1 6455 118 THYMOQUINONE ENHANCES APOPTOSIS OF K562 CHRONIC MYELOID LEUKEMIA CELLS THROUGH HYPOMETHYLATION OF SHP-1 AND INHIBITION OF JAK/STAT SIGNALING PATHWAY. THE EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES (TSGS) IS CRITICAL IN THE DEVELOPMENT OF CHRONIC MYELOID LEUKEMIA (CML). SHP-1 FUNCTIONS AS A TSG AND NEGATIVELY REGULATES JAK/STAT SIGNALING. ENHANCEMENT OF SHP-1 EXPRESSION BY DEMETHYLATION PROVIDES MOLECULAR TARGETS FOR THE TREATMENT OF VARIOUS CANCERS. THYMOQUINONE (TQ), A CONSTITUENT OF NIGELLA SATIVA SEEDS, HAS SHOWN ANTI-CANCER ACTIVITIES IN VARIOUS CANCERS. HOWEVER, TQS EFFECT ON METHYLATION IS NOT FULLY CLEAR. THEREFORE, THE AIM OF THIS STUDY IS TO ASSESS TQS ABILITY TO ENHANCE THE EXPRESSION OF SHP-1 THROUGH MODIFYING DNA METHYLATION IN K562 CML CELLS. THE ACTIVITIES OF TQ ON CELL CYCLE PROGRESSION AND APOPTOSIS WERE EVALUATED USING A FLUOROMETRIC-RED CELL CYCLE ASSAY AND ANNEXIN V-FITC/PI, RESPECTIVELY. THE METHYLATION STATUS OF SHP-1 WAS STUDIED BY PYROSEQUENCING ANALYSIS. THE EXPRESSION OF SHP-1, TET2, WT1, DNMT1, DNMT3A, AND DNMT3B WAS DETERMINED USING RT-QPCR. THE PROTEIN PHOSPHORYLATION OF STAT3, STAT5, AND JAK2 WAS ASSESSED USING JESS WESTERN ANALYSIS. TQ SIGNIFICANTLY DOWNREGULATED THE DNMT1 GENE, DNMT3A GENE, AND DNMT3B GENE AND UPREGULATED THE WT1 GENE AND TET2 GENE. THIS LED TO HYPOMETHYLATION AND RESTORATION OF SHP-1 EXPRESSION, RESULTING IN INHIBITION OF JAK/STAT SIGNALING, INDUCTION OF APOPTOSIS, AND CELL CYCLE ARREST. THE OBSERVED FINDINGS IMPLY THAT TQ PROMOTES APOPTOSIS AND CELL CYCLE ARREST IN CML CELLS BY INHIBITING JAK/STAT SIGNALING VIA RESTORATION OF THE EXPRESSION OF JAK/STAT-NEGATIVE REGULATOR GENES. 2023 2 5295 22 PROTECTIVE POTENTIAL OF THYMOQUINONE AGAINST CADMIUM, ARSENIC, AND LEAD TOXICITY: A SHORT REVIEW WITH EMPHASIS ON OXIDATIVE PATHWAYS. HEAVY METALS ARE AMONG THE MOST IMPORTANT ENVIRONMENTAL POLLUTIONS USED IN VARIOUS INDUSTRIES. THEIR EXTENSIVE USE HAS INCREASED HUMAN SUSCEPTIBILITY TO DIFFERENT CHRONIC DISEASES. TOXIC METAL EXPOSURE, ESPECIALLY CADMIUM, ARSENIC, AND LEAD, CAUSES OXIDATIVE DAMAGES, MITOCHONDRIAL DYSFUNCTION, AND GENETIC AND EPIGENETIC MODIFICATIONS. MEANWHILE, THYMOQUINONE (TQ) IS AN EFFECTIVE COMPONENT OF NIGELLA SATIVA OIL THAT PLAYS AN IMPORTANT ROLE IN PREVENTING THE DESTRUCTIVE EFFECTS OF HEAVY METALS. THE PRESENT REVIEW DISCUSSES HOW TQ CAN PROTECT VARIOUS TISSUES AGAINST OXIDATIVE DAMAGE OF HEAVY METALS. THIS REVIEW IS BASED ON THE RESEARCH REPORTED ABOUT THE PROTECTIVE EFFECTS OF TQ IN THE TOXICITY OF HEAVY METALS, APPROXIMATELY THE LAST 10 YEARS (2010-2021). SCIENTIFIC DATABASES, INCLUDING SCOPUS, WEB OF SCIENCE, AND PUBMED, WERE SEARCHED USING THE FOLLOWING KEYWORDS EITHER ALONE OR IN COMBINATION: CADMIUM, ARSENIC, LEAD, TQ, AND OXIDATIVE STRESS. TQ, AS A POTENT ANTIOXIDANT, CAN DISTRIBUTE TO CELLULAR COMPARTMENTS AND PREVENT OXIDATIVE DAMAGE OF TOXIC METALS. HOWEVER, DEPENDING ON THE TYPE OF TOXIC METAL AND THE CARRIER SYSTEM USED TO RELEASE TQ IN BIOLOGICAL SYSTEMS, ITS THERAPEUTIC DOSAGE RANGE MAY BE VARIED. 2023 3 242 28 ADOLESCENT CANNABINOID EXPOSURE MODULATES THE VULNERABILITY TO COCAINE-INDUCED CONDITIONED PLACE PREFERENCE AND DNMT3A EXPRESSION IN THE PREFRONTAL CORTEX IN SWISS MICE. RATIONALE: CANNABIS SATIVA IS THE MOST WIDELY USED DRUG BY ADOLESCENTS GLOBALLY. THE RECREATIONAL USE OF SYNTHETIC CANNABINOIDS BY TEENAGERS HAS ALSO GROWN IN RECENT YEARS. DESPITE THE WRONG PERCEPTION THAT EXPOSURE TO THESE DRUGS DOES NOT CAUSE HARM, REPEATED EXPOSURE TO CANNABINOIDS AT EARLY STAGES OF LIFE COMPROMISES IMPORTANT MATURATION PROCESSES AND BRAIN DEVELOPMENT. CHRONIC EARLY CANNABINOID USE HAS BEEN RELATED TO A HIGHER RISK OF PSYCHIATRIC OUTCOMES, INCLUDING COCAINE ADDICTION. EVIDENCE SUGGESTS THAT EXPOSURE TO NATURAL AND SYNTHETIC CANNABINOIDS DURING ADOLESCENCE MODIFIES MOLECULAR AND BEHAVIORAL EFFECTS OF COCAINE IN ADULTHOOD. RESPONSES TO COCAINE ARE REGULATED BY EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, IN THE BRAIN'S REWARD REGIONS. HOWEVER, THE INVOLVEMENT OF THESE PROCESSES IN MODULATION OF THE VULNERABILITY TO THE EFFECTS OF COCAINE INDUCED BY PRIOR EXPOSURE TO CANNABINOIDS REMAINS POORLY UNDERSTOOD. OBJECTIVES: INVESTIGATE WHETHER EXPOSURE TO THE SYNTHETIC CANNABINOID WIN55,212-2 DURING ADOLESCENCE MODULATES ANXIETY- AND DEPRESSION-LIKE BEHAVIOR, MEMORY, AND COCAINE REWARD IN ADULT MICE. WE ALSO EVALUATED WHETHER EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE MODULATES THE EXPRESSION OF ENZYMES THAT ARE INVOLVED IN DNA METHYLATION. RESULTS: EXPOSURE TO WIN55,212-2 DURING ADOLESCENCE DID NOT ALTER ANXIETY- OR DEPRESSIVE-LIKE BEHAVIOR. HOWEVER, PRIOR EXPOSURE TO CANNABINOIDS INHIBITED COCAINE-INDUCED CONDITIONED PLACE PREFERENCE WITHOUT MODULATING COCAINE-INDUCED HYPERLOCOMOTION, ACCOMPANIED BY AN INCREASE IN EXPRESSION OF THE ENZYME DNA METHYLTRANSFERASE 3A (DNMT3A) IN THE PREFRONTAL CORTEX. CONCLUSIONS: OUR FINDINGS SUGGEST THAT EXPOSURE TO WIN55,212-2 DURING ADOLESCENCE LEADS TO CHANGES IN DNMT3A EXPRESSION, AND THIS PATHWAY APPEARS TO BE RELEVANT TO MODULATING THE REWARDING EFFECTS OF COCAINE. 2021 4 3279 21 HERITABLE ALTERATION IN DNA METHYLATION INDUCED BY NITROGEN-DEFICIENCY STRESS ACCOMPANIES ENHANCED TOLERANCE BY PROGENIES TO THE STRESS IN RICE (ORYZA SATIVA L.). CYTOSINE METHYLATION IS RESPONSIVE TO VARIOUS BIOTIC- AND ABIOTIC-STRESSES, WHICH MAY PRODUCE HERITABLE EPIALLELES. NITROGEN (N)-DEFICIENCY IS AN ABIOTIC STRESS BEING REPEATEDLY EXPERIENCED BY PLANTS. TO ADDRESS POSSIBLE EPIGENETIC CONSEQUENCES OF N-DEFICIENCY-STRESS, WE INVESTIGATED THE STABILITY OF CYTOSINE METHYLATION IN RICE (ORYZA SATIVA L.) SUBSEQUENT TO A CHRONIC (A WHOLE-GENERATION) N-DEFICIENCY AT TWO LEVELS, MODERATE (20MG/L) AND SEVERE (10MG/L), UNDER HYDROPONIC CULTURE. MSAP ANALYSIS REVEALED THAT LOCUS-SPECIFIC METHYLATION ALTERATION OCCURRED IN LEAF-TISSUE OF THE STRESSED PLANTS (S(0)) EXPERIENCING EITHER LEVEL OF N-DEFICIENCY, WHICH WAS VALIDATED BY GEL-BLOTTING. ANALYSIS ON THREE NON-STRESSED SELF-FED PROGENIES (S(1), S(2) AND S(3)) BY GEL-BLOTTING INDICATED THAT CA. 50% OF THE ALTERED METHYLATION PATTERNS IN SOMATIC CELLS (LEAF) OF THE STRESSED S(0) PLANTS WERE RECAPTURED IN S(1), WHICH WERE THEN STABLY INHERITED TO S(2) AND S(3). BISULFITE SEQUENCING OF TWO VARIANT MSAP LOCI WITH HOMOLOGY TO LOW-COPY RETROTRANSPOSONS ON ONE STRESSED PLANT (S(0)) AND ITS NON-STRESSED PROGENIES (S(1) AND S(2)) SHOWED THAT WHEREAS ONE LOCUS EXHIBITED LIMITED AND NON-HERITABLE CHH METHYLATION ALTERATION, THE OTHER LOCUS MANIFESTED DRAMATIC HERITABLE HYPERMETHYLATION AT NEARLY ALL CYTOSINE SITES WITHIN THE ASSAYED REGION. INTRIGUINGLY, WHEN TWO GROUPS OF S(2) PLANTS DESCENDED FROM THE SAME N-DEFICIENCY-STRESSED S(0) PLANT WERE RE-SUBJECTED TO THE STRESS, THE GROUP INHERITING THE MODIFIED METHYLATION PATTERNS SHOWED ENHANCED TOLERANCE TO THE N-DEFICIENCY-STRESS COMPARED WITH THE GROUP BEARING THE ORIGINAL PATTERNS. OUR RESULTS THUS DEMONSTRATE HERITABILITY OF AN ACQUIRED ADAPTIVE TRAIT IN RICE, WHICH WAS ACCOMPANIED BY EPIGENETIC INHERITANCE OF MODIFIED CYTOSINE METHYLATION PATTERNS, IMPLICATING AN EPIGENETIC BASIS UNDERLYING THE INHERITANCE OF AN ACQUIRED TRAIT IN PLANTS. 2011 5 1613 35 DNA METHYLTRANSFERASE 1 MEDIATED ABERRANT METHYLATION AND SILENCING OF SHP-1 GENE IN CHRONIC MYELOGENOUS LEUKEMIA CELLS. INTRODUCTION: EXTENSIVE STUDIES ON SHP-1 PROTEIN AND SHP-1 MRNA REVEALED THAT THE DIMINISHMENT OR ABOLISHMENT OF THE EXPRESSION OF SHP-1 IN LEUKEMIAS/LYMPHOMAS WAS DUE TO ABERRANT PROMOTER METHYLATION. THUS FAR, THE MECHANISM OF EPIGENETIC SILENCING OF THE SHP-1 TYROSINE PHOSPHATASE GENE THAT OCCURS IN CHRONIC MYELOGENOUS LEUKEMIA CELLS REMAINS POORLY UNDERSTOOD. METHODS: THE EXPRESSIONS OF THE TARGET MOLECULES WERE DETERMINED BY QUANTITATIVE REAL TIME PCR AND WESTERN BLOT, RESPECTIVELY. BISULFITE SEQUENCING PCR WAS USED TO DETECT METHYLATION STATUS OF DNA CPG. THE LENTIVIRAL VECTORS WERE APPLIED TO MODIFY GENE EXPRESSION. RESULTS: IN THE PRESENT STUDY, WE FOUND THAT THE PROMOTER 2 OF SHP-1 GENE IS LOCATED BETWEEN POSITIONS FROM -577BP TO +300BP, AND 22 CPG SITES CONTAINED IN POSITIONS -353BP APPROXIMATELY +182BP ARE ABERRANTLY METHYLATED IN K562 CELLS. IN VITRO, WE DEMONSTRATED THAT DNMT1 SILENCING INDUCED DEMETHYLATION OF THE 22 CPG SITES LOCATED IN THE SHP-1 PROMOTER AND RE-EXPRESSION OF SHP-1 GENE IN K562 CELLS. MOREOVER, WE PROVED THAT THE EXPRESSION LEVELS OF DNMT1 AND SHP-1 MRNA AND PROTEIN WERE NEGATIVELY CORRELATED IN K562 CELLS AND BM ASPIRATES MONONUCLEAR CELLS FROM CML PATIENTS. CONCLUSION: COLLECTIVELY, THESE RESULTS INDICATE THAT DNMT1 MEDIATES ABERRANT METHYLATION AND SILENCING OF SHP-1 GENE IN CHRONIC MYELOGENOUS LEUKEMIA CELLS, AND PROVIDE A NOVEL THERAPEUTIC TARGET FOR CML. 2017 6 3584 26 IMPACT OF SOCIAL DEFEAT STRESS ON DNA METHYLATION IN DRD2, NR3C1, AND STMN1 IN WILD-TYPE AND STMN1 KNOCK-OUT MICE. OBJECTIVE: EPIGENETIC PROFILES CAN BE MODIFIED BY STRESS. DOPAMINE RECEPTOR D2 (DRD2), GLUCOCORTICOID RECEPTOR GENE (NR3C1) AND STATHMIN 1 (STMN1) GENES ARE ALL IMPLICATED IN ADAPTATION TO STRESS. THE AIM OF STUDY IS TO INVESTIGATE IMPACT OF SOCIAL DEFEAT ON DNA METHYLATION IN DRD2, NR3C1, AND STMN1 IN WILD-TYPE (WT) AND STMN1 KNOCK-OUT (KO) MICE. METHODS: THE WT AND STMN1 KO MICE WERE SUBJECTED TO CHRONIC SOCIAL DEFEAT. BRAIN TISSUES OF THE PREFRONTAL CORTEX (PFC), AMYGDALA (AMY) AND HIPPOCAMPUS (HIP) WERE OBTAINED. WE MEASURED DNA METHYLATION LEVELS OF THE DRD2, NR3C1, AND STMN1 GENES IN THE PFC, AMY, AND HIP USING PYROSEQUENCING. RESULTS: IN WT MICE, SOCIAL DEFEAT STRESS DID NOT INDUCE ANY CHANGES IN DRD2 METHYLATION, WHEREAS SIGNIFICANT HYPERMETHYLATION OCCURRED IN NR3C1 AND STMN1 IN THE SUSCEPTIBLE AND UNSUSCEPTIBLE GROUPS, RESPECTIVELY, COMPARED TO THE CONTROL GROUP. THE METHYLATION RESPONSES IN THE STMN1 KO MICE DIFFERED FROM THOSE SEEN IN THE WT MICE, SUCH THAT HYPERMETHYLATION WAS EVIDENT IN ALL THREE GENES IN THE SUSCEPTIBLE AND UNSUSCEPTIBLE GROUPS COMPARED TO CONTROL GROUP. COMPARISON OF THE STMN1 KO AND WT MICE REVEALED THE SAME PATTERN OF HYPERMETHYLATION FOR ALL THREE GENES. CONCLUSION: SOCIAL DEFEAT STRESS INDUCED DIFFERENT EPIGENETIC MODIFICATIONS IN THREE GENES AMONG CONTROL, UNSUSCEPTIBLE, AND SUSCEPTIBLE GROUPS OF WT AND STMN1 KO MICE. IN PARTICULAR, HYPERMETHYLATION OF NR3C1 IN THE HIP OF THE SUSCEPTIBLE GROUP, AND OF STMN1 IN THE AMY OF THE UNSUSCEPTIBLE GROUP IN WT MICE, COULD SERVE AS EPIGENETIC BIOMARKERS OF STRESS SUSCEPTIBILITY AND STRESS RESILIENCE, RESPECTIVELY. 2022 7 586 26 BEHAVIOURAL AND EPIGENETIC EFFECTS OF PATERNAL EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE ON OFFSPRING VULNERABILITY TO STRESS. CHRONIC CANNABINOID EXPOSURE DURING ADOLESCENCE IN MALE RATS INDUCES CHRONIC COGNITIVE AND EMOTIONAL IMPAIRMENTS. HOWEVER, THE IMPACT OF THIS FORM OF EXPOSURE ON OFFSPRING VULNERABILITY TO STRESS IS UNKNOWN. THE AIM OF THIS STUDY WAS TO EVALUATE THE BEHAVIOURAL AND EPIGENETIC EFFECTS OF STRESS IN THE OFFSPRING OF MALE RATS WHOSE FATHERS WERE EXPOSED TO CANNABINOIDS DURING ADOLESCENCE. MALE ADOLESCENT OFFSPRING OF WIN55,212-2 (1.2 MG/KG) TREATED RATS WERE EXPOSED DURING ONE WEEK TO VARIABLE STRESSORS AND SUBJECTED TO BEHAVIOURAL TESTS OF ANXIETY AND EPISODIC-LIKE MEMORY, FOLLOWED BY AN ASSESSMENT OF GLOBAL DNA METHYLATION AND EXPRESSION OF DNA METHYLTRANSFERASES ENZYMES DNMT1 AND DNMT3A MRNA IN THE PREFRONTAL CORTEX. STRESS EXPOSURE INDUCED A SIGNIFICANT ANXIOGENIC-LIKE EFFECT BUT DID NOT AFFECT THE EPISODIC-LIKE MEMORY IN THE OFFSPRING OF WIN55,212-2 EXPOSED FATHERS IN COMPARISON TO THE OFFSPRING OF NON-EXPOSED FATHERS. THESE BEHAVIOURAL CHANGES WERE SUBSEQUENT TO A SIGNIFICANT INCREASE IN GLOBAL DNA METHYLATION AND DNMT1 AND DNMTA3 TRANSCRIPTION IN THE PREFRONTAL CORTEX. THESE DATA SUGGEST THAT THE DELETERIOUS EFFECT OF CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE ARE NOT LIMITED TO THE EXPOSED INDIVIDUALS BUT MAY INCREASE THE VULNERABILITY TO STRESS-INDUCED ANXIETY IN THE OFFSPRING AND ALTER THEIR EPIGENETIC PROGRAMMING. 