1 1980 133 EPIGENETIC ALTERATIONS IN CYTOCHROME P450 OXIDOREDUCTASE (POR) IN SPERM OF RATS EXPOSED TO TETRAHYDROCANNABINOL (THC). AS MARIJUANA LEGALIZATION IS INCREASING, RESEARCH REGARDING POSSIBLE LONG-TERM RISKS FOR USERS AND THEIR OFFSPRING IS NEEDED. LITTLE DATA EXISTS ON EFFECTS OF PATERNAL TETRAHYDROCANNABINOL (THC) EXPOSURE PRIOR TO REPRODUCTION. THIS STUDY DETERMINED IF CHRONIC THC EXPOSURE ALTERS SPERM DNA METHYLATION (DNAM) AND IF SUCH EFFECTS ARE INTERGENERATIONALLY TRANSMITTED. ADULT MALE RATS UNDERWENT ORAL GAVAGE WITH THC OR VEHICLE CONTROL. DIFFERENTIALLY METHYLATED (DM) LOCI IN MOTILE SPERM WERE IDENTIFIED USING REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS). ANOTHER COHORT WAS INJECTED WITH VEHICLE OR THC, AND SPERM DNAM WAS ANALYZED. FINALLY, THC-EXPOSED AND CONTROL ADULT MALE RATS WERE MATED WITH THC-NAIVE FEMALES. DNAM LEVELS OF TARGET GENES IN BRAIN TISSUES OF THE OFFSPRING WERE DETERMINED BY PYROSEQUENCING. RRBS IDENTIFIED 2,940 DM CPGS MAPPING TO 627 GENES. SIGNIFICANT HYPERMETHYLATION WAS CONFIRMED (P < 0.05) FOLLOWING ORAL THC ADMINISTRATION FOR CYTOCHROME P450 OXIDOREDUCTASE (POR), INVOLVED IN TOXIN PROCESSING AND DISORDERS OF SEXUAL DEVELOPMENT. POR HYPERMETHYLATION WAS NOT OBSERVED AFTER THC INJECTION OR IN THE SUBSEQUENT GENERATION. THESE RESULTS SUPPORT THAT THC ALTERS DNAM IN SPERM AND THAT ROUTE OF EXPOSURE CAN HAVE DIFFERENTIAL EFFECTS. ALTHOUGH WE DID NOT OBSERVE EVIDENCE OF INTERGENERATIONAL TRANSMISSION OF THE DNAM CHANGE, LARGER STUDIES ARE REQUIRED TO DEFINITIVELY EXCLUDE THIS POSSIBILITY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  909  40 CHRONIC EXPOSURE TO ETHANOL IN MALE MICE MAY BE ASSOCIATED WITH HEARING LOSS IN OFFSPRING. ALTHOUGH PATERNAL ETHANOL (ETOH) ABUSE HAS BEEN SHOWN TO AFFECT THE GROWTH AND BEHAVIOR OF OFFSPRING, THE EXACT MOLECULAR AND MECHANISTIC BASIS REMAINS LARGELY UNCLEAR. METHYLATION ALTERATIONS IN IMPRINTED GENES MAY BE RELATED TO WELL-DOCUMENTED TERATOGENIC EFFECTS OF ETHANOL. HERE WE SHOW THAT CHRONIC PATERNAL ETHANOL EXPOSURE INCREASES THE SUSCEPTIBILITY TO ABNORMAL BEHAVIOR IN OFFSPRING THROUGH MALE GAME EPIGENETIC ALTERATION. IN OUR STUDY, DIFFERENT DOSES OF ETHANOL (0, 1.1, 3.3 G KG-1 ) WERE ADMINISTERED INTRA-GASTRICALLY TO MALE MICE AND DECREASED SPERM MOTILITY WAS FOUND IN THE HIGHEST ETHANOL-EXPOSED GROUP COMPARED WITH THE CONTROLS. DATA ALSO SHOWED A DOSE-DEPENDENT INCREASE IN DEAF MICE OF THE PATERNALLY ETHANOL-EXPOSED GROUPS. THE METHYLATION OF H19, PEG3, NDN AND SNRPN WAS ASSESSED IN PATERNAL SPERMATOZOA AND IN THE CEREBRAL CORTICES OF DEAF MICE. ETOH AFFECTED METHYLATION OF PEG3 (CPG 3, 7 AND 9) IN PATERNAL SPERMATOZOA AND IN THE CEREBRAL CORTICES OF DEAF MICE, BUT THE LEVEL OF MRNA EXPRESSION DID NOT CHANGE, SUGGESTING THAT OTHER GENE REGULATION MAY BE INVOLVED IN THESE PROCESSES. OVERALL, CHRONIC PATERNAL ETHANOL EXPOSURE COULD ALTER THE METHYLATION OF IMPRINTED GENES IN SIRE SPERMATOZOA THAT COULD ALSO BE PASSED ON TO OFFSPRING, GIVING RISE TO DEVELOPMENTAL DISORDERS. OUR RESULTS PROVIDE POSSIBLE EPIGENETIC EVIDENCE FOR A PATERNAL ETHANOL EXPOSURE CONTRIBUTION TO FETAL ALCOHOL SYNDROME (FAS).	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3 1418  41 DIFFERENCES IN DNA METHYLATION REPROGRAMMING UNDERLIE THE SEXUAL DIMORPHISM OF BEHAVIORAL DISORDER CAUSED BY PRENATAL STRESS IN RATS. PRENATAL STRESS (PS) CAN LEAD TO NEUROENDOCRINE AND EMOTIONAL DISORDERS LATER IN ADOLESCENCE. SEXUAL DIMORPHISM IN THESE NEