1 2265 124 EPIGENETIC PROGRAMMING IN THE PREIMPLANTATION RAT EMBRYO IS DISRUPTED BY CHRONIC PATERNAL CYCLOPHOSPHAMIDE EXPOSURE. PRECONCEPTIONAL PATERNAL EXPOSURE TO CYCLOPHOSPHAMIDE, A WIDELY USED ANTICANCER AGENT, LEADS TO INCREASES IN EMBRYO LOSS, MALFORMATIONS, AND BEHAVIORAL DEFICITS IN OFFSPRING; THESE ABNORMALITIES ARE TRANSMISSIBLE TO SUBSEQUENT GENERATIONS [AUROUX, M., DULIOUST, E., SELVA, J. & RINCE, P. (1990) MUTAT. RES. 229, 189-200]. LITTLE INFORMATION EXISTS ON THE MECHANISMS UNDERLYING THIS MALE-MEDIATED DEVELOPMENTAL TOXICITY. WE ASSESSED THE IMPACT OF PATERNAL CYCLOPHOSPHAMIDE EXPOSURE ON THE DYNAMIC REGULATION OF HISTONE H4 ACETYLATION AT LYSINE 5 AND DNA METHYLATION IN PREIMPLANTATION RAT EMBRYOS. ZYGOTES SIRED BY DRUG-TREATED MALES DISPLAYED ADVANCED DEVELOPMENTAL PROGRESSION, INCREASED PRONUCLEAR AREAS, AND DISRUPTION OF THE EPIGENETIC PROGRAMMING OF BOTH PARENTAL GENOMES. EARLY POSTFERTILIZATION ZYGOTIC PRONUCLEI WERE HYPERACETYLATED; BY MID-ZYGOTIC DEVELOPMENT, MALE PRONUCLEI WERE DRAMATICALLY HYPOMETHYLATED, WHEREAS FEMALE PRONUCLEI WERE HYPERMETHYLATED. MICRONUCLEI WERE SUBSTANTIALLY ELEVATED, AND HISTONE H4 ACETYLATION AT LYSINE 5 LOCALIZATION TO THE NUCLEAR PERIPHERY WAS DISRUPTED IN TWO-CELL EMBRYOS FERTILIZED BY CYCLOPHOSPHAMIDE-EXPOSED SPERMATOZOA. THIS FINDING DEMONSTRATES THAT PATERNAL EXPOSURE TO THIS DRUG INDUCES ABERRANT EPIGENETIC PROGRAMMING IN EARLY EMBRYOS. WE HYPOTHESIZE THAT DISTURBANCES IN EPIGENETIC PROGRAMMING CONTRIBUTE TO HERITABLE INSTABILITIES LATER IN DEVELOPMENT, EMPHASIZING THE IMPORTANCE OF EPIGENETIC RISK ASSESSMENT AFTER CHEMOTHERAPY.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2 6594  24 TUMOR-AUGMENTING EFFECTS OF GESTATIONAL ARSENIC EXPOSURE ON F1 AND F2 IN MICE. THE CONSEQUENCES OF EARLY-LIFE EXPOSURE TO CHEMICALS IN THE ENVIRONMENT ARE EMERGING CONCERNS. CHRONIC EXPOSURE TO NATURALLY OCCURRING INORGANIC ARSENIC HAS BEEN KNOWN TO CAUSE VARIOUS ADVERSE HEALTH EFFECTS, INCLUDING CANCERS, IN HUMANS. ON THE OTHER HAND, ANIMAL STUDIES BY DR. M. WAALKES' GROUP REPORTED THAT ARSENITE EXPOSURE OF PREGNANT F0 FEMALES, ONLY FROM GESTATIONAL DAY 8 TO 18, INCREASED HEPATIC TUMORS IN THE F1 (ARSENITE-F1) MALES OF C3H MICE, WHOSE MALES TEND TO DEVELOP SPONTANEOUS HEPATIC TUMORS LATER IN LIFE. SINCE THIS MICE MODEL ILLUMINATED NOVEL UNIDENTIFIED CONSEQUENCES OF ARSENIC EXPOSURE, WE WISHED TO FURTHER INVESTIGATE THE BACKGROUND MECHANISMS. IN THE SAME EXPERIMENTAL MODEL, WE IDENTIFIED A VARIETY OF FACTORS THAT WERE AFFECTED BY GESTATIONAL ARSENIC EXPOSURE, INCLUDING EPIGENETIC AND GENETIC CHANGES, AS POSSIBLE CONSTITUENTS OF MULTIPLE STEPS OF LATE-ONSET HEPATIC TUMOR AUGMENTATION IN ARSENITE-F1 MALES. FURTHERMORE, OUR STUDY DISCOVERED THAT THE F2 MALES BORN TO ARSENITE-F1 MALES DEVELOPED HEPATIC TUMORS AT A SIGNIFICANTLY HIGHER RATE THAN THE CONTROL F2 MALES. THE RESULTS IMPLY THAT THE TUMOR AUGMENTING EFFECT IS INHERITED BY ARSENITE-F2 MALES THROUGH THE SPERM OF ARSENITE-F1. IN THIS ARTICLE, WE SUMMARIZED OUR STUDIES ON THE CONSEQUENCES OF GESTATIONAL ARSENITE EXPOSURE IN F1 AND F2 MICE TO DISCUSS NOVEL ASPECTS OF BIOLOGICAL EFFECTS OF GESTATIONAL ARSENIC EXPOSURE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3 6008  33 THE ANTI-INFLAMMATORY AGENT 5-ASA REDUCES THE LEVEL OF SPECIFIC TSRNAS IN SPERM CELLS OF HIGH-FAT FED C57BL/6J MOUSE SIRES AND IMPROVES GLUCOSE