1 1748 145 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 2 5966 32 TERMINAL ADDITION IN A CELLULAR WORLD. RECENT ADVANCES IN OUR UNDERSTANDING OF EVOLUTIONARY DEVELOPMENT PERMIT A REFRAMED APPRAISAL OF TERMINAL ADDITION AS A CONTINUOUS HISTORICAL PROCESS OF CELLULAR-ENVIRONMENTAL COMPLEMENTARITY. WITHIN THIS FRAME OF REFERENCE, EVOLUTIONARY TERMINAL ADDITIONS CAN BE IDENTIFIED AS ENVIRONMENTAL INDUCTION OF EPISODIC ADJUSTMENTS TO CELL-CELL SIGNALING PATTERNS THAT YIELD THE CELLULAR-MOLECULAR PATHWAYS THAT LEAD TO DIFFERING DEVELOPMENTAL FORMS. PHENOTYPES DERIVE, THEREBY, THROUGH CELLULAR MUTUALISTIC/COMPETITIVE NICHE CONSTRUCTIONS IN RECIPROCATING RESPONSIVENESS TO ENVIRONMENTAL STRESSES AND EPIGENETIC IMPACTS. IN SUCH TERMS, TERMINAL ADDITION FLOWS ACCORDING TO A LOGIC OF CELLULAR NEEDS CONFRONTING ENVIRONMENTAL CHALLENGES OVER SPACE-TIME. A RECONCILIATION OF EVOLUTIONARY DEVELOPMENT AND TERMINAL ADDITION CAN BE ACHIEVED THROUGH A COMBINED FOCUS ON CELL-CELL SIGNALING, MOLECULAR PHYLOGENIES AND A BROADER UNDERSTANDING OF EPIGENETIC PHENOMENA AMONG EUKARYOTIC ORGANISMS. WHEN UNDERSTOOD IN THIS MANNER, TERMINAL ADDITION HAS AN IMPORTANT ROLE IN EVOLUTIONARY DEVELOPMENT, AND CHRONIC DISEASE MIGHT BE CONSIDERED AS A FORM OF 'REVERSE EVOLUTION' OF THE SELF-SAME PROCESSES. 2018 3 372 31 AN EMERGING EPIDEMIC OF NONCOMMUNICABLE DISEASES IN DEVELOPING POPULATIONS DUE TO A TRIPLE EVOLUTIONARY MISMATCH. WITH THEIR TRANSITION FROM ADVERSE TO AFFLUENT ENVIRONMENTS, DEVELOPING POPULATIONS EXPERIENCE A RAPID INCREASE IN THE NUMBER OF INDIVIDUALS WITH NONCOMMUNICABLE DISEASES. HERE, WE EMPHASIZE THAT DEVELOPING POPULATIONS ARE MORE SUSCEPTIBLE THAN WESTERN POPULATIONS TO ACQUIRE THESE CHRONIC DISEASES, BECAUSE THEIR GENETIC, CULTURAL, AND EPIGENETIC CHARACTERISTICS DO NOT MATCH WITH THE EAGERLY AWAITED AFFLUENT ENVIRONMENTS. IN REGARD TO THIS, THERE IS AN URGENT NEED FOR PUBLIC HEALTH ORGANIZATIONS TO REORGANIZE CURRENT ENVIRONMENTS IN DEVELOPING POPULATIONS SO AS TO FIT THEIR INHERITED CHARACTERISTICS. UNFORTUNATELY, THIS NEED IS NEGLECTED AS AN ESSENTIAL PART OF THE SUSTAINABLE DEVELOPMENT GOALS THAT FORM THE CORE OF THE UNITED NATIONS' POST-2015 DEVELOPMENT AGENDA. ONLY THROUGH GLOBAL COLLABORATIVE EFFORTS CAN THE ENVIRONMENTS IN DEVELOPING POPULATIONS BE REORGANIZED AND, THEREBY, THE EMERGING EPIDEMIC OF NONCOMMUNICABLE DISEASES BE STALLED. 