1 1365 150 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 2 357 32 ALTERNATIVE MODELS FOR TRANSGENERATIONAL EPIGENETIC INHERITANCE: MOLECULAR PSYCHIATRY BEYOND MICE AND MAN. MENTAL ILLNESS REMAINS THE GREATEST CHRONIC HEALTH BURDEN GLOBALLY WITH FEW IN-ROADS HAVING BEEN MADE DESPITE SIGNIFICANT ADVANCES IN GENOMIC KNOWLEDGE IN RECENT DECADES. THE FIELD OF PSYCHIATRY IS CONSTANTLY CHALLENGED TO BRING NEW APPROACHES AND TOOLS TO ADDRESS AND TREAT THE NEEDS OF VULNERABLE INDIVIDUALS AND SUBPOPULATIONS, AND THAT HAS TO BE SUPPORTED BY A CONTINUOUS GROWTH IN KNOWLEDGE. THE MAJORITY OF NEUROPSYCHIATRIC SYMPTOMS REFLECT COMPLEX GENE-ENVIRONMENT INTERACTIONS, WITH EPIGENETICS BRIDGING THE GAP BETWEEN GENETIC SUSCEPTIBILITY AND ENVIRONMENTAL STRESSORS THAT TRIGGER DISEASE ONSET AND DRIVE THE ADVANCEMENT OF SYMPTOMS. IT HAS MORE RECENTLY BEEN DEMONSTRATED IN PRECLINICAL MODELS THAT EPIGENETICS UNDERPINS THE TRANSGENERATIONAL INHERITANCE OF STRESS-RELATED BEHAVIOURAL PHENOTYPES IN BOTH PATERNAL AND MATERNAL LINEAGES, PROVIDING FURTHER SUPPORTING EVIDENCE FOR HERITABILITY IN HUMANS. HOWEVER, UNBIASED PROSPECTIVE STUDIES OF THIS NATURE ARE PRACTICALLY IMPOSSIBLE TO CONDUCT IN HUMANS SO PRECLINICAL MODELS REMAIN OUR BEST OPTION FOR RESEARCHING THE MOLECULAR PATHOPHYSIOLOGIES UNDERLYING MANY NEUROPSYCHIATRIC CONDITIONS. WHILE RODENTS WILL REMAIN THE DOMINANT MODEL SYSTEM FOR PRECLINICAL STUDIES (ESPECIALLY FOR ADDRESSING COMPLEX BEHAVIOURAL PHENOTYPES), THERE IS SCOPE TO EXPAND CURRENT RESEARCH OF THE MOLECULAR AND EPIGENETIC PATHOLOGIES BY USING INVERTEBRATE MODELS. HERE, WE WILL DISCUSS THE UTILITY AND ADVANTAGES OF TWO ALTERNATIVE MODEL ORGANISMS-CAENORHABDITIS ELEGANS AND DROSOPHILA MELANOGASTER-AND SUMMARISE THE COMPELLING INSIGHTS OF THE EPIGENETIC REGULATION OF TRANSGENERATIONAL INHERITANCE THAT ARE POTENTIALLY RELEVANT TO HUMAN PSYCHIATRY. 2021 3 4863 38 ORIGINS OF LIFETIME HEALTH AROUND THE TIME OF CONCEPTION: CAUSES AND CONSEQUENCES. PARENTAL ENVIRONMENTAL FACTORS, INCLUDING DIET, BODY COMPOSITION, METABOLISM, AND STRESS, AFFECT THE HEALTH AND CHRONIC DISEASE RISK OF PEOPLE THROUGHOUT THEIR LIVES, AS CAPTURED IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT. RESEARCH ACROSS THE EPIDEMIOLOGICAL, CLINICAL, AND BASIC SCIENCE FIELDS HAS IDENTIFIED THE PERIOD AROUND CONCEPTION AS BEING CRUCIAL FOR THE PROCESSES MEDIATING PARENTAL INFLUENCES ON THE HEALTH OF THE NEXT GENERATION. DURING THIS TIME, FROM THE MATURATION OF GAMETES THROUGH TO EARLY EMBRYONIC DEVELOPMENT, PARENTAL LIFESTYLE CAN ADVERSELY INFLUENCE LONG-TERM RISKS OF OFFSPRING CARDIOVASCULAR, METABOLIC, IMMUNE, AND NEUROLOGICAL MORBIDITIES, OFTEN TERMED DEVELOPMENTAL PROGRAMMING. WE REVIEW PERICONCEPTIONAL INDUCTION OF DISEASE RISK FROM FOUR BROAD EXPOSURES: MATERNAL OVERNUTRITION AND OBESITY; MATERNAL UNDERNUTRITION; RELATED PATERNAL FACTORS; AND THE USE OF ASSISTED REPRODUCTIVE TREATMENT. STUDIES IN BOTH HUMANS AND ANIMAL MODELS HAVE DEMONSTRATED THE UNDERLYING BIOLOGICAL MECHANISMS, INCLUDING EPIGENETIC, CELLULAR, PHYSIOLOGICAL, AND METABOLIC PROCESSES. WE ALSO PRESENT A META-ANALYSIS OF MOUSE PATERNAL AND MATERNAL PROTEIN UNDERNUTRITION THAT SUGGESTS DISTINCT PARENTAL PERICONCEPTIONAL CONTRIBUTIONS TO POSTNATAL OUTCOMES. WE PROPOSE THAT THE EVIDENCE FOR PERICONCEPTIONAL EFFECTS ON LIFETIME HEALTH IS NOW SO COMPELLING THAT IT CALLS FOR NEW GUIDANCE ON PARENTAL PREPARATION FOR PREGNANCY, BEGINNING BEFORE CONCEPTION, TO PROTECT THE HEALTH OF OFFSPRING. 2018 4 1374 37 DEVELOPMENTAL PROGRAMMING OF ADULT DISEASE: REPROGRAMMING BY MELATONIN? ADULT-ONSET CHRONIC NON-COMMUNICABLE DISEASES (NCDS) CAN ORIGINATE FROM EARLY LIFE THROUGH SO-CALLED THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) OR "DEVELOPMENTAL PROGRAMMING". THE DOHAD CONCEPT OFFERS THE "REPROGRAMMING" STRATEGY TO SHIFT THE TREATMENT FROM ADULTHOOD TO EARLY LIFE, BEFORE CLINICAL DISEASE IS APPARENT. MELATONIN, AN ENDOGENOUS INDOLEAMINE PRODUCED BY THE PINEAL GLAND, HAS PLEIOTROPIC BIOACTIVITIES THOSE ARE BENEFICIAL IN A VARIETY OF HUMAN DISEASES. EMERGING EVIDENCE SUPPORT THAT MELATONIN IS CLOSELY INTER-RELATED TO OTHER PROPOSED MECHANISMS CONTRIBUTING TO THE DEVELOPMENTAL PROGRAMMING OF A VARIETY OF CHRONIC NCDS. RECENT ANIMAL STUDIES HAVE BEGUN TO UNRAVEL THE MULTIFUNCTIONAL ROLES OF MELATONIN IN MANY EXPERIMENTAL MODELS OF DEVELOPMENTAL PROGRAMMING. EVEN THOUGH SOME PROGRESS HAS BEEN MADE IN RESEARCH ON MELATONIN AS A REPROGRAMMING STRATEGY TO PREVENT DOHAD-RELATED NCDS, FUTURE HUMAN STUDIES SHOULD AIM AT FILLING THE TRANSLATIONAL GAP BETWEEN ANIMAL MODELS AND CLINICAL TRIALS. HERE, WE REVIEW SEVERAL KEY THEMES ON THE REPROGRAMMING EFFECTS OF MELATONIN IN DOHAD RESEARCH. WE HAVE PARTICULARLY FOCUSED ON THE FOLLOWING AREAS: MECHANISMS OF DEVELOPMENTAL PROGRAMMING; THE INTERRELATIONSHIP BETWEEN MELATONIN AND MECHANISMS UNDERLYING DEVELOPMENTAL PROGRAMMING; PATHOPHYSIOLOGICAL ROLES OF MELATONIN IN PREGNANCY AND FETAL DEVELOPMENT; AND INSIGHT PROVIDED BY ANIMAL MODELS TO SUPPORT MELATONIN AS A REPROGRAMMING THERAPY. RATES OF NCDS ARE INCREASING FASTER THAN ANTICIPATED ALL OVER THE WORLD. HENCE, THERE IS AN URGENT NEED TO UNDERSTAND REPROGRAMMING MECHANISMS OF MELATONIN AND TO TRANSLATE EXPERIMENTAL RESEARCH INTO CLINICAL PRACTICE FOR HALTING A GROWING LIST OF DOHAD-RELATED NCDS. 2017 5 498 36 ASSOCIATION BETWEEN DIABETES AND CANCER. CURRENT MECHANISTIC INSIGHTS INTO THE ASSOCIATION AND FUTURE CHALLENGES. COMPELLING PIECES OF EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL RESEARCH HAVE DEMONSTRATED THAT DIABETES MELLITUS (DM) IS A MAJOR RISK FACTOR ASSOCIATED WITH INCREASED CANCER INCIDENCE AND MORTALITY IN MANY HUMAN NEOPLASMS. IN THE PATHOPHYSIOLOGY CONTEXT OF DM, MANY OF THE MAIN CLASSICAL ACTORS ARE RELEVANT ELEMENTS THAT CAN FUEL THE DIFFERENT STEPS OF THE CARCINOGENESIS PROCESS. HYPERGLYCEMIA, HYPERINSULINEMIA, METABOLIC INFLAMMATION, AND DYSLIPIDEMIA ARE AMONG THE CLASSIC