1 3815 176 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	
                        
2 6601  61 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3 3812  67 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	
                                                                                                                                                                                                                                                                                                                                
4 5253  64 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	
                                                                                                                                                                                                                                             
5 1839  59 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6 5191  58 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
7 4089  43 MATERNAL OBESITY PROGRAMS SENESCENCE SIGNALING AND GLUCOSE METABOLISM IN OSTEO-PROGENITORS FROM RAT AND HUMAN. NUTRITIONAL STATUS DURING INTRAUTERINE AND EARLY POSTNATAL LIFE IMPACTS THE RISK OF CHRONIC DISEASES, PRESUMABLY VIA EPIGENETIC MECHANISMS. HOWEVER, EVIDENCE ON THE IMPACT OF GESTATIONAL EVENTS ON REGULATION OF EMBRYONIC BONE CELL FATE IS SPARSE. WE INVESTIGATED THE EFFECTS OF MATERNAL OBESITY ON FETAL OSTEOBLAST DEVELOPMENT IN BOTH RODENTS AND HUMANS. FEMALE RATS WERE FED CONTROL OR AN OBESOGENIC HIGH-FAT DIET (HFD) FOR 12 WEEKS AND MATED WITH MALE RATS FED CONTROL DIETS, AND RESPECTIVE MATERNAL DIETS WERE CONTINUED DURING PREGNANCY. EMBRYONIC RAT OSTEOGENIC CALVARIAL CELLS (EOCCS) WERE TAKEN FROM GESTATIONAL DAY 18.5 FETUSES FROM CONTROL AND HFD DAMS. EOCCS FROM HFD OBESE DAMS SHOWED INCREASES IN P53/P21-MEDIATED CELL SENESCENCE SIGNALING BUT DECREASED GLUCOSE METABOLISM. DECREASED AEROBIC GLYCOLYSIS IN HFD-EOCCS WAS ASSOCIATED WITH DECREASED OSTEOBLASTIC CELL DIFFERENTIATION AND PROLIFERATION. UMBILICAL CORD HUMAN MESENCHYMAL STEM CELLS (MSCS) FROM 24 PREGNANT WOMEN (12 OBESE AND 12 LEAN) ALONG WITH PLACENTAS WERE COLLECTED UPON DELIVERY. THE UMBILICAL CORD MSCS OF OBESE MOTHERS DISPLAYED LESS POTENTIAL TOWARD OSTEOBLASTOGENESIS AND MORE TOWARDS ADIPOGENESIS. HUMAN MSCS AND PLACENTA FROM OBESE MOTHERS ALSO EXHIBITED INCREASED CELL SENESCENCE SIGNALING, WHEREAS MSCS SHOWED DECREASED GLUCOSE METABOLISM AND INSULIN RESISTANCE. FINALLY, WE SHOWED THAT OVEREXPRESSION OF P53 LINKED INCREASED CELL SENESCENCE SIGNALING AND DECREASED GLUCOSE METABOLISM IN FETAL OSTEO-PROGENITORS FROM OBESE RATS AND HUMANS. THESE FINDINGS SUGGEST PROGRAMMING OF FETAL PREOSTEOBLASTIC CELL SENESCENCE SIGNALING AND GLUCOSE METABOLISM BY MATERNAL OBESITY.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8 3816  58 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9 3978  49 LONG-TERM EFFECTS OF PRENATAL SEVERE HYPOXIA ON CENTRAL AND PERIPHERAL COMPONENTS OF THE GLUCOCORTICOID SYSTEM IN RATS. INTRODUCTION: PRENATAL HYPOXIA IS A RISK FACTOR FOR THE DEVELOPMENT OF NUMEROUS NEUROLOGICAL DISORDERS. IT IS KNOWN THAT THE MATERNAL STRESS RESPONSE TO HYPOXIA DETERMINES THE EPIGENETIC IMPAIRMENT OF THE PERINATAL EXPRESSION OF GLUCOCORTICOID RECEPTORS (GR) IN THE HIPPOCAMPUS OF THE PROGENY, BUT SO FAR NO DETAILED STUDY OF HOW THIS AFFECTS THE FUNCTIONAL STATE OF THE GLUCOCORTICOID SYSTEM DURING FURTHER ONTOGENESIS HAS BEEN PERFORMED. OBJECTIVE: THE GOAL OF THE PRESENT STUDY WAS TO EXAMINE THE LONG-TERM EFFECTS OF THE PRENATAL HYPOXIA ON THE FUNCTIONING OF THE GLUCOCORTICOID SYSTEM THROUGHOUT LIFE. METHODS: PRENATAL SEVERE HYPOBARIC HYPOXIA (PSH) WAS INDUCED IN THE CRITICAL PERIOD OF EMBRYONIC HIPPOCAMPAL FORMATION ON DAYS 14-16 OF GESTATION IN A HYPOBARIC CHAMBER (180 TORR, 5% OXYGEN, 3 H). THE ACTIVITY OF CENTRAL (HIPPOCAMPUS) AND PERIPHERAL (LIVER) COMPONENTS OF THE GLUCOCORTICOID SYSTEM WAS ASSESSED IN 1-DAY-OLD (NEWBORN), 2-WEEK-OLD (JUVENILE), 3-MONTH-OLD (ADULT), AND 18-MONTH-OLD (AGED) MALE RATS. RESULTS: THE PSH RESULTED IN CONTINUOUSLY ELEVATED BASELINE CORTICOSTERONE BLOOD LEVELS IN THE ADULT AND AGED RATS. THE CHRONIC ELEVATION OF THE CORTICOSTERONE LEVELS WAS ACCOMPANIED BY A PROGRESSIVE DEFICIT OF THE GR EXPRESSION IN THE LIVER, INCREASED HEPATIC GLYCOGEN CONTENT, DYSREGULATED GLUCOSE-6-PHOSPHATASE ACTIVITY, AND EVENTUALLY HYPOGLYCEMIA. ELEVATED CORTICOSTERONE APPEARS TO RESULT FROM THE IMPAIRMENT OF THE MECHANISMS OF GLUCOCORTICOID NEGATIVE FEEDBACK SINCE A SUBSTANTIAL DECREASE IN BOTH THE TOTAL NUMBER OF GR AND THEIR NUCLEAR LOCALIZATION WAS OBSERVED ALREADY IN THE HIPPOCAMPUS OF NEWBORN RAT PUPS AND PERSISTED THROUGHOUT LIFE. CORRESPONDING STABLE HIPPOCAMPAL DOWNREGULATION OF GR-DEPENDENT GENES WAS OBSERVED AS WELL. SUPPRESSION OF THE MATERNAL GLUCOCORTICOID STRESS RESPONSE TO HYPOXIA BY METYRAPONE INJECTION TO PREGNANT RATS PRIOR TO EACH HYPOXIC CHALLENGE CONSIDERABLY REDUCED CORTICOSTERONE OVER-RESPONSE TO HYPOXIA AND PREVENTED REDUCED HIPPOCAMPAL GR. CONCLUSIONS: OUR FINDINGS DEMONSTRATE THAT IN PROGENY A DEFICIT OF HIPPOCAMPAL GR RESULTING FROM MATERNAL GLUCOCORTICOID RESPONSE TO HYPOXIA REMAINS STABLE THROUGHOUT LIFE AND IS ACCOMPANIED BY SEVERE DISTURBANCES OF BASELINE GLUCOCORTICOID LEVELS AND ITS PERIPHERAL RECEPTION. NEGATIVE CONSEQUENCES OF PSH CAN BE PREVENTED BY INJECTION WITH AN INHIBITOR OF CORTICOSTERONE SYNTHESIS (METYRAPONE) TO PREGNANT FEMALES UNDERGOING HYPOXIA.	2020	

10 5206  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  982  50 CHRONIC PRENATAL HYPOXIA INDUCES EPIGENETIC PROGRAMMING OF PKCEPSILON GENE REPRESSION IN RAT HEARTS. RATIONALE: EPIDEMIOLOGICAL STUDIES DEMONSTRATE A CLEAR ASSOCIATION OF ADVERSE INTRAUTERINE ENVIRONMENT WITH AN INCREASED RISK OF ISCHEMIC HEART DISEASE IN ADULTHOOD. HYPOXIA IS A COMMON STRESS TO THE FETUS AND RESULTS IN DECREASED PROTEIN KINASE C EPSILON (PKCEPSILON) EXPRESSION IN THE HEART AND INCREASED CARDIAC VULNERABILITY TO ISCHEMIA AND REPERFUSION INJURY IN ADULT OFFSPRING IN RATS. OBJECTIVES: THE PRESENT STUDY TESTED THE HYPOTHESIS THAT FETAL HYPOXIA-INDUCED METHYLATION OF CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDES AT THE PKCEPSILON PROMOTER IS REPRESSIVE AND CONTRIBUTES TO PKCEPSILON GENE REPRESSION IN THE HEART OF ADULT OFFSPRING. METHODS AND RESULTS: HYPOXIC TREATMENT OF PREGNANT RATS FROM DAYS 15 TO 21 OF GESTATION RESULTED IN SIGNIFICANT DECREASES IN PKCEPSILON PROTEIN AND MRNA IN FETAL HEARTS. SIMILAR RESULTS WERE OBTAINED IN EX VIVO HYPOXIC TREATMENT OF ISOLATED FETAL HEARTS AND RAT EMBRYONIC VENTRICULAR MYOCYTE CELL LINE H9C2. INCREASED METHYLATION OF PKCEPSILON PROMOTER AT SP1 BINDING SITES, -346 AND -268, WERE DEMONSTRATED IN BOTH FETAL HEARTS OF MATERNAL HYPOXIA AND H9C2 CELLS TREATED WITH 1% O(2) FOR 24 HOURS. WHEREAS HYPOXIA HAD NO SIGNIFICANT EFFECT ON THE BINDING AFFINITY OF SP1 TO THE UNMETHYLATED SITES IN H9C2 CELLS, HEARTS OF FETUSES AND ADULT OFFSPRING, METHYLATION OF BOTH SP1 SITES REDUCED SP1 BINDING. THE ADDITION OF 5-AZA-2'-DEOXYCYTIDINE BLOCKED THE HYPOXIA-INDUCED INCREASE IN METHYLATION OF BOTH SP1 BINDING SITES AND RESTORED PKCEPSILON MRNA AND PROTEIN TO THE CONTROL LEVELS. IN HEARTS OF BOTH FETUSES AND ADULT OFFSPRING, HYPOXIA-INDUCED METHYLATION OF SP1 SITES WAS SIGNIFICANTLY GREATER IN MALES THAN IN FEMALES, AND DECREASED PKCEPSILON MRNA WAS SEEN ONLY IN MALES. IN FETAL HEARTS, THERE WAS SIGNIFICANTLY HIGHER ABUNDANCE OF ESTROGEN RECEPTOR ALPHA AND BETA ISOFORMS IN FEMALES THAN IN MALES. BOTH ESTROGEN RECEPTOR ALPHA AND BETA INTERACTED WITH THE SP1 BINDING SITES IN THE FETAL HEART, WHICH MAY EXPLAIN THE SEX DIFFERENCES IN SP1 METHYLATION IN THE FETAL HEART. ADDITIONALLY, SELECTIVE ACTIVATION OF PKCEPSILON RESTORED THE HYPOXIA-INDUCED CARDIAC VULNERABILITY TO ISCHEMIC INJURY IN OFFSPRING. CONCLUSIONS: THE FINDINGS DEMONSTRATE A DIRECT EFFECT OF HYPOXIA ON EPIGENETIC MODIFICATION OF DNA METHYLATION AND PROGRAMMING OF CARDIAC PKCEPSILON GENE REPRESSION IN A SEX-DEPENDENT MANNER, LINKING FETAL HYPOXIA AND PATHOPHYSIOLOGICAL CONSEQUENCES IN THE HEARTS OF ADULT OFFSPRING.	2010	
                