2016 4 46 55 A CONCEPTUAL FRAMEWORK FOR THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE. IN THE LAST DECADES, THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) HAVE EMERGED AS A VIGOROUS FIELD COMBINING EXPERIMENTAL, CLINICAL, EPIDEMIOLOGICAL AND PUBLIC HEALTH RESEARCH. ITS GOAL IS TO UNDERSTAND HOW EVENTS IN EARLY LIFE SHAPE LATER MORBIDITY RISK, ESPECIALLY OF NON-COMMUNICABLE CHRONIC DISEASES. AS THESE DISEASES BECOME THE MAJOR CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE, RESEARCH ARISING FROM DOHAD IS LIKELY TO GAIN SIGNIFICANCE TO PUBLIC HEALTH AND ECONOMIC DEVELOPMENT. BUT ACTION MAY BE HINDERED BY THE LACK OF A FIRM MECHANISTIC EXPLANATION AND OF A CONCEPTUAL BASIS, ESPECIALLY REGARDING THE EVOLUTIONARY SIGNIFICANCE OF THE DOHAD PHENOMENON. IN THIS ARTICLE, WE PROVIDE A SUCCINCT HISTORICAL REVIEW OF THE RESEARCH INTO THE RELATIONSHIP BETWEEN DEVELOPMENT AND LATER DISEASE, CONSIDER THE EVOLUTIONARY AND DEVELOPMENTAL SIGNIFICANCE AND DISCUSS THE UNDERLYING MECHANISMS OF THE DOHAD PHENOMENON. DOHAD SHOULD BE VIEWED AS A PART OF A BROADER BIOLOGICAL MECHANISM OF PLASTICITY BY WHICH ORGANISMS, IN RESPONSE TO CUES SUCH AS NUTRITION OR HORMONES, ADAPT THEIR PHENOTYPE TO ENVIRONMENT. THESE RESPONSES MAY BE DIVIDED INTO THOSE FOR IMMEDIATE BENEFIT AND THOSE AIMED AT PREDICTION OF A FUTURE ENVIRONMENT: DISEASE OCCURS IN THE MISMATCH BETWEEN PREDICTED AND REALIZED FUTURE. THE LIKELY MECHANISMS THAT ENABLE PLASTICITY INVOLVE EPIGENETIC PROCESSES, AFFECTING THE EXPRESSION OF GENES ASSOCIATED WITH REGULATORY PATHWAYS. THERE IS NOW EVIDENCE THAT EPIGENETIC MARKS MAY BE INHERITED AND SO CONTRIBUTE TO NON-GENOMIC HERITABLE DISEASE RISK. WE END BY DISCUSSING THE GLOBAL SIGNIFICANCE OF THE DOHAD PHENOMENON AND ITS POTENTIAL APPLICATIONS FOR PUBLIC HEALTH PURPOSES. 2010 5 1352 44 DEVELOPMENT AND APPLICATION OF THE ADVERSE OUTCOME PATHWAY FRAMEWORK FOR UNDERSTANDING AND PREDICTING CHRONIC TOXICITY: I. CHALLENGES AND RESEARCH NEEDS IN ECOTOXICOLOGY. TO ELUCIDATE THE EFFECTS OF CHEMICALS ON POPULATIONS OF DIFFERENT SPECIES IN THE ENVIRONMENT, EFFICIENT TESTING AND MODELING APPROACHES ARE NEEDED THAT CONSIDER MULTIPLE STRESSORS AND ALLOW RELIABLE EXTRAPOLATION OF RESPONSES ACROSS SPECIES. AN ADVERSE OUTCOME PATHWAY (AOP) IS A CONCEPT THAT PROVIDES A FRAMEWORK FOR ORGANIZING KNOWLEDGE ABOUT THE PROGRESSION OF TOXICITY EVENTS ACROSS SCALES OF BIOLOGICAL ORGANIZATION THAT LEAD TO ADVERSE OUTCOMES RELEVANT FOR RISK ASSESSMENT. IN THIS PAPER, WE FOCUS ON EXPLORING HOW THE AOP CONCEPT CAN BE USED TO GUIDE RESEARCH AIMED AT IMPROVING BOTH OUR UNDERSTANDING OF CHRONIC TOXICITY, INCLUDING DELAYED TOXICITY AS WELL AS EPIGENETIC AND TRANSGENERATIONAL EFFECTS OF CHEMICALS, AND OUR ABILITY TO PREDICT ADVERSE OUTCOMES. A BETTER UNDERSTANDING OF THE INFLUENCE OF SUBTLE TOXICITY ON INDIVIDUAL AND POPULATION FITNESS WOULD SUPPORT A BROADER INTEGRATION OF SUBLETHAL ENDPOINTS INTO RISK ASSESSMENT FRAMEWORKS. DETAILED MECHANISTIC KNOWLEDGE WOULD FACILITATE THE DEVELOPMENT OF ALTERNATIVE TESTING METHODS AS