1  5191 137 PRENATAL DEXAMETHASONE EXPOSURE PROGRAMS THE DECREASED TESTOSTERONE SYNTHESIS IN OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS. PRENATAL DEXAMETHASONE EXPOSURE (PDE) CAN DECREASE MATERNAL ENDOGENOUS GLUCOCORTICOID LEVEL AND INDUCE TESTICULAR DYSPLASIA IN MALE OFFSPRING RATS. IN THIS STUDY WE INVESTIGATED LOW LEVEL ENDOGENOUS GLUCOCORTICOID-MEDIATED TESTICULAR DYSPLASIA IN PDE OFFSPRING AND ELUCIDATED THE INTRAUTERINE EPIGENETIC PROGRAMMING MECHANISMS. PREGNANT RATS WERE INJECTED WITH DEXAMETHASONE (0.2 MG.KG(-1).D(-1), SC) ON GESTATIONAL DAY (GD) 9-20. THE OFFSPRING RAT BLOOD AND TESTIS WERE COLLECTED AFTER EUTHANASIA ON GD20, POSTNATAL WEEK (PW) 12 OR PW28. WE SHOWED THAT PDE INDUCED ABNORMAL MORPHOLOGY OF TESTIS AND SIGNIFICANTLY DECREASED THE EXPRESSION OF TESTOSTERONE SYNTHESIS-RELATED GENES AS WELL AS TESTOSTERONE PRODUCTION BEFORE AND AFTER BIRTH. MEANWHILE, SERUM CORTICOSTERONE, THE EXPRESSION AND HISTONE 3 LYSINE 14 ACETYLATION (H3K14AC) OF TESTICULAR INSULIN-LIKE GROWTH FACTOR 1 (IGF1) WERE SIGNIFICANTLY DECREASED. AFTER THE PREGNANT RATS WERE SUBJECTED TO CHRONIC STRESS FOR 2 WEEKS (PW10-12), SERUM CORTICOSTERONE LEVEL WAS INCREASED IN THE ADULT PDE OFFSPRING, AND THE ABOVE-MENTIONED OTHER INDICATORS WERE ALSO IMPROVED. CULTURED LEYDIG CELLS (TM3) WERE TREATED WITH CORTICOSTERONE (62.5-500 NM) IN VITRO. WE SHOWED THAT CORTICOSTERONE CONCENTRATION-DEPENDENTLY INHIBITED GLUCOCORTICOID RECEPTOR ALPHA (GRALPHA) AND MIR-124-3P EXPRESSION, INCREASED HISTONE DEACETYLASE 5 (HDAC5) EXPRESSION, AND DECREASED IGF1 H3K14AC LEVEL AND THE EXPRESSION OF IGF1/STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR), SUGGESTING THAT CORTICOSTERONE AT LOWER THAN PHYSIOLOGICAL LEVEL (<500 NM) INHIBITED TESTOSTERONE SYNTHESIS BY REDUCING H3K14AC AND THE EXPRESSION LEVEL OF IGF1 THROUGH GRALPHA/MIR-124-3P/HDAC5 PATHWAY. IN CONCLUSION, PDE CAN CAUSE PERSISTENT INHIBITION OF TESTOSTERONE SYNTHESIS BEFORE AND AFTER BIRTH IN THE OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  5253  58 PROGRAMMING CHANGES OF HIPPOCAMPAL MIR-134-5P/SOX2 SIGNAL MEDIATE THE SUSCEPTIBILITY TO DEPRESSION IN PRENATAL DEXAMETHASONE-EXPOSED FEMALE OFFSPRING. DEPRESSION IS A NEUROPSYCHIATRIC DISORDER AND HAS INTRAUTERINE DEVELOPMENTAL ORIGINS. THIS STUDY AIMED TO CONFIRM THE DEPRESSION SUSCEPTIBILITY IN OFFSPRING RATS INDUCED BY PRENATAL DEXAMETHASONE EXPOSURE (PDE) AND TO FURTHER EXPLORE THE INTRAUTERINE PROGRAMMING MECHANISM. WISTAR RATS WERE INJECTED WITH DEXAMETHASONE (0.2 MG/KG.D) SUBCUTANEOUSLY DURING THE GESTATIONAL DAYS 9-20 AND PART OF THE OFFSPRING WAS GIVEN CHRONIC STRESS AT POSTNATAL WEEKS 10-12. BEHAVIORAL RESULTS SHOWED THAT THE ADULT PDE FEMALE OFFSPRING WAS SUSCEPTIBLE TO DEPRESSION, ACCOMPANIED BY INCREASED HIPPOCAMPAL MIR-134-5P EXPRESSION AND DECREASED SEX-DETERMINING REGION Y-BOX 2 (SOX2) EXPRESSION, AS WELL AS DISORDERS OF NEURAL PROGENITOR CELLS PROLIFERATION AND HIPPOCAMPAL NEUROGENESIS. THE PDE FEMALE FETAL RATS PRESENTED CONSISTENT CHANGES WITH THE ADULT OFFSPRING, ACCOMPANIED BY THE UPREGULATION OF GLUCOCORTICOID RECEPTOR (GR) EXPRESSION AND DECREASED SIRTUIN 1 (SIRT1) EXPRESSION. WE FURTHER FOUND THAT THE H3K9AC LEVEL OF THE MIR-134-5P PROMOTER WAS SIGNIFICANTLY INCREASED IN THE PDE FETAL HIPPOCAMPUS, AS WELL AS IN ADULT OFFSPRING BEFORE AND AFTER CHRONIC STRESS. IN VITRO, THE CHANGES OF GR/SIRT1/MIR-134-5P/SOX2 SIGNAL BY DEXAMETHASONE WERE CONSISTENT WITH IN VIVO EXPERIMENTS, WHICH COULD BE REVERSED BY GR RECEPTOR ANTAGONIST, SIRT1 AGONIST, AND MIR-134-5P INHIBITOR. THIS STUDY CONFIRMED THAT PDE LED TO AN INCREASED EXPRESSION LEVEL AS WELL AS H3K9AC LEVEL OF MIR-134-5P BY ACTIVATING THE GR/SIRT1 PATHWAY IN THE FETAL HIPPOCAMPUS AND THEN INHIBITED THE SOX2 EXPRESSION. THE PROGRAMMING EFFECT MEDIATED BY THE ABNORMAL EPIGENETIC MODIFICATION COULD LAST FROM INTRAUTERINE TO ADULTHOOD, WHICH CONSTITUTES THE INTRAUTERINE PROGRAMMING MECHANISM LEADING TO HIPPOCAMPAL NEUROGENESIS DISORDERS AND DEPRESSION SUSCEPTIBILITY IN FEMALE OFFSPRING. INTRAUTERINE PROGRAMMING MECHANISM FOR THE INCREASED DEPRESSIVE SUSCEPTIBILITY IN ADULT FEMALE OFFSPRING BY PRENATAL DEXAMETHASONE EXPOSURE (PDE). GR, GLUCOCORTICOID RECEPTOR; SIRT1, SIRTUIN 1; SOX2, SEX-DETERMINING REGION Y-BOX 2; NPCS, NEUROPROGENITOR CELLS; H3K9AC, HISTONE 3 LYSINE 9 ACETYLATION; GRE, GLUCOCORTICOID RESPONSE ELEMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3  4095  49 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4  2905  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  1332  39 DEPRESSIVE-LIKE PHENOTYPE INDUCED BY PRENATAL DEXAMETHASONE IN MICE IS REVERSED BY DESIPRAMINE. EXPOSURE TO PRENATAL INSULTS HAS BEEN ASSOCIATED WITH AN INCREASED RISK FOR NEUROPSYCHIATRIC DISORDERS, INCLUDING DEPRESSION, BUT THE MECHANISMS ARE STILL POORLY UNDERSTOOD. PERSISTENT ALTERATIONS OF THE HPA AXIS FEEDBACK MECHANISM AS WELL AS ADULT IMPAIRED NEUROGENESIS ARE BELIEVED TO PLAY A RELEVANT ROLE IN THE ETIOLOGY OF DEPRESSION. IN ADDITION, GROWING EVIDENCE POINTS AT EPIGENETIC REPROGRAMMING AS A KEY FACTOR. WE HAVE PREVIOUSLY SHOWN THAT PRENATAL EXPOSURE TO THE SYNTHETIC GLUCOCORTICOID DEXAMETHASONE (DEX) IMPAIRS NEUROGENESIS AND LEADS TO LATE ONSET OF DEPRESSION-LIKE BEHAVIOR THAT DOES NOT RESPOND TO THE SSRI ANTIDEPRESSANT FLUOXETINE (FLX). THE AIMS OF THIS STUDY WERE TO ASSESS THE EFFECT OF DEX PRENATAL EXPOSURE ON THE MORPHOLOGY OF HIPPOCAMPAL GRANULE NEURONS AND ON THE EXPRESSION OF GENES RELATED TO PLASTICITY; AND TO TEST WHETHER THE SNRI ANTIDEPRESSANT DESIPRAMINE (DMI), UNLIKE FLX, COULD COUNTERACT THE EFFECT OF PRENATAL-DEX. C57BL/6 MICE WERE EXPOSED TO DEX (0.05 MG/KG/DAY) IN UTERO AND RECEIVED INTRA-HIPPOCAMPAL INJECTION OF GFP EXPRESSING RETROVIRAL VECTOR FOR LABELING OF NEWBORN GRANULE CELLS AT ELEVEN MONTHS. BY TWELVE MONTHS, DEX MICE SHOWED DEPRESSION-LIKE BEHAVIOR ASSOCIATED WITH DECREASED NEUROGENESIS AND MORPHOLOGICAL ALTERATIONS OF THE NEWBORN GRANULE CELLS IN THE DENTATE GYRUS (DG). FURTHERMORE DEX MICE DISPLAYED ALTERED EXPRESSION OF GENES CONTROLLING NEUROGENESIS AND NEURONAL MORPHOLOGY, SUCH AS CDKN1C, P16, TRKB, DISC1 AND REELIN. CHRONIC TREATMENT WITH DMI LED TO A SIGNIFICANT DECREASE IN IMMOBILITY TIME IN THE FORCED SWIM TEST. IN ADDITION, DMI RESTORED NEUROGENESIS, NEURONAL MORPHOLOGY IN THE DG, AS WELL AS THE EXPRESSION OF ALL RELATED GENES. OUR RESULTS SUGGEST THAT (1) PRENATAL DEX INDUCES EARLY AND PERSISTENT REPROGRAMMING EFFECTS RESULTING IN ALTERED NEUROGENESIS AND NEURONAL MORPHOLOGY; AND (2) DMI TREATMENT REVERSES DEX-INDUCED DEPRESSION BY RESTORING THE EXPRESSION OF GENES RELEVANT TO NEURONAL PLASTICITY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6  3812  56 INTRAUTERINE ENDOGENOUS HIGH GLUCOCORTICOIDS PROGRAM OVARIAN DYSFUNCTION IN FEMALE OFFSPRING SECONDARY TO PRENATAL CAFFEINE EXPOSURE. OVARIAN DYSFUNCTION HAS AN INTRAUTERINE ORIGIN, AND PRENATAL CAFFEINE EXPOSURE (PCE) COULD LEAD TO ABNORMAL FOLLICLE COUNTS IN OFFSPRING AFTER BIRTH. HOWEVER, THE EFFECT OF PCE ON OFFSPRING OVARIAN FUNCTION AND ITS MECHANISM OF INTRAUTERINE PROGRAMMING HAVE NOT BEEN REPORTED THUS FAR. IN THIS STUDY, PREGNANT WISTAR RATS WERE INTRAGASTRICALLY ADMINISTERED CAFFEINE (30 AND 120 MG/KG.D) AT GESTATIONAL DAYS 9-20 (GD9-20). CERTAIN TESTS WERE PERFORMED ON THE BLOOD, OVARIES AND HYPOTHALAMUS OF FEMALE OFFSPRING AT DIFFERENT TIME POINTS. PCE FEMALE OFFSPRING HAD OVARIAN DYSFUNCTION IN ADULTHOOD COMPARED WITH THE CONTROL. FURTHER RESULTS SHOWED THAT IN UTERO OVARIAN MORPHOLOGICAL DEVELOPMENT AND ESTRADIOL SYNTHESIS WERE INHIBITED BUT RAPIDLY INCREASED DURING PUBERTY IN THE PCE GROUP. THE HISTONE 3 LYSINE 27 ACETYLATION (H3K27AC) LEVEL OF THE INSULIN-LIKE GROWTH FACTOR 1 (IGF1) PROMOTER REGION AND ITS EXPRESSION WERE DECREASED IN THE OVARY, WHICH WAS DUE TO EXPOSURE TO HIGH LEVELS OF FETAL BLOOD CORTICOSTERONE, AND THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION SHIFTED TO INCREASE AFTER BIRTH WITH A DECREASE IN SERUM CORTICOSTERONE LEVELS. CHRONIC STRESS LED TO INCREASED SERUM CORTICOSTERONE LEVELS IN ADULT OFFSPRING, WHEREAS OVARIAN MORPHOLOGICAL DEVELOPMENT, THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION, AND ESTRADIOL SYNTHESIS WERE SIGNIFICANTLY