1 1779 201 EDITORIAL: MATERNAL INFLAMMATION DURING PREGNANCY: A MODIFIABLE PATHWAY TOWARD IMPROVING OFFSPRING SOCIOEMOTIONAL OUTCOMES IN CHILDHOOD AND ADOLESCENCE. CHILDHOOD PSYCHOPATHOLOGY IS A WELL-ESTABLISHED PREDICTOR OF POOR ADULT LIFE-COURSE OUTCOMES INCLUDING LOWER RATES OF EDUCATIONAL ATTAINMENT AND REDUCED FAMILY INCOME, WITH A TOTAL ECONOMIC LOSS OF $2.1 TRILLION IN THE UNITED STATES.(1) GIVEN THIS HIGH LEVEL OF INDIVIDUAL AND SOCIETAL BURDEN, MUCH EFFORT HAS BEEN DEVOTED TO IDENTIFYING THE MODIFIABLE RISK FACTORS THAT CONFER RISK FOR PSYCHIATRIC DISORDERS DURING EARLY CHILDHOOD. INDEED, NUMEROUS ASPECTS OF EARLY LIFE ADVERSITY, SUCH AS SOCIOECONOMIC DISADVANTAGE, STRESSFUL/TRAUMATIC LIFE EVENTS, AND DISRUPTED PARENT-CHILD RELATIONSHIPS, DEMONSTRATE STRONG ASSOCIATIONS WITH SOCIOEMOTIONAL PROBLEMS AND PSYCHIATRIC DISORDERS INTO ADOLESCENCE.(2) HOWEVER, THE UNDERLYING BIOLOGICAL MECHANISMS THAT ALSO CONTRIBUTE TO THIS RISK TRAJECTORY REMAIN LESS WELL UNDERSTOOD. ONE PROPOSED BIOLOGICAL MECHANISM THAT IS RAPIDLY GAINING MOMENTUM IN THE FIELD OF DEVELOPMENTAL PSYCHOPATHOLOGY CONCERNS EXCESSIVE IMMUNE SYSTEM ACTIVATION AND/OR PROINFLAMMATORY RESPONSES IN THE ORIGINS OF HEALTH AND DISEASE.(3) OF PARTICULAR INTEREST IS THE PRENATAL PERIOD, REPRESENTING A WINDOW OF VULNERABILITY IN WHICH PRENATAL EXPOSURES PREPARE OR PROGRAM THE FETUS FOR THE EXPECTED POSTNATAL ENVIRONMENT.(3-5) MORE SPECIFICALLY, FETAL PROGRAMMING POSITS THAT THE EFFECTS OF MATERNAL ADVERSITY DURING PREGNANCY ARE, AT LEAST IN PART, TRANSMITTED TO THE FETUS VIA MULTIPLE RELATED PATHWAYS INCLUDING CHRONIC MATERNAL INFLAMMATION AND/OR OVERACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, RESULTING IN ABERRANT MATERNAL-FETAL IMMUNE/GLUCOCORTICOID SYSTEMS AND DOWNSTREAM EPIGENETIC ALTERATIONS IN THE DEVELOPING FETUS. TOGETHER, THESE FACTORS WORK TO INCREASE THE SUSCEPTIBILITY OF OFFSPRING TO ADVERSITY IN THE POSTNATAL ENVIRONMENT AND, IN TURN, ENHANCE RISK FOR PSYCHIATRIC DISORDERS.(3-6) HOWEVER, MUCH OF THE EXISTING LITERATURE IS BASED ON PRECLINICAL ANIMAL MODELS WITH COMPARATIVELY FEWER CLINICAL STUDIES.(3) AS SUCH, THERE REMAINS A PAUCITY OF LARGE, PROSPECTIVELY DESIGNED CLINICAL STUDIES EXAMINING MATERNAL PROINFLAMMATORY CONDITIONS DURING PREGNANCY IN RELATION TO PSYCHOPATHOLOGY IN OFFSPRING. AS PART OF THE LANDMARK NATIONAL INSTITUTES OF HEALTH-FUNDED ECHO (ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOMES) CONSORTIUM, THE STUDY BY FRAZIER ET AL.(7) REPRESENTS ONE OF THE LARGEST INVESTIGATIONS LINKING PERINATAL MATERNAL PROINFLAMMATORY CONDITIONS WITH CO-OCCURRING PSYCHIATRIC SYMPTOMS IN CHILDREN AND ADOLESCENTS. 