1 5616 122 SAMUL-TANG AMELIORATES OOCYTE DAMAGE DUE TO CYCLOPHOSPHAMIDE-INDUCED CHRONIC OVARIAN DYSFUNCTION IN MICE. SAMUL-TANG (SM), A TRADITIONAL HERBAL MEDICINE, HAS BEEN USED TO TREAT MENSTRUAL IRREGULARITIES AND INFERTILITY IN WOMEN. HOWEVER, THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THE EFFECTS OF SM REMAIN ELUSIVE. WE INVESTIGATED THE POTENTIAL PROTECTIVE EFFECT OF SM AGAINST CHRONIC OVARIAN DYSFUNCTION AND USED BIOINFORMATICS ANALYSIS TO IDENTIFY ITS UNDERLYING MECHANISM IN A MOUSE MODEL OF CYCLOPHOSPHAMIDE (CP)-INDUCED DIMINISHED OVARIAN RESERVE. FEMALE C57BL/6 MICE WERE INTRAPERITONEALLY INJECTED WITH CP THREE TIMES A WEEK, FOLLOWED BY ORAL ADMINISTRATION OF DISTILLED WATER (CP GROUP) OR SM (CP + SM GROUP) FOR 4 WEEKS. FOUR WEEKS LATER, THE EFFECT OF SM WAS ASSESSED BY OVARIAN TISSUE HISTOLOGICAL ANALYSIS, STEROID HORMONE MEASUREMENT, OOCYTE QUALITY, AND MRNA AND MICRORNA MICROARRAY ANALYSIS IN THE OVARIES. ALTHOUGH SM ADMINISTRATION DID NOT PREVENT CP-INDUCED FOLLICLE LOSS IN MICE, THE QUALITY OF OOCYTES WAS BETTER IN CP + SM MICE THAN IN CP MICE. GENE EXPRESSION ANALYSIS REVEALED THAT THE EXPRESSION OF FERTILISATION- AND OVARIAN FOLLICLE DEVELOPMENT-RELATED GENES WAS ALTERED BY CP TREATMENT BUT NORMALIZED AFTER SM ADMINISTRATION. FURTHER BIOINFORMATICS ANALYSIS SHOWED POSSIBLE INTERACTIONS BETWEEN DIFFERENTIALLY EXPRESSED MRNAS AND MICRORNAS. THEREFORE, WE DEMONSTRATED THE PROTECTIVE EFFECTS OF SM ON OVARIAN FUNCTION AND OOCYTE MATURATION AGAINST CP-INDUCED DAMAGE VIA MULTIPLE EPIGENETIC MECHANISMS. 2020 2 2255 29 EPIGENETIC MODULATIONS IN EARLY ENDOTHELIAL CELLS AND DNA HYPERMETHYLATION IN HUMAN SKIN AFTER SULFUR MUSTARD EXPOSURE. VICTIMS THAT WERE EXPOSED TO THE CHEMICAL WARFARE AGENT SULFUR MUSTARD (SM) SUFFER FROM CHRONIC DERMAL AND OCULAR LESIONS, SEVERE PULMONARY PROBLEMS AND CANCER DEVELOPMENT. IT HAS BEEN PROPOSED THAT EPIGENETIC PERTURBATIONS MIGHT BE INVOLVED IN THAT PROCESS BUT THIS HAS NOT BEEN INVESTIGATED SO FAR. IN THIS STUDY, WE INVESTIGATED EPIGENETIC MODULATIONS IN VITRO USING EARLY ENDOTHELIAL CELLS (EEC) THAT WERE EXPOSED TO DIFFERENT SM CONCENTRATIONS (0.5, 1.0, 23.5 AND 50MUM). A COMPREHENSIVE ANALYSIS OF 78 GENES RELATED TO EPIGENETIC PATHWAYS (I.E., DNA-METHYLATION AND POST-TRANSLATIONAL HISTONE MODIFICATIONS) WAS PERFORMED. MOREOVER, WE ANALYZED GLOBAL DNA METHYLATION IN VITRO IN EEC AFTER SM EXPOSURE AS A MAKER FOR EPIGENETIC MODULATIONS AND IN VIVO USING HUMAN SKIN SAMPLES THAT WERE OBTAINED FROM A PATIENT 1 YEAR AFTER AN ACCIDENTLY EXPOSURE TO PURE SM. SM EXPOSURE RESULTED IN A COMPLEX REGULATION PATTERN OF EPIGENETIC MODULATORS WHICH WAS ACCOMPANIED BY A GLOBAL INCREASE OF DNA METHYLATION IN VITRO. EXAMINATION OF THE SM EXPOSED HUMAN SKIN SAMPLES ALSO REVEALED A SIGNIFICANT INCREASE OF GLOBAL DNA METHYLATION IN VIVO, UNDERLINING THE BIOLOGICAL RELEVANCE OF OUR FINDINGS. THUS, WE DEMONSTRATED FOR THE FIRST TIME THAT SM AFFECTS EPIGENETIC PATHWAYS AND CAUSES EPIGENETIC MODULATIONS BOTH IN VIVO AND IN VITRO. 2016 3 2297 23 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT. 2014 4 3726 33 INHIBITION OF HISTONE METHYLTRANSFERASE EZH2 SUPPRESSES ENDOMETRIOTIC VESICLE DEVELOPMENT IN A RAT MODEL OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A PAINFUL GYNECOLOGICAL DISEASE WITH NO CURE AND LIMITED THERAPEUTIC OPTIONS. IT HAS BEEN HYPOTHESIZED THAT EPIGENETIC DRUGS CAN BE USED AS A NONHORMONAL TREATMENT FOR ENDOMETRIOSIS. THIS STUDY WAS CONDUCTED TO STUDY THE EFFICACY OF AN INHIBITOR OF THE HISTONE METHYLTRANSFERASE EZH2 USING AN ESTABLISHED RAT MODEL OF ENDOMETRIOSIS. WE HYPOTHESIZED THAT TREATMENT WILL BLOCK OR REDUCE THE NUMBER OF ENDOMETRIOTIC VESICLES IN THIS MODEL. WE CONDUCTED A PRECLINICAL DRUG STUDY IN FEMALE RATS WITH EXPERIMENTAL ENDOMETRIOSIS (UTERINE TISSUE TRANSPLANTED NEXT TO THE INTESTINAL MESENTERY) OR CONTROL SHAM (SUTURES ONLY). RATS WITH ENDOMETRIOSIS OR SHAM SURGERY RECEIVED EITHER TREATMENT WITH EZH2 INHIBITOR (5 MG/KG OR 10 MG/KG) OR VEHICLE (0.1%, 67% DMSO) EVERY OTHER DAY DURING 4 WEEKS. AFTER TREATMENT COMPLETION, THE NUMBER, AREA, VOLUME, AND WEIGHT OF VESICLES WERE EVALUATED. RT [2] PROFILER ARRAYS FOR NEUROPATHIC AND INFLAMMATION, EPITHELIAL TO MESENCHYMAL TRANSITION, INFLAMMATORY RESPONSE, AND AUTOIMMUNITY PATHWAYS WERE USED TO EXAMINE GENE EXPRESSION CHANGES IN THE VESICLES THAT DEVELOPED. TREATMENT WITH EZH2 INHIBITOR (10 MG/KG) SUPPRESSED THE DEVELOPMENT OF VESICLES, BY SIGNIFICANTLY DECREASING THE TOTAL VESICLE NUMBER, AREA, VOLUME, AND WEIGHT. IN ADDITION, EZH2 INHIBITION SIGNIFICANTLY INCREASED THE EXPRESSION OF CACNA1B AND FKBP1A GENES, INVOLVED IN PAIN AND PROLIFERATION, RESPECTIVELY. EZH2 INHIBITION SUPPRESSES THE GROWTH OF VESICLES WITHOUT APPARENT DETRIMENTAL EFFECTS TO OTHER ORGANS. TREATMENT WITH THIS EPIGENETIC INHIBITOR LEADS TO UPREGULATION OF A LIMITED NUMBER OF GENES RELATED TO ENDOMETRIOSIS-RELEVANT PATHWAYS. IN CONCLUSION, THESE DATA SUPPORT FOLLOW-UP STUDIES TO EVALUATE ITS POTENTIAL AS A THERAPEUTIC APPROACH FOR ENDOMETRIOSIS. 2020 5 3981 37 LONG-TERM EPIGENETIC THERAPY WITH ORAL ZEBULARINE HAS MINIMAL SIDE EFFECTS AND PREVENTS INTESTINAL TUMORS IN MICE. RECENT SUCCESSES IN THE APPLICATION OF EPIGENETIC DRUGS FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME HAVE RAISED QUESTIONS ON THE SAFETY OF LONG-TERM ADMINISTRATION OF DNA METHYLATION INHIBITORS. WE TREATED PREWEANED CANCER PRONE APC(MIN/+) (MIN) MICE CONTINUOUSLY WITH THE DNA METHYLATION INHIBITOR ZEBULARINE IN THEIR DRINKING WATER TO DETERMINE THE EFFECTS OF THE DRUG ON NORMAL MOUSE DEVELOPMENT AS WELL AS CANCER PREVENTION. ZEBULARINE CAUSED A TISSUE-SPECIFIC REDUCTION IN DNA METHYLATION AT B1 SHORT INTERSPERSED NUCLEOTIDE ELEMENTS IN THE SMALL AND LARGE INTESTINES OF FEMALE MIN MICE BUT NOT IN OTHER ORGANS EXAMINED AFTER CHRONIC ORAL TREATMENT. NO SIGNIFICANT DIFFERENCE IN THE AVERAGE WEIGHTS OF MICE WAS OBSERVED DURING THE TREATMENT. IN ADDITION, ANALYSIS OF GLOBAL GENE EXPRESSION OF COLONIC EPITHELIAL CELLS FROM THE FEMALES INDICATED THAT ONLY 3% TO 6% OF THE GENES WERE AFFECTED IN THEIR EXPRESSION. WE DID NOT DETECT TOXICITY AND ABNORMALITIES FROM THE HISTOPATHOLOGIC ANALYSIS OF LIVER AND INTESTINAL TISSUES. LASTLY, WE TESTED WHETHER PREVENTION OF TUMORIGENESIS CAN BE ACHIEVED WITH CHRONIC ORAL ADMINISTRATION OF ZEBULARINE IN MIN MICE. THE AVERAGE NUMBER OF POLYPS IN MIN FEMALES DECREASED FROM 58 TO 1, WHEREAS THE AVERAGE POLYP NUMBER REMAINED UNAFFECTED IN MIN MALES POSSIBLY DUE TO DIFFERENTIAL ACTIVITY OF ALDEHYDE OXIDASE. TAKEN TOGETHER, OUR RESULTS SHOW FOR THE FIRST TIME THAT LONG-TERM ORAL ADMINISTRATION OF ZEBULARINE CAUSES A GENDER-SPECIFIC ABROGATION OF INTESTINAL TUMORS WHILE CAUSING A TISSUE-SPECIFIC DNA DEMETHYLATION. IMPORTANTLY, PROLONGED TREATMENT OF MICE WITH EPIGENETIC DRUGS RESULTED IN ONLY MINOR DEVELOPMENTAL AND HISTOLOGIC CHANGES. 2008 6 2683 37 EVALUATION OF THE IMPACT OF S-ADENOSYLMETHIONINE-DEPENDENT METHYLTRANSFERASE INHIBITOR, 3-DEAZANEPLANOCIN A, ON TISSUE INJURY AND COGNITIVE FUNCTION IN MICE. CANCER PATIENTS DISPLAY COGNITIVE IMPAIRMENT DUE, AT LEAST PARTLY, TO THE TREATMENTS. ADDITIONALLY, CHEMOTHERAPEUTIC TREATMENTS CAN LEAD TO ORGAN INJURY, LIMITING THEIR USE, AND ARE LIKELY TO HAVE NEGATIVE IMPACTS ON PATIENTS' QUALITY OF LIFE. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE TOXICITY OF 3-DEAZANEPLANOCIN A (DZNEP) ON SEVERAL TISSUES AND ORGANS, AS WELL AS ON COGNITIVE FUNCTIONS. DZNEP IS AN INHIBITOR OF S-ADENOSYLMETHIONINE-DEPENDENT METHYLTRANSFERASE (IN PARTICULAR OF THE HISTONE METHYLTRANSFERASE EZH2) WHICH SHOWED ANTITUMORAL FUNCTIONS IN PRECLINICAL TRIALS BUT WHOSE EFFECTS ON BEHAVIOR AND ON ORGANS (SIDE EFFECTS) ARE NOT KNOWN. CHRONIC INJECTIONS OF DZNEP WERE PERFORMED INTRAPERITONEALLY IN MALE NMRI MICE (2 MG/KG; I.P.; THREE TIMES PER WEEK) DURING 8 WEEKS. A FOLLOW-UP OF BODY WEIGHT WAS ASSESSED DURING ALL EXPERIMENTS. HISTOLOGICAL ANALYSIS WERE PERFORMED ON SEVERAL ORGANS. EZH2 EXPRESSION AND H3K27ME3 