2019 8 2387 33 EPIGENETIC REMODELING BY VITAMIN C POTENTIATES PLASMA CELL DIFFERENTIATION. ASCORBATE (VITAMIN C) IS AN ESSENTIAL MICRONUTRIENT IN HUMANS. THE SEVERE CHRONIC DEFICIENCY OF ASCORBATE, TERMED SCURVY, HAS LONG BEEN ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO INFECTIONS. HOW ASCORBATE AFFECTS THE IMMUNE SYSTEM AT THE CELLULAR AND MOLECULAR LEVELS REMAINED UNCLEAR. FROM A MICRONUTRIENT ANALYSIS, WE IDENTIFIED ASCORBATE AS A POTENT ENHANCER FOR ANTIBODY RESPONSE BY FACILITATING THE IL-21/STAT3-DEPENDENT PLASMA CELL DIFFERENTIATION IN MOUSE AND HUMAN B CELLS. THE EFFECT OF ASCORBATE IS UNIQUE AS OTHER ANTIOXIDANTS FAILED TO PROMOTE PLASMA CELL DIFFERENTIATION. ASCORBATE IS ESPECIALLY CRITICAL DURING EARLY B CELL ACTIVATION BY POISING THE CELLS TO PLASMA CELL LINEAGE WITHOUT AFFECTING THE PROXIMAL IL-21/STAT3 SIGNALING AND THE OVERALL TRANSCRIPTOME. AS A COFACTOR FOR EPIGENETIC ENZYMES, ASCORBATE FACILITATES TET2/3-MEDIATED DNA MODIFICATION AND DEMETHYLATION OF MULTIPLE ELEMENTS AT THE PRDM1 LOCUS. DNA DEMETHYLATION AUGMENTS STAT3 ASSOCIATION AT THE PRDM1 PROMOTER AND A DOWNSTREAM ENHANCER, THUS ENSURING EFFICIENT GENE EXPRESSION AND PLASMA CELL DIFFERENTIATION. THE RESULTS SUGGEST THAT AN ADEQUATE LEVEL OF ASCORBATE IS REQUIRED FOR ANTIBODY RESPONSE AND HIGHLIGHT HOW MICRONUTRIENTS MAY REGULATE THE ACTIVITY OF EPIGENETIC ENZYMES TO REGULATE GENE EXPRESSION. OUR FINDINGS IMPLY THAT EPIGENETIC ENZYMES CAN FUNCTION AS SENSORS TO GAUGE THE AVAILABILITY OF METABOLITES AND INFLUENCE CELL FATE DECISIONS. 2022 9 243 21 ADOLESCENT CHRONIC INTERMITTENT TOLUENE INHALATION DYNAMICALLY REGULATES THE TRANSCRIPTOME AND NEURONAL METHYLOME WITHIN THE RAT MEDIAL PREFRONTAL CORTEX. INHALANTS CONTAINING THE VOLATILE SOLVENT TOLUENE ARE MISUSED TO INDUCE EUPHORIA OR INTOXICATION. INHALANT ABUSE IS MOST COMMON DURING ADOLESCENCE AND CAN RESULT IN COGNITIVE IMPAIRMENTS DURING AN IMPORTANT MATURATIONAL PERIOD. DESPITE EVIDENCE SUGGESTING THAT EPIGENETIC MODIFICATIONS MAY UNDERPIN THE COGNITIVE EFFECTS OF INHALANTS, NO STUDIES TO DATE HAVE THOROUGHLY INVESTIGATED TOLUENE-INDUCED REGULATION OF THE TRANSCRIPTOME OR DISCRETE EPIGENETIC MODIFICATIONS WITHIN THE BRAIN. TO ADDRESS THIS, WE INVESTIGATED EFFECTS OF ADOLESCENT CHRONIC INTERMITTENT TOLUENE (CIT) INHALATION ON GENE EXPRESSION AND DNA METHYLATION PROFILES WITHIN THE RAT MEDIAL PREFRONTAL CORTEX (MPFC), WHICH UNDERGOES MATURATION THROUGHOUT ADOLESCENCE AND HAS BEEN IMPLICATED IN TOLUENE-INDUCED COGNITIVE DEFICITS. EMPLOYING BOTH RNA-SEQ AND GENOME-WIDE METHYL CPG BINDING DOMAIN (MBD) ULTRA-SEQ ANALYSIS, WE DEMONSTRATE THAT ADOLESCENT CIT INHALATION (10 000 PPM FOR 1 H/DAY, 3 DAYS/WEEK FOR 4 WEEKS) INDUCES BOTH TRANSIENT AND PERSISTENT CHANGES TO THE TRANSCRIPTOME AND DNA METHYLOME WITHIN THE RAT MPFC FOR AT LEAST 2 WEEKS FOLLOWING TOLUENE EXPOSURE. WE DEMONSTRATE FOR THE FIRST TIME THAT ADOLESCENT CIT EXPOSURE RESULTS IN DYNAMIC REGULATION OF THE MPFC TRANSCRIPTOME LIKELY RELATING TO ACUTE INFLAMMATORY RESPONSES AND PERSISTENT DEFICITS IN SYNAPTIC PLASTICITY. THESE ADAPTATIONS MAY CONTRIBUTE TO THE COGNITIVE DEFICITS ASSOCIATED WITH CHRONIC TOLUENE EXPOSURE AND PROVIDE NOVEL MOLECULAR TARGETS FOR PREVENTING LONG-TERM NEUROPHYSIOLOGICAL ABNORMALITIES FOLLOWING CHRONIC TOLUENE INHALATION. 2021 10 5485 32 REVERSAL OF COCAINE-CONDITIONED PLACE PREFERENCE THROUGH METHYL SUPPLEMENTATION IN MICE: ALTERING GLOBAL DNA METHYLATION IN THE PREFRONTAL CORTEX. ANALYSIS OF GLOBAL METHYLATION IN CELLS HAS REVEALED CORRELATIONS BETWEEN OVERALL DNA METHYLATION STATUS AND SOME BIOLOGICAL STATES. RECENT STUDIES SUGGEST THAT EPIGENETIC REGULATION THROUGH DNA METHYLATION COULD BE RESPONSIBLE FOR NEUROADAPTATIONS INDUCED BY ADDICTIVE DRUGS. HOWEVER, THERE IS NO INVESTIGATION TO DETERMINE GLOBAL DNA METHYLATION STATUS FOLLOWING REPEATED EXPOSURE TO ADDICTIVE DRUGS. USING MICE CONDITIONED PLACE PREFERENCE (CPP) PROCEDURE, WE MEASURED GLOBAL DNA METHYLATION LEVEL IN THE NUCLEUS ACCUMBENS (NAC) AND THE PREFRONTAL CORTEX (PFC) ASSOCIATED WITH DRUG REWARDING EFFECTS. WE FOUND THAT COCAINE-, BUT NOT MORPHINE- OR FOOD-CPP TRAINING DECREASED GLOBAL DNA METHYLATION IN THE PFC. CHRONIC TREATMENT WITH METHIONINE, A METHYL DONOR, FOR 25 CONSECUTIVE DAYS PRIOR TO AND DURING CPP TRAINING INHIBITED THE ESTABLISHMENT OF COCAINE, BUT NOT MORPHINE OR FOOD CPP. WE ALSO FOUND THAT BOTH MRNA AND PROTEIN LEVEL OF DNMT (DNA METHYTRANSFERASE) 3B IN THE PFC WERE DOWNREGULATED FOLLOWING THE ESTABLISHMENT OF COCAINE CPP, AND THE DOWNREGULATION COULD BE REVERSED BY REPEATED ADMINISTRATION OF METHIONINE. OUR STUDY INDICATES A CRUCIAL ROLE OF GLOBAL PFC DNA HYPOMETHYLATION IN THE REWARDING EFFECTS OF COCAINE. REVERSAL OF GLOBAL DNA HYPOMETHYLATION COULD SIGNIFICANTLY ATTENUATE THE REWARDING EFFECTS INDUCED BY COCAINE. OUR RESULTS SUGGEST THAT METHIONINE MAY HAVE BECOME A POTENTIAL THERAPEUTIC TARGET TO TREAT COCAINE ADDICTION. 2012 11 5941 35 TARGETING MICRORNAS WITH THYMOQUINONE: A NEW APPROACH FOR CANCER THERAPY. CANCER IS A GLOBAL DISEASE INVOLVING TRANSFORMATION OF NORMAL CELLS INTO TUMOR TYPES VIA NUMEROUS MECHANISMS, WITH MORTALITY AMONG ALL GENERATIONS, IN SPITE OF THE BREAKTHROUGHS IN CHEMOTHERAPY, RADIOTHERAPY AND/OR SURGERY FOR CANCER TREATMENT. SINCE ONE IN SIX DEATHS IS DUE TO CANCER, IT IS ONE OF THE OVERRIDING PRIORITIES OF WORLD HEALTH. RECENTLY, BIOACTIVE NATURAL COMPOUNDS HAVE BEEN WIDELY RECOGNIZED DUE TO THEIR THERAPEUTIC EFFECTS FOR TREATMENT OF VARIOUS CHRONIC DISORDERS, NOTABLY CANCER. THYMOQUINONE (TQ), THE MOST VALUABLE CONSTITUENT OF BLACK CUMIN SEEDS, HAS SHOWN ANTI-CANCER CHARACTERISTICS IN A WIDE RANGE OF ANIMAL MODELS. THE REVOLUTIONARY FINDINGS HAVE REVEALED TQ'S ABILITY TO REGULATE MICRORNA (MIRNA) EXPRESSION, OFFERING A PROMISING APPROACH FOR CANCER THERAPY. MIRNAS ARE SMALL NONCODING RNAS THAT MODULATE GENE EXPRESSION BY MEANS OF VARIATION IN FEATURES OF MRNA. MIRNAS MANAGE SEVERAL BIOLOGICAL PROCESSES INCLUDING GENE EXPRESSION AND CELLULAR SIGNALING PATHWAYS. ACCORDINGLY, MIRNAS CAN BE CONSIDERED AS HALLMARKS FOR CANCER DIAGNOSIS, PROGNOSIS AND THERAPY. THE PURPOSE OF THIS STUDY WAS TO REVIEW THE VARIOUS MOLECULAR MECHANISMS BY WHICH TQ EXERTS ITS POTENTIAL AS AN ANTI-CANCER AGENT THROUGH MODULATING MIRNAS. 2021 12 431 26 ANTIDEPRESSANT ADMINISTRATION MODULATES STRESS-INDUCED DNA METHYLATION AND DNA METHYLTRANSFERASE EXPRESSION IN RAT PREFRONTAL CORTEX AND HIPPOCAMPUS. STRESS AND ANTIDEPRESSANT TREATMENT CAN MODULATE DNA METHYLATION IN PROMOTER REGION OF GENES RELATED TO NEUROPLASTICITY AND MOOD REGULATION, THUS IMPLICATING THIS EPIGENETIC MECHANISM IN DEPRESSION NEUROBIOLOGY AND TREATMENT. ACCORDINGLY, SYSTEMIC ADMINISTRATION OF DNA METHYLTRANSFERASE (DNMT) INHIBITORS INDUCES ANTIDEPRESSANT-LIKE EFFECTS IN RODENTS. DNA METHYLATION IS CONVEYED BY DNMT 1, 3A AND 3B ISOFORMS, WHICH ARE DIFFERENTIALLY EXPRESSED IN THE BRAIN. IN ORDER TO INVESTIGATE IF THE BEHAVIORAL EFFECTS OF ANTIDEPRESSANTS COULD BE ASSOCIATED WITH CHANGES IN DNA METHYLATION AND DNMT EXPRESSION, WE INVESTIGATED THE EFFECTS INDUCED BY ACUTE AND REPEATED ANTIDEPRESSANT TREATMENT ON DNA METHYLATION AND DNMT EXPRESSION (1, 3A AND 3B ISOFORMS) IN DIFFERENT BRAIN REGIONS OF RATS EXPOSED TO A STRESS MODEL OF DEPRESSION, THE LEARNED HELPLESSNESS (LH). THEREFORE, RATS WERE EXPOSED TO PRETEST AND TREATED WITH ONE OR SEVEN INJECTIONS OF VEHICLE OR IMIPRAMINE (15 MG KG(-1)), WITH TEST SESSION PERFORMED ONE HOUR AFTER THE LAST INJECTION. CHRONIC, BUT NOT ACUTE, IMIPRAMINE ADMINISTRATION ATTENUATED ESCAPE FAILURES DURING THE TEST, A WELL DESCRIBED ANTIDEPRESSANT-LIKE EFFECT IN THIS MODEL. DNA METHYLATION AND DNMT (1, 3A AND 3B) LEVELS WERE MEASURED IN THE DORSAL AND VENTRAL HIPPOCAMPUS (DHPC, VHPC) AND IN THE PREFRONTAL CORTEX (PFC) OF RATS EXPOSED TO STRESS AND TREATMENT. STRESS INCREASED DNA METHYLATION, DNMT3A AND DNMT3B EXPRESSION IN THE DHPC AND PFC. CHRONIC, BUT NOT ACUTE, IMIPRAMINE ADMINISTRATION ATTENUATED STRESS EFFECTS ONLY IN THE PFC. THESE RESULTS SUGGEST THE REGULATION OF DNA METHYLATION IN THE PFC MAY BE AN IMPORTANT MECHANISM FOR ANTIDEPRESSANT-LIKE EFFECTS IN THE LH MODEL. 2018 13 1789 27 EFFECT OF CHRONIC HEROIN AND COCAINE ADMINISTRATION ON GLOBAL DNA METHYLATION IN BRAIN AND LIVER. DRUG ABUSE IS ASSOCIATED WITH EPIGENETIC CHANGES, SUCH AS HISTONE MODIFICATIONS AND DNA METHYLATION. THE PURPOSE OF THE PRESENT STUDY WAS TO EXAMINE THE EFFECT OF CHRONIC COCAINE AND HEROIN ADMINISTRATION ON GLOBAL DNA METHYLATION IN BRAIN AND LIVER. MALE, 8 WEEK OLD, C57BL/6J MICE RECEIVED HEROIN IN A CHRONIC 'INTERMITTENT' ESCALATING DOSE PARADIGM, OR COCAINE IN A CHRONIC ESCALATING DOSE 'BINGE' PARADIGM, WHICH MIMIC THE HUMAN PATTERN OF OPIOID OR COCAINE ABUSE RESPECTIVELY. FOLLOWING SACRIFICE, LIVERS AND BRAINS WERE REMOVED AND DNA WAS EXTRACTED FROM THEM. THE EXTRACTED DNA WAS HYDROLYZED AND 2'-DEOXYCYTIDINE AND 5-METHYL-2'-DEOXYCYTIDINE WERE DETERMINED BY HPLC-UV. THE % 5-METHYL-2'-DEOXYCYTIDINE CONTENT OF DNA WAS SIGNIFICANTLY HIGHER IN THE BRAIN COMPARED TO THE LIVER. THERE WERE NO DIFFERENCES BETWEEN THE CONTROL ANIMALS AND THE COCAINE OR HEROIN TREATED ANIMALS IN NEITHER OF THE TISSUES EXAMINED, WHICH IS SURPRISING SINCE COCAINE ADMINISTRATION INDUCED GROSS MORPHOLOGICAL CHANGES IN THE LIVER. MOREOVER, THERE WAS NO DIFFERENCE IN THE % 5-METHYL-2'-DEOXYCYTIDINE CONTENT OF DNA BETWEEN THE COCAINE AND THE HEROIN TREATED ANIMALS. THE GLOBAL DNA METHYLATION STATUS IN THE BRAIN AND LIVER OF MICE CHRONICALLY TREATED WITH COCAINE OR HEROIN REMAINS UNAFFECTED, BUT THIS FINDING CANNOT EXCLUDE THE EXISTENCE OF ANATOMICAL REGION OR GENE-SPECIFIC METHYLATION DIFFERENCES. THIS IS THE FIRST TIME THAT GLOBAL DNA METHYLATION IN THE LIVER AND WHOLE BRAIN HAS BEEN STUDIED FOLLOWING CHRONIC COCAINE OR HEROIN TREATMENT. 2013 14 907 28 CHRONIC EXPOSURE TO ENVIRONMENTALLY RELEVANT CONCENTRATION OF FLUORIDE ALTERS OGG1 AND RAD51 EXPRESSIONS IN MICE: INVOLVEMENT OF EPIGENETIC REGULATION. CHRONIC EXPOSURE TO FLUORIDE (F) BEYOND THE PERMISSIBLE LIMIT (1.5 PPM) IS KNOWN TO CAUSE DETRIMENTAL HEALTH EFFECTS BY INDUCTION OF OXIDATIVE STRESS-MEDIATED DNA DAMAGE OVERPOWERING THE DNA REPAIR MACHINERY. IN THE PRESENT STUDY, WE ASSESSED F INDUCED OXIDATIVE STRESS THROUGH MONITORING BIOCHEMICAL PARAMETERS AND LOOKED INTO THE EFFECT OF CHRONIC F EXPOSURE ON TWO CRUCIAL DNA REPAIR GENES OGG1 AND RAD51 HAVING IMPORTANT ROLE AGAINST ROS INDUCED DNA DAMAGES. TO ADDRESS THIS ISSUE, WE EXPOSED SWISS ALBINO MICE TO AN ENVIRONMENTALLY RELEVANT CONCENTRATION OF FLUORIDE (15 PPM NAF) FOR 8 MONTHS. RESULTS REVEALED HISTOARCHITECTURAL DAMAGES IN LIVER, BRAIN, KIDNEY AND SPLEEN. DEPLETION OF GSH, INCREASE IN LIPID PEROXIDATION AND CATALASE ACTIVITY IN LIVER AND BRAIN CONFIRMED THE GENERATION OF OXIDATIVE STRESS. QRT-PCR RESULT SHOWED THAT EXPRESSIONS OF OGG1 AND RAD51 WERE ALTERED AFTER F EXPOSURE IN THE AFFECTED ORGANS. PROMOTER HYPERMETHYLATION WAS ASSOCIATED WITH THE DOWNREGULATION OF RAD51. F-INDUCED DNA DAMAGE AND THE COMPROMISED DNA REPAIR MACHINERY TRIGGERED INTRINSIC PATHWAY OF APOPTOSIS IN LIVER AND BRAIN. THE PRESENT STUDY INDICATES THE POSSIBLE ASSOCIATION OF EPIGENETIC REGULATION WITH F INDUCED NEUROTOXICITY. 2020 15 5749 19 SOCIAL DEFEAT INDUCES CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE MODIFYING ENZYMES IN THE VENTRAL HIPPOCAMPUS, PREFRONTAL CORTEX, AND DORSAL RAPHE NUCLEUS. CHRONIC EXPOSURE TO STRESS IS ASSOCIATED WITH A NUMBER OF PSYCHIATRIC DISORDERS, BUT LITTLE IS KNOWN ABOUT THE EPIGENETIC MECHANISMS THAT UNDERLIE THE STRESS RESPONSE OR RESILIENCE TO CHRONIC STRESS. WE INVESTIGATED HISTONE ACETYLATION IN SEVEN DIFFERENT BRAIN REGIONS OF RATS EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS: THE DORSAL HIPPOCAMPUS (DHPC), VENTRAL HIPPOCAMPUS (VHPC), MEDIAL PREFRONTAL CORTEX (MPFC), BASOLATERAL AMYGDALA (BLA), LOCUS COERULEUS (LC), PARAVENTRICULAR THALAMUS (PVT), AND DORSAL RAPHE (DR) NUCLEUS. THIS STRESS PARADIGM WAS UNIQUE IN THAT IT ALLOWED RATS TO DISPLAY