2023 2 2802 46 FETAL AND INFANT ORIGINS OF ASTHMA. PREVIOUS STUDIES HAVE SUGGESTED THAT ASTHMA, LIKE OTHER COMMON DISEASES, HAS AT LEAST PART OF ITS ORIGIN EARLY IN LIFE. LOW BIRTH WEIGHT HAS BEEN SHOWN TO BE ASSOCIATED WITH INCREASED RISKS OF ASTHMA, CHRONIC OBSTRUCTIVE AIRWAY DISEASE, AND IMPAIRED LUNG FUNCTION IN ADULTS, AND INCREASED RISKS OF RESPIRATORY SYMPTOMS IN EARLY CHILDHOOD. THE DEVELOPMENTAL PLASTICITY HYPOTHESIS SUGGESTS THAT THE ASSOCIATIONS BETWEEN LOW BIRTH WEIGHT AND DISEASES IN LATER LIFE ARE EXPLAINED BY ADAPTATION MECHANISMS IN FETAL LIFE AND INFANCY IN RESPONSE TO VARIOUS ADVERSE EXPOSURES. VARIOUS PATHWAYS LEADING FROM ADVERSE FETAL AND INFANT EXPOSURES TO GROWTH ADAPTATIONS AND RESPIRATORY HEALTH OUTCOMES HAVE BEEN STUDIED, INCLUDING FETAL AND EARLY INFANT GROWTH PATTERNS, MATERNAL SMOKING AND DIET, CHILDREN'S DIET, RESPIRATORY TRACT INFECTIONS AND ACETAMINOPHEN USE, AND GENETIC SUSCEPTIBILITY. STILL, THE SPECIFIC ADVERSE EXPOSURES IN FETAL AND EARLY POSTNATAL LIFE LEADING TO RESPIRATORY DISEASE IN ADULT LIFE ARE NOT YET FULLY UNDERSTOOD. CURRENT STUDIES SUGGEST THAT BOTH ENVIRONMENTAL AND GENETIC FACTORS IN VARIOUS PERIODS OF LIFE, AND THEIR EPIGENETIC MECHANISMS MAY UNDERLIE THE COMPLEX ASSOCIATIONS OF LOW BIRTH WEIGHT WITH RESPIRATORY DISEASE IN LATER LIFE. NEW WELL-DESIGNED EPIDEMIOLOGICAL STUDIES ARE NEEDED TO IDENTIFY THE SPECIFIC UNDERLYING MECHANISMS. THIS REVIEW IS FOCUSED ON SPECIFIC ADVERSE FETAL AND INFANT GROWTH PATTERNS AND EXPOSURES, GENETIC SUSCEPTIBILITY, POSSIBLE RESPIRATORY ADAPTATIONS AND PERSPECTIVES FOR NEW STUDIES. 2012 3 1766 50 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 4 6554 36 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 5 585 44 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 6 4078 48 MATERNAL INFLAMMATION, GROWTH RETARDATION, AND PRETERM BIRTH: INSIGHTS INTO ADULT CARDIOVASCULAR DISEASE. THE "FETAL ORIGIN OF ADULT DISEASE HYPOTHESIS" ORIGINALLY DESCRIBED BY BARKER ET AL. IDENTIFIED THE RELATIONSHIP BETWEEN IMPAIRED IN UTERO GROWTH AND ADULT CARDIOVASCULAR DISEASE RISK AND DEATH. SINCE THEN, NUMEROUS CLINICAL AND EXPERIMENTAL STUDIES HAVE CONFIRMED THAT EARLY DEVELOPMENTAL INFLUENCES CAN LEAD TO CARDIOVASCULAR, PULMONARY, METABOLIC, AND PSYCHOLOGICAL DISEASES DURING ADULTHOOD WITH AND WITHOUT ALTERATIONS IN BIRTH WEIGHT. THIS SO CALLED "FETAL PROGRAMMING" INCLUDES DEVELOPMENTAL DISRUPTION, IMMEDIATE ADAPTATION, OR PREDICTIVE ADAPTATION AND CAN LEAD TO EPIGENETIC CHANGES AFFECTING A SPECIFIC ORGAN OR OVERALL HEALTH. THE INTRAUTERINE ENVIRONMENT IS DRAMATICALLY IMPACTED BY THE OVERALL MATERNAL HEALTH. BOTH PREMATURE BIRTH OR LOW BIRTH WEIGHT CAN RESULT FROM A VARIETY OF MATERNAL CONDITIONS INCLUDING UNDERNUTRITION OR DYSNUTRITION, METABOLIC DISEASES, CHRONIC MATERNAL STRESSES INDUCED BY INFECTIONS AND INFLAMMATION, AS WELL AS HYPERCHOLESTEROLEMIA AND SMOKING. NUMEROUS ANIMAL STUDIES HAVE SUPPORTED THE IMPORTANCE OF BOTH MATERNAL HEALTH AND MATERNAL ENVIRONMENT ON THE LONG TERM OUTCOMES OF THE OFFSPRING. WITH INCREASING RATES OF OBESITY AND DIABETES AND SURVIVAL OF PRETERM INFANTS BORN AT EARLY GESTATIONAL AGES, THE NEED TO ELUCIDATE MECHANISMS RESPONSIBLE FOR PROGRAMMING OF ADULT CARDIOVASCULAR DISEASE IS ESSENTIAL FOR THE TREATMENT OF UPCOMING GENERATIONS. 