1 1152 116 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 2 4107 73 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 3 3859 23 ISLET STRUCTURE AND FUNCTION IN THE GK RAT. TYPE 2 DIABETES MELLITUS (T2D) ARISES WHEN THE ENDOCRINE PANCREAS FAILS TO SECRETE SUFFICIENT INSULIN TO COPE WITH THE METABOLIC DEMAND BECAUSE OF BETA-CELL SECRETORY DYSFUNCTION AND/OR DECREASED BETA-CELL MASS. DEFINING THE NATURE OF THE PANCREATIC ISLET DEFECTS PRESENT IN T2D HAS BEEN DIFFICULT, IN PART BECAUSE HUMAN ISLETS ARE INACCESSIBLE FOR DIRECT STUDY. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTENT THE GOTO-KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED TO BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THIS ASPECT. A COMPREHENSIVE COMPENDIUM OF THE MULTIPLE FUNCTIONAL GK ISLET ABNORMALITIES SO FAR IDENTIFIED IS PROPOSED IN THIS PERSPECTIVE. THE PATHOGENESIS OF DEFECTIVE BETA-CELL NUMBER AND FUNCTION IN THE GK MODEL IS ALSO DISCUSSED. IT IS PROPOSED THAT THE DEVELOPMENT OF T2D IN THE GK MODEL RESULTS FROM THE COMPLEX INTERACTION OF MULTIPLE EVENTS: (I) SEVERAL SUSCEPTIBILITY LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS (DISTINCT LOCI ENCODING IMPAIRMENT OF BETA-CELL METABOLISM AND INSULIN EXOCYTOSIS, BUT NO QUANTITATIVE TRAIT LOCUS FOR DECREASED BETA-CELL MASS); (II) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE OFFSPRING PANCREAS (DECREASED BETA-CELL NEOGENESIS AND PROLIFERATION) TRANSMITTED OVER GENERATIONS; AND (III) LOSS OF BETA-CELL DIFFERENTIATION RELATED TO CHRONIC EXPOSURE TO HYPERGLYCAEMIA/HYPERLIPIDAEMIA, ISLET INFLAMMATION, ISLET OXIDATIVE STRESS, ISLET FIBROSIS AND PERTURBED ISLET VASCULATURE. 2010 4 6164 23 THE GK RAT: A PROTOTYPE FOR THE STUDY OF NON-OVERWEIGHT TYPE 2 DIABETES. TYPE 2 DIABETES MELLITUS (T2D) ARISES WHEN THE ENDOCRINE PANCREAS FAILS TO SECRETE SUFFICIENT INSULIN TO COPE WITH THE METABOLIC DEMAND BECAUSE OF BETA-CELL SECRETORY DYSFUNCTION AND/OR DECREASED BETA-CELL MASS. DEFINING THE NATURE OF THE PANCREATIC ISLET DEFECTS PRESENT IN T2D HAS BEEN DIFFICULT, IN PART BECAUSE HUMAN ISLETS ARE INACCESSIBLE FOR DIRECT STUDY. THIS REVIEW IS AIMED TO ILLUSTRATE TO WHAT EXTENT THE GOTO KAKIZAKI RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2D, HAS PROVED TO BE A VALUABLE TOOL OFFERING SUFFICIENT COMMONALITIES TO STUDY THIS ASPECT. A COMPREHENSIVE COMPENDIUM OF THE MULTIPLE FUNCTIONAL GK ABNORMALITIES SO FAR IDENTIFIED IS PROPOSED IN THIS PERSPECTIVE, TOGETHER WITH THEIR TIME-COURSE AND INTERACTIONS. A SPECIAL FOCUS IS GIVEN TOWARD THE PATHOGENESIS OF DEFECTIVE BETA-CELL NUMBER AND FUNCTION IN THE GK MODEL. IT IS PROPOSED THAT THE DEVELOPMENT OF T2D IN THE GK MODEL RESULTS FROM THE COMPLEX INTERACTION OF MULTIPLE EVENTS: (1) SEVERAL SUSCEPTIBILITY LOCI CONTAINING GENES RESPONSIBLE FOR SOME DIABETIC TRAITS; (2) GESTATIONAL METABOLIC IMPAIRMENT INDUCING AN EPIGENETIC PROGRAMMING OF THE OFFSPRING PANCREAS AND THE MAJOR INSULIN TARGET TISSUES; AND (3) ENVIRONMENTALLY INDUCED LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA/HYPERLIPIDEMIA, INFLAMMATION, AND OXIDATIVE STRESS. 