1 6267 146 THE NEUROENDOCRINOLOGY OF STRESS: A NEVER ENDING STORY. EVOLUTIONARY SUCCESS DEPENDS ON OUR ABILITY TO ADAPT TO CHANGING CIRCUMSTANCES. THE NEUROENDOCRINE RESPONSE TO STRESS IS AN EXCELLENT EXAMPLE OF A PLASTIC SYSTEM THAT RESPONDS TO THREATS TO HOMEOSTASIS AND ALTERS ITS OUTPUT TO MEET CURRENT AND EXPECTED FUTURE DEMANDS. AT THE LEVEL OF THE HYPOTHALAMUS, THE CORTICOTROPH SECRETAGOGUES CORTICOTROPHIN-RELEASING HORMONE (CRH) AND ARGININE VASOPRESSIN (AVP) RESPOND RAPIDLY TO AN ACUTE STRESSOR BUT, FOLLOWING CHRONIC STRESS, THEY ADAPT WITH A REDUCTION OF CRH BUT A MAJOR INCREASE IN AVP. THE RELEASE OF CRH AND AVP ACTIVATES PRO-OPIOMELANOCORTIN IN ANTERIOR PITUITARY CORTICOTROPH CELLS AND THE RELEASE OF ADRENOCORTICOTROPHIC HORMONE INTO PERIPHERAL BLOOD FROM WHERE IT TARGETS RECEPTORS IN THE ADRENAL CORTEX TO RELEASE GLUCOCORTICOID HORMONES. THESE HORMONES (I.E. CORTICOSTERONE IN THE RAT AND CORTISOL IN MAN) ARE RELEASED IN A PULSATILE ULTRADIAN PATTERN WHICH DEFINES THE NORMAL CIRCADIAN RHYTHM. THE FREQUENCY OF THE PULSES IS INCREASED UNDER STATES OF CHRONIC STRESS, AND IN RATS WITH GENETICALLY DETERMINED HYPER-RESPONSIVENESS OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. INTERESTINGLY, NEONATAL INFLUENCES CAN ALSO PROGRAMME ALTERATIONS IN ULTRADIAN RHYTHMICITY, IMPLICATING EPIGENETIC FACTORS IN ITS REGULATION. AT THE LEVEL OF TISSUE RECEPTORS, THE ALTERATION IN PATTERN OF GLUCOCORTICOID ULTRADIAN RHYTHM HAS DIFFERENTIAL EFFECTS ON MINERALOCORTICOID RECEPTOR AND GLUCOCORTICOID RECEPTOR (GR) BINDING TO DNA AND OFFERS A MECHANISM FOR TISSUE SPECIFIC RESPONSES TO ALTERED GLUCOCORTICOID DYNAMICS. THE EFFECTS OF NEONATAL EXPERIENCE ARE NOT ONLY SEEN AT THE LEVEL OF CRH AND GR REGULATION, BUT ALSO ARE EVIDENT IN BEHAVIOURAL RESPONSES TO STRESS AND IN THE RESPONSIVENESS OF BRAIN STEM SEROTONERGIC PATHWAYS, AS MEASURED BY TRYPTOPHAN HYDROXYLASE MRNA IN THE BRAIN STEM. 2008 2 4095 30 MATERNALLY DERIVED LOW GLUCOCORTICOID MEDIATES ADRENAL DEVELOPMENTAL PROGRAMMING ALTERATION IN OFFSPRING INDUCED BY DEXAMETHASONE. ADVERSE ENVIRONMENTS DURING PREGNANCY CAN INCREASE SUSCEPTIBILITY TO CHRONIC DISEASES IN ADULT OFFSPRING. THE OCCURRENCE AND DEVELOPMENT OF FETAL-ORIGINATED DISEASES WERE ASSOCIATED WITH ADRENAL DEVELOPMENTAL PROGRAMMING AND HOMEOSTASIS ALTERATION IN OFFSPRING. DEXAMETHASONE IS WIDELY USED FOR PRETERM DELIVERY-RELATED PREGNANCY DISEASES, BUT THE INTRAUTERINE PROGRAMMING ALTERATION AND ITS OCCURRENCE MECHANISM OF PRENATAL DEXAMETHASONE EXPOSURE (PDE) ON ADRENAL DEVELOPMENT IN OFFSPRING HAVE NOT BEEN CLARIFIED. IN THIS STUDY, PRENATAL DEXAMETHASONE THERAPY COULD INHIBIT NEONATAL DEVELOPMENT AND CAUSE A LOW EXPOSURE OF MATERNALLY DERIVED GLUCOCORTICOID IN CLINIC. THEN, WE ESTABLISHED A RAT MODEL OF PDE AND OBSERVED A SIMILAR PHENOMENON. FURTHER, THE ADRENAL STEROIDOGENIC FUNCTION WAS CONTINUOUSLY INHIBITED IN THE PDE MALE OFFSPRING RATS, ACCOMPANIED BY THE DECREASED H3K27AC LEVEL OF ADRENAL INSULIN-LIKE GROWTH FACTOR 1 (IGF1) AND ITS EXPRESSION. MOREOVER, CHRONIC STRESS IN PDE ADULT OFFSPRING RATS COULD REVERSE THE CHANGES OF THE ABOVE INDICATORS THROUGH THE HIGH LEVEL OF GLUCOCORTICOID. IN COMBINATION