12 2757  43 EXPRESSION OF EPIGENETIC MACHINERY GENES IS SENSITIVE TO MATERNAL OBESITY AND WEIGHT LOSS IN RELATION TO FETAL GROWTH IN MICE. BACKGROUND: MATERNAL OBESITY IMPACTS FETAL GROWTH AND PREGNANCY OUTCOMES. TO COUNTERACT THE DELETERIOUS EFFECTS OF OBESITY ON FERTILITY AND PREGNANCY ISSUE, PRECONCEPTIONAL WEIGHT LOSS IS RECOMMENDED TO OBESE WOMEN. WHETHER THIS WEIGHT LOSS IS BENEFICIAL/DETRIMENTAL FOR OFFSPRING REMAINS POORLY EXPLORED. EPIGENETIC MECHANISMS COULD BE AFFECTED BY MATERNAL WEIGHT CHANGES, PERTURBING EXPRESSION OF KEY DEVELOPMENTAL GENES IN THE PLACENTA OR FETUS. OUR AIM WAS TO INVESTIGATE THE EFFECTS OF CHRONIC MATERNAL OBESITY ON FETO-PLACENTAL GROWTH ALONG WITH THE UNDERLYING EPIGENETIC MECHANISMS. WE ALSO TESTED WHETHER PRECONCEPTIONAL WEIGHT LOSS COULD ALLEVIATE THESE EFFECTS. RESULTS: FEMALE MICE WERE FED EITHER A CONTROL DIET (CTRL GROUP), A HIGH-FAT DIET (OBESE (OB) GROUP), OR A HIGH-FAT DIET SWITCHED TO A CONTROL DIET 2 MONTHS BEFORE CONCEPTION (WEIGHT LOSS (WL) GROUP). AT MATING, OB FEMALES PRESENTED AN OBESE PHENOTYPE WHILE WL FEMALES NORMALIZED METABOLIC PARAMETERS. AT EMBRYONIC DAY 18.5 (E18.5), FETUSES FROM OB FEMALES PRESENTED FETAL GROWTH RESTRICTION (FGR; -13 %) AND 28 % OF THE FETUSES WERE SMALL FOR GESTATIONAL AGE (SGA). FETUSES FROM WL FEMALES NORMALIZED THIS PHENOTYPE. THE EXPRESSION OF 60 EPIGENETIC MACHINERY GENES AND 32 METABOLIC GENES WAS MEASURED IN THE FETAL LIVER, PLACENTAL LABYRINTH, AND JUNCTIONAL ZONE. WE REVEALED 23 GENES ALTERED BY MATERNAL WEIGHT TRAJECTORIES IN AT LEAST ONE OF THREE TISSUES. THE FETAL LIVER AND PLACENTAL LABYRINTH WERE MORE RESPONSIVE TO MATERNAL OBESITY THAN JUNCTIONAL ZONE. ONE THIRD (18/60) OF THE EPIGENETIC MACHINERY GENES WERE DIFFERENTIALLY EXPRESSED BETWEEN AT LEAST TWO MATERNAL GROUPS. INTERESTINGLY, GENES INVOLVED IN THE HISTONE ACETYLATION PATHWAY WERE PARTICULARLY ALTERED (13/18). IN OB GROUP, LYSINE ACETYLTRANSFERASES AND BROMODOMAIN-CONTAINING PROTEIN 2 WERE UPREGULATED, WHILE MOST HISTONE DEACETYLASES WERE DOWNREGULATED. IN WL GROUP, THE EXPRESSION OF ONLY A SUBSET OF THESE GENES WAS NORMALIZED. CONCLUSIONS: THIS STUDY HIGHLIGHTS THE HIGH SENSITIVITY OF THE EPIGENETIC MACHINERY GENE EXPRESSION, AND PARTICULARLY THE HISTONE ACETYLATION PATHWAY, TO MATERNAL OBESITY. THESE OBESITY-INDUCED TRANSCRIPTIONAL CHANGES COULD ALTER THE PLACENTAL AND THE HEPATIC EPIGENOME, LEADING TO FGR. PRECONCEPTIONAL WEIGHT LOSS APPEARS BENEFICIAL TO FETAL GROWTH, BUT SOME EFFECTS OF PREVIOUS OBESITY WERE RETAINED IN OFFSPRING PHENOTYPE.	2016	
                                
13 4079  47 MATERNAL L-CARNITINE SUPPLEMENTATION AMELIORATES RENAL UNDERDEVELOPMENT AND EPIGENETIC CHANGES IN MALE MICE OFFSPRING DUE TO MATERNAL SMOKING. OBJECTIVES: EPIDEMIOLOGICAL AND ANIMAL STUDIES SHOWED THAT L-CARNITINE (LC) SUPPLEMENTATION CAN AMELIORATE OXIDATIVE STRESS-INDUCED TISSUES DAMAGE. WE HAVE PREVIOUSLY SHOWN THAT MATERNAL CIGARETTE SMOKE EXPOSURE (SE) CAN INCREASE RENAL OXIDATIVE STRESS IN NEWBORN OFFSPRING WITH POSTNATAL KIDNEY UNDERDEVELOPMENT AND RENAL DYSFUNCTION IN ADULTHOOD, WHICH WERE NORMALISED BY LC ADMINISTRATION IN THE SE DAMS DURING PREGNANCY. EXPOSURE TO AN ADVERSE INTRAUTERINE ENVIRONMENT MAY LEAD TO ALTERATION IN