1 260 92 ADVANCES IN RESEARCH INTO GAMETE AND EMBRYO-FETAL ORIGINS OF ADULT DISEASES. THE FETAL AND INFANT ORIGINS OF ADULT DISEASE HYPOTHESIS PROPOSED THAT THE ROOTS OF ADULT CHRONIC DISEASE LIE IN THE EFFECTS OF ADVERSE ENVIRONMENTS IN FETAL LIFE AND EARLY INFANCY. IN ADDITION TO THE FETAL PERIOD, FERTILIZATION AND EARLY EMBRYONIC STAGES, THE CRITICAL TIME WINDOWS OF EPIGENETIC REPROGRAMMING, RAPID CELL DIFFERENTIATION AND ORGANOGENESIS, ARE THE MOST SENSITIVE STAGES TO ENVIRONMENTAL DISTURBANCES. COMPARED WITH EMBRYO AND FETAL DEVELOPMENT, GAMETOGENESIS AND MATURATION TAKE DECADES AND ARE MORE VULNERABLE TO POTENTIAL DAMAGE FOR A LONGER EXPOSURE PERIOD. THEREFORE, WE SHOULD SHIFT THE FOCUS OF ADULT DISEASE OCCURRENCE AND PATHOGENESIS FURTHER BACK TO GAMETOGENESIS AND EMBRYONIC DEVELOPMENT EVENTS, WHICH MAY RESULT IN INTERGENERATIONAL, EVEN TRANSGENERATIONAL, EPIGENETIC RE-PROGRAMMING WITH TRANSMISSION OF ADVERSE TRAITS AND CHARACTERISTICS TO OFFSPRING. HERE, WE FOCUS ON THE RESEARCH PROGRESS RELATING TO DISEASES THAT ORIGINATED FROM EVENTS IN THE GAMETES AND EARLY EMBRYOS AND THE POTENTIAL EPIGENETIC MECHANISMS INVOLVED. 2019 2 5197 26 PRENATAL GLUCOCORTICOIDS EXPOSURE AND FETAL ADRENAL DEVELOPMENTAL PROGRAMMING. CLINICALLY, WE APPLY SYNTHETIC GLUCOCORTICOIDS TO TREAT FETAL AND MATERNAL DISEASES, SUCH AS PREMATURE LABOR AND AUTOIMMUNE DISEASES. ALTHOUGH ITS CLINICAL EFFICACY IS POSITIVE, THE FETUS WILL BE EXPOSED TO EXOGENOUS SYNTHETIC GLUCOCORTICOIDS. PRENATAL ADVERSE ENVIRONMENTS (SUCH AS XENOBIOTICS EXPOSURE, MALNUTRITION, INFECTION, HYPOXIA AND STRESS) CAN CAUSE FETUSES OVEREXPOSURE TO EXCESSIVE ENDOGENOUS MATERNAL GLUCOCORTICOIDS. THE LEVEL OF GLUCOCORTICOIDS IS THE KEY TO FETAL TISSUE MATURATION AND POSTNATAL FATE. A LARGE NUMBER OF STUDIES HAVE FOUND THAT PRENATAL GLUCOCORTICOIDS EXPOSURE CAN LEAD TO FETAL ADRENAL DYSPLASIA AND DYSFUNCTION, CONTINUING AFTER BIRTH AND EVEN INTO ADULTHOOD. AS THE CORE ORGAN OF FETAL-ORIGINATED ADULT DISEASES, FETAL ADRENAL DYSPLASIA IS CLOSELY RELATED TO THE SUSCEPTIBILITY AND OCCURRENCE OF MULTIPLE CHRONIC DISEASES, AND THERE ARE ALSO OBVIOUS GENDER DIFFERENCES. HOWEVER, ITS INTRAUTERINE PROGRAMMING MECHANISMS HAVE NOT BEEN FULLY ELUCIDATED. THIS REVIEW SUMMARIZES RECENT ADVANCES IN PRENATAL GLUCOCORTICOIDS EXPOSURE AND FETAL ADRENAL DEVELOPMENTAL PROGRAMMING ALTERATIONS, WHICH IS OF GREAT SIGNIFICANCE FOR EXPLAINING ADRENAL DEVELOPMENTAL TOXICITY AND THE INTRAUTERINE ORIGIN OF FETAL-ORIGINATED ADULT DISEASES. 