2011 7 3582 39 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 8 2274 40 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 9 1911 47 ENVIRONMENT IN CHILDREN'S HEALTH: A NEW CHALLENGE FOR RISK ASSESSMENT. IN THE LAST FEW YEARS, MANY STUDIES HAVE FOCUSED ON THE EFFECTS OF ENVIRONMENTAL CONTAMINANT EXPOSURE DURING THE PRENATAL PERIOD OR INFANCY AS PREDICTORS OF HEALTH OUTCOMES IN THE FUTURE. IN THESE TIME WINDOWS, DUE TO THEIR RAPID GROWTH, AND PHYSIOLOGIC AND METABOLIC DEVELOPMENT, WE CAN OBSERVE A HIGHER VULNERABILITY TO THE EFFECTS OF ENVIRONMENT, WITH RESPECT TO ADULTHOOD. THE EVIDENCE OF POSSIBLE INFLUENCES, PARTLY MEDIATED BY EPIGENETIC MECHANISMS, INVOLVE NEUROBEHAVIORAL RESPONSES AND IMMUNE, ENDOCRINE, AND RESPIRATORY SYSTEMS, ACTING DIRECTLY ON THE CHILD OR INDIRECTLY WHEN MEDIATED BY PLACENTAL TRANSFER OR BREAST FEEDING. IN PARTICULAR, DUE TO A GREATER INTAKE OF AIR, FOOD, AND FLUIDS RELATIVE TO BODY WEIGHT, CRAWLING BEHAVIORS AND SHORT STATURE, THE RISK OF EXCESSIVE EXPOSURE IS GREATER IN CHILDREN. HOWEVER, DATA ON THE LONG-TERM IMPLICATIONS OF EARLY EXPOSURES ARE SCARCE. ADDITIONALLY, SO THAT PHYSICIANS AND INSTITUTIONS FOR CHILD CARE AND ASSISTANCE OF PREGNANT WOMEN CAN TAKE ACTIONS TO COUNTERACT THE EFFECTS OF CHEMICAL POLLUTION (I.E., BY EDUCATIONAL OPPORTUNITIES), A RISK ASSESSMENT PERSPECTIVE THAT RESPONDS TO THE BIOCOMPLEXITY OF THE HUMAN BEING IS NEEDED. THE PRESENT PAPER PROVIDES AN OVERVIEW OF PHYSIOLOGIC AND BEHAVIORAL CHARACTERISTICS DURING THE PERINATAL PERIOD AND IN CHILDHOOD, SUGGESTING IN A MORE INTEGRATED WAY, THE NEED OF A NEW RISK-ASSESSMENT APPROACH TO MANAGING CHRONIC DISEASE IN PEDIATRIC PATIENTS. 2021 10 4189 41 METABOLIC DISEASE PROGRAMMING: FROM MITOCHONDRIA TO EPIGENETICS, GLUCOCORTICOID SIGNALLING AND BEYOND. EMBRYONIC AND FOETAL DEVELOPMENT ARE CRITICAL PERIODS OF DEVELOPMENT IN WHICH SEVERAL ENVIRONMENTAL CUES DETERMINE HEALTH AND DISEASE IN ADULTHOOD. MATERNAL CONDITIONS AND AN UNFAVOURABLE INTRAUTERINE ENVIRONMENT IMPACT FOETAL DEVELOPMENT AND MAY PROGRAMME THE OFFSPRING FOR INCREASED PREDISPOSITION TO METABOLIC DISEASES AND OTHER CHRONIC PATHOLOGIC CONDITIONS THROUGHOUT ADULT LIFE. PREVIOUSLY, NON-COMMUNICABLE CHRONIC DISEASES WERE ONLY ASSOCIATED WITH GENETICS AND LIFESTYLE. NOW THE ORIGINS OF NON-COMMUNICABLE CHRONIC DISEASES ARE ASSOCIATED WITH EARLY-LIFE ADAPTATIONS THAT PRODUCE LONG-TERM DYSFUNCTION. EARLY-LIFE ENVIRONMENT SETS THE LONG-TERM HEALTH AND DISEASE RISK AND CAN SPAN THROUGH MULTIPLE GENERATIONS. RECENT RESEARCH IN DEVELOPMENTAL PROGRAMMING AIMS AT IDENTIFYING THE MOLECULAR MECHANISMS RESPONSIBLE FOR DEVELOPMENTAL PROGRAMMING OUTCOMES