1 5188 175 PRENATAL ALCOHOL EXPOSURE ALTERS EXPRESSION OF NEUROGENESIS-RELATED GENES IN AN EX VIVO CELL CULTURE MODEL. PRENATAL ALCOHOL EXPOSURE CAN LEAD TO LONG-LASTING CHANGES IN FUNCTIONAL AND GENETIC PROGRAMS OF THE BRAIN, WHICH MAY UNDERLIE BEHAVIORAL ALTERATIONS SEEN IN FETAL ALCOHOL SPECTRUM DISORDER (FASD). ABERRANT FETAL PROGRAMMING DURING GESTATIONAL ALCOHOL EXPOSURE IS A POSSIBLE MECHANISM BY WHICH ALCOHOL IMPARTS TERATOGENIC EFFECTS ON THE BRAIN; HOWEVER, CURRENT METHODS USED TO INVESTIGATE THE EFFECTS OF ALCOHOL ON DEVELOPMENT OFTEN RELY ON EITHER DIRECT APPLICATION OF ALCOHOL IN VITRO OR ACUTE HIGH DOSES IN VIVO. IN THIS STUDY, WE USED OUR ESTABLISHED MODERATE PRENATAL ALCOHOL EXPOSURE (PAE) MODEL, RESULTING IN MATERNAL BLOOD ALCOHOL CONTENT OF APPROXIMATELY 20 MM, AND SUBSEQUENT EX VIVO CELL CULTURE TO ASSESS EXPRESSION OF GENES RELATED TO NEUROGENESIS. PROLIFERATING AND DIFFERENTIATING NEURAL PROGENITOR CELL CULTURE CONDITIONS WERE ESTABLISHED FROM TELENCEPHALIC TISSUE DERIVED FROM EMBRYONIC DAY (E) 15-17 TISSUE EXPOSED TO ALCOHOL VIA MATERNAL DRINKING THROUGHOUT PREGNANCY. GENE EXPRESSION ANALYSIS ON MRNA DERIVED IN VITRO WAS PERFORMED USING A MICROARRAY, AND QUANTITATIVE PCR WAS CONDUCTED FOR GENES TO VALIDATE THE MICROARRAY. STUDENT'S T TESTS WERE PERFORMED FOR STATISTICAL COMPARISON OF EACH EXPOSURE UNDER EACH CULTURE CONDITION USING A 95% CONFIDENCE INTERVAL. ELEVEN PERCENT OF GENES ON THE ARRAY HAD SIGNIFICANTLY ALTERED MRNA EXPRESSION IN THE PRENATAL ALCOHOL-EXPOSED NEURAL PROGENITOR CULTURE UNDER PROLIFERATING CONDITIONS. THESE INCLUDE REDUCED EXPRESSION OF ADORA2A, CXCL1, DLG4, HES1, NPTX1, AND VEGFA AND INCREASED EXPRESSION OF FGF13, NDN, AND SOX3; BIOINFORMATICS ANALYSIS INDICATED THAT THESE GENES ARE INVOLVED IN CELL GROWTH AND PROLIFERATION. DECREASED LEVELS OF DNMT1 AND DNMT3A WERE ALSO FOUND UNDER PROLIFERATING CONDITIONS. UNDER DIFFERENTIATING CONDITIONS, 7.3% OF GENES HAD DECREASED MRNA EXPRESSION; THESE INCLUDE CDK5RAP3, GDNF, HEY2, HEYL, PARD6B, AND PTN, WHICH ARE ASSOCIATED WITH SURVIVAL AND DIFFERENTIATION AS INDICATED BY BIOINFORMATICS ANALYSIS. THIS STUDY IS THE FIRST TO USE CHRONIC LOW TO MODERATE PAE, TO MORE ACCURATELY REFLECT MATERNAL ALCOHOL CONSUMPTION, AND SUBSEQUENT NEURAL PROGENITOR CELL CULTURE TO DEMONSTRATE THAT PAE THROUGHOUT GESTATION ALTERS EXPRESSION OF GENES INVOLVED IN NEURAL DEVELOPMENT AND EMBRYONIC NEUROGENESIS.	2014	

2 6794  37 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3 4528  29 MULTIGENERATIONAL EFFECTS OF CADMIUM ON THE LIFESPAN AND FERTILITY OF DROSOPHILA MELANOGASTER. ALTHOUGH THE DAMAGE AND TOLERANCE MECHANISMS OF CD STRESS ARE KNOWN, THE DATA ON GENETIC RISK ARE LIMITED. THE AIM OF THIS STUDY WAS TO ASSESS THE CHRONIC TOXICITY OF CD, GENETIC RESPONSES, AND MULTIGENERATIONAL EFFECTS IN FIVE GENERATIONS OF DROSOPHILA MELANOGASTER. FOR EACH GENERATION, LIFESPAN AND FERTILITY WERE STATISTICALLY ANALYSED AND THE EXPRESSION OF APOPTOSIS- (P53 AND CASPASE-3) AND EPIGENESIS-RELATED (DDNMT2 AND DMBD2/3) GENES WAS EXAMINED. LIFESPAN AND FERTILITY SIGNIFICANTLY DECLINED UNDER CD STRESS AND THESE EFFECTS WERE MAINTAINED FOR TWO GENERATIONS AND ONE GENERATION, RESPECTIVELY, WHEN CD STRESS WAS REMOVED. THE EXPRESSION OF P53 AND CASPASE-3 WAS SIGNIFICANTLY UP-REGULATED AFTER EXPOSURE, SUGGESTING THAT APOPTOSIS CONTRIBUTES TO THE RESISTANCE MECHANISM. THEIR ALTERED EXPRESSION WAS RETAINED FOR TWO GENERATIONS. FURTHERMORE, HIGH EXPRESSION OF DDNMT2 AND DMBD2/3 ACCOMPANIED CD EXPOSURE, WHICH