WERE ASSAYED BY WESTERN-BLOT. SEVERAL BEHAVIORAL TESTS WERE PERFORMED DURING TREATMENT AND 2 WEEKS AFTER. A PARTICULAR FOCUS WAS MADE ON SPONTANEOUS LOCOMOTOR ACTIVITY, COGNITIVE FUNCTIONS (SPONTANEOUS ALTERNATION AND RECOGNITION MEMORY), AND ANXIETY- AND DEPRESSION-RELATED BEHAVIOR. HEMATOLOGICAL MODIFICATIONS WERE ALSO ASSESSED. CHRONIC DZNEP TREATMENT TRANSIENTLY REDUCED ANIMAL GROWTH. IT HAD NO EFFECT ON MOST ORGANS BUT PROVOKED A REVERSIBLE SPLENOMEGALY, AND PERSISTENT TESTIS REDUCTION AND ERYTHROPOIESIS. DZNEP ADMINISTRATION DID NOT ALTER ANIMAL BEHAVIOR. IN CONCLUSION, THIS STUDY IS ENCOURAGING FOR THE USE OF DZNEP FOR CANCER TREATMENT. INDEED, IT HAS NO EFFECT ON ANIMAL BEHAVIOR, CONFERRING AN ADVANTAGEOUS SAFETY, AND INDUCES IRREVERSIBLE SIDE EFFECTS LIMITED ON TESTIS WHICH ARE UNFORTUNATELY FOUND IN MOST CHEMOTHERAPY TREATMENTS. 2018 7 468 32 ARGININE METHYLTRANSFERASES MEDIATE AN EPIGENETIC OVARIAN RESPONSE TO ENDOMETRIOSIS. ENDOMETRIOSIS IS ASSOCIATED WITH INFERTILITY AND DEBILITATING CHRONIC PAIN. ABNORMAL EPIGENETIC MODIFICATIONS IN THE HUMAN ENDOMETRIUM HAVE RECENTLY BEEN IMPLICATED IN THE PATHOGENESIS OF THIS CONDITION. HOWEVER, WHETHER AN ALTERED EPIGENETIC LANDSCAPE CONTRIBUTES TO PATHOLOGICAL CHANGES IN THE OVARY IS UNKNOWN. USING AN ESTABLISHED BABOON ENDOMETRIOSIS MODEL, EARLY-, AND LATE-STAGE EPIGENETIC CHANGES IN THE OVARY WERE INVESTIGATED. TRANSCRIPT PROFILING OF KEY CHROMATIN-MODIFYING ENZYMES USING PATHWAY-FOCUSED PCR ARRAYS ON OVARIAN TISSUE FROM HEALTHY CONTROL ANIMALS AND AT 3 AND 15 MONTHS OF ENDOMETRIOSIS REVEALED DRAMATIC CHANGES IN GENE EXPRESSION IN A DISEASE DURATION-DEPENDENT MANNER. INGENUITY PATHWAY ANALYSIS INDICATED THAT TRANSCRIPTS FOR CHROMATIN-REMODELING ENZYMES ASSOCIATED WITH REPRODUCTIVE SYSTEM DISEASE AND CANCER DEVELOPMENT WERE ABNORMALLY REGULATED, MOST PROMINENTLY THE ARGININE METHYLTRANSFERASES CARM1, PRMT2, AND PRMT8. DOWNREGULATION OF CARM1 PROTEIN EXPRESSION WAS ALSO DETECTED IN THE OVARY, FULLY-GROWN OOCYTES AND EUTOPIC ENDOMETRIUM FOLLOWING 15 MONTHS OF ENDOMETRIOSIS. SODIUM BISULFITE SEQUENCING REVEALED DNA HYPERMETHYLATION WITHIN THE PRMT8 PROMOTER, SUGGESTING THAT DEREGULATED CPG METHYLATION MAY PLAY A ROLE IN TRANSCRIPTIONAL REPRESSION OF THIS GENE. THESE RESULTS DEMONSTRATE THAT ENDOMETRIOSIS IS ASSOCIATED WITH CHANGES OF EPIGENETIC PROFILES IN THE PRIMATE OVARY AND SUGGEST THAT ARGININE METHYLTRANSFERASES PLAY A PROMINENT ROLE IN MEDIATING THE OVARIAN RESPONSE TO ENDOMETRIOSIS. OWING TO THE CRITICAL ROLE OF CARM1 IN NUCLEAR RECEPTOR-MEDIATED TRANSCRIPTION AND MAINTENANCE OF PLURIPOTENCY IN THE CLEAVAGE STAGE EMBRYO, OUR RESULTS SUGGEST THAT EPIGENETIC ALTERATIONS IN THE OVARY MAY HAVE FUNCTIONAL CONSEQUENCES FOR OOCYTE QUALITY AND THE ETIOLOGY OF INFERTILITY ASSOCIATED WITH ENDOMETRIOSIS. 2015 8 531 33 ASTROCYTE REACTIVITY FOLLOWING BLAST EXPOSURE INVOLVES ABERRANT HISTONE ACETYLATION. BLAST INDUCED NEUROTRAUMA (BINT) IS A PREVALENT INJURY WITHIN MILITARY AND CIVILIAN POPULATIONS. THE INJURY IS CHARACTERIZED BY PERSISTENT INFLAMMATION AT THE CELLULAR LEVEL WHICH MANIFESTS AS A MULTITUDE OF COGNITIVE AND FUNCTIONAL IMPAIRMENTS. EPIGENETIC REGULATION OF TRANSCRIPTION OFFERS AN IMPORTANT CONTROL MECHANISM FOR GENE EXPRESSION AND CELLULAR FUNCTION WHICH MAY UNDERLIE CHRONIC INFLAMMATION AND RESULT IN NEURODEGENERATION. WE HYPOTHESIZE THAT ALTERED HISTONE ACETYLATION PATTERNS MAY BE INVOLVED IN BLAST INDUCED INFLAMMATION AND THE CHRONIC ACTIVATION OF GLIAL CELLS. THIS STUDY AIMED TO ELUCIDATE CHANGES TO HISTONE ACETYLATION OCCURRING FOLLOWING INJURY AND THE ROLES THESE CHANGES MAY HAVE WITHIN THE PATHOLOGY. SPRAGUE DAWLEY RATS WERE SUBJECTED TO EITHER A 10 OR 17 PSI BLAST OVERPRESSURE WITHIN AN ADVANCED BLAST SIMULATOR (ABS). SHAM ANIMALS UNDERWENT THE SAME PROCEDURES WITHOUT BLAST EXPOSURE. MEMORY IMPAIRMENTS WERE MEASURED USING THE NOVEL OBJECT RECOGNITION (NOR) TEST AT 2 AND 7 DAYS POST-INJURY. TISSUES WERE COLLECTED AT 7 DAYS FOR WESTERN BLOT AND