THAT IMPACT CELLULAR PHYSIOLOGY AND TRIGGER ADULTHOOD DISEASE. THE IDENTIFICATION OF NEW THERAPEUTIC TARGETS CAN IMPROVE OFFSPRING'S HEALTH MANAGEMENT AND PREVENT OR OVERCOME ADVERSE CONSEQUENCES OF FOETAL PROGRAMMING. THIS REVIEW SUMMARIZES RECENT BIOMEDICAL DISCOVERIES IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) HYPOTHESIS AND HIGHLIGHT POSSIBLE DEVELOPMENTAL PROGRAMMING MECHANISMS, INCLUDING PRENATAL STRUCTURAL DEFECTS, METABOLIC (MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, PROTEIN MODIFICATION), EPIGENETIC AND GLUCOCORTICOID SIGNALLING-RELATED MECHANISMS SUGGESTING MOLECULAR CLUES FOR THE CAUSES AND CONSEQUENCES OF PROGRAMMING OF INCREASED SUSCEPTIBILITY OF OFFSPRING TO METABOLIC DISEASE AFTER BIRTH. IDENTIFYING MECHANISMS INVOLVED IN DOHAD CAN CONTRIBUTE TO EARLY INTERVENTIONS IN PREGNANCY OR EARLY CHILDHOOD, TO RE-SET THE METABOLIC HOMEOSTASIS AND BREAK THE CHAIN OF SUBSEQUENT EVENTS THAT COULD LEAD TO THE DEVELOPMENT OF DISEASE. 2021 11 4802 46 OBESITY AND LIFESPAN HEALTH--IMPORTANCE OF THE FETAL ENVIRONMENT. A MARKED INCREASE IN THE FREQUENCY OF OBESITY AT THE POPULATION LEVEL HAS RESULTED IN AN INCREASING NUMBER OF OBESE WOMEN ENTERING PREGNANCY. THE INCREASING REALIZATION OF THE IMPORTANCE OF THE FETAL ENVIRONMENT IN RELATION TO CHRONIC DISEASE ACROSS THE LIFESPAN HAS FOCUSED ATTENTION ON THE ROLE OF MATERNAL OBESITY IN FETAL DEVELOPMENT. PREVIOUS STUDIES HAVE DEMONSTRATED THAT OBESITY DURING ADOLESCENCE AND ADULTHOOD CAN BE TRACED BACK TO FETAL AND EARLY CHILDHOOD EXPOSURES. THIS REVIEW FOCUSES ON FACTORS THAT CONTRIBUTE TO EARLY DEVELOPMENTAL EVENTS, SUCH AS EPIGENETIC MODIFICATIONS, THE POTENTIAL FOR AN INCREASE IN INFLAMMATORY BURDEN, EARLY DEVELOPMENTAL PROGRAMMING CHANGES SUCH AS THE VARIABLE DEVELOPMENT OF WHITE VERSUS BROWN ADIPOSE TISSUE, AND ALTERATIONS IN ORGAN ONTOGENY. WE HYPOTHESIZE THAT THESE MECHANISMS PROMOTE AN UNFAVORABLE FETAL ENVIRONMENT AND CAN HAVE A LONG-STANDING IMPACT, WITH EARLY MANIFESTATIONS OF CHRONIC DISEASE THAT CAN RESULT IN AN INCREASED DEMAND FOR FUTURE HEALTH CARE. IN ORDER TO IDENTIFY APPROPRIATE PREVENTIVE MEASURES, ATTENTION NEEDS TO BE PLACED BOTH ON REDUCING MATERNAL OBESITY AS WELL AS UNDERSTANDING THE MOLECULAR, CELLULAR, AND EPIGENETIC MECHANISMS THAT MAY BE RESPONSIBLE FOR THE PRENATAL ONSET OF CHRONIC DISEASE. 2014 12 6803 34 [EPIGENETIC MECHANISMS IN PHYSIOLOGIC AND PATHOLOGIC PREGNANCIES]. EPIGENETIC FACTORS ARE NOWADAYS IN THE FOCUS OF SCIENTIFIC INTEREST IN MEDICINE INCLUDING OBSTETRICS. THE ENVIRONMENT IN UTERO AND EARLY NEONATAL LIFE MAY INDUCE A PERMANENT RESPONSE IN THE FETUS AND THE NEWBORN LEADING TO ENHANCED SUSCEPTIBILITY TO LATER DISEASES. THERE IS NOW GROWING EVIDENCE THAT THE EFFECTS OF DEVELOPMENTAL PROGRAMMING MAY ALSO MANIFEST THEMSELVES IN THE NEXT GENERATIONS WITHOUT FURTHER SUBOPTIMAL EXPOSURE. THE SO-CALLED FETAL PROGRAMMING MAY ALSO HIGHLIGHT A TIGHT CONNECTION BETWEEN PATHOLOGICAL CONDITIONS IN PREGNANCY, ENVIRONMENTAL FACTORS AND THE DEVELOPMENT OF CHRONIC DISEASES IN ADULTHOOD. INVESTIGATION OF EPIGENETIC FACTORS MAY YIELD NEW POSSIBILITIES FOR THE PREVENTION OF CHRONIC DISEASES AFFECTING A SIGNIFICANT PART OF THE POPULATION. 