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  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5  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	
                                                                                                                                                                                                                                                                                                                                                        
6  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  6601  51 TWO INTRAUTERINE PROGRAMMING MECHANISMS OF ADULT HYPERCHOLESTEROLEMIA INDUCED BY PRENATAL NICOTINE EXPOSURE IN MALE OFFSPRING RATS. EPIDEMIOLOGIC STUDIES SHOWED THAT LOW BIRTH WEIGHT IS ASSOCIATED WITH HIGH CHOLESTEROL AND AN INCREASED RISK OF CARDIOVASCULAR DISEASES IN ADULTHOOD. THIS STUDY AIMED TO ELUCIDATE THE INTRAUTERINE PROGRAMMING MECHANISMS OF ADULT HYPERCHOLESTEROLEMIA. THE RESULTS SHOWED THAT PRENATAL NICOTINE EXPOSURE (PNE) CAUSED INTRAUTERINE GROWTH RETARDATION AND HYPERCHOLESTEROLEMIA IN MALE ADULT OFFSPRING RATS. HEPATIC CHOLESTEROL SYNTHESIS AND OUTPUT WERE DECEASED IN UTERO BUT INCREASED IN ADULTS; HEPATIC REVERSE CHOLESTEROL TRANSPORT (RCT) PERSISTENTLY DECEASED BEFORE AND AFTER BIRTH. MEANWHILE, PNE ELEVATED SERUM CORTICOSTERONE LEVEL AND DECREASED HEPATIC IGF1 PATHWAY ACTIVITY IN MALE FETUSES, WHEREAS CONVERSE CHANGES WERE OBSERVED IN MALE ADULTS. THE CHRONIC STRESS MODEL AND CORTISOL-TREATED HEPG2 CELLS VERIFIED THAT EXCESSIVE GLUCOCORTICOID (GC)-INDUCED GC-IGF1 AXIS PROGRAMMING ENHANCED HEPATIC CHOLESTEROL SYNTHESIS AND OUTPUT. IN ADDITION, PNE DECREASED THE EXPRESSION OF SPECIFIC PROTEIN 1 AND P300 ENRICHMENT AND H3K27 ACETYLATION AT THE PROMOTER REGION OF GENES RESPONSIBLE FOR RCT BOTH IN FETAL AND ADULT, MALE LIVERS AND REDUCED EXPRESSION OF THOSE GENES, SIMILAR ALTERATIONS WERE ALSO CONFIRMED IN CORTISOL-TREATED HEPG2 CELLS, SUGGESTING THAT EXCESSIVE GC-RELATED PROGRAMMING INDUCED CONTINUOUS RCT REDUCTION BY EPIGENETIC MODIFICATION. TAKEN TOGETHER, THE "2-PROGRAMMING" APPROACH DISCUSSED ABOVE MAY ULTIMATELY CONTRIBUTE TO THE DEVELOPMENT OF HYPERCHOLESTEROLEMIA IN MALE ADULT OFFSPRING.-ZHOU, J., ZHU, C., LUO, H., SHEN, L., GONG, J., WU, Y., MAGDALOU, J., CHEN, L., GUO, Y., WANG, H. TWO INTRAUTERINE PROGRAMMING MECHANISMS OF ADULT HYPERCHOLESTEROLEMIA INDUCED BY PRENATAL NICOTINE EXPOSURE IN MALE OFFSPRING RATS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11  1740  32 EARLY ENRICHED ENVIRONMENT PREVENTS EPIGENETIC P11 GENE CHANGES INDUCED BY ADULTHOOD STRESS IN