WELL AS HELP PRIORITIZE HIGHER TIER TOXICITY TESTING. WE ARGUE THAT TARGETED DEVELOPMENT OF AOPS SUPPORTS BOTH OF THESE ASPECTS BY PROMOTING THE ELUCIDATION OF MOLECULAR MECHANISMS AND THEIR CONTRIBUTION TO RELEVANT TOXICITY OUTCOMES ACROSS BIOLOGICAL SCALES. WE FURTHER DISCUSS INFORMATION REQUIREMENTS AND CHALLENGES IN APPLICATION OF AOPS FOR CHEMICAL- AND SITE-SPECIFIC RISK ASSESSMENT AND FOR EXTRAPOLATION ACROSS SPECIES. WE PROVIDE RECOMMENDATIONS FOR POTENTIAL EXTENSION OF THE AOP FRAMEWORK TO INCORPORATE INFORMATION ON EXPOSURE, TOXICOKINETICS AND SITUATION-SPECIFIC ECOLOGICAL CONTEXTS, AND DISCUSS COMMON INTERFACES THAT CAN BE EMPLOYED TO COUPLE AOPS WITH COMPUTATIONAL MODELING APPROACHES AND WITH EVOLUTIONARY LIFE HISTORY THEORY. THE EXTENDED AOP FRAMEWORK CAN SERVE AS A VENUE FOR INTEGRATION OF KNOWLEDGE DERIVED FROM VARIOUS SOURCES, INCLUDING EMPIRICAL DATA AS WELL AS MOLECULAR, QUANTITATIVE AND EVOLUTIONARY-BASED MODELS DESCRIBING SPECIES RESPONSES TO TOXICANTS. THIS WILL ALLOW A MORE EFFICIENT APPLICATION OF AOP KNOWLEDGE FOR QUANTITATIVE CHEMICAL- AND SITE-SPECIFIC RISK ASSESSMENT AS WELL AS FOR EXTRAPOLATION ACROSS SPECIES IN THE FUTURE. 2015 6 621 51 BIOENERGETIC EVOLUTION EXPLAINS PREVALENCE OF LOW NEPHRON NUMBER AT BIRTH: RISK FACTOR FOR CKD. THERE IS GREATER THAN TENFOLD VARIATION IN NEPHRON NUMBER OF THE HUMAN KIDNEY AT BIRTH. ALTHOUGH LOW NEPHRON NUMBER IS A RECOGNIZED RISK FACTOR FOR CKD, ITS DETERMINANTS ARE POORLY UNDERSTOOD. EVOLUTIONARY MEDICINE REPRESENTS A NEW DISCIPLINE THAT SEEKS EVOLUTIONARY EXPLANATIONS FOR DISEASE, BROADENING PERSPECTIVES ON RESEARCH AND PUBLIC HEALTH INITIATIVES. EVOLUTION OF THE KIDNEY, AN ORGAN RICH IN MITOCHONDRIA, HAS BEEN DRIVEN BY NATURAL SELECTION FOR REPRODUCTIVE FITNESS CONSTRAINED BY ENERGY AVAILABILITY. OVER THE PAST 2 MILLION YEARS, RAPID GROWTH OF AN ENERGY-DEMANDING BRAIN IN HOMO SAPIENS ENABLED HOMINID ADAPTATION TO ENVIRONMENTAL EXTREMES THROUGH SELECTION FOR MUTATIONS IN MITOCHONDRIAL AND NUCLEAR DNA EPIGENETICALLY REGULATED BY ALLOCATION OF ENERGY TO DEVELOPING ORGANS. MATERNAL UNDERNUTRITION OR HYPOXIA RESULTS IN INTRAUTERINE GROWTH RESTRICTION OR PRETERM BIRTH, RESULTING IN LOW BIRTH WEIGHT AND LOW NEPHRON NUMBER. REGULATED THROUGH PLACENTAL TRANSFER, ENVIRONMENTAL OXYGEN AND NUTRIENTS SIGNAL NEPHRON PROGENITOR CELLS TO REPROGRAM METABOLISM FROM GLYCOLYSIS TO OXIDATIVE PHOSPHORYLATION. THESE PROCESSES ARE MODULATED BY COUNTERBALANCING ANABOLIC AND CATABOLIC METABOLIC PATHWAYS THAT EVOLVED FROM PROKARYOTE HOMOLOGS AND BY HYPOXIA-DRIVEN AND AUTOPHAGY PATHWAYS THAT EVOLVED IN EUKARYOTES. REGULATION OF NEPHRON DIFFERENTIATION BY HISTONE MODIFICATIONS AND DNA METHYLTRANSFERASES PROVIDE EPIGENETIC CONTROL