WAS PASSED ON TO THREE GENERATIONS, SUGGESTING THAT GENETIC MODIFICATIONS IN APOPTOSIS-RELATED GENES ARE CARRIED TO THE OFFSPRING THROUGH EPIGENETIC REGULATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4 2776  44 EXTRAUTERINE GROWTH RESTRICTION ON PULMONARY VASCULAR ENDOTHELIAL DYSFUNCTION IN ADULT MALE RATS: THE ROLE OF EPIGENETIC MECHANISMS. OBJECTIVE: EARLY POSTNATAL LIFE IS CONSIDERED AS A CRITICAL TIME WINDOW FOR THE DETERMINATION OF LONG-TERM METABOLIC STATES AND ORGAN FUNCTIONS. EXTRAUTERINE GROWTH RESTRICTION (EUGR) CAUSES THE DEVELOPMENT OF ADULT-ONSET CHRONIC DISEASES, INCLUDING PULMONARY HYPERTENSION. HOWEVER, THE EFFECTS OF NUTRITIONAL DISADVANTAGES DURING THE EARLY POSTNATAL PERIOD ON PULMONARY VASCULAR CONSEQUENCES IN LATER LIFE ARE NOT FULLY UNDERSTOOD. OUR STUDY WAS DESIGNED TO TEST WHETHER EPIGENETICS DYSREGULATION MEDIATES THE CELLULAR MEMORY OF THIS EARLY POSTNATAL EVENT. METHODS AND RESULTS: TO TEST THIS HYPOTHESIS, WE ISOLATED PULMONARY VASCULAR ENDOTHELIAL CELLS BY MAGNETIC-ACTIVATED CELL SORTING FROM EUGR AND CONTROL RATS. A POSTNATAL INSULT, NUTRITIONAL RESTRICTION-INDUCED EUGR CAUSED DEVELOPMENT OF AN INCREASED PULMONARY ARTERY PRESSURE AT 9 WEEKS OF AGE IN MALE SPRAGUE-DAWLEY RATS. METHYL-DNA IMMUNE PRECIPITATION CHIP, GENOME-SCALE MAPPING STUDIES TO SEARCH FOR DIFFERENTIALLY METHYLATED LOCI BETWEEN CONTROL AND EUGR RATS, REVEALED SIGNIFICANT DIFFERENCE IN CYTOSINE METHYLATION BETWEEN EUGR AND CONTROL RATS. EUGR CHANGES THE CYTOSINE METHYLATION AT APPROXIMATELY 500 LOCI IN MALE RATS AT 9 WEEKS OF AGE, PRECEDING THE DEVELOPMENT OF PULMONARY HYPERTENSION AND THESE REPRESENT THE CANDIDATE LOCI FOR MEDIATING THE PATHOGENESIS OF PULMONARY VASCULAR DISEASE THAT OCCURS LATER IN LIFE. GENE ONTOLOGY ANALYSIS ON DIFFERENTIALLY METHYLATED GENES SHOWED THAT HYPERMETHYLATED GENES IN EUGR ARE VASCULAR DEVELOPMENT-ASSOCIATED GENES AND HYPOMETHYLATED GENES IN EUGR ARE LATE-DIFFERENTIATION-ASSOCIATED AND SIGNAL TRANSDUCTION GENES. WE VALIDATED CANDIDATE DYSREGULATED LOCI WITH THE QUANTITATIVE ASSAYS OF CYTOSINE METHYLATION AND GENE EXPRESSIONS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT EPIGENETICS DYSREGULATION IS A STRONG MECHANISM FOR PROPAGATING THE CELLULAR MEMORY OF EARLY POSTNATAL EVENTS, CAUSING CHANGES IN THE EXPRESSION OF GENES AND LONG-TERM SUSCEPTIBILITY TO PULMONARY HYPERTENSION, AND FURTHER PROVIDING A NEW INSIGHT INTO THE PREVENTION AND TREATMENT OF EUGR-RELATED PULMONARY HYPERTENSION.	2014	
                                                                                                                                                                   
5 5205  42 PRENATAL STRESS CHANGES THE GLYCOPROTEIN GPM6A GENE EXPRESSION AND INDUCES EPIGENETIC CHANGES IN RAT OFFSPRING BRAIN. PRENATAL STRESS (PS) EXERTS STRONG IMPACT ON FETAL BRAIN DEVELOPMENT AND ON ADULT OFFSPRING BRAIN FUNCTIONS. PREVIOUS WORK DEMONSTRATED THAT CHRONIC STRESS ALTERS THE MRNA EXPRESSION OF GPM6A, A NEURONAL GLYCOPROTEIN INVOLVED IN FILOPODIUM EXTENSION. IN THIS WORK, WE ANALYZED THE EFFECT OF PS ON GPM6A EXPRESSION AND THE EPIGENETIC MECHANISMS INVOLVED. PREGNANT WISTAR RATS RECEIVED RESTRAINT STRESS DURING THE LAST WEEK OF GESTATION. MALE OFFSPRING WERE SACRIFICED ON POSTNATAL DAYS 28 AND 60. HIPPOCAMPUS AND PREFRONTAL CORTEX SAMPLES WERE ANALYZED FOR GENE EXPRESSION (QPCR FOR MRNAS AND MICRORNAS), METHYLATION STATUS (BISULFITE CONVERSION) AND PROTEIN LEVELS. HIPPOCAMPAL NEURONS IN CULTURE WERE USED TO ANALYZE MICRORNA OVEREXPRESSION