INHIBITED. MOREOVER, THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-OVARIAN (HPO) AXIS WAS INCREASED IN THE EARLY POSTNATAL PERIOD OF PCE OFFSPRING, AND CHRONIC STRESS REVERSED THESE CHANGES. IN THE KGN CELL LINE, IT WAS FOUND THAT CORTISOL COULD PROMOTE THE TRANSLOCATION OF THE GLUCOCORTICOID RECEPTOR (GR) INTO THE NUCLEUS AND UPREGULATE HISTONE DEACETYLASE 10 (HDAC10) TO INHIBIT THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION AND ESTRADIOL SYNTHESIS. IN SUMMARY, PCE IS ASSOCIATED WITH OVARIAN DYSFUNCTION IN FEMALE ADULT OFFSPRING, AND THE POTENTIAL MECHANISM IS RELATED TO INTRAUTERINE HIGH GLUCOCORTICOID EXPOSURE BY ACTIVATING THE GR AND RECRUITING HDAC10 TO AFFECT OVARIAN GLUCOCORTICOID-IGF1 AXIS PROGRAMMING AND TO INHIBIT ESTRADIOL SYNTHESIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  3816  46 INTRAUTERINE PROGRAMMING OF CARTILAGINOUS 11BETA-HSD2 INDUCED BY CORTICOSTERONE AND CAFFEINE MEDIATED SUSCEPTIBILITY TO ADULT OSTEOARTHRITIS. OUR PREVIOUS STUDY REPORTED THAT PRENATAL CAFFEINE EXPOSURE (PCE) COULD INDUCE CHONDRODYSPLASIA AND INCREASE THE SUSCEPTIBILITY TO OSTEOARTHRITIS IN OFFSPRING RATS. HOWEVER, THE POTENTIAL MECHANISMS AND INITIATING FACTORS REMAIN UNKNOWN. THIS STUDY AIMS TO INVESTIGATE WHETHER 11BETA-HSD2, A GLUCOCORTICOID-METABOLIZING ENZYME, IS INVOLVED IN THE SUSCEPTIBILITY OF OSTEOARTHRITIS INDUCED BY PCE AND TO FURTHER EXPLORE ITS POTENTIAL MECHANISMS AND INITIATING FACTORS. FIRSTLY, WE FOUND THAT PCE REDUCED CARTILAGE MATRIX SYNTHESIS (AGGRECAN/COL2A1 EXPRESSION) IN MALE ADULT OFFSPRING RATS AND EXHIBITED AN OSTEOARTHRITIS PHENOTYPE FOLLOWING CHRONIC STRESS, WHICH WAS ASSOCIATED WITH PERSISTENTLY REDUCED H3K9AC AND H3K27AC LEVELS AT THE PROMOTER OF 11BETA-HSD2 AS WELL AS ITS EXPRESSION IN THE CARTILAGE FROM FETUS TO ADULTHOOD. THE EXPRESSION OF 11BETA-HSD2, AGGRECAN AND COL2A1 WERE ALL DECREASED BY CORTICOSTERONE IN THE FETAL CHONDROCYTES, WHILE OVEREXPRESSION OF 11BETA-HSD2 COULD PARTIALLY ALLEVIATE THE DECREASE OF MATRIX SYNTHESIS INDUCED BY CORTICOSTERONE IN VITRO. FURTHERMORE, THE GLUCOCORTICOID RECEPTOR (GR) ACTIVATED BY GLUCOCORTICOIDS DIRECTLY BONDED TO THE PROMOTER REGION OF 11BETA-HSD2 TO INHIBIT ITS EXPRESSION. MEANWHILE, THE ACTIVATED GR REDUCED THE H3K9AC AND H3K27AC LEVELS OF 11BETA-HSD2 BY RECRUITING HDAC4 AND PROMOTING GR-HDAC4 PROTEIN INTERACTION TO INHIBIT THE 11BETA-HSD2 EXPRESSION. MOREOVER, CAFFEINE COULD REDUCE THE EXPRESSION OF 11BETA-HSD2 BY INHIBITING THE CAMP/PKA SIGNALING PATHWAY BUT WITHOUT REDUCING THE H3K9AC AND H3K27AC LEVELS OF 11BETA-HSD2, THEREBY SYNERGISTICALLY ENHANCING THE CORTICOSTERONE EFFECT. IN CONCLUSION, THE PERSISTENTLY REDUCED H3K9AC AND H3K27AC LEVELS OF 11BETA-HSD2 FROM FETUS TO ADULTHOOD MEDIATED THE INHIBITION OF CARTILAGE MATRIX SYNTHESIS AND THE INCREASED SUSCEPTIBILITY TO OSTEOARTHRITIS. THIS EPIGENETIC PROGRAMMING CHANGE IN UTERO WAS INDUCED BY GLUCOCORTICOIDS WITH SYNERGISTIC EFFECT OF CAFFEINE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8  1839  52 EFFECTS OF PRENATAL NICOTINE EXPOSURE ON HEPATIC GLUCOSE AND LIPID METABOLISM IN OFFSPRING RATS AND ITS HEREDITABILITY. PRENATAL NICOTINE EXPOSURE (PNE) COULD INDUCE AN INCREASED SUSCEPTIBILITY TO MULTIPLE CHRONIC DISEASES IN ADULT OFFSPRING, THAT MAINLY CAUSED BY INTRAUTERINE MATERNAL GLUCOCORTICOID (GC) OVER-EXPOSURE. WE INVESTIGATED THE CHANGES AND INHERITABILITY OF HEPATIC GLUCOSE AND LIPID METABOLISM CAUSED BY PNE, TO DECIPHER THE POSSIBLE INTRAUTERINE PROGRAMMING MECHANISM. PREGNANT WISTAR RATS WERE ADMINISTERED SUBCUTANEOUSLY WITH 2 MG/KG.D NICOTINE FROM GESTATIONAL DAY (GD) 9 APPROXIMATELY 20, AND SECOND-GENERATION (F2) WERE SET ACCORDING TO THE MATING BETWEEN CONTROL FEMALES AND PNE MALES. THE RESULTS SHOWED THAT SERUM PHENOTYPES AND HEPATIC ENZYMES OF GLUCOSE AND LIPID METABOLISM WERE LOWER IN F1 FETAL RATS OF PNE BUT HIGHER IN THE F1 ADULT RATS. MEANWHILE, THE ACTIVATED STATES OF HEPATIC GLUCOCORTICOID-ACTIVATION SYSTEM, INCLUDING TYPE 1 AND TYPE 2 11BETA-HYDROXYSTEROID DEHYDROGENASES (HSD11B1/2), NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1 (NR3C1) AND CCAAT ENHANCER BINDING PROTEIN ALPHA (CEBPA), WERE POSITIVELY CORRELATED WITH SERUM CORTICOSTERONE LEVELS BUT NEGATIVELY CORRELATED WITH THE HISTONE ACETYLATION (H3K27AC) AND EXPRESSION LEVELS OF INSULIN-LIKE GROWTH FACTOR 1 (IGF1) BEFORE AND AFTER BIRTH. FURTHERMORE, SERUM PHENOTYPES AND HEPATIC ENZYMES OF GLUCOSE AND LIPID METABOLISM WERE LOWER IN BOTH F2 FETAL AND ADULT RATS OF PNE, WHICH WERE CONSISTENT WITH THE HEPATIC CHANGES OF GC-IGF1 AXIS AND THE GLUCOCORTICOID-ACTIVATION SYSTEM. IN CONCLUSION, PNE COULD LEAD TO INHERITABLE CHANGES OF HEPATIC GLUCOSE AND LIPID METABOLISM, WHICH ARE RELATED TO THE INTRAUTERINE PROGRAMMING OF GC-IGF1 AXIS INDUCED BY THE GLUCOCORTICOID-ACTIVATION SYSTEM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  5651  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10  5279  30 PROMOTER-SPECIFIC RELEVANCE OF HISTONE MODIFICATIONS INDUCED BY DEXAMETHASONE DURING THE REGULATION OF PRO-INFLAMMATORY MEDIATORS. GLUCOCORTICOSTEROIDS (GCS) ARE WIDELY USED TO TREAT DIFFERENT KINDS OF CHRONIC INFLAMMATORY AND IMMUNE DISEASES THROUGH TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES. MODULATION OF GENE EXPRESSION BY GCS IS KNOWN TO OCCUR THROUGH DIVERSE MECHANISMS OF VARYING RELEVANCE TO SPECIFIC CLASSES OF GENES. EPIGENETIC MODIFICATIONS ARE INDEED A PIVOTAL REGULATORY FEATURE OF GLUCOCORTICOID RECEPTOR AND OTHER TRANSCRIPTION FACTORS. IN THIS STUDY, HISTONE POST-TRANSLATIONAL MODIFICATIONS WERE INVESTIGATED FOR THEIR INVOLVEMENT IN THE REGULATION OF SELECTED PRO-INFLAMMATORY GENES - EXPRESSED IN HUMAN MONOCYTE-DERIVED MACROPHAGES - IN RESPONSE TO TREATMENT WITH SYNTHETIC GC DEXAMETHASONE (DEX). WE SHOW THAT HISTONE TAIL ACETYLATION STATUS IS MODIFIED FOLLOWING DEX ADMINISTRATION, THROUGH DISTINCT AND ALTERNATIVE MECHANISMS AT THE PROMOTERS OF INTERLEUKIN-8 AND INTERLEUKIN-23. IN ADDITION TO HISTONE H3 ACETYLATION, OUR RESULTS DEMONSTRATE THAT H3 LYSINE 4 TRIMETHYLATION IS AFFECTED FOLLOWING DRUG TREATMENT.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11  3815  58 INTRAUTERINE PROGRAMMING MECHANISM FOR HYPERCHOLESTEROLEMIA IN PRENATAL CAFFEINE-EXPOSED FEMALE ADULT RAT OFFSPRING. CLINICAL AND ANIMAL STUDIES HAVE INDICATED THAT HYPERCHOLESTEROLEMIA AND ITS ASSOCIATED DISEASES HAVE INTRAUTERINE DEVELOPMENTAL ORIGINS. OUR PREVIOUS STUDIES SHOWED THAT PRENATAL CAFFEINE EXPOSURE (PCE) LED TO FETAL OVEREXPOSURE TO MATERNAL GLUCOCORTICOIDS (GCS) AND INCREASED SERUM TOTAL CHOLESTEROL LEVELS IN ADULT RAT OFFSPRING. THIS STUDY FURTHER CONFIRMS THE INTRAUTERINE PROGRAMMING OF PCE-INDUCED HYPERCHOLESTEROLEMIA IN FEMALE ADULT RAT OFFSPRING. PREGNANT WISTAR RATS WERE INTRAGASTRICALLY ADMINISTERED CAFFEINE (30, 60, AND 120 MG/KG/D) FROM GESTATIONAL DAY (GD)9 TO 20. FEMALE RAT OFFSPRING WERE EUTHANIZED AT GD20 AND POSTNATAL WK 12; SEVERAL ADULT RAT OFFSPRING WERE ADDITIONALLY SUBJECTED TO ICE-WATER SWIMMING STIMULATION TO INDUCE CHRONIC STRESS PRIOR TO DEATH. THE EFFECTS OF GCS ON CHOLESTEROL METABOLISM AND EPIGENETIC REGULATION WERE VERIFIED USING THE L02 CELL LINE. THE RESULTS SHOWED THAT PCE INDUCED HYPERCHOLESTEROLEMIA IN ADULT OFFSPRING, WHICH MANIFESTED AS SIGNIFICANTLY HIGHER LEVELS OF SERUM TOTAL CHOLESTEROL AND LDL CHOLESTEROL (LDL-C) AS WELL AS HIGHER RATIOS OF LDL-C/HDL CHOLESTEROL. WE FURTHER FOUND THAT THE CHOLESTEROL LEVELS WERE INCREASED IN FETAL LIVERS BUT WERE DECREASED IN FETAL BLOOD, ACCOMPANIED BY INCREASED MATERNAL BLOOD CHOLESTEROL LEVELS AND REDUCED PLACENTAL CHOLESTEROL TRANSPORT. FURTHERMORE, ANALYSIS OF PCE OFFSPRING IN THE UTERUS AND IN A POSTNATAL BASAL/CHRONIC STRESS STATE AND THE RESULTS OF IN VITRO EXPERIMENTS SHOWED THAT HEPATIC CHOLESTEROL METABOLISM UNDERWENT GC-DEPENDENT CHANGES AND WAS ASSOCIATED WITH CHOLESTEROL SYNTHASE VIA ABNORMALITIES IN 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE (HMGCR) HISTONE ACETYLATION. WE CONCLUDED THAT, TO COMPENSATE FOR INTRAUTERINE PLACENTALLY DERIVED DECREASES IN FETAL BLOOD CHOLESTEROL LEVELS, HIGH INTRAUTERINE GC LEVELS ACTIVATED FETAL HEPATIC CCAAT ENHANCER BINDING PROTEIN ALPHA SIGNALING AND DOWN-REGULATED SIRTUIN1 EXPRESSION, WHICH MEDIATED THE HIGH LEVELS OF HISTONE ACETYLATION ( VIA H3K9AC AND H3K14AC) AND EXPRESSION OF HMGCR. THIS GC-DEPENDENT CHOLESTEROL METABOLISM PROGRAMMING EFFECT WAS SUSTAINED THROUGH ADULTHOOD, LEADING TO THE OCCURRENCE OF HYPERCHOLESTEROLEMIA.