2019 3 1152 24 CONSEQUENCES OF EARLY LIFE PROGRAMING BY GENETIC AND ENVIRONMENTAL INFLUENCES: A SYNTHESIS REGARDING PUBERTAL TIMING. SEXUAL MATURATION IS CLOSELY TIED TO GROWTH AND BODY WEIGHT GAIN, SUGGESTING THAT REGULATIVE METABOLIC PATHWAYS ARE SHARED BETWEEN SOMATIC AND PUBERTAL DEVELOPMENT. THE PRE- AND POSTNATAL ENVIRONMENT AFFECTS BOTH GROWTH AND PUBERTAL DEVELOPMENT, INDICATING THAT COMMON PATHWAYS ARE AFFECTED BY THE ENVIRONMENT. INTRAUTERINE AND EARLY INFANTILE DEVELOPMENTAL PHASES ARE CHARACTERIZED BY HIGH PLASTICITY AND THEREBY SUSCEPTIBILITY TO FACTORS THAT AFFECT METABOLIC FUNCTION AS WELL AS RELATED REPRODUCTIVE FUNCTION THROUGHOUT LIFE. IN CHILDREN BORN SMALL FOR GESTATIONAL AGE, POOR NUTRITIONAL CONDITIONS DURING GESTATION CAN MODIFY METABOLIC SYSTEMS TO ADAPT TO EXPECTATIONS OF CHRONIC UNDERNUTRITION. THESE CHILDREN ARE POTENTIALLY POORLY EQUIPPED TO COPE WITH ENERGY-DENSE DIETS AND ARE POSSIBLY PROGRAMMED TO STORE AS MUCH ENERGY AS POSSIBLE, CAUSING RAPID WEIGHT GAIN WITH THE RISK FOR ADULT DISEASE AND PREMATURE ONSET OF PUBERTY. ENVIRONMENTAL FACTORS CAN CAUSE MODIFICATIONS TO THE GENOME, SO-CALLED EPIGENETIC CHANGES, TO AFFECT GENE EXPRESSION AND SUBSEQUENTLY MODIFY PHENOTYPIC EXPRESSION OF GENOMIC INFORMATION. EPIGENETIC MODIFICATIONS, WHICH OCCUR IN CHILDREN BORN SMALL FOR GESTATIONAL AGE, ARE THOUGHT TO UNDERLIE PART OF THE METABOLIC PROGRAMMING THAT SUBSEQUENTLY EFFECTS BOTH SOMATIC AND PUBERTAL DEVELOPMENT. 2016 4 4107 27 MECHANISMS AFFECTING NEUROENDOCRINE AND EPIGENETIC REGULATION OF BODY WEIGHT AND ONSET OF PUBERTY: POTENTIAL IMPLICATIONS IN THE CHILD BORN SMALL FOR GESTATIONAL AGE (SGA). SIGNALING PEPTIDES PRODUCED IN PERIPHERAL TISSUES SUCH AS GUT, ADIPOSE TISSUE, AND PANCREAS COMMUNICATE WITH BRAIN CENTERS, SUCH AS HYPOTHALAMUS AND HINDBRAIN TO MANAGE ENERGY HOMEOSTASIS. THESE REGULATORY MECHANISMS OF ENERGY INTAKE AND STORAGE HAVE EVOLVED DURING LONG PERIODS OF HUNGER IN THE EVOLUTION OF MAN TO PROTECT THE SPECIES FROM EXTINCTION. IT IS NOW CLEAR THAT THESE CIRCUITRIES ARE INFLUENCED BY PRENATAL AND POSTNATAL ENVIRONMENTAL FACTORS INCLUDING ENDOCRINE DISRUPTIVE CHEMICALS. HYPOTHALAMIC APPETITE REGULATORY SYSTEMS DEVELOP AND MATURE IN UTERO AND EARLY INFANCY, AND INVOLVE SIGNALING PATHWAYS THAT ARE IMPORTANT ALSO FOR THE REGULATION OF PUBERTY ONSET. RECENT STUDIES IN HUMANS AND ANIMALS HAVE SHOWN THAT METABOLIC PATHWAYS INVOLVED IN REGULATION OF GROWTH, BODY WEIGHT GAIN AND SEXUAL MATURATION ARE LARGELY AFFECTED BY EPIGENETIC PROGRAMMING THAT CAN IMPACT BOTH CURRENT AND FUTURE GENERATIONS. IN PARTICULAR, INTRAUTERINE AND EARLY INFANTILE DEVELOPMENTAL PHASES OF HIGH PLASTICITY ARE SUSCEPTIBLE TO FACTORS THAT AFFECT METABOLIC PROGRAMMING THAT THEREFORE, AFFECT METABOLIC FUNCTION THROUGHOUT LIFE. IN CHILDREN BORN SMALL FOR GESTATIONAL AGE, POOR NUTRITIONAL CONDITIONS DURING GESTATION CAN MODIFY METABOLIC SYSTEMS TO ADAPT TO EXPECTATIONS OF CHRONIC UNDERNUTRITION. THESE CHILDREN ARE POTENTIALLY POORLY EQUIPPED TO COPE WITH ENERGY-DENSE DIETS AND ARE POSSIBLY PROGRAMMED TO STORE AS MUCH ENERGY AS POSSIBLE, LEADING TO LATER OBESITY, METABOLIC SYNDROME, DISTURBED REGULATION OF NORMAL PUBERTY AND EARLY ONSET OF CARDIOVASCULAR DISEASE. MOST CASES OF DISTURBED ENERGY BALANCE ARE LIKELY A RESULT OF A COMBINATION OF GENETICS, EPIGENETICS AND ENVIRONMENT. THIS REVIEW WILL DISCUSS POTENTIAL MECHANISMS LINKING INTRAUTERINE GROWTH RETARDATION WITH CHANGES IN GROWTH, ENERGY HOMEOSTASIS AND SEXUAL MATURATION. 