EFFECTS. PRENATAL STRESS INDUCED CHANGES IN GPM6A LEVELS IN BOTH TISSUES AND AT BOTH AGES ANALYZED, INDICATING A PERSISTENT EFFECT. TWO CPG ISLANDS IN THE GPM6A GENE WERE IDENTIFIED. VARIATIONS IN THE METHYLATION PATTERN AT THREE SPECIFIC CPGS WERE FOUND IN HIPPOCAMPUS, BUT NOT IN PFC SAMPLES FROM PS OFFSPRING. MICRORNAS PREDICTED TO TARGET GPM6A WERE IDENTIFIED IN SILICO. QPCR MEASUREMENTS SHOWED THAT PS MODIFIED THE EXPRESSION OF SEVERAL MICRORNAS IN BOTH TISSUES, BEING MICRORNA-133B THE MOST SIGNIFICANTLY ALTERED. FURTHER STUDIES OVEREXPRESSING THIS MICRORNA IN NEURONAL CULTURES SHOWED A REDUCTION IN GMP6A MRNA AND PROTEIN LEVEL. MOREOVER FILOPODIUM DENSITY WAS ALSO REDUCED, SUGGESTING THAT GPM6A FUNCTION WAS AFFECTED. GESTATIONAL STRESS AFFECTED GPM6A GENE EXPRESSION IN OFFSPRING LIKELY THROUGH CHANGES IN METHYLATION STATUS AND IN POSTTRANSCRIPTIONAL REGULATION BY MICRORNAS. THUS, OUR FINDINGS PROPOSE GPM6A AS A NOVEL TARGET FOR EPIGENETIC REGULATION DURING PRENATAL STRESS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 1117  40 COMPARATIVE AND EXPERIMENTAL STUDIES ON THE GENES ALTERED BY CHRONIC HYPOXIA IN HUMAN BRAIN MICROENDOTHELIAL CELLS. BACKGROUND : HYPOXIA INDUCIBLE FACTOR 1 ALPHA (HIF1A) IS A MASTER REGULATOR OF ACUTE HYPOXIA; HOWEVER, WITH CHRONIC HYPOXIA, HIF1A LEVELS RETURN TO THE NORMOXIC LEVELS. IMPORTANTLY, THE GENES THAT ARE INVOLVED IN THE CELL SURVIVAL AND VIABILITY UNDER CHRONIC HYPOXIA ARE NOT KNOWN. THEREFORE, WE TESTED THE HYPOTHESIS THAT CHRONIC HYPOXIA LEADS TO THE UPREGULATION OF A CORE GROUP OF GENES WITH ASSOCIATED CHANGES IN THE PROMOTER DNA METHYLATION THAT MEDIATES THE CELL SURVIVAL UNDER HYPOXIA. RESULTS : WE EXAMINED THE EFFECT OF CHRONIC HYPOXIA (3 DAYS; 0.5% OXYGEN) ON HUMAN BRAIN MICRO ENDOTHELIAL CELLS (HBMEC) VIABILITY AND APOPTOSIS. HYPOXIA CAUSED A SIGNIFICANT REDUCTION IN CELL VIABILITY AND AN INCREASE IN APOPTOSIS. NEXT, WE EXAMINED CHRONIC HYPOXIA ASSOCIATED CHANGES IN TRANSCRIPTOME AND GENOME-WIDE PROMOTER METHYLATION. THE DATA OBTAINED WAS COMPARED WITH 16 OTHER MICROARRAY STUDIES ON CHRONIC HYPOXIA. NINE GENES WERE ALTERED IN RESPONSE TO CHRONIC HYPOXIA IN ALL 17 STUDIES. INTERESTINGLY, HIF1A WAS NOT ALTERED WITH CHRONIC HYPOXIA IN ANY OF THE STUDIES. FURTHERMORE, WE COMPARED OUR DATA TO THREE OTHER STUDIES THAT IDENTIFIED HIF-RESPONSIVE GENES BY VARIOUS APPROACHES. ONLY TWO GENES WERE FOUND TO BE HIF DEPENDENT. WE SILENCED EACH OF THESE 9 GENES USING CRISPR/CAS9 SYSTEM. DOWNREGULATION OF EGLN3 SIGNIFICANTLY INCREASED THE CELL DEATH UNDER CHRONIC HYPOXIA, WHEREAS DOWNREGULATION OF ERO1L, ENO2, ADRENOMEDULLIN, AND SPAG4 REDUCED THE CELL DEATH UNDER HYPOXIA. CONCLUSIONS : WE PROVIDE A CORE GROUP OF GENES THAT REGULATES CELLULAR ACCLIMATIZATION UNDER CHRONIC HYPOXIC STRESS, AND MOST OF THEM ARE HIF INDEPENDENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7 1584  31 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8  887  34 CHRONIC CORTISOL EXPOSURE IN EARLY DEVELOPMENT LEADS TO NEUROENDOCRINE DYSREGULATION IN ADULTHOOD. OBJECTIVE: CHRONIC EARLY LIFE STRESS CAN AFFECT DEVELOPMENT OF THE NEUROENDOCRINE STRESS SYSTEM, LEADING TO ITS PERSISTENT DYSREGULATION AND CONSEQUENTLY INCREASED DISEASE RISK IN ADULTHOOD. ONE CONTRIBUTING FACTOR IS THOUGHT TO BE EPIGENETIC PROGRAMMING IN RESPONSE TO CHRONIC CORTISOL EXPOSURE DURING EARLY DEVELOPMENT. WE HAVE PREVIOUSLY SHOWN THAT ZEBRAFISH EMBRYOS TREATED CHRONICALLY WITH CORTISOL DEVELOP INTO ADULTS WITH CONSTITUTIVELY ELEVATED WHOLE-BODY CORTISOL AND ABERRANT IMMUNE GENE EXPRESSION. HERE WE FURTHER CHARACTERIZE THAT PHENOTYPE BY ASSESSING PERSISTENT EFFECTS OF THE TREATMENT ON CORTISOL TISSUE DISTRIBUTION AND DYNAMICS, CHROMATIN ACCESSIBILITY, AND ACTIVITIES OF GLUCOCORTICOID-RESPONSIVE REGULATORY GENES KLF9 AND FKBP5. TO THAT END CORTISOL LEVELS IN DIFFERENT TISSUES OF FED AND FASTED ADULTS WERE MEASURED USING ELISA, OPEN CHROMATIN IN ADULT BLOOD CELLS WAS MAPPED USING ATAC-SEQ, AND GENE ACTIVITY IN ADULT BLOOD AND BRAIN CELLS WAS MEASURED USING QRT-PCR. RESULTS: ADULTS DERIVED FROM CORTISOL-TREATED EMBRYOS HAVE ELEVATED WHOLE-BODY CORTISOL WITH ABERRANTLY REGULATED TISSUE DISTRIBUTION AND DYNAMICS THAT CORRELATE WITH DIFFERENTIAL ACTIVITY OF KLF9 AND FKBP5 IN BLOOD AND BRAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9 1820  40 EFFECTS OF CHRONIC RESTRAINT STRESS ON THE GLOBAL DNA METHYLATION PROFILE OF RAT LUNG CELLS: MODULATION BY PHYSICAL EXERCISE. THE POTENTIAL OF BEHAVIORAL STRESS TO AFFECT EPIGENETIC MECHANISMS OF NON-ENCEPHALIC TISSUES IS STILL UNDERESTIMATED. IN THE PRESENT STUDY WE EVALUATED THE EFFECTS OF CHRONIC BEHAVIORAL STRESS ON THE DNA METHYLATION PROFILE OF RAT LUNG CELLS. FURTHERMORE, WE EVALUATED THE POTENTIAL OF PHYSICAL EXERCISE TO MODULATE THE CHANGES EVOKED BY BEHAVIORAL STRESS IN LUNG CELLS. MALE WISTAR RATS WERE DIVIDED INTO FOUR EXPERIMENTAL GROUPS: (1) ANIMALS SUBMITTED TO CHRONIC RESTRAINT STRESS (CRS) (ST GROUP) DURING THE PERIOD OF THE 67TH-80TH POSTNATAL DAY (PND); (2) ANIMALS SUBMITTED TO PHYSICAL EXERCISE (EX GROUP) DURING THE 53RD-79TH PND; (3) ANIMALS SUBMITTED TO SWIMMING DURING THE 53RD-79TH PND AND TO CRS DURING THE 67TH-80TH PND (EX-ST GROUP); AND (4) ANIMALS NOT SUBMITTED TO STRESS OR SWIMMING PROTOCOLS (CTL). GLOBAL DNA METHYLATION WAS QUANTIFIED USING AN ELISA-BASED APPROACH AND GENE EXPRESSION WAS EVALUATED BY REAL TIME PCR. A DECREASED GLOBAL DNA METHYLATION PROFILE WAS OBSERVED IN THE ST GROUP, HOWEVER PHYSICAL EXERCISE DEMONSTRATED PROTECTION OF LUNG CELLS FROM THIS STRESS-RELATED HYPOMETHYLATION. INCREASED EXPRESSION OF THE DNMT1 GENE WAS EVIDENCED IN THE ST GROUP, WHEREAS PHYSICAL EXERCISE WAS SHOWN TO PROTECT LUNG CELLS FROM THIS STRESS-RELATED EFFECT IN THE EX-ST GROUP. COMPARATIVE ANALYSIS OF THE ST AND EX GROUPS REVEALED OPPOSITE EFFECTS ON THE EXPRESSION OF DNMT3A AND DNMT3B; HOWEVER, A STRESS-RELATED INCREASE IN EXPRESSION OF DNMT3A AND DNMT3B WAS NOT SEEN IN THE EX-ST GROUP. OUR DATA SHOWED THAT BEHAVIORAL STRESS INDUCED SIGNIFICANT CHANGES IN THE DNA METHYLATION PROFILE OF RAT LUNG CELLS AND THAT THIS COULD BE MODULATED BY PHYSICAL EXERCISE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10 5189  36 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11 1567  41 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12 3991  36 LONGITUDINAL EFFECTS OF DEVELOPMENTAL BISPHENOL A, VARIABLE DIET, AND PHYSICAL ACTIVITY ON AGE-RELATED METHYLATION IN BLOOD. RESEARCH INDICATES THAT ENVIRONMENTAL FACTORS CAN ALTER DNA METHYLATION, BUT THE SPECIFIC EFFECTS OF ENVIRONMENTAL EXPOSURES ON EPIGENETIC AGING REMAIN UNCLEAR. HERE, USING A MOUSE MODEL OF HUMAN-RELEVANT EXPOSURES, WE TESTED THE HYPOTHESIS THAT EARLY-LIFE EXPOSURE TO BISPHENOL A (BPA), VARIABLE DIET, AND/OR CHANGES IN PHYSICAL ACTIVITY WOULD MODIFY RATES OF AGE-RELATED METHYLATION AT SEVERAL TARGET REGIONS, AS MEASURED FROM LONGITUDINAL BLOOD SAMPLES (2, 4, AND 10 MONTHS OLD). DNA METHYLATION WAS QUANTIFIED AT TWO REPETITIVE ELEMENTS (LINE-1, IAP), TWO IMPRINTED GENES (IGF2, H19), AND