WITH IN VIVO, IN VITRO AND A SERIES OF INTERFERENCE EXPERIMENTS, WE CONFIRMED THAT THE LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS INHIBITED THE ADRENAL IGF1 EXPRESSION AND STEROIDOGENIC FUNCTION THROUGH THE GRALPHA/MIR-370-3P/SIRT3 PATHWAY. IN SUMMARY, PDE COULD CONTINUOUSLY INHIBIT THE ADRENAL STEROIDOGENIC FUNCTION IN THE MALE OFFSPRING, WHICH IS ASSOCIATED WITH THE MATERNALLY DERIVED LOW GLUCOCORTICOID-MEDIATED THE ADRENAL DEVELOPMENTAL PROGRAMMING ALTERATION IN OFFSPRING. THIS STUDY PROVIDES A THEORETICAL AND EXPERIMENTAL BASIS FOR EXPLAINING THE ADRENAL DEVELOPMENT ORIGIN OF PDE-INDUCED ADULT CHRONIC DISEASES. 2021 3 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 4 3463 38 HYPOTHALAMIC-PITUITARY-ADRENAL AND HYPOTHALAMIC-PITUITARY-GONADAL AXES: SEX DIFFERENCES IN REGULATION OF STRESS RESPONSIVITY. GONADAL HORMONES PLAY A KEY ROLE IN THE ESTABLISHMENT, ACTIVATION, AND REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. BY INFLUENCING THE RESPONSE AND SENSITIVITY TO RELEASING FACTORS, NEUROTRANSMITTERS, AND HORMONES, GONADAL STEROIDS HELP ORCHESTRATE THE GAIN OF THE HPA AXIS TO FINE-TUNE THE LEVELS OF STRESS HORMONES IN THE GENERAL CIRCULATION. FROM EARLY LIFE TO ADULTHOOD, GONADAL STEROIDS CAN DIFFERENTIALLY AFFECT THE HPA AXIS, RESULTING IN SEX DIFFERENCES IN THE RESPONSIVITY OF THIS AXIS. THE HPA AXIS INFLUENCES MANY PHYSIOLOGICAL FUNCTIONS MAKING AN ORGANISM'S RESPONSE TO CHANGES IN THE ENVIRONMENT APPROPRIATE FOR ITS REPRODUCTIVE STATUS. ALTHOUGH THE ACUTE HPA RESPONSE TO STRESSORS IS A BENEFICIAL RESPONSE, CONSTANT ACTIVATION OF THIS CIRCUITRY BY CHRONIC OR TRAUMATIC STRESSFUL EPISODES MAY LEAD TO A DYSREGULATION OF THE HPA AXIS AND CAUSE PATHOLOGY. COMPARED TO MALES, FEMALE MICE AND RATS SHOW A MORE ROBUST HPA AXIS RESPONSE, AS A RESULT OF CIRCULATING ESTRADIOL LEVELS WHICH ELEVATE STRESS HORMONE LEVELS DURING NON-THREATENING SITUATIONS, AND DURING AND AFTER STRESSORS. FLUCTUATING LEVELS OF GONADAL STEROIDS IN FEMALES ACROSS THE ESTROUS CYCLE ARE A MAJOR FACTOR CONTRIBUTING TO SEX DIFFERENCES IN THE ROBUSTNESS OF HPA ACTIVITY IN FEMALES COMPARED TO MALES. MOREOVER, GONADAL STEROIDS MAY ALSO CONTRIBUTE TO EPIGENETIC AND ORGANIZATIONAL INFLUENCES ON THE HPA AXIS EVEN BEFORE PUBERTY. CORRESPONDINGLY, CROSSTALK BETWEEN THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AND HPA AXES COULD LEAD TO ABNORMALITIES OF STRESS RESPONSES. IN HUMANS, A DYSREGULATED STRESS RESPONSE IS ONE OF THE MOST COMMON SYMPTOMS SEEN ACROSS MANY NEUROPSYCHIATRIC DISORDERS, AND AS A RESULT, SUCH INTERACTIONS MAY EXACERBATE PERIPHERAL PATHOLOGIES. IN THIS REVIEW, WE DISCUSS THE HPA AND HPG AXES AND REVIEW HOW GONADAL STEROIDS INTERACT WITH THE HPA AXIS TO REGULATE THE STRESS CIRCUITRY DURING ALL STAGES IN LIFE. 2017 5 5209 35 PRENATAL XENOBIOTIC EXPOSURE AND INTRAUTERINE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS PROGRAMMING ALTERATION. THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IS ONE OF THE MOST IMPORTANT NEUROENDOCRINE AXES AND PLAYS AN IMPORTANT ROLE IN STRESS DEFENSE RESPONSES BEFORE AND AFTER BIRTH. PRENATAL EXPOSURE TO XENOBIOTICS, INCLUDING ENVIRONMENTAL TOXINS (SUCH AS