TOLERANCE IN FEMALE OFFSPRING. INTRODUCTION: THE PREVALENCE OF OBESITY AND ASSOCIATED COMORBIDITIES HAVE INCREASED TO EPIDEMIC PROPORTIONS GLOBALLY. PATERNAL OBESITY IS AN INDEPENDENT RISK FACTOR FOR DEVELOPING OBESITY AND TYPE 2 DIABETES IN THE FOLLOWING GENERATION, AND GROWING EVIDENCE SUGGESTS EPIGENETIC INHERITANCE AS A MECHANISM FOR THIS PREDISPOSITION. HOW AND WHY OBESITY INDUCES EPIGENETIC CHANGES IN SPERM CELLS REMAIN TO BE CLARIFIED IN DETAIL. YET, RECENT STUDIES SHOW THAT ALTERATIONS IN SPERM CONTENT OF TRANSFER RNA-DERIVED SMALL RNAS (TSRNAS) CAN TRANSMIT THE EFFECTS OF PATERNAL OBESITY TO OFFSPRING. OBESITY IS CLOSELY ASSOCIATED WITH LOW-GRADE CHRONIC INFLAMMATION. THUS, WE EVALUATED WHETHER THE ANTI-INFLAMMATORY AGENT 5-AMINOSALICYLIC ACID (5-ASA) COULD INTERVENE IN THE TRANSMISSION OF EPIGENETIC INHERITANCE OF PATERNAL OBESITY BY REDUCING THE INFLAMMATORY STATE IN OBESE FATHERS. METHODS: MALE C57BL/6JBOMTAC MICE WERE EITHER FED A HIGH-FAT DIET OR A HIGH-FAT DIET WITH 5-ASA FOR TEN WEEKS BEFORE MATING. THE OFFSPRING METABOLIC PHENOTYPE WAS EVALUATED, AND SPERMATOZOA FROM SIRES WERE ISOLATED FOR ASSESSMENT OF SPECIFIC TSRNAS LEVELS. RESULTS: 5-ASA INTERVENTION REDUCED THE LEVELS OF GLU-CTC TSRNAS IN SPERM CELLS AND IMPROVED GLUCOSE TOLERANCE IN FEMALE OFFSPRING FED A CHOW DIET. PATERNAL HIGH-FAT DIET-INDUCED OBESITY PER SE HAD ONLY A MODERATE IMPACT ON THE METABOLIC PHENOTYPE OF BOTH MALE AND FEMALE OFFSPRING IN OUR SETTING. CONCLUSION: THE RESULTS INDICATE THAT THE LOW-GRADE INFLAMMATORY RESPONSE ASSOCIATED WITH OBESITY MAY BE AN IMPORTANT FACTOR IN EPIGENETIC INHERITANCE OF PATERNAL OBESITY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4 4736  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5 5205  28 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 2776  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7 4528  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 2886  22 GABA-AALPHA5 MIGHT BE INVOLVED IN LEARNING-MEMORY DYSFUNCTION IN THE OFFSPRINGS OF CHRONIC ETHANOL-TREATED RATS VIA GABA-AALPHA5 HISTONE H3K9 ACETYLATION. RECENTLY, NUMEROUS STUDIES HAVE BEEN FOCUSED ON THE RELATIONSHIP BETWEEN GABA-A RECEPTORS AND ALCOHOL-INDUCED SPATIAL LEARNING AND MEMORY DEFICITS. GABA-AALPHA5, A SUBUNIT OF GABA-A RECEPTORS, IS CONSIDERED TO PLAY AN IMPORTANT ROLE IN ALCOHOL-INDUCED COGNITIVE IMPAIRMENT, HOWEVER, THE MECHANISM REMAINS OBSCURE. IN THIS STUDY, WE FOUND THAT THE EXPRESSION OF GABA-AALPHA5 INCREASED IN RATS TREATED WITH CHRONIC ETHANOL VIA HISTONE H3K9 ACETYLATION. FURTHERMORE, THIS EPIGENETIC MODIFICATION COULD BE INHERITED BY THE NEXT GENERATIONS, WHICH EVENTUALLY EXHIBIT SIMILAR SPATIAL LEARNING AND MEMORY DEFICITS IN THE OFFSPRINGS. IN SUMMARY, OUR RESULTS SUGGESTED THAT GABA-AALPHA5 MIGHT BE INVOLVED IN CHRONIC ETHANOL TREATMENT-INDUCED LEARNING-MEMORY DYSFUNCTION AND FOR THE FIRST TIME PROVED THAT LEARNING-MEMORY DYSFUNCTION COULD BE INHERITED BY THE OFFSPRINGS VIA HISTONE H3K9 ACETYLATION. HOPEFULLY, IN THE NEAR FUTURE, GABA-AALPHA5 INHIBITORS WOULD BE AN EFFECTIVE WAY TO TREAT ALCOHOL-INDUCED COGNITION IMPAIRMENT.