ONE NON-IMPRINTED GENE (ESR1) IN ISOGENIC MICE DEVELOPMENTALLY EXPOSED TO CONTROL, CONTROL + BPA (50 MICROG/KG DIET), WESTERN HIGH-FAT DIET (WHFD), OR WESTERN + BPA DIETS. IN BLOOD SAMPLES, ESR1 DNA METHYLATION INCREASED SIGNIFICANTLY WITH AGE, BUT NO OTHER INVESTIGATED LOCI SHOWED SIGNIFICANT AGE-RELATED METHYLATION. LINE-1 AND IAP BOTH SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE (P < 0.05). ESR1ALSO SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE IN FEMALE MICE (P = 0.02), BUT NOT MALE MICE. PHYSICAL ACTIVITY HAD A NON-SIGNIFICANT POSITIVE EFFECT ON AGE-RELATED ESR1 METHYLATION IN FEMALE BLOOD, SUGGESTING THAT IT MAY PARTIALLY ABROGATE THE EFFECTS OF WHFD ON THE AGING EPIGENOME. THESE RESULTS SUGGEST THAT DEVELOPMENTAL NUTRITIONAL EXPOSURES CAN MODIFY AGE-RELATED DNA METHYLATION PATTERNS AT A GENE RELATED TO GROWTH AND DEVELOPMENT. AS SUCH, ENVIRONMENTAL DEFLECTION OF THE AGING EPIGENOME MAY HELP TO EXPLAIN THE GROWING PREVALENCE OF CHRONIC DISEASES IN HUMAN POPULATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13 1545  43 DNA METHYLATION IN LIVER TUMORIGENESIS IN FISH FROM THE ENVIRONMENT. THE LINK BETWEEN ENVIRONMENT, ALTERATION IN DNA METHYLATION AND CANCER HAS BEEN WELL ESTABLISHED IN HUMANS; YET, IT IS UNDER-STUDIED IN UNSEQUENCED NON-MODEL ORGANISMS. THE OCCURRENCE OF LIVER TUMORS IN THE FLATFISH DAB COLLECTED AT CERTAIN UK SAMPLING SITES EXCEEDS 20%, YET THE CAUSATIVE AGENTS AND THE MOLECULAR MECHANISMS OF TUMOR FORMATION ARE NOT KNOWN, ESPECIALLY REGARDING THE BALANCE BETWEEN EPIGENETIC AND GENETIC FACTORS. METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) COMBINED WITH DE NOVO HIGH-THROUGHPUT DNA SEQUENCING WERE USED TO INVESTIGATE DNA METHYLATION CHANGES IN DAB HEPATOCELLULAR ADENOMA TUMORS FOR THE FIRST TIME IN AN UNSEQUENCED SPECIES. NOVEL CUSTOM-MADE DAB GENE EXPRESSION ARRAYS WERE DESIGNED AND USED TO DETERMINE THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION. IN ADDITION, THE CONFIRMATORY TECHNIQUES OF BISULFITE SEQUENCING PCR (BSP) AND RT-PCR WERE APPLIED. GENES INVOLVED IN PATHWAYS RELATED TO CANCER, INCLUDING APOPTOSIS, WNT/BETA-CATENIN SIGNALING AND GENOMIC AND NON-GENOMIC ESTROGEN RESPONSES, WERE ALTERED BOTH IN METHYLATION AND TRANSCRIPTION. GLOBAL METHYLATION WAS STATISTICALLY SIGNIFICANTLY 1.8-FOLD REDUCED IN HEPATOCELLULAR ADENOMA AND NON-CANCEROUS SURROUNDING TISSUES COMPARED WITH LIVER FROM NON-CANCER BEARING DAB. BASED ON THE IDENTIFIED CHANGES AND CHEMICAL EXPOSURE DATA, OUR STUDY SUPPORTS THE EPIGENETIC MODEL OF CANCER. WE HYPOTHESIZE THAT CHRONIC EXPOSURE TO A MIXTURE OF ENVIRONMENTAL CONTAMINANTS CONTRIBUTES TO A GLOBAL HYPOMETHYLATION FOLLOWED BY FURTHER EPIGENETIC AND GENOMIC CHANGES. THE FINDINGS SUGGEST A LINK BETWEEN ENVIRONMENT, EPIGENETICS AND CANCER IN FISH TUMORS IN THE WILD AND SHOW THE UTILITY OF THIS METHODOLOGY FOR STUDIES IN NON-MODEL ORGANISMS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14  891  47 CHRONIC EFFECTS OF CLOFIBRIC ACID IN ZEBRAFISH (DANIO RERIO): A MULTIGENERATIONAL STUDY. CLOFIBRIC ACID (CA) IS AN ACTIVE METABOLITE OF THE BLOOD LIPID LOWERING AGENT CLOFIBRATE, A PHARMACEUTICAL DESIGNED TO WORK AS AGONIST OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA (PPARA). IT IS THE MOST COMMONLY REPORTED FIBRATE IN AQUATIC ENVIRONMENTS WITH LOW DEGRADATION RATE AND POTENTIAL ENVIRONMENTAL PERSISTENCE. PREVIOUS FISH EXPOSURES SHOWED THAT CA MAY IMPACT SPERMATOGENESIS, GROWTH AND THE EXPRESSION OF FAT BINDING PROTEIN GENES. HOWEVER, THERE ARE