SMOKE, SULFUR DIOXIDE AND CARBON MONOXIDE), DRUGS (SUCH AS SYNTHETIC GLUCOCORTICOIDS), AND FOODS AND BEVERAGE CATEGORIES (SUCH AS ETHANOL AND CAFFEINE), AFFECTS FETAL DEVELOPMENT INDIRECTLY BY CHANGING THE MATERNAL STATUS OR DAMAGING THE PLACENTA. CERTAIN XENOBIOTICS (SUCH AS CAFFEINE, ETHANOL AND DEXAMETHASONE) MAY ALSO AFFECT THE FETUS DIRECTLY BY CROSSING THE PLACENTA INTO THE FETUS DUE TO THEIR LIPOPHILIC PROPERTIES AND LOWER MOLECULAR WEIGHTS. ALL OF THESE FACTORS PROBABLY RESULT IN INTRAUTERINE PROGRAMMING ALTERATION OF THE HPA AXIS, WHICH SHOWED A LOW BASAL ACTIVITY BUT HYPERSENSITIVITY TO CHRONIC STRESS. THESE ALTERATIONS WILL, THEREFORE, INCREASE THE SUSCEPTIBILITY TO ADULT NEUROPSYCHIATRIC (SUCH AS DEPRESSION AND SCHIZOPHRENIA) AND METABOLIC DISEASES (SUCH AS HYPERTENSION, DIABETES AND NON-ALCOHOLIC FATTY LIVER DISEASE). THE "OVER-EXPOSURE OF FETUSES TO MATERNAL GLUCOCORTICOIDS" MAY BE THE MAIN INITIATION FACTOR BY WHICH THE FETAL HPA AXIS PROGRAMMING IS ALTERED. MEANTIME, XENOBIOTICS CAN DIRECTLY INDUCE ABNORMAL EPIGENETIC MODIFICATIONS AND EXPRESSION ON THE IMPORTANT FETAL GENES (SUCH AS HIPPOCAMPAL GLUCOCORTICOID RECEPTOR, ADRENAL STEROIDOGENIC ACUTE REGULATORY PROTEIN, ET AL) OR DAMAGE BY IN SITU OXIDATIVE METABOLISM OF FETAL ADRENALS, WHICH MAY ALSO BE CONTRIBUTED TO THE PROGRAMMING ALTERATION OF FETAL HPA AXIS. 2014 6 5815 45 STRESS AND GLUCOCORTICOID RECEPTOR TRANSCRIPTIONAL PROGRAMMING IN TIME AND SPACE: IMPLICATIONS FOR THE BRAIN-GUT AXIS. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ENHANCED ABDOMINAL PAIN AND ALTERED INTESTINAL BARRIER FUNCTION THAT MAY RESULT FROM A PERTURBATION IN THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. THE GLUCOCORTICOID RECEPTOR (GR) EXPLOITS DIVERSE MECHANISMS TO ACTIVATE OR SUPPRESS CONGENERIC GENE EXPRESSION, WITH REGULATORY VARIATION ASSOCIATED WITH STRESS-RELATED DISORDERS IN PSYCHIATRY AND GASTROENTEROLOGY. PURPOSE: DURING ACUTE AND CHRONIC STRESS, CORTICOTROPIN-RELEASING HORMONE DRIVES SECRETION OF ADRENOCORTICOTROPIC HORMONE FROM THE PITUITARY, ULTIMATELY LEADING TO THE RELEASE OF CORTISOL (HUMAN) AND CORTICOSTERONE (RODENT) FROM THE ADRENAL GLANDS. CORTISOL BINDS WITH THE GR IN THE CYTOSOL, TRANSLOCATES TO THE NUCLEUS, AND ACTIVATES THE NR3C1 (NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1 [GR]) GENE. THIS REVIEW FOCUSES ON THE RAPIDLY DEVELOPING OBSERVATIONS THAT CORTISOL IS RESPONSIBLE FOR DRIVING CIRCADIAN AND ULTRADIAN BURSTS OF TRANSCRIPTIONAL ACTIVITY IN THE CLOCK (CLOCK CIRCADIAN REGULATOR) AND PER (PERIOD CIRCADIAN CLOCK 1) GENE FAMILIES, AND THIS RHYTHM IS DISRUPTED IN MAJOR DEPRESSIVE DISORDER, BIPOLAR DISORDER, AND STRESS-RELATED GASTROINTESTINAL AND IMMUNE DISORDERS. GLUCOCORTICOID RECEPTOR REGULATES DIFFERENT SETS OF TRANSCRIPTS IN A TISSUE-SPECIFIC MANNER, THROUGH PULSATILE WAVES OF GENE EXPRESSION THAT INCLUDES OCCUPANCY OF GLUCOCORTICOID RESPONSE ELEMENTS LOCATED WITHIN CONSTITUTIVELY OPEN SPATIAL DOMAINS IN CHROMATIN. EMERGING EVIDENCE SUPPORTS A POTENTIALLY PIVOTAL ROLE FOR EPIGENETIC REGULATION OF HOW GR INTERACTS WITH OTHER CHROMATIN REGULATORS TO CONTROL THE EXPRESSION OF ITS TARGET GENES. DYSREGULATION OF THE CENTRAL AND PERIPHERAL GR REGULOME HAS POTENTIALLY SIGNIFICANT CONSEQUENCES FOR STRESS-RELATED DISORDERS AFFECTING THE BRAIN-GUT AXIS. 2016 7 5200 30 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES. 2016 8 4343 35 MINIREVIEW: STRESS-RELATED PSYCHIATRIC DISORDERS WITH LOW CORTISOL LEVELS: A METABOLIC HYPOTHESIS. SEVERAL STRESS-ASSOCIATED NEUROPSYCHIATRIC DISORDERS, NOTABLY POSTTRAUMATIC STRESS DISORDER AND CHRONIC PAIN AND FATIGUE SYNDROMES, PARADOXICALLY EXHIBIT SOMEWHAT LOW PLASMA LEVELS OF THE STRESS HORMONE CORTISOL. THE EFFECTS APPEAR GREATEST IN THOSE INITIALLY TRAUMATIZED IN EARLY LIFE, IMPLYING A DEGREE OF DEVELOPMENTAL PROGRAMMING, PERHAPS OF BOTH LOWER CORTISOL AND VULNERABILITY TO PSYCHOPATHOLOGY. IN THESE CONDITIONS, LOWERED CORTISOL IS NOT DUE TO ANY ADRENAL OR PITUITARY INSUFFICIENCY. INSTEAD, TWO PROCESSES APPEAR INVOLVED. FIRST, THERE IS INCREASED TARGET CELL SENSITIVITY TO GLUCOCORTICOID ACTION, NOTABLY NEGATIVE FEEDBACK UPON THE HYPOTHALAMIC-PITUITARY-ADRENAL (STRESS) AXIS. ALTERED DENSITY OF THE GLUCOCORTICOID RECEPTOR IS INFERRED, SQUARING WITH MUCH PRECLINICAL DATA SHOWING EARLY LIFE CHALLENGES CAN PERMANENTLY PROGRAM GLUCOCORTICOID RECEPTORS IN A TISSUE-SPECIFIC MANNER. THESE EFFECTS INVOLVE EPIGENETIC MECHANISMS. SECOND, EARLY LIFE TRAUMA/STARVATION INDUCES LONG-LASTING LOWERING OF GLUCOCORTICOID CATABOLISM, SPECIFICALLY BY 5ALPHA-REDUCTASE TYPE 1 (PREDOMINANTLY A LIVER ENZYME) AND 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 2 (IN KIDNEY), AN EFFECT ALSO SEEN IN MODEL SYSTEMS. THESE CHANGES REFLECT A PLAUSIBLE EARLY-LIFE ADAPTATION TO INCREASE THE PERSISTENCE OF ACTIVE CORTISOL IN LIVER (TO MAXIMIZE FUEL OUTPUT) AND KIDNEY (TO INCREASE SALT RETENTION) WITHOUT ELEVATION OF CIRCULATING LEVELS, THUS AVOIDING THEIR DELETERIOUS EFFECTS ON BRAIN AND MUSCLE. MODESTLY LOWERED CIRCULATING CORTISOL AND INCREASED VULNERABILITY TO STRESS-ASSOCIATED DISORDERS MAY BE THE OUTCOME. THIS NOTION IMPLIES A VULNERABLE EARLY-LIFE PHENOTYPE MAY BE DISCERNABLE AND INDICATES POTENTIAL THERAPY BY MODEST GLUCOCORTICOID REPLACEMENT. INDEED, EARLY CLINICAL TRIALS WITH CORTISOL HAVE SHOWN A MODICUM OF PROMISE. 2011 9 4944 25 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING. 2016 10 4948 37 PATERNAL STRESS EXPOSURE ALTERS SPERM MICRORNA CONTENT AND REPROGRAMS OFFSPRING HPA STRESS AXIS REGULATION. NEUROPSYCHIATRIC DISEASE FREQUENTLY PRESENTS WITH AN UNDERLYING HYPOREACTIVITY OR HYPERREACTIVITY OF THE HPA STRESS AXIS, SUGGESTING AN EXCEPTIONAL VULNERABILITY OF THIS CIRCUITRY TO EXTERNAL PERTURBATIONS. PARENTAL LIFETIME EXPOSURES TO ENVIRONMENTAL CHALLENGES ARE ASSOCIATED WITH INCREASED OFFSPRING NEUROPSYCHIATRIC DISEASE RISK, AND LIKELY CONTRIBUTE TO STRESS DYSREGULATION. WHILE MATERNAL INFLUENCES HAVE BEEN EXTENSIVELY EXAMINED, MUCH LESS IS KNOWN REGARDING THE SPECIFIC ROLE OF PATERNAL FACTORS. TO INVESTIGATE THE POTENTIAL MECHANISMS BY WHICH PATERNAL STRESS MAY CONTRIBUTE TO OFFSPRING HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSREGULATION, WE EXPOSED MICE TO 6 WEEKS OF CHRONIC STRESS BEFORE BREEDING. AS EPIDEMIOLOGICAL STUDIES SUPPORT VARIATION IN PATERNAL GERM CELL SUSCEPTIBILITY TO