OF NEPHRON NUMBER IN RESPONSE TO ENERGY AVAILABLE TO THE FETUS. DEVELOPMENTAL PLASTICITY OF NEPHROGENESIS REPRESENTS AN EVOLVED LIFE HISTORY STRATEGY THAT PRIORITIZES ENERGY TO EARLY BRAIN GROWTH WITH ADEQUATE KIDNEY FUNCTION THROUGH REPRODUCTIVE YEARS, THE TRADE-OFF BEING INCREASING PREVALENCE OF CKD DELAYED UNTIL LATER ADULTHOOD. THE RESEARCH IMPLICATIONS OF THIS EVOLUTIONARY ANALYSIS ARE TO IDENTIFY REGULATORY PATHWAYS OF ENERGY ALLOCATION DIRECTING NEPHROGENESIS WHILE ACCOUNTING FOR THE DIFFERENT LIFE HISTORY STRATEGIES OF ANIMAL MODELS SUCH AS THE MOUSE. THE CLINICAL IMPLICATIONS ARE TO OPTIMIZE NUTRITION AND MINIMIZE HYPOXIC/TOXIC STRESSORS IN CHILDBEARING WOMEN AND CHILDREN IN EARLY POSTNATAL DEVELOPMENT. 2020 7 4973 35 PATHOPHYSIOLOGICAL EFFECTS OF CONTEMPORARY LIFESTYLE ON EVOLUTIONARY-CONSERVED SURVIVAL MECHANISMS IN POLYCYSTIC OVARY SYNDROME. POLYCYSTIC OVARY SYNDROME (PCOS) IS INCREASINGLY BEING CHARACTERIZED AS AN EVOLUTIONARY MISMATCH DISORDER THAT PRESENTS WITH A COMPLEX MIXTURE OF METABOLIC AND ENDOCRINE SYMPTOMS. THE EVOLUTIONARY MODEL PROPOSES THAT PCOS ARISES FROM A COLLECTION OF INHERITED POLYMORPHISMS THAT HAVE BEEN CONSISTENTLY DEMONSTRATED IN A VARIETY OF ETHNIC GROUPS AND RACES. IN UTERO DEVELOPMENTAL PROGRAMMING OF SUSCEPTIBLE GENOMIC VARIANTS ARE THOUGHT TO PREDISPOSE THE OFFSPRING TO DEVELOP PCOS. POSTNATAL EXPOSURE TO LIFESTYLE AND ENVIRONMENTAL RISK FACTORS RESULTS IN EPIGENETIC ACTIVATION OF DEVELOPMENTALLY PROGRAMMED GENES AND DISTURBANCE OF THE HALLMARKS OF HEALTH. THE RESULTING PATHOPHYSIOLOGICAL CHANGES REPRESENT THE CONSEQUENCES OF POOR-QUALITY DIET, SEDENTARY BEHAVIOUR, ENDOCRINE DISRUPTING CHEMICALS, STRESS, CIRCADIAN DISRUPTION, AND OTHER LIFESTYLE FACTORS. EMERGING EVIDENCE SUGGESTS THAT LIFESTYLE-INDUCED GASTROINTESTINAL DYSBIOSIS PLAYS A CENTRAL ROLE IN THE PATHOGENESIS OF PCOS. LIFESTYLE AND ENVIRONMENTAL EXPOSURES INITIATE CHANGES THAT RESULT IN DISTURBANCE OF THE GASTROINTESTINAL MICROBIOME (DYSBIOSIS), IMMUNE DYSREGULATION (CHRONIC INFLAMMATION), ALTERED METABOLISM (INSULIN RESISTANCE), ENDOCRINE AND REPRODUCTIVE IMBALANCE (HYPERANDROGENISM), AND CENTRAL NERVOUS SYSTEM DYSFUNCTION (NEUROENDOCRINE AND AUTONOMIC NERVOUS SYSTEM). PCOS CAN BE A PROGRESSIVE METABOLIC CONDITION THAT LEADS TO OBESITY, GESTATIONAL DIABETES, TYPE TWO DIABETES, METABOLIC-ASSOCIATED FATTY LIVER DISEASE, METABOLIC SYNDROME, CARDIOVASCULAR DISEASE, AND CANCER. THIS REVIEW EXPLORES THE MECHANISMS THAT UNDERPIN THE EVOLUTIONARY MISMATCH BETWEEN ANCIENT SURVIVAL PATHWAYS AND CONTEMPORARY LIFESTYLE FACTORS INVOLVED IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF PCOS. 2023 8 1365 46 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 9 3377 29 