CONTRIBUTORS TO THIS ASSOCIATION. FURTHERMORE, NEW EMERGING ACTORS HAVE RECEIVED PARTICULAR ATTENTION IN THE LAST FEW YEARS, AND COMPELLING DATA SUPPORT THAT THE MICROBIOME, THE EPIGENETIC CHANGES, THE RETICULUM ENDOPLASMIC STRESS, AND THE INCREASED GLYCOLYTIC INFLUX ALSO PLAY IMPORTANT ROLES IN PROMOTING THE DEVELOPMENT OF MANY CANCER TYPES. THE ARSENAL OF GLUCOSE-LOWERING THERAPEUTIC AGENTS USED FOR TREATING DIABETES IS WIDE AND DIVERSE, AND A GROWING BODY OF DATA RAISED DURING THE LAST TWO DECADES HAS TRIED TO CLARIFY THE CONTRIBUTION OF THERAPEUTIC AGENTS TO THIS ASSOCIATION. HOWEVER, THIS RESEARCH AREA REMAINS CONTROVERSIAL, BECAUSE SOME ANTI-DIABETIC DRUGS ARE NOW CONSIDERED AS EITHER PROMOTORS OR PROTECTING ELEMENTS. IN THE PRESENT REVIEW, WE INTEND TO HIGHLIGHT THE COMPELLING EPIDEMIOLOGICAL SHREDS OF EVIDENCE THAT SUPPORT THIS ASSOCIATION, AS WELL AS THE MECHANISTIC CONTRIBUTIONS OF MANY OF THESE POTENTIAL PATHOLOGICAL MECHANISMS, SOME CONTROVERSIAL POINTS AS WELL AS FUTURE CHALLENGES. 2023 6 4790 42 NUTRITIONAL ADVERSITY, SEX AND REPRODUCTION: 30 YEARS OF DOHAD AND WHAT HAVE WE LEARNED? IT IS WELL ESTABLISHED THAT EARLY LIFE ENVIRONMENTAL SIGNALS, INCLUDING NUTRITION, SET THE STAGE FOR LONG-TERM HEALTH AND DISEASE RISK - EFFECTS THAT SPAN MULTIPLE GENERATIONS. THIS RELATIONSHIP BEGINS EARLY, IN THE PERICONCEPTIONAL PERIOD AND EXTENDS INTO EMBRYONIC, FETAL AND EARLY INFANT PHASES OF LIFE. NOW KNOWN AS THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD), THIS CONCEPT DESCRIBES THE ADAPTATIONS THAT A DEVELOPING ORGANISM MAKES IN RESPONSE TO EARLY LIFE CUES, RESULTING IN ADJUSTMENTS IN HOMEOSTATIC SYSTEMS THAT MAY PROVE MALADAPTIVE IN POSTNATAL LIFE, LEADING TO AN INCREASED RISK OF CHRONIC DISEASE AND/OR THE INHERITANCE OF RISK FACTORS ACROSS GENERATIONS. REPRODUCTIVE MATURATION AND FUNCTION IS SIMILARLY INFLUENCED BY EARLY LIFE EVENTS. THIS SHOULD NOT BE SURPRISING, SINCE PRIMORDIAL GERM CELLS ARE ESTABLISHED EARLY IN LIFE AND THUS VULNERABLE TO EARLY LIFE ADVERSITY. A MULTITUDE OF 'MODIFYING' CUES INDUCING DEVELOPMENTAL ADAPTATIONS HAVE BEEN IDENTIFIED THAT RESULT IN CHANGES IN REPRODUCTIVE DEVELOPMENT AND IMPAIRMENTS IN REPRODUCTIVE FUNCTION. MANY TYPES OF NUTRITIONAL CHALLENGES INCLUDING CALORIC RESTRICTION, MACRONUTRIENT EXCESS AND MICRONUTRIENT INSUFFICIENCIES HAVE BEEN SHOWN TO INDUCE EARLY LIFE ADAPTATIONS THAT PRODUCE LONG-TERM REPRODUCTIVE DYSFUNCTION. MANY PATHWAYS HAVE BEEN SUGGESTED TO UNDERPIN THESE ASSOCIATIONS, INCLUDING EPIGENETIC REPROGRAMMING OF GERM CELLS. WHILE THE MECHANISMS STILL REMAIN TO BE FULLY INVESTIGATED, IT IS CLEAR THAT A LIFECOURSE APPROACH TO UNDERSTANDING LIFETIME REPRODUCTIVE FUNCTION IS NECESSARY. FURTHERMORE, INVESTIGATIONS OF THE IMPACTS OF EARLY LIFE ADVERSITY MUST BE EXTENDED TO INCLUDE THE PATERNAL ENVIRONMENT, ESPECIALLY IN EPIDEMIOLOGICAL AND CLINICAL STUDIES OF OFFSPRING REPRODUCTIVE FUNCTION. 