MICE. POSITIVE EXPERIENCES IN EARLY LIFE MAY IMPROVE THE CAPACITY TO COPE WITH ADULTHOOD STRESS THROUGH EPIGENETIC MODIFICATION. WE INVESTIGATED WHETHER AN ENRICHED ENVIRONMENT (EE) IN THE POSTNATAL PERIOD AFFECTED EPIGENETIC CHANGES IN THE P11 GENE INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS) IN ADULT C57BL/6J MICE. EE WAS INTRODUCED FOR 5 WEEKS DURING POSTNATAL DAYS 21-55. AFTER EE, THE MICE WERE SUBJECTED TO CUS FOR 4 WEEKS. EE PREVENTED DEPRESSION-LIKE BEHAVIOR INDUCED BY ADULT CUS. EE PREVENTED A DECREASE IN P11 MRNA AND HISTONE H3 ACETYLATION INDUCED BY CUS, WITH CHANGES IN THE EXPRESSION OF HISTONE DEACETYLASE 5. MOREOVER, EE PREVENTED CHANGES IN TRIMETHYLATION OF HISTONE H3 LYSINE 4 (H3K4) AND H3K27 INDUCED BY CUS. FURTHERMORE, EE HAD POSITIVE EFFECTS ON BEHAVIOR AND EPIGENETIC ALTERATIONS IN ADULT MICE WITHOUT CUS. THESE RESULTS SUGGEST THAT ONE OF THE UNDERLYING MECHANISMS OF EARLY-LIFE EE MAY INVOLVE EPIGENETIC MODIFICATION OF THE HIPPOCAMPAL P11 GENE PROMOTER.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  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	

13  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  2482  28 EPIGENETIC UPREGULATION OF METABOTROPIC GLUTAMATE RECEPTOR 2 IN THE SPINAL CORD ATTENUATES OESTROGEN-INDUCED VISCERAL HYPERSENSITIVITY. OBJECTIVE: EPIGENETIC MECHANISMS ARE POTENTIAL TARGETS TO RELIEVE SOMATIC PAIN. HOWEVER, LITTLE IS KNOWN WHETHER EPIGENETIC REGULATION INTERFERES WITH VISCERAL PAIN. PREVIOUS STUDIES SHOW THAT OESTROGEN FACILITATES VISCERAL PAIN. THIS STUDY AIMED TO DETERMINE WHETHER HISTONE HYPERACETYLATION IN THE SPINAL CORD COULD ATTENUATE OESTROGEN-FACILITATED VISCERAL PAIN. DESIGN: THE EFFECT OF THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ON THE MAGNITUDE OF THE VISCEROMOTOR RESPONSE (VMR) TO COLORECTAL DISTENTION WAS EXAMINED IN OVARIECTOMISED RATS WITH/WITHOUT OESTROGEN REPLACEMENT. AN ADDITIONAL INTERACTION WITH THE METABOTROPIC GLUTAMATE RECEPTOR 2/3 (MGLUR2/3) ANTAGONIST LY341495 WAS TESTED. THE LEVELS OF ACETYLATED HISTONE AND MGLUR2 MRNA AND PROTEIN WERE ANALYSED. THE BINDING OF ACETYLATED H3 AND OESTROGEN RECEPTOR ALPHA (ERALPHA) TO THE GRM2 PROMOTER WAS MEASURED BY CHROMATIN IMMUNOPRECIPITATION COUPLED WITH QPCR. RESULTS: IN OVARIECTOMISED RATS, 17BETA-ESTRADIOL (E2), BUT NOT SAFFLOWER OIL, INCREASED THE MAGNITUDE OF THE VMR TO COLORECTAL DISTENTION. SAHA ATTENUATED THE E2-FACILITATED VMR, BUT HAD NO EFFECT IN SAFFLOWER OIL-TREATED RATS. SUBSEQUENT SPINAL ADMINISTRATION OF LY341495 REVERSED THE ANTINOCICEPTIVE EFFECT OF SAHA IN E2 RATS. IN ADDITION, SAHA INCREASED MGLUR2 MRNA