IMMUNOHISTOCHEMISTRY (IHC) ANALYSIS. SHAM ANIMALS SHOWED INTACT MEMORY AT EACH TIME POINT. THE NOVEL OBJECT DISCRIMINATION DECREASED SIGNIFICANTLY BETWEEN TWO AND 7 DAYS FOR EACH INJURY GROUP (P < 0.05). THIS IS INDICATIVE OF THE ONSET OF MEMORY IMPAIRMENT. WESTERN BLOT ANALYSIS SHOWED GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP), A KNOWN MARKER OF ACTIVATED ASTROCYTES, WAS ELEVATED IN THE PREFRONTAL CORTEX (PFC) FOLLOWING BLAST EXPOSURE FOR BOTH INJURY GROUPS. ANALYSIS OF HISTONE PROTEIN EXTRACT SHOWED NO CHANGES IN THE LEVEL OF ANY TOTAL HISTONE PROTEINS WITHIN THE PFC. HOWEVER, ACETYLATION LEVELS OF HISTONE H2B, H3, AND H4 WERE DECREASED IN BOTH GROUPS (P < 0.05). CO-LOCALIZATION IMMUNOFLUORESCENCE WAS USED TO FURTHER INVESTIGATE ANY POTENTIAL CORRELATION BETWEEN DECREASED HISTONE ACETYLATION AND ASTROCYTE ACTIVATION. THESE EXPERIMENTS SHOWED A SIMILAR DECREASE IN H3 ACETYLATION IN ASTROCYTES EXPOSED TO A 17 PSI BLAST BUT NOT A 10 PSI BLAST. FURTHER INVESTIGATION OF GENE EXPRESSION BY POLYMERASE CHAIN REACTION (PCR) ARRAY, SHOWED DYSREGULATION OF SEVERAL CYTOKINE AND CYTOKINE RECEPTORS THAT ARE INVOLVED IN NEUROINFLAMMATORY PROCESSES. WE HAVE SHOWN ABERRANT HISTONE ACETYLATION PATTERNS INVOLVED IN BLAST INDUCED ASTROGLIOSIS AND COGNITIVE IMPAIRMENTS. FURTHER UNDERSTANDING OF THEIR ROLE IN THE INJURY PROGRESSION MAY LEAD TO NOVEL THERAPEUTIC TARGETS. 2016 9 2119 25 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 10 904 38 CHRONIC EXPOSURE TO CADMIUM INDUCES DIFFERENTIAL METHYLATION IN MICE SPERMATOZOA. CADMIUM EXPOSURE IS UBIQUITOUS AND HAS BEEN LINKED TO DISEASES INCLUDING CANCERS AND REPRODUCTIVE DEFECTS. SINCE CADMIUM IS NONMUTAGENIC, IT IS THOUGHT TO EXERT ITS GENE DYSREGULATORY EFFECTS THROUGH EPIGENETIC REPROGRAMMING. SEVERAL STUDIES HAVE IMPLICATED GERMLINE EXPOSURE TO CADMIUM IN DEVELOPMENTAL REPROGRAMMING. HOWEVER, MOST OF THESE STUDIES HAVE FOCUSED ON MATERNAL EXPOSURE, WHILE THE IMPACT ON SPERM FERTILITY AND DISEASE SUSCEPTIBILITY HAS RECEIVED LESS ATTENTION. IN THIS STUDY, WE USED REDUCED REPRESENTATION BISULFITE SEQUENCING TO COMPREHENSIVELY INVESTIGATE THE IMPACT OF CHRONIC CADMIUM EXPOSURE ON MOUSE SPERMATOZOA DNA METHYLATION. ADULT MALE C57BL/J6 MICE WERE PROVIDED WATER WITH OR WITHOUT CADMIUM CHLORIDE FOR 9 WEEKS. SPERM, TESTES, LIVER, AND KIDNEY TISSUES WERE COLLECTED AT THE END OF THE TREATMENT PERIOD. CADMIUM EXPOSURE WAS CONFIRMED THROUGH GENE EXPRESSION ANALYSIS OF METALLOTHIONEIN-1 AND 2, 2 WELL-KNOWN CADMIUM-INDUCED GENES. ANALYSIS OF SPERM DNA METHYLATION CHANGES REVEALED 1788 DIFFERENTIALLY METHYLATED SITES PRESENT AT REGULATORY REGIONS IN SPERM OF MICE EXPOSED TO CADMIUM COMPARED WITH VEHICLE (CONTROL) MICE. FURTHERMORE, MOST OF THESE DIFFERENTIAL METHYLATION CHANGES POSITIVELY CORRELATED WITH CHANGES IN GENE EXPRESSION AT BOTH THE TRANSCRIPTION INITIATION STAGE AS WELL AS THE SPLICING LEVELS. INTERESTINGLY, THE GENES TARGETED BY CADMIUM EXPOSURE ARE INVOLVED IN SEVERAL CRITICAL DEVELOPMENTAL PROCESSES. OUR RESULTS PRESENT A COMPREHENSIVE ANALYSIS OF THE SPERM METHYLOME IN RESPONSE TO CHRONIC CADMIUM EXPOSURE. THESE DATA, THEREFORE, HIGHLIGHT A FOUNDATIONAL FRAMEWORK TO STUDY GENE EXPRESSION PATTERNS THAT MAY AFFECT FERTILITY IN THE EXPOSED INDIVIDUAL AS WELL AS THEIR OFFSPRING, THROUGH PATERNAL INHERITANCE. 2021 11 6564 28 TRANSIENT EXPOSURE TO ELEVATED GLUCOSE LEVELS CAUSES PERSISTENT CHANGES IN DERMAL MICROVASCULAR ENDOTHELIAL CELL RESPONSES TO INJURY. BACKGROUND: THE PURPOSE OF THIS STUDY WAS TO DETERMINE WHETHER ELEVATED GLUCOSE CAN INDUCE A DERMAL MICROVASCULAR ENDOTHELIAL CELL METABOLIC MEMORY, THUS AFFECTING ANGIOGENESIS IN THE REPAIR PROCESS OF MAMMALIAN CUTANEOUS WOUND. WE HYPOTHESIZED THAT TRANSIENT ELEVATED GLUCOSE LEVELS CAUSE SUSTAINED ALTERATION OF ENDOTHELIAL CELL RESPONSES TO INJURY AND PERSISTENT EPIGENETIC CHANGES IN GENE EXPRESSION. METHODS: HUMAN DERMAL MICROVASCULAR ENDOTHELIAL CELLS WERE EXPOSED TO EXPERIMENTAL CONDITIONS WITH OR WITHOUT 30 MM D-GLUCOSE. THE