2019 7 4084 37 MATERNAL NUTRITION DURING PREGNANCY AND HEALTH OF THE OFFSPRING. THE ABILITY OF MOTHER TO PROVIDE NUTRIENTS AND OXYGEN FOR HER BABY IS A CRITICAL FACTOR FOR FETAL HEALTH AND ITS SURVIVAL. FAILURE IN SUPPLYING THE ADEQUATE AMOUNT OF NUTRIENTS TO MEET FETAL DEMAND CAN LEAD TO FETAL MALNUTRITION. THE FETUS RESPONDS AND ADAPTS TO UNDERNUTRITION BUT BY DOING SO IT PERMANENTLY ALTERS THE STRUCTURE AND FUNCTION OF THE BODY. MATERNAL OVERNUTRITION ALSO HAS LONG-LASTING AND DETRIMENTAL EFFECTS ON THE HEALTH OF THE OFFSPRING. THERE IS GROWING EVIDENCE THAT MATERNAL NUTRITION CAN INDUCE EPIGENETIC MODIFICATIONS OF THE FETAL GENOME. ONLY RELATIVELY RECENTLY HAS EVIDENCE FROM EPIDEMIOLOGICAL AND ANIMAL STUDIES EMERGED SUGGESTING THAT FETAL RESPONSES TO THE INTRAUTERINE ENVIRONMENT MAY UNDERLIE THE PREVALENCE OF MANY CHRONIC DISEASES OF ADULTHOOD INCLUDING TYPE 2 (NON-INSULIN-DEPENDENT) DIABETES. IT IS NOW OF CRUCIAL IMPORTANCE TO GAIN THE UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THE RELATIONSHIP BETWEEN FETAL ALTERATIONS TO THE INTRA-UTERINE ENVIRONMENT AND THEIR LONG-TERM EFFECTS ON THE HEALTH OF AN INDIVIDUAL. 2006 8 1366 38 DEVELOPMENTAL ORIGINS OF CHRONIC KIDNEY DISEASE: SHOULD WE FOCUS ON EARLY LIFE? CHRONIC KIDNEY DISEASE (CKD) IS BECOMING A GLOBAL BURDEN, DESPITE RECENT ADVANCES IN MANAGEMENT. CKD CAN BEGIN IN EARLY LIFE BY SO-CALLED "DEVELOPMENTAL PROGRAMMING" OR "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD). EARLY-LIFE INSULTS CAUSE STRUCTURAL AND FUNCTIONAL CHANGES IN THE DEVELOPING KIDNEY, WHICH IS CALLED RENAL PROGRAMMING. EPIDEMIOLOGICAL AND EXPERIMENTAL EVIDENCE SUPPORTS THE PROPOSITION THAT EARLY-LIFE ADVERSE EVENTS LEAD TO RENAL PROGRAMMING AND MAKE SUBJECTS VULNERABLE TO DEVELOPING CKD AND ITS COMORBIDITIES IN LATER LIFE. IN ADDITION TO LOW NEPHRON ENDOWMENT, SEVERAL MECHANISMS HAVE BEEN PROPOSED FOR RENAL PROGRAMMING. THE DOHAD CONCEPT OPENS A NEW WINDOW TO OFFSET THE PROGRAMMING PROCESS IN EARLY LIFE TO PREVENT THE DEVELOPMENT OF ADULT KIDNEY DISEASE, NAMELY REPROGRAMMING. HERE, WE REVIEW THE KEY THEMES ON THE DEVELOPMENTAL ORIGINS OF CKD. WE HAVE PARTICULARLY FOCUSED ON THE FOLLOWING AREAS: EVIDENCE FROM HUMAN STUDIES SUPPORT FETAL PROGRAMMING OF KIDNEY DISEASE; INSIGHT FROM ANIMAL MODELS OF RENAL PROGRAMMING; HYPOTHETICAL MECHANISMS OF RENAL PROGRAMMING; ALTERATIONS OF RENAL TRANSCRIPTOME IN RESPONSE TO EARLY-LIFE INSULTS; AND THE APPLICATION OF REPROGRAMMING INTERVENTIONS TO PREVENT THE PROGRAMMING OF KIDNEY DISEASE. 2017 9 4189 43 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 10 6792 29 [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 11 6192 41 THE IMPACT OF NUTRITIONAL INSULTS DURING FETAL LIFE ON BLOOD PRESSURE. NUMEROUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES PROVIDE COMPELLING EVIDENCE THAT NUTRITIONAL INSULTS THAT IMPACT FETAL GROWTH PROGRAM A MARKED INCREASE IN BLOOD PRESSURE IN LATER LIFE. SEX AND AGE ALSO INFLUENCE THE DEVELOPMENTAL PROGRAMMING OF HYPERTENSION; YET THE EXACT MECHANISMS THAT