-XU, D., LUO, H. W., HU, W., HU, S. W., YUAN, C., WANG, G. H., ZHANG, L., YU, H., MAGDALOU, J., CHEN, L. B., WANG, H. INTRAUTERINE PROGRAMMING MECHANISM FOR HYPERCHOLESTEROLEMIA IN PRENATAL CAFFEINE-EXPOSED FEMALE ADULT RAT OFFSPRING.	2018	
                                                                                                                                                                                                                                                                                                                                                       
12  1163  37 CONTRIBUTION OF AMYGDALA HISTONE ACETYLATION IN EARLY LIFE STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND EMOTIONAL COMORBIDITY. PATIENTS WITH IRRITABLE BOWEL SYNDROME (IBS) EXPERIENCE NOT ONLY ENHANCED VISCERAL PAIN BUT ALSO EMOTIONAL COMORBIDITIES, SUCH AS ANXIETY AND DEPRESSION. EARLY LIFE STRESS (ELS) IS A HIGH-RISK FOR THE DEVELOPMENT OF IBS. LITERATURES HAVE REPORTED AN IMPORTANT EPIGENETIC MODULATION IN SUSTAINING EXTRINSIC PHENOTYPES. THE AMYGDALA IS CLOSELY RELATED TO THE REGULATION OF VISCERAL FUNCTIONS AND EMOTIONAL EXPERIENCES. IN THIS STUDY, WE HYPOTHESIZED THAT ELS-INDUCED REPROGRAMMING INAPPROPRIATE ADAPTATION OF HISTONE ACETYLATION MODIFICATION IN THE AMYGDALA MAY RESULT IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN ELS RATS. TO TEST THIS HYPOTHESIS, THE MODEL OF ELS RATS WAS ESTABLISHED BY NEONATAL COLORECTAL DILATATION (CRD). VISCERAL HYPERSENSITIVITY WAS ASSESSED BASED ON THE ELECTROMYOGRAPHY RESPONSE OF THE ABDOMINAL EXTERNAL OBLIQUE MUSCLE TO CRD. EMOTIONAL COMORBIDITIES WERE EXAMINED USING THE ELEVATED PLUS MAZE TEST, OPEN FIELD TEST, AND SUCROSE PREFERENCE TEST. TRICHOSTATIN A (TSA) AND C646 WERE MICROINJECTED INTO THE CENTRAL AMYGDALA (CEA) INDIVIDUALLY TO INVESTIGATE THE EFFECTS OF DIFFERENT LEVELS OF HISTONE ACETYLATION MODIFICATION ON VISCERAL HYPERSENSITIVITY AND EMOTION. WE FOUND NEONATAL CRD RESULTED IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS AFTER ADULTHOOD. INHIBITING HISTONE DEACETYLASES (HDACS) IN THE CEA BY TSA ENHANCED VISCERAL SENSITIVITY BUT DID NOT AFFECT ANXIETY-LIKE BEHAVIORS, WHEREAS INHIBITING HAT BY C646 ATTENUATED VISCERAL HYPERSENSITIVITY IN ELS RATS. INTERESTINGLY, CEA TREATMENT WITH TSA INDUCED VISCERAL SENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN THE CONTROL RATS. WESTERN BLOT SHOWED THAT THE EXPRESSIONS OF ACETYLATED 9 RESIDUE OF HISTONE 3 (H3K9) AND PROTEIN KINASE C ZETA TYPE (PKMZETA) WERE HIGHER IN THE ELS RATS COMPARED TO THOSE OF THE CONTROLS. THE ADMINISTRATION OF THE PKMZETA INHIBITOR ZIP INTO THE CEA ATTENUATED VISCERAL HYPERSENSITIVITY OF ELS RATS. FURTHERMORE, THE EXPRESSION OF AMYGDALA PKMZETA WAS ENHANCED BY TSA TREATMENT IN CONTROL RATS. FINALLY, WESTERN BLOT AND IMMUNOFLUORESCENCE RESULTS INDICATED THE DECREASE OF HDAC1 AND HDAC2 EXPRESSIONS, BUT NOT HDAC3 EXPRESSION, CONTRIBUTED TO THE ENHANCEMENT OF HISTONE ACETYLATION IN ELS RATS. OUR RESULTS SUPPORT OUR HYPOTHESIS THAT AMYGDALA-ENHANCED HISTONE ACETYLATION INDUCED BY STRESS IN EARLY LIFE RESULTS IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN ELS RATS, AND REVERSING THE ABNORMAL EPIGENETIC MECHANISMS MAY BE CRUCIAL TO RELIEVE CHRONIC SYMPTOMS IN ELS RATS.	2022	
                                                                                                                                                                                                                                      