2014 13 6064 42 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 14 317 50 ALCOHOL-INDUCED DEVELOPMENTAL ORIGINS OF ADULT-ONSET DISEASES. FETAL ALCOHOL EXPOSURE MAY IMPAIR GROWTH, DEVELOPMENT, AND FUNCTION OF MULTIPLE ORGAN SYSTEMS AND IS ENCOMPASSED BY THE TERM FETAL ALCOHOL SPECTRUM DISORDERS (FASD). RESEARCH HAS SO FAR FOCUSED ON THE MECHANISMS, PREVENTION, AND DIAGNOSIS OF FASD, WHILE THE RISK FOR ADULT-ONSET CHRONIC DISEASES IN INDIVIDUALS EXPOSED TO ALCOHOL IN UTERO IS NOT WELL EXPLORED. DAVID BARKER'S HYPOTHESIS ON DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) SUGGESTS THAT INSULTS TO THE MILIEU OF THE DEVELOPING FETUS PROGRAM IT FOR ADULT DEVELOPMENT OF CHRONIC DISEASES. IN THE 25 YEARS SINCE THE INTRODUCTION OF THIS HYPOTHESIS, EPIDEMIOLOGICAL AND ANIMAL MODEL STUDIES HAVE MADE SIGNIFICANT ADVANCEMENTS IN IDENTIFYING IN UTERO DEVELOPMENTAL ORIGINS OF CHRONIC ADULT-ONSET DISEASES AFFECTING CARDIOVASCULAR, ENDOCRINE, MUSCULOSKELETAL, AND PSYCHOBEHAVIORAL SYSTEMS. TERATOGEN EXPOSURE IS AN ESTABLISHED PROGRAMMING AGENT FOR ADULT DISEASES, AND RECENT STUDIES SUGGEST THAT PRENATAL ALCOHOL EXPOSURE CORRELATES WITH ADULT ONSET OF NEUROBEHAVIORAL DEFICITS, CARDIOVASCULAR DISEASE, ENDOCRINE DYSFUNCTION, AND NUTRIENT HOMEOSTASIS INSTABILITY, WARRANTING ADDITIONAL INVESTIGATION OF ALCOHOL-INDUCED DOHAD, AS WELL AS PATIENT FOLLOW-UP WELL INTO ADULTHOOD FOR AFFECTED INDIVIDUALS. IN UTERO EPIGENETIC ALTERATIONS DURING CRITICAL PERIODS OF METHYLATION ARE A KEY POTENTIAL MECHANISM FOR PROGRAMMING AND SUSCEPTIBILITY OF ADULT-ONSET CHRONIC DISEASES, WITH IMPRINTED GENES AFFECTING METABOLISM BEING CRITICAL TARGETS. ADDITIONAL STUDIES IN EPIDEMIOLOGY, PHENOTYPIC CHARACTERIZATION IN RESPONSE TO TIMING, DOSE, AND DURATION OF EXPOSURE, AS WELL AS ELUCIDATION OF MECHANISMS UNDERLYING FASD-DOHAD INTER RELATION, ARE THUS NEEDED TO CLINICALLY DEFINE CHRONIC DISEASE ASSOCIATED WITH PRENATAL ALCOHOL EXPOSURE. THESE STUDIES ARE CRITICAL TO ESTABLISH INTERVENTIONAL STRATEGIES THAT DECREASE INCIDENCE OF THESE ADULT-ONSET DISEASES AND PROMOTE HEALTHIER AGING AMONG INDIVIDUALS AFFECTED WITH FASD. 2016 15 4790 51 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 16 6483 38 TOXIC STRESS, EPIGENETICS AND CHILD DEVELOPMENT. OBJECTIVES: TO DESCRIBE THE CONCEPT OF TOXIC STRESS, PRESENT THE BASICS OF EPIGENETICS AND DISCUSS THEIR RELATIONSHIP WITH CHILD DEVELOPMENT. DATA SOURCE: NARRATIVE LITERATURE REVIEW THROUGH A SEARCH IN THE SCIELO, LILACS, MEDLINE DATABASES USING THE TERMS ADVERSE CHILDHOOD EXPERIENCE