THE EPIGENOME, A MECHANISM BY WHICH ADVERSE PRENATAL CONDITIONS INCREASE THE SUSCEPTIBILITY TO CHRONIC DISEASE LATER IN LIFE. THE CURRENT STUDY AIMED TO DETERMINE WHETHER MATERNAL SE INDUCES EPIGENETIC CHANGES IN THE OFFSPRING'S KIDNEY ARE ASSOCIATED WITH RENAL UNDERDEVELOPMENT, AND THE PROTECTIVE EFFECT OF MATERNAL LC SUPPLEMENTATION. METHOD: FEMALE BALB/C MICE (7 WEEKS) WERE EXPOSED TO CIGARETTE SMOKE (SE) OR AIR (SHAM) FOR 6 WEEKS PRIOR TO MATING, DURING GESTATION AND LACTATION. A SUBGROUP OF THE SE DAMS RECEIVED LC VIA DRINKING WATER (SE + LC, 1.5 MMOL/L) THROUGHOUT GESTATION AND LACTATION. MALE OFFSPRING WERE STUDIED AT POSTNATAL DAY (P)1, P20, AND 13 WEEKS. RESULTS: MATERNAL SE ALTERED THE EXPRESSION OF RENAL DEVELOPMENT MARKERS GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR AND FIBROBLAST GROWTH FACTOR 2, WHICH WERE ASSOCIATED WITH INCREASED RENAL GLOBAL DNA METHYLATION AND DNA METHYLTRANSFERASE 1 MRNA EXPRESSION AT BIRTH. THESE DISORDERS WERE REVERSED BY MATERNAL LC ADMINISTRATION. CONCLUSION: THE EFFECT OF MATERNAL SE ON RENAL UNDERDEVELOPMENT INVOLVES GLOBAL EPIGENETIC ALTERATIONS FROM BIRTH, WHICH CAN BE PREVENTED BY MATERNAL LC SUPPLEMENTATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14 4095  50 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15 1418  40 DIFFERENCES IN DNA METHYLATION REPROGRAMMING UNDERLIE THE SEXUAL DIMORPHISM OF BEHAVIORAL DISORDER CAUSED BY PRENATAL STRESS IN RATS. PRENATAL STRESS (PS) CAN LEAD TO NEUROENDOCRINE AND EMOTIONAL DISORDERS LATER IN ADOLESCENCE. SEXUAL DIMORPHISM IN THESE NEURODEVELOPMENTAL OUTCOMES HAVE BEEN OBSERVED; HOWEVER, THE UNDERLYING MECHANISMS ARE NOT FULLY UNDERSTOOD. TO ADDRESS THIS ISSUE, WE INVESTIGATED WHETHER THERE ARE SEX DIFFERENCES IN EPIGENETIC REPROGRAMMING IN RATS EXPOSED TO PS. PREGNANT FEMALE RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS FROM GESTATIONAL DAY (G)12 TO G18. FROM POSTNATAL DAY (P)38 TO P45, SUBGROUPS OF OFFSPRING INCLUDING BOTH MALES AND FEMALES WERE SUBJECTED TO BEHAVIORAL TESTING AND BRAIN TISSUE SPECIMENS WERE ANALYZED BY DNA PYROSEQUENCING, WESTERN BLOTTING, AND GOLGI STAINING TO ASSESS CHANGES IN METHYLATION PATTERN OF GLUCOCORTICOID RECEPTOR (GR) GENE, EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) AND DNA DEMETHYLASE, AND DENDRITE MORPHOLOGY, RESPECTIVELY. THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE WAS ADMINISTERED TO RATS PRIOR TO PS TO FURTHER EVALUATE THE ROLE OF METHYLATION IN THE SEXUALLY DIMORPHIC EFFECTS OF PS. THE RESULTS SHOWED THAT PS INCREASED ANXIETY-LIKE BEHAVIOR IN OFFSPRING, ESPECIALLY IN FEMALES, WHILE DEPRESSION-LIKE BEHAVIOR WAS INCREASED IN MALE OFFSPRING COMPARED TO CONTROL LITTERMATES. THE METHYLATION PATTERN IN THE PROMOTER REGION OF THE GR GENE DIFFERED BETWEEN MALES AND FEMALES. SEX-SPECIFIC CHANGES IN THE EXPRESSION OF