1 1488 123 DNA DAMAGE RECOGNITION IN THE RAT ZYGOTE FOLLOWING CHRONIC PATERNAL CYCLOPHOSPHAMIDE EXPOSURE. THE DETRIMENTAL EFFECTS OF PRECONCEPTIONAL PATERNAL EXPOSURE TO THE ALKYLATING ANTICANCER AGENT, CYCLOPHOSPHAMIDE, INCLUDE ABERRANT EPIGENETIC PROGRAMMING, DYSREGULATED ZYGOTIC GENE ACTIVATION, AND ABNORMALITIES IN THE OFFSPRING THAT ARE TRANSMITTED TO THE NEXT GENERATION. THE ADVERSE DEVELOPMENTAL CONSEQUENCES OF GENOMIC INSTABILITIES TRANSMITTED VIA THE SPERMATOZOON EMPHASIZE THE NEED TO ELUCIDATE THE MECHANISMS BY WHICH THE EARLY EMBRYO RECOGNIZES DNA DAMAGE IN THE PATERNAL GENOME. LITTLE INFORMATION EXISTS ON DNA DAMAGE DETECTION IN THE ZYGOTE. WE ASSESSED THE IMPACT OF PATERNAL CYCLOPHOSPHAMIDE EXPOSURE ON PHOSPHORYLATED H2AX (GAMMAH2AX) AND POLY(ADP-RIBOSE) POLYMERASE-1(PARP-1), BIOMARKERS OF DNA DAMAGE, TO DETERMINE THE CAPACITY IN THE RAT ZYGOTE TO RECOGNIZE GENOMIC DAMAGE AND INITIATE A RESPONSE TO DNA LESIONS. AN AMPLIFIED BIPHASIC GAMMAH2AX RESPONSE WAS TRIGGERED IN THE PATERNAL PRONUCLEUS IN ZYGOTES SIRED BY DRUG-TREATED MALES; THE MATERNAL GENOME WAS NOT AFFECTED. PARP-1 IMMUNOREACTIVITY WAS SUBSTANTIALLY ELEVATED IN BOTH PARENTAL GENOMES, COINCIDENT WITH THE SECOND PHASE OF GAMMAH2AX INDUCTION IN EMBRYOS SIRED BY CYCLOPHOSPHAMIDE-EXPOSED SPERMATOZOA. THUS, PATERNAL EXPOSURE TO A DNA DAMAGING AGENT RAPIDLY ACTIVATES SIGNALS IMPLEMENTAL FOR DNA DAMAGE RECOGNITION IN THE ZYGOTE. INEFFICIENT REPAIR OF DNA LESIONS MAY LEAD TO PERSISTENT ALTERATIONS OF THE HISTONE CODE AND CHROMATIN INTEGRITY, RESULTING IN ABERRANT EMBRYOGENESIS. WE PROPOSE THAT THE RESPONSE OF THE EARLY EMBRYO TO DISTURBANCES IN SPERMATOZOAL GENOMIC INTEGRITY PLAYS A VITAL ROLE IN DETERMINING ITS OUTCOME. 2007 2 1761 23 EARLY STRESS EVOKES AGE-DEPENDENT BIPHASIC CHANGES IN HIPPOCAMPAL NEUROGENESIS, BDNF EXPRESSION, AND COGNITION. BACKGROUND: ADULT-ONSET STRESSORS EXERT OPPOSING EFFECTS ON HIPPOCAMPAL NEUROGENESIS AND COGNITION, WITH ENHANCEMENT OBSERVED FOLLOWING MILD STRESS AND DYSFUNCTION FOLLOWING SEVERE CHRONIC STRESS. WHILE EARLY LIFE STRESS EVOKES PERSISTENT CHANGES IN ANXIETY, IT IS UNKNOWN WHETHER EARLY STRESS DIFFERENTIALLY REGULATES HIPPOCAMPAL NEUROGENESIS, TROPHIC FACTOR EXPRESSION, AND COGNITION ACROSS THE LIFE SPAN. METHODS: HIPPOCAMPAL-DEPENDENT COGNITIVE BEHAVIOR, NEUROGENESIS, AND EPIGENETIC REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION WAS EXAMINED AT DISTINCT TIME POINTS ACROSS THE LIFE SPAN IN RATS SUBJECTED TO THE EARLY STRESS OF MATERNAL SEPARATION (ES) AND CONTROL GROUPS. WE ALSO EXAMINED THE INFLUENCE OF CHRONIC ANTIDEPRESSANT TREATMENT ON THE NEUROGENIC, NEUROTROPHIC, AND COGNITIVE CHANGES IN MIDDLE-AGED ES ANIMALS. RESULTS: ANIMALS SUBJECTED TO EARLY STRESS OF MATERNAL SEPARATION EXAMINED DURING POSTNATAL LIFE AND YOUNG ADULTHOOD EXHIBITED ENHANCED HIPPOCAMPAL NEUROGENESIS, DECREASED REPRESSIVE HISTONE METHYLATION AT THE BDNF IV PROMOTER ALONG WITH ENHANCED BDNF LEVELS, AND IMPROVED PERFORMANCE ON THE STRESS-ASSOCIATED MORRIS WATER MAZE. STRIKINGLY, OPPOSING CHANGES IN HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC REGULATION OF BDNF IV EXPRESSION, CONCOMITANT WITH IMPAIRMENTS ON HIPPOCAMPAL-DEPENDENT COGNITIVE TASKS, WERE OBSERVED IN MIDDLE-AGED ES ANIMALS. CHRONIC ANTIDEPRESSANT TREATMENT WITH AMITRIPTYLINE ATTENUATED THE MALADAPTIVE NEUROGENIC, EPIGENETIC, TRANSCRIPTIONAL, AND COGNITIVE EFFECTS IN MIDDLE-AGED ES ANIMALS. CONCLUSIONS: OUR STUDY PROVIDES NOVEL INSIGHTS INTO THE SHORT- AND LONG-TERM CONSEQUENCES OF ES, DEMONSTRATING BOTH BIPHASIC AND UNIQUE, AGE-DEPENDENT CHANGES AT THE MOLECULAR, EPIGENETIC, NEUROGENIC, AND BEHAVIORAL LEVELS. THESE RESULTS INDICATE THAT EARLY STRESS MAY TRANSIENTLY ENDOW ANIMALS WITH A POTENTIAL ADAPTIVE ADVANTAGE IN STRESSFUL ENVIRONMENTS BUT ACROSS A LIFE SPAN IS ASSOCIATED WITH LONG-TERM DELETERIOUS EFFECTS. 