OR EARLY LIFE STRESS, EPIGENOMIC OR EPIGENETIC, CHILD DEVELOPMENT OR INFANT DEVELOPMENT. DATA SYNTHESIS: CONTINUING STRESS RESPONSE, KNOWN AS TOXIC STRESS, CAN OCCUR WHEN A CHILD EXPERIENCES INTENSE, FREQUENT, AND/OR PROLONGED ADVERSITY-SUCH AS PHYSICAL OR EMOTIONAL ABUSE, CHRONIC NEGLECT, FOR EXAMPLE-WITHOUT ADEQUATE ADULT SUPPORT. THIS TOXIC STRESS CAN HAVE HARMFUL EFFECTS ON LEARNING, BEHAVIOR, AND HEALTH THROUGHOUT LIFE. EPIGENETICS, AN EMERGING SCIENTIFIC RESEARCH AREA?, SHOWS HOW ENVIRONMENTAL INFLUENCES AFFECT GENE EXPRESSIONS AND EXPLAINS HOW EARLY EXPERIENCES CAN IMPACT THROUGHOUT LIFE. CONCLUSIONS: TOXIC STRESS CAUSES CHANGES IN THE HUMAN BODY RESPONSE SYSTEMS THAT CAN BE EXPLAINED IN PART BY EPIGENETIC CHANGES, WHICH CAN BE TEMPORARY OR LONG-LASTING. PEDIATRICIANS MUST BE AWARE OF THESE MECHANISMS AND THEIR CONSEQUENCES, SEEKING TO PREVENT THEM AND THUS PROMOTE THE HEALTH, WELL-BEING, AND QUALITY OF LIFE OF CHILDREN, CONTRIBUTING TO THEIR FULL DEVELOPMENT. 2022 17 5316 39 PSYCHOLOGICAL STRESS IN EARLY LIFE AS A PREDISPOSING FACTOR FOR THE DEVELOPMENT OF CHRONIC PAIN: CLINICAL AND PRECLINICAL EVIDENCE AND NEUROBIOLOGICAL MECHANISMS. A WEALTH OF RESEARCH OVER THE PAST 2 DECADES HAS EXPANDED OUR UNDERSTANDING OF THE IMPACT OF EARLY-LIFE ADVERSITY ON PHYSIOLOGICAL FUNCTION AND, CONSEQUENTLY, HEALTH AND WELLBEING IN LATER LIFE. EARLY-LIFE ADVERSITY INCREASES THE RISK OF DEVELOPING A NUMBER OF DISORDERS, SUCH AS CHRONIC PAIN, FIBROMYALGIA, AND IRRITABLE BOWEL SYNDROME. ALTHOUGH MUCH OF THE RESEARCH HAS EXAMINED THE IMPACT OF PHYSICAL MALTREATMENT, AN INCREASING NUMBER OF STUDIES HAVE BEEN PUBLISHED OVER THE PAST FEW YEARS EXAMINING THE EFFECT OF CHILDHOOD PSYCHOLOGICAL STRESS AND TRAUMA ON THE DEVELOPMENT OF VARIOUS TYPES OF CHRONIC PAIN CONDITIONS. WE REVIEW THE CLINICAL AND PRECLINICAL DATA EXAMINING THE LINK AMONG EARLY-LIFE PSYCHOLOGICAL STRESS, ALTERED NOCICEPTIVE BEHAVIOR, AND CHRONIC PAIN IN LATER LIFE. EVIDENCE SUPPORTING A ROLE FOR CERTAIN KEY NEUROBIOLOGICAL SUBSTRATES, INCLUDING THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS; MONOAMINERGIC, OPIOIDERGIC, ENDOCANNABINOID AND IMMUNE SYSTEMS; AND EPIGENETIC MECHANISMS IN THE ASSOCIATION BETWEEN EARLY-LIFE PSYCHOLOGICAL STRESS AND CHRONIC PAIN, IS PROVIDED. GREATER UNDERSTANDING OF THE IMPACT OF EARLY-LIFE STRESS MAY INFORM THE DEVELOPMENT OF PERSONALIZED TREATMENTS FOR CHRONIC PAIN IN LATER LIFE AND STRATEGIES TO PREVENT ITS ONSET IN SUSCEPTIBLE INDIVIDUALS. (C) 2016 WILEY PERIODICALS, INC. 2017 18 1755 43 EARLY NUTRITION AND LATER OUTCOMES IN PRETERM INFANTS. THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE IS AN EMERGING AREA OF INTEREST THAT AMALGAMATES MANY AREAS OF SCIENTIFIC STUDIES AND ENCOMPASSES A WIDE RANGE OF DIVERSE DISCIPLINES FROM EPIDEMIOLOGY TO MOLECULAR BIOLOGY. EVIDENCE HAS ACCUMULATED TO SHOW THAT EARLY LIFE