2012 5 4790 33 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 6 4863 28 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 7 6818 30 [FETAL PROGRAMMING AS A CAUSE OF CHRONIC DISEASES IN ADULT LIFE]. LONG-TERM ADAPTIVE CHANGES OCCURRING IN A DEVELOPING FETUS IN RESPONSE TO UNSTABLE IN UTERO ENVIRONMENTAL CONDITIONS, WHICH APPEAR AT A PARTICULAR TIME (CRITICAL WINDOW), ARE CALLED INTRAUTERINE OR FETAL PROGRAMMING. THESE ADAPTIVE CHANGES ARE BENEFICIAL DURING THE INTRAUTERINE PERIOD BECAUSE THEY ADAPT THE FETUS TO CURRENT NEEDS, BUT MAY TURN OUT TO BE HARMFUL IN THE END AND LEAD TO DEVELOPMENT OF CHRONIC DISEASES IN ADULT LIFE. FETAL PROGRAMMING MEANS THE STRUCTURAL AND FUNCTIONAL CHANGING OF AN ORGANISM, METABOLISM AND FUNCTION OF SOME CELLS, TISSUES AND SYSTEMS, THAT OCCUR EVEN DESPITE INTRAUTERINE LIMITATIONS. EVENTS OF FETAL LIFE INFLUENCE THE DETERMINATION OF PHYSIOLOGICAL PATTERNS WHICH MAY MANIFEST AS DISEASE PROCESSES IN THE ADULTHOOD (BARKER'S HYPOTHESIS). GENETIC AND ENVIRONMENTAL FACTORS (POOR DIET IN PREGNANCY CHRONIC INTRAUTERINE FETAL HYPOXIA, THE EFFECTS OF XENOBIOTICS AND DRUGS, AS WELL AS HORMONAL DISORDERS) INFLUENCE THE PHENOTYPE OF A NEWBORN AND ARE INVOLVED IN THE INTRAUTERINE PROGRAMMING PROCESS. THE EFFECTS OF FETAL PROGRAMMING MAY BE PASSED ALONG TO THE NEXT GENERATIONS VIA NOT FULLY UNDERSTOOD PATHWAYS, WHICH PROBABLY INCLUDE EPIGENETIC MECHANISMS. MOST OF THE MECHANISMS UNDERLYING THIS PROCESS REMAIN UNCLEAR AND NEED TO BE ELUCIDATED. 2014 8 2803 25 FETAL DEVELOPMENTAL PROGRAMING: INSIGHTS FROM HUMAN STUDIES AND EXPERIMENTAL MODELS. BACKGROUND: ENVIRONMENTAL FACTORS, PARTICULARLY NUTRITION DURING PREGNANCY AND EARLY LIFE CAN INFLUENCE THE RISK OF CHRONIC DISEASES IN LATER LIFE. THE UNDERLYING MECHANISM, TERMED "PROGRAMING", POSTULATES THAT AN ENVIRONMENTAL STIMULUS DURING A CRITICAL WINDOW OF TIME, EARLY IN LIFE, HAS A PERMANENT EFFECT ON SUBSEQUENT STRUCTURE AND FUNCTION OF THE ORGANISM. OBJECTIVE: IN THIS STUDY WE REVIEW THE CONCEPT OF FETAL PROGRAMING ON CHRONIC DISEASES AND THE PROPOSED HYPOTHESES FOR THE ASSOCIATION BETWEEN EARLY DEVELOPMENT AND LATER DISEASE, INCLUDING EPIGENETIC VARIATION. WE CONCENTRATE ON SPECIFIC ASPECTS OF MATERNAL NUTRITION, PARTICULARLY UNDER-NUTRITION AND OVER-NUTRITION, IN HUMANS AND ANIMAL MODELS. CONCLUSION: AN ADEQUATE MATERNAL NUTRITION DURING PREGNANCY IS CRUCIAL FOR THE HEALTH OUTCOME OF THE OFFSPRING AT ADULTHOOD. 