2012 5 4067 22 MATERNAL AND PEDIATRIC HEALTH AND DISEASE: INTEGRATING BIOPSYCHOSOCIAL MODELS AND EPIGENETICS. THE CONCEPTS OF ALLOSTASIS (STABILITY THROUGH ADAPTATION) AND ACCUMULATED LIFE STRESS (MCEWEN'S ALLOSTATIC LOAD) AIM TO UNDERSTAND CHILDHOOD AND ADULT OUTCOMES. CHRONIC MALNUTRITION, CHANGES IN SOCIAL CONDITION, AND ADVERSE EARLY-LIFE EXPERIENCES MAY PROGRAM PHENOTYPES AND CONTRIBUTE TO LONG-LASTING DISEASE RISK. HOWEVER, INTEGRATION OF LIFE COURSE APPROACHES, SOCIAL AND ECONOMIC CONTEXTS, AND COMPARISON AMONG DIFFERENT BIOPSYCHOSOCIAL MODELS HAS NOT GENERALLY BEEN EXPLORED. THIS REVIEW CRITICALLY EXAMINES THE LITERATURE AND EVALUATES RECENT INSIGHTS INTO HOW ENVIRONMENTAL STRESS CAN ALTER LIFELONG HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IMMUNE SYSTEM RESPONSIVENESS AND INDUCE METABOLIC AND NEURODEVELOPMENTAL MALADAPTATION. MODELS OF BIOPSYCHOSOCIAL STRESS OVERLAP BUT MAY CONSIDER DIFFERENT CONDITIONS. CONCEPTS INCLUDE ALLOSTASIS, WHICH INCORPORATES HORMONAL RESPONSES TO PREDICTABLE ENVIRONMENTAL CHANGES, AND GERONIMUS'S "WEATHERING," WHICH AIMS TO EXPLAIN HOW SOCIALLY STRUCTURED, REPEATED STRESS CAN ACCUMULATE AND INCREASE DISEASE VULNERABILITY. WEATHERING EMPHASIZES ROLES OF INTERNALIZED/INTERPERSONAL RACISM IN OUTCOMES DISPARITIES. FOR MEXICAN IMMIGRANTS AND MEXICAN AMERICANS, THE "ACCULTURATION" FRAMEWORK HAS PROVEN ESPECIALLY USEFUL TO EXPLORE DISPARITIES, INCLUDING PRETERM BIRTH AND NEUROPSYCHIATRIC RISKS IN CHILDHOOD. COMPLEXITIES OF STRESS ASSESSMENTS AND RECENT RESEARCH INTO EPIGENETIC MECHANISMS MEDIATING EFFECTS OF PHYSICAL, NUTRITIONAL, PSYCHOLOGICAL, AND SOCIAL STRESS ARE REVIEWED. 2016 6 4909 28 PAIN AND STRESS IN A SYSTEMS PERSPECTIVE: RECIPROCAL NEURAL, ENDOCRINE, AND IMMUNE INTERACTIONS. THIS PAPER ADVANCES A PSYCHOPHYSIOLOGICAL SYSTEMS VIEW OF PAIN IN WHICH PHYSICAL INJURY, OR WOUNDING, GENERATES A COMPLEX STRESS RESPONSE THAT EXTENDS BEYOND THE NERVOUS SYSTEM AND CONTRIBUTES TO THE EXPERIENCE OF PAIN. THROUGH A COMMON CHEMICAL LANGUAGE COMPRISING NEUROTRANSMITTERS, PEPTIDES, ENDOCANNABINOIDS, CYTOKINES, AND HORMONES, AN ENSEMBLE OF INTERDEPENDENT NERVOUS, ENDOCRINE, AND IMMUNE PROCESSES OPERATES IN CONCERT TO COPE WITH THE INJURY. THESE PROCESSES ACT AS A SINGLE AGENT AND COMPRISE A SUPERSYSTEM. ACUTE PAIN IN ITS MULTIPLE DIMENSIONS, AND THE RELATED SYMPTOMS THAT COMMONLY OCCUR WITH IT, ARE PRODUCTS OF THE SUPERSYSTEM. CHRONIC PAIN CAN DEVELOP AS A RESULT OF UNUSUAL STRESS. SOCIAL STRESSORS CAN COMPOUND THE STRESS RESULTING FROM A WOUND OR ACT ALONE TO DYSREGULATE THE SUPERSYSTEM. WHEN THE SUPERSYSTEM SUFFERS DYSREGULATION, HEALTH, FUNCTION, AND SENSE OF WELL-BEING SUFFER. SOME CHRONIC PAIN CONDITIONS ARE THE PRODUCT OF SUPERSYSTEM DYSREGULATION. INDIVIDUALS VARY AND ARE VULNERABLE TO DYSREGULATION AND DYSFUNCTION IN PARTICULAR ORGAN SYSTEMS DUE TO THE UNIQUE INTERACTIONS OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS, AS WELL AS THE PAST EXPERIENCES THAT CHARACTERIZE EACH PERSON. PERSPECTIVE: ACUTE TISSUE INJURY ACTIVATES AN ENSEMBLE OF INTERDEPENDENT NERVOUS, ENDOCRINE, AND IMMUNE PROCESSES THAT OPERATE IN CONCERT AND COMPRISE A SUPERSYSTEM. SOME CHRONIC PAIN CONDITIONS RESULT FROM SUPERSYSTEM DYSREGULATION. INDIVIDUALS VARY AND ARE VULNERABLE TO DYSREGULATION DUE TO THE UNIQUE INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS AND PAST EXPERIENCES THAT CHARACTERIZE EACH PERSON. THIS PERSPECTIVE CAN POTENTIALLY ASSIST CLINICIANS IN ASSESSING AND MANAGING CHRONIC PAIN PATIENTS. 