EXPERIENCES, BOTH IN UTERO AND IN INFANCY HAVE LONG-TERM EFFECTS ON MANY BODY SYSTEMS. THERE ARE NOW GOOD DATA TO SHOW THAT SUBOPTIMAL IN UTERO GROWTH, ESPECIALLY WHEN COMBINED WITH RAPID GROWTH ACCELERATION IN EARLY POSTNATAL LIFE MAY INCREASE THE RISK OF LATER LIFE METABOLIC DISEASE. THE MECHANISMS ARE COMPLEX BUT LIKELY TO INVOLVE EPIGENETIC MARKS SUCH AS DNA METHYLATION. PRETERM INFANTS FREQUENTLY EXPERIENCE SUBOPTIMAL NUTRIENT INTAKES IN EARLY POSTNATAL LIFE AND EXHIBIT GROWTH FAILURE WITHIN THE NICU. THEY ALSO RECEIVE PRODUCTS THAT MAY NOT PROVIDE EITHER AN OPTIMAL QUANTITY OR QUALITY OF NUTRIENTS. FOLLOW-UP STUDIES HAVE NOW SHOWN MUCH HIGHER RISKS FOR LONG-TERM CHRONIC DISEASE IN CHILDREN AND ADULTS WHO WERE BORN PRETERM. THERE ARE HIGHER LEVELS OF INSULIN RESISTANCE AND ABNORMAL PARTITIONING OF FAT DEPOSITION. THE ONSET OF PUBERTY SEEMS EARLIER, AVERAGE HEIGHT IS LESS AND BLOOD PRESSURE, MEASURES OF VASCULAR HEALTH AND LIPID PROFILES SUGGEST CARDIOVASCULAR HEALTH IS LIKELY TO DIFFER FROM HEALTHY TERM BORN CONTROLS. DESPITE THIS, THERE ARE NO DATA TO SUGGEST AN OVERALL BENEFIT OF LIMITING NUTRIENT INTAKE, OR RESTRICTING GROWTH IN PRETERM INFANTS. THERE ARE STRONG DATA TO SHOW THAT THE PRETERM BRAIN IS EXQUISITELY VULNERABLE TO UNDERNUTRITION, AND THAT SUBOPTIMAL NUTRIENT INTAKES MAY PERMANENTLY AFFECT LATER COGNITIVE ATTAINMENT. A CLINICAL FOCUS ON EARLY NUTRIENT INTAKES AND BREAST MILK PROVISION IS KEY TO OPTIMISING LONG-TERM HEALTH OUTCOMES. 2013 19 6088 50 THE EFFECTS OF ASSISTED REPRODUCTION TECHNOLOGIES ON METABOLIC HEALTH AND DISEASEDAGGER. THE INCREASING PREVALENCE OF METABOLIC DISEASES PLACES A SUBSTANTIAL BURDEN ON HUMAN HEALTH THROUGHOUT THE WORLD. IT IS BELIEVED THAT PREDISPOSITION TO METABOLIC DISEASE STARTS EARLY IN LIFE, A PERIOD OF GREAT SUSCEPTIBILITY TO EPIGENETIC REPROGRAMMING DUE TO ENVIRONMENTAL INSULTS. ASSISTED REPRODUCTIVE TECHNOLOGIES (ART), I.E., TREATMENTS FOR INFERTILITY, MAY AFFECT EMBRYO DEVELOPMENT, RESULTING IN MULTIPLE ADVERSE HEALTH OUTCOMES IN POSTNATAL LIFE. THE MOST FREQUENTLY OBSERVED ALTERATION IN ART PREGNANCIES IS IMPAIRED PLACENTAL NUTRIENT TRANSFER. MOREOVER, CONSEQUENT INTRAUTERINE GROWTH RESTRICTION AND LOW BIRTH WEIGHT FOLLOWED BY CATCH-UP GROWTH CAN ALL PREDICT FUTURE OBESITY, INSULIN RESISTANCE, AND CHRONIC METABOLIC DISEASES. IN THIS REVIEW, WE HAVE FOCUSED ON EVIDENCE OF ADVERSE METABOLIC ALTERATIONS ASSOCIATED WITH ART, WHICH CAN CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC ADULT-ONSET DISEASES, SUCH AS METABOLIC SYNDROME, TYPE 2 DIABETES, AND CARDIOVASCULAR DISEASE. DUE TO HIGH PHENOTYPIC PLASTICITY, ART PREGNANCIES CAN PRODUCE BOTH OFFSPRING WITH ADVERSE HEALTH OUTCOMES, AS WELL AS HEALTHY INDIVIDUALS. WE FURTHER DISCUSS THE SEX-SPECIFIC AND AGE-DEPENDENT METABOLIC ALTERATIONS REFLECTED IN ART OFFSPRING, AND HOW THE DEGREE OF INTERFERENCE OF