REPROGRAMMING ACROSS THE LIFESPAN, MALE STRESS EXPOSURE OCCURRED EITHER THROUGHOUT PUBERTY OR IN ADULTHOOD. REMARKABLY, OFFSPRING OF SIRES FROM BOTH PATERNAL STRESS GROUPS DISPLAYED SIGNIFICANTLY REDUCED HPA STRESS AXIS RESPONSIVITY. GENE SET ENRICHMENT ANALYSES IN OFFSPRING STRESS REGULATING BRAIN REGIONS, THE PARAVENTRICULAR NUCLEUS (PVN) AND THE BED NUCLEUS OF STRIA TERMINALIS, REVEALED GLOBAL PATTERN CHANGES IN TRANSCRIPTION SUGGESTIVE OF EPIGENETIC REPROGRAMMING AND CONSISTENT WITH ALTERED OFFSPRING STRESS RESPONSIVITY, INCLUDING INCREASED EXPRESSION OF GLUCOCORTICOID-RESPONSIVE GENES IN THE PVN. IN EXAMINING POTENTIAL EPIGENETIC MECHANISMS OF GERM CELL TRANSMISSION, WE FOUND ROBUST CHANGES IN SPERM MICRORNA (MIR) CONTENT, WHERE NINE SPECIFIC MIRS WERE SIGNIFICANTLY INCREASED IN BOTH PATERNAL STRESS GROUPS. OVERALL, THESE RESULTS DEMONSTRATE THAT PATERNAL EXPERIENCE ACROSS THE LIFESPAN CAN INDUCE GERM CELL EPIGENETIC REPROGRAMMING AND IMPACT OFFSPRING HPA STRESS AXIS REGULATION, AND MAY THEREFORE OFFER NOVEL INSIGHT INTO FACTORS INFLUENCING NEUROPSYCHIATRIC DISEASE RISK. 2013 11 3092 38 GENOMIC AND EPIGENOMIC MECHANISMS OF GLUCOCORTICOIDS IN THE BRAIN. FOLLOWING THE DISCOVERY OF GLUCOCORTICOID RECEPTORS IN THE HIPPOCAMPUS AND OTHER BRAIN REGIONS, RESEARCH HAS FOCUSED ON UNDERSTANDING THE EFFECTS OF GLUCOCORTICOIDS IN THE BRAIN AND THEIR ROLE IN REGULATING EMOTION AND COGNITION. GLUCOCORTICOIDS ARE ESSENTIAL FOR ADAPTATION TO STRESSORS (ALLOSTASIS) AND IN MALADAPTATION RESULTING FROM ALLOSTATIC LOAD AND OVERLOAD. ALLOSTATIC OVERLOAD, WHICH CAN OCCUR DURING CHRONIC STRESS, CAN RESHAPE THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS THROUGH EPIGENETIC MODIFICATION OF GENES IN THE HIPPOCAMPUS, HYPOTHALAMUS AND OTHER STRESS-RESPONSIVE BRAIN REGIONS. GLUCOCORTICOIDS EXERT THEIR EFFECTS ON THE BRAIN THROUGH GENOMIC MECHANISMS THAT INVOLVE BOTH GLUCOCORTICOID RECEPTORS AND MINERALOCORTICOID RECEPTORS DIRECTLY BINDING TO DNA, AS WELL AS BY NON-GENOMIC MECHANISMS. FURTHERMORE, GLUCOCORTICOIDS SYNERGIZE BOTH GENOMICALLY AND NON-GENOMICALLY WITH NEUROTRANSMITTERS, NEUROTROPHIC FACTORS, SEX HORMONES AND OTHER STRESS MEDIATORS TO SHAPE AN ORGANISM'S PRESENT AND FUTURE RESPONSES TO A STRESSFUL ENVIRONMENT. HERE, WE DISCUSS THE MECHANISMS OF GLUCOCORTICOID ACTION IN THE BRAIN AND REVIEW HOW GLUCOCORTICOIDS INTERACT WITH STRESS MEDIATORS IN THE CONTEXT OF ALLOSTASIS, ALLOSTATIC LOAD AND STRESS-INDUCED NEUROPLASTICITY. 2017 12 4222 34 METHYLATION AT THE CPG ISLAND SHORE REGION UPREGULATES NR3C1 PROMOTER ACTIVITY AFTER EARLY-LIFE STRESS. EARLY-LIFE STRESS (ELS) INDUCES LONG-LASTING CHANGES IN GENE EXPRESSION CONFERRING AN INCREASED RISK FOR THE DEVELOPMENT OF STRESS-RELATED MENTAL DISORDERS. GLUCOCORTICOID RECEPTORS (GR) MEDIATE THE NEGATIVE FEEDBACK ACTIONS OF GLUCOCORTICOIDS (GC) IN THE PARAVENTRICULAR NUCLEUS (PVN) OF THE HYPOTHALAMUS AND ANTERIOR PITUITARY AND THEREFORE PLAY A KEY ROLE IN THE REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND THE ENDOCRINE RESPONSE TO STRESS. WE HERE SHOW THAT ELS PROGRAMS THE EXPRESSION OF THE GR GENE (NR3C1) BY SITE-SPECIFIC HYPERMETHYLATION AT THE CPG ISLAND (CGI) SHORE