13  2187  48 EPIGENETIC MECHANISMS UNDERLYING STRESS-INDUCED VISCERAL PAIN: RESILIENCE VERSUS VULNERABILITY IN A TWO-HIT MODEL OF EARLY LIFE STRESS AND CHRONIC ADULT STRESS. BACKGROUND: WOMEN WITH A HISTORY OF EARLY LIFE STRESS (ELS) HAVE A HIGHER RISK OF DEVELOPING IRRITABLE BOWEL SYNDROME (IBS). IN ADDITION, CHRONIC STRESS IN ADULTHOOD CAN EXACERBATE IBS SYMPTOMS SUCH AS ABDOMINAL PAIN DUE TO VISCERAL HYPERSENSITIVITY. WE PREVIOUSLY SHOWED THAT SEX AND THE PREDICTABILITY OF ELS DETERMINE WHETHER RATS DEVELOP VISCERAL HYPERSENSITIVITY IN ADULTHOOD. IN FEMALE RATS, UNPREDICTABLE ELS CONFERS VULNERABILITY AND RESULTS IN VISCERAL HYPERSENSITIVITY, WHEREAS PREDICTABLE ELS INDUCES RESILIENCE AND DOES NOT INDUCE VISCERAL HYPERSENSITIVITY IN ADULTHOOD. HOWEVER, THIS RESILIENCE IS LOST AFTER EXPOSURE TO CHRONIC STRESS IN ADULTHOOD LEADING TO AN EXACERBATION OF VISCERAL HYPERSENSITIVITY. EVIDENCE SUGGESTS THAT CHANGES IN HISTONE ACETYLATION AT THE PROMOTER REGIONS OF GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING FACTOR (CRF) IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA) UNDERLIE STRESS-INDUCED VISCERAL HYPERSENSITIVITY. HERE, WE AIMED TO INVESTIGATE THE ROLE OF HISTONE ACETYLATION IN THE CEA ON VISCERAL HYPERSENSITIVITY IN A TWO-HIT MODEL OF ELS FOLLOWED BY CHRONIC STRESS IN ADULTHOOD. METHODS: MALE AND FEMALE NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS. RATS WERE EXPOSED TO CHRONIC WATER AVOIDANCE STRESS (WAS, 1 H/DAY FOR 7 DAYS) OR SHAM STRESS AND RECEIVED INFUSIONS OF VEHICLE, THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA) OR THE HISTONE ACETYLTRANSFERASE INHIBITOR GARCINOL (GAR) AFTER EACH WAS SESSION. 24 H AFTER THE FINAL INFUSION, VISCERAL SENSITIVITY WAS ASSESSED AND THE CEA WAS REMOVED FOR MOLECULAR EXPERIMENTS. RESULTS: IN THE TWO-HIT MODEL (ELS + WAS), FEMALE RATS PREVIOUSLY EXPOSED TO PREDICTABLE ELS, SHOWED A SIGNIFICANT REDUCTION IN HISTONE 3 LYSINE 9 (H3K9) ACETYLATION AT THE GR PROMOTER AND A SIGNIFICANT INCREASE IN H3K9 ACETYLATION AT THE CRF PROMOTER. THESE EPIGENETIC CHANGES WERE ASSOCIATED WITH CHANGES IN GR AND CRF MRNA EXPRESSION IN THE CEA AND AN EXACERBATION OF STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN FEMALE ANIMALS. TSA INFUSIONS IN THE CEA ATTENUATED THE EXACERBATED STRESS-INDUCED VISCERAL HYPERSENSITIVITY, WHEREAS GAR INFUSIONS ONLY PARTIALLY AMELIORATED ELS+WAS INDUCED VISCERAL HYPERSENSITIVITY. CONCLUSION: THE TWO-HIT MODEL OF ELS FOLLOWED BY WAS IN ADULTHOOD REVEALED THAT EPIGENETIC DYSREGULATION OCCURS AFTER EXPOSURE TO STRESS IN TWO IMPORTANT PERIODS OF LIFE AND CONTRIBUTES TO THE DEVELOPMENT OF VISCERAL HYPERSENSITIVITY. THESE ABERRANT UNDERLYING EPIGENETIC CHANGES MAY EXPLAIN THE EXACERBATION OF STRESS-INDUCED ABDOMINAL PAIN IN IBS PATIENTS.	2023	

14  4397  34 MODULATION OF DNA METHYLATION AND GENE EXPRESSION IN RODENT CORTICAL NEUROPLASTICITY PATHWAYS EXERTS RAPID ANTIDEPRESSANT-LIKE EFFECTS. BACKGROUND: STRESS INCREASES DNA METHYLATION, PRIMARILY A SUPPRESSIVE EPIGENETIC MECHANISM CATALYZED BY DNA METHYLTRANSFERASES (DNMT), AND DECREASES THE EXPRESSION OF GENES INVOLVED IN NEURONAL PLASTICITY AND MOOD REGULATION. DESPITE CHRONIC ANTIDEPRESSANT TREATMENT DECREASES STRESS-INDUCED DNA METHYLATION, IT IS NOT KNOWN WHETHER INHIBITION OF DNMT WOULD CONVEY RAPID ANTIDEPRESSANT-LIKE EFFECTS. AIM: THIS WORK TESTED SUCH A HYPOTHESIS AND EVALUATED WHETHER A BEHAVIORAL EFFECT INDUCED BY DNMT INHIBITORS (DNMTI) CORRESPONDS WITH CHANGES IN DNA METHYLATION AND TRANSCRIPT LEVELS IN GENES CONSISTENTLY ASSOCIATED WITH THE NEUROBIOLOGY OF DEPRESSION AND SYNAPTIC PLASTICITY (BDNF, TRKB, 5-HT(1A), NMDA, AND AMPA). METHODS: MALE WISTAR RATS RECEIVED INTRAPERITONEAL (I.P.) INJECTION OF TWO PHARMACOLOGICALLY DIFFERENT DNMTI (5-AZAD 0.2 AND 0.6 MG/KG OR RG108 0.6 MG/KG) OR VEHICLE (1 ML/KG), 1 H OR 7 DAYS BEFORE THE LEARNED HELPLESSNESS TEST (LH). DNA METHYLATION IN TARGET GENES AND THE CORRESPONDENT TRANSCRIPT LEVELS WERE MEASURED IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) USING MEDIP-QPCR. IN PARALLEL SEPARATE GROUPS, THE ANTIDEPRESSANT-LIKE EFFECT OF 5-AZAD AND RG108 WAS INVESTIGATED IN THE FORCED SWIMMING TEST (FST). THE INVOLVEMENT OF CORTICAL BDNF-TRKB-MTOR PATHWAYS WAS ASSESSED BY INTRA-VENTRAL MEDIAL PFC (VMPFC) INJECTIONS OF RAPAMYCIN (MTOR INHIBITOR), K252A (TRKB RECEPTOR ANTAGONIST), OR VEHICLE (0.2 MUL/SIDE). RESULTS: WE FOUND THAT BOTH 5-AZAD AND RG108 ACUTELY AND 7 DAYS BEFORE THE TEST DECREASED ESCAPE FAILURES IN THE LH. LH STRESS INCREASED DNA METHYLATION AND DECREASED TRANSCRIPT LEVELS OF BDNF IV AND TRKB IN THE PFC, EFFECTS THAT WERE NOT SIGNIFICANTLY ATTENUATED BY RG108 TREATMENT. THE SYSTEMIC ADMINISTRATION OF 5-AZAD (0.2 MG/KG) AND RG108 (0.2 MG/KG) INDUCED AN ANTIDEPRESSANT-LIKE EFFECT IN FST, WHICH WAS, HOWEVER, ATTENUATED BY TRKB AND MTOR INHIBITION INTO THE VMPFC. CONCLUSION: THESE FINDINGS SUGGEST THAT ACUTE INHIBITION OF STRESS-INDUCED DNA METHYLATION PROMOTES RAPID AND SUSTAINED ANTIDEPRESSANT EFFECTS ASSOCIATED WITH INCREASED BDNF-TRKB-MTOR SIGNALING IN THE PFC.