PERMANENTLY CHANGE THE STRUCTURE, PHYSIOLOGY, AND ENDOCRINE HEALTH OF AN INDIVIDUAL ACROSS THEIR LIFESPAN FOLLOWING EXPOSURE TO A NUTRITIONAL INSULT ARE NOT ENTIRELY CLEAR. FETAL EXPOSURE TO MATERNAL GLUCOCORTICOIDS IS POSTULATED AS AN INITIATING EVENT. IN ADDITION, INAPPROPRIATE SUPPRESSION OR ACTIVATION OF THE RENIN ANGIOTENSIN SYSTEM (RAS) AND/OR ACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM (SNS) LEADING TO MARKED INCREASES IN OXIDATIVE STRESS AND ENDOTHELIN PRODUCTION ARE IMPLICATED IN THE ETIOLOGY OF HYPERTENSION THAT HAS ITS ORIGINS IN FETAL LIFE. THE RISK OF HYPERTENSION AND CHRONIC DISEASE IN ONE GENERATION IS TRANSMITTED TO THE NEXT IN THE ABSENCE OF AN ADDITIONAL PRENATAL INSULT IMPLICATING EPIGENETIC PROCESSES. YET, FURTHER STUDIES ARE NEEDED TO FULLY ELUCIDATE THE MECHANISMS THAT CONTRIBUTE TO HYPERTENSION PROGRAMMED IN RESPONSE TO NUTRITIONAL INSULTS DURING EARLY LIFE IN ORDER TO IMPROVE THE CARDIOVASCULAR HEALTH OF AN INDIVIDUAL ACROSS THEIR LIFESPAN. 2015 12 2103 37 EPIGENETIC EPIDEMIOLOGY OF THE DEVELOPMENTAL ORIGINS HYPOTHESIS. EXTENSIVE HUMAN EPIDEMIOLOGIC AND ANIMAL MODEL DATA INDICATE THAT DURING CRITICAL PERIODS OF PRENATAL AND POSTNATAL MAMMALIAN DEVELOPMENT, NUTRITION AND OTHER ENVIRONMENTAL STIMULI INFLUENCE DEVELOPMENTAL PATHWAYS AND THEREBY INDUCE PERMANENT CHANGES IN METABOLISM AND CHRONIC DISEASE SUSCEPTIBILITY. THE BIOLOGIC MECHANISMS UNDERLYING THIS "DEVELOPMENTAL ORIGINS HYPOTHESIS" ARE POORLY UNDERSTOOD. THIS REVIEW FOCUSES ON THE LIKELY INVOLVEMENT OF EPIGENETIC MECHANISMS IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD). WE DESCRIBE PERMANENT EFFECTS OF TRANSIENT ENVIRONMENTAL INFLUENCES ON THE DEVELOPMENTAL ESTABLISHMENT OF EPIGENETIC GENE REGULATION AND EVIDENCE LINKING EPIGENETIC DYSREGULATION WITH HUMAN DISEASE. WE PROPOSE A DEFINITION OF "EPIGENETIC EPIDEMIOLOGY" AND DELINEATE HOW THIS EMERGING FIELD PROVIDES A BASIS FROM WHICH TO EXPLORE THE ROLE OF EPIGENETIC MECHANISMS IN DOHAD. WE SUGGEST STRATEGIES FOR FUTURE HUMAN EPIDEMIOLOGIC STUDIES TO IDENTIFY CAUSAL ASSOCIATIONS BETWEEN EARLY EXPOSURES, LONG-TERM CHANGES IN EPIGENETIC REGULATION, AND DISEASE, WHICH MAY ULTIMATELY ENABLE SPECIFIC EARLY-LIFE INTERVENTIONS TO IMPROVE HUMAN HEALTH. 2007 13 4541 51 MULTISYSTEMIC ALTERATIONS IN HUMANS INDUCED BY BISPHENOL A AND PHTHALATES: EXPERIMENTAL, EPIDEMIOLOGICAL AND CLINICAL STUDIES REVEAL THE NEED TO CHANGE HEALTH POLICIES. A VAST AMOUNT OF EVIDENCE INDICATES THAT BISPHENOL A (BPA) AND PHTHALATES ARE WIDELY DISTRIBUTED IN THE ENVIRONMENT SINCE THESE COMPOUNDS ARE MASS-PRODUCED FOR THE MANUFACTURE OF PLASTICS AND PLASTICIZERS. THESE COMPOUNDS BELONG TO A LARGE GROUP OF SUBSTANCES TERMED ENDOCRINE-DISRUPTING CHEMICALS (EDC). IT IS WELL KNOWN THAT HUMANS AND LIVING ORGANISMS ARE UNAVOIDABLY AND UNINTENTIONALLY EXPOSED TO BPA AND PHTHALATES FROM FOOD PACKAGING MATERIALS AND MANY OTHER EVERYDAY PRODUCTS. BPA AND PHTHALATES EXERT THEIR EFFECT BY INTERFERING WITH