HISTORICAL APPROACH AND EVOLUTION OF THE STRESS CONCEPT: A PERSONAL ACCOUNT. AS A MATTER OF RESEARCH OR AS A PROCESS, STRESS REMAINS ONE OF THE MOST CITED CONSTRUCT IN BIOMEDICAL LITERATURE; A MEDLINE SURVEY ACCOUNTS FOR MORE THAN 210,000 CITATIONS SINCE 1970. IT IS DIFFICULT TO DEFINE. IT IS FREQUENTLY USED IN A VAGUE MANNER, INCLUDING UNDIFFERENTLY THE AGENT, THE PROCESS, AND THE RESPONSE. THE CONCEPT IS MULTIDIMENSIONAL AND COMPOSITE, INCLUDING EMOTION AND AROUSAL. STRESS HAS AN IMPLICIT: IT IMPLIES ALTERATION OF A THEORETICAL BALANCE OR EQUILIBRIUM WITHIN PHYSIOLOGICAL SYSTEMS, AND IT SEEMS TO CHARACTERIZE A PROCESS LEADING TO DISEASE. LARGE INDIVIDUAL DIFFERENCES EXIST IN THE WAY TO REACT TO A STRESSOR. PSYCHOLOGICAL AND COGNITIVE DETERMINANTS ARE CENTRAL FOR THE COURSE OF THE PROCESS. THE HOMEOSTASIS CONCEPT IS NOT USEFUL ANYMORE AND HAS BEEN REPLACED BY THE MORE ACCURATE AND FLEXIBLE CONCEPT OF ALLOSTASIS. THE PHYSIOLOGICAL HORMONAL AND NEURAL BASES OF THIS PROCESS ARE NOW IDENTIFIED. NEW PERSPECTIVES IDENTIFY STRESSORS, CHRONIC OR NOT, TO BE A SOURCE OF VULNERABILITIES THROUGH EPIGENETIC MECHANISMS AND A SERIES OF BIOBEHAVIORAL DISORDERS CHARACTERISTIC OF OUR MODERN CIVILIZATIONS. THE EVOLUTION OF THE CONCEPT IS NOT LINEAR. IT HAS BEEN ENRICHED BY RECENT NEUROBIOLOGICAL-NEUROENDOCRINOLOGICAL DISCOVERIES AND ALSO BY BEHAVIORAL-COGNITIVE SCIENCES. 2007 10 229 40 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 11 4717 43 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 12 2137 37 EPIGENETIC INHERITANCE AND EVOLUTION: A PATERNAL PERSPECTIVE ON DIETARY INFLUENCES. THE EARLIEST INDICATIONS FOR PATERNALLY INDUCED TRANSGENERATIONAL EFFECTS FROM THE ENVIRONMENT TO FUTURE GENERATIONS WERE BASED ON A SMALL NUMBER OF LONG-TERM EPIDEMIOLOGICAL STUDIES AND SOME EMPIRICAL OBSERVATIONS. ONLY RECENTLY HAVE EXPERIMENTAL ANIMAL MODELS AND A FEW ANALYSES ON HUMAN DATA EXPLORED THE TRANSGENERATIONAL NATURE OF PHENOTYPIC CHANGES OBSERVED IN OFFSPRING. CHANGES INCLUDE MULTIPLE METABOLIC DISORDERS, CANCER AND OTHER CHRONIC DISEASES. THESE PHENOTYPES CANNOT ALWAYS BE EXPLAINED BY MENDELIAN INHERITANCE, DNA MUTATIONS OR GENETIC DAMAGE. HENCE, A NEW COMPELLING THEORY ON EPIGENETIC INHERITANCE IS GAINING INTEREST, PROVIDING NEW CONCEPTS THAT EXTEND DARWIN'S EVOLUTIONARY THEORY. EPIGENETIC ALTERATIONS OR "EPIMUTATIONS" ARE BEING CONSIDERED TO EXPLAIN TRANSGENERATIONAL INHERITANCE OF PARENTALLY ACQUIRED TRAITS. THE RESPONSIBLE MECHANISMS FOR THESE EPIMUTATIONS INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND RNA-MEDIATED EFFECTS. THIS REVIEW EXPLORES THE LITERATURE ON A NUMBER OF TIME-DEPENDENT ENVIRONMENTALLY INDUCED EPIGENETIC ALTERATIONS, SPECIFICALLY THOSE FROM DIETARY EXPOSURES. WE SUGGEST A ROLE FOR THE MALE GERM LINE AS ONE OF NATURE'S TOOLS TO CAPTURE MESSAGES FROM OUR CONTINUOUSLY CHANGING ENVIRONMENT AND TO TRANSFER THIS INFORMATION TO SUBSEQUENT GENERATIONS. FURTHER, WE OPEN THE DISCUSSION THAT THE PATERNALLY INHERITED EPIGENETIC INFORMATION MAY CONTRIBUTE TO EVOLUTIONARY ADAPTATION. 