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15  3412  27 HPA AXIS REGULATION AND EPIGENETIC PROGRAMMING OF IMMUNE-RELATED GENES IN CHRONICALLY STRESSED AND NON-STRESSED MID-LIFE WOMEN. HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSREGULATION HAS BEEN ASSOCIATED WITH ALTERED IMMUNE FUNCTION, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, RESPOND TO THE GLUCOCORTICOID END-PRODUCTS OF THE HPA AXIS (CORTISOL IN HUMANS) AND COULD BE INVOLVED IN THIS NEUROENDOCRINE-IMMUNE CROSSTALK. HERE WE EXAMINED THE EXTENT TO WHICH VARIATIONS IN HPA AXIS REGULATION ARE ASSOCIATED WITH PERIPHERAL BLOOD DNA (CPG) METHYLATION CHANGES IN 57 CHRONICALLY STRESSED CAREGIVERS AND 67 CONTROL WOMEN. DNA METHYLATION WAS DETERMINED WITH THE ILLUMINA 450K ARRAY FOR A PANEL OF GENES INVOLVED IN HPA AXIS AND IMMUNE FUNCTION. HPA AXIS FEEDBACK WAS ASSESSED WITH THE LOW-DOSE DEXAMETHASONE SUPPRESSION TEST (DST), MEASURING THE EXTENT TO WHICH CORTISOL SECRETION IS SUPPRESSED BY THE SYNTHETIC GLUCOCORTICOID DEXAMETHASONE. AFTER MULTIPLE TESTING CORRECTION IN THE ENTIRE COHORT, HIGHER POST-DST CORTISOL, REFLECTING BLUNTED HPA AXIS NEGATIVE FEEDBACK, BUT NOT BASELINE WAKING CORTISOL, WAS ASSOCIATED WITH LOWER DNA METHYLATION AT EIGHT TNF AND TWO FKBP5 CPG SITES. CAREGIVER GROUP STATUS WAS ASSOCIATED WITH LOWER METHYLATION AT TWO IL6 CPG SITES. SINCE ASSOCIATIONS WERE MOST ROBUST WITH TNF METHYLATION (32% OF THE 450K-COVERED SITES), WE FURTHER EXAMINED FUNCTIONALITY OF THIS EPIGENETIC SIGNATURE IN CULTURED PERIPHERAL BLOOD MONONUCLEAR CELLS IN 33 PARTICIPANTS; INTRIGUINGLY, LOWER TNF METHYLATION RESULTED IN HIGHER EX VIVO TNF MRNA FOLLOWING IMMUNE STIMULATION. TAKEN TOGETHER, OUR FINDINGS LINK CHRONIC STRESS AND HPA AXIS REGULATION WITH EPIGENETIC SIGNATURES AT IMMUNE-RELATED GENES, THEREBY PROVIDING NOVEL INSIGHTS INTO HOW ABERRANT HPA AXIS FUNCTION MAY CONTRIBUTE TO HEIGHTENED INFLAMMATION AND DISEASE RISK.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  5209  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17  3600  37 IMPORTANCE OF EPIGENETIC MECHANISMS IN VISCERAL PAIN INDUCED BY CHRONIC WATER AVOIDANCE STRESS. EPIGENETIC MOLECULAR MECHANISMS, WHICH INCLUDE DNA METHYLATION AND HISTONE DEACETYLATION, ARE IMPLICATED IN THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. PREVIOUSLY, WE DEMONSTRATED THAT REPEATED WATER AVOIDANCE STRESS (WAS), A VALIDATED MODEL OF CHRONIC PSYCHOLOGICAL STRESS, INDUCES HEIGHTENED VISCERAL PAIN BEHAVIORS IN RODENTS THAT RESEMBLE IRRITABLE BOWEL SYNDROME (IBS) SEQUELAE. HOWEVER, THE INVOLVEMENT OF EPIGENETIC MOLECULAR MECHANISMS IN THE PATHOPHYSIOLOGY OF STRESS-INDUCED VISCERAL PAIN HAS NOT BEEN EXPLORED. OUR HYPOTHESIS IS THAT EPIGENETIC MECHANISMS WITHIN THE CENTRAL NERVOUS SYSTEM (CNS) ARE IMPORTANT TO CHRONIC STRESS-INDUCED VISCERAL HYPERSENSITIVITY. ADULT MALE F-344 RATS WITH INTRACEREBROVENTRICULAR (I.C.V.) CANNULAE WERE EXPOSED TO 7 DAYS OF REPEATED WAS. CONTROLS RECEIVED A SHAM STRESS. FOLLOWING THE DAILY 1H STRESSOR, TRICHOSTATIN A (TSA; 100 NG/ML), A POTENT HISTONE DEACETYLASE INHIBITOR, OR VEHICLE (VEH; 0.1% DMSO/SALINE,) AS CONTROL WAS ADMINISTERED VIA THE I.C.V. CANNULA. VISCERAL SENSITIVITY WAS ASSESSED 24H AFTER THE FINAL WAS AND QUANTIFIED THE VISCEROMOTOR RESPONSE (VMR) BY RECORDING THE NUMBER OF ABDOMINAL CONTRACTIONS IN RESPONSE TO GRADED PRESSURES (20-60 MMHG) OF COLORECTAL DISTENSIONS (CRD). FROM A SEPARATE GROUP OF RATS THAT WERE EXPOSED TO REPEATED WAS OR SHAM STRESS, THE AMYGDALA WAS ISOLATED TO ASSESS THE METHYLATION STATUS OF GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPIN RELEASING-FACTOR (CRF) GENES VIA BISULFITE SEQUENCING AND VERIFIED BY PYROSEQUENCING. GR AND CRF GENE EXPRESSION WAS QUANTIFIED VIA QRT-PCR. STRESSED RATS EXHIBITED VISCERAL HYPERSENSITIVITY THAT WAS SIGNIFICANTLY ATTENUATED BY TSA. COMPARED TO SHAM CONTROLS, METHYLATION OF THE GR GENE WAS INCREASED FOLLOWING WAS WHILE EXPRESSION OF THE GR GENE WAS DECREASED. METHYLATION OF THE CRF PROMOTER WAS DECREASED WITH WAS WITH A CONCOMITANT INCREASE IN CRF EXPRESSION. THIS STUDY DEMONSTRATES THE INVOLVEMENT OF CENTRAL EPIGENETIC MECHANISMS IN REGULATING STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND PROVIDES A FOUNDATION FOR EXPLORING THE EPIGENETIC MECHANISMS THAT MAY CONTRIBUTE TO IBS-LIKE SYMPTOMATOLOGY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  4222  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19   886  31 CHRONIC CORTICOSTERONE EXPOSURE INCREASES EXPRESSION AND DECREASES DEOXYRIBONUCLEIC ACID METHYLATION OF FKBP5 IN MICE. THERE IS EVIDENCE FOR HYPERCORTISOLEMIA PLAYING A ROLE IN THE GENERATION OF PSYCHIATRIC SYMPTOMS AND FOR EPIGENETIC VARIATION WITHIN HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS GENES MEDIATING BEHAVIORAL CHANGES. WE TESTED THE HYPOTHESIS THAT EXPRESSION CHANGES WOULD BE INDUCED IN FKBP5 AND OTHER HPA AXIS GENES BY CHRONIC EXPOSURE TO CORTICOSTERONE AND THAT THESE CHANGES WOULD OCCUR THROUGH THE EPIGENETIC MECHANISM OF LOSS OR GAIN OF DNA METHYLATION (DNAM). WE ADMINISTERED CORTICOSTERONE (CORT) TO C57BL/6J MICE VIA THEIR DRINKING WATER FOR 4 WK AND TESTED FOR BEHAVIORAL AND PHYSIOLOGICAL CHANGES AND CHANGES IN GENE EXPRESSION LEVELS USING RNA EXTRACTED FROM HIPPOCAMPUS, HYPOTHALAMUS, AND BLOOD FOR THE FOLLOWING HPA GENES: FKBP5, NR3C1, HSP90, CRH, AND CRHR1. THE CORT MICE EXHIBITED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE TEST. CHRONIC EXPOSURE TO CORT ALSO CAUSED A SIGNIFICANT DECREASE IN THE HIPPOCAMPAL AND BLOOD MRNA LEVELS OF NR3C1 AND A DECREASE IN HSP90 IN BLOOD AND CAUSED AN INCREASE IN FKBP5 FOR ALL TISSUES. DIFFERENCES WERE SEEN IN FKBP5 METHYLATION IN HIPPOCAMPUS AND HYPOTHALAMUS. TO ISOLATE A SINGLE-CELL TYPE, WE FOLLOWED UP WITH AN HT-22 MOUSE HIPPOCAMPAL NEURONAL CELL LINE EXPOSED TO CORT. AFTER 7 D, WE OBSERVED A 2.4-FOLD INCREASE IN FKBP5 EXPRESSION AND A DECREASE IN DNAM. IN THE CORT-TREATED MICE, WE ALSO OBSERVED CHANGES IN BLOOD DNAM IN FKBP5. OUR RESULTS SUGGEST DNAM PLAYS A ROLE IN MEDIATING EFFECTS OF GLUCOCORTICOID EXPOSURE ON FKBP5 FUNCTION, WITH POTENTIAL CONSEQUENCES FOR BEHAVIOR.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  5834  31 STRESS-INDUCED VISCERAL PAIN IN FEMALE RATS IS ASSOCIATED WITH EPIGENETIC REMODELING IN THE CENTRAL NUCLEUS OF THE AMYGDALA. STRESS AND ANXIETY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF IRRITABLE BOWEL SYNDROME (IBS), A FEMALE-PREDOMINANT DISORDER OF THE GUT-BRAIN AXIS, CHARACTERIZED BY ABDOMINAL PAIN DUE TO HEIGHTENED VISCERAL SENSITIVITY. IN THE CURRENT STUDY, WE AIMED TO EVALUATE IN FEMALE RATS WHETHER EPIGENETIC REMODELING IN THE LIMBIC BRAIN, SPECIFICALLY IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA), IS A CONTRIBUTING FACTOR IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY. OUR RESULTS SHOWED THAT 1 H EXPOSURE TO WATER AVOIDANCE STRESS (WAS) FOR 7 CONSECUTIVE DAYS DECREASED HISTONE ACETYLATION AT THE GR PROMOTER AND INCREASED HISTONE ACETYLATION AT THE CRH PROMOTER IN THE CEA. CHANGES IN HISTONE ACETYLATION WERE MEDIATED BY THE HISTONE DEACETYLASE (HDAC) SIRT-6 AND THE HISTONE ACETYLTRANSFERASE CBP, RESPECTIVELY. ADMINISTRATION OF THE HDAC INHIBITOR TRICHOSTATIN A (TSA) INTO THE CEA PREVENTED STRESS-INDUCED VISCERAL HYPERSENSITIVITY THROUGH BLOCKADE OF SIRT-6 MEDIATED HISTONE ACETYLATION AT THE GR PROMOTER. IN ADDITION, HDAC INHIBITION WITHIN THE CEA PREVENTED STRESS-INDUCED HISTONE ACETYLATION OF THE CRH PROMOTER. OUR RESULTS SUGGEST THAT, IN FEMALES, EPIGENETIC MODIFICATIONS IN THE LIMBIC BRAIN REGULATING GR AND CRH EXPRESSION CONTRIBUTE TO STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND OFFER A POTENTIAL EXPLANATION OF HOW STRESS CAN TRIGGER SYMPTOMS IN IBS PATIENTS.	2021