HORMONE SYNTHESIS, BIOAVAILABILITY, AND ACTION, THEREBY ALTERING CELLULAR PROLIFERATION AND DIFFERENTIATION, TISSUE DEVELOPMENT, AND THE REGULATION OF SEVERAL PHYSIOLOGICAL PROCESSES. IN FACT, THESE EDC CAN ALTER FETAL PROGRAMMING AT AN EPIGENETIC LEVEL, WHICH CAN BE TRANSGENERATIONAL TRANSMITTED AND MAY BE INVOLVED IN THE DEVELOPMENT OF VARIOUS CHRONIC PATHOLOGIES LATER IN THE ADULTHOOD, INCLUDING METABOLIC, REPRODUCTIVE AND DEGENERATIVE DISEASES, AND CERTAIN TYPES OF CANCER. IN THIS REVIEW, WE DESCRIBE THE MOST RECENT PROPOSED MECHANISMS OF ACTION OF THESE EDC AND OFFER A COMPELLING SELECTION OF EXPERIMENTAL, EPIDEMIOLOGICAL AND CLINICAL STUDIES, WHICH SHOW EVIDENCE OF HOW EXPOSURE TO THESE POLLUTANTS AFFECTS OUR HEALTH DURING DEVELOPMENT, AND THEIR ASSOCIATION WITH A WIDE RANGE OF REPRODUCTIVE, METABOLIC AND NEUROLOGICAL DISEASES, AS WELL AS HORMONE-RELATED CANCERS. WE STRESS THE IMPORTANCE OF CONCERN IN THE GENERAL POPULATION AND THE URGENT NEED FOR THE MEDICAL HEALTH CARE SYSTEM TO CLOSELY MONITOR EDC LEVELS IN THE POPULATION DUE TO UNAVOIDABLE AND INVOLUNTARY EXPOSURE TO THESE POLLUTANTS AND THEIR IMPACT ON HUMAN HEALTH. 2021 14 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 15 5167 24 PRECONCEPTION PATERNAL MENTAL DISORDERS AND CHILD HEALTH: MECHANISMS AND INTERVENTIONS. MENTAL ILLNESS IS A SIGNIFICANT GLOBAL HEALTH ISSUE WITH A STEADY PREVALENCE. HIGH HERITABILITY IS SUSPECTED, BUT GENOME-WIDE ASSOCIATION STUDIES ONLY IDENTIFIED A SMALL NUMBER OF RISK GENES ASSOCIATED WITH MENTAL DISORDERS. THIS 'MISSING INHERITANCE' CAN BE PARTIALLY EXPLAINED BY EPIGENETIC HEREDITY. EVIDENCE FROM NUMEROUS ANIMAL MODELS AND HUMAN STUDIES SUPPORTS THE POSSIBILITY THAT PRECONCEPTION PATERNAL MENTAL HEALTH INFLUENCES THEIR OFFSPRING'S MENTAL HEALTH VIA NONGENETIC MEANS. HERE, WE REVIEW TWO POTENTIAL PATHWAYS, INCLUDING SPERM EPIGENETICS AND SEMINAL PLASMA COMPONENTS. THE CURRENT REVIEW HIGHLIGHTS THE ROLE OF SPERM EPIGENETICS AND EXPLORES EPIGENETIC MESSAGE ORIGINATION AND SUSCEPTIBILITY TO CHRONIC STRESS. MEANWHILE, POSSIBLE SPATIOTEMPORAL WINDOWS AND EVENTS THAT INDUCE SEXUALLY DIMORPHIC MODES AND EFFECTS OF PATERNAL STRESS TRANSMISSION ARE INFERRED IN THIS REVIEW. ADDITIONALLY, WE DISCUSS EMERGING INTERVENTIONS THAT COULD POTENTIALLY BLOCK THE INTERGENERATIONAL TRANSMISSION OF PATERNAL PSYCHIATRIC DISORDERS AND REDUCE THE INCIDENCE OF MENTAL ILLNESS. UNDERSTANDING THE UNDERLYING MECHANISMS BY WHICH PRECONCEPTION PATERNAL STRESS IMPACTS OFFSPRING HEALTH IS CRITICAL FOR IDENTIFYING STRATEGIES SUPPORTING HEALTHY DEVELOPMENT AND SUCCESSFULLY CONTROLLING THE PREVALENCE OF MENTAL ILLNESS. 