AND PROTEIN IN THE SPINAL DORSAL HORN FOLLOWING E2, BUT NOT VEHICLE, TREATMENT. IN CONTRAST, NEITHER E2 NOR SAHA ALONE ALTERED MGLUR2 MRNA. SAHA INCREASED BINDING OF H3K9AC AND ERALPHA TO THE SAME REGIONS OF THE GRM2 PROMOTER IN E2-SAHA-TREATED ANIMALS. CONCLUSIONS: HISTONE HYPERACETYLATION IN THE SPINAL CORD ATTENUATES THE PRONOCICEPTIVE EFFECTS OF OESTROGEN ON VISCERAL SENSITIVITY, SUGGESTING THAT EPIGENETIC REGULATION MAY BE A POTENTIAL APPROACH TO RELIEVE VISCERAL PAIN.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15  2745  29 EXPRESS: HISTONE HYPERACETYLATION MODULATES SPINAL TYPE II METABOTROPIC GLUTAMATE RECEPTOR ALLEVIATING STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN FEMALE RATS. STRESS IS OFTEN A TRIGGER TO EXACERBATE CHRONIC PAIN INCLUDING VISCERAL HYPERSENSITIVITY ASSOCIATED WITH IRRITABLE BOWEL SYNDROME, A FEMALE PREDOMINANT FUNCTIONAL BOWEL DISORDER. EPIGENETIC MECHANISMS THAT MEDIATE STRESS RESPONSES ARE A POTENTIAL TARGET TO INTERFERE WITH VISCERAL PAIN. THE PURPOSE OF THIS STUDY WAS TO EXAMINE THE EFFECT OF A HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID, ON VISCERAL HYPERSENSITIVITY INDUCED BY A SUBCHRONIC STRESSOR IN FEMALE RATS AND TO INVESTIGATE THE INVOLVEMENT OF SPINAL GLUTAMATE RECEPTORS. THREE DAILY SESSIONS OF FORCED SWIM INDUCED VISCERAL HYPERSENSITIVITY. INTRATHECAL SUBEROYLANILIDE HYDROXAMIC ACID PREVENTED OR REVERSED THE STRESS-INDUCED VISCERAL HYPERSENSITIVITY, INCREASED SPINAL HISTONE 3 ACETYLATION AND INCREASED MGLUR2 AND MGLUR3 EXPRESSION. CHROMATIN IMMUNOPRECIPITATION (CHIP) ANALYSIS REVEALED ENRICHMENT OF H3K9AC AND H3K18AC AT SEVERAL PROMOTER GRM2 AND GRM3 REGIONS. THE MGLUR2/3 ANTAGONIST LY341495 REVERSED THE INHIBITORY EFFECT OF SUBEROYLANILIDE HYDROXAMIC ACID ON THE STRESS-INDUCED VISCERAL HYPERSENSITIVITY. IN SURPRISING CONTRAST, STRESS AND/OR SUBEROYLANILIDE HYDROXAMIC ACID HAD NO EFFECT ON SPINAL NMDA RECEPTOR EXPRESSION OR FUNCTION. THESE DATA REVEAL HISTONE MODIFICATION MODULATES MGLUR2/3 EXPRESSION IN THE SPINAL CORD TO ATTENUATE STRESSINDUCED VISCERAL HYPERSENSITIVITY. HDAC INHIBITORS MAY PROVIDE A POTENTIAL APPROACH TO RELIEVE VISCERAL HYPERSENSITIVITY ASSOCIATED WITH IRRITABLE BOWEL SYNDROME.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  5206  42 PRENATAL STRESS INDUCES LONG-TERM BEHAVIORAL SEX-DEPENDENT CHANGES IN RATS OFFSPRING: THE ROLE OF THE HPA AXIS AND EPIGENETICS. PRECLINICAL GENETIC STUDIES HAVE RELATED STRESS EARLY EXPOSURES WITH CHANGES IN GENE REGULATORY MECHANISMS, INCLUDING EPIGENETIC ALTERATIONS, SUCH AS MODIFICATIONS OF DNA METHYLATION, HISTONE DEACETYLATION, AND