A GIVEN ART PROCEDURE (FROM MILD TO MORE SEVERE MANIPULATION OF THE EGG) AFFECTS THE OCCURRENCE AND DEGREE OF OFFSPRING ALTERATIONS. OVER THE LAST FEW YEARS, STUDIES HAVE REPORTED SIGNS OF CARDIOMETABOLIC ALTERATIONS IN ART OFFSPRING THAT ARE DETECTABLE AT A YOUNG AGE BUT THAT DO NOT APPEAR TO CONSTITUTE A HIGH RISK OF DISEASE AND MORBIDITY PER SE. THESE ABNORMAL PHENOTYPES COULD BE EARLY INDICATORS OF THE DEVELOPMENT OF CHRONIC DISEASES, INCLUDING METABOLIC SYNDROME, IN ADULTHOOD. THE EARLY DETECTION OF METABOLIC ALTERATIONS COULD CONTRIBUTE TO PREVENTING THE ONSET OF DISEASE IN ADULTHOOD. SUCH EARLY INTERVENTIONS MAY COUNTERACT THE RISK FACTORS AND IMPROVE THE LONG-TERM HEALTH OF THE INDIVIDUAL. 2021 20 6822 53 [GENDER MEDICINE. SEX- AND GENDER-SPECIFIC ASPECTS OF CLINICAL MEDICINE]. GENDER MEDICINE STUDIES SEX- AND GENDER-BASED DIFFERENCES IN THE DEVELOPMENT AND PREVENTION OF DISEASES, THE AWARENESS AND PRESENTATION OF SYMPTOMS, AND THE EFFECTIVENESS OF THERAPY. GENDER MEDICINE IS PART OF PERSONALIZED MEDICINE, CONSIDERING DIFFERENCES IN BIOLOGICAL AND PSYCHOSOCIAL FACTORS INDIVIDUALLY. THERE ARE DIFFERENCES IN GENES, CHROMOSOMES, HORMONES, AND METABOLISM AS WELL AS DIFFERENCES IN CULTURE, ENVIRONMENT, AND SOCIETY. LIFELONG INTERACTIONS BETWEEN PHYSICAL AND PSYCHOSOCIAL FACTORS WILL INFLUENCE THE HEALTH AND ILL-HEALTH OF MEN AND WOMEN IN DIFFERENT WAYS. EPIGENETIC MODIFICATIONS PROVIDE EVIDENCE OF THE IMPACT OF ENVIRONMENT AND LIFESTYLE DURING VULNERABLE PHASES ON BIOLOGICAL PROCESSES, EFFECTING FUTURE GENERATIONS. MATERNAL LIFESTYLE AND ENVIRONMENTAL FACTORS DURING PREGNANCY CAN IMPACT THE HEALTH OF OFFSPRING IN LATER LIFE ALREADY IN UTERO IN A SEX-SPECIFIC WAY. PAIN, STRESS, AND COPING STYLES DIFFER BETWEEN MEN AND WOMEN. WOMEN EXPERIENCE MORE DRAMATIC PHYSICAL CHANGES DURING THEIR LIFETIME, WHICH ARE ASSOCIATED WITH SPECIFIC BURDENS AND PSYCHOSOCIAL ALTERATIONS. WOMEN WITH MULTIPLE ROLES AND RESPONSIBILITIES SUFFERING FROM STRESS DEVELOP DEPRESSION MORE FREQUENTLY. HOWEVER, MEN ARE OFTEN NOT DIAGNOSED AND TREATED APPROPRIATELY IN CASES OF DEPRESSION OR OSTEOPOROSIS, DISEASES THAT ARE TYPICALLY CONSIDERED "FEMALE." THERE ARE PROMINENT DIFFERENCES BETWEEN MEN AND WOMEN IN MEDICINE REGARDING THE IMMUNE SYSTEM, INFLAMMATION, AND NONCOMMUNICABLE DISEASES SUCH AS OBESITY, TYPE 2 DIABETES, HYPERTENSION, AND CARDIOVASCULAR DISEASE. WOMEN EXPERIENCE MORE OFTEN AUTOIMMUNE DISEASES AND SUFFER MORE FREQUENTLY FROM (CHRONIC) PAIN, NEURODEGENERATIVE CHANGES, AND FUNCTIONAL DISABILITIES. MEN HAVE SHORTER LIFE EXPECTANCY BUT RELATIVELY MORE HEALTHY YEARS OF LIFE, WHICH IS IN GREATER PART ASCRIBED TO PSYCHOSOCIAL DETERMINANTS. STATE-OF-THE-ART CLINICAL MEDICINE COMPRISES INDIVIDUAL RISK FACTORS BASED ON SEX- AND GENDER-SENSITIVE HEALTH PROGRAMS IN ORDER TO IMPROVE THE HEALTH-RELATED QUALITY OF LIFE FOR MEN AND WOMEN. 2014