2023 16 46 37 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 17 1769 36 EARLY-LIFE NUTRITIONAL PROGRAMMING OF LONGEVITY. AVAILABLE DATA FROM BOTH EXPERIMENTAL AND EPIDEMIOLOGICAL STUDIES SUGGEST THAT INADEQUATE DIET IN EARLY LIFE CAN PERMANENTLY CHANGE THE STRUCTURE AND FUNCTION OF SPECIFIC ORGANS OR HOMOEOSTATIC PATHWAYS, THEREBY 'PROGRAMMING' THE INDIVIDUAL'S HEALTH STATUS AND LONGEVITY. SUFFICIENT EVIDENCE HAS ACCUMULATED SHOWING SIGNIFICANT IMPACT OF EPIGENETIC REGULATION MECHANISMS IN NUTRITIONAL PROGRAMMING PHENOMENON. THE ESSENTIAL ROLE OF EARLY-LIFE DIET IN THE DEVELOPMENT OF AGING-RELATED CHRONIC DISEASES IS WELL ESTABLISHED AND DESCRIBED IN MANY SCIENTIFIC PUBLICATIONS. HOWEVER, THE PROGRAMMING EFFECTS ON LIFESPAN HAVE NOT BEEN EXTENSIVELY REVIEWED SYSTEMATICALLY. THE AIM OF THE REVIEW IS TO PROVIDE A SUMMARY OF RESEARCH FINDINGS AND THEORETICAL EXPLANATIONS THAT INDICATE THAT LONGEVITY CAN BE INFLUENCED BY EARLY NUTRITION. 2014 18 2496 31 EPIGENETICS AND EARLY LIFE ORIGINS OF CHRONIC NONCOMMUNICABLE DISEASES. IN LIGHT OF THE INCREASING THREATS OF CHRONIC NONCOMMUNICABLE DISEASES IN DEVELOPING COUNTRIES, THE GROWING RECOGNITION OF THE EARLY LIFE ORIGINS OF CHRONIC DISEASE, AND INNOVATIVE BREAKTHROUGHS IN BIOMEDICAL RESEARCH AND TECHNOLOGY, IT IS IMPERATIVE THAT WE HARNESS CUTTING-EDGE DATA TO IMPROVE HEALTH PROMOTION AND MAINTENANCE. IT IS WELL RECOGNIZED THAT CHRONIC DISEASES ARE COMPLEX TRAITS AFFECTED BY A WIDE RANGE OF ENVIRONMENTAL AND GENETIC FACTORS; HOWEVER, THE ROLE OF EPIGENETIC FACTORS, PARTICULARLY WITH REGARD TO EARLY LIFE ORIGINS, REMAINS LARGELY UNEXPLORED. GIVEN THE UNIQUE PROPERTIES OF THE EPIGENOME-FUNCTIONALITY DURING CRITICAL TIME WINDOWS, SUCH AS THE INTRAUTERINE PERIOD, HERITABILITY, AND REVERSIBILITY-ENHANCING OUR UNDERSTANDING OF EPIGENETIC MECHANISMS MAY OFFER NEW OPPORTUNITIES FOR THE DEVELOPMENT OF NOVEL EARLY PREDICTION AND PREVENTION PARADIGMS. THIS MAY PRESENT AN UNPARALLELED OPPORTUNITY TO OFFER MATERNAL AND CHILD HEALTH PROFESSIONALS IMPORTANT TOOLS WITH THE TRANSLATIONAL VALUE TO PREDICT, DETECT, AND PREVENT DISEASE AT AN EARLY AGE, LONG BEFORE ITS CLINICAL OCCURRENCE, AND AS SUCH, BREAK LIFELONG AND TRANSGENERATIONAL CYCLES OF DISEASE. IN DOING SO, MODERN TECHNOLOGY CAN BE LEVERAGED TO MAKE GREAT CONTRIBUTIONS TO POPULATION HEALTH, QUALITY OF LIFE, AND REDUCING THE BURDENSOME ECONOMIC COSTS OF NONCOMMUNICABLE DISEASES IN DEVELOPING COUNTRIES. 2013 19 5254 47 PROGRAMMING OF RESPIRATORY HEALTH IN CHILDHOOD: INFLUENCE OF OUTDOOR AIR POLLUTION. PURPOSE OF REVIEW: THIS OVERVIEW HIGHLIGHTS RECENT EXPERIMENTAL AND EPIDEMIOLOGICAL EVIDENCE FOR THE PROGRAMMING EFFECTS OF OUTDOOR AIR POLLUTION EXPOSURES DURING EARLY DEVELOPMENT ON LUNG FUNCTION AND CHRONIC RESPIRATORY DISORDERS, SUCH AS ASTHMA AND RELATED ALLERGIC DISORDERS. RECENT FINDINGS: AIR POLLUTANTS MAY IMPACT ANATOMY AND/OR PHYSIOLOGICAL FUNCTIONING OF THE LUNG AND INTERRELATED SYSTEMS. PROGRAMMING EFFECTS MAY RESULT FROM POLLUTANT-INDUCED SHIFTS IN A NUMBER OF MOLECULAR, CELLULAR, AND PHYSIOLOGICAL STATES AND THEIR INTERACTING SYSTEMS. SPECIFIC KEY REGULATORY SYSTEMS SUSCEPTIBLE TO PROGRAMMING MAY INFLUENCE LUNG DEVELOPMENT AND VULNERABILITY TO RESPIRATORY DISEASES, INCLUDING BOTH CENTRAL AND PERIPHERAL COMPONENTS OF NEUROENDOCRINE PATHWAYS AND