HISTONES ACETYLATION. THIS STUDY EVALUATES THE EFFECTS OF PRENATAL STRESS ON THE BEHAVIOR, HYPOTHALAMUS-PITUITARY-ADRENAL (HPA)-AXIS, AND EPIGENETIC PARAMETERS IN STRESSED DAMS AND THEIR OFFSPRING. THE RATS WERE SUBJECTED TO A PROTOCOL OF CHRONIC UNPREDICTABLE MILD STRESS ON THE FOURTEENTH DAY OF PREGNANCY UNTIL THE BIRTH OF OFFSPRING. AFTER BIRTH, MATERNAL CARE WAS EVALUATED FOR SIX DAYS. FOLLOWING WEANING, THE LOCOMOTOR AND DEPRESSIVE-LIKE BEHAVIORS OF THE DAMS AND THEIR OFFSPRING (60 DAYS OLD) WERE ASSESSED. THE HPA AXIS PARAMETERS WERE EVALUATED IN SERUM FROM DAMS AND OFFSPRING, AND EPIGENETIC PARAMETERS (HISTONE ACETYLTRANSFERASE (HAT), HISTONE DEACETYLASE (HDAC), DNA METHYLTRANSFERASE (DNMT) ACTIVITIES, AND THE LEVELS OF HISTONE H3 ACETYLATED AT LYSINE RESIDUE 9 (H3K9AC) AND HISTONE 3 ACETYLATED AT LYSINE RESIDUE 14 (H3K14AC)) WERE ASSESSED IN DAMS' AND OFFSPRING' BRAINS. PRENATAL STRESS DID NOT SIGNIFICANTLY INFLUENCE MATERNAL CARE; HOWEVER, IT INDUCED MANIC BEHAVIOR IN FEMALE OFFSPRING. THESE BEHAVIORAL ALTERATIONS IN THE OFFSPRING WERE ACCOMPANIED BY HYPERACTIVITY OF THE HPA-AXIS, EPIGENETIC ADAPTATIONS IN THE ACTIVITY OF HDAC AND DNMT, AND ACETYLATION IN THE HISTONES H3K9 AND H3K14. IN ADDITION, THE PRENATAL STRESSED FEMALE OFFSPRING SHOWED INCREASED LEVELS OF ACTH COMPARED TO THEIR MALE COUNTERPART. OUR FINDINGS REINFORCE THE IMPACT OF PRENATAL STRESS ON BEHAVIOR, STRESS RESPONSE, AND EPIGENETIC PROFILE OF OFFSPRING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  5197  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
18  6612  30 ULTRA-LOW-DOSE NALOXONE ENHANCES THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN PTX-TREATED RATS: REGULATION ON GLOBAL HISTONE METHYLATION. OBJECTIVE: EPIGENETIC REPROGRAMMING MAY HAVE A POSSIBLE ROLE IN NEUROPATHIC PAIN DEVELOPMENT; THE PRESENT STUDY EXAMINED THE GLOBAL PATTERNS OF LYSINE HISTONE MODIFICATION. IN THIS SERIAL STUDY WE ANALYZED THE LEVELS OF HISTONE 3 LYSINE 4 MONOMETHYLATION, HISTONE 3 LYSINE 4 DIMETHYLATION, AND HISTONE 3 LYSINE 9 TRIMETHYLATION IN PERTUSSIS TOXIN (PTX)-INDUCED THERMAL HYPERALGESIC RAT SPINAL CORDS. METHODS: MALE WISTAR RATS IMPLANTED WITH AN INTRATHECAL CATHETER RECEIVED A SINGLE INTRATHECAL PTX (1 MUG IN 5 MUL SALINE) INJECTION. FOUR DAYS LATER, THEY WERE RANDOMLY ASSIGNED TO RECEIVE EITHER A SINGLE INJECTION OF SALINE, OR ULTRA-LOW-DOSE NALOXONE (15 NG IN 5 MUL SALINE), FOLLOWED BY MORPHINE (10 MUG IN 5 MUL SALINE) INJECTION 30 MINUTES LATER. RESULTS: THE RESULTS SHOWED THAT PTX INJECTION INDUCED THERMAL HYPERALGESIA AND SIGNIFICANT INCREASE OF GLOBAL HISTONE METHYLATION