2017 9 4094 27 MATERNAL SIGNALS FOR PROGENY PREVENTION AGAINST ALLERGY AND ASTHMA. ALLERGY AND ASTHMA ARE CHRONIC INFLAMMATORY DISEASES WHICH RESULT FROM COMPLEX GENE-ENVIRONMENT INTERACTIONS. RECENT EVIDENCE INDICATES THE IMPORTANCE OF PRENATAL AND POSTNATAL DEVELOPMENTAL PROCESSES IN TERMS OF MATURATION OF BALANCED IMMUNE RESPONSES. ACCORDING TO THE CURRENT VIEW, GENE-ENVIRONMENT INTERACTIONS DURING A RESTRICTED TIME FRAME ARE RESPONSIBLE FOR PROGRAMMING OF THE IMMUNE SYSTEM IN FAVOR OF ALLERGIC IMMUNE MECHANISMS LATER IN LIFE. THE INTERACTION BETWEEN GENES AND ENVIRONMENT IS COMPLEX AND ONLY PARTIALLY UNDERSTOOD; HOWEVER, HERITABLE EPIGENETIC MODIFICATIONS INCLUDING CHEMICAL ADDITIONS IN AND ALTERNATIVE PACKAGING OF THE DNA HAVE BEEN SHOWN TO PLAY A CRUCIAL ROLE IN THIS CONTEXT. NOVEL DATA INDICATE THAT EPIGENETIC MECHANISMS CONTRIBUTE TO THE DEVELOPMENT OF T-HELPER CELL FUNCTION. ENVIRONMENTAL FACTORS, INCLUDING DIESEL EXHAUST PARTICLES (DEP), VITAMINS AND TOBACCO SMOKE, OPERATE THROUGH SUCH MECHANISMS. FURTHERMORE, THE ROLE OF ENVIRONMENTAL MICROBES PROVIDES ANOTHER AND MAYBE EVEN MORE IMPORTANT GROUP OF EXOGENOUS EXPOSURES WHICH OPERATES IN THIS CRITICAL TIME FRAME. 2011 10 5202 30 PRENATAL ORIGINS OF ADULT DISEASE. PURPOSE OF REVIEW: HUMAN EPIDEMIOLOGICAL AND ANIMAL STUDIES SHOW THAT MANY CHRONIC ADULT CONDITIONS HAVE THEIR ANTECEDENTS IN COMPROMISED FETAL AND EARLY POSTNATAL DEVELOPMENT. DEVELOPMENTAL PROGRAMMING IS DEFINED AS THE RESPONSE BY THE DEVELOPING MAMMALIAN ORGANISM TO A SPECIFIC CHALLENGE DURING A CRITICAL TIME WINDOW THAT ALTERS THE TRAJECTORY OF DEVELOPMENT WITH RESULTING PERSISTENT EFFECTS ON PHENOTYPE. MAMMALS PASS MORE BIOLOGICAL MILESTONES BEFORE BIRTH THAN ANY OTHER TIME IN THEIR LIVES. EACH INDIVIDUAL'S PHENOTYPE IS INFLUENCED BY THE DEVELOPMENTAL ENVIRONMENT AS MUCH AS THEIR GENES. A BETTER UNDERSTANDING IS REQUIRED OF GENE-ENVIRONMENT INTERACTIONS LEADING TO ADULT DISEASE. RECENT FINDINGS: DURING DEVELOPMENT, THERE ARE CRITICAL PERIODS OF VULNERABILITY TO SUBOPTIMAL CONDITIONS WHEN PROGRAMMING MAY PERMANENTLY MODIFY DISEASE SUSCEPTIBILITY. PROGRAMMING INVOLVES STRUCTURAL CHANGES IN IMPORTANT ORGANS; ALTERED CELL NUMBER, IMBALANCE IN DISTRIBUTION OF DIFFERENT CELL TYPES WITHIN THE ORGAN, AND ALTERED BLOOD SUPPLY OR RECEPTOR NUMBERS. COMPENSATORY EFFORTS BY THE FETUS MAY CARRY A PRICE. EFFECTS OF PROGRAMMING MAY PASS ACROSS GENERATIONS BY MECHANISMS THAT DO NOT NECESSARILY INVOLVE STRUCTURAL GENE CHANGES. PROGRAMMING OFTEN HAS DIFFERENT EFFECTS IN MALES AND FEMALES. SUMMARY: DEVELOPMENTAL PROGRAMMING SHOWS THAT EPIGENETIC FACTORS PLAY MAJOR ROLES IN DEVELOPMENT OF PHENOTYPE AND PREDISPOSITION TO DISEASE IN LATER LIFE. 2008 11 5156 26 PRE-BIRTH ORIGINS OF ALLERGY AND ASTHMA. ALLERGY IS A CHRONIC DISEASE THAT CAN DEVELOP AS EARLY AS INFANCY, SUGGESTING THAT EARLY LIFE FACTORS ARE IMPORTANT IN ITS AETIOLOGY. VARIABLE ASSOCIATIONS BETWEEN SIZE AT BIRTH, A CRUDE MARKER OF THE FETAL ENVIRONMENT, AND ALLERGY HAVE BEEN REPORTED IN HUMANS AND REQUIRE COMPREHENSIVE REVIEW. ASSOCIATIONS BETWEEN BIRTH WEIGHT AND ALLERGY ARE HOWEVER CONFOUNDED IN HUMANS, AND