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9  891  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10 1162  22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11 6681  29 USING ZEBRAFISH EMBRYO BIOASSAYS TO IDENTIFY CHEMICALS MODULATING THE REGULATION OF THE EPIGENOME: A CASE STUDY WITH SIMVASTATIN. CONTAMINANTS OF EMERGING CONCERN HAVE BEEN INCREASINGLY ASSOCIATED WITH THE MODULATION OF THE EPIGENOME, LEADING TO POTENTIALLY INHERITED AND PERSISTENT IMPACTS ON APICAL ENDPOINTS. HERE, WE ADDRESS THE PERFORMANCE OF THE OECD TEST NO. 236 FET (FISH EMBRYO ACUTE TOXICITY) IN THE IDENTIFICATION OF CHEMICALS ABLE TO MODULATE THE EPIGENOME. USING ZEBRAFISH (DANIO RERIO) EMBRYOS, ACUTE AND CHRONIC EXPOSURES WERE PERFORMED WITH THE PHARMACEUTICAL, SIMVASTATIN (SIM), A WIDELY PRESCRIBED HYPOCHOLESTEROLEMIC DRUG REPORTED TO INDUCE INTER AND TRANSGENERATIONAL EFFECTS. IN THE PRESENT STUDY, THE EPIGENETIC EFFECTS OF ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF SIM (FROM 8 NG/L TO 2000 NG/L) WERE ADDRESSED FOLLOWING (1) AN ACUTE EMBRYO ASSAY BASED ON OECD TEST NO. 236 FET, (2) A CHRONIC PARTIAL LIFE-CYCLE EXPOSURE USING ADULT ZEBRAFISH (90 DAYS), AND (3) F1 EMBRYOS OBTAINED FROM PARENTAL EXPOSED ANIMALS. SIMVASTATIN INDUCED SIGNIFICANT EFFECTS IN GENE EXPRESSION OF KEY EPIGENETIC BIOMARKERS (DNA METHYLATION AND HISTONE ACETYLATION/DEACETYLATION) IN THE GONADS OF EXPOSED ADULT ZEBRAFISH AND IN 80 HPF ZEBRAFISH EMBRYOS (ACUTE AND CHRONIC PARENTAL INTERGENERATIONAL EXPOSURE), ALBEIT WITH DISTINCT EFFECT PROFILES BETWEEN BIOLOGICAL SAMPLES. IN THE CHRONIC EXPOSURE, SIM IMPACTED PARTICULARLY DNA METHYLTRANSFERASE GENES IN MALES AND FEMALE GONADS, WHEREAS IN F1 EMBRYOS SIM AFFECTED MOSTLY GENES ASSOCIATED WITH HISTONE ACETYLATION/DEACETYLATION. IN THE EMBRYO ACUTE DIRECT EXPOSURE, SIM MODULATED THE EXPRESSION OF BOTH GENES INVOLVED IN DNA METHYLATION AND HISTONE DEACETYLASE. THESE FINDINGS FURTHER SUPPORT THE USE OF EPIGENETIC BIOMARKERS IN ZEBRAFISH EMBRYOS IN A HIGH THROUGHPUT APPROACH TO IDENTIFY AND PRIORITIZE EPIGENOME-MODULATING CHEMICALS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
12 4089  28 MATERNAL OBESITY PROGRAMS SENESCENCE SIGNALING AND GLUCOSE METABOLISM IN OSTEO-PROGENITORS FROM RAT AND HUMAN. NUTRITIONAL STATUS DURING INTRAUTERINE AND EARLY POSTNATAL LIFE IMPACTS THE RISK OF CHRONIC DISEASES, PRESUMABLY VIA EPIGENETIC MECHANISMS. HOWEVER, EVIDENCE ON THE IMPACT OF GESTATIONAL EVENTS ON REGULATION OF EMBRYONIC BONE CELL FATE IS SPARSE. WE INVESTIGATED THE EFFECTS OF MATERNAL OBESITY ON FETAL OSTEOBLAST DEVELOPMENT IN BOTH RODENTS AND HUMANS. FEMALE RATS WERE FED CONTROL OR AN OBESOGENIC HIGH-FAT DIET (HFD) FOR 12 WEEKS AND MATED WITH MALE RATS FED CONTROL DIETS, AND RESPECTIVE MATERNAL DIETS WERE CONTINUED DURING PREGNANCY. EMBRYONIC RAT OSTEOGENIC CALVARIAL CELLS (EOCCS) WERE TAKEN FROM GESTATIONAL DAY 18.5 FETUSES FROM CONTROL AND HFD DAMS. EOCCS FROM HFD OBESE DAMS SHOWED INCREASES IN P53/P21-MEDIATED CELL SENESCENCE SIGNALING BUT DECREASED GLUCOSE METABOLISM. DECREASED AEROBIC GLYCOLYSIS IN HFD-EOCCS WAS ASSOCIATED WITH DECREASED OSTEOBLASTIC CELL DIFFERENTIATION AND PROLIFERATION. UMBILICAL CORD HUMAN MESENCHYMAL STEM CELLS (MSCS) FROM 24 PREGNANT WOMEN (12 OBESE AND 12 LEAN) ALONG WITH PLACENTAS WERE COLLECTED UPON DELIVERY. THE UMBILICAL CORD MSCS OF OBESE MOTHERS DISPLAYED LESS POTENTIAL TOWARD OSTEOBLASTOGENESIS AND MORE TOWARDS ADIPOGENESIS. HUMAN MSCS AND PLACENTA FROM OBESE MOTHERS ALSO EXHIBITED INCREASED CELL SENESCENCE SIGNALING, WHEREAS MSCS SHOWED DECREASED GLUCOSE METABOLISM AND INSULIN RESISTANCE. FINALLY, WE SHOWED THAT OVEREXPRESSION OF P53 LINKED INCREASED CELL SENESCENCE SIGNALING AND DECREASED GLUCOSE METABOLISM IN FETAL OSTEO-PROGENITORS FROM OBESE RATS AND HUMANS. THESE FINDINGS SUGGEST PROGRAMMING OF FETAL PREOSTEOBLASTIC CELL SENESCENCE SIGNALING AND GLUCOSE METABOLISM BY MATERNAL OBESITY.