IN THE SPINAL CORDS. INTRATHECAL MORPHINE ALONE DID NOT AFFECT THE THERMAL HYPERALGESIA AND GLOBAL HISTONE METHYLATION. IN CONTRAST, INTRATHECAL ADMINISTRATION OF ULTRA-LOW-DOSE NALOXONE PLUS MORPHINE SIGNIFICANTLY ATTENUATED THE PTX-INDUCED THERMAL HYPERALGESIA AND DOWN-REGULATED THE GLOBAL HISTONE METHYLATION. CONCLUSION: THE RESULTS SUGGEST THAT ULTRA-LOW-DOSE NALOXONE MIGHT BE CLINICAL VALUABLE FOR NEUROPATHIC PAIN MANAGEMENT VIA REGULATING GLOBAL HISTONE MODIFICATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19  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	
                                                                                                                                                                                                                                      
20  2667  38 ESTROGEN AND SEROTONIN ENHANCE STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN FEMALE RATS BY UP-REGULATING BRAIN-DERIVED NEUROTROPHIC FACTOR IN SPINAL CORD. BACKGROUND: WE PREVIOUSLY REPORTED THAT FEMALE OFFSPRING OF DAMS SUBJECTED TO CHRONIC PRENATAL STRESS (CPS) DEVELOP ENHANCED VISCERAL HYPERSENSITIVITY (VHS) FOLLOWING EXPOSURE TO CHRONIC STRESS IN ADULT LIFE THAT IS MEDIATED BY UP-REGULATION OF SPINAL CORD BDNF. THE AIMS OF THIS STUDY WERE TO EXAMINE THE ROLES OF ESTROGEN RECEPTOR ALPHA (ERALPHA) AND AN INCREASE IN SPINAL SEROTONIN SIGNALING IN PROMOTING THIS ENHANCED VHS IN FEMALE RATS AND UP-REGULATION OF SPINAL CORD BDNF TRANSCRIPTION. METHODS: PREGNANT DAMS WERE EXPOSED TO CHRONIC STRESS FROM E11 UNTIL DELIVERY. AT 8 WEEKS, A CHRONIC ADULT STRESS (CAS) PROTOCOL WAS APPLIED FOR NINE DAYS. KEY RESULTS: OVARIECTOMY BEFORE CAS OR TREATMENT WITH LETROZOLE BEFORE AND DURING CAS SIGNIFICANTLY PREVENTED THE DEVELOPMENT OF ENHANCED VHS IN FEMALE CPS+CAS RATS. INTRATHECAL APPLICATION OF ERALPHA SIRNA SIGNIFICANTLY REDUCED VHS, DECREASED LUMBAR-SACRAL SPINAL CORD EXPRESSION OF BOTH ERALPHA AND BDNF, AND REVERSED PRO-TRANSCRIPTIONAL EPIGENETIC MODIFICATIONS AT BDNF PROMOTER LX. CEREBROSPINAL FLUID SEROTONIN LEVELS AND 5HT3A RECEPTOR EXPRESSION IN THE LS SPINAL CORD WERE BOTH SIGNIFICANTLY INCREASED IN FEMALE CPS+CAS RATS. DURING CAS, INTRATHECAL INFUSION OF ALOSETRON SIGNIFICANTLY DECREASED VHS, REDUCED BDNF AND ERALPHA EXPRESSION IN THE LS SPINAL CORD, AND ATTENUATED RNA POL II AND ERALPHA BINDING TO THE BNDF CORE PROMOTER IX. CONCLUSIONS & INFERENCES: SEROTONIN-MEDIATED ACTIVATION OF 5HT3A RECEPTORS IN THE SPINAL CORD DRIVES THE DEVELOPMENT OF ENHANCED FEMALE-SPECIFIC VHS IN OUR TWO HIT CPS+CAS THROUGH UP-REGULATION OF SPINAL CORD ERALPHA.	2021