IN HYPOTHALAMIC NEURONS THAT PRODUCE CORTICOTROPIN-RELEASING HORMONE (CRH), THUS PREVENTING CRH UPREGULATION UNDER CONDITIONS OF CHRONIC STRESS. CPGS MAPPING TO THE NR3C1 CGI SHORE REGION ARE DYNAMICALLY REGULATED BY ELS AND UNDERPIN METHYLATION-SENSITIVE CONTROL OF THIS REGION'S INSULATION-LIKE FUNCTION VIA YING YANG 1 (YY1) BINDING. OUR RESULTS PROVIDE NEW INSIGHT INTO HOW A GENOMIC ELEMENT INTEGRATES EXPERIENCE-DEPENDENT EPIGENETIC PROGRAMMING OF THE COMPOSITE PROXIMAL NR3C1 PROMOTER, AND ASSIGNS AN INSULATING ROLE TO THE CGI SHORE. 2015 13 5651 32 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD. 2020 14 3973 38 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES. 2008 15 6478 27 TOPICAL REVIEW: THE EMERGING FIELD OF EPIGENETICS: INFORMING MODELS OF PEDIATRIC TRAUMA AND PHYSICAL HEALTH. OBJECTIVE: TRAUMA EXPERIENCED DURING CHILDHOOD AND ADOLESCENCE HAS BEEN LINKED TO A NUMBER OF CHRONIC MEDICAL CONCERNS. WE HIGHLIGHT MAJOR FINDINGS FROM THE PEDIATRIC TRAUMA LITERATURE TO PROVIDE A MODEL FOR UNDERSTANDING THIS ASSOCIATION. METHODS: STUDIES EXAMINING THE EFFECTS OF TRAUMA WERE SYSTEMATICALLY REVIEWED AND SYNTHESIZED INTO A MODEL PROPOSING A CENTRAL ROLE FOR EPIGENETICS IN THE WAYS THAT CHILDHOOD EXPERIENCES CAN AFFECT HEALTH. RESULTS: EARLY HYPOTHALAMIC PITUITARY ADRENAL (HPA) AXIS RESPONSE MAY IMPACT INITIAL TRAUMA EXPERIENCE, WITH DOWNSTREAM EFFECTS ON POSTTRAUMA ADJUSTMENT REFLECTED IN POSTTRAUMA NEUROBIOLOGY, PSYCHOLOGICAL HEALTH, AND PHYSICAL HEALTH. CONCLUSIONS: PROSPECTIVE RESEARCH WITH CHILDREN AND ADOLESCENTS EXPOSED TO TRAUMA IS NEEDED TO BETTER CHARACTERIZE THE GENETIC AND EPIGENETIC INFLUENCES ON THE COURSE OF HPA AND IMMUNE PROCESSES AS RELATED TO POSTTRAUMA PSYCHOLOGICAL AND PHYSICAL HEALTH OUTCOMES. 2016 16 3405 42 HOW STRESS GETS UNDER THE SKIN: EARLY LIFE ADVERSITY AND GLUCOCORTICOID RECEPTOR EPIGENETIC REGULATION. EARLY LIFE ADVERSITY IS ASSOCIATED WITH BOTH PERSISTENT DISRUPTIONS IN THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND PSYCHIATRIC SYMPTOMS. GLUCOCORTICOID RECEPTORS (GRS), WHICH ARE ENCODED BY THE NR3C1 GENE, BIND TO CORTISOL AND OTHER GLUCOCORTICOIDS TO CREATE A NEGATIVE FEEDBACK LOOP WITHIN THE HPA AXIS TO REGULATE THE BODY'S NEUROENDOCRINE RESPONSE TO STRESS. EXCESS METHYLATION OF A PROMOTER SEQUENCE WITHIN NR3C1 THAT ATTENUATES GR EXPRESSION, HOWEVER, HAS BEEN ASSOCIATED WITH BOTH EARLY LIFE ADVERSITY AND PSYCHOPATHOLOGY. AS CRITICAL REGULATORS WITHIN THE HPA AXIS, GRS AND THEIR EPIGENETIC REGULATION MAY MEDIATE THE LINK BETWEEN EARLY LIFE ADVERSITY AND THE ONSET OF PSYCHOPATHOLOGY. THE PRESENT REVIEW DISCUSSES THIS WORK AS ONE MECHANISM BY WHICH STRESS MAY GET UNDER THE SKIN TO DISRUPT HPA FUNCTIONING AT AN EPIGENETIC LEVEL AND CREATE LONG-LASTING VULNERABILITIES IN THE STRESS REGULATORY SYSTEM THAT SUBSEQUENTLY PREDISPOSE INDIVIDUALS TO PSYCHOPATHOLOGY. SPANNING PRENATAL INFLUENCES TO CRITICAL PERIODS OF EARLY LIFE AND ADOLESCENCE, WE DETAIL THE IMPACT THAT EARLY ADVERSITY HAS ON GR EXPRESSION, PHYSIOLOGICAL RESPONSES TO STRESS, AND THEIR IMPLICATIONS FOR LONG-TERM STRESS MANAGEMENT. WE NEXT PROPOSE A DUAL TRANSMISSION HYPOTHESIS REGARDING BOTH GENOMIC AND NON-GENOMIC MECHANISMS BY WHICH CHRONIC AND ACUTE STRESS PROPAGATE THROUGH NUMEROUS GENERATIONS. LASTLY, WE OUTLINE SEVERAL DIRECTIONS FOR FUTURE RESEARCH, INCLUDING POTENTIAL REVERSIBILITY OF METHYLATION PATTERNS AND ITS FUNCTIONAL IMPLICATIONS, VARIATION IN BEHAVIOR DETERMINED SOLELY BY NR3C1, AND CONSENSUS ON WHICH SPECIFIC PROMOTER REGIONS SHOULD BE STUDIED. 