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  905  28 CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE CAUSES LONG-LASTING BEHAVIORAL DEFICITS IN ADULT MICE. REGULAR USE OF MARIJUANA DURING ADOLESCENCE ENHANCES THE RISK OF LONG-LASTING NEUROBIOLOGICAL CHANGES IN ADULTHOOD. THE PRESENT STUDY WAS AIMED AT ASSESSING THE EFFECT OF LONG-TERM ADMINISTRATION OF THE SYNTHETIC CANNABINOID WIN55212.2 DURING ADOLESCENCE IN YOUNG ADULT MICE. ADOLESCENT MICE AGED 5 WEEKS WERE SUBJECTED DAILY TO THE PHARMACOLOGICAL ACTION OF WIN55212.2 FOR 3 WEEKS AND WERE THEN LEFT UNDISTURBED IN THEIR HOME CAGE FOR A 5-WEEK PERIOD AND FINALLY EVALUATED BY BEHAVIORAL TESTING. MICE THAT RECEIVED THE DRUG DURING ADOLESCENCE SHOWED MEMORY IMPAIRMENT IN THE MORRIS WATER MAZE, AS WELL AS A DOSE-DEPENDENT MEMORY IMPAIRMENT IN FEAR CONDITIONING. IN ADDITION, THE ADMINISTRATION OF 3 MG/KG WIN55212.2 IN ADOLESCENCE INCREASED ADULT HIPPOCAMPAL AEA LEVELS AND PROMOTED DNA HYPERMETHYLATION AT THE INTRAGENIC REGION OF THE INTRACELLULAR SIGNALING MODULATOR RGS7, WHICH WAS ACCOMPANIED BY A LOWER RATE OF MRNA TRANSCRIPTION OF THIS GENE, SUGGESTING A POTENTIAL CAUSAL RELATION. ALTHOUGH THE CONCRETE MECHANISMS UNDERLYING THE BEHAVIORAL OBSERVATIONS REMAIN TO BE ELUCIDATED, WE DEMONSTRATE THAT LONG-TERM ADMINISTRATION OF 3 MG/KG OF WIN DURING ADOLESCENCE LEADS TO INCREASED ENDOCANNABINOID LEVELS AND ALTERED RGS7 EXPRESSION IN ADULTHOOD AND ESTABLISH A POTENTIAL LINK TO EPIGENETIC CHANGES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14 1174  36 CONTRIBUTION OF TRANSPOSABLE ELEMENTS TO TRANSGENERATIONAL EFFECTS OF CHRONIC RADIOACTIVE EXPOSURE OF NATURAL POPULATIONS OF DROSOPHILA MELANOGASTER LIVING FOR A LONG TIME IN THE ZONE OF THE CHERNOBYL NUCLEAR DISASTER. THE ACCIDENT AT THE CHERNOBYL NUCLEAR POWER PLANT (CHNPP) LED TO THE NEGATIVE IMPACT OF CHRONIC RADIOACTIVE CONTAMINATION ON POPULATIONS OF ORGANISMS ASSOCIATED WITH THE TRANSGENERATIONAL TRANSMISSION OF GENOME INSTABILITY. WHEN THE DESTABILIZATION OF GENOME, DIFFERENT GENETIC DAMAGES OCCUR, THE ACCUMULATION OF WHICH LEADS TO THE FORMATION OF MUTATIONS, MORPHOLOGICAL ANOMALIES, AND MORTALITY IN THE OFFSPRING. THE MECHANISMS UNDERLYING THE MANIFESTATION OF TRANSGENERATIONAL EVENTS IN THE OFFSPRING OF IRRADIATED PARENTS ARE NOT WELL UNDERSTOOD. IN THIS STUDY, FOR THE FIRST TIME, THE FEATURES OF THE INFLUENCE OF TRANSPOSABLE ELEMENTS (TES) ON THE LONG-TERM BIOLOGICAL CONSEQUENCES OF THE CHNPP ARE CONSIDERED. IN THIS WORK, SPECIMENS OF D. MELANOGASTER OBTAINED FROM NATURAL POPULATIONS IN 2007 IN THE AREAS OF THE CHNPP WITH HETEROGENEOUS RADIOACTIVE CONTAMINATION WERE STUDIED. THE DESCENDANTS FROM THESE POPULATIONS WERE MAINTAINED IN LABORATORY (INBRED) CONDITIONS FOR 160 GENERATIONS. A STABLE TRANSGENERATIONAL TRANSMISSION OF DOMINANT LETHAL MUTATIONS (DLMS) TO THE OFFSPRING OF ALL STUDIED POPULATIONS WAS SHOWN. THE DLM FREQUENCIES STRONGLY WERE CORRELATED WITH THE LEVEL OF SURVIVAL OF OFFSPRING. THE MEAN FREQUENCIES OF RECESSIVE SEX-LINKED LETHAL MUTATIONS VARIED AT THE LEVEL OF SPONTANEOUS POINT MUTATIONS. THE SIMULTANEOUS PRESENCE