CONTROL GROUP WAS MAINTAINED AT 5 MM D-GLUCOSE; WHILE IN THE TRANSIENT GLUCOSE GROUP, AFTER BEING EXPOSED TO 30 MM D-GLUCOSE FOR TWO DAYS, THEN BEING PUT UNDER THE CONTROL CONDITIONS DURING THE EXPERIMENT. BESIDES, IN THE WHOLE PROCESS OF THE EXPERIMENT, THE CHRONIC GLUCOSE GROUP WAS KEPT IN THE CONDITION WITH 30 MM D-GLUCOSE. PROLIFERATION, MIGRATION, TUBE FORMATION, GENE EXPRESSION AND HISTONE METHYLATION WERE ASSESSED FOR INDIVIDUAL CONDITIONS. RESULTS: TRANSIENT ELEVATED GLUCOSE CAUSED SUSTAINED EFFECTS ON ENDOTHELIAL CELL MIGRATION, TUBE FORMATION AND TIMP3 GENE EXPRESSION. THE EFFECTS ON TIMP3 EXPRESSION WERE ASSOCIATED WITH PERSISTENT CHANGES IN HISTONE MODIFICATION AT THE 5' END OF THE TIMP3 GENE, SUGGESTING AN EPIGENETIC EFFECT. CONCLUSIONS: HYPERGLYCEMIA INDUCED METABOLIC MEMORY COULD PROMOTE THE REGULATION OF TIMP3, AND IT CAN BE USED AS A POSSIBLE INNOVATIVE MOLECULAR TARGET FOR THERAPEUTIC INTERVENTION IN THE TREATMENT OF CHRONIC NON-HEALING DIABETIC WOUNDS. 2021 12 2736 37 EXPLORING THE TRANSCRIPTOME OF RESIDENT SPINAL MICROGLIA AFTER COLLAGEN ANTIBODY-INDUCED ARTHRITIS. RECENT STUDIES HAVE SUGGESTED A SEXUALLY DIMORPHIC ROLE OF SPINAL GLIAL CELLS IN THE MAINTENANCE OF MECHANICAL HYPERSENSITIVITY IN RODENT MODELS OF CHRONIC PAIN. WE HAVE USED THE COLLAGEN ANTIBODY-INDUCED ARTHRITIS (CAIA) MOUSE MODEL TO EXAMINE DIFFERENCES BETWEEN MALES AND FEMALES IN THE CONTEXT OF SPINAL REGULATION OF ARTHRITIS-INDUCED PAIN. WE HAVE FOCUSED ON THE LATE PHASE OF THIS MODEL WHEN JOINT INFLAMMATION HAS RESOLVED, BUT MECHANICAL HYPERSENSITIVITY PERSISTS. ALTHOUGH THE INTENSITY OF SUBSTANCE P, CALCITONIN GENE-RELATED PEPTIDE, AND GALANIN IMMUNOREACTIVITY IN THE SPINAL CORD WAS NOT DIFFERENT FROM CONTROLS, THE INTENSITY OF MICROGLIA (IBA-1) AND ASTROCYTE (GLIAL FIBRILLARY ACIDIC PROTEIN) MARKERS WAS ELEVATED IN BOTH MALES AND FEMALES. INTRATHECAL ADMINISTRATION OF THE GLIAL INHIBITORS MINOCYCLINE AND PENTOXIFYLLINE REVERSED MECHANICAL THRESHOLDS IN MALE, BUT NOT IN FEMALE MICE. WE ISOLATED RESIDENT MICROGLIA FROM THE LUMBAR DORSAL HORNS AND OBSERVED A SIGNIFICANTLY LOWER NUMBER OF MICROGLIAL CELLS IN FEMALES BY FLOW CYTOMETRY ANALYSIS. HOWEVER, ALTHOUGH GENOME-WIDE RNA SEQUENCING RESULTS POINTED TO SEVERAL TRANSCRIPTIONAL DIFFERENCES BETWEEN MALE AND FEMALE MICROGLIA, NO CONVINCING DIFFERENCES WERE IDENTIFIED BETWEEN CONTROL AND CAIA GROUPS. TAKEN TOGETHER, THESE FINDINGS SUGGEST THAT THERE ARE SUBTLE SEX DIFFERENCES IN MICROGLIAL EXPRESSION PROFILES INDEPENDENT OF ARTHRITIS. OUR EXPERIMENTS FAILED TO IDENTIFY THE UNDERLYING MRNA CORRELATES OF MICROGLIAL ACTIONS IN THE LATE PHASE OF THE CAIA MODEL. IT IS LIKELY THAT TRANSCRIPTIONAL CHANGES ARE EITHER SUBTLE AND HIGHLY LOCALISED AND THEREFORE DIFFICULT TO IDENTIFY WITH BULK ISOLATION TECHNIQUES OR THAT OTHER FACTORS, SUCH AS CHANGES IN PROTEIN EXPRESSION OR EPIGENETIC MODIFICATIONS, ARE AT PLAY. 2019 13 4292 42 MICRORNA PROFILES OF MATERNAL AND NEONATAL ENDOTHELIAL PROGENITOR CELLS IN PREECLAMPSIA. PREECLAMPSIA IS ASSOCIATED WITH AN INCREASED CARDIOVASCULAR MORBIDITY OF MOTHER AND OFFSPRING, THUS CONTRIBUTING TO A SUBSTANTIAL BURDEN IN WOMEN AND CHILDREN'S HEALTH. IT HAS BEEN PROVEN THAT ENDOTHELIAL PROGENITOR CELL (EPC) NUMBERS AND FUNCTIONAL CHARACTERISTICS ARE IMPAIRED IN CARDIOVASCULAR DISEASE AND PREECLAMPSIA, ALTHOUGH CAUSATIVE FACTORS FOR THE LATTER HAVE REMAINED ELUSIVE. MICRORNA (MIRNA) MODIFICATIONS ARE A POTENTIAL MECHANISM THROUGH WHICH EXPOSURE TO AN ALTERED ENVIRONMENT TRANSLATES INTO THE DEVELOPMENT OF CHRONIC DISEASE. IN THIS STUDY, WE EXAMINED WHETHER DEVELOPMENT OF PREECLAMPSIA CORRESPONDS TO ALTERATIONS OF MIRNAS IN MATERNAL- AND CORD-BLOOD-DERIVED EPC. TO TEST THIS END, WE ANALYZED MATERNAL AND NEONATAL MIRNAS VIA RNA SEQUENCING FROM ENDOTHELIAL CELLS OF PREECLAMPTIC AND HEALTHY CONTROLS IN DIFFERENT CELL CULTURE PASSAGES. WE WERE ABLE TO DEMONSTRATE DIFFERENTIALLY REPRESENTED MIRNAS IN ALL GROUPS. HSA-MIR-1270 SHOWED SIGNIFICANTLY DIFFERENT LEVELS