1   696 138 BROMATE-INDUCED CHANGES IN P21 DNA METHYLATION AND HISTONE ACETYLATION IN RENAL CELLS. BROMATE (BRO3-) IS A WATER DISINFECTION BYPRODUCT (DBP) PREVIOUSLY SHOWN TO INDUCE NEPHROTOXICITY IN VITRO AND IN VIVO. WE RECENTLY SHOWED THAT INHIBITORS OF DNA METHYLTRANSFERASE 5-AZA-2'-DEOXYCYTIDINE (5-AZA) AND HISTONE DEACETYLASE TRICHOSTATIN A (TSA) INCREASED BRO3- NEPHROTOXICITY WHEREAS ALTERING THE EXPRESSION OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P21. HUMAN EMBRYONIC KIDNEY CELLS (HEK293) AND NORMAL RAT KIDNEY (NRK) CELLS WERE SUB-CHRONICALLY EXPOSED TO BRO3- OR EPIGENETIC INHIBITORS FOR 18 DAYS, FOLLOWED BY 9 DAYS OF WITHDRAWAL. DNA METHYLATION WAS STUDIED USING A MODIFICATION OF BISULFITE AMPLICON SEQUENCING CALLED TARGETED GENE BISULFITE SEQUENCING. BASAL PROMOTER METHYLATION IN THE HUMAN P21 PROMOTER REGION WAS SUBSTANTIALLY LOWER THAN THAT OF THE RAT DNA. FURTHERMORE, 5-AZA DECREASED DNA METHYLATION IN HEK293 CELLS AT THE SIS-INDUCIBLE ELEMENT AT 3 DISTINCT CPG SITES LOCATED AT 691, 855, AND 895 BP UPSTREAM OF TRANSCRIPTION START SITE (TSS). 5-AZA ALSO DECREASED METHYLATION AT THE RAT P21 PROMOTER ABOUT 250 BP UPSTREAM OF THE P21 TSS. IN CONTRAST, SUB-CHRONIC BRO3- EXPOSURE FAILED TO ALTER METHYLATION IN HUMAN OR RAT RENAL CELLS. BRO3- EXPOSURE ALTERED HISTONE ACETYLATION IN NRK CELLS AT THE P21 TSS, BUT NOT IN HEK293 CELLS. INTERESTINGLY, CHANGES IN DNA METHYLATION INDUCED BY 5-AZA PERSISTED AFTER ITS REMOVAL; HOWEVER, TSA- AND BRO3--INDUCED HISTONE HYPERACETYLATION RETURNED TO BASAL LEVELS AFTER 3 DAYS OF WITHDRAWAL. THESE DATA DEMONSTRATE NOVEL SITES WITHIN THE P21 GENE THAT ARE EPIGENETICALLY REGULATED AND FURTHER SHOW THAT SIGNIFICANT DIFFERENCES EXIST IN THE EPIGENETIC LANDSCAPE BETWEEN RAT AND HUMAN P21, ESPECIALLY WITH REGARDS TO TOXICANT-INDUCED CHANGES IN HISTONE ACETYLATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2  5097  33 PLASTICS DERIVED ENDOCRINE-DISRUPTING COMPOUNDS AND THEIR EFFECTS ON EARLY DEVELOPMENT. DESPITE THE FACT THAT THE ESTROGENIC EFFECTS OF BISPHENOLS WERE FIRST DESCRIBED 80 YEARS AGO, RECENT DATA ABOUT ITS POTENTIAL NEGATIVE IMPACT ON BIRTH OUTCOME PARAMETERS RAISES A STRONG RATIONALE TO INVESTIGATE FURTHER. THE ADVERSE HEALTH EFFECTS OF PLASTICS RECOMMEND TO MEASURE THE IMPACTS OF ENDOCRINE-DISRUPTING COMPOUNDS (EDCS) SUCH AS BISPHENOLS (BPA, BPS, BPF), BIS(2-ETHYLHEXYL) PHTHALATE, AND DIBUTYL PHTHALATE (DBP) IN HUMAN HEALTH. EXPOSURE TO THESE COMPOUNDS IN UTERO MAY PROGRAM THE DISEASES OF THE TESTIS, PROSTATE, KIDNEY AND ABNORMALITIES IN THE IMMUNE SYSTEM, AND CAUSE TUMORS, UTERINE HEMORRHAGE DURING PREGNANCY AND POLYCYSTIC OVARY. THESE COMPOUNDS ALSO CONTROL THE PROCESSES OF EPIGENETIC TRANSGENERATIONAL INHERITANCE OF ADULT-ONSET DISEASES BY MODULATING DNA METHYLATION AND EPIMUTATIONS IN REPRODUCTIVE CELLS. THE EARLY DEVELOPMENTAL STAGE IS THE MOST SUSCEPTIBLE WINDOW FOR DEVELOPMENTAL AND GENOMIC PROGRAMMING. THE CRITICAL STAGES OF THE EVENTS FOR A NORMAL HUMAN BIRTH LIE BETWEEN THE MANY TRANSITIONS OCCURRING BETWEEN SPERMATOGENESIS, EGG FERTILIZATION AND THE FULLY FORMED FETUS. AS THE CELLS BEGIN TO GROW AND DIFFERENTIATE, THERE ARE CRITICAL BALANCES OF HORMONES, AND PROTEIN SYNTHESIS. DATA ARE EMERGING ON HOW THESE PLASTIC-DERIVED COMPOUNDS AFFECT EMBRYOGENESIS, PLACENTATION AND FETO-PLACENTAL DEVELOPMENT SINCE PREGNANT WOMEN AND UNBORN FETUSES ARE OFTEN EXPOSED TO THESE FACTORS DURING PRECONCEPTION AND THROUGHOUT GESTATION. IMPAIRED EARLY DEVELOPMENT THAT ULTIMATELY INFLUENCES FETAL OUTCOMES IS AT THE CENTER OF MANY DEVELOPMENTAL DISORDERS AND CONTRIBUTES AN INDEPENDENT RISK FACTOR FOR ADULT CHRONIC DISEASES. THIS REVIEW WILL SUMMARIZE THE CURRENT STATUS ON THE IMPACT OF EXPOSURE TO PLASTIC DERIVED EDCS ON THE GROWTH, GENE EXPRESSION, EPIGENETIC AND ANGIOGENIC ACTIVITIES OF THE EARLY FETAL DEVELOPMENT PROCESS AND THEIR POSSIBLE EFFECTS ON BIRTH OUTCOMES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3  4015  31 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4   654  36 BISPHENOL S INDUCED EPIGENETIC AND TRANSCRIPTIONAL CHANGES IN HUMAN BREAST CANCER CELL LINE MCF-7. IN RECENT YEARS, CONCERNS ABOUT USING BISPHENOL A (BPA) IN DAILY CONSUME PRODUCTS AND ITS EFFECTS IN MANY CHRONIC HUMAN DISEASES HAVE PROMPTED THE REMOVAL OF BPA. HOWEVER, THE WIDELY USED BPA ALTERNATIVES, INCLUDING BISPHENOL S (BPS), HAVE A HIGH STRUCTURAL SIMILARITY WITH BPA, SUGGESTING THAT THEY MAY HAVE SIMILAR BIOLOGICAL EFFECTS TOWARDS HUMAN BEINGS. INDEED, BPS WAS ALSO FOUND TO HAVE ENDOCRINE-DISRUPTING EFFECTS. EPIGENETIC MECHANISM WAS REPORTED TO BE INVOLVED IN BPA-INDUCED BIOLOGICAL EFFECTS IN BOTH IN VITRO AND IN VIVO MODELS. HOWEVER, THERE IS NO ASSESSMENT ON WHETHER BPS COULD CAUSE EPIGENETIC CHANGES. IN THIS WORK, WE INVESTIGATED THE POSSIBLE EPIGENETIC EFFECTS OF BPS THAT MIGHT INDUCE IN HUMAN BREAST CANCER CELL LINE MCF-7. WE FOUND THAT BPS COULD CHANGE DNA METHYLATION LEVEL OF TRANSPOSONS. BESIDES, METHYLATION STATUS IN PROMOTER OF BREAST CANCER RELATED GENES CDH1, SFN, TNFRSF10C WERE ALSO CHANGED, WHICH IMPLIED THAT BPS MIGHT PLAY A ROLE IN THE DEVELOPMENT OF BREAST CANCER. GENE EXPRESSION PROFILING SHOWED THAT SOME GENES RELATED TO BREAST CANCER PROGRESSION WERE UPREGULATED, INCLUDING THBS4, PPARGC1A, CREB5, COL5A3. GENE ONTOLOGY (GO) ANALYSIS OF THE DIFFERENTIALLY EXPRESSED GENES REVEALED THE SIGNIFICANTLY CHANGES IN PI3K-AKT SIGNALING PATHWAY AND EXTRACELLULAR MATRIX, WHICH WERE RELATED TO THE PROLIFERATION, MIGRATION AND INVASION OF BREAST CANCER CELLS. THESE RESULTS ILLUSTRATED THAT BPS EXPOSURE MIGHT PLAY ROLES IN THE PROGRESSION OF BREAST CANCER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5   899  25 CHRONIC EXPOSURE TO A LOW CONCENTRATION OF BISPHENOL A DURING FOLLICLE CULTURE AFFECTS THE EPIGENETIC STATUS OF GERMINAL VESICLES AND METAPHASE II OOCYTES. OBJECTIVE: TO DETERMINE WHETHER EXPOSURE TO LOW CONCENTRATIONS OF THE ENDOCRINE DISRUPTING CHEMICAL BISPHENOL A (BPA) DURING FOLLICLE CULTURE AND OOCYTE GROWTH ALTERS THE METHYLATION STATUS OF DIFFERENTIALLY METHYLATED REGIONS (DMRS) OF IMPRINTED GENES AND HISTONE POSTTRANSLATIONAL MODIFICATION PATTERNS IN MAMMALIAN OOCYTES. DESIGN: COMPARATIVE AND CONTROL STUDY. SETTING: EXPERIMENTAL LABORATORY. ANIMAL(S): C57/BL6JXCBA/CA MICE. INTERVENTION(S): EXPOSURE OF OOCYTES TO 3 NM OR 300 NM BPA DURING FOLLICLE CULTURE FROM PREANTRAL TO ANTRAL STAGE. MAIN OUTCOME MEASURE(S): METHYLATION STATUS OF DMRS OF MATERNALLY IMPRINTED (SNRPN, IGF2R, AND MEST) AND PATERNALLY IMPRINTED GENE(S) (H19) IN MOUSE GERMINAL VESICLE OOCYTES; TRIMETHYLATION OF HISTONE H3K9, ACETYLATION OF HISTONE H4K12, AND DISTANCE BETWEEN CENTROMERES OF SISTER CHROMATIDS IN METAPHASE II OOCYTES. RESULT(S): EXPOSURE TO 3 NM BPA WAS ASSOCIATED WITH SLIGHTLY ACCELERATED FOLLICLE DEVELOPMENT, STATISTICALLY SIGNIFICANT INCREASES IN ALLELE METHYLATION ERRORS IN DMRS OF MATERNALLY IMPRINTED GENES, AND STATISTICALLY SIGNIFICANT DECREASES IN HISTONE H3K9 TRIMETHYLATION AND INTERKINETOCHORE DISTANCE. CONCLUSION(S): THE DISTURBANCES IN OOCYTE GENOMIC IMPRINTING AND MODIFICATION OF POSTTRANSLATIONAL HISTONE AND CENTROMERE ARCHITECTURE PROVIDE THE FIRST LINK BETWEEN LOW BPA EXPOSURES AND INDUCTION OF EPIGENETIC CHANGES THAT MAY CONTRIBUTE TO CHROMOSOME CONGRESSION FAILURES AND MEIOTIC ERRORS, AND TO ALTERED GENE EXPRESSION THAT MIGHT AFFECT HEALTH OF THE OFFSPRING.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6  3812  37 INTRAUTERINE ENDOGENOUS HIGH GLUCOCORTICOIDS PROGRAM OVARIAN DYSFUNCTION IN FEMALE OFFSPRING SECONDARY TO PRENATAL CAFFEINE EXPOSURE. OVARIAN DYSFUNCTION HAS AN INTRAUTERINE ORIGIN, AND PRENATAL CAFFEINE EXPOSURE (PCE) COULD LEAD TO ABNORMAL FOLLICLE COUNTS IN OFFSPRING AFTER BIRTH. HOWEVER, THE EFFECT OF PCE ON OFFSPRING OVARIAN FUNCTION AND ITS MECHANISM OF INTRAUTERINE PROGRAMMING HAVE NOT BEEN REPORTED THUS FAR. IN THIS STUDY, PREGNANT WISTAR RATS WERE INTRAGASTRICALLY ADMINISTERED CAFFEINE (30 AND 120 MG/KG.D) AT GESTATIONAL DAYS 9-20 (GD9-20). CERTAIN TESTS WERE PERFORMED ON THE BLOOD, OVARIES AND HYPOTHALAMUS OF FEMALE OFFSPRING AT DIFFERENT TIME POINTS. PCE FEMALE OFFSPRING HAD OVARIAN DYSFUNCTION IN ADULTHOOD COMPARED WITH THE CONTROL. FURTHER RESULTS SHOWED THAT IN UTERO OVARIAN MORPHOLOGICAL DEVELOPMENT AND ESTRADIOL SYNTHESIS WERE INHIBITED BUT RAPIDLY INCREASED DURING PUBERTY IN THE PCE GROUP. THE HISTONE 3 LYSINE 27 ACETYLATION (H3K27AC) LEVEL OF THE INSULIN-LIKE GROWTH FACTOR 1 (IGF1) PROMOTER REGION AND ITS EXPRESSION WERE DECREASED IN THE OVARY, WHICH WAS DUE TO EXPOSURE TO HIGH LEVELS OF FETAL BLOOD CORTICOSTERONE, AND THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION SHIFTED TO INCREASE AFTER BIRTH WITH A DECREASE IN SERUM CORTICOSTERONE LEVELS. CHRONIC STRESS LED TO INCREASED SERUM CORTICOSTERONE LEVELS IN ADULT OFFSPRING, WHEREAS OVARIAN MORPHOLOGICAL DEVELOPMENT, THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION, AND ESTRADIOL SYNTHESIS WERE SIGNIFICANTLY INHIBITED. MOREOVER, THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-OVARIAN (HPO) AXIS WAS INCREASED IN THE EARLY POSTNATAL PERIOD OF PCE OFFSPRING, AND CHRONIC STRESS REVERSED THESE CHANGES. IN THE KGN CELL LINE, IT WAS FOUND THAT CORTISOL COULD PROMOTE THE TRANSLOCATION OF THE GLUCOCORTICOID RECEPTOR (GR) INTO THE NUCLEUS AND UPREGULATE HISTONE DEACETYLASE 10 (HDAC10) TO INHIBIT THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION AND ESTRADIOL SYNTHESIS. IN SUMMARY, PCE IS ASSOCIATED WITH OVARIAN DYSFUNCTION IN FEMALE ADULT OFFSPRING, AND THE POTENTIAL MECHANISM IS RELATED TO INTRAUTERINE HIGH GLUCOCORTICOID EXPOSURE BY ACTIVATING THE GR AND RECRUITING HDAC10 TO AFFECT OVARIAN GLUCOCORTICOID-IGF1 AXIS PROGRAMMING AND TO INHIBIT ESTRADIOL SYNTHESIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7   579  34 BEHAVIORAL AND MOLECULAR NEUROEPIGENETIC ALTERATIONS IN PRENATALLY STRESSED MICE: RELEVANCE FOR THE STUDY OF CHROMATIN REMODELING PROPERTIES OF ANTIPSYCHOTIC DRUGS. WE HAVE RECENTLY REPORTED THAT MICE BORN FROM DAMS STRESSED DURING PREGNANCY (PRS MICE), IN ADULTHOOD, HAVE BEHAVIORAL DEFICITS REMINISCENT OF BEHAVIORS OBSERVED IN SCHIZOPHRENIA (SZ) AND BIPOLAR (BP) DISORDER PATIENTS. FURTHERMORE, WE HAVE SHOWN THAT THE FRONTAL CORTEX (FC) AND HIPPOCAMPUS OF ADULT PRS MICE, LIKE THAT OF POSTMORTEM CHRONIC SZ PATIENTS, ARE CHARACTERIZED BY INCREASES IN DNA-METHYLTRANSFERASE 1 (DNMT1), TEN-ELEVEN METHYLCYTOSINE DIOXYGENASE 1 (TET1) AND EXHIBIT AN ENRICHMENT OF 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC) AT NEOCORTICAL GABAERGIC AND GLUTAMATERGIC GENE PROMOTERS. HERE, WE SHOW THAT THE BEHAVIORAL DEFICITS AND THE INCREASED 5MC AND 5HMC AT GLUTAMIC ACID DECARBOXYLASE 67 (GAD1), REELIN (RELN) AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROMOTERS AND THE REDUCED EXPRESSION OF THE MESSENGER RNAS (MRNAS) AND PROTEINS CORRESPONDING TO THESE GENES IN FC OF ADULT PRS MICE IS REVERSED BY TREATMENT WITH CLOZAPINE (5 MG KG(-1) TWICE A DAY FOR 5 DAYS) BUT NOT BY HALOPERIDOL (1 MG KG(-1) TWICE A DAY FOR 5 DAYS). INTERESTINGLY, CLOZAPINE HAD NO EFFECT ON EITHER THE BEHAVIOR, PROMOTER METHYLATION OR THE EXPRESSION OF THESE MRNAS AND PROTEINS WHEN ADMINISTERED TO OFFSPRING OF NONSTRESSED PREGNANT MICE. CLOZAPINE, BUT NOT HALOPERIDOL, REDUCED THE ELEVATED LEVELS OF DNMT1 AND TET1, AS WELL AS THE ELEVATED LEVELS OF DNMT1 BINDING TO GAD1, RELN AND BDNF PROMOTERS IN PRS MICE SUGGESTING THAT CLOZAPINE, UNLIKE HALOPERIDOL, MAY LIMIT DNA METHYLATION BY INTERFERING WITH DNA METHYLATION DYNAMICS. WE CONCLUDE THAT THE PRS MOUSE MODEL MAY BE USEFUL PRECLINICALLY IN SCREENING FOR THE POTENTIAL EFFICACY OF ANTIPSYCHOTIC DRUGS ACTING ON ALTERED EPIGENETIC MECHANISMS. FURTHERMORE, PRS MICE MAY BE INVALUABLE FOR UNDERSTANDING THE ETIOPATHOGENESIS OF SZ AND BP DISORDER AND FOR PREDICTING TREATMENT RESPONSES AT EARLY STAGES OF THE ILLNESS ALLOWING FOR EARLY DETECTION AND REMEDIAL INTERVENTION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8    73  28 A MULTI-GENERATIONAL STUDY ON LOW-DOSE BPA EXPOSURE IN WISTAR RATS: EFFECTS ON MATERNAL BEHAVIOR, FLAVOR INTAKE AND DEVELOPMENT. BISPHENOL A (BPA) IS A COMMON ENDOCRINE DISRUPTOR FOUND AS AN ENVIRONMENTAL AND FOOD CONTAMINANT. IT EXERTS BOTH DEVELOPMENTAL AND BEHAVIORAL EFFECTS, MAINLY WHEN EXPOSURE OCCURS IN EARLY LIFE. THE AIM OF THIS STUDY WAS TO DETERMINE THE MULTI-GENERATIONAL EFFECTS OF CHRONIC, HUMAN-RELEVANT LOW-DOSE EXPOSURE TO BPA ON DEVELOPMENT, MATERNAL BEHAVIOR AND FLAVOR PREFERENCE IN WISTAR RATS. BPA WAS ORALLY ADMINISTERED AT A DAILY DOSE OF 5 MUG/KG BODY WEIGHT TO F0 PREGNANT DAMS FROM THE FIRST DAY OF GESTATION (GD 1) UNTIL THE LAST DAY OF LACTATION (LD 21), AND THEN TO F1 OFFSPRING FROM WEANING (PND 21) TO ADULTHOOD (PND 100). F2 OFFSPRING WERE NOT EXPOSED. DEVELOPMENT AND CLINICAL SIGNS OF TOXICITY WERE ASSESSED DAILY. MATERNAL BEHAVIOR WAS EVALUATED BY OBSERVING NURSING AND PUP-CARING ACTIONS, AS WELL AS "NON-MATERNAL" BEHAVIORS IN F0 AND F1 DAMS FROM PARTURITION UNTIL LD 8. THE FLAVOR PREFERENCES OF F1 AND F2 OFFSPRING WERE EVALUATED BASED ON THE INTAKE OF SWEET, SALT AND FAT SOLUTIONS USING THE TWO-BOTTLE CHOICE TEST ON PND 21-34 AND PND 86-99. BPA EXPOSURE: 1) DECREASED MATERNAL BEHAVIOR IN F1 DAMS, 2) CAUSED DEVELOPMENTAL DEFECTS IN BOTH F1 AND F2 OFFSPRING, WITH A NOTICEABLE DECREASE IN ANOGENITAL DISTANCE IN MALE RATS, AND 3) DID NOT AFFECT FLAVORED SOLUTION INTAKE IN F1, BUT INDUCED CHANGES IN SWEET PREFERENCE IN F2 JUVENILES AND IN SALT AND FAT SOLUTION INTAKES IN F2 ADULTS, AND 4) INDUCED A BODY WEIGHT INCREASE IN THE F2 GENERATION ONLY, WHEREAS FOOD INTAKE AND WATER CONSUMPTION DID NOT CHANGE. TAKEN AS A WHOLE, OUR FINDINGS SHOWED THAT BOTH GESTATIONAL (F0) AND LIFELONG (F1) EXPOSURES TO A HUMAN-RELEVANT DOSE OF BPA COULD INDUCE MULTI-GENERATIONAL EFFECTS ON BOTH DEVELOPMENT AND BEHAVIOR. THESE RESULTS SUGGEST POSSIBLE SELECTIVE NEUROENDOCRINE DEFECTS AND/OR EPIGENETIC CHANGES CAUSED BY BPA EXPOSURE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  5253  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  4752  27 NOVEL ROLE OF GESTATIONAL HYDRALAZINE IN LIMITING MATERNAL AND DIETARY OBESITY-RELATED CHRONIC KIDNEY DISEASE. BACKGROUND: MATERNAL OBESITY IS A RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD) IN OFFSPRING, UNDERPINNING THE THEORY OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PROGRAMMING OF ADULT CHRONIC DISEASE BY MATERNAL OBESITY, THEREFORE, DNA DEMETHYLATING AGENTS MAY MITIGATE OFFSPRING RISK OF DISEASE. IN RODENT MODELS, LOW-DOSE HYDRALAZINE HAS PREVIOUSLY BEEN SHOWN TO REDUCE RENAL FIBROSIS VIA DNA DEMETHYLATION. WE USED MOUSE MODELS OF MATERNAL OBESITY AND OFFSPRING OBESITY TO DETERMINE WHETHER ADMINISTRATION OF LOW-DOSE HYDRALAZINE DURING GESTATION CAN PREVENT FETAL PROGRAMMING OF CKD IN OFFSPRING. METHODS: FEMALE C57BL/6 MICE RECEIVED HIGH FAT DIET (HFD) OR CHOW PRIOR TO MATING, DURING GESTATION AND LACTATION. DURING GESTATION, DAMS RECEIVED SUBCUTANEOUS HYDRALAZINE (5 MG/KG) OR SALINE THRICE-WEEKLY. MALE OFFSPRING WEANED TO HFD OR CHOW, WHICH CONTINUED UNTIL ENDPOINT AT 32 WEEKS. BIOMETRIC AND METABOLIC PARAMETERS, RENAL GLOBAL DNA METHYLATION, RENAL FUNCTIONAL AND STRUCTURAL CHANGES, AND RENAL MARKERS OF FIBROSIS, INFLAMMATION AND OXIDATIVE STRESS WERE ASSESSED AT ENDPOINT. RESULTS: OFFSPRING EXPOSED TO MATERNAL OBESITY OR DIET-INDUCED OBESITY HAD SIGNIFICANTLY INCREASED RENAL GLOBAL DNA METHYLATION, TOGETHER WITH OTHER ADVERSE RENAL EFFECTS INCLUDING ALBUMINURIA, GLOMERULOSCLEROSIS, RENAL FIBROSIS, AND OXIDATIVE STRESS. OFFSPRING EXPOSED TO GESTATIONAL HYDRALAZINE HAD SIGNIFICANTLY REDUCED RENAL GLOBAL DNA METHYLATION. IN OBESE OFFSPRING OF OBESE MOTHERS, GESTATIONAL HYDRALAZINE SIGNIFICANTLY DECREASED ALBUMINURIA, GLOMERULOSCLEROSIS, AND SERUM CREATININE. OBESE OFFSPRING OF HYDRALAZINE-TREATED LEAN MOTHERS DISPLAYED REDUCED MARKERS OF RENAL FIBROSIS AND OXIDATIVE STRESS. CONCLUSION: GESTATIONAL HYDRALAZINE DECREASED RENAL GLOBAL DNA METHYLATION AND EXERTED RENOPROTECTIVE EFFECTS IN OFFSPRING. THIS SUPPORTS A POTENTIAL THERAPEUTIC EFFECT OF HYDRALAZINE IN PREVENTING MATERNAL OBESITY OR DIETARY OBESITY-RELATED CKD, THROUGH AN EPIGENETIC MECHANISM.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11  3304  41 HIGH-GLUCOSE CONCENTRATIONS CHANGE DNA METHYLATION LEVELS IN HUMAN IVM OOCYTES. STUDY QUESTION: WHAT ARE THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON DNA METHYLATION OF HUMAN OOCYTES? SUMMARY ANSWER: HIGH-GLUCOSE CONCENTRATIONS ALTERED DNA METHYLATION LEVELS OF PEG3 AND ADIPONECTIN IN HUMAN IN VITRO MATURATION OOCYTES. WHAT IS KNOWN ALREADY: MATERNAL DIABETES HAS A DETRIMENTAL INFLUENCE ON OOCYTE QUALITY INCLUDING EPIGENETIC MODIFICATIONS, AS SHOWN IN NON-HUMAN MAMMALIAN SPECIES. STUDY DESIGN, SIZE, DURATION: IMMATURE METAPHASE I (MI) STAGE OOCYTES OF GOOD QUALITY WERE RETRIEVED FROM PATIENTS WHO HAD NORMAL OVARIAN POTENTIAL AND WHO UNDERWENT ICSI IN THE REPRODUCTIVE MEDICINE CENTER OF PEOPLE'S HOSPITAL OF ZHENGZHOU UNIVERSITY. MI OOCYTES WERE CULTURED IN MEDIUM WITH DIFFERENT GLUCOSE CONCENTRATIONS (CONTROL, 10 MM AND 15 MM) IN VITRO AND 48 H LATER, OOCYTES WITH FIRST POLAR BODY EXTRUSION WERE COLLECTED TO CHECK THE DNA METHYLATION LEVELS. PARTICIPANTS/MATERIALS, SETTING, METHODS: MI OOCYTES UNDERWENT IN VITRO MATURATION (IVM) AT 37 DEGREES C WITH 5% MIXED GAS FOR 48 H. THEN THE MATURE OOCYTES WERE TREATED WITH BISULFITE BUFFER. TARGET SEQUENCES WERE AMPLIFIED USING NESTED OR HALF-NESTED PCR AND THE DNA METHYLATION STATUS WAS TESTED USING COMBINED BISULFITE RESTRICTION ANALYSIS (COBRA) AND BISULFITE SEQUENCING (BS). MAIN RESULTS AND THE ROLE OF CHANCE: HIGH-GLUCOSE CONCENTRATIONS SIGNIFICANTLY DECREASED THE FIRST POLAR BODY EXTRUSION RATE. COMPARED TO CONTROLS, THE DNA METHYLATION LEVELS OF PEG3 IN HUMAN IVM OOCYTES WERE SIGNIFICANTLY HIGHER IN 10 MM (P < 0.001) AND 15 MM (P < 0.001) CONCENTRATIONS OF GLUCOSE. BUT THE DNA METHYLATION LEVEL OF H19 WAS NOT AFFECTED BY HIGH-GLUCOSE CONCENTRATIONS IN HUMAN IVM OOCYTES. WE ALSO FOUND THAT THERE WAS A DECREASE IN DNA METHYLATION LEVELS IN THE PROMOTER OF ADIPONECTIN IN HUMAN IVM OOCYTES BETWEEN CONTROLS AND OOCYTES EXPOSED TO 10 MM GLUCOSE (P = 0.028). LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: IT IS NOT CLEAR WHETHER THE ALTERATIONS ARE BENEFICIAL OR NOT FOR THE EMBRYO DEVELOPMENT AND OFFSPRING HEALTH. THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON THE WHOLE PROCESS OF OOCYTE MATURATION ARE STILL NOT ELUCIDATED. ANOTHER ISSUE IS THAT THE NUMBER OF OOCYTES USED IN THIS STUDY WAS LIMITED. WIDER IMPLICATIONS OF THE FINDINGS: THIS IS THE FIRST TIME THAT THE EFFECTS OF HIGH-GLUCOSE CONCENTRATION ON DNA METHYLATION OF HUMAN OOCYTES HAVE BEEN ELUCIDATED. OUR RESULT INDICATES THAT IN HUMANS, THE HIGH RISK OF CHRONIC DISEASES IN OFFSPRING FROM DIABETIC MOTHERS MAY ORIGINATE FROM ABNORMAL DNA MODIFICATIONS IN OOCYTES. STUDY FUNDING/COMPETING INTEREST(S): THIS WORK WAS SUPPORTED BY THE FUND OF NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA (81401198) AND DOCTOR FOUNDATION OF QINGDAO AGRICULTURAL UNIVERSITY (1116008).THE AUTHORS DECLARE THAT THERE ARE NO POTENTIAL CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.	2018	

12  2156  42 EPIGENETIC MECHANISMS ARE INVOLVED IN THE REGULATION OF ETHANOL CONSUMPTION IN MICE. BACKGROUND: REPEATED ALCOHOL EXPOSURE IS KNOWN TO INCREASE SUBSEQUENT ETHANOL CONSUMPTION IN MICE. HOWEVER, THE UNDERLYING MECHANISMS HAVE NOT BEEN FULLY ELUCIDATED. ONE POSTULATED MECHANISM INVOLVES EPIGENETIC MODIFICATIONS, INCLUDING HISTONE MODIFICATIONS AND DNA METHYLATION OF RELEVANT GENES SUCH AS NR2B OR BDNF. METHODS: TO INVESTIGATE THE ROLE OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF ALCOHOL DRINKING BEHAVIOR, AN ESTABLISHED CHRONIC INTERMITTENT ETHANOL EXPOSURE REINFORCED ETHANOL DRINKING MOUSE MODEL WITH VAPOR INHALATION OVER TWO 9-DAY TREATMENT REGIMENS WAS USED. THE DNA METHYLTRANSFERASE INHIBITOR, 5-AZACYTIDINE OR THE HISTONE DEACETYLASE INHIBITOR, TRICHOSTATIN A WAS ADMINISTERED (INTRAPERITONEALLY) TO C57BL/6 MICE 30 MIN BEFORE DAILY EXPOSURE TO CHRONIC INTERMITTENT ETHANOL. CHANGES IN ETHANOL CONSUMPTION WERE MEASURED USING THE 2-BOTTLE CHOICE TEST. RESULTS: THE RESULTS INDICATED THAT SYSTEMIC ADMINISTRATION OF TRICHOSTATIN A (2.5 MICROG/G) FACILITATED CHRONIC INTERMITTENT ETHANOL-INDUCED ETHANOL DRINKING, BUT SYSTEMIC ADMINISTRATION OF 5-AZACYTIDINE (2 MICROG/G) DID NOT CAUSE THE SAME EFFECT. HOWEVER, WHEN 5-AZACYTIDINE WAS ADMINISTERED BY INTRACEREBROVENTRICULAR INJECTION, IT FACILITATED CHRONIC INTERMITTENT ETHANOL-INDUCED ETHANOL DRINKING. FURTHERMORE, THE INCREASED DRINKING CAUSED BY CHRONIC INTERMITTENT ETHANOL WAS PREVENTED BY INJECTION OF A METHYL DONOR, S-ADENOSYL-L-METHIONINE. TO PROVIDE EVIDENCE THAT CHRONIC INTERMITTENT ETHANOL- OR TRICHOSTATIN A-INDUCED DNA DEMETHYLATION AND HISTONE MODIFICATIONS OF THE NR2B PROMOTER MAY UNDERLIE THE ALTERED ETHANOL CONSUMPTION, WE EXAMINED EPIGENETIC MODIFICATIONS AND NR2B EXPRESSION IN THE PREFRONTAL CORTEX OF THESE MICE. CHRONIC INTERMITTENT ETHANOL OR TRICHOSTATIN A DECREASED DNA METHYLATION AND INCREASED HISTONE ACETYLATION IN THE NR2B GENE PROMOTER, AS WELL AS MRNA LEVELS OF NR2B IN THESE MICE. CONCLUSIONS: TAKEN TOGETHER, THESE RESULTS INDICATE THAT EPIGENETIC MODIFICATIONS ARE INVOLVED IN REGULATING ETHANOL DRINKING BEHAVIOR, PARTIALLY THROUGH ALTERING NR2B EXPRESSION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13   651  35 BISPHENOL A AND PHTHALATES MODULATE PERITONEAL MACROPHAGE FUNCTION IN FEMALE MICE INVOLVING SYMD2-H3K36 DIMETHYLATION. AMPLE EVIDENCE SUGGESTS THAT ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO BISPHENOL A (BPA) AND PHTHALATE, TWO CHEMICALS WIDELY USED IN THE PLASTICS INDUSTRY, DISTURBS HOMEOSTASIS OF INNATE IMMUNITY AND CAUSES INFLAMMATORY DISEASES. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS OF THESE TOXICANTS IN THE REGULATION OF MACROPHAGE INFLAMMATORY FUNCTIONS REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE ADDRESSED THE EFFECT OF CHRONIC EXPOSURE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE, EITHER IN VITRO OR IN VIVO, ON THE INFLAMMATORY REPROGRAMING OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT BPA AND PHTHALATES ADVERSELY AFFECTED EXPRESSION LEVELS OF THE PROINFLAMMATORY CYTOKINES AND MEDIATORS IN RESPONSE TO LIPOPOLYSACCHARIDE STIMULATION. EXPOSURE TO THESE TOXICANTS ALSO AFFECTED GENE EXPRESSION OF SCAVENGER RECEPTORS AND PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT THE EPIGENETIC INHIBITORS DIFFERENTIALLY MODULATED TARGET GENE EXPRESSION IN THESE CELLS. FURTHER ANALYSIS REVEALED THAT CERTAIN HISTONE MODIFICATION ENZYMES WERE ABERRANTLY EXPRESSED IN RESPONSE TO BPA OR PHTHALATE EXPOSURE, LEADING TO ALTERATION IN THE LEVELS OF H3K36 ACETYLATION AND DIMETHYLATION, TWO CHROMATIN MODIFICATIONS THAT ARE CRITICAL FOR TRANSCRIPTIONAL EFFICACY AND ACCURACY. OUR RESULTS FURTHER REVEALED THAT SILENCING OF H3K36-SPECIFIC METHYLTRANSFERASE SMYD2 EXPRESSION OR INHIBITION OF SMYD2 ENZYMATIC ACTIVITY ATTENUATED H3K36 DIMETHYLATION AND ENHANCED INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR-ALPHA EXPRESSION BUT DAMPENED THE PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. IN SUMMARY, OUR RESULTS INDICATE THAT PERITONEAL MACROPHAGES ARE VULNERABLE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE. THESE ENVIRONMENTAL TOXICANTS AFFECT PHENOTYPIC PROGRAMMING OF MACROPHAGES VIA EPIGENETIC MECHANISMS INVOLVING SMYD2-MEDIATED H3K36 MODIFICATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  1381  45 DI-(2-ETHYLHEXYL) PHTHALATE TRIGGERS DNA METHYLTRANSFERASE 1 EXPRESSION RESULTING IN ELEVATED CPG-METHYLATION AND ENRICHMENT OF MECP2 IN THE P21 PROMOTER IN VITRO. LEACHING OF THE PLASTIC CONSTITUENTS LEADING TO THEIR CHRONIC EXPOSURE TO HUMANS IS A MAJOR CONCERN FOR OUR ENVIRONMENTAL AND OCCUPATIONAL HEALTH. OUR PREVIOUS AND OTHER NUMEROUS STUDIES HAVE DEMONSTRATED THAT ENVIRONMENTAL CHEMICALS LIKE DI (2-ETHYLHEXYL)-PHTHALATE (DEHP) COULD POSE A RISK TOWARDS THE EPIGENETIC MECHANISMS. YET, THE MECHANISMS UNDERLYING ITS POSSIBLE EPIGENOTOXICITY ARE POORLY UNDERSTOOD. WE AIMED TO ASSESS THE IMPACT OF DEHP EXPOSURE TO THE HUMAN BREAST CANCER CELLS (MCF-7) AND RESULTANT CHANGES IN DNA METHYLATION REGULATORS ULTIMATELY ALTERING THE EXPRESSION OF THE CELL CYCLE REGULATOR P21 AS A MODEL GENE. THE MCF-7 CELLS WERE EXPOSED TO ENVIRONMENTALLY RELEVANT CONCENTRATIONS (50-500 NM) FOR 24 H. THE RESULTS SHOWED THAT DEHP WAS PROLIFERATIVE TOWARDS THE MCF-7 CELLS WHILE IT INDUCED GLOBAL DNA HYPERMETHYLATION WITH SELECTIVE UPREGULATION OF DNMT1 AND MECP2. IN ADDITION, DEHP SIGNIFICANTLY REDUCED P53 PROTEIN AND ITS ENRICHMENT TO THE DNMT1 PROMOTER BINDING SITE, WHILE ELEVATING SP1 AND E2F1 TRANSCRIPTION FACTOR LEVELS, STIMULATING THEIR BINDING TO THE PROMOTER DNA. COINCIDENTLY, INCREASED DNMT1 LEVEL WAS HIGHLY ASSOCIATED WITH LOSS OF P21 EXPRESSION AND INCREASED CYCLIN D1 LEVELS. IMPORTANTLY, THE P21, BUT NOT CYCLIN D1 PROMOTER CPG-DINUCLEOTIDES WERE HYPERMETHYLATED AFTER EXPOSURE TO 500 NM DEHP FOR 24 H. FURTHERMORE, IT WAS OBSERVED THAT DEHP SIGNIFICANTLY ENRICHED DNMT1 AND MECP2 TO THE P21 PROMOTER TO INDUCE DNA METHYLATION-BASED EPIGENETIC SILENCING OF P21, RESULTING IN INCREASED CELL PROLIFERATION. OUR RESULTS SUGGEST DEHP COULD POTENTIALLY INDUCE THE EPIGENETIC ALTERATIONS THAT MIGHT INCREASE THE RISK OF BREAST CANCER, GIVEN THAT THE UNDERLYING MECHANISMS SHOULD BE FULLY ELUCIDATED.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  1086  44 COCAINE ADMINISTRATION AND ITS WITHDRAWAL ENHANCE THE EXPRESSION OF GENES ENCODING HISTONE-MODIFYING ENZYMES AND HISTONE ACETYLATION IN THE RAT PREFRONTAL CORTEX. CHRONIC EXPOSURE TO COCAINE, CRAVING, AND RELAPSE ARE ATTRIBUTED TO LONG-LASTING CHANGES IN GENE EXPRESSION ARISING THROUGH EPIGENETIC AND TRANSCRIPTIONAL MECHANISMS. ALTHOUGH SEVERAL BRAIN REGIONS ARE INVOLVED IN THESE PROCESSES, THE PREFRONTAL CORTEX SEEMS TO PLAY A CRUCIAL ROLE NOT ONLY IN MOTIVATION AND DECISION-MAKING BUT ALSO IN EXTINCTION AND SEEKING BEHAVIOR. IN THIS STUDY, WE APPLIED COCAINE SELF-ADMINISTRATION AND EXTINCTION TRAINING PROCEDURES IN RATS WITH A YOKED TRIAD TO DETERMINE DIFFERENTIALLY EXPRESSED GENES IN PREFRONTAL CORTEX. MICROARRAY ANALYSIS SHOWED SIGNIFICANT UPREGULATION OF SEVERAL GENES ENCODING HISTONE MODIFICATION ENZYMES DURING EARLY EXTINCTION TRAINING. SUBSEQUENT REAL-TIME PCR TESTING OF THESE GENES FOLLOWING COCAINE SELF-ADMINISTRATION OR EARLY (THIRD DAY) AND LATE (TENTH DAY) EXTINCTION REVEALED ELEVATED LEVELS OF THEIR TRANSCRIPTS. INTERESTINGLY, WE FOUND THE ENRICHMENT OF BRD1 MESSENGER RNA IN RATS SELF-ADMINISTERING COCAINE THAT LASTED UNTIL EXTINCTION TRAINING DURING COCAINE WITHDRAWAL WITH CONCOMITANT INCREASED ACETYLATION OF H3K9 AND H4K8. HOWEVER, DESPITE ELEVATED LEVELS OF METHYL- AND DEMETHYLTRANSFERASE-ENCODED TRANSCRIPTS, NO CHANGES IN GLOBAL DI- AND TRI-METHYLATION OF HISTONE H3 AT LYSINE 4, 9, 27, AND 79 WERE OBSERVED. SURPRISINGLY, AT THE END OF EXTINCTION TRAINING (10 DAYS OF COCAINE WITHDRAWAL), MOST OF THE ANALYZED GENES IN THE RATS ACTIVELY AND PASSIVELY ADMINISTERING COCAINE RETURNED TO THE CONTROL LEVEL. TOGETHER, THE ALTERATIONS IDENTIFIED IN THE RAT PREFRONTAL CORTEX MAY SUGGEST ENHANCED CHROMATIN REMODELING AND TRANSCRIPTIONAL ACTIVITY INDUCED BY EARLY COCAINE ABSTINENCE; HOWEVER, TO KNOW WHETHER THEY ARE BENEFICIAL OR NOT FOR THE EXTINCTION OF DRUG-SEEKING BEHAVIOR, FURTHER IN VIVO EVALUATION IS REQUIRED.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16   949  29 CHRONIC METHAMPHETAMINE TREATMENT REDUCES THE EXPRESSION OF SYNAPTIC PLASTICITY GENES AND CHANGES THEIR DNA METHYLATION STATUS IN THE MOUSE BRAIN. METHAMPHETAMINE (METH) IS A HIGHLY ADDICTIVE PSYCHOSTIMULANT THAT MAY CAUSE LONG-LASTING SYNAPTIC DYSFUNCTION AND ABNORMAL GENE EXPRESSION. WE AIMED TO EXPLORE THE DIFFERENTIAL EXPRESSION OF SYNAPTIC PLASTICITY GENES IN CHRONIC METH-TREATED MOUSE BRAIN. WE USED THE RT(2) PROFILER PCR ARRAY AND THE REAL-TIME QUANTITATIVE PCR TO CHARACTERIZE DIFFERENTIALLY EXPRESSED SYNAPTIC PLASTICITY GENES IN THE FRONTAL CORTEX AND THE HIPPOCAMPUS OF CHRONIC METH-TREATED MICE COMPARED WITH NORMAL SALINE-TREATED MICE. WE FURTHER USED PYROSEQUENCING TO ASSESS DNA METHYLATION CHANGES IN THE CPG REGION OF THE FIVE IMMEDIATE EARLY GENES (IEGS) IN CHRONIC METH-TREATED MOUSE BRAIN. WE DETECTED SIX DOWNREGULATED GENES IN THE FRONTAL CORTEX AND THE HIPPOCAMPUS OF CHRONIC METH-TREATED MICE, INCLUDING FIVE IEGS (ARC, EGR2, FOS, KLF10, AND NR4A1) AND ONE NEURONAL RECEPTOR GENE (GRM1), COMPARED WITH NORMAL SALINE-TREATED GROUP, BUT ONLY FOUR GENES (ARC, EGR2, FOS, AND NR4A1) WERE CONFIRMED TO BE DIFFERENT. FURTHERMORE, WE FOUND SEVERAL CPG SITES OF THE ARC AND THE FOS THAT HAD SIGNIFICANT CHANGES IN DNA METHYLATION STATUS IN THE FRONTAL CORTEX OF CHRONIC METH-TREATED MICE, WHILE THE KLF10 AND THE NR4A1 THAT HAD SIGNIFICANT CHANGES IN THE HIPPOCAMPUS. OUR RESULTS SHOW THAT CHRONIC ADMINISTRATION OF METH MAY LEAD TO SIGNIFICANT DOWNREGULATION OF THE IEGS EXPRESSION IN BOTH THE FRONTAL CORTEX AND THE HIPPOCAMPUS, WHICH MAY PARTLY ACCOUNT FOR THE MOLECULAR MECHANISM OF THE ACTION OF METH. FURTHERMORE, THE CHANGES IN DNA METHYLATION STATUS OF THE IEGS IN THE BRAIN INDICATE THAT AN EPIGENETIC MECHANISM-DEPENDENT TRANSCRIPTIONAL REGULATION MAY CONTRIBUTE TO METH ADDICTION, WHICH WARRANTS ADDITIONAL STUDY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  5020  34 PERSISTENT OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 ATTENUATING GABAERGIC INHIBITION IN BASOLATERAL AMYGDALA ACCOUNTS FOR ANXIETY IN RAT OFFSPRING EXPOSED PERINATALLY TO LOW-DOSE BISPHENOL A. SUBSTANTIAL EVIDENCE INDICATES THAT PREDISPOSITION TO DISEASES CAN BE ACQUIRED DURING EARLY STAGES OF DEVELOPMENT AND INTERACTIONS BETWEEN ENVIRONMENTAL AND GENETIC FACTORS MAY BE IMPLICATED IN THE ONSET OF MANY PATHOLOGICAL CONDITIONS. WE HAVE SHOWN THAT PERINATAL EXPOSURE TO BISPHENOL A (BPA) AT ENVIRONMENTAL DOSE LEVEL CAUSES LONG-TERM ANXIETY-LIKE BEHAVIORS IN RATS. THE AIM OF THIS STUDY WAS TO EXAMINE EPIGENETIC REPROGRAMMING EFFECT OF BPA ON ANXIETY-RELATED NEUROBEHAVIOR IN THE RAT OFFSPRING. THE RESULTS OF REAL-TIME RT-PCR DISPLAYED THAT THE OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 (DNMT1) MRNA WAS ACCOMPANIED BY THE REDUCTION OF GLUTAMIC ACID DECARBOXYLASE 67 (GAD67) MRNA LEVEL IN THE BASOLATERAL AMYGDALA (BLA) OF POSTNATAL DAY 45 BPA-EXPOSED FEMALE RATS. CHRONIC INTRO-BLA INJECTION WITH 5-ADA-CDR COULD RECTIFY THE GAD67 MRNA EXPRESSION. BEHAVIORAL DATA SHOWED THAT THE ANXIETY-LIKE BEHAVIORS IN BPA-EXPOSED RATS WERE REVERSED BY INTRO-BLA TREATMENT WITH 5-ADA-CDR WHICH COULD BE FURTHER BLOCKED BY PTX. ELECTROPHYSIOLOGICAL STUDY REVEALED BEHAVIORAL ALTERATIONS WERE ASSOCIATED WITH THE INCREASE OF POSTSYNAPTIC NEURONAL EXCITABILITY IN THE CORTICAL-BLA PATHWAY WHICH APPEARED AS MULTISPIKE RESPONSES, PAIRED-PULSE FACILITATION INSTEAD OF PAIRED-PULSE INHIBITION AND LONG-TERM POTENTIATION AND 5-AZA-CDR TREATMENT RESTORED THE INCREASED SYNAPTIC TRANSMISSION IN THE BLA VIA IMPROVING GABAERGIC SYSTEM. THE ABOVE RESULTS SUGGEST THAT THE OVEREXPRESSION OF DNMT1 IN THE BLA IS RESPONSIBLE FOR THE ETIOLOGY OF ANXIETY ASSOCIATED WITH BPA EXPOSURE VIA GABAERGIC DISINHIBITION. IN ADDITION, WE ALSO FIND THESE LONG-TERM NEUROBEHAVIORAL EFFECTS OF DEVELOPMENTAL BPA EXPOSURE ARE REVERSIBLE IN ADOLESCENT PERIOD.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18  1087  33 COCAINE ALTERS THE MOUSE TESTICULAR EPIGENOME WITH DIRECT IMPACT ON HISTONE ACETYLATION AND DNA METHYLATION MARKS. RESEARCH QUESTION: RECENT EVIDENCE SUGGESTS THAT COCAINE ADMINISTRATION IN ANIMAL MODELS CAN TRIGGER NON-GENETIC INHERITANCE OF ADDICTION TRAITS FROM FATHER TO OFFSPRING, AFFECTING DEVELOPMENT AND BEHAVIOUR. IS CHRONIC COCAINE INTAKE INVOLVED IN ALTERATIONS OF EPIGENETIC HOMEOSTASIS IN THE TESTIS? DESIGN: EPIGENETIC MARKS AND MEDIATORS IN TESTIS AND ISOLATED GERM CELLS OF ADULT MICE TREATED WITH COCAINE (10 MG/KG) OR VEHICLE (STERILE SALINE SOLUTION) WERE EVALUATED IN AN INTERMITTENT BINGE PROTOCOL: THREE INTRAPERITONEAL INJECTIONS, 1 H APART, ONE DAY ON/OFF FOR 13 DAYS, COLLECTING TISSUE 24 H AFTER THE LAST BINGE ADMINISTRATION (DAY 14). RESULTS: IT WAS SHOWN THAT CHRONIC COCAINE INTAKE IN MICE DISRUPTS TESTICULAR EPIGENETIC HOMEOSTASIS, INCREASING GLOBAL METHYLATED CYTOSINE LEVELS IN DNA FROM GERM CELLS AND SPERM. COCAINE ALSO INCREASED TESTICULAR AND GERM CELL ACETYLATED HISTONE 3 AND 4 AND DECREASED EXPRESSION OF HISTONE DEACETYLASES HDAC1/2. IMMUNOLOCALIZATION STUDIES SHOWED THAT HDAC1/2 AND ACETYLATED HISTONE 3 AND 4 PROTEINS LOCALIZE TO MEIOTIC GERM CELLS. ANALYSIS OF MRNA EXPRESSION IN ISOLATED GERM CELLS SHOWS DECREASED LEVELS OF HDAC1/2/8, DNMT3B AND TET1 AND INCREASED LEVELS OF DNMT3A GENE EXPRESSION AFTER COCAINE TREATMENT. CONCLUSIONS: COCAINE INTAKE IS ASSOCIATED WITH TESTICULAR TOXICITY AND SIGNIFICANT REPRODUCTIVE FUNCTION IMPAIRMENT. THE RESULTS PRESENTED HERE BROADEN THE BASIC KNOWLEDGE OF THE IMPACT OF ADDICTIVE STIMULANTS ON TESTICULAR PATHOPHYSIOLOGY, FERTILITY AND MALE REPRODUCTIVE HEALTH AND IMPLY THAT ALTERED EPIGENETIC HOMEOSTASIS BY COCAINE MAY HAVE POTENTIAL CONSEQUENCES ON FUTURE GENERATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  1161  46 CONTINUOUS DEVELOPMENTAL AND EARLY LIFE TRICHLOROETHYLENE EXPOSURE PROMOTED DNA METHYLATION ALTERATIONS IN POLYCOMB PROTEIN BINDING SITES IN EFFECTOR/MEMORY CD4(+) T CELLS. TRICHLOROETHYLENE (TCE) IS AN INDUSTRIAL SOLVENT AND DRINKING WATER POLLUTANT ASSOCIATED WITH CD4(+) T CELL-MEDIATED AUTOIMMUNITY. IN OUR MOUSE MODEL, DISCONTINUATION OF TCE EXPOSURE DURING ADULTHOOD AFTER DEVELOPMENTAL EXPOSURE DID NOT PREVENT IMMUNOTOXICITY. TO DETERMINE WHETHER PERSISTENT EFFECTS WERE LINKED TO EPIGENETIC CHANGES WE CONDUCTED WHOLE GENOME REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TO EVALUATE METHYLATION OF CPG SITES IN AUTOSOMAL CHROMOSOMES IN ACTIVATED EFFECTOR/MEMORY CD4(+) T CELLS. FEMALE MRL+/+ MICE WERE EXPOSED TO VEHICLE CONTROL OR TCE IN THE DRINKING WATER FROM GESTATION UNTIL ~37 WEEKS OF AGE [POSTNATAL DAY (PND) 259]. IN A SUBSET OF MICE, TCE EXPOSURE WAS DISCONTINUED AT ~22 WEEKS OF AGE (PND 154). AT PND 259, RRBS ASSESSMENT REVEALED MORE GLOBAL METHYLATION CHANGES IN THE CONTINUOUS EXPOSURE GROUP VS. THE DISCONTINUOUS EXPOSURE GROUP. A MAJORITY OF THE DIFFERENTIALLY METHYLATED CPG REGIONS (DMRS) ACROSS PROMOTERS, ISLANDS, AND REGULATORY ELEMENTS WERE HYPERMETHYLATED (~90%). HOWEVER, CONTINUOUS DEVELOPMENTAL TCE EXPOSURE ALTERED THE METHYLATION OF 274 CPG SITES IN PROMOTERS AND CPG ISLANDS. IN CONTRAST, ONLY 4 CPG ISLAND REGIONS WERE DIFFERENTIALLY METHYLATED (HYPERMETHYLATED) IN THE DISCONTINUOUS GROUP. INTERESTINGLY, 2 OF THESE 4 SITES WERE ALSO HYPERMETHYLATED IN THE CONTINUOUS EXPOSURE GROUP, AND BOTH OF THESE ISLAND REGIONS ARE ASSOCIATED WITH LYSINE 27 ON HISTONE H3 (H3K27) INVOLVED IN POLYCOMB COMPLEX-DEPENDENT TRANSCRIPTIONAL REPRESSION VIA H3K27 TRI-METHYLATION. CPG SITES WERE OVERLAPPED WITH THE OPEN REGULATORY ANNOTATION DATABASE. UNLIKE THE DISCONTINUOUS GROUP, CONTINUOUS TCE TREATMENT RESULTED IN 129 DMRS INCLUDING 12 UNIQUE TRANSCRIPTION FACTORS AND REGULATORY ELEMENTS; 80% OF WHICH WERE ENRICHED FOR ONE OR MORE POLYCOMB GROUP (PCG) PROTEIN BINDING REGIONS (I.E., SUZ12, EZH2, JARID2, AND MTF2). PATHWAY ANALYSIS OF THE DMRS INDICATED THAT TCE PRIMARILY ALTERED THE METHYLATION OF GENES ASSOCIATED WITH REGULATION OF CELLULAR METABOLISM AND CELL SIGNALING. THE RESULTS DEMONSTRATED THAT CONTINUOUS DEVELOPMENTAL EXPOSURE TO TCE DIFFERENTIALLY METHYLATED BINDING SITES OF PCG PROTEINS IN EFFECTOR/MEMORY CD4(+) CELLS. THERE WERE MINIMAL YET POTENTIALLY BIOLOGICALLY SIGNIFICANT EFFECTS THAT OCCURRED WHEN EXPOSURE WAS DISCONTINUED. THESE RESULTS POINT TOWARD A NOVEL MECHANISM BY WHICH CHRONIC DEVELOPMENTAL TCE EXPOSURE MAY ALTER TERMINALLY DIFFERENTIATED CD4(+) T CELL FUNCTION IN ADULTHOOD.	2019	
                                                                                                                                                                                                                                                                    
20  5191  37 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