OF P, HOBO AND I ELEMENTS INDICATES THAT THE STUDIED POPULATIONS DO NOT HAVE A DEFINITE CYTOTYPE, THEIR PHENOTYPIC STATUS IS UNSTABLE. THE BEHAVIOR OF TES IN THE GENOMES OF OFFSPRING DEPENDS NOT ONLY ON PARENTAL EXPOSURE, BUT ALSO ON ORIGIN OF POPULATION, DISTANCE TO THE CHNPP, AND INBRED CONDITIONS. THE OBTAINED RESULTS CONFIRM THE HYPOTHESIS THAT TES ARE INVOLVED IN TRANSGENERATIONAL TRANSMISSION AND ACCUMULATION OF MUTATIONS BY THE OFFSPRING OF IRRADIATED PARENTS. THE TES PATTERN PRESENT IN THE CHERNOBYL GENOMES OF D. MELANOGASTER IS A PECULIAR OF EPIGENETIC MECHANISM FOR THE REGULATION OF PLASTICITY AND ADAPTATION OF POPULATIONS LIVING FOR MANY GENERATIONS UNDER CONDITIONS OF A TECHNOGENICALLY CAUSED RADIATION BACKGROUND.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15 3122  32 GESTATIONAL VALPROIC ACID EXPOSURE INDUCES EPIGENETIC MODIFICATIONS IN MURINE DECIDUA. INTRODUCTION: VALPROIC ACID (VPA), A WIDELY PRESCRIBED ANTIEPILEPTIC DRUG AND AN EFFECTIVE TREATMENT FOR BIPOLAR DISORDER AND NEUROPATHIC PAIN, RESULTS IN MULTIPLE DEVELOPMENTAL DEFECTS FOLLOWING IN UTERO EXPOSURE. UTERINE DECIDUA PROVIDES NUTRITIONAL AND PHYSICAL SUPPORT DURING IMPLANTATION AND EARLY EMBRYONIC DEVELOPMENT. PERTURBATIONS IN THE MOLECULAR MECHANISMS WITHIN DECIDUAL TISSUE DURING EARLY PREGNANCY MIGHT AFFECT EARLY EMBRYONIC GROWTH, RESULT IN EARLY PREGNANCY LOSS OR CAUSE COMPLICATIONS IN THE LATER GESTATIONAL STAGE. VPA IS A KNOWN HISTONE DEACETYLASE INHIBITOR AND EPIGENETIC CHANGES SUCH AS HISTONE HYPERACETYLATION AND METHYLATION HAVE BEEN PROPOSED AS A MECHANISM OF VPA-INDUCED TERATOGENESIS. METHODS: THIS STUDY INVESTIGATED THE EFFECTS OF IN UTERO VPA EXPOSURE ON HISTONE MODIFICATIONS IN MURINE DECIDUAL TISSUE. PREGNANT CD-1 MICE WERE EXPOSED TO 400 MG/KG VPA OR SALINE ON GD9 VIA SUBCUTANEOUS INJECTION. DECIDUAL TISSUE FROM EACH GESTATIONAL SAC WAS HARVESTED AT 1, 3 AND 6 H FOLLOWING EXPOSURE. LEVELS OF ACETYLATED HISTONES H3, H4 AND H3K56, AS WELL AS METHYLATED HISTONES H3K9 AND H3K27 WERE ACID EXTRACTED AND ASSESSED BY WESTERN BLOTTING FOLLOWED BY ACID HISTONE EXTRACTION. RESULTS: VPA EXPOSURE INDUCED A SIGNIFICANT INCREASE (P < 0.05) IN THE LEVELS OF ACETYLATED H3 AT 1, 3 H; ACETYLATED H4 AT 1, 3 AND 6 H AND TRIMETHYLATED H3K9 AT 6 H. IN CONTRAST, NO SIGNIFICANT PERTURBATIONS WERE NOTED IN THE LEVELS OF MONOMETHYLATED H3K9, TRIMETHYLATED H3K27 AND ACETYLATED H3K56. DISCUSSION: THE RESULTS FROM THIS STUDY SUGGEST THAT VPA-INDUCED DECIDUAL HISTONE MODIFICATIONS MIGHT PLAY AN IMPORTANT ROLE AS A MECHANISM OF VPA-INDUCED TERATOGENESIS DURING EARLY EMBRYONIC GROWTH.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16  341  21 ALTERATIONS IN SPERM-INHERITED NONCODING RNAS ASSOCIATE WITH LATE-TERM FETAL GROWTH RESTRICTION INDUCED BY PRECONCEPTION PATERNAL ALCOHOL USE. USING A MOUSE MODEL, OUR GROUP RECENTLY DESCRIBED AN ASSOCIATION BETWEEN CHRONIC PATERNAL ALCOHOL USE PRIOR TO CONCEPTION AND DEFICITS IN OFFSPRING GROWTH. HERE, WE SOUGHT TO DETERMINE THE IMPACT OF ALCOHOL EXPOSURE ON MALE REPRODUCTIVE PHYSIOLOGY AND THE ASSOCIATION OF SPERM-INHERITED NONCODING RNAS WITH THE TRANSMISSION OF THE OBSERVED GROWTH DEFECTS. ALCOHOL EXPOSURE DID NOT APPRECIABLY ALTER MALE REPRODUCTIVE PHYSIOLOGY OR FERTILITY. HOWEVER, CHRONIC ALCOHOL USE REPRODUCIBLY INDUCED LATE-TERM FETAL GROWTH RESTRICTION IN THE OFFSPRING, WHICH CORRELATED WITH A SHIFT