DNMTS (DNMT1 AND DNMT3A) AND DNA DEMETHYLASE (TET METHYLCYTOSINE DIOXYGENASE 2) WERE ALSO OBSERVED. INTERESTINGLY, DECITABINE ALLEVIATED THE BEHAVIORAL DISORDER CAUSED BY PS AND RESTORED DENDRITE DENSITY AND MORPHOLOGY IN FEMALE BUT NOT MALE RATS. THESE FINDINGS SUGGEST THAT DIFFERENT CHANGE PATTERNS OF DNMT AND DEMETHYLASE IN THE TWO SEXES AFTER PS ARE RESPONSIBLE FOR THE SEXUALLY DIMORPHISM, WHICH COULD HAVE IMPLICATIONS FOR THE CLINICAL MANAGEMENT OF STRESS-RELATED DISORDERS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  218  40 ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL TOTAL CHANGES IN PLACENTAL EPIGENETIC MODIFICATIONS. PREECLAMPSIA IS A COMMON OBSTETRICAL COMPLICATION, HALLMARKED BY NEW-ONSET HYPERTENSION. BELIEVED TO RESULT FROM PLACENTAL INSUFFICIENCY AND CHRONIC PLACENTAL ISCHEMIA, THE SYMPTOMS OF PREECLAMPSIA ARE CAUSED BY RELEASE OF PATHOGENIC FACTORS FROM THE PLACENTA ITSELF, ALTHOUGH THE MECHANISMS OF THEIR REGULATION ARE IN MANY CASES UNKNOWN. ONE POTENTIAL MECHANISM IS THROUGH CHANGES IN PLACENTAL EPIGENETIC CHROMATIN MODIFICATIONS, PARTICULARLY HISTONE ACETYLATION AND DNA METHYLATION. HERE, WE DETERMINED THE EFFECTS OF CHRONIC ISCHEMIA ON GLOBAL EPIGENETIC MODIFICATIONS IN THE RODENT PLACENTA IN VIVO AND ACUTE HYPOXIA IN BEWO PLACENTAL TROPHOBLAST CELLS IN VITRO. PLACENTAL INSUFFICIENCY VIA UTERINE ARTERY RESTRICTION INCREASED MATERNAL BLOOD PRESSURE AND FETAL DEMISE WHILE DECREASING PLACENTAL AND FETAL MASS. GLOBAL PLACENTAL HISTONE H3 ACETYLATION LEVELS WERE SIGNIFICANTLY DECREASED AT H3 K9, K14, K18, K27, AND K56. INTERESTINGLY, WHEN BEWO-IMMORTALIZED PLACENTAL TROPHOBLAST CELLS WERE CULTURED IN OXYGEN CONCENTRATIONS MIMICKING HEALTHY AND ISCHEMIC PLACENTAS, THERE WAS A SIGNIFICANT INCREASE IN ACETYLATED AT K9, K18, K27, AND K56. THIS WAS ASSOCIATED WITH A SMALL BUT SIGNIFICANT DECREASE IN PLACENTAL ACETYL-COA, SUGGESTING DEPLETION IN THE SOURCE OF ACETYL GROUP DONORS. FINALLY, WHILE GLOBAL METHYLATION OF CYTOSINE FROM PLACENTAL DNA WAS LOW IN BOTH GROUPS OF ANIMALS (<1%), THERE WAS APPROXIMATELY 50% INCREASE IN 5-MC IN RESPONSE TO CHRONIC ISCHEMIA. THIS SUGGESTS ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL GLOBAL CHANGES IN HISTONE ACETYLATION IN THE PLACENTA AND THAT CHRONICALLY ALTERED METABOLIC PROFILES COULD AFFECT HISTONE ACETYLATION IN THE PLACENTA, THEREBY REGULATING PRODUCTION OF PATHOGENIC FACTORS FROM THE PLACENTA DURING PREECLAMPSIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17 2077  41 EPIGENETIC DISRUPTION OF PLACENTAL GENES BY CHRONIC MATERNAL CAFETERIA DIET IN RATS. MATERNAL DIET HAS IMPACT ON REPRODUCTION, FETAL DEVELOPMENT AND OFFSPRING BEHAVIOR, ALTHOUGH MOLECULAR MECHANISMS REMAINED UNKNOWN. OUR AIMS WERE TO ASSESS (1) THE EFFECTS OF A CAFETERIA (CAF) DIET (WESTERN DIET HABITS) ON FEMALE REPRODUCTIVE