RESILIENCE IN THE FORM OF AN ACTIVE COPING MECHANISM. WE FOUND THAT THERE WAS AN INCREASE IN ACETYLATION OF H3K9/14 (H3K9/14AC) AND BULK ACETYLATION OF H4K5,8,12,16 (H4K5,8,12,16AC) IN THE DR NUCLEUS OF RATS THAT WERE LESS RESILIENT. LESS RESILIENT RATS ALSO DISPLAYED INCREASED LEVELS OF H3K18 ACETYLATION (H3K18AC) IN THE MPFC WHEN COMPARED TO NON-STRESSED CONTROLS. IN THE VHPC, THERE WAS AN INCREASE IN H3K18AC AND H4K12 (H4K12AC) IN RATS THAT WERE LESS RESILIENT WHEN COMPARED TO NON-STRESSED CONTROL RATS. IN ADDITION, THERE WAS A DECREASE IN LEVELS OF H4K8 ACETYLATION (H4K8AC) IN BOTH RESILIENT AND NON-RESILIENT RATS AS COMPARED TO CONTROLS. WE ASSESSED EXPRESSION OF HISTONE MODIFYING ENZYMES IN THE VHPC AND THE MPFC USING QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (PCR) AND FOUND CHANGES IN EXPRESSION OF A NUMBER OF TARGETS. THESE INCLUDED CHANGES IN SIRT1 AND SIRT2 IN THE VHPC AND CHANGES IN KAT5 IN THE MPFC. OVERALL, THESE RESULTS SUGGEST THAT CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE MODIFYING ENZYMES IN THESE REGIONS CORRELATE WITH THE BEHAVIORAL RESPONSE TO STRESS IN SOCIALLY DEFEATED RATS. 2014 16 1534 24 DNA METHYLATION DYNAMICS IN A COASTAL FOUNDATION SEAGRASS SPECIES UNDER ABIOTIC STRESSORS. DNA METHYLATION (DNAM) HAS BEEN INTENSIVELY STUDIED IN TERRESTRIAL PLANTS IN RESPONSE TO ENVIRONMENTAL CHANGES, BUT ITS DYNAMIC CHANGES IN A TEMPORAL SCALE REMAIN UNEXPLORED IN MARINE PLANTS. THE SEAGRASS POSIDONIA OCEANICA RANKS AMONG THE SLOWEST-GROWING AND LONGEST-LIVING PLANTS ON EARTH, AND IS PARTICULARLY VULNERABLE TO SEA WARMING AND LOCAL ANTHROPOGENIC PRESSURES. HERE, WE ANALYSED THE DYNAMICS OF DNAM CHANGES IN PLANTS COLLECTED FROM COASTAL AREAS DIFFERENTIALLY IMPACTED BY EUTROPHICATION (I.E. OLIGOTROPHIC, OL; EUTROPHIC, EU) AND EXPOSED TO ABIOTIC STRESSORS (NUTRIENTS, TEMPERATURE INCREASE AND THEIR COMBINATION). LEVELS OF GLOBAL DNAM (% 5-MC) AND THE EXPRESSION OF KEY GENES INVOLVED IN DNAM WERE ASSESSED AFTER ONE, TWO AND FIVE WEEKS OF EXPOSURE. RESULTS REVEALED A CLEAR DIFFERENTIATION BETWEEN PLANTS, DEPENDING ON ENVIRONMENTAL STIMULI, TIME OF EXPOSURE AND PLANTS' ORIGIN. % 5-MC LEVELS WERE HIGHER DURING THE INITIAL STRESS EXPOSURE ESPECIALLY IN OL PLANTS, WHICH UPREGULATED ALMOST ALL GENES INVOLVED IN DNAM. CONTRARILY, EU PLANTS SHOWED LOWER EXPRESSION LEVELS, WHICH INCREASED UNDER CHRONIC EXPOSURE TO STRESSORS, PARTICULARLY TO TEMPERATURE. THESE FINDINGS SHOW THAT DNAM IS DYNAMIC IN P. OCEANICA DURING STRESS EXPOSURE AND UNDERLINED THAT ENVIRONMENTAL EPIGENETIC VARIATIONS COULD BE IMPLICATED IN THE REGULATION OF ACCLIMATION AND PHENOTYPIC DIFFERENCES DEPENDING ON LOCAL CONDITIONS. 2023 17 6477 26 TOLUENE IMPAIRS LEARNING AND MEMORY, HAS ANTINOCICEPTIVE EFFECTS, AND MODIFIES HISTONE ACETYLATION IN THE DENTATE GYRUS OF ADOLESCENT AND ADULT RATS. TOLUENE MISUSE USUALLY INITIATES AT AN EARLY AGE WHEN THE CENTRAL NERVOUS SYSTEM IS STILL IMMATURE, CAUSING DELETERIOUS EFFECTS SUCH AS COGNITIVE IMPAIRMENT. EPIGENETIC REGULATORY MECHANISMS HAVE BEEN PROPOSED TO EXPLAIN LONG-TERM CHANGES INVOLVED NOT ONLY IN MEMORY, BUT ALSO IN TOLUENE'S ACTIONS. THE AIM OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF ACUTE AND CHRONIC TOLUENE EXPOSURE ON LEARNING, MEMORY AND HISTONE ACETYLATION IN THE RAT HIPPOCAMPUS DURING TWO STAGES OF LIFE: ADOLESCENCE AND YOUNG ADULTHOOD. BECAUSE THE MEMORY TESTS USED IN THIS WORK INVOLVED OBJECT EXPLORATION AND THE PERCEPTION OF A NOXIOUS STIMULUS, GENERAL ACTIVITY AND NOCICEPTION TESTS WERE ALSO CONDUCTED. ACUTE AND CHRONIC TOLUENE INHALATION IMPAIRED LEARNING, SHORT-TERM AND LONG-TERM MEMORY IN AN OBJECT-RECOGNITION TEST AND IN AN INHIBITORY AVOIDANCE TASK IN BOTH GROUPS OF AGE. THIS EFFECT WAS CONCENTRATION-DEPENDENT AND OCCURRED EVEN AT LOW TOLUENE CONCENTRATIONS (1000, 2000 PPM) THAT WERE OTHERWISE NON-EFFECTIVE. ACUTE TOLUENE INHALATION PRODUCED ANTINOCICEPTION, AND TOLERANCE TO THIS EFFECT DEVELOPED AFTER CHRONIC EXPOSURE. HISTONE ACETYLATION IN THE DENTATE GYRUS SHOWED DIFFERENCES DEPENDING ON THE HISTONE, TREATMENT AND AGE: A SINGLE TOLUENE EXPOSURE INCREASED H4 ACETYLATION IN ADOLESCENTS AND YOUNG ADULT RATS, WHEREAS CHRONIC EXPOSURE DECREASED H3 ACETYLATION, BUT ONLY IN ADULTS. IN CONCLUSION, THIS WORK PROVIDES EVIDENCE OF TOLUENE-INDUCED IMPAIRMENT ON LEARNING, SHORT- AND LONG-TERM MEMORY IN ADOLESCENT AND YOUNG ADULT RATS, AND SHOWS THAT EVEN A SINGLE TOLUENE EXPOSURE CAN INDUCE EPIGENETIC MODIFICATIONS IN THE RAT HIPPOCAMPUS. 