IN THE PROPORTIONAL RATIO OF TRANSFER RNA-DERIVED SMALL RNAS TO PIWI-INTERACTING RNAS, AS WELL AS ALTERED ENRICHMENT OF MICRORNAS MIR21, MIR30, AND MIR142 IN ALCOHOL-EXPOSED SPERM. ALTHOUGH OUR DATASET SHARE SIMILARITIES TO PRIOR WORKS EXAMINING THE IMPACT OF PATERNAL STRESS ON OFFSPRING PHENOTYPE, WE WERE UNABLE TO IDENTIFY ANY CHANGES IN PLASMA CORTICOSTERONE, INDICATING ALCOHOL MAY ALTER SPERM-INHERITED NONCODING RNAS THROUGH DISTINCT MECHANISMS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17 4538  23 MULTISCALE APPROACH TO DECIPHERING THE MOLECULAR MECHANISMS INVOLVED IN THE DIRECT AND INTERGENERATIONAL EFFECT OF IBUPROFEN ON MOSQUITO AEDES AEGYPTI. THE ANTI-INFLAMMATORY IBUPROFEN IS A UBIQUITOUS SURFACE WATER CONTAMINANT. HOWEVER, THE CHRONIC IMPACT OF THIS PHARMACEUTICAL ON AQUATIC INVERTEBRATE POPULATIONS REMAINS POORLY UNDERSTOOD. IN MODEL INSECT AEDES AEGYPTI, WE INVESTIGATED THE INTERGENERATIONAL CONSEQUENCES OF PARENTAL CHRONIC EXPOSURE TO AN ENVIRONMENTALLY RELEVANT CONCENTRATION OF IBUPROFEN. WHILE EXPOSED INDIVIDUALS DID NOT SHOW ANY PHENOTYPIC CHANGES, THEIR PROGENY SHOWED ACCELERATED DEVELOPMENT AND AN INCREASED TOLERANCE TO STARVATION. IN ORDER TO UNDERSTAND THE MECHANISTIC PROCESSES UNDERPINNING THE DIRECT AND INTERGENERATIONAL IMPACTS OF IBUPROFEN, WE COMBINED TRANSCRIPTOMIC, METABOLOMICS, AND HORMONE KINETICS STUDIES AT SEVERAL LIFE STAGES IN EXPOSED INDIVIDUALS AND THEIR PROGENY. THIS INTEGRATIVE APPROACH REVEALED MODERATE TRANSCRIPTIONAL CHANGES IN EXPOSED LARVAE CONSISTENT WITH THE PHARMACOLOGICAL MODE OF ACTION OF IBUPROFEN. PARENTAL EXPOSURE LED TO LOWER LEVELS OF SEVERAL POLAR METABOLITES IN PROGENY EGGS AND TO MAJOR TRANSCRIPTIONAL CHANGES IN THE FOLLOWING LARVAL STAGE. THESE TRANSCRIPTIONAL CHANGES, MOST LIKELY DRIVEN BY CHANGES IN THE EXPRESSION OF NUMEROUS TRANSCRIPTION FACTORS AND EPIGENETIC REGULATORS, LED TO ECDYSONE SIGNALING AND STRESS RESPONSE POTENTIATION. OVERALL, THE PRESENT STUDY ILLUSTRATES THE COMPLEXITY OF THE MOLECULAR BASIS OF THE INTERGENERATIONAL POLLUTANT RESPONSE IN INSECTS AND THE IMPORTANCE OF CONSIDERING THE ENTIRE LIFE CYCLE OF EXPOSED ORGANISMS AND OF THEIR PROGENY IN ORDER TO FULLY UNDERSTAND THE MODE OF ACTION OF POLLUTANTS AND THEIR IMPACT ON ECOSYSTEMS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 1368  35 DEVELOPMENTAL ORIGINS OF DISEASE AND DETERMINANTS OF CHROMATIN STRUCTURE: MATERNAL DIET MODIFIES THE PRIMATE FETAL EPIGENOME. CHROMATIN STRUCTURE IS EPIGENETICALLY ALTERED VIA COVALENT MODIFICATIONS OF HISTONES TO ALLOW FOR HERITABLE GENE REGULATION WITHOUT ALTERING THE NUCLEOTIDE SEQUENCE. MULTIPLE LINES OF EVIDENCE FROM RODENTS HAVE ESTABLISHED A ROLE FOR EPIGENETIC REMODELING IN REGULATING GENE TRANSCRIPTION IN RESPONSE TO AN ALTERED GESTATIONAL MILIEU. HOWEVER, TO DATE, IT IS UNKNOWN WHETHER VARIATIONS IN THE INTRAUTERINE ENVIRONMENT IN PRIMATES SIMILARLY INDUCE CHANGES IN KEY DETERMINANTS OF HEPATIC CHROMATIN STRUCTURE. WE HYPOTHESIZED THAT A MATERNAL HIGH-FAT DIET WOULD ALTER THE EPIGENOMIC PROFILE OF THE DEVELOPING OFFSPRING, WHICH WOULD RESULT IN ALTERATIONS IN FETAL GENE EXPRESSION. AGE- AND WEIGHT-MATCHED ADULT FEMALE JAPANESE MACAQUES WERE PLACED ON CONTROL (13% FAT) OR HIGH-FAT (35% FAT) BREEDER DIETS AND MATED ANNUALLY OVER A 4-YEAR INTERVAL. FETUSES IN SUCCESSIVE YEARS WERE DELIVERED NEAR TERM (E130 OF 167 DAYS) AND UNDERWENT NECROPSY