2015 13 2931 37 GENES AND ENVIRONMENTS, DEVELOPMENT AND TIME. A NOW SUBSTANTIAL BODY OF SCIENCE IMPLICATES A DYNAMIC INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL VARIATION IN THE DEVELOPMENT OF INDIVIDUAL DIFFERENCES IN BEHAVIOR AND HEALTH. SUCH OUTCOMES ARE AFFECTED BY MOLECULAR, OFTEN EPIGENETIC, PROCESSES INVOLVING GENE-ENVIRONMENT (G-E) INTERPLAY THAT CAN INFLUENCE GENE EXPRESSION. EARLY ENVIRONMENTS WITH EXPOSURES TO POVERTY, CHRONIC ADVERSITIES, AND ACUTELY STRESSFUL EVENTS HAVE BEEN LINKED TO MALADAPTIVE DEVELOPMENT AND COMPROMISED HEALTH AND BEHAVIOR. GENETIC DIFFERENCES CAN IMPART EITHER ENHANCED OR BLUNTED SUSCEPTIBILITY TO THE EFFECTS OF SUCH PATHOGENIC ENVIRONMENTS. HOWEVER, LARGELY MISSING FROM PRESENT DISCOURSE REGARDING G-E INTERPLAY IS THE ROLE OF TIME, A "THIRD FACTOR" GUIDING THE EMERGENCE OF COMPLEX DEVELOPMENTAL ENDPOINTS ACROSS DIFFERENT SCALES OF TIME. TRAJECTORIES OF DEVELOPMENT INCREASINGLY APPEAR BEST ACCOUNTED FOR BY A COMPLEX, DYNAMIC INTERCHANGE AMONG THE HIGHLY LINKED ELEMENTS OF GENES, CONTEXTS, AND TIME AT MULTIPLE SCALES, INCLUDING NEUROBIOLOGICAL (MINUTES TO MILLISECONDS), GENOMIC (HOURS TO MINUTES), DEVELOPMENTAL (YEARS AND MONTHS), AND EVOLUTIONARY (CENTURIES AND MILLENNIA) TIME. THIS SPECIAL ISSUE OF PNAS THUS EXPLORES TIME AND TIMING AMONG G-E TRANSACTIONS: THE IMPORTANCE OF TIMING AND TIMESCALES IN PLASTICITY AND CRITICAL PERIODS OF BRAIN DEVELOPMENT; EPIGENETICS AND THE MOLECULAR UNDERPINNINGS OF BIOLOGICALLY EMBEDDED EXPERIENCE; THE ENCODING OF EXPERIENCE ACROSS TIME AND BIOLOGICAL LEVELS OF ORGANIZATION; AND GENE-REGULATORY NETWORKS IN BEHAVIOR AND DEVELOPMENT AND THEIR LINKAGES TO NEURONAL NETWORKS. TAKEN TOGETHER, THE COLLECTION OF PAPERS OFFERS PERSPECTIVES ON HOW G-E INTERPLAY OPERATES CONTINGENTLY WITHIN AND AGAINST A BACKDROP OF TIME AND TIMESCALES. 2020 14 4790 46 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 15 3684 34 INFLAMMATION, PHYSICAL ACTIVITY, AND CHRONIC DISEASE: AN EVOLUTIONARY PERSPECTIVE. LOW-GRADE INFLAMMATION IS EMERGING AS A COMMON FEATURE OF CONTEMPORARY METABOLIC, PSYCHIATRIC, AND NEURODEGENERATIVE DISEASES. BOTH PHYSICAL INACTIVITY AND ABDOMINAL ADIPOSITY ARE ASSOCIATED WITH PERSISTENT SYSTEMIC LOW-GRADE INFLAMMATION. THUS, THE BEHAVIORAL, BIOLOGICAL, AND PHYSIOLOGICAL CHANGES THAT CAUSE A PREDISPOSITION TO OBESITY AND OTHER CO-MORBIDITIES COULD HAVE