2013 3 1986 29 EPIGENETIC ALTERATIONS MAY REGULATE TEMPORARY REVERSAL OF CD4(+) T CELL ACTIVATION CAUSED BY TRICHLOROETHYLENE EXPOSURE. PREVIOUS STUDIES HAVE SHOWN THAT SHORT-TERM (4 WEEKS) OR CHRONIC (32 WEEKS) EXPOSURE TO TRICHLOROETHYLENE (TCE) IN DRINKING WATER OF FEMALE MRL+/+ MICE GENERATED CD4(+) T CELLS THAT SECRETED INCREASED LEVELS OF INTERFERON (IFN)-GAMMA AND EXPRESSED AN ACTIVATED (CD44(HI)CD62L(LO)) PHENOTYPE. IN CONTRAST, THE CURRENT STUDY OF SUBCHRONIC TCE EXPOSURE SHOWED THAT MIDWAY IN THE DISEASE PROCESS BOTH OF THESE PARAMETERS OF CD4(+) T CELL ACTIVATION WERE REVERSED. THIS PHASE OF THE DISEASE PROCESS MAY REPRESENT AN ATTEMPT BY THE BODY TO COUNTERACT THE INFLAMMATORY EFFECTS OF TCE. THE DECREASE IN CD4(+) T CELL PRODUCTION OF IFN-GAMMA FOLLOWING SUBCHRONIC TCE EXPOSURE COULD NOT BE ATTRIBUTED TO SKEWING TOWARD A TH2 OR TH17 PHENOTYPE OR TO AN INCREASE IN TREG CELLS. INSTEAD, THE SUPPRESSION CORRESPONDED TO ALTERATIONS IN MARKERS USED TO ASSESS DNA METHYLATION, NAMELY INCREASED EXPRESSION OF RETROTRANSPOSONS IAP (INTRACISTERNAL A PARTICLE) AND MUERV (MURINE ENDOGENOUS RETROVIRUS). ALSO OBSERVED WAS AN INCREASE IN THE EXPRESSION OF DNMT1 (DNA METHYLTRANSFERASE-1) AND DECREASED EXPRESSION OF SEVERAL GENES KNOWN TO BE DOWNREGULATED BY DNA METHYLATION, NAMELY IFNG, IL2, AND CDKN1A. CD4(+) T CELLS FROM A SECOND STUDY IN WHICH MRL+/+ MICE WERE TREATED FOR 17 WEEKS WITH TCE SHOWED A SIMILAR INCREASE IN IAP AND DECREASE IN CDKN1A. IN ADDITION, DNA COLLECTED FROM THE CD4(+) T CELLS IN THE SECOND STUDY SHOWED TCE-DECREASED GLOBAL DNA METHYLATION. THUS, THESE RESULTS DESCRIBED THE BIPHASIC NATURE OF TCE-INDUCED ALTERATIONS IN CD4(+) T CELL FUNCTION AND SUGGESTED THAT THESE CHANGES REPRESENTED POTENTIALLY REVERSIBLE ALTERATIONS IN EPIGENETIC PROCESSES. 2012 4 2265 54 EPIGENETIC PROGRAMMING IN THE PREIMPLANTATION RAT EMBRYO IS DISRUPTED BY CHRONIC PATERNAL CYCLOPHOSPHAMIDE EXPOSURE. PRECONCEPTIONAL PATERNAL EXPOSURE TO CYCLOPHOSPHAMIDE, A WIDELY USED ANTICANCER AGENT, LEADS TO INCREASES IN EMBRYO LOSS, MALFORMATIONS, AND BEHAVIORAL DEFICITS IN OFFSPRING; THESE ABNORMALITIES ARE TRANSMISSIBLE TO SUBSEQUENT GENERATIONS [AUROUX, M., DULIOUST, E., SELVA, J. & RINCE, P. (1990) MUTAT. RES. 229, 189-200]. LITTLE INFORMATION EXISTS ON THE MECHANISMS UNDERLYING THIS MALE-MEDIATED DEVELOPMENTAL TOXICITY. WE ASSESSED THE IMPACT OF PATERNAL CYCLOPHOSPHAMIDE EXPOSURE ON THE DYNAMIC REGULATION OF HISTONE H4 ACETYLATION AT LYSINE 5 AND DNA METHYLATION IN PREIMPLANTATION RAT EMBRYOS. ZYGOTES SIRED BY DRUG-TREATED MALES DISPLAYED ADVANCED DEVELOPMENTAL PROGRESSION, INCREASED PRONUCLEAR AREAS, AND DISRUPTION OF THE EPIGENETIC PROGRAMMING OF BOTH PARENTAL GENOMES. EARLY POSTFERTILIZATION ZYGOTIC PRONUCLEI WERE HYPERACETYLATED; BY MID-ZYGOTIC DEVELOPMENT, MALE PRONUCLEI WERE DRAMATICALLY HYPOMETHYLATED, WHEREAS FEMALE PRONUCLEI WERE HYPERMETHYLATED. MICRONUCLEI WERE SUBSTANTIALLY ELEVATED, AND HISTONE H4 ACETYLATION AT LYSINE 5 LOCALIZATION TO THE NUCLEAR PERIPHERY WAS DISRUPTED IN TWO-CELL EMBRYOS FERTILIZED BY CYCLOPHOSPHAMIDE-EXPOSED SPERMATOZOA. THIS FINDING DEMONSTRATES THAT PATERNAL EXPOSURE TO THIS DRUG INDUCES ABERRANT EPIGENETIC PROGRAMMING IN EARLY EMBRYOS. WE HYPOTHESIZE THAT DISTURBANCES IN EPIGENETIC PROGRAMMING CONTRIBUTE TO HERITABLE INSTABILITIES LATER IN DEVELOPMENT, EMPHASIZING THE IMPORTANCE OF EPIGENETIC RISK ASSESSMENT AFTER CHEMOTHERAPY. 2005 5 2032 27 EPIGENETIC CHANGES IN P21 EXPRESSION IN RENAL CELLS AFTER EXPOSURE TO BROMATE. THIS STUDY TESTED THE HYPOTHESIS THAT BROMATE (KBRO3)-INDUCED RENAL CELL DEATH IS MEDIATED BY EPIGENETIC MECHANISMS. GLOBAL DNA METHYLATION, AS ASSESSED BY 5-METHYLCYTOSINE STAINING, WAS NOT CHANGED IN NORMAL RAT KIDNEY CELLS TREATED WITH ACUTE CYTOTOXIC DOSES OF KBRO3 (100 AND 200 PPM), AS COMPARED WITH CONTROLS. HOWEVER, KBRO3 TREATMENT DID INCREASE P38, P53 AND HISTONE 2AX (H2AX) PHOSPHORYLATION, AND P21 EXPRESSION. TREATMENT OF CELLS WITH INHIBITORS OF DNA METHYLTRANSFERASE (5-AZACYTIDINE OR 5-AZA) AND HISTONE DEACETYLASE (TRICHOSTATIN A OR TSA) IN ADDITION TO KBRO3 INCREASED CYTOTOXICITY, AS COMPARED WITH CELLS EXPOSED TO KBRO3 ALONE. 5-AZA AND TSA CO-TREATMENT DID NOT ALTER P38 OR P53 PHOSPHORYLATION, BUT SLIGHTLY DECREASED H2AX PHOSPHORYLATION AND SIGNIFICANTLY DECREASED P21 EXPRESSION. WE ALSO ASSESSED EPIGENETIC CHANGES IN CELLS TREATED UNDER SUB-CHRONIC CONDITIONS WITH ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF KBRO3. UNDER THESE CONDITIONS (0-10PPM KBRO3 FOR UP TO 18 DAYS), WE DETECTED NO INCREASES IN CELL DEATH OR DNA DAMAGE. IN CONTRAST, SLIGHT ALTERATIONS WERE DETECTED IN THE PHOSPHORYLATION OF H2AX, P38, AND P53. SUB-CHRONIC LOW-DOSE KBRO3 TREATMENT ALSO INDUCED A BIPHASIC RESPONSE IN P21 EXPRESSION, WITH LOWER CONCENTRATIONS INCREASING EXPRESSION, BUT HIGHER CONCENTRATIONS DECREASING EXPRESSION. METHYLATION-SPECIFIC PCR DEMONSTRATED THAT SUB-CHRONIC KBRO3 TREATMENT ALTERED THE METHYLATION OF CYTOSINE BASES IN THE P21 GENE, AS COMPARED WITH CONTROLS, CORRELATING TO ALTERATIONS IN P21 PROTEIN EXPRESSION. COLLECTIVELY, THESE DATA SHOW THE NOVEL FINDING THAT KBRO3-INDUCED RENAL CELL DEATH IS ALTERED BY INHIBITORS OF EPIGENETIC MODIFYING ENZYMES AND THAT KBRO3 ITSELF INDUCES EPIGENETIC CHANGES IN THE P21 GENE. 2014 6 4935 23 PATERNAL COCAINE TAKING ELICITS EPIGENETIC REMODELING AND MEMORY DEFICITS IN MALE PROGENY. PATERNAL ENVIRONMENTAL PERTURBATIONS INCLUDING EXPOSURE TO DRUGS OF ABUSE CAN PRODUCE PROFOUND EFFECTS ON THE PHYSIOLOGY AND BEHAVIOR OF OFFSPRING VIA EPIGENETIC MODIFICATIONS. HERE WE SHOW THAT ADULT DRUG-NAIVE MALE OFFSPRING OF COCAINE-EXPOSED SIRES HAVE MEMORY FORMATION DEFICITS AND ASSOCIATED REDUCTIONS IN NMDA RECEPTOR-MEDIATED HIPPOCAMPAL SYNAPTIC PLASTICITY. REDUCED LEVELS OF THE ENDOGENOUS NMDA RECEPTOR CO-AGONIST D-SERINE WERE ACCOMPANIED BY INCREASED EXPRESSION OF THE D-SERINE DEGRADING ENZYME D-AMINO ACID OXIDASE (DAO1) IN THE HIPPOCAMPUS OF COCAINE-SIRED MALE PROGENY. INCREASED DAO1 TRANSCRIPTION WAS ASSOCIATED WITH ENRICHMENT OF PERMISSIVE EPIGENETIC MARKS ON HISTONE PROTEINS IN THE HIPPOCAMPUS OF MALE COCAINE-SIRED PROGENY, SOME OF WHICH WERE ENHANCED NEAR THE DAO1 LOCUS. FINALLY, HIPPOCAMPAL ADMINISTRATION OF D-SERINE REVERSED BOTH THE MEMORY FORMATION AND SYNAPTIC PLASTICITY DEFICITS. COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT PATERNAL COCAINE EXPOSURE PRODUCES EPIGENETIC REMODELING IN THE HIPPOCAMPUS LEADING TO NMDA RECEPTOR-DEPENDENT MEMORY FORMATION AND SYNAPTIC PLASTICITY IMPAIRMENTS ONLY IN MALE PROGENY, WHICH HAS SIGNIFICANT IMPLICATIONS FOR THE MALE DESCENDANTS OF CHRONIC COCAINE USERS. 2017 7 4944 25 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING. 2016 8 968 24 CHRONIC NICOTINE EXPOSURE SYSTEMICALLY ALTERS MICRORNA EXPRESSION PROFILES DURING POST-EMBRYONIC STAGES IN CAENORHABDITIS ELEGANS. TOBACCO SMOKING IS ASSOCIATED WITH MANY DISEASES. ADDICTION IS OF THE MOST NOTORIOUS TOBACCO-RELATED SYNDROME AND IS MAINLY ATTRIBUTED TO NICOTINE. IN THIS STUDY, WE EMPLOYED CAENORHABDITIS ELEGANS AS A BIOLOGICAL MODEL TO SYSTEMICALLY INVESTIGATE THE EFFECT OF CHRONIC NICOTINE EXPOSURE ON MICRORNA (MIRNA) EXPRESSION PROFILE AND THEIR REGULATED BIOCHEMICAL PATHWAYS. NICOTINE TREATMENT (20 MICROM AND 20 MM) WAS LIMITED TO THE POST-EMBRYONIC STAGE FROM L1 TO L4 ( APPROXIMATELY 31 H) PERIOD AFTER WHICH WORMS WERE COLLECTED FOR GENOME-WIDE MIRNA PROFILING. OUR RESULTS SHOW THAT NICOTINE SIGNIFICANTLY ALTERED THE EXPRESSION PATTERNS OF 40 MIRNAS. THE EFFECT WAS PROPORTIONAL TO THE NICOTINE DOSE AND WAS EXPECTED TO HAVE AN ADDITIVE, MORE ROBUST RESPONSE. BASED ON PATHWAY ENRICHMENT ANALYSES COUPLED WITH NICOTINE-INDUCED MIRNA PATTERNS, WE INFERRED THAT MIRNAS AS A SYSTEM MEDIATES "REGULATORY HORMESIS", MANIFESTED IN BIPHASIC BEHAVIORAL AND PHYSIOLOGICAL PHENOTYPES. WE PROPOSED A MODEL WHERE NICOTINE ADDICTION IS MEDIATED BY MIRNAS' REGULATION OF FOS-1 AND IS MAINTAINED BY EPIGENETIC FACTORS. THUS, OUR STUDY OFFERS NEW INSIGHTS FOR A BETTER UNDERSTANDING OF THE SENSITIVITY OF EARLY DEVELOPMENTAL STAGES TO NICOTINE. 2014 9 4939 33 PATERNAL NICOTINE EXPOSURE IN RATS PRODUCES LONG-LASTING NEUROBEHAVIORAL EFFECTS IN THE OFFSPRING. STUDIES OF INTERGENERATIONAL EFFECTS OF PARENTAL CHEMICAL EXPOSURE HAVE PRINCIPALLY FOCUSED ON MATERNAL EXPOSURE, PARTICULARLY FOR STUDIES OF ADVERSE NEUROBEHAVIORAL CONSEQUENCES ON THE OFFSPRING. MATERNAL NICOTINE EXPOSURE HAS LONG BEEN KNOWN TO CAUSE ADVERSE NEUROBEHAVIORAL EFFECTS ON THE OFFSPRING. HOWEVER, PATERNAL TOXICANT EXPOSURE HAS ALSO BEEN FOUND TO CAUSE NEUROBEHAVIORAL TOXICITY IN THEIR OFFSPRING. RECENT WORK SUGGESTS THAT PATERNAL NICOTINE EXPOSURE CAN HAVE EPIGENETIC EFFECTS, ALTHOUGH IT REMAINS UNCLEAR WHETHER SUCH CHANGES LEAD TO NEUROBEHAVIORAL EFFECTS. IN THE CURRENT STUDY, WE INVESTIGATED THE EFFECTS OF PATERNAL NICOTINE EXPOSURE ON NEUROBEHAVIORAL DEVELOPMENT OF THEIR OFFSPRING. MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO 0 OR 2 MG/KG/DAY NICOTINE (SC) FOR 56 CONSECUTIVE DAYS WITH TWO CONSECUTIVE 2ML4 OSMOTIC MINIPUMPS. FOLLOWING TREATMENT, THESE MALES WERE MATED WITH DRUG-NAIVE FEMALE RATS. OFFSPRING OF BOTH SEXES WERE TESTED IN A BEHAVIORAL BATTERY TO ASSESS LOCOMOTION, EMOTIONAL FUNCTION AND COGNITION. PATERNAL NICOTINE EXPOSURE DID NOT IMPACT OFFSPRING VIABILITY, HEALTH OR GROWTH. HOWEVER, BEHAVIORAL FUNCTION OF THE OFFSPRING WAS SIGNIFICANTLY ALTERED BY PATERNAL NICOTINE EXPOSURE. MALE OFFSPRING WITH PATERNAL NICOTINE EXPOSURE EXHIBITED LOCOMOTOR HYPERACTIVITY IN THE FIGURE-8 APPARATUS WHEN TESTED DURING ADOLESCENCE. WHEN RETESTED IN ADULTHOOD AND REGARDLESS OF SEX, OFFSPRING OF THE NICOTINE EXPOSED FATHER SHOWED SIGNIFICANTLY REDUCED HABITUATION OF LOCOMOTOR ACTIVITY OVER THE COURSE OF THE SESSION. COMPARED TO CONTROLS, FEMALE OFFSPRING OF NICOTINE-EXPOSED FATHERS SHOWED SIGNIFICANTLY REDUCED RESPONSE LATENCY IN THE RADIAL ARM MAZE TEST. IN ADDITION TO LOCOMOTOR HYPERACTIVITY, THE OFFSPRING OF NICOTINE-EXPOSED FATHERS ALSO SHOWED SIGNIFICANTLY DIMINISHED HABITUATION IN THE NOVEL OBJECT RECOGNITION TEST. THESE RESULTS INDICATE THAT CHRONIC PATERNAL NICOTINE EXPOSURE CAN IMPACT THE BEHAVIOR OF OFFSPRING, PRODUCING LOCOMOTOR HYPERACTIVITY AND IMPAIRED HABITUATION. 2019 10 5020 31 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 11 2810 22 FGF23 AND FETUIN-A INTERACTION IN THE LIVER AND IN THE CIRCULATION. RECENTLY IT HAS BEEN DEMONSTRATED THAT FETUIN-A, AN ANTI-INFLAMMATORY PROTEIN SYNTHESIZED BY THE LIVER, IS PRODUCED ALSO IN BONE BY AN FGF23-REGULATED PATHWAY. FGF23 HAS BEEN ALSO DEMONSTRATED TO INDUCE INFLAMMATORY CYTOKINE PRODUCTION IN THE LIVER. THIS STUDY AIMED TO EXPLORE IF FGF23 PLAYS A ROLE IN THE FETUIN-A PRODUCTION IN THE LIVER CELLS TOO AND THE POSSIBLE RELATIONSHIPS WITH FGF23 PRO-INFLAMMATORY EFFECTS. FGF23 AND FETUIN-A WERE STUDIED IN LIVER, KIDNEY AND IN PLASMA WITH IMMUNOCHEMISTRY, IMMUNOPRECIPITATION, WESTERN BLOT, CHROMATIN IMMUNOPRECIPITATION, DUOLINK, ELISA, QRTPCR METHODOLOGY. FGF23 IS PRODUCED, BUT NOT SECRETED BY THE LIVER CELLS. IN HEPATOCYTES AND CIRCULATION, FGF23 WAS PRESENT ONLY STRICTLY LINKED TO FETUIN-A, WHILE FETUIN-A WAS FOUND ALSO IN UNBOUNDED FORM. NO LINK WAS OBSERVED IN THE KIDNEY. FGF23 UP TO 600 PG/ML STIMULATES, WHILE, AT HIGHER CONCENTRATIONS, REDUCES FETUIN-A EXPRESSION. NOTABLY, OVERALL THE RANGE OF CONCENTRATIONS, FGF23 STIMULATES FETUIN-A PROMOTER, TNFALPHA AND IL6 EXPRESSION. IN THE NUCLEUS, FGF23 SEEMS TO ACT AS A DIRECT TRANSCRIPTION FACTOR OF FETUIN-A PROMOTER. THESE RESULTS SUGGEST THAT FGF23 PLAYED A DIRECT REGULATORY ROLE IN FETUIN-A EXPRESSION IN LIVER CELLS WITH A BIPHASIC EFFECT: FETUIN-A PROGRESSIVELY INCREASES WHEN FGF23 INCREASES UP TO 400-600 PG/ML, AND DECLINES AT HIGHER FGF23 CONCENTRATIONS. THESE RESULTS LEAD US TO HYPOTHESIZE: A) A POSSIBLE EPIGENETIC POST-TRANSCRIPTIONAL REGULATION; B) A POSSIBLE COUNTER-REGULATORY EFFECT OF FGF23 INDUCED INFLAMMATORY CYTOKINES (TNFALPHA/ NF-KAPPAB MECHANISM). THIS STUDY COULD ADD AN ADDITIONAL KEY FOR THE INTERPRETATION OF THE POSSIBLE MECHANISMS LINKING FGF23, FETUIN-A AND INFLAMMATION IN CKD PATIENTS AND SUGGESTS A ROLE FOR FGF23 AS TRANSCRIPTION FACTOR. 