WITH TISSUE HARVEST. FETAL HISTONES WERE ACID EXTRACTED FOR CHARACTERIZATION OF H3 MODIFICATION AND CHROMATIN IMMUNOPRECIPITATION (CHIP) WITH DIFFERENTIAL DISPLAY PCR; FETAL RNA, DNA, AND CYTOPLASMIC AND NUCLEAR PROTEIN EXTRACTS WERE SIMILARLY EXTRACTED FOR COMPARISON. CHRONIC CONSUMPTION OF A MATERNAL HIGH-FAT DIET RESULTS IN A THREEFOLD INCREASE IN FETAL LIVER TRIGLYCERIDES AND HISTOLOGIC CORRELATES OF NON-ALCOHOLIC FATTY LIVER DISEASE. THESE GROSS CHANGES IN THE FETAL LIVER ARE ACCOMPANIED BY A STATISTICALLY SIGNIFICANT HYPERACETYLATION OF FETAL HEPATIC TISSUE AT H3K14 (199.85+/-9.64 VS 88.8+/-45.4; P=0.038) WITH A TREND TOWARDS THE INCREASED ACETYLATION AT H3K9 (140.9+/-38.7 VS 46.6+/-6.53; P=0.097) AND AT H3K18 (69.0+/-3.54 VS 58.0+/-4.04; P=0.096). HOWEVER, EPIGENETIC MODIFICATIONS ON FETAL HEPATIC H3 ASSOCIATED WITH GENE REPRESSION WERE ABSENT OR SUBTLE (P>0.05). SUBSEQUENT CHARACTERIZATION OF KEY EPIGENETIC DETERMINANTS ASSOCIATED WITH H3 ACETYLATION MARKS REVEALED SIMILAR SIGNIFICANT ALTERATIONS IN ASSOCIATION WITH A HIGH-FAT MATERNAL DIET (E.G., RELATIVE FETAL HISTONE DEACETYLASE 1 (HDAC1) GENE EXPRESSION 0.61+/-0.25; P=0.011). CONSISTENT WITH OUR MRNA EXPRESSION PROFILE, FETAL NUCLEAR EXTRACTS FROM OFFSPRING OF HIGH-FAT DIET ANIMALS WERE OBSERVED TO BE SIGNIFICANTLY RELATIVELY DEPLETE OF HDAC1 PROTEIN (36.07+/-6.73 VS 83.18+/-7.51; P=0.006) AND IN VITRO HDAC FUNCTIONAL ACTIVITY (0.252+/-0.03 VS 0.698+/-0.02; P<0.001). WE EMPLOY THESE OBSERVATIONS IN CHIP DIFFERENTIAL DISPLAY PCR TO ATTEMPT TO IDENTIFY POTENTIAL FETAL GENES WHOSE EXPRESSION IS REPROGRAMED UNDER CONDITIONS OF A HIGH-FAT MATERNAL DIET. WE QUANTITATIVELY CONFIRM A MINIMUM OF A 40% ALTERATION IN THE EXPRESSION OF SEVERAL GENES OF INTEREST: GLUTAMIC PYRUVATE TRANSAMINASE (ALANINE AMINOTRANSFERASE) 2 (GPT2) (1.59+/-0.23-FOLD; P=0.08), DNAJA2 (1.36+/-0.21; P=0.09), AND RDH12 (1.88+/-0.15; P=0.01) ARE APPRECIABLY INCREASED IN FETAL HEPATIC TISSUE FROM MATERNAL CALORIC-DENSE DIET ANIMALS WHEN COMPARED WITH CONTROL WHILE NPAS2, A PERIPHERAL CIRCADIAN REGULATOR, WAS SIGNIFICANTLY DOWNMODULATED IN THE OFFSPRING OF HIGH-FAT DIET ANIMALS (0.66+/-0.08; P=0.03). IN THIS STUDY, WE SHOW THAT A CURRENT SIGNIFICANT IN UTERO EXPOSURE (CALORIC-DENSE HIGH-FAT MATERNAL DIET) INDUCES SITE-SPECIFIC ALTERATIONS IN FETAL HEPATIC H3 ACETYLATION. EMPLOYING CHIP, WE EXTEND THESE OBSERVATIONS TO LINK MODIFICATIONS OF H3 ACETYLATION WITH ALTERATIONS IN GENE-SPECIFIC EXPRESSION. THESE RESULTS SUGGEST THAT A CALORIC-DENSE MATERNAL DIET LEADING TO OBESITY EPIGENETICALLY ALTERS FETAL CHROMATIN STRUCTURE IN PRIMATES VIA COVALENT MODIFICATIONS OF HISTONES AND HENCE LENDS A MOLECULAR BASIS TO THE FETAL ORIGINS OF ADULT DISEASE HYPOTHESIS.	2008	

19 1609  30 DNA METHYLATION-INDEPENDENT GROWTH RESTRICTION AND ALTERED DEVELOPMENTAL PROGRAMMING IN A MOUSE MODEL OF PRECONCEPTION MALE ALCOHOL EXPOSURE. THE PRECONCEPTION ENVIRONMENT IS A SIGNIFICANT MODIFIER OF DYSGENESIS AND THE DEVELOPMENT OF ENVIRONMENTALLY-INDUCED DISEASE. TO DATE, FETAL ALCOHOL SPECTRUM DISORDERS (FASDS) HAVE BEEN EXCLUSIVELY ASSOCIATED WITH MATERNAL EXPOSURES, YET EMERGING EVIDENCE SUGGESTS MALE-INHERITED ALTERATIONS IN THE DEVELOPMENTAL PROGRAM OF SPERM MAY BE RELEVANT TO THE GROWTH-RESTRICTION PHENOTYPES OF THIS CONDITION. USING A MOUSE MODEL OF VOLUNTARY CONSUMPTION, WE FIND CHRONIC PRECONCEPTION MALE ETHANOL