EPIGENETIC UNDERPINNINGS IN ADDITION TO VARIOUS EVOLUTIONARY SCENARIOS. A KEY ASSUMPTION INVOLVES THE POTENTIAL FOR A MISMATCH BETWEEN THE HUMAN GENOME MOLDED OVER GENERATIONS, AND THE ISSUE OF ADAPTING TO THE MODERN HIGH CALORIE DIET AND COMMON BUILT ENVIRONMENTS PROMOTING INACTIVITY. THIS BIOLOGICAL MISMATCH APPEARS TO HAVE DIRE HEALTH CONSEQUENCES. THEREFORE, THE GOAL OF THIS ARTICLE IS TO PROVIDE A BRIEF OVERVIEW ON THE IMPORTANCE OF INFLAMMATION AS PART OF HUMAN SURVIVAL AND HOW PHYSICAL ACTIVITY (PA) AND PHYSICAL INACTIVITY ARE CRITICAL REGULATORS OF SYSTEMIC INFLAMMATION. THE REVIEW WILL HIGHLIGHT ANTI-INFLAMMATORY EFFECTS OF PA AND EXERCISE TRAINING FROM A METABOLIC AND SYSTEMIC SIGNALING PERSPECTIVE, WHICH INCLUDES SKELETAL MUSCLE TO UTILIZATION OF FATTY ACIDS, TLR4 SIGNALING, AND MYOKINE/ADIPOKINE EFFECTS. THE AVAILABLE EVIDENCE SUGGESTS THAT PA, REGULAR EXERCISE, AND WEIGHT LOSS OFFER BOTH PROTECTION AGAINST AND TREATMENT FOR A WIDE VARIETY OF CHRONIC DISEASES ASSOCIATED WITH LOW-GRADE INFLAMMATION THROUGH AN IMPROVED INFLAMMATORY PROFILE. 2020 16 6792 30 [DOHAD AND EPIGENETIC INFORMATION: SOCIETAL CHALLENGES]. THE CONCEPT OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) ALTERS OUR UNDERSTANDING OF WHAT CONSTITUTES "HEALTH" OR "DISEASE" INTENDED AS CHRONIC, NON-COMMUNICABLE DISEASES, WHICH DEVELOP OVER THE LIFE COURSE IN HIGH INCOME AND EMERGING COUNTRIES. IT IMPLIES A CHANGE IN PARADIGM FORMING A BASIS FOR PREVENTION POLICIES ACROSS THE GLOBE. IT ALSO IMPACTS PSYCHOLOGICAL, SOCIAL, ECONOMIC, ETHICAL AND LEGAL SCIENCES. IN LINE WITH THE UNANTICIPATED UNDERPINNING EPIGENETIC MECHANISMS ARE ALSO THE SOCIAL ISSUES (INCLUDING PUBLIC POLICIES) THAT COULD BE PRODUCED BY THE KNOWLEDGE RELATED TO DOHAD THAT OPENS A WIDE FIELD OF INQUIRY. THE INFORMATION UNVEILED BY EPIGENETICS COUPLED WITH INFORMATION ON LIFESTYLE INCLUDING DURING THE DEVELOPMENT PHASE, IS OF UNFORESEEN NATURE, RAISING ISSUES OF DIFFERENT NATURE. THEREFORE IT REQUIRES SPECIFIC ATTENTION AND RESEARCH, AND A SPECIFIC SUPPORT BY A PLURIDISCIPLINARY REFLECTION SINCE THE VERY BEGINNING OF ITS PRODUCTION, TO ANTICIPATE THE QUESTIONS THAT MIGHT BE RAISED IN THE FUTURE. 2016 17 6626 34 UNDERSTANDING RESILIENCE. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. STRESSFUL LIFE EVENTS, TRAUMA, AND CHRONIC ADVERSITY CAN HAVE A SUBSTANTIAL IMPACT ON BRAIN FUNCTION AND STRUCTURE, AND CAN RESULT IN THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD), DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. HOWEVER, MOST INDIVIDUALS DO NOT DEVELOP SUCH ILLNESSES AFTER EXPERIENCING STRESSFUL LIFE EVENTS, AND ARE THUS THOUGHT TO BE RESILIENT. RESILIENCE AS SUCCESSFUL ADAPTATION RELIES ON EFFECTIVE RESPONSES