WE AND OTHERS HAVE THEREFORE BEGUN EXPLORING THE EFFECTS OF EARLY LIFE EVENTS ON ALLERGY IN EXPERIMENTAL MODELS. IN PARTICULAR, WE ARE USING OVINE MODELS TO INVESTIGATE WHETHER AND HOW A RESTRICTED ENVIRONMENT BEFORE BIRTH PROTECTS AGAINST ALLERGY, WHETHER METHYL DONOR AVAILABILITY CONTRIBUTES TO ALLERGIC PROTECTION IN IUGR, AND WHY MATERNAL ASTHMA DURING PREGNANCY IS ASSOCIATED WITH INCREASED RISKS OF ALLERGIC DISEASE IN CHILDREN. WE FOUND THAT EXPERIMENTAL INTRAUTERINE GROWTH RESTRICTION (IUGR) IN SHEEP REDUCED CUTANEOUS RESPONSES TO ANTIGENS IN PROGENY, DESPITE NORMAL OR ELEVATED IGE RESPONSES. FURTHERMORE, MATERNAL METHYL DONOR SUPPLEMENTATION IN LATE PREGNANCY PARTIALLY REVERSED EFFECTS OF EXPERIMENTAL IUGR, CONSISTENT WITH THE PROPOSAL THAT EPIGENETIC PATHWAYS UNDERLIE SOME BUT NOT ALL EFFECTS OF IUGR ON ALLERGIC SUSCEPTIBILITY. OVINE EXPERIMENTAL ALLERGIC ASTHMA WITH EXACERBATIONS REDUCES RELATIVE FETAL SIZE IN LATE GESTATION, WITH SOME CHANGES IN IMMUNE POPULATIONS IN FETAL THYMUS SUGGESTIVE OF INCREASED ACTIVATION. MATERNAL ALLERGIC ASTHMA IN MICE ALSO PREDISPOSES PROGENY TO ALLERGY DEVELOPMENT. IN CONCLUSION, THESE FINDINGS IN EXPERIMENTAL MODELS PROVIDE DIRECT EVIDENCE THAT A PERTURBED ENVIRONMENT BEFORE BIRTH ALTERS IMMUNE SYSTEM DEVELOPMENT AND POSTNATAL FUNCTION, AND PROVIDE OPPORTUNITIES TO INVESTIGATE UNDERLYING MECHANISMS AND DEVELOP AND EVALUATE INTERVENTIONS. 2017 12 1930 33 ENVIRONMENTAL EXPOSURES AROUND CONCEPTION: DEVELOPMENTAL PATHWAYS LEADING TO LIFETIME DISEASE RISK. ENVIRONMENT AROUND CONCEPTION CAN INFLUENCE THE DEVELOPMENTAL PROGRAMME WITH LASTING EFFECTS ON GESTATIONAL AND POSTNATAL PHENOTYPE AND WITH CONSEQUENCES FOR ADULT HEALTH AND DISEASE RISK. PERI-CONCEPTION EXPOSURE COMPRISES A CRUCIAL PART OF THE 'DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE' (DOHAD) CONCEPT. IN THIS REVIEW, WE CONSIDER THE EFFECTS OF MATERNAL UNDERNUTRITION EXPERIENCED DURING THE PERI-CONCEPTION PERIOD IN SELECT HUMAN MODELS AND IN A MOUSE EXPERIMENTAL MODEL OF PROTEIN RESTRICTION. HUMAN DATASETS INDICATE THAT MACRONUTRIENT DEPRIVATION AROUND CONCEPTION AFFECT THE EPIGENOME, WITH ENDURING EFFECTS ON CARDIOMETABOLIC AND NEUROLOGICAL HEALTH. THE MOUSE MODEL, COMPRISING MATERNAL LOW PROTEIN DIET EXCLUSIVELY DURING THE PERI-CONCEPTION PERIOD, HAS REVEALED A STEPWISE PROGRESSION IN ALTERED DEVELOPMENTAL PROGRAMMING FOLLOWING INDUCTION THROUGH MATERNAL METABOLITE DEFICIENCY. THIS PROGRESSION INCLUDES DIFFERENTIAL EFFECTS IN EXTRA-EMBRYONIC AND EMBRYONIC CELL LINEAGES AND TISSUES, LEADING TO MALADAPTATION IN THE GROWTH TRAJECTORY AND INCREASED CHRONIC DISEASE COMORBIDITIES. THE TIMELINE EMBRACES AN ARRAY OF MECHANISMS ACROSS NUTRIENT SENSING AND SIGNALLING, CELLULAR, METABOLIC, EPIGENETIC AND PHYSIOLOGICAL PROCESSES WITH A COORDINATING ROLE FOR MTORC1 SIGNALLING PROPOSED. EARLY EMBRYOS APPEAR ACTIVE PARTICIPANTS IN ENVIRONMENTAL SENSING TO OPTIMISE THE DEVELOPMENTAL PROGRAMME FOR SURVIVAL BUT WITH THE TRADE-OFF OF LATER DISEASE. SIMILAR ADVERSE HEALTH OUTCOMES MAY DERIVE FROM OTHER PERI-CONCEPTION ENVIRONMENTAL EXPERIENCES, INCLUDING MATERNAL OVERNUTRITION, MICRONUTRIENT AVAILABILITY, POLLUTANT EXPOSURE AND ASSISTED REPRODUCTIVE TREATMENTS (ART) AND SUPPORT THE NEED FOR PRECONCEPTION HEALTH BEFORE PREGNANCY. 