2018 12 1783 22 EFFECT OF AGOMELATINE ON MEMORY DEFICITS AND HIPPOCAMPAL GENE EXPRESSION INDUCED BY CHRONIC SOCIAL DEFEAT STRESS IN MICE. CHRONIC STRESS IS KNOWN TO INDUCE NOT ONLY ANXIETY AND DEPRESSIVE-LIKE PHENOTYPES IN MICE BUT ALSO COGNITIVE IMPAIRMENTS, FOR WHICH THE ACTION OF CLASSICAL ANTIDEPRESSANT COMPOUNDS REMAINS UNSATISFACTORY. IN THIS CONTEXT, WE INVESTIGATED THE EFFECTS OF CHRONIC SOCIAL DEFEAT STRESS (CSDS) ON ANXIETY-, SOCIAL- AND COGNITIVE-RELATED BEHAVIORS, AS WELL AS HIPPOCAMPAL BDNF, SYNAPTIC PLASTICITY MARKERS (PSD-95, SYNAPTOPHYSIN, SPINOPHILIN, SYNAPSIN I AND MAP-2), AND EPIGENETIC MODIFYING ENZYMES (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) GENE EXPRESSION IN C57BL/6J MICE. CSDS FOR 10 DAYS PROVOKED LONG-LASTING ANXIOUS-LIKE PHENOTYPE IN THE OPEN FIELD AND EPISODIC MEMORY DEFICITS IN THE NOVEL OBJECT RECOGNITION TEST. WHILE TOTAL BDNF MRNA LEVEL WAS UNCHANGED, BDNF EXON IV, MAP-2, HDAC2, HDAC6 AND MLL3 GENE EXPRESSION WAS SIGNIFICANTLY DECREASED IN THE CSDS MOUSE HIPPOCAMPUS. IN CSDS MICE TREATED 3 WEEKS WITH 50 MG/KG/D AGOMELATINE, AN ANTIDEPRESSANT WITH MELATONERGIC RECEPTOR AGONIST AND 5-HT(2C) RECEPTOR ANTAGONIST PROPERTIES, THE ANXIOUS-LIKE PHENOTYPE WAS NOT REVERSED, BUT THE TREATMENT SUCCESSFULLY PREVENTED THE COGNITIVE IMPAIRMENTS AND HIPPOCAMPAL GENE EXPRESSION MODIFICATIONS. ALTOGETHER, THESE DATA EVIDENCED THAT, IN MICE, AGOMELATINE WAS EFFECTIVE IN ALLEVIATING STRESS-INDUCED ALTERED COGNITIVE FUNCTIONS, POSSIBLY THROUGH A MECHANISM INVOLVING BDNF SIGNALING, SYNAPTIC PLASTICITY AND EPIGENETIC REMODELING. 2017 13 910 29 CHRONIC EXPOSURE TO ETHANOL OF MALE MICE BEFORE MATING PRODUCES ATTENTION DEFICIT HYPERACTIVITY DISORDER-LIKE PHENOTYPE ALONG WITH EPIGENETIC DYSREGULATION OF DOPAMINE TRANSPORTER EXPRESSION IN MOUSE OFFSPRING. PRECONCEPTION EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE MAY AFFECT NEUROBEHAVIORAL AND DEVELOPMENTAL FEATURES OF OFFSPRING. THIS STUDY INVESTIGATES THE EFFECTS OF PATERNAL EXPOSURE TO ETOH BEFORE CONCEPTION ON THE HYPERACTIVITY, INATTENTION, AND IMPULSIVITY BEHAVIOR OF MALE OFFSPRING IN MICE. SIRE MICE WERE TREATED WITH ETOH IN A CONCENTRATION RANGE APPROXIMATING HUMAN BINGE DRINKING (0-4 G/KG/DAY ETOH) FOR 7 WEEKS AND MATED WITH UNTREATED FEMALES MICE TO PRODUCE OFFSPRING. ETOH EXPOSURE TO SIRE MICE INDUCED ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)-LIKE HYPERACTIVE, INATTENTIVE, AND IMPULSIVE BEHAVIORS IN OFFSPRING. AS A MECHANISTIC LINK, BOTH PROTEIN AND MRNA EXPRESSION OF DOPAMINE TRANSPORTER (DAT), A KEY DETERMINANT OF ADHD-LIKE PHENOTYPES IN EXPERIMENTAL ANIMALS AND HUMANS, WERE SIGNIFICANTLY DECREASED BY PATERNAL ETOH EXPOSURE IN CEREBRAL CORTEX AND STRIATUM OF OFFSPRING MICE ALONG WITH INCREASED METHYLATION OF A CPG REGION OF THE DAT GENE PROMOTER. THE INCREASE IN METHYLATION OF DAT GENE PROMOTER WAS ALSO OBSERVED IN THE SPERM OF SIRE MICE, SUGGESTING GERMLINE CHANGES IN THE EPIGENETIC METHYLATION SIGNATURE OF DAT GENE BY ETOH EXPOSURE. IN ADDITION, THE EXPRESSION OF TWO KEY REGULATORS OF METHYLATION-DEPENDENT EPIGENETIC REGULATION OF FUNCTIONAL GENE EXPRESSION, NAMELY, MECP2 AND DNMT1, WAS MARKEDLY DECREASED IN OFFSPRING CORTEX AND STRIATUM SIRED BY ETOH-EXPOSED MICE. THESE RESULTS SUGGEST THAT PRECONCEPTIONAL EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE INDUCES BEHAVIORAL CHANGES IN OFFSPRING, POSSIBLY VIA EPIGENETIC CHANGES IN GENE EXPRESSION, WHICH IS ESSENTIAL FOR THE REGULATION OF ADHD-LIKE BEHAVIORS. 