LIMITED DATA ON THE EFFECTS OF CHRONIC MULTIGENERATIONAL CA EXPOSURES. HERE, WE ASSESSED CHRONIC MULTIGENERATIONAL EFFECTS OF CA EXPOSURE USING ZEBRAFISH (DANIO RERIO) AS A TELEOST MODEL. ZEBRAFISH WERE EXPOSED THROUGH THE DIET TO CA (1 AND 10MG/G) DURING THEIR WHOLE LIFETIME. GROWTH, REPRODUCTION-RELATED PARAMETERS AND EMBRYONIC DEVELOPMENT WERE ASSESSED IN THE EXPOSED FISH (F1 GENERATION) AND THEIR OFFSPRING (F2 GENERATION), TOGETHER WITH MUSCLE TRIGLYCERIDE CONTENT AND GONAD HISTOLOGY. IN ORDER TO STUDY THE POTENTIAL UNDERLYING MECHANISMS, THE TRANSCRIPTION LEVELS OF GENES CODING FOR ENZYMES INVOLVED IN LIPID METABOLISM PATHWAYS WERE DETERMINED. THE RESULTS SHOW THAT CHRONIC LIFE-CYCLE EXPOSURE TO CA INDUCED A SIGNIFICANT REDUCTION IN GROWTH OF F1 GENERATION AND LOWERED TRIGLYCERIDE MUSCLE CONTENT (10MG/G GROUP). ALSO, AN IMPACT IN MALE GONAD DEVELOPMENT WAS OBSERVED TOGETHER WITH A DECREASE IN THE FECUNDITY (10MG/G GROUP) AND HIGHER FREQUENCY OF EMBRYO ABNORMALITIES IN THE OFFSPRING OF FISH EXPOSED TO THE LOWEST CA DOSE. THE PROFILE OF THE TARGET GENES WAS SEX- AND TISSUE-DEPENDENT. IN F1 AN UP-REGULATION OF MALE HEPATIC PPARAA, PPARB AND ACOX TRANSCRIPT LEVELS WAS OBSERVED, SUGGESTING AN ACTIVATION OF THE FATTY ACID METABOLISM (PROVIDED THAT TRANSCRIPT LEVEL CHANGE INDICATES ALSO A PROTEIN LEVEL CHANGE). INTERESTINGLY, THE F2 GENERATION, RAISED WITH CONTROL DIET, DISPLAYED A RESPONSE PATTERN DIFFERENT FROM THAT OBSERVED IN F1, SHOWING AN INCREASE IN WEIGHT IN THE DESCENDANTS OF CA EXPOSED FISH, IN COMPARISON WITH CONTROL ANIMALS, WHICH POINTS TO A MULTIGENERATIONAL EFFECT.	2015	
                                                                                                                                                                                                                                              
15 1162  38 CONTRASTING EFFECTS OF ACUTE AND CHRONIC STRESS ON THE TRANSCRIPTOME, EPIGENOME, AND IMMUNE RESPONSE OF ATLANTIC SALMON. STRESS EXPERIENCED DURING EARLY LIFE MAY HAVE LASTING EFFECTS ON THE IMMUNE SYSTEM, WITH IMPACTS ON HEALTH AND DISEASE DEPENDENT ON THE NATURE AND DURATION OF THE STRESSOR. THE EPIGENOME IS ESPECIALLY SENSITIVE TO ENVIRONMENTAL STIMULI DURING EARLY LIFE AND REPRESENTS A POTENTIAL MECHANISM THROUGH WHICH STRESS MAY CAUSE LONG-LASTING HEALTH EFFECTS. HOWEVER, THE EXTENT TO WHICH THE EPIGENOME RESPONDS DIFFERENTLY TO CHRONIC VS ACUTE STRESSORS IS UNCLEAR, ESPECIALLY FOR NON-MAMMALIAN SPECIES. WE EXAMINED THE EFFECTS OF ACUTE STRESS (COLD-SHOCK DURING EMBRYOGENESIS) AND CHRONIC STRESS (ABSENCE OF TANK ENRICHMENT DURING LARVAL-STAGE) ON GLOBAL GENE EXPRESSION (USING RNA-SEQ) AND DNA METHYLATION (USING RRBS) IN THE GILLS OF ATLANTIC SALMON (SALMO SALAR) FOUR MONTHS AFTER HATCHING. CHRONIC STRESS INDUCED PRONOUNCED TRANSCRIPTIONAL DIFFERENCES, WHILE ACUTE STRESS CAUSED FEW LASTING TRANSCRIPTIONAL EFFECTS. HOWEVER, BOTH ACUTE AND CHRONIC STRESS CAUSED LASTING AND CONTRASTING CHANGES IN THE METHYLOME. CRUCIALLY, WE FOUND THAT ACUTE STRESS ENHANCED TRANSCRIPTIONAL IMMUNE RESPONSE TO A PATHOGENIC CHALLENGE (BACTERIAL LIPOPOLYSACCHARIDE, LPS), WHILE CHRONIC STRESS SUPPRESSED IT. WE IDENTIFIED STRESS-INDUCED CHANGES IN PROMOTER AND GENE-BODY METHYLATION THAT WERE ASSOCIATED WITH ALTERED EXPRESSION FOR A SMALL PROPORTION OF IMMUNE-RELATED GENES, AND EVIDENCE OF WIDER EPIGENETIC REGULATION WITHIN SIGNALLING PATHWAYS INVOLVED IN IMMUNE RESPONSE. OUR RESULTS SUGGEST THAT STRESS CAN AFFECT IMMUNO-COMPETENCE THROUGH EPIGENETIC