PERFORMANCE, FETAL AND PLACENTAL PARAMETERS ON GESTATIONAL DAY 21 AND LITTER SIZE AND PUP WEIGHT AT BIRTH; AND (2) PLACENTAL MESSENGER RNA (MRNA) EXPRESSION AND EPIGENETIC REGULATION OF INSULIN-LIKE GROWTH FACTOR (IGF) AND VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND THEIR RECEPTORS. FEMALE WISTAR RATS WERE FED WITH CONTROL OR CAF DIET FROM WEANING UNTIL PARTURITION. AT WEEK 14 AFTER DIETS STARTED, FEMALES WERE MATED AND HALF OF THE ANIMALS WERE EUTHANIZED ON GESTATIONAL DAY 21 TO EVALUATE REPRODUCTIVE PARAMETERS INCLUDING THE PREGNANCY RATE, NUMBER OF CORPORA LUTEA, IMPLANTATION SITES AND RESORPTION SITES. MOREOVER, FETAL WEIGHT AND LENGTH, PLACENTAL WEIGHT, AND PLACENTAL INDEX WERE RECORDED. PLACENTAS WERE COLLECTED FOR MRNA QUANTIFICATION AND DNA METHYLATION ANALYSIS. THE REMAINING ANIMALS WERE ALLOWED TO GIVE BIRTH AND THE NUMBER AND WEIGHT OF THE PUPS WERE EVALUATED. CAF DIET DID NOT AFFECT REPRODUCTIVE PERFORMANCE OR FETAL WEIGHT AND LENGTH. HOWEVER, CAF-FED ANIMALS SHOWED A DECREASE IN PLACENTAL WEIGHT AND INDEX AND THE PUPS EXHIBITED A LOW BIRTH WEIGHT. ADDITIONALLY, WE FOUND AN UPREGULATION OF IGF2 AND A DOWN REGULATION OF VEGF PLACENTAL MRNA EXPRESSION IN CAF DAMS, ASSOCIATED WITH METHYLATION STATUS CHANGES OF THEIR PROMOTERS. WE CONCLUDE THAT FEMALE CHRONIC CAF DIET CONSUMPTION IMPAIRS FETO-PLACENTAL DEVELOPMENT AND COULD BE EXPLAINED BY AN EPIGENETIC DISRUPTION OF IGF AND VEGF SYSTEMS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  891  45 CHRONIC EFFECTS OF CLOFIBRIC ACID IN ZEBRAFISH (DANIO RERIO): A MULTIGENERATIONAL STUDY. CLOFIBRIC ACID (CA) IS AN ACTIVE METABOLITE OF THE BLOOD LIPID LOWERING AGENT CLOFIBRATE, A PHARMACEUTICAL DESIGNED TO WORK AS AGONIST OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA (PPARA). IT IS THE MOST COMMONLY REPORTED FIBRATE IN AQUATIC ENVIRONMENTS WITH LOW DEGRADATION RATE AND POTENTIAL ENVIRONMENTAL PERSISTENCE. PREVIOUS FISH EXPOSURES SHOWED THAT CA MAY IMPACT SPERMATOGENESIS, GROWTH AND THE EXPRESSION OF FAT BINDING PROTEIN GENES. HOWEVER, THERE ARE LIMITED DATA ON THE EFFECTS OF CHRONIC MULTIGENERATIONAL CA EXPOSURES. HERE, WE ASSESSED CHRONIC MULTIGENERATIONAL EFFECTS OF CA EXPOSURE USING ZEBRAFISH (DANIO RERIO) AS A TELEOST MODEL. ZEBRAFISH WERE EXPOSED THROUGH THE DIET TO CA (1 AND 10MG/G) DURING THEIR WHOLE LIFETIME. GROWTH, REPRODUCTION-RELATED PARAMETERS AND EMBRYONIC DEVELOPMENT WERE ASSESSED IN THE EXPOSED FISH (F1 GENERATION) AND THEIR OFFSPRING (F2 GENERATION), TOGETHER WITH MUSCLE TRIGLYCERIDE CONTENT AND GONAD HISTOLOGY. IN ORDER TO STUDY THE POTENTIAL UNDERLYING MECHANISMS, THE TRANSCRIPTION LEVELS OF GENES CODING FOR ENZYMES INVOLVED IN LIPID METABOLISM PATHWAYS WERE DETERMINED. THE RESULTS SHOW THAT CHRONIC LIFE-CYCLE EXPOSURE TO CA INDUCED A SIGNIFICANT REDUCTION IN GROWTH OF F1 GENERATION AND LOWERED