2008 7 6483 35 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 8 3700 22 INFLAMMATORY MEMORY AND TISSUE ADAPTATION IN SICKNESS AND IN HEALTH. OUR BODY HAS A REMARKABLE ABILITY TO REMEMBER ITS PAST ENCOUNTERS WITH ALLERGENS, PATHOGENS, WOUNDS AND IRRITANTS, AND TO REACT MORE QUICKLY TO THE NEXT EXPERIENCE. THIS ACCENTUATED SENSITIVITY ALSO HELPS US TO COPE WITH NEW THREATS. DESPITE MAINTAINING A STATE OF READINESS AND BROADENED RESISTANCE TO SUBSEQUENT PATHOGENS, MEMORIES CAN ALSO BE MALADAPTIVE, LEADING TO CHRONIC INFLAMMATORY DISORDERS AND CANCERS. WITH THE EVER-INCREASING EMERGENCE OF NEW PATHOGENS, ALLERGENS AND POLLUTANTS IN OUR WORLD, THE URGENCY TO UNRAVEL THE MOLECULAR UNDERPINNINGS OF THESE PHENOMENA HAS RISEN TO NEW HEIGHTS. HERE WE REFLECT ON HOW THE FIELD OF INFLAMMATORY MEMORY HAS EVOLVED, SINCE 2007, WHEN RESEARCHERS REALIZED THAT NON-SPECIFIC MEMORY IS CONTAINED IN THE NUCLEUS AND PROPAGATED AT THE EPIGENETIC LEVEL. WE REVIEW THE FLURRY OF RECENT DISCOVERIES REVEALING THAT MEMORY IS NOT JUST A PRIVILEGE OF THE IMMUNE SYSTEM BUT ALSO EXTENDS TO EPITHELIA OF THE SKIN, LUNG, INTESTINE AND PANCREAS, AND TO NEURONS. ALTHOUGH STILL UNFOLDING, EPIGENETIC MEMORIES OF INFLAMMATION HAVE NOW BEEN LINKED TO POSSIBLE BRAIN DISORDERS SUCH AS ALZHEIMER DISEASE, AND TO AN ELEVATED RISK OF CANCER. IN THIS REVIEW, WE CONSIDER THE CONSEQUENCES-GOOD AND BAD-OF THESE EPIGENETIC MEMORIES AND THEIR IMPLICATIONS FOR HUMAN HEALTH AND DISEASE. 2022 9 5310 24 PSYCHOBIOLOGY AND MOLECULAR GENETICS OF RESILIENCE. EVERY INDIVIDUAL EXPERIENCES STRESSFUL LIFE EVENTS. IN SOME CASES ACUTE OR CHRONIC STRESS LEADS TO DEPRESSION AND OTHER PSYCHIATRIC DISORDERS, BUT MOST PEOPLE ARE RESILIENT TO SUCH EFFECTS. RECENT RESEARCH HAS BEGUN TO IDENTIFY THE ENVIRONMENTAL, GENETIC, EPIGENETIC AND NEURAL MECHANISMS THAT UNDERLIE RESILIENCE, AND HAS SHOWN THAT RESILIENCE IS MEDIATED BY ADAPTIVE CHANGES IN SEVERAL NEURAL CIRCUITS INVOLVING NUMEROUS NEUROTRANSMITTER AND MOLECULAR PATHWAYS. THESE CHANGES SHAPE THE FUNCTIONING OF THE NEURAL CIRCUITS THAT REGULATE REWARD, FEAR, EMOTION REACTIVITY AND SOCIAL BEHAVIOUR, WHICH TOGETHER ARE THOUGHT TO MEDIATE SUCCESSFUL COPING WITH STRESS. 2009 10 6626 26 UNDERSTANDING RESILIENCE. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. STRESSFUL LIFE EVENTS, TRAUMA, AND CHRONIC ADVERSITY CAN HAVE A SUBSTANTIAL IMPACT ON BRAIN FUNCTION AND STRUCTURE, AND CAN RESULT IN THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD), DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. HOWEVER, MOST INDIVIDUALS DO NOT DEVELOP SUCH ILLNESSES AFTER EXPERIENCING STRESSFUL LIFE EVENTS, AND ARE THUS THOUGHT TO BE RESILIENT. RESILIENCE AS SUCCESSFUL ADAPTATION RELIES ON EFFECTIVE RESPONSES TO