MECHANISMS, AND HIGHLIGHT THE MARKEDLY DIFFERENT EFFECTS OF CHRONIC LARVAL AND ACUTE EMBRYONIC STRESS. THIS KNOWLEDGE COULD BE USED TO HARNESS THE STIMULATORY EFFECTS OF ACUTE STRESS ON IMMUNITY, PAVING THE WAY FOR IMPROVED STRESS AND DISEASE MANAGEMENT THROUGH EPIGENETIC CONDITIONING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16 1295  36 DECREASED GLOBAL DNA METHYLATION IN THE WHITE BLOOD CELLS OF HIGH FAT DIET FED VERVET MONKEYS (CHLOROCEBUS AETHIOPS). EPIGENETIC MECHANISMS ARE ASSOCIATED WITH THE DEVELOPMENT OF MANY CHRONIC DISEASES AND DUE TO THEIR REVERSIBLE NATURE OFFER A UNIQUE WINDOW OF OPPORTUNITY TO REVERSE THE DISEASE PHENOTYPE. THIS STUDY INVESTIGATED WHETHER GLOBAL DNA METHYLATION CORRELATES WITH DYSGLYCEMIA IN THE VERVET MONKEY (CHLOROCEBUS AETHIOPS). DIET-INDUCED CHANGES IN DNA METHYLATION WERE OBSERVED WHERE GLOBAL DNA METHYLATION WAS TWOFOLD LOWER IN MONKEYS FED A HIGH FAT DIET (N = 10) COMPARED TO MONKEYS FED A STANDARD DIET (N = 15). AN INVERSE CORRELATION WAS OBSERVED BETWEEN DNA METHYLATION, BLOOD GLUCOSE CONCENTRATIONS, BODYWEIGHT, AND AGE, ALTHOUGH THE ASSOCIATION WAS NOT STATISTICALLY SIGNIFICANT. CONSUMPTION OF A HIGH FAT DIET IS ASSOCIATED WITH THE DEVELOPMENT OF METABOLIC DISEASE; THUS, THESE RESULTS SUGGEST THE USE OF GLOBAL DNA METHYLATION AS A BIOMARKER TO ASSESS THE RISK FOR METABOLIC DISEASE. MOREOVER, THIS STUDY PROVIDES FURTHER SUPPORT FOR THE USE OF THE VERVET MONKEY AS A MODEL SYSTEM TO STUDY METABOLIC DISEASES SUCH AS TYPE 2 DIABETES. INTEGRATION OF ALTERED DNA METHYLATION PROFILES INTO PREDICTIVE MODELS COULD FACILITATE RISK STRATIFICATION AND ENABLE INTERVENTION STRATEGIES TO INHIBIT DISEASE PROGRESSION. SUCH INTERVENTIONS COULD INCLUDE LIFESTYLE MODIFICATIONS, FOR EXAMPLE, THE INCREASED CONSUMPTION OF FUNCTIONAL FOODS WITH THE CAPACITY TO MODULATE DNA METHYLATION, THUS POTENTIALLY REVERSING THE DISEASE PHENOTYPE AND PREVENTING DISEASE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17  989  36 CHRONIC SOCIAL DEFEAT STRESS DIFFERENTIALLY REGULATES THE EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE. OBJECTIVES: ALTHOUGH STRESS IS CONSIDERED A PRIMARY RISK FACTOR FOR NEUROPSYCHIATRIC DISORDERS, A MAJORITY OF INDIVIDUALS ARE RESILIENT TO THE EFFECTS OF STRESS EXPOSURE AND SUCCESSFULLY ADAPT TO ADVERSE LIFE EVENTS, WHILE OTHERS, THE SO-CALLED SUSCEPTIBLE INDIVIDUALS, MAY HAVE PROBLEMS TO PROPERLY ADAPT TO ENVIRONMENTAL CHANGES. HOWEVER, THE MECHANISMS UNDERLYING THESE DIFFERENT RESPONSES TO STRESS EXPOSURE ARE POORLY UNDERSTOOD.METHODS: ADULT MALE C57BL/6J MICE WERE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS PROTOCOL AND LEVELS OF BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES WERE ANALYSED BY REAL-TIME PCR IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) OF SUSCEPTIBLE AND RESILIENT MICE.RESULTS: WE FOUND A SELECTIVE REDUCTION OF BDNF-6 TRANSCRIPT IN THE HPC AND AN INCREASE OF BDNF-4 TRANSCRIPT IN THE PFC OF SUSCEPTIBLE MICE. MOREOVER, SUSCEPTIBLE MICE SHOWED A SELECTIVE REDUCTION OF THE G9A MRNA LEVELS IN THE HPC, WHILE HDAC-5 AND DNMT3A MRNA LEVELS WERE SPECIFICALLY REDUCED IN THE PFC.CONCLUSIONS: OVERALL, OUR RESULTS, SHOWING A DIFFERENT EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE, SUGGEST THAT STRESS RESILIENCE IS NOT SIMPLY A LACK OF ACTIVATION OF STRESS-RELATED PATHWAYS, BUT IS RELATED TO THE ACTIVATION OF ADDITIONAL DIFFERENT SPECIFIC MECHANISMS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18 6195  31 THE IMPACT OF RECENT ALCOHOL USE ON