TO ENVIRONMENTAL CHALLENGES AND ULTIMATE RESISTANCE TO THE DELETERIOUS EFFECTS OF STRESS, THEREFORE A GREATER UNDERSTANDING OF THE FACTORS THAT PROMOTE SUCH EFFECTS IS OF GREAT RELEVANCE. THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS THAT ARE CONSIDERED ESSENTIAL CONTRIBUTORS TO THE DEVELOPMENT OF RESILIENCE. NEURAL CIRCUITS AND PATHWAYS INVOLVED IN MEDIATING RESILIENCE ARE ALSO DISCUSSED. THE GROWING UNDERSTANDING OF RESILIENCE FACTORS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL AND PSYCHOLOGICAL INTERVENTIONS FOR ENHANCING RESILIENCE AND MITIGATING THE UNTOWARD CONSEQUENCES. 2013 18 375 23 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 19 3594 46 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 20 421 42 ANIMAL MODELS IN EPIGENETIC RESEARCH: INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE CONSIDERATIONS ACROSS THE LIFESPAN. THE RAPID EXPANSION AND EVOLUTION OF EPIGENETICS AS A CORE SCIENTIFIC DISCIPLINE HAVE RAISED NEW QUESTIONS ABOUT HOW ENDOGENOUS AND ENVIRONMENTAL FACTORS CAN INFORM THE MECHANISMS THROUGH WHICH BIOLOGICAL FORM AND FUNCTION ARE REGULATED. EXISTING AND PROPOSED ANIMAL MODELS USED FOR EPIGENETIC RESEARCH HAVE TARGETED A MYRIAD OF HEALTH AND DISEASE ENDPOINTS THAT MAY BE ACUTE, CHRONIC, AND TRANSGENERATIONAL IN NATURE. INITIATING EVENTS AND OUTCOMES MAY EXTEND ACROSS THE ENTIRE LIFESPAN TO ELICIT UNANTICIPATED PHENOTYPES THAT ARE OF PARTICULAR CONCERN TO INSTITUTIONAL ANIMAL CARE AND USE COMMITTEES (IACUCS). THE DYNAMICS AND PLASTICITY OF EPIGENETIC MECHANISMS PRODUCE EFFECTS AND CONSEQUENCES THAT ARE MANIFEST DIFFERENTIALLY WITHIN DISCREET SPATIAL AND TEMPORAL CONTEXTS, INCLUDING PRENATAL DEVELOPMENT, STEM CELLS, ASSISTED REPRODUCTIVE TECHNOLOGIES, PRODUCTION OF SEXUAL DIMORPHISMS, SENESCENCE, AND OTHERS. MANY DIETARY AND NUTRITIONAL INTERVENTIONS HAVE ALSO BEEN SHOWN TO HAVE A SIGNIFICANT IMPACT ON BIOLOGICAL FUNCTIONS AND DISEASE SUSCEPTIBILITIES THROUGH ALTERED EPIGENETIC PROGRAMMING. THE ENVIRONMENTAL, CHEMICAL, TOXIC, THERAPEUTIC, AND PSYCHOSOCIAL STRESSORS USED IN ANIMAL STUDIES TO ELICIT EPIGENETIC CHANGES CAN BECOME EXTREME AND SHOULD RAISE IACUC CONCERNS FOR THE WELL-BEING AND PROPER CARE OF ALL RESEARCH ANIMALS INVOLVED. EPIGENETICS RESEARCH IS RAPIDLY BECOMING AN INTEGRAL PART OF THE SEARCH FOR MECHANISMS IN EVERY MAJOR AREA OF BIOMEDICAL AND BEHAVIORAL RESEARCH AND WILL FOSTER THE CONTINUED DEVELOPMENT OF NEW ANIMAL MODELS. FROM THE IACUC PERSPECTIVE, CARE MUST BE TAKEN TO ACKNOWLEDGE THE PARTICULAR NEEDS AND CONCERNS CREATED BY SUPERIMPOSITION OF EPIGENETIC MECHANISMS OVER DIVERSE FIELDS OF INVESTIGATION TO ENSURE THE PROPER CARE AND USE OF ANIMALS WITHOUT IMPEDING SCIENTIFIC PROGRESS. 2012