2018 17 2905 33 GENE DYSREGULATION IN THE ADULT RAT PARAVENTRICULAR NUCLEUS AND AMYGDALA BY PRENATAL EXPOSURE TO DEXAMETHASONE. FETAL PROGRAMMING IS THE CONCEPT THAT MATERNAL STRESSORS DURING CRITICAL PERIODS OF FETAL DEVELOPMENT CAN ALTER OFFSPRING PHENOTYPES POSTNATALLY. EXCESS GLUCOCORTICOIDS CAN INTERACT WITH THE FETUS TO EFFECT GENETIC AND EPIGENETIC CHANGES IMPLICATED IN ADVERSE DEVELOPMENTAL OUTCOMES. THE PRESENT STUDY INVESTIGATES HOW CHRONIC EXPOSURE TO THE SYNTHETIC GLUCOCORTICOID DEXAMETHASONE DURING LATE GESTATION ALTERS THE EXPRESSION OF GENES RELATED TO BEHAVIOR IN BRAIN AREAS RELEVANT TO THE REGULATION AND FUNCTION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. PREGNANT WISTAR KYOTO RATS RECEIVED SUBCUTANEOUS INJECTIONS OF DEXAMETHASONE (100 MUG/KG) DAILY FROM GESTATIONAL DAY 15-21 OR VEHICLE ONLY AS SHAM CONTROLS. THE AMYGDALA AND PARAVENTRICULAR NUCLEUS (PVN) WERE MICRO-PUNCHED TO EXTRACT MRNA FOR REVERSE TRANSCRIPTION AND QUANTITATIVE POLYMERASE CHAIN REACTION FOR THE ANALYSIS OF THE EXPRESSION OF SPECIFIC GENES. IN THE PVN, THE EXPRESSION OF THE GLUCOCORTICOID RECEPTOR NR3C1 WAS DOWNREGULATED IN FEMALE RATS IN RESPONSE TO PROGRAMMING. THE EXPRESSION OF CACNA1C ENCODING THE CA(V)1.2 PORE SUBUNIT OF L-TYPE VOLTAGE-GATED CALCIUM CHANNELS WAS DOWNREGULATED IN MALE AND FEMALE RATS PRENATALLY EXPOSED TO DEXAMETHASONE. COLLECTIVELY, THE RESULTS SUGGEST THAT PRENATAL EXPOSURE TO ELEVATED LEVELS OF GLUCOCORTICOIDS PLAYS A ROLE IN THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND POTENTIALLY LEARNING AND MEMORY BY ALTERING THE EXPRESSION OF SPECIFIC GENES WITHIN THE AMYGDALA AND PVN. 2022 18 2371 42 EPIGENETIC REGULATION OF THE GLUCOCORTICOID RECEPTOR PROMOTER 1(7) IN ADULT RATS. REGULATION OF GLUCOCORTICOID RECEPTOR (GR) LEVELS IS AN IMPORTANT STRESS ADAPTATION MECHANISM. TRANSCRIPTION FACTOR NFGI-A AND ENVIRONMENTALLY INDUCED GR PROMOTER 1 7 METHYLATION HAVE BEEN IMPLICATED IN FINE-TUNING THE EXPRESSION OF GR 1 7 TRANSCRIPTS. HERE, WE INVESTIGATED GR PROMOTER 1 7 METHYLATION AND GR 1 7 EXPRESSION IN ADULT RATS EXPOSED TO EITHER ACUTE OR CHRONIC STRESS PARADIGMS. A STRONG NEGATIVE CORRELATION WAS OBSERVED BETWEEN THE SUM OF PROMOTER-WIDE METHYLATION LEVELS AND GR 1 7 TRANSCRIPT LEVELS, INDEPENDENT OF THE STRESSOR. METHYLATION OF INDIVIDUAL SITES DID NOT, HOWEVER, CORRELATE WITH TRANSCRIPT LEVELS. THIS SUGGESTED THAT PROMOTER 1 7 WAS DIRECTLY REGULATED BY PROMOTER-WIDE DNA METHYLATION. ALTHOUGH ACUTE STRESS INCREASED NGFI-A EXPRESSION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS (PVN), GR 1 7 TRANSCRIPT LEVELS REMAINED UNAFFECTED DESPITE LOW METHYLATION LEVELS. ACUTE STRESS HAD LITTLE EFFECT ON THESE LOW METHYLATION LEVELS, EXCEPT AT FOUR HIPPOCAMPAL CPGS. CHRONIC STRESS ALTERED THE CORTICOSTERONE RESPONSE TO AN ACUTE