GENOME WIDE DNA METHYLATION SIGNATURES. CHRONIC ALCOHOL INTAKE IS ASSOCIATED WITH A WIDE VARIETY OF ADVERSE HEALTH OUTCOMES INCLUDING DEPRESSION, DIABETES, AND HEART DISEASE. UNFORTUNATELY, THE MOLECULAR MECHANISMS THROUGH WHICH THESE EFFECTS ARE CONVEYED ARE NOT CLEARLY UNDERSTOOD. TO EXAMINE THE POTENTIAL ROLE OF EPIGENETIC FACTORS IN THIS PROCESS, WE EXAMINED THE RELATIONSHIP OF RECENT ALCOHOL INTAKE TO GENOME WIDE METHYLATION PATTERNS USING THE ILLUMINA 450 METHYLATION BEAD CHIP AND LYMPHOBLAST DNA DERIVED FROM 165 FEMALE SUBJECTS PARTICIPATING IN THE IOWA ADOPTION STUDIES. WE FOUND THAT THE PATTERN OF ALCOHOL USE OVER THE 6-MONTHS IMMEDIATELY PRIOR TO PHLEBOTOMY WAS ASSOCIATED WITH, SEVERITY-DEPENDENT CHANGES IN THE DEGREE OF GENOME WIDE METHYLATION THAT PREFERENTIALLY HYPERMETHYLATE THE CENTRAL PORTION OF CPG ISLANDS WITH METHYLATION AT CG05600126, A PROBE IN ABR, AND THE 5' UNTRANSLATED REGION OF BLCAP ATTAINING GENOME WIDE SIGNIFICANCE IN TWO POINT AND SLIDING WINDOW ANALYSES OF PROBE METHYLATION DATA, RESPECTIVELY. WE CONCLUDE THAT RECENT ALCOHOL USE IS ASSOCIATED WITH WIDESPREAD CHANGES IN DNA METHYLATION IN WOMEN AND THAT FURTHER STUDY TO CONFIRM THESE FINDINGS AND DETERMINE THEIR RELATIONSHIP TO SOMATIC FUNCTION ARE IN ORDER.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19 2653  46 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES.	2008	
                                                                                                                                                                                                                                                                                                                                                                             
20 4736  40 NOVEL EPIGENETIC BIOMARKERS MEDIATING BISPHENOL A EXPOSURE AND METABOLIC PHENOTYPES IN FEMALE MICE. THERE IS COMPELLING EVIDENCE THAT EPIGENETIC MODIFICATIONS LINK DEVELOPMENTAL ENVIRONMENTAL INSULTS TO ADULT DISEASE SUSCEPTIBILITY. ANIMAL STUDIES HAVE ASSOCIATED PERINATAL BISPHENOL A (BPA) EXPOSURE TO ALTERED DNA METHYLATION, BUT THESE STUDIES ARE OFTEN LIMITED TO CANDIDATE GENE AND GLOBAL NON-LOCI-SPECIFIC APPROACHES. BY USING AN EPIGENOME-WIDE DISCOVERY PLATFORM, WE ELUCIDATED EPIGENETIC ALTERATIONS IN LIVER TISSUE FROM ADULT MICE OFFSPRING (10 MONTHS) FOLLOWING PERINATAL BPA EXPOSURE AT HUMAN PHYSIOLOGICALLY RELEVANT DOSES (50-NG, 50-MUG, AND 50-MG BPA/KG DIET). BIOLOGICAL PATHWAY ANALYSIS IDENTIFIED AN ENRICHMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS IN METABOLIC PATHWAYS AMONG FEMALES. FURTHERMORE, THROUGH THE USE OF TOP ENRICHED BIOLOGICAL PATHWAYS, 4 CANDIDATE GENES WERE CHOSEN TO ASSESS DNA METHYLATION AS A MEDIATING FACTOR LINKING THE ASSOCIATION OF PERINATAL BPA EXPOSURE TO METABOLIC PHENOTYPES PREVIOUSLY OBSERVED IN FEMALE OFFSPRING. DNA METHYLATION STATUS AT JANUS KINASE-2 (JAK-2), RETINOID X RECEPTOR (RXR), REGULATORY FACTOR X-ASSOCIATED PROTEIN (RFXAP), AND TRANSMEMBRANE PROTEIN 238 (TMEM238) WAS USED WITHIN A MEDIATIONAL REGRESSION ANALYSIS. DNA METHYLATION IN ALL FOUR OF THE CANDIDATE GENES WAS IDENTIFIED AS A MEDIATOR IN THE MECHANISTIC PATHWAY OF DEVELOPMENTAL BPA EXPOSURE AND FEMALE-SPECIFIC ENERGY EXPENDITURE, BODY WEIGHT, AND BODY FAT PHENOTYPES. DATA GENERATED FROM THIS STUDY ARE CRUCIAL FOR DECIPHERING THE MECHANISTIC ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC DISEASE AND THE DEVELOPMENT OF EPIGENETIC-BASED PREVENTION AND THERAPEUTIC STRATEGIES FOR COMPLEX HUMAN DISEASE.	2017