IN CORD BLOOD EPC FROM PREECLAMPSIA VERSUS CONTROL AND WAS NEGATIVELY CORRELATED WITH MRNA LEVELS OF ITS PREDICTED TARGETS ANGPTL7 AND TFRC. TRANSFECTION WITH AN HSA-MIR-1270 INHIBITOR DECREASED THE TUBE FORMATION CAPACITY AND CHEMOTACTIC MOTILITY BUT DID NOT CHANGE PROLIFERATION IN VITRO. TARGET PREDICTIONS AND GENE SET ENRICHMENT ANALYSES IDENTIFIED ALTERNATIVE SPLICING AS A SIGNIFICANTLY ENRICHED PATHWAY FOR HSA-MIR-1270. THE TOP MIRNAS IN THREE OTHER GROUPS WERE PREDICTED TO TARGET TRANSCRIPTIONAL AND DEVELOPMENTAL PATHWAYS. HERE, WE SHOWED FOR THE FIRST TIME SIGNIFICANTLY DIFFERENT LEVELS OF MIRNAS AND DIFFERENTLY REPRESENTED MRNA LEVELS OF PREDICTED TARGET GENES IN EPC DERIVED FROM PREECLAMPSIA. UNDERSTANDING THE EFFECTS OF PREECLAMPSIA ON THE EPIGENETIC MECHANISMS OF EPC WILL BE CRUCIAL AND MAY PROVIDE INITIAL INSIGHTS FOR FURTHER EVALUATION OF THE BENEFITS OF THERAPIES TARGETING THIS CELL POPULATION. 2021 14 4093 29 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 15 457 31 APPLYING A MULTISCALE SYSTEMS BIOLOGY APPROACH TO STUDY THE EFFECT OF CHRONIC LOW-DOSE EXPOSURE TO URANIUM IN RAT KIDNEYS. PURPOSE: TO EXAMINE THE EFFECTS OF LOW-DOSE EXPOSURE TO URANIUM WITH A SYSTEMS BIOLOGY APPROACH, A MULTISCALE HIGH-THROUGHPUT MULTI-OMICS ANALYSIS WAS APPLIED WITH A PROTOCOL FOR CHRONIC EXPOSURE TO THE RAT KIDNEY. METHODS: MALE AND FEMALE RATS WERE CONTAMINATED FOR NINE MONTHS THROUGH THEIR DRINKING WATER WITH A NONTOXIC SOLUTION OF URANYL NITRATE. A MULTISCALE APPROACH ENABLED CLINICAL MONITORING ASSOCIATED WITH METABOLOMIC AND TRANSCRIPTOMIC (MRNA AND MICRORNA) ANALYSES. RESULTS: A SEX-INTERACTION EFFECT WAS OBSERVED IN THE KIDNEY, URINE, AND PLASMA METABOLOMES OF CONTAMINATED RATS. MOREOVER, URINE AND KIDNEY METABOLIC PROFILES CORRELATED AND CONFIRMED THAT THE PRIMARY DYSREGULATED METABOLISMS ARE THOSE OF NICOTINATE-NICOTINAMIDE AND OF UNSATURATED FATTY ACID BIOSYNTHESIS. UPSTREAM OF THE METABOLIC PATHWAYS, TRANSCRIPTOMIC PROFILES OF THE KIDNEY REVEAL GENE ACTIVITY FOCUSED ON GENE REGULATION MECHANISMS, CELL SIGNALING, CELL STRUCTURE, DEVELOPMENTAL PROCESSES, AND CELL PROLIFERATION. EXAMINATION OF EPIGENETIC POST-TRANSCRIPTIONAL GENE REGULATION PROCESSES SHOWED SIGNIFICANT DYSREGULATION OF 70 MICRO-RNAS. THE MULTI-OMICS APPROACH HIGHLIGHTED THE ACTIVITIES OF THE CELLS' BIOLOGICAL PROCESSES ON MULTIPLE SCALES THROUGH ANALYSIS OF GENE EXPRESSION, CONFIRMED BY CHANGES OBSERVED IN THE METABOLOME. CONCLUSION: OUR RESULTS SHOWED CHANGES IN MULTI-OMIC PROFILES OF RATS EXPOSED TO LOW DOSES OF URANIUM CONTAMINATION, COMPARED WITH CONTROLS. THESE CHANGES INVOLVED GENE EXPRESSION AS WELL AS MODIFICATIONS IN THE TRANSCRIPTOME AND THE METABOLOME. THE METABOLOMIC PROFILE CONFIRMED THAT THE MAIN MOLECULAR TARGETS OF URANIUM IN KIDNEY CELLS ARE THE METABOLISM OF NICOTINATE-NICOTINAMIDE AND THE BIOSYNTHESIS OF UNSATURATED FATTY ACIDS. ADDITIONALLY, GENE EXPRESSION ANALYSIS SHOWED THAT THE METABOLISM OF FATTY ACIDS IS TARGETED BY PROCESSES ASSOCIATED WITH CELL FUNCTION. THESE RESULTS DEMONSTRATE THAT MULTISCALE SYSTEMS BIOLOGY IS USEFUL IN ELUCIDATING THE MOST DISCRIMINATIVE PATHWAYS FROM GENOMIC TO METABOLOMIC LEVELS FOR ASSESSING THE BIOLOGICAL IMPACT OF THIS LOW-LEVEL ENVIRONMENTAL EXPOSURE, I.E. THE EXPOSOME. 2019 16 978 32 CHRONIC OXIDATIVE STRESS CAUSES ESTROGEN-INDEPENDENT AGGRESSIVE PHENOTYPE, AND EPIGENETIC INACTIVATION OF ESTROGEN RECEPTOR ALPHA IN MCF-7 BREAST CANCER CELLS. THE ROLE OF CHRONIC OXIDATIVE STRESS IN THE DEVELOPMENT AND AGGRESSIVE GROWTH OF ESTROGEN RECEPTOR (ER)-POSITIVE BREAST CANCER IS WELL KNOWN; HOWEVER, THE MECHANISTIC UNDERSTANDING IS NOT CLEAR. ESTROGEN-INDEPENDENT GROWTH IS ONE OF THE FEATURES OF AGGRESSIVE SUBTYPE OF BREAST CANCER. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECT OF OXIDATIVE STRESS ON ESTROGEN SENSITIVITY AND EXPRESSION OF NUCLEAR ESTROGEN RECEPTORS IN ER-POSITIVE BREAST CANCER CELLS. MCF-7 CELLS CHRONICALLY EXPOSED TO HYDROGEN PEROXIDE WERE USED AS A CELL MODEL IN THIS STUDY, AND THEIR GROWTH IN RESPONSE TO 17-BETA ESTRADIOL WAS EVALUATED BY CELL VIABILITY, CELL CYCLE, AND CELL MIGRATION ANALYSIS. RESULTS WERE FURTHER CONFIRMED AT MOLECULAR LEVEL BY ANALYSIS OF GENE EXPRESSIONS AT TRANSCRIPT AND PROTEIN LEVELS. HISTONE H3 MODIFICATIONS, EXPRESSION OF EPIGENETIC REGULATORY GENES, AND THE EFFECT OF DNA DEMETHYLATION WERE ALSO ANALYZED. LOSS OF GROWTH IN RESPONSE TO ESTROGEN WITH A DECREASE IN ERALPHA EXPRESSION WAS OBSERVED IN MCF-7 CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS. INCREASES IN MTTFA AND NRF1 IN THESE CELLS FURTHER SUGGESTED THE ROLE OF MITOCHONDRIA-DEPENDENT REDOX-SENSITIVE GROWTH SIGNALING AS AN ALTERNATIVE PATHWAY TO ESTROGEN-DEPENDENT GROWTH. CHANGES IN EXPRESSION OF EPIGENETIC REGULATORY GENES, LEVELS OF HISTONE H3 MODIFICATIONS AS WELL AS SIGNIFICANT RESTORATIONS OF BOTH ERALPHA EXPRESSION AND ESTROGEN RESPONSE BY 5-AZA-2'-DEOXYCYTIDINE FURTHER CONFIRMED THE EPIGENETIC BASIS FOR ESTROGEN-INDEPENDENT GROWTH IN THESE CELLS. IN CONCLUSION, RESULTS OF THIS STUDY SUGGEST THAT CHRONIC OXIDATIVE STRESS CAN CONVERT ESTROGEN-DEPENDENT NONAGGRESSIVE BREAST CANCER CELLS INTO ESTROGEN-INDEPENDENT AGGRESSIVE FORM POTENTIALLY BY EPIGENETIC MECHANISM. 2015 17 6794 32 [EFFECT OF BENZO(A)PYRENE ON THE EXPRESSION OF AHR-REGULATED MICRORNA IN FEMALE AND MALE RAT LUNGS]. SMOKING IS THE MAIN RISK FACTOR FOR LUNG CANCER, MAINLY DUE TO PRESENCE OF NITROSAMINES AND POLYCYCLIC AROMATIC HYDROCARBONS, INCLUDING BENZO[A]PYRENE (BP) IN TOBACCO SMOKE COMPOSITION. THE GENOTOXIC EFFECT OF BP IS BASED ON THE HIGH DNA-BINDING ABILITY OF ITS METABOLITES, WHILE THE EPIGENETIC EFFECTS ARE MEDIATED BY A CHANGE IN THE EXPRESSION OF CANCER RELATED GENES OR REGULATORY RNAS. IT HAS BEEN SHOWN THAT WOMEN HAVE A HIGHER RISK TO DEVELOP LUNG CANCER UPON SMOKING RATHER THAN MEN. WE HYPOTHESIZED THAT CROSSTALK BETWEEN SIGNALING PATHWAYS ACTIVATED BY BP AND ESTROGENS COULD UNDERLIE THE SEX-DEPENDENT DIFFERENCES IN MIRNAS EXPRESSION. TO TEST THIS HYPOTHESIS, MALE AND FEMALE RATS WERE SUBJECTED TO SHORT-TERM OR LONG-TERM BP EXPOSURE. USING IN SILICO ANALYSIS, MIRNAS CONTAINING THE ER- AND AHR-BINDING SITES IN THE PROMOTERS OF THE GENES (OR HOST GENES) WERE SELECTED. DURING CHRONIC EXPOSURE OF BP THE EXPRESSION OF MIR-22-3P, -29A-3P, -126A-3P, -193B-5P IN THE LUNGS OF MALE RATS WERE SIGNIFICANTLY INCREASED, WHILE THE LEVEL OF MIRNA-483-3P WERE DECREASED. EXPRESSION OF MIRNA-483-3P WAS UP-REGULATED DURING CHRONIC BP EXPOSURE IN THE LUNGS OF FEMALE RATS AND THE LEVELS OF OTHER STUDIED MIRNAS WERE UNCHANGED. IN TURN, CHANGES IN THE EXPRESSION OF MIRNAS WERE FOLLOWED BY CHANGES IN THE EXPRESSION OF THEIR TARGET GENES, INCLUDING PTEN, EMP2, IGF1, ITGA6, SLC34A2, AND THE OBSERVED CHANGES IN FEMALE AND MALE RAT LUNGS WERE VARIED. THUS, OUR RESULTS SUGGEST THAT SEX-DEPENDENT EPIGENETIC EFFECTS OF BP MAY BE BASED ON DIFFERENT EXPRESSION OF AHR- AND ER- REGULATED MIRNAS. 2020 18 1655 22 DOSE-DEPENDENCE, SEX- AND TISSUE-SPECIFICITY, AND PERSISTENCE OF RADIATION-INDUCED GENOMIC DNA METHYLATION CHANGES. RADIATION IS A WELL-KNOWN GENOTOXIC AGENT AND HUMAN CARCINOGEN THAT GIVES RISE TO A VARIETY OF LONG-TERM EFFECTS. ITS DETRIMENTAL INFLUENCE ON CELLULAR FUNCTION IS ACTIVELY STUDIED NOWADAYS. ONE OF THE MOST ANALYZED, YET LEAST UNDERSTOOD LONG-TERM EFFECTS OF IONIZING RADIATION IS TRANSGENERATIONAL GENOMIC INSTABILITY. THE INHERITANCE OF GENOMIC INSTABILITY SUGGESTS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS, SUCH AS CHANGES OF THE METHYLATION OF CYTOSINE RESIDUES LOCATED WITHIN CPG DINUCLEOTIDES. IN THE CURRENT STUDY WE EVALUATED THE DOSE-DEPENDENCE OF THE RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION CHANGES. WE ALSO ANALYZED THE EFFECTS OF ACUTE AND CHRONIC HIGH DOSE (5GY) EXPOSURE ON DNA METHYLATION IN LIVER, SPLEEN, AND LUNG TISSUES OF MALE AND FEMALE MICE AND EVALUATED THE POSSIBLE PERSISTENCE OF THE RADIATION-INDUCED DNA METHYLATION CHANGES. HERE WE REPORT THAT RADIATION-INDUCED DNA METHYLATION CHANGES WERE SEX- AND TISSUE-SPECIFIC, DOSE-DEPENDENT, AND PERSISTENT. IN PARALLEL WE HAVE STUDIED THE LEVELS OF DNA DAMAGE IN THE EXPOSED TISSUES. BASED ON THE CORRELATION BETWEEN THE LEVELS OF DNA METHYLATION AND DNA DAMAGE WE PROPOSE THAT RADIATION-INDUCED GLOBAL GENOME DNA HYPOMETHYLATION IS DNA REPAIR-RELATED. 