2012 18 1819 19 EFFECTS OF CHRONIC OCHRATOXIN A EXPOSURE ON P53 HETEROZYGOUS AND P53 HOMOZYGOUS MICE. EXPOSURE TO THE MYCOTOXIN OCHRATOXIN A (OTA) CAUSES NEPHROPATHY IN DOMESTIC ANIMALS AND RODENTS AND RENAL TUMORS IN RODENTS AND POULTRY. HUMANS ARE EXPOSED TO OTA BY CONSUMING FOODS MADE WITH CONTAMINATED CEREAL GRAINS AND OTHER COMMODITIES. MANAGEMENT OF HUMAN HEALTH RISKS DUE TO OTA EXPOSURE DEPENDS, IN PART, ON ESTABLISHING A MODE OF ACTION (MOA) FOR OTA CARCINOGENESIS. TO FURTHER INVESTIGATE OTA'S MOA, P53 HETEROZYGOUS (P53+/-) AND P53 HOMOZYGOUS (P53+/+) MICE WERE EXPOSED TO OTA IN DIET FOR 26 WEEKS. THE FORMER ARE SUSCEPTIBLE TO TUMORIGENESIS UPON CHRONIC EXPOSURE TO GENOTOXIC CARCINOGENS. OTA-INDUCED RENAL DAMAGE BUT NO TUMORS WERE OBSERVED IN EITHER STRAIN, INDICATING THAT P53 HETEROZYGOSITY CONFERRED LITTLE ADDITIONAL SENSITIVITY TO OTA. RENAL CHANGES INCLUDED DOSE-DEPENDENT INCREASES IN CELLULAR PROLIFERATION, APOPTOSIS, KARYOMEGALY, AND TUBULAR DEGENERATION IN PROXIMAL TUBULES, WHICH WERE CONSISTENT WITH OCHRATOXICOSIS. THE LOWEST OBSERVED EFFECT LEVEL FOR RENAL CHANGES IN P53+/- AND P53+/+ MICE WAS 200 MUG OTA/KG BW/DAY. BASED ON THE LACK OF TUMORS AND THE SEVERITY OF RENAL AND BODY WEIGHT CHANGES AT A MAXIMUM TOLERATED DOSE, THE RESULTS WERE INTERPRETED AS SUGGESTIVE OF A PRIMARILY NONGENOTOXIC (EPIGENETIC) MOA FOR OTA CARCINOGENESIS IN THIS MOUSE MODEL. 2015 19 1818 22 EFFECTS OF CHRONIC METHAMPHETAMINE EXPOSURE ON REWARDING BEHAVIOR AND NEURODEGENERATION MARKERS IN ADULT MICE. RECREATIONAL AND MEDICAL USE OF STIMULANTS AMONG YOUNG ADULTS HAVE GAINED POPULARITY IN THE UNITED STATES OVER THE LAST DECADE AND THEIR USE MAY INCREASE VULNERABILITY TO BRAIN BIOCHEMICAL CHANGES AND ADDICTIVE BEHAVIORS. THE LONG-TERM EFFECTS OF CHRONIC STIMULANT EXPOSURE IN LATER ADULTHOOD HAVE NOT BEEN FULLY ELUCIDATED.OUR STUDY INVESTIGATED WHETHER CHRONIC EXPOSURE TO METHAMPHETAMINE (METH), AT A DOSE DESIGNED TO EMULATE HUMAN THERAPEUTIC DOSING FOR ADHD, WOULD PROMOTE BIOCHEMICAL ALTERATIONS AND AFFECT SENSITIVITY TO THE REWARDING EFFECTS OF SUBSEQUENT METH DOSING.GROUPS OF 3.5-MONTH-OLD MALE AND FEMALE C57BL/6J MICE WERE ADMINISTERED NON-CONTINGENT INTRAPERITONEAL INJECTIONS OF EITHER SALINE OR METH (1.4 MG/KG) TWICE A DAY FOR 1 MONTH (5 DAYS/WEEK). METH (0.5 MG/KG)-INDUCED CONDITIONED PLACE PREFERENCE (CPP) WAS TESTED IN MICE TO DETERMINE THE EFFECTS OF PREVIOUS METH EXPOSURE ON REWARD-RELATED BEHAVIOR. MICE WERE RANDOMLY ASSIGNED TO EXPERIMENT I (MALES AND FEMALES) OR EXPERIMENT II (FEMALES ONLY) IN WHICH CPP TESTING WAS RESPECTIVELY PERFORMED EITHER 0.5 OR 5 MONTHS AFTER THE END OF METH INJECTIONS, AT ~5 OR 10 MONTHS OLD RESPECTIVELY. THE MIDBRAIN AND STRIATUM, REGIONS INVOLVED IN REWARD CIRCUIT, WERE ASSESSED FOR MARKERS ASSOCIATED WITH NEUROTOXICITY, DOPAMINERGIC FUNCTION, NEUROINFLAMMATION AND EPIGENETIC CHANGES AFTER BEHAVIORAL TESTING.PREVIOUS EXPOSURE TO CHRONIC METH DID NOT HAVE SIGNIFICANT SHORT-TERM EFFECTS ON CPP RESPONSE BUT LED TO A DECREASED CPP RESPONSE IN 10-MONTH-OLD FEMALES. PREVIOUS EXPOSURE TO METH INDUCED SOME SHORT-TERM CHANGES TO BIOCHEMICAL MARKERS MEASURED IN A BRAIN REGION AND SEX-DEPENDENT MANNER, WHILE LONG-TERM CHANGES WERE ONLY OBSERVED WITH GFAP AND KDM5C.IN CONCLUSION, OUR DATA SUGGEST SEX- AND POST-EXPOSURE DURATION-DEPENDENT OUTCOMES AND WARRANT FURTHER EXPLORATION OF THE LONG-TERM NEUROBEHAVIORAL CONSEQUENCES OF PSYCHOSTIMULANT USE IN BOTH SEXES. 2023 20 4935 18 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