TRIGLYCERIDE MUSCLE CONTENT (10MG/G GROUP). ALSO, AN IMPACT IN MALE GONAD DEVELOPMENT WAS OBSERVED TOGETHER WITH A DECREASE IN THE FECUNDITY (10MG/G GROUP) AND HIGHER FREQUENCY OF EMBRYO ABNORMALITIES IN THE OFFSPRING OF FISH EXPOSED TO THE LOWEST CA DOSE. THE PROFILE OF THE TARGET GENES WAS SEX- AND TISSUE-DEPENDENT. IN F1 AN UP-REGULATION OF MALE HEPATIC PPARAA, PPARB AND ACOX TRANSCRIPT LEVELS WAS OBSERVED, SUGGESTING AN ACTIVATION OF THE FATTY ACID METABOLISM (PROVIDED THAT TRANSCRIPT LEVEL CHANGE INDICATES ALSO A PROTEIN LEVEL CHANGE). INTERESTINGLY, THE F2 GENERATION, RAISED WITH CONTROL DIET, DISPLAYED A RESPONSE PATTERN DIFFERENT FROM THAT OBSERVED IN F1, SHOWING AN INCREASE IN WEIGHT IN THE DESCENDANTS OF CA EXPOSED FISH, IN COMPARISON WITH CONTROL ANIMALS, WHICH POINTS TO A MULTIGENERATIONAL EFFECT.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                             
19 3122  35 GESTATIONAL VALPROIC ACID EXPOSURE INDUCES EPIGENETIC MODIFICATIONS IN MURINE DECIDUA. INTRODUCTION: VALPROIC ACID (VPA), A WIDELY PRESCRIBED ANTIEPILEPTIC DRUG AND AN EFFECTIVE TREATMENT FOR BIPOLAR DISORDER AND NEUROPATHIC PAIN, RESULTS IN MULTIPLE DEVELOPMENTAL DEFECTS FOLLOWING IN UTERO EXPOSURE. UTERINE DECIDUA PROVIDES NUTRITIONAL AND PHYSICAL SUPPORT DURING IMPLANTATION AND EARLY EMBRYONIC DEVELOPMENT. PERTURBATIONS IN THE MOLECULAR MECHANISMS WITHIN DECIDUAL TISSUE DURING EARLY PREGNANCY MIGHT AFFECT EARLY EMBRYONIC GROWTH, RESULT IN EARLY PREGNANCY LOSS OR CAUSE COMPLICATIONS IN THE LATER GESTATIONAL STAGE. VPA IS A KNOWN HISTONE DEACETYLASE INHIBITOR AND EPIGENETIC CHANGES SUCH AS HISTONE HYPERACETYLATION AND METHYLATION HAVE BEEN PROPOSED AS A MECHANISM OF VPA-INDUCED TERATOGENESIS. METHODS: THIS STUDY INVESTIGATED THE EFFECTS OF IN UTERO VPA EXPOSURE ON HISTONE MODIFICATIONS IN MURINE DECIDUAL TISSUE. PREGNANT CD-1 MICE WERE EXPOSED TO 400 MG/KG VPA OR SALINE ON GD9 VIA SUBCUTANEOUS INJECTION. DECIDUAL TISSUE FROM EACH GESTATIONAL SAC WAS HARVESTED AT 1, 3 AND 6 H FOLLOWING EXPOSURE. LEVELS OF ACETYLATED HISTONES H3, H4 AND H3K56, AS WELL AS METHYLATED HISTONES H3K9 AND H3K27 WERE ACID EXTRACTED AND ASSESSED BY WESTERN BLOTTING FOLLOWED BY ACID HISTONE EXTRACTION. RESULTS: VPA EXPOSURE INDUCED A SIGNIFICANT INCREASE (P < 0.05) IN THE LEVELS OF ACETYLATED H3 AT 1, 3 H; ACETYLATED H4 AT 1, 3 AND 6 H AND TRIMETHYLATED H3K9 AT 6 H. IN CONTRAST, NO SIGNIFICANT PERTURBATIONS WERE NOTED IN THE LEVELS OF MONOMETHYLATED H3K9, TRIMETHYLATED H3K27 AND ACETYLATED H3K56. DISCUSSION: THE RESULTS FROM THIS STUDY SUGGEST THAT VPA-INDUCED DECIDUAL HISTONE MODIFICATIONS MIGHT PLAY AN IMPORTANT ROLE AS A MECHANISM OF VPA-INDUCED TERATOGENESIS DURING EARLY EMBRYONIC GROWTH.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20 5189  38 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE.	2022