2004 19 5754 25 SOCIAL PSYCHOGENIC STRESS PROMOTES THE DEVELOPMENT OF ENDOMETRIOSIS IN MOUSE. EXPOSURE TO CHRONIC STRESS BEFORE AND WELL AFTER THE INDUCTION OF ENDOMETRIOSIS IS REPORTED TO INCREASE LESION SIZES IN RATS, BUT IT IS UNCLEAR WHETHER STRESS, EXPOSED SHORTLY AFTER THE INDUCTION OF ENDOMETRIOSIS, WOULD ALSO PROMOTE THE DEVELOPMENT OF ENDOMETRIOSIS, NOR IS IT CLEAR WHAT THE UNDERLYING POSSIBLE MOLECULAR MECHANISM IS. THIS STUDY WAS UNDERTAKEN TO TEST THE HYPOTHESIS THAT CHRONIC STRESS CAN PROMOTE THE DEVELOPMENT OF ENDOMETRIOSIS. A PROSPECTIVE RANDOMIZED MOUSE EXPERIMENT WAS CONDUCTED THAT SUBJECTED MICE WITH INDUCED ENDOMETRIOSIS TO PREDATOR STRESS. IN ADDITION, A CROSS-SECTIONAL IMMUNOHISTOCHEMISTRY STUDY WAS PERFORMED IN ECTOPIC AND EUTOPIC ENDOMETRIAL TISSUE SAMPLES FROM AGE- AND ROUGHLY MENSTRUAL PHASE-MATCHED WOMEN WITH OVARIAN ENDOMETRIOMAS. IT WAS FOUND THAT THE CHRONIC PSYCHOGENIC STRESS INDUCED EPIGENETIC CHANGES IN THE HIPPOCAMPUS IN MOUSE INDEPENDENT OF ENDOMETRIOSIS. IT WAS ALSO FOUND THAT CHRONIC PSYCHOGENIC STRESS INDUCED EPIGENETIC CHANGES IN THE HIPPOCAMPUS OF MICE WITH ENDOMETRIOSIS, AND SEEMINGLY ACTIVATED THE ADRENERGIC SIGNALLING IN ECTOPIC ENDOMETRIUM, RESULTING IN INCREASED ANGIOGENESIS AND ACCELERATED GROWTH OF ENDOMETRIOTIC LESIONS. THUS, CHRONIC PSYCHOGENIC STRESS PROMOTES ENDOMETRIOSIS DEVELOPMENT, RAISING THE POSSIBILITY THAT THE USE OF ANTI-DEPRESSANTS IN CASES OF PROLONGED AND INTENSE STRESS MIGHT FORESTALL THE NEGATIVE IMPACT OF STRESS ON THE DEVELOPMENT OF ENDOMETRIOSIS. 2017 20 4224 29 METHYLATION CHANGES IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE EXPOSED TO ACUTE AND CHRONIC LOW-DOSE X-RAY-IRRADIATION. THE BIOLOGICAL AND GENETIC EFFECTS OF CHRONIC LOW-DOSE RADIATION (LDR) EXPOSURE AND ITS RELATIONSHIP TO CARCINOGENESIS HAVE RECEIVED A LOT OF ATTENTION IN THE RECENT YEARS. FOR EXAMPLE, RADIATION-INDUCED GENOME INSTABILITY, WHICH IS THOUGHT TO BE A PRECURSOR OF TUMOROGENESIS, WAS SHOWN TO HAVE A TRANSGENERATIONAL NATURE. THIS INDICATES A POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LDR-INDUCED GENOME INSTABILITY. GENOMIC DNA METHYLATION IS ONE OF THE MOST IMPORTANT EPIGENETIC MECHANISMS. EXISTING DATA ON RADIATION EFFECTS ON DNA METHYLATION PATTERNS IS LIMITED, AND NO ONE HAS SPECIFICALLY STUDIED THE EFFECTS OF THE LDR. WE REPORT THE FIRST STUDY OF THE EFFECTS OF WHOLE-BODY LDR EXPOSURE ON GLOBAL GENOME METHYLATION IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE. IN PARALLEL, WE EVALUATED CHANGES IN PROMOTER METHYLATION AND EXPRESSION OF THE TUMOR SUPPRESSOR GENE P16(INKA) AND DNA REPAIR GENE O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT). WE OBSERVED DIFFERENT PATTERNS OF RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION IN THE LIVER AND MUSCLE OF EXPOSED MALES AND FEMALES. WE ALSO FOUND SEX AND TISSUE-SPECIFIC DIFFERENCES IN P16(INKA) PROMOTER METHYLATION UPON LDR EXPOSURE. IN MALE LIVER TISSUE, P16(INKA) PROMOTER METHYLATION WAS MORE PRONOUNCED THAN IN FEMALE TISSUE. IN CONTRAST, NO SIGNIFICANT RADIATION-INDUCED CHANGES IN P16(INKA) PROMOTER METHYLATION WERE NOTED IN THE MUSCLE TISSUE OF EXPOSED MALES AND FEMALES. RADIATION ALSO DID NOT SIGNIFICANTLY AFFECT METHYLATION STATUS OF MGMT PROMOTER. WE ALSO OBSERVED SUBSTANTIAL SEX DIFFERENCES IN ACUTE AND CHRONIC RADIATION-INDUCED EXPRESSION OF P16(INKA) AND MGMT GENES. ANOTHER IMPORTANT OUTCOME OF OUR STUDY WAS THE FACT THAT CHRONIC LOW-DOSE RADIATION EXPOSURE PROVED TO BE A MORE POTENT INDUCER OF EPIGENETIC EFFECTS THAN THE ACUTE EXPOSURE. THIS SUPPORTS PREVIOUS FINDINGS THAT CHRONIC EXPOSURE LEADS TO GREATER GENOME DESTABILIZATION THAN ACUTE EXPOSURE. 2004