ENVIRONMENTAL CHALLENGES AND ULTIMATE RESISTANCE TO THE DELETERIOUS EFFECTS OF STRESS, THEREFORE A GREATER UNDERSTANDING OF THE FACTORS THAT PROMOTE SUCH EFFECTS IS OF GREAT RELEVANCE. THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS THAT ARE CONSIDERED ESSENTIAL CONTRIBUTORS TO THE DEVELOPMENT OF RESILIENCE. NEURAL CIRCUITS AND PATHWAYS INVOLVED IN MEDIATING RESILIENCE ARE ALSO DISCUSSED. THE GROWING UNDERSTANDING OF RESILIENCE FACTORS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL AND PSYCHOLOGICAL INTERVENTIONS FOR ENHANCING RESILIENCE AND MITIGATING THE UNTOWARD CONSEQUENCES. 2013 11 1365 38 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 12 3594 41 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 13 4084 27 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 14 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 15 6818 37 [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 16 23 31 60 YEARS OF NEUROENDOCRINOLOGY: REDEFINING NEUROENDOCRINOLOGY: STRESS, SEX AND COGNITIVE AND EMOTIONAL REGULATION. THE DISCOVERY OF STEROID HORMONE RECEPTORS IN BRAIN REGIONS THAT MEDIATE EVERY ASPECT OF BRAIN FUNCTION HAS BROADENED THE DEFINITION OF 'NEUROENDOCRINOLOGY' TO INCLUDE THE RECIPROCAL COMMUNICATION BETWEEN THE BRAIN AND THE BODY VIA HORMONAL AND NEURAL PATHWAYS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT AND DEVELOPING BRAIN POSSESS REMARKABLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESS, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. STRESS CAUSES AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION-MAKING, ANXIETY AND MOOD THAT CAN ALTER EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE. BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC ANXIETY AND DEPRESSION. THERE ARE IMPORTANT SEX DIFFERENCES IN THE BRAIN RESPONSES TO STRESSORS THAT ARE IN URGENT NEED OF FURTHER EXPLORATION. MOREOVER, ADVERSE EARLY-LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCE LASTING EFFECTS ON BRAIN AND BODY OVER THE LIFE-COURSE VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS MOST IMPORTANT, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT TAKE INTO CONSIDERATION BRAIN-BODY INTERACTIONS. 2015 17 4621 31 NEUROBIOLOGICAL AND SYSTEMIC EFFECTS OF CHRONIC STRESS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR, WHICH PROMOTE ADAPTATION ("ALLOSTASIS") BUT ALSO CONTRIBUTE TO PATHOPHYSIOLOGY ("ALLOSTATIC LOAD/OVERLOAD") WHEN OVERUSED AND DYSREGULATED. THE ADULT AS WELL AS DEVELOPING BRAIN POSSESSES A REMARKABLE ABILITY TO SHOW STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESSFUL AND OTHER EXPERIENCES, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING AND SYNAPSE TURNOVER. STRESS CAN CAUSE AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION MAKING, ANXIETY AND MOOD THAT CAN INCREASE OR DECREASE EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, THESE CHANGES MAY BE ADAPTIVE; BUT, IF THE THREAT PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION REQUIRES INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES. THERE ARE IMPORTANT SEX DIFFERENCES IN HOW THE BRAIN RESPONDS TO STRESSORS. MOREOVER, ADVERSE EARLY LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCES LASTING EFFECTS ON BRAIN AND BODY VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS KEY, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT UTILIZE BRAIN-BODY INTERACTIONS. POLICIES OF GOVERNMENT AND THE PRIVATE SECTOR ARE IMPORTANT TO PROMOTE HEALTH AND INCREASE "HEALTHSPAN." 