2021 13 2804 24 FETAL EPIGENETIC MECHANISMS AND INNATE IMMUNITY IN ASTHMA. ALLERGY AND ASTHMA ARE CHRONIC INFLAMMATORY DISEASES THAT RESULT FROM COMPLEX GENE-ENVIRONMENT INTERACTIONS. RECENT EVIDENCE POINTS TO THE IMPORTANCE OF PRENATAL AND POSTNATAL DEVELOPMENTAL PROCESSES IN THE MATURATION OF BALANCED IMMUNE RESPONSES. NOVEL DATA INDICATE THAT EPIGENETIC MECHANISMS CONTRIBUTE TO THE DEVELOPMENT OF T-HELPER-CELL FUNCTION. ENVIRONMENTAL FACTORS, INCLUDING DIESEL EXHAUST PARTICLES, VITAMINS, AND TOBACCO SMOKE, OPERATE THROUGH SUCH MECHANISMS. FURTHERMORE, THE ROLE OF ENVIRONMENTAL MICROBES PROVIDES ANOTHER-AND MAYBE AN EVEN MORE IMPORTANT-GROUP OF EXOGENOUS EXPOSURES THAT OPERATE IN THIS CRITICAL TIME FRAME. A BETTER UNDERSTANDING OF FETAL IMMUNO-MATURATION CONDITIONS WILL PROVIDE THE BASIS FOR THE DEVELOPMENT OF NOVEL ALLERGO-PROTECTIVE CLINICAL STRATEGIES. 2010 14 1365 28 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 15 4798 26 NUTRITIONALLY MEDIATED PROGRAMMING OF THE DEVELOPING IMMUNE SYSTEM. A GROWING BODY OF EVIDENCE HIGHLIGHTS THE IMPORTANCE OF A MOTHER'S NUTRITION FROM PRECONCEPTION THROUGH LACTATION IN PROGRAMMING THE EMERGING ORGAN SYSTEMS AND HOMEOSTATIC PATHWAYS OF HER OFFSPRING. THE DEVELOPING IMMUNE SYSTEM MAY BE PARTICULARLY VULNERABLE. INDEED, EXAMPLES OF NUTRITION-MEDIATED IMMUNE PROGRAMMING CAN BE FOUND IN THE LITERATURE ON INTRA-UTERINE GROWTH RETARDATION, MATERNAL MICRONUTRIENT DEFICIENCIES, AND INFANT FEEDING. CURRENT MODELS OF IMMUNE ONTOGENY DEPICT A "LAYERED" EXPANSION OF INCREASINGLY COMPLEX DEFENSES, WHICH MAY BE PERMANENTLY ALTERED BY MATERNAL MALNUTRITION. ONE PROGRAMMING MECHANISM INVOLVES ACTIVATION OF THE MATERNAL HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN RESPONSE TO NUTRITIONAL STRESS. FETAL OR NEONATAL EXPOSURE TO ELEVATED STRESS HORMONES IS LINKED IN ANIMAL STUDIES TO PERMANENT CHANGES IN NEUROENDOCRINE-IMMUNE INTERACTIONS, WITH DIVERSE MANIFESTATIONS SUCH AS AN ATTENUATED INFLAMMATORY RESPONSE OR REDUCED RESISTANCE TO TUMOR COLONIZATION. MATERNAL MALNUTRITION MAY ALSO HAVE A DIRECT INFLUENCE, AS EVIDENCED BY NUTRIENT-DRIVEN EPIGENETIC CHANGES TO DEVELOPING T REGULATORY CELLS AND SUBSEQUENT RISK OF ALLERGY OR ASTHMA. A 3RD PROGRAMMING PATHWAY INVOLVES PLACENTAL OR BREAST MILK TRANSFER OF MATERNAL IMMUNE FACTORS WITH IMMUNOMODULATORY FUNCTIONS (E.G. CYTOKINES). MATERNAL MALNUTRITION CAN DIRECTLY AFFECT TRANSFER MECHANISMS OR INFLUENCE THE QUALITY OR QUANTITY OF TRANSFERRED FACTORS. THE PUBLIC HEALTH