STRESSOR. IN THE ADRENAL AND PITUITARY GLANDS, BUT NOT IN THE BRAIN, THIS WAS ACCOMPANIED BY AN INCREASE IN METHYLATION LEVELS IN ORCHESTRATED CLUSTERS RATHER THAN INDIVIDUAL CPGS. PVN METHYLATION LEVELS, UNAFFECTED BY ACUTE OR CHRONIC STRESS, WERE SIGNIFICANTLY MORE VARIABLE WITHIN- THAN BETWEEN-GROUPS, SUGGESTING THAT THEY WERE INSTATED PROBABLY DURING THE PERINATAL PERIOD AND REPRESENT A PRE-ESTABLISHED TRAIT. THUS, IN ADDITION TO THE KNOWN PERINATAL PROGRAMMING, THE GR 1 7 PROMOTER IS EPIGENETICALLY REGULATED BY CHRONIC STRESS IN ADULTHOOD, AND RETAINS PROMOTER-WIDE TISSUE-SPECIFIC PLASTICITY. DIFFERENCES IN METHYLATION SUSCEPTIBILITY BETWEEN THE PVN IN THE PERINATAL PERIOD AND THE PERIPHERAL HPA AXIS TISSUES IN ADULTHOOD MAY REPRESENT AN IMPORTANT "TRAIT" VS. "STATE" REGULATION OF THE GR GENE. 2012 19 1750 30 EARLY LIFE STRESS AND PEDIATRIC POSTTRAUMATIC STRESS DISORDER. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS. TWO THIRDS OF YOUTH ARE EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17, AND APPROXIMATELY 5% OF ADOLESCENTS MEET LIFETIME CRITERIA FOR POSTTRAUMATIC STRESS DISORDER (PTSD). THE ROLE OF THE STRESS SYSTEM IS THE MAINTENANCE OF HOMEOSTASIS IN THE PRESENCE OF REAL/PERCEIVED AND ACUTE/CHRONIC STRESSORS. EARLY-LIFE STRESS (ELS) HAS AN IMPACT ON NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING. STUDIES ON PEDIATRIC PTSD REVEAL DIVERSE NEUROENDOCRINE RESPONSES TO ADVERSE EVENTS AND RELATED LONG-TERM NEUROENDOCRINE AND EPIGENETIC ALTERATIONS. NEUROENDOCRINE, NEUROIMAGING, AND GENETIC STUDIES IN CHILDREN WITH PTSD AND ELS EXPERIENCES ARE CRUCIAL IN UNDERSTANDING RISK AND RESILIENCE FACTORS, AND ALSO THE NATURAL HISTORY OF PTSD. 2020 20 5662 32 SEXUAL DIMORPHISM IN GLUCOCORTICOID STRESS RESPONSE. CHRONIC STRESS IS ENCOUNTERED IN OUR EVERYDAY LIFE AND IS THOUGHT TO CONTRIBUTE TO A NUMBER OF DISEASES. MANY OF THESE STRESS-RELATED DISORDERS DISPLAY A SEX BIAS. BECAUSE GLUCOCORTICOID HORMONES ARE THE MAIN BIOLOGICAL MEDIATOR OF CHRONIC STRESS, RESEARCHERS HAVE BEEN INTERESTED IN UNDERSTANDING THE SEXUAL DIMORPHISM IN GLUCOCORTICOID STRESS RESPONSE TO BETTER EXPLAIN THE SEX BIAS IN STRESS-RELATED DISEASES. ALTHOUGH NOT YET DEMONSTRATED FOR GLUCOCORTICOID REGULATION, SEX CHROMOSOMES DO INFLUENCE SEX-SPECIFIC BIOLOGY AS SOON AS CONCEPTION. THEN A TRANSIENT RISE IN TESTOSTERONE START TO SHAPE THE MALE BRAIN DURING THE PRENATAL PERIOD DIFFERENTLY TO THE FEMALE BRAIN. THESE ORGANIZATIONAL EFFECTS ARE COMPLETED JUST BEFORE PUBERTY. THE CEREBRAL REGIONS IMPLICATED IN GLUCOCORTICOID REGULATION AT REST AND AFTER STRESS ARE THEREBY IMPACTED IN A SEX-SPECIFIC MANNER. AFTER PUBERTY, THE HIGH LEVELS OF ALL GONADAL HORMONES WILL INTERACT WITH GLUCOCORTICOID HORMONES IN SPECIFIC CROSSTALK THROUGH THEIR RESPECTIVE NUCLEAR RECEPTORS. IN ADDITION, STRESS OCCURRING EARLY IN LIFE, IN PARTICULAR DURING THE PRENATAL PERIOD AND IN ADOLESCENCE WILL PRIME IN THE LONG-TERM GLUCOCORTICOID STRESS RESPONSE THROUGH EPIGENETIC MECHANISMS, AGAIN IN A SEX-SPECIFIC MANNER. ALTOGETHER, VARIOUS MOLECULAR MECHANISMS EXPLAIN SEX-SPECIFIC GLUCOCORTICOID STRESS RESPONSES THAT DO NOT EXCLUDE IMPORTANT GENDER EFFECTS IN HUMANS. 2021