AUTONOMIC NERVOUS SYSTEM (ANS) FUNCTIONING WHICH, IN TURN, INFLUENCE THE IMMUNE SYSTEM. STARTING IN UTERO, ENVIRONMENTAL FACTORS, INCLUDING AIR POLLUTANTS, MAY PERMANENTLY ORGANIZE THESE SYSTEMS TOWARD TRAJECTORIES OF ENHANCED PEDIATRIC (E.G., ASTHMA, ALLERGY) AS WELL AS ADULT DISEASE RISK (E.G., CHRONIC OBSTRUCTIVE PULMONARY DISEASE). EVIDENCE SUPPORTS A CENTRAL ROLE OF OXIDATIVE STRESS IN THE TOXIC EFFECTS OF AIR POLLUTION. ADDITIONAL RESEARCH SUGGESTS XENOBIOTIC METABOLISM AND SUBCELLULAR COMPONENTS, SUCH AS MITOCHONDRIA ARE TARGETS OF AMBIENT AIR POLLUTION AND PLAY A ROLE IN ASTHMA AND ALLERGY PROGRAMMING. MECHANISMS OPERATING AT THE LEVEL OF THE PLACENTA ARE BEING ELUCIDATED. EPIGENETIC MECHANISMS MAY BE AT THE ROOTS OF ADAPTIVE DEVELOPMENTAL PROGRAMMING. SUMMARY: OPTIMAL COORDINATED FUNCTIONING OF MANY COMPLEX PROCESSES AND THEIR NETWORKS OF INTERACTION ARE NECESSARY FOR NORMAL LUNG DEVELOPMENT AND THE MAINTENANCE OF RESPIRATORY HEALTH. OUTDOOR AIR POLLUTION MAY PLAY AN IMPORTANT ROLE IN EARLY PROGRAMMING OF RESPIRATORY HEALTH AND IS POTENTIALLY AMENABLE TO INTERVENTION. 2013 20 4082 39 MATERNAL MODIFIERS OF THE INFANT GUT MICROBIOTA: METABOLIC CONSEQUENCES. TRANSMISSION OF METABOLIC DISEASES FROM MOTHER TO CHILD IS MULTIFACTORIAL AND INCLUDES GENETIC, EPIGENETIC AND ENVIRONMENTAL INFLUENCES. EVIDENCE IN RODENTS, HUMANS AND NON-HUMAN PRIMATES SUPPORT THE SCIENTIFIC PREMISE THAT EXPOSURE TO MATERNAL OBESITY OR HIGH-FAT DIET DURING PREGNANCY CREATES A LONG-LASTING METABOLIC SIGNATURE ON THE INFANT INNATE IMMUNE SYSTEM AND THE JUVENILE MICROBIOTA, WHICH PREDISPOSES THE OFFSPRING TO OBESITY AND METABOLIC DISEASES. IN NEONATES, GASTROINTESTINAL MICROBES INTRODUCED THROUGH THE MOTHER ARE NOTED FOR THEIR ABILITY TO SERVE AS DIRECT INDUCERS/REGULATORS OF THE INFANT IMMUNE SYSTEM. NEONATES HAVE A LIMITED CAPACITY TO INITIATE AN IMMUNE RESPONSE. THUS, DISRUPTION OF MICROBIAL COLONIZATION DURING THE EARLY NEONATAL PERIOD RESULTS IN DISRUPTED POSTNATAL IMMUNE RESPONSES THAT HIGHLIGHT THE NEONATAL PERIOD AS A CRITICAL DEVELOPMENTAL WINDOW. ALTHOUGH THE MECHANISMS ARE POORLY UNDERSTOOD, INCREASING EVIDENCE SUGGESTS THAT MATERNAL OBESITY OR POOR DIET INFLUENCES THE DEVELOPMENT AND MODULATION OF THE INFANT LIVER AND OTHER END ORGANS THROUGH DIRECT COMMUNICATION VIA THE PORTAL SYSTEM, METABOLITE PRODUCTION, ALTERATIONS IN GUT BARRIER INTEGRITY AND THE HEMATOPOIETIC IMMUNE CELL AXIS. THIS REVIEW WILL FOCUS ON HOW MATERNAL OBESITY AND DIETARY INTAKE INFLUENCE THE COMPOSITION OF THE INFANT GUT MICROBIOTA AND HOW AN IMBALANCE OR MALADAPTATION IN THE MICROBIOTA, INCLUDING CHANGES IN EARLY PIONEERING MICROBES, MIGHT CONTRIBUTE TO THE PROGRAMMING OF OFFSPRING METABOLISM WITH SPECIAL EMPHASIS ON MECHANISMS THAT PROMOTE CHRONIC INFLAMMATION IN THE LIVER. COMPREHENSION OF THESE PATHWAYS AND MECHANISMS WILL ELUCIDATE OUR UNDERSTANDING OF DEVELOPMENTAL PROGRAMMING AND MAY EXPAND THE AVENUE OF OPPORTUNITIES FOR NOVEL THERAPEUTICS. 2017