IMPLICATIONS OF NUTRITION-MEDIATED IMMUNE PROGRAMMING ARE OF PARTICULAR IMPORTANCE IN THE DEVELOPING WORLD, WHERE PREVALENT MATERNAL UNDERNUTRITION IS COUPLED WITH PERSISTENT INFECTIOUS CHALLENGES. HOWEVER, EARLY ALTERATIONS TO THE IMMUNE SYSTEM, RESULTING FROM EITHER NUTRITIONAL DEFICIENCIES OR EXCESSES, HAVE BROAD RELEVANCE FOR IMMUNE-MEDIATED DISEASES, SUCH AS ASTHMA, AND CHRONIC INFLAMMATORY CONDITIONS LIKE CARDIOVASCULAR DISEASE. 2011 16 1922 36 ENVIRONMENTAL EPIGENETIC INTERACTION OF GAMETES AND EARLY EMBRYOSDAGGER. IN RECENT YEARS, THE DEVELOPMENTAL ORIGINS OF DISEASES HAVE BEEN INCREASINGLY RECOGNIZED AND ACCEPTED. AS SUCH, IT HAS BEEN SUGGESTED THAT MOST ADULTHOOD CHRONIC DISEASES SUCH AS DIABETES, OBESITY, CARDIOVASCULAR DISEASE, AND EVEN TUMORS MAY DEVELOP AT A VERY EARLY STAGE. IN ADDITION TO INTRAUTERINE ENVIRONMENTAL EXPOSURE, GERM CELLS CARRY AN IMPORTANT INHERITANCE ROLE AS THE PRIMARY LINK BETWEEN THE TWO GENERATIONS. ADVERSE EXTERNAL INFLUENCES DURING DIFFERENTIATION AND DEVELOPMENT CAN CAUSE DAMAGE TO GERM CELLS, WHICH MAY THEN INCREASE THE RISK OF CHRONIC DISEASE DEVELOPMENT LATER IN LIFE. HERE, WE FURTHER ELUCIDATE AND CLARIFY THE CONCEPT OF GAMETE AND EMBRYO ORIGINS OF ADULT DISEASES BY FOCUSING ON THE ENVIRONMENTAL INSULTS ON GERM CELLS, FROM DIFFERENTIATION TO MATURATION AND FERTILIZATION. 2022 17 3594 32 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 18 4064 27 MATERNAL AND EARLY-LIFE CIRCADIAN DISRUPTION HAVE LONG-LASTING NEGATIVE CONSEQUENCES ON OFFSPRING DEVELOPMENT AND ADULT BEHAVIOR IN MICE. MODERN LIFE INVOLVES CHRONIC CIRCADIAN DISRUPTION THROUGH ARTIFICIAL LIGHT AND THESE DISRUPTIONS ARE ASSOCIATED WITH NUMEROUS MENTAL AND PHYSICAL HEALTH MALADIES. BECAUSE THE DEVELOPING NERVOUS SYSTEM IS PARTICULARLY VULNERABLE TO PERTURBATION, WE HYPOTHESIZED THAT EARLY-LIFE CIRCADIAN DISRUPTION WOULD NEGATIVELY IMPACT OFFSPRING DEVELOPMENT AND ADULT FUNCTION. PREGNANT MICE WERE SUBJECTED TO CHRONIC CIRCADIAN DISRUPTION FROM THE TIME OF UTERINE IMPLANTATION THROUGH WEANING. TO DISSOCIATE IN UTERO FROM POSTNATAL EFFECTS, A SUBSET OF LITTERS WAS CROSS-FOSTERED AT BIRTH FROM DISRUPTED DAMS TO CONTROL DAMS AND VICE VERSA. POSTNATAL CIRCADIAN DISRUPTION WAS ASSOCIATED WITH REDUCED ADULT BODY MASS, SOCIAL AVOIDANCE, AND HYPERACTIVITY. IN UTERO DISRUPTION RESULTED IN MORE PRONOUNCED SOCIAL AVOIDANCE AND HYPERACTIVITY, PHENOTYPES NOT ABROGATED BY CROSS-FOSTERING TO CONTROL MOTHERS. TO EXAMINE WHETHER CIRCADIAN DISRUPTION AFFECTS DEVELOPMENT BY ACTING AS AN EARLY LIFE STRESSOR, WE EXAMINED BIRTHWEIGHT, LITTER SIZE, MATERNAL CANNIBALISM, AND EPIGENETIC MODIFICATIONS. NONE OF THESE VARIABLES DIFFERED BETWEEN CONTROL AND DISRUPTED DAMS, OR RESEMBLED PATTERNS SEEN FOLLOWING EARLY-LIFE STRESS. OUR FINDINGS INDICATE THAT DEVELOPMENTAL CHRONIC CIRCADIAN DISRUPTION PERMANENTLY AFFECTS SOMATIC AND BEHAVIORAL DEVELOPMENT IN A STAGE-OF-LIFE-DEPENDENT MANNER, INDEPENDENT OF EARLY LIFE STRESS MECHANISMS, UNDERSCORING THE IMPORTANCE OF TEMPORAL STRUCTURE DURING DEVELOPMENT, BOTH IN UTERO AND EARLY POSTNATAL LIFE. 2017 19 4083 24 MATERNAL NUTRITION AND FETAL DEVELOPMENT. NUTRITION IS THE MAJOR INTRAUTERINE ENVIRONMENTAL FACTOR THAT ALTERS EXPRESSION OF THE FETAL GENOME AND MAY HAVE LIFELONG CONSEQUENCES. THIS PHENOMENON, TERMED "FETAL PROGRAMMING," HAS LED TO THE RECENT THEORY OF "FETAL ORIGINS OF ADULT DISEASE." NAMELY, ALTERATIONS IN FETAL NUTRITION AND ENDOCRINE STATUS MAY RESULT IN DEVELOPMENTAL ADAPTATIONS THAT PERMANENTLY CHANGE THE STRUCTURE, PHYSIOLOGY, AND METABOLISM OF THE OFFSPRING, THEREBY PREDISPOSING INDIVIDUALS TO METABOLIC, ENDOCRINE, AND CARDIOVASCULAR DISEASES IN ADULT LIFE. ANIMAL STUDIES SHOW THAT BOTH MATERNAL UNDERNUTRITION AND OVERNUTRITION REDUCE PLACENTAL-FETAL BLOOD FLOWS AND STUNT FETAL GROWTH. IMPAIRED PLACENTAL SYNTHESES OF NITRIC OXIDE (A MAJOR VASODILATOR AND ANGIOGENESIS FACTOR) AND POLYAMINES (KEY REGULATORS OF DNA AND PROTEIN SYNTHESIS) MAY PROVIDE A UNIFIED EXPLANATION FOR INTRAUTERINE GROWTH RETARDATION IN RESPONSE TO THE 2 EXTREMES OF NUTRITIONAL PROBLEMS WITH THE SAME PREGNANCY OUTCOME. THERE IS GROWING EVIDENCE THAT MATERNAL NUTRITIONAL STATUS CAN ALTER THE EPIGENETIC STATE (STABLE ALTERATIONS OF GENE EXPRESSION THROUGH DNA METHYLATION AND HISTONE MODIFICATIONS) OF THE FETAL GENOME. THIS MAY PROVIDE A MOLECULAR MECHANISM FOR THE IMPACT OF MATERNAL NUTRITION ON BOTH FETAL PROGRAMMING AND GENOMIC IMPRINTING. PROMOTING OPTIMAL NUTRITION WILL NOT ONLY ENSURE OPTIMAL FETAL DEVELOPMENT, BUT WILL ALSO REDUCE THE RISK OF CHRONIC DISEASES IN ADULTS. 2004 20 3595 23 IMPLICATIONS OF MATERNAL CONDITIONS AND PREGNANCY COURSE ON OFFSPRING'S MEDICAL PROBLEMS IN ADULT LIFE. IN THE LAST DECADE, NUMEROUS EPIDEMIOLOGICAL, CLINICAL AND EXPERIMENTAL DATA SHOW THAT PERICONCEPTIONAL, PERINATAL AND POSTNATAL ENVIRONMENT DETERMINES THE OFFSPRING'S RISK FOR LATER-LIFE CHRONIC DISEASE. FOR THIS PHENOMENON, THE TERM "FETAL" OR "PERINATAL PROGRAMMING" IS USED. IN EXPOSED OFFSPRING ALREADY IN CHILDHOOD AND EARLY ADULTHOOD, METABOLIC AND CARDIOVASCULAR CHANGES CAN BE OBSERVED, LEADING TO OBESITY, DIABETES AND HYPERTENSION. NOWADAYS, THE MODE OF CONCEPTION (E.G., IN VITRO FERTILIZATION), MATERNAL METABOLIC CONDITIONS (E.G., UNDERNUTRITION, OVERNUTRITION, DIABETES) AND COMPLICATIONS DURING PREGNANCY (E.G., PREECLAMPSIA, INTRAUTERINE GROWTH RESTRICTION) ARE SUSPECTED TO BE NEGATIVE PREDICTORS FOR OFFSPRING'S LONG-TERM HEALTH. MECHANISMS RESPONSIBLE FOR THESE EFFECTS STILL REMAIN MAINLY UNCLEAR, BUT INCLUDE EPIGENETIC, TRANSCRIPTIONAL, ENDOPLASMIC RETICULUM STRESS, AND REACTIVE OXYGEN SPECIES. THIS REVIEW PRESENTS A PIECE OF THE PUZZLE WITH REGARDS TO PERICONCEPTIONAL AND EARLY PERINATAL CONDITIONS DETERMINING LATER-LIFE RISK FOR CHRONIC ADULT DISEASE. 2016