EXPOSURE ASSOCIATES WITH FETAL GROWTH RESTRICTION, DECREASED PLACENTAL EFFICIENCY, ABNORMALITIES IN CHOLESTEROL TRAFFICKING, SEX-SPECIFIC ALTERATIONS IN THE GENETIC PATHWAYS REGULATING HEPATIC FIBROSIS, AND DISRUPTIONS IN THE REGULATION OF IMPRINTED GENES. ALTERATIONS IN THE DNA METHYLATION PROFILES OF IMPRINTED LOCI HAVE BEEN IDENTIFIED IN CLINICAL STUDIES OF ALCOHOLIC SPERM, SUGGESTING THE LEGACY OF PATERNAL DRINKING MAY TRANSMIT VIA HERITABLE DISRUPTIONS IN THE REGULATION OF IMPRINTED GENES. HOWEVER, THE CAPACITY OF SPERM-INHERITED CHANGES IN DNA METHYLATION TO BROADLY TRANSMIT ENVIRONMENTALLY-INDUCED PHENOTYPES REMAINS UNCONFIRMED. USING BISULPHITE MUTAGENESIS AND SECOND-GENERATION DEEP SEQUENCING, WE FIND NO EVIDENCE TO SUGGEST THAT THESE PHENOTYPES OR ANY OF THE ASSOCIATED TRANSCRIPTIONAL CHANGES ARE LINKED TO ALTERATIONS IN THE SPERM-INHERITED DNA METHYLATION PROFILE. THESE OBSERVATIONS ARE CONSISTENT WITH RECENT STUDIES EXAMINING THE MALE TRANSMISSION OF DIET-INDUCED PHENOTYPES AND EMPHASIZE THE IMPORTANCE OF EPIGENETIC MECHANISMS OF PATERNAL INHERITANCE BEYOND DNA METHYLATION. THIS STUDY CHALLENGES THE SINGULAR IMPORTANCE OF MATERNAL ALCOHOL EXPOSURES AND SUGGESTS PATERNAL ALCOHOL ABUSE IS A SIGNIFICANT, YET OVERLOOKED EPIDEMIOLOGICAL FACTOR COMPLICIT IN THE GENESIS OF ALCOHOL-INDUCED GROWTH DEFECTS, AND MAY PROVIDE MECHANISTIC INSIGHT INTO THE FAILURE OF FASD CHILDREN TO THRIVE POSTNATALLY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20  218  26 ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL TOTAL CHANGES IN PLACENTAL EPIGENETIC MODIFICATIONS. PREECLAMPSIA IS A COMMON OBSTETRICAL COMPLICATION, HALLMARKED BY NEW-ONSET HYPERTENSION. BELIEVED TO RESULT FROM PLACENTAL INSUFFICIENCY AND CHRONIC PLACENTAL ISCHEMIA, THE SYMPTOMS OF PREECLAMPSIA ARE CAUSED BY RELEASE OF PATHOGENIC FACTORS FROM THE PLACENTA ITSELF, ALTHOUGH THE MECHANISMS OF THEIR REGULATION ARE IN MANY CASES UNKNOWN. ONE POTENTIAL MECHANISM IS THROUGH CHANGES IN PLACENTAL EPIGENETIC CHROMATIN MODIFICATIONS, PARTICULARLY HISTONE ACETYLATION AND DNA METHYLATION. HERE, WE DETERMINED THE EFFECTS OF CHRONIC ISCHEMIA ON GLOBAL EPIGENETIC MODIFICATIONS IN THE RODENT PLACENTA IN VIVO AND ACUTE HYPOXIA IN BEWO PLACENTAL TROPHOBLAST CELLS IN VITRO. PLACENTAL INSUFFICIENCY VIA UTERINE ARTERY RESTRICTION INCREASED MATERNAL BLOOD PRESSURE AND FETAL DEMISE WHILE DECREASING PLACENTAL AND FETAL MASS. GLOBAL PLACENTAL HISTONE H3 ACETYLATION LEVELS WERE SIGNIFICANTLY DECREASED AT H3 K9, K14, K18, K27, AND K56. INTERESTINGLY, WHEN BEWO-IMMORTALIZED PLACENTAL TROPHOBLAST CELLS WERE CULTURED IN OXYGEN CONCENTRATIONS MIMICKING HEALTHY AND ISCHEMIC PLACENTAS, THERE WAS A SIGNIFICANT INCREASE IN ACETYLATED AT K9, K18, K27, AND K56. THIS WAS ASSOCIATED WITH A SMALL BUT SIGNIFICANT DECREASE IN PLACENTAL ACETYL-COA, SUGGESTING DEPLETION IN THE SOURCE OF ACETYL GROUP DONORS. FINALLY, WHILE GLOBAL METHYLATION OF CYTOSINE FROM PLACENTAL DNA WAS LOW IN BOTH GROUPS OF ANIMALS (<1%), THERE WAS APPROXIMATELY 50% INCREASE IN 5-MC IN RESPONSE TO CHRONIC ISCHEMIA. THIS SUGGESTS ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL GLOBAL CHANGES IN HISTONE ACETYLATION IN THE PLACENTA AND THAT CHRONICALLY ALTERED METABOLIC PROFILES COULD AFFECT HISTONE ACETYLATION IN THE PLACENTA, THEREBY REGULATING PRODUCTION OF PATHOGENIC FACTORS FROM THE PLACENTA DURING PREECLAMPSIA.	2019