2017 18 1774 22 EARLY-LIFE STRESS: FROM NEUROENDOCRINE MECHANISMS TO STRESS-RELATED DISORDERS. STRESS EXPOSURE IS HIGHLY PREVALENT IN THE GENERAL POPULATION; HOWEVER, THE EXPERIENCE OF STRESS DURING VULNERABLE PERIODS OF DEVELOPMENT HAS SUBSTANTIAL AND PERMANENT EFFECTS ON BRAIN STRUCTURE AND FUNCTION AND PHYSICAL HEALTH IN ADULTHOOD. STRESS, THE STATE OF THREATENED HOMEOSTASIS, IS GENERALLY ASSOCIATED WITH A TIME-LIMITED ACTIVATION OF THE STRESS SYSTEM, I.E., THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE AROUSAL/SYMPATHETIC NERVOUS SYSTEM, TAILORED TO THE STRESSFUL STIMULUS ALSO KNOWN AS THE STRESSOR. ON THE OTHER HAND, CHRONIC STRESS MAY BE ASSOCIATED WITH LINGERING HYPER- OR HYPOSECRETION OF MEDIATORS OF THE STRESS SYSTEM. THIS CHRONIC CONDITION IS CALLED DYSHOMEOSTASIS, ALLOSTASIS, OR CACOSTASIS AND IS ASSOCIATED WITH INCREASED MENTAL AND PHYSICAL MORBIDITY IN THE LONG TERM. STRESSFUL OR TRAUMATIC EXPERIENCES DURING FETAL LIFE, EARLY CHILDHOOD, AND ADOLESCENCE HAVE BEEN RELATED TO PERSISTENT NEUROENDOCRINE AND EPIGENETIC CHANGES. FURTHER, BRAIN STRUCTURES INVOLVED IN THE STRESS RESPONSE, SUCH AS THOSE OF THE STRESS SYSTEM, THE HIPPOCAMPUS, AND THE AMYGDALA, MAY BE PROGRAMMED EARLY ON FOR A LIFE OF ADVERSITY. 2018 19 5250 29 PROGRAMMED DISORDERS OF BETA-CELL DEVELOPMENT AND FUNCTION AS ONE CAUSE FOR TYPE 2 DIABETES? THE GK RAT PARADIGM. NOW THAT THE REDUCTION IN BETA-MASS HAS BEEN CLEARLY ESTABLISHED IN HUMANS WITH TYPE 2 DIABETES MELLITUS (T2DM) 1-4, THE DEBATE FOCUSES ON THE POSSIBLE MECHANISMS RESPONSIBLE FOR DECREASED BETA-CELL NUMBER AND IMPAIRED BETA-CELL FUNCTION AND THEIR MULTIFACTORIAL ETIOLOGY. APPROPRIATE INBRED RODENT MODELS ARE ESSENTIAL TOOLS FOR IDENTIFICATION OF GENES AND ENVIRONMENTAL FACTORS THAT INCREASE THE RISK OF ABNORMAL BETA-CELL FUNCTION AND OF T2DM. THE INFORMATION AVAILABLE IN THE GOTO-KAKIZAKI (GK) RAT, ONE OF THE BEST CHARACTERIZED ANIMAL MODELS OF SPONTANEOUS T2DM, ARE REVIEWED IN SUCH A PERSPECTIVE. WE PROPOSE THAT THE DEFECTIVE BETA-CELL MASS AND FUNCTION IN THE GK MODEL REFLECT THE COMPLEX INTERACTIONS OF THREE PATHOGENIC PLAYERS: (1) SEVERAL INDEPENDENT LOCI CONTAINING GENES CAUSING IMPAIRED INSULIN SECRETION; (2) GESTATIONAL METABOLIC IMPAIRMENT INDUCING A PROGRAMMING OF ENDOCRINE PANCREAS (DECREASED BETA-CELL NEOGENESIS) WHICH IS TRANSMITTED TO THE NEXT GENERATION; AND (3) SECONDARY (ACQUIRED) LOSS OF BETA-CELL DIFFERENTIATION DUE TO CHRONIC EXPOSURE TO HYPERGLYCEMIA (GLUCOTOXICITY). AN IMPORTANT MESSAGE IS THAT THE 'HERITABLE' DETERMINANTS OF T2DM ARE NOT SIMPLY DEPENDANT ON GENETIC FACTORS, BUT PROBABLY INVOLVE TRANSGENERATIONAL EPIGENETIC RESPONSES. 2005 20 3595 31 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