2014 14 4397 22 MODULATION OF DNA METHYLATION AND GENE EXPRESSION IN RODENT CORTICAL NEUROPLASTICITY PATHWAYS EXERTS RAPID ANTIDEPRESSANT-LIKE EFFECTS. BACKGROUND: STRESS INCREASES DNA METHYLATION, PRIMARILY A SUPPRESSIVE EPIGENETIC MECHANISM CATALYZED BY DNA METHYLTRANSFERASES (DNMT), AND DECREASES THE EXPRESSION OF GENES INVOLVED IN NEURONAL PLASTICITY AND MOOD REGULATION. DESPITE CHRONIC ANTIDEPRESSANT TREATMENT DECREASES STRESS-INDUCED DNA METHYLATION, IT IS NOT KNOWN WHETHER INHIBITION OF DNMT WOULD CONVEY RAPID ANTIDEPRESSANT-LIKE EFFECTS. AIM: THIS WORK TESTED SUCH A HYPOTHESIS AND EVALUATED WHETHER A BEHAVIORAL EFFECT INDUCED BY DNMT INHIBITORS (DNMTI) CORRESPONDS WITH CHANGES IN DNA METHYLATION AND TRANSCRIPT LEVELS IN GENES CONSISTENTLY ASSOCIATED WITH THE NEUROBIOLOGY OF DEPRESSION AND SYNAPTIC PLASTICITY (BDNF, TRKB, 5-HT(1A), NMDA, AND AMPA). METHODS: MALE WISTAR RATS RECEIVED INTRAPERITONEAL (I.P.) INJECTION OF TWO PHARMACOLOGICALLY DIFFERENT DNMTI (5-AZAD 0.2 AND 0.6 MG/KG OR RG108 0.6 MG/KG) OR VEHICLE (1 ML/KG), 1 H OR 7 DAYS BEFORE THE LEARNED HELPLESSNESS TEST (LH). DNA METHYLATION IN TARGET GENES AND THE CORRESPONDENT TRANSCRIPT LEVELS WERE MEASURED IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) USING MEDIP-QPCR. IN PARALLEL SEPARATE GROUPS, THE ANTIDEPRESSANT-LIKE EFFECT OF 5-AZAD AND RG108 WAS INVESTIGATED IN THE FORCED SWIMMING TEST (FST). THE INVOLVEMENT OF CORTICAL BDNF-TRKB-MTOR PATHWAYS WAS ASSESSED BY INTRA-VENTRAL MEDIAL PFC (VMPFC) INJECTIONS OF RAPAMYCIN (MTOR INHIBITOR), K252A (TRKB RECEPTOR ANTAGONIST), OR VEHICLE (0.2 MUL/SIDE). RESULTS: WE FOUND THAT BOTH 5-AZAD AND RG108 ACUTELY AND 7 DAYS BEFORE THE TEST DECREASED ESCAPE FAILURES IN THE LH. LH STRESS INCREASED DNA METHYLATION AND DECREASED TRANSCRIPT LEVELS OF BDNF IV AND TRKB IN THE PFC, EFFECTS THAT WERE NOT SIGNIFICANTLY ATTENUATED BY RG108 TREATMENT. THE SYSTEMIC ADMINISTRATION OF 5-AZAD (0.2 MG/KG) AND RG108 (0.2 MG/KG) INDUCED AN ANTIDEPRESSANT-LIKE EFFECT IN FST, WHICH WAS, HOWEVER, ATTENUATED BY TRKB AND MTOR INHIBITION INTO THE VMPFC. CONCLUSION: THESE FINDINGS SUGGEST THAT ACUTE INHIBITION OF STRESS-INDUCED DNA METHYLATION PROMOTES RAPID AND SUSTAINED ANTIDEPRESSANT EFFECTS ASSOCIATED WITH INCREASED BDNF-TRKB-MTOR SIGNALING IN THE PFC. 2021 15 4945 26 PATERNAL PRECONCEPTION EVERY-OTHER-DAY ETHANOL DRINKING ALTERS BEHAVIOR AND ETHANOL CONSUMPTION IN OFFSPRING. ALCOHOL USE DISORDER IS A DEVASTATING DISEASE WITH A COMPLEX ETIOLOGY. RECENT PRECLINICAL STUDIES HAVE REVEALED THAT PATERNAL PRECONCEPTION CHRONIC INTERMITTENT ETHANOL (ETOH) EXPOSURE VIA VAPORIZED ETOH ALTERED DRINKING BEHAVIORS AND SENSITIVITY TO ETOH SELECTIVELY IN MALE OFFSPRING. IN THE CURRENT STUDY, WE USED A VOLUNTARY ORAL ROUTE OF PATERNAL PRECONCEPTION ETOH EXPOSURE, I.E., INTERMITTENT EVERY-OTHER-DAY TWO-BOTTLE CHOICE DRINKING, AND TESTED OFFSPRING FOR BEHAVIORAL ALTERATIONS. FIFTEEN ETOH DRINKING SIRES AND 10 CONTROL SIRES WERE MATED TO ETOH NAIVE FEMALES TO PRODUCE ETOH-SIRED AND CONTROL-SIRED OFFSPRING. THESE OFFSPRING WERE TESTED USING THE ELEVATED PLUS MAZE, OPEN FIELD, DRINKING IN THE DARK, AND UNLIMITED ACCESS TWO-BOTTLE CHOICE ASSAYS. WE FOUND THAT PATERNAL PRECONCEPTION EVERY-OTHER-DAY TWO-BOTTLE CHOICE DRINKING RESULTED IN REDUCED ETOH CONSUMPTION SELECTIVELY IN MALE OFFSPRING IN THE DRINKING IN THE DARK ASSAY COMPARED TO CONTROL-SIRED OFFSPRING. NO DIFFERENCES WERE DETECTED IN EITHER SEX IN THE UNLIMITED ACCESS TWO-BOTTLE CHOICE AND ELEVATED PLUS MAZE ASSAYS. OPEN FIELD ANALYSIS REVEALED COMPLEX CHANGES IN BASAL BEHAVIOR AND ETOH-INDUCED BEHAVIORS THAT WERE SEX SPECIFIC. WE CONCLUDED THAT PATERNAL PRECONCEPTION VOLUNTARY ETOH CONSUMPTION HAS PERSISTENT EFFECTS THAT IMPACT THE NEXT GENERATION. THIS STUDY ADDS TO A GROWING APPRECIATION THAT ONE'S BEHAVIORAL RESPONSE TO ETOH AND ETOH DRINKING BEHAVIOR ARE IMPACTED BY ETOH EXPOSURE OF THE PRIOR GENERATION. 2019 16 912 18 CHRONIC EXPOSURE TO WATER POLLUTANT TRICHLOROETHYLENE INCREASED EPIGENETIC DRIFT IN CD4(+) T CELLS. AIM: AUTOIMMUNE DISEASE AND CD4(+) T-CELL ALTERATIONS ARE INDUCED IN MICE EXPOSED TO THE WATER POLLUTANT TRICHLOROETHYLENE (TCE). WE EXAMINED HERE WHETHER TCE ALTERED GENE-SPECIFIC DNA METHYLATION IN CD4(+) T CELLS AS A POSSIBLE MECHANISM OF IMMUNOTOXICITY. MATERIALS & METHODS: NAIVE AND EFFECTOR/MEMORY CD4(+) T CELLS FROM MICE EXPOSED TO TCE (0.5 MG/ML IN DRINKING WATER) FOR 40 WEEKS WERE EXAMINED BY BISULFITE NEXT-GENERATION DNA SEQUENCING. RESULTS: A PROBABILISTIC MODEL CALCULATED FROM MULTIPLE GENES SHOWED THAT TCE DECREASED METHYLATION CONTROL IN CD4(+) T CELLS. DATA FROM INDIVIDUAL GENES FITTED TO A QUADRATIC REGRESSION MODEL SHOWED THAT TCE INCREASED GENE-SPECIFIC METHYLATION VARIANCE IN BOTH CD4 SUBSETS. CONCLUSION: TCE INCREASED EPIGENETIC DRIFT OF SPECIFIC CPG SITES IN CD4(+) T CELLS. 2016 17 1332 25 DEPRESSIVE-LIKE PHENOTYPE INDUCED BY PRENATAL DEXAMETHASONE IN MICE IS REVERSED BY DESIPRAMINE. EXPOSURE TO PRENATAL INSULTS HAS BEEN ASSOCIATED WITH AN INCREASED RISK FOR NEUROPSYCHIATRIC DISORDERS, INCLUDING DEPRESSION, BUT THE MECHANISMS ARE STILL POORLY UNDERSTOOD. PERSISTENT ALTERATIONS OF THE HPA AXIS FEEDBACK MECHANISM AS WELL AS ADULT IMPAIRED NEUROGENESIS ARE BELIEVED TO PLAY A RELEVANT ROLE IN THE ETIOLOGY OF DEPRESSION. IN ADDITION, GROWING EVIDENCE POINTS AT EPIGENETIC REPROGRAMMING AS A KEY FACTOR. WE HAVE PREVIOUSLY SHOWN THAT PRENATAL EXPOSURE TO THE SYNTHETIC GLUCOCORTICOID DEXAMETHASONE (DEX) IMPAIRS NEUROGENESIS AND LEADS TO LATE ONSET OF DEPRESSION-LIKE BEHAVIOR THAT DOES NOT RESPOND TO THE SSRI ANTIDEPRESSANT FLUOXETINE (FLX). THE AIMS OF THIS STUDY WERE TO ASSESS THE EFFECT OF DEX PRENATAL EXPOSURE ON THE MORPHOLOGY OF HIPPOCAMPAL GRANULE NEURONS AND ON THE EXPRESSION OF GENES RELATED TO PLASTICITY; AND TO TEST WHETHER THE SNRI ANTIDEPRESSANT DESIPRAMINE (DMI), UNLIKE FLX, COULD COUNTERACT THE EFFECT OF PRENATAL-DEX. C57BL/6 MICE WERE EXPOSED TO DEX (0.05 MG/KG/DAY) IN UTERO AND RECEIVED INTRA-HIPPOCAMPAL INJECTION OF GFP EXPRESSING RETROVIRAL VECTOR FOR LABELING OF NEWBORN GRANULE CELLS AT ELEVEN MONTHS. BY TWELVE MONTHS, DEX MICE SHOWED DEPRESSION-LIKE BEHAVIOR ASSOCIATED WITH DECREASED NEUROGENESIS AND MORPHOLOGICAL ALTERATIONS OF THE NEWBORN GRANULE CELLS IN THE DENTATE GYRUS (DG). FURTHERMORE DEX MICE DISPLAYED ALTERED EXPRESSION OF GENES CONTROLLING NEUROGENESIS AND NEURONAL MORPHOLOGY, SUCH AS CDKN1C, P16, TRKB, DISC1 AND REELIN. CHRONIC TREATMENT WITH DMI LED TO A SIGNIFICANT DECREASE IN IMMOBILITY TIME IN THE FORCED SWIM TEST. IN ADDITION, DMI RESTORED NEUROGENESIS, NEURONAL MORPHOLOGY IN THE DG, AS WELL AS THE EXPRESSION OF ALL RELATED GENES. OUR RESULTS SUGGEST THAT (1) PRENATAL DEX INDUCES EARLY AND PERSISTENT REPROGRAMMING EFFECTS RESULTING IN ALTERED NEUROGENESIS AND NEURONAL MORPHOLOGY; AND (2) DMI TREATMENT REVERSES DEX-INDUCED DEPRESSION BY RESTORING THE EXPRESSION OF GENES RELEVANT TO NEURONAL PLASTICITY. 2017 18 3318 23 HISTONE ACETYLATION AND EXPRESSION OF MONO-AMINERGIC TRANSMITTERS SYNTHETASES INVOLVED IN CUS-INDUCED DEPRESSIVE RATS. HISTONE ACETYLATION HAS BEEN LINKED TO DEPRESSION, THE ETIOLOGY OF WHICH INVOLVES MANY FACTORS SUCH AS GENETICS, ENVIRONMENTS, AND EPIGENETICS. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE WHETHER IT WAS ASSOCIATED WITH EPIGENETIC HISTONE MODIFICATION AND GENE EXPRESSION OF ENZYMES RESPONSIBLE FOR THE BIOSYNTHESIS OF NOREPINEPHRINE AND SEROTONIN IN RAT DEPRESSION MODEL INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS). EIGHT-WEEK-OLD MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO CUS OVER 28 DAYS. IT WAS SHOWN THAT THE CUS-INDUCED RATS DISPLAYED REMARKED ANXIETY- AND DEPRESSION-LIKE BEHAVIOR WITH WEAKENED LOCOMOTOR ACTIVITY IN OPEN FIELD TEST AND PROLONGED IMMOBILITY IN FORCED SWIMMING TEST. WESTERN BLOT REVEALED THAT CUS LED TO SIGNIFICANT DECREASE IN ACETYLATION OF H3 AT LYSINE 9 (K9) AND H4 AT LYSINE 12 (K12) WITH OBVIOUSLY INCREASING HISTONE DEACETYLASES 5 (HDAC5) EXPRESSION IN HIPPOCAMPUS OF CUS-INDUCED RATS. MEANWHILE, THERE WAS AN OBVIOUSLY DECREASED EXPRESSION OF TYROSINE HYDROXYLASE (TH) AND TRYPTOPHAN HYDROXYLASE (TPH) BOTH AT PROTEIN AND MRNA LEVELS. ADMINISTRATION OF SODIUM VALPROATE (VPA), A HISTONE DEACETYLASE 5 (HDAC5) INHIBITOR, NOT ONLY SIGNIFICANTLY RELIEVED THE ANXIETY- AND DEPRESSION-LIKE BEHAVIORS OF CUS-INDUCED RATS BUT ALSO CLEARLY BLUNTED DECREASE OF H3(K9) AND H4(K12) ACETYLATION AND EXPRESSION OF TH AND TPH, AND PREVENTED INCREASE OF HDAC5 EXPRESSION. THE RESULTS INDICATE THAT THERE EXISTS POSSIBLE INTERRELATION BETWEEN TH AND TPH GENE EXPRESSION AND EPIGENETIC HISTONE ACETYLATION IN CUS-INDUCED DEPRESSIVE RATS, WHICH AT LEAST PARTLY CONTRIBUTES TO THE ETIOLOGY OF DEPRESSION. 2014 19 2905 27 GENE DYSREGULATION IN THE ADULT RAT PARAVENTRICULAR NUCLEUS AND AMYGDALA BY PRENATAL EXPOSURE TO DEXAMETHASONE. FETAL PROGRAMMING IS THE CONCEPT THAT MATERNAL STRESSORS DURING CRITICAL PERIODS OF FETAL DEVELOPMENT CAN ALTER OFFSPRING PHENOTYPES POSTNATALLY. EXCESS GLUCOCORTICOIDS CAN INTERACT WITH THE FETUS TO EFFECT GENETIC AND EPIGENETIC CHANGES IMPLICATED IN ADVERSE DEVELOPMENTAL OUTCOMES. THE PRESENT STUDY INVESTIGATES HOW CHRONIC EXPOSURE TO THE SYNTHETIC GLUCOCORTICOID DEXAMETHASONE DURING LATE GESTATION ALTERS THE EXPRESSION OF GENES RELATED TO BEHAVIOR IN BRAIN AREAS RELEVANT TO THE REGULATION AND FUNCTION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. PREGNANT WISTAR KYOTO RATS RECEIVED SUBCUTANEOUS INJECTIONS OF DEXAMETHASONE (100 MUG/KG) DAILY FROM GESTATIONAL DAY 15-21 OR VEHICLE ONLY AS SHAM CONTROLS. THE AMYGDALA AND PARAVENTRICULAR NUCLEUS (PVN) WERE MICRO-PUNCHED TO EXTRACT MRNA FOR REVERSE TRANSCRIPTION AND QUANTITATIVE POLYMERASE CHAIN REACTION FOR THE ANALYSIS OF THE EXPRESSION OF SPECIFIC GENES. IN THE PVN, THE EXPRESSION OF THE GLUCOCORTICOID RECEPTOR NR3C1 WAS DOWNREGULATED IN FEMALE RATS IN RESPONSE TO PROGRAMMING. THE EXPRESSION OF CACNA1C ENCODING THE CA(V)1.2 PORE SUBUNIT OF L-TYPE VOLTAGE-GATED CALCIUM CHANNELS WAS DOWNREGULATED IN MALE AND FEMALE RATS PRENATALLY EXPOSED TO DEXAMETHASONE. COLLECTIVELY, THE RESULTS SUGGEST THAT PRENATAL EXPOSURE TO ELEVATED LEVELS OF GLUCOCORTICOIDS PLAYS A ROLE IN THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND POTENTIALLY LEARNING AND MEMORY BY ALTERING THE EXPRESSION OF SPECIFIC GENES WITHIN THE AMYGDALA AND PVN. 2022 20 3177 22 H3K9ME2 REGULATION OF BDNF EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IS INVOLVED IN THE DEPRESSIVE-LIKE PHENOTYPE INDUCED BY MATERNAL SEPARATION IN MALE RATS. BACKGROUND: EARLY LIFE STRESS (ELS) INDUCES A DEPRESSIVE-LIKE PHENOTYPE AND INCREASES THE RISK OF DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN CONFIRMED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION. HOWEVER, THE MECHANISM BY WHICH ELS ALTERS THE EPIGENETIC REGULATION OF BDNF AND CHANGES SUSCEPTIBILITY TO DEPRESSION HAS NOT BEEN FULLY CLARIFIED. METHODS: THE PRESENT STUDY USED MATERNAL SEPARATION (MS) AND CHRONIC UNPREDICTED MILD STRESS (CUMS) TO ESTABLISH AN MS ANIMAL MODEL AND A DEPRESSIVE ANIMAL MODEL. WE ASSESSED DEPRESSIVE-LIKE BEHAVIOURS, INCLUDING ANHEDONIA, LOCOMOTOR ACTIVITY, ANXIETY-LIKE BEHAVIOUR, AND SPATIAL MEMORY, USING THE SUCROSE PREFERENCE TEST, THE OPEN FIELD TEST, THE ELEVATED PLUS MAZE TEST, AND THE MORRIS WATER MAZE TEST. WE ALSO INVESTIGATED BDNF AND H3K9ME2 EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX (MPFC) BY IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND QPCR ANALYSIS. ADDITIONALLY, WE USED UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (G9A), AS AN INTERVENTION. RESULTS: THE RESULTS SHOWED THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIOURS IN RATS AND RESULTED IN INCREASED H3K9ME2 EXPRESSION AND DECREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND MPFC. MORE IMPORTANTLY, ADULT MS RATS EXPERIENCING CUMS HAD MORE SEVERE DEPRESSIVE BEHAVIOURS, HAD HIGHER EXPRESSION OF H3K9ME2 IN THE HIPPOCAMPUS AND MPFC, AND HAD LOWER EXPRESSION OF BDNF IN THE HIPPOCAMPUS AND MPFC. IN ADDITION, ADMINISTRATION OF THE G9A INHIBITOR REVERSED MOST OF THE CHANGES. CONCLUSIONS: OUR STUDY SUGGESTS THAT ELS CHANGED BDNF AND H3K9ME2 EXPRESSION IN THE RAT BRAIN, RESULTING IN A DEPRESSIVE-LIKE PHENOTYPE. 2021