLY-LIFE ADVERSITY-INDUCED LONG-TERM EPIGENETIC PROGRAMMING ASSOCIATED WITH EARLY ONSET OF CHRONIC PHYSICAL AGGRESSION: STUDIES IN HUMANS AND ANIMALS. OBJECTIVES: TO EXAMINE WHETHER CHRONIC PHYSICAL AGGRESSION (CPA) IN ADULTHOOD CAN BE EPIGENETICALLY PROGRAMMED EARLY IN LIFE DUE TO EXPOSURE TO EARLY-LIFE ADVERSITY. METHODS: LITERATURE SEARCH OF PUBLIC DATABASES SUCH AS PUBMED/MEDLINE AND SCOPUS. RESULTS: CHILDREN/ADOLESCENTS SUSCEPTIBLE FOR CPA AND EXPOSED TO EARLY-LIFE ABUSE FAIL TO EFFICIENTLY COPE WITH STRESS THAT IN TURN RESULTS IN THE DEVELOPMENT OF CPA LATER IN LIFE. THIS PHENOMENON WAS OBSERVED IN HUMANS AND ANIMAL MODELS OF AGGRESSION. THE SUSCEPTIBILITY TO AGGRESSION IS A COMPLEX TRAIT THAT IS REGULATED BY THE INTERACTION BETWEEN ENVIRONMENTAL AND GENETIC FACTORS. EPIGENETIC MECHANISMS MEDIATE THIS INTERACTION. SUBJECTS EXPOSED TO STRESS EARLY IN LIFE EXHIBITED LONG-TERM EPIGENETIC PROGRAMMING THAT CAN INFLUENCE THEIR BEHAVIOUR IN ADULTHOOD. THIS PROGRAMMING AFFECTS EXPRESSION OF MANY GENES NOT ONLY IN THE BRAIN BUT ALSO IN OTHER SYSTEMS SUCH AS NEUROENDOCRINE AND IMMUNE. CONCLUSIONS: THE PROPENSITY TO ADULT CPA BEHAVIOUR IN SUBJECTS EXPERIENCED TO EARLY-LIFE ADVERSITY IS MEDIATED BY EPIGENETIC PROGRAMMING THAT INVOLVES LONG-TERM SYSTEMIC EPIGENETIC ALTERATIONS IN A WHOLE GENOME. 2019 7 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 8 6133 37 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 9 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 10 585 30 BEHAVIORAL PERINATOLOGY: BIOBEHAVIORAL PROCESSES IN HUMAN FETAL DEVELOPMENT. BEHAVIORAL PERINATOLOGY IS AS AN INTERDISCIPLINARY AREA OF RESEARCH THAT INVOLVES CONCEPTUALIZATION OF THEORETICAL MODELS AND CONDUCT OF EMPIRICAL STUDIES OF THE DYNAMIC TIME-, PLACE-, AND CONTEXT-DEPENDENT INTERPLAY BETWEEN BIOLOGICAL AND BEHAVIORAL PROCESSES IN FETAL, NEONATAL, AND INFANT LIFE USING AN EPIGENETIC FRAMEWORK OF DEVELOPMENT. THE BIOBEHAVIORAL PROCESSES OF PARTICULAR INTEREST TO OUR RESEARCH GROUP RELATE TO THE EFFECTS OF MATERNAL PRE- AND PERINATAL STRESS AND MATERNAL-PLACENTAL-FETAL STRESS PHYSIOLOGY. WE PROPOSE THAT BEHAVIORAL PERINATOLOGY RESEARCH MAY HAVE IMPORTANT IMPLICATIONS FOR A BETTER UNDERSTANDING OF THE PROCESSES THAT UNDERLIE OR CONTRIBUTE TO THE RISK OF THREE SETS OF OUTCOMES: PREMATURITY, ADVERSE NEURODEVELOPMENT, AND CHRONIC DEGENERATIVE DISEASES IN ADULTHOOD. BASED ON OUR UNDERSTANDING OF THE ONTOGENY OF HUMAN FETAL DEVELOPMENT AND THE PHYSIOLOGY OF PREGNANCY AND FETAL DEVELOPMENT, WE HAVE ARTICULATED A NEUROBIOLOGICAL MODEL OF PRE- AND PERINATAL STRESS. OUR MODEL PROPOSES THAT CHRONIC MATERNAL STRESS MAY EXERT A SIGNIFICANT INFLUENCE ON FETAL DEVELOPMENTAL OUTCOMES. MATERNAL STRESS MAY ACT VIA ONE OR MORE OF THREE MAJOR PHYSIOLOGICAL PATHWAYS: NEUROENDOCRINE, IMMUNE/INFLAMMATORY, AND VASCULAR. WE FURTHER SUGGEST THAT PLACENTAL CORTICOTROPIN-RELEASING HORMONE (CRH) MAY PLAY A CENTRAL ROLE IN COORDINATING THE EFFECTS OF ENDOCRINE, IMMUNE/INFLAMMATORY, AND VASCULAR PROCESSES ON FETAL DEVELOPMENTAL OUTCOMES. FINALLY, WE HYPOTHESIZE THAT THE EFFECTS OF MATERNAL STRESS ARE MODULATED BY THE NATURE, DURATION, AND TIMING OF OCCURRENCE OF STRESS DURING GESTATION. IN THIS PAPER, WE ELABORATE ON THE CONCEPTUAL AND EMPIRICAL BASIS FOR THIS MODEL, HIGHLIGHT SOME RELEVANT ISSUES AND QUESTIONS, AND MAKE RECOMMENDATIONS FOR FUTURE RESEARCH IN THIS AREA. 2002 11 4125 31 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 12 6554 28 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 13 1360 43 DEVELOPMENTAL ASPECTS OF A LIFE COURSE APPROACH TO HEALTHY AGEING. WE EXAMINE THE MECHANISTIC BASIS AND WIDER IMPLICATIONS OF ADOPTING A DEVELOPMENTAL PERSPECTIVE ON HUMAN AGEING. PREVIOUS MODELS OF AGEING HAVE CONCENTRATED ON ITS GENETIC BASIS, OR THE DETRIMENTAL EFFECTS OF ACCUMULATED DAMAGE, BUT ALSO HAVE RAISED ISSUES ABOUT WHETHER AGEING CAN BE VIEWED AS ADAPTIVE ITSELF, OR IS A CONSEQUENCE OF OTHER ADAPTIVE PROCESSES, FOR EXAMPLE IF MAINTENANCE AND REPAIR PROCESSES IN THE PERIOD UP TO REPRODUCTION ARE TRADED OFF AGAINST LATER DECLINE IN FUNCTION. A LIFE COURSE MODEL PLACES AGEING IN THE CONTEXT OF THE ATTAINMENT OF PEAK CAPACITY FOR A BODY SYSTEM, STARTING IN EARLY DEVELOPMENT WHEN PLASTICITY PERMITS CHANGES IN STRUCTURE AND FUNCTION INDUCED BY A RANGE OF ENVIRONMENTAL STIMULI, FOLLOWED BY A PERIOD OF DECLINE, THE RATE OF WHICH DEPENDS ON THE PEAK ATTAINED AS WELL AS THE LATER LIFE CONDITIONS. SUCH PATH DEPENDENCY IN THE RATE OF AGEING MAY OFFER NEW INSIGHTS INTO ITS MODIFICATION. FOCUSING ON MUSCULOSKELETAL AND CARDIOVASCULAR FUNCTION, WE DISCUSS THIS MODEL AND THE POSSIBLE UNDERLYING MECHANISMS, INCLUDING ENDOTHELIAL FUNCTION, OXIDATIVE STRESS, STEM CELLS AND NUTRITIONAL FACTORS SUCH AS VITAMIN D STATUS. EPIGENETIC CHANGES INDUCED DURING DEVELOPMENTAL PLASTICITY, AND IMMUNE FUNCTION MAY PROVIDE A COMMON MECHANISTIC PROCESS UNDERLYING A LIFE COURSE MODEL OF AGEING. THE LIFE COURSE TRAJECTORY DIFFERS IN HIGH AND LOW RESOURCE SETTINGS. NEW INSIGHTS INTO THE DEVELOPMENTAL COMPONENTS OF THE LIFE COURSE MODEL OF AGEING MAY LEAD TO THE DESIGN OF BIOMARKERS OF LATER CHRONIC DISEASE RISK AND TO NEW INTERVENTIONS TO PROMOTE HEALTHY AGEING, WITH IMPORTANT IMPLICATIONS FOR PUBLIC HEALTH. 2016 14 291 29 AGING AND STRESS: PAST HYPOTHESES, PRESENT APPROACHES AND PERSPECTIVES. BRAIN AGING HAS BEEN SUGGESTED TO BE CONDITIONED BY AN EXCESSIVE GLUCOCORTIOID SECRETION LEADING TO DAMAGES ON BRAIN AREAS INVOLVED NOT ONLY IN COGNITIVE AND EMOTIONAL PROCESSES BUT ALSO IN THE CONTROL OF THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY ADRENAL AXIS. THIS REVIEW DESCRIBES SOME OF THE HYPOTHESIS THAT TRY TO EXPLAIN THE RELATION BETWEEN THE DYSREGULATION OF THE STRESS RESPONSE AND BRAIN AGING, FOCUSING ON CORTICOSTERONE BUT ALSO ON NEUROTRANSMISSION IN THE HIPPOCAMPUS, THE PREFRONTAL CORTEX AND THE AMYGDALA. MOREOVER, DIFFERENT MOLECULAR FACTORS CAN ACCOUNT FOR AN ENHANCED VULNERABILITY OF THE AGED BRAIN TO STRESS EXPOSURE, SPECIALLY FOR RESILIENCE. AMONG THEM, GOOD CANDIDATES COULD BE THOSE MECHANISMS DETERMINING THE LEVELS OF CORTICOSTERONE IN THE BRAIN, SEVERAL MOLECULES DOWNSTREAM GLUCOCORTICOID RECEPTOR ACTIVATION (IE: HEAT SHOCK PROTEINS, BAG-1) OR EVEN THE EPIGENETIC PROGRAMMING OF THE HPA AXIS IN EARLY STAGES. IN CONCLUSION, GENETIC AND ENVIRONMENTAL FACTORS (EARLY LIFE STRESS, CHRONIC STRESS DURING ADULTHOOD) CAN PRODUCE AN ENHANCED VULNERABILITY AND A REDUCED RESILIENCE OF THE BRAIN TO SUBSEQUENT STRESS EXPOSURES OR TO METABOLIC CHALLENGES LEADING, IN TURN, TO AN UNSUCCESSFUL AGING OF THE BRAIN. HOWEVER, RESULTS OBTAINED WITH THE USE OF THE ENVIRONMENTAL ENRICHMENT MODEL IN ANIMALS, ADDED TO SEVERAL RESULTS IN HUMANS ALSO DESCRIBED IN THIS REVIEW SUGGEST THAT POSITIVE ENVIRONMENTAL FACTORS (COGNITIVE-DEMANDING TASKS OR PHYSICAL EXERCISE) CAN HELP TO MAINTAIN NEURONAL PLASTICITY DURING AGING AND TO PROTECT THE BRAIN AGAINST THE DAMAGING EFFECTS OF STRESS EXPOSURE. 2011 15 6729 35 VULNERABILITY TO STROKE: IMPLICATIONS OF PERINATAL PROGRAMMING OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. CHRONIC STRESS IS CAPABLE OF EXACERBATING EACH MAJOR, MODIFIABLE, ENDOGENOUS RISK FACTOR FOR CEREBROVASCULAR AND CARDIOVASCULAR DISEASE. INDEED, EXPOSURE TO STRESS CAN INCREASE BOTH THE INCIDENCE AND SEVERITY OF STROKE, PRESUMABLY THROUGH ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. NOW THAT CHARACTERIZATION OF THE MECHANISMS UNDERLYING EPIGENETIC PROGRAMMING OF THE HPA AXIS IS WELL UNDERWAY, THERE HAS BEEN RENEWED INTEREST IN EXAMINING THE ROLE OF EARLY ENVIRONMENT ON THE EVOLUTION OF HEALTH CONDITIONS ACROSS THE ENTIRE LIFESPAN. INDEED, NEONATAL MANIPULATIONS IN RODENTS THAT REDUCE STRESS RESPONSIVITY, AND SUBSEQUENT LIFE-TIME EXPOSURE TO GLUCOCORTICOIDS, ARE ASSOCIATED WITH A REDUCTION IN THE DEVELOPMENT OF NEUROENDOCRINE, NEUROANATOMICAL, AND COGNITIVE DYSFUNCTIONS THAT TYPICALLY PROGRESS WITH AGE. ALTHOUGH IMPROVED DAY TO DAY REGULATION OF THE HPA AXIS ALSO MAY BE ACCOMPANIED BY A DECREASE IN STROKE RISK, EVIDENCE FROM RODENT STUDIES SUGGEST THAT AN ASSOCIATED COST COULD BE INCREASED SUSCEPTIBILITY TO INFLAMMATION AND NEURONAL DEATH IN THE EVENT THAT A STROKE DOES OCCUR AND THE INDIVIDUAL IS EXPOSED TO PERSISTENTLY ELEVATED CORTICOSTEROIDS. GIVEN ITS IMPORTANCE IN REGULATION OF HEALTH AND DISEASE STATES, ANY LONG-TERM MODULATION OF THE HPA AXIS IS LIKELY TO BE ASSOCIATED WITH BOTH BENEFITS AND POTENTIAL RISKS. THE GOALS OF THIS REVIEW ARTICLE ARE TO EXAMINE (1) THE CLINICAL AND EXPERIMENTAL DATA SUGGESTING THAT NEONATAL EXPERIENCES CAN SHAPE HPA AXIS REGULATION, (2) THE INFLUENCE OF STRESS AND THE HPA AXIS ON STROKE INCIDENCE AND SEVERITY, AND (3) THE POTENTIAL FOR NEONATAL PROGRAMMING OF THE HPA AXIS TO IMPACT ADULT CEREBROVASCULAR HEALTH. 2009 16 2274 29 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 17 2958 38 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 18 229 30 ADAPTATION OR PATHOLOGY? THE ROLE OF PRENATAL STRESSOR TYPE AND INTENSITY IN THE DEVELOPMENTAL PROGRAMING OF ADULT PHENOTYPE. THE MOTHER IS THE MAJOR INTERFACE BETWEEN THE OFFSPRING AND ITS PRENATAL ENVIRONMENT. PRENATAL TOXINS AND STRESS-INDUCING PHYSICAL AGENTS ARE IMPORTANT FACTORS PROGRAMMING THE DEVELOPMENTAL TRAJECTORY OF MAMMALS THAT LIKELY INVOLVE EPIGENETIC MODIFICATIONS. HOWEVER, PRENATAL STRESSORS COMMONLY-USED IN THE LABORATORY (E.G. PRENATAL RESTRAINT STRESS AND PRENATAL CHRONIC VARIABLE STRESS) ARE TYPICALLY ADMINISTERED AT HIGH INTENSITIES. THESE EXPOSURES TYPICALLY LEAD TO PATHOLOGICAL PHENOTYPES SUPPORTING THE DEVELOPMENT ORIGIN OF HEALTH AND DISEASE HYPOTHESIS. IN THIS REVIEW, WE COMPARE THE PHENOTYPIC OUTCOMES OF THESE COMMONLY-USED PRENATAL STRESSORS TO AN ECOLOGICALLY-RELEVANT, PSYCHOGENIC STRESSOR THAT HAS BEEN PRESENT OVER EVOLUTIONARY TIMES, PREDATOR OR PREDATOR CUES PRESENCE. PRENATAL STRESS BY PREDATOR THREAT RESULTS IN BEHAVIORAL, PHYSIOLOGICAL, ENDOCRINE, TRANSCRIPT ABUNDANCE AND EPIGENETIC (DNA METHYLATION) MODIFICATIONS. THESE PHENOTYPIC MODIFICATIONS ARE CONSISTENT WITH DEVELOPMENTAL FORECASTING ACCORDING TO THE PREDICTIVE ADAPTIVE RESPONSE HYPOTHESIS, YIELDING ADAPTIVE RESPONSES IN ENVIRONMENTS WHERE SUCH PREDATION STRESS IS PRESENT. THE EVIDENCE DESCRIBED IN THIS REVIEW SUGGESTS THAT THE TYPE OF PRENATAL STRESS AGENT AND ITS INTENSITY MODIFIES THE PHENOTYPE EXPRESSED, WHICH CAN RANGE FROM ADAPTIVE TO PATHOLOGICAL. PRENATAL BISPHENOL A EXPOSURE STUDIES ARE PRESENTED AS AN EXAMPLE WHERE GRADED INTENSITIES (CONCENTRATIONS) OF PRENATAL TOXIN EXPOSURE CAN BE COMPARED DIRECTLY. FINALLY, WE EMPHASIZE THE IMPORTANCE OF STUDYING BOTH SEXES IN THESE STUDIES, AS SEX DIFFERENCES APPEAR TO BE A COMMON FEATURE OF THE RESPONSE TO PRENATAL STRESS. 2018 19 1766 40 EARLY-LIFE EXPERIENCES AND THE DEVELOPMENT OF ADULT DISEASES WITH A FOCUS ON MENTAL ILLNESS: THE HUMAN BIRTH THEORY. IN MAMMALS, EARLY ADVERSE EXPERIENCES, INCLUDING MOTHER-PUP INTERACTIONS, SHAPE THE RESPONSE OF AN INDIVIDUAL TO CHRONIC STRESS OR TO STRESS-RELATED DISEASES DURING ADULT LIFE. THIS HAS LED TO THE ELABORATION OF THE THEORY OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE, IN PARTICULAR ADULT DISEASES SUCH AS CARDIOVASCULAR AND METABOLIC DISORDERS. IN ADDITION, IN HUMANS, AS STATED BY MASSIMO FAGIOLI'S HUMAN BIRTH THEORY, BIRTH IS HEALTHY AND EQUAL FOR ALL INDIVIDUALS, SO THAT MENTAL ILLNESS DEVELOP EXCLUSIVELY IN THE POSTNATAL PERIOD BECAUSE OF THE QUALITY OF THE RELATIONSHIP IN THE FIRST YEAR OF LIFE. THUS, THIS REVIEW FOCUSES ON THE IMPORTANCE OF PROGRAMMING DURING THE EARLY DEVELOPMENTAL PERIOD ON THE MANIFESTATION OF ADULT DISEASES IN BOTH ANIMAL MODELS AND HUMANS. CONSIDERING THE OBVIOUS DIFFERENCES BETWEEN ANIMALS AND HUMANS WE CANNOT SYSTEMATICALLY MOVE FROM ANIMAL MODELS TO HUMANS. CONSEQUENTLY, IN THE FIRST PART OF THIS REVIEW, WE WILL DISCUSS HOW ANIMAL MODELS CAN BE USED TO DISSECT THE INFLUENCE OF ADVERSE EVENTS OCCURRING DURING THE PRENATAL AND POSTNATAL PERIODS ON THE DEVELOPMENTAL TRAJECTORIES OF THE OFFSPRING, AND IN THE SECOND PART, WE WILL DISCUSS THE ROLE OF POSTNATAL CRITICAL PERIODS ON THE DEVELOPMENT OF MENTAL DISEASES IN HUMANS. EPIGENETIC MECHANISMS THAT CAUSE REVERSIBLE MODIFICATIONS IN GENE EXPRESSION, DRIVING THE DEVELOPMENT OF A PATHOLOGICAL PHENOTYPE IN RESPONSE TO A NEGATIVE EARLY POSTNATAL ENVIRONMENT, MAY LIE AT THE CORE OF THIS PROGRAMMING, THEREBY PROVIDING POTENTIAL NEW THERAPEUTIC TARGETS. THE CONCEPT OF THE HUMAN BIRTH THEORY LEADS TO A COMPREHENSION OF THE MENTAL ILLNESS AS A PATHOLOGY OF THE HUMAN RELATIONSHIP IMMEDIATELY AFTER BIRTH AND DURING THE FIRST YEAR OF LIFE. 2017 20 4996 37 PERINATAL EPIGENETIC DETERMINANTS OF COGNITIVE AND METABOLIC DISORDERS. MULTIPLE CUES FROM THE ENVIRONMENT OF OUR INDIRECT AND IMMEDIATE ANCESTORS, WHICH OFTEN PERSIST THROUGHOUT THE PRENATAL PERIOD AND ADULTHOOD, ARE SHAPING OUR PHENOTYPES THROUGH EITHER DIRECT, PARENT-TO-CHILD INFLUENCES, OR TRANSGENERATIONAL INHERITANCE. THESE EFFECTS ARE DUE TO GENE-ENVIRONMENT INTERACTIONS, WHICH ARE INTENDED TO BE A PREDICTIVE TOOL AND A MECHANISM OF QUICK ADAPTATION TO THE ENVIRONMENT, AS COMPARED WITH GENETIC VARIATIONS THAT ARE INHERITED OVER MANY GENERATIONS. IN CERTAIN CIRCUMSTANCES THE INFLUENCES INDUCED BY THE GENE-ENVIRONMENT INTERACTIONS CAN HAVE DELETERIOUS EFFECTS UPON THE HEALTH STATUS, IN THE CONTEXT OF A RADICAL CHANGE IN THE ENVIRONMENT THAT DOES NOT FIT WITH THE PREDICTED CONDITIONS, VIA EPIGENETIC ALTERATIONS. CONVERSELY THE BEST FIT TO THE EXPECTED ENVIRONMENT MIGHT HAVE A DELAYED AGING PROCESS AND A LONGER LIFE SPAN. THIS REVIEW WILL TOUCH UPON THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) CONCEPT, WHILE DISCUSSING RECENT ADVANCES IN THE UNDERSTANDING OF METABOLIC AND COGNITIVE DISRUPTIONS, WITH A FOCUS ON EPIGENETIC FACTORS, THEIR TRANSGENERATIONAL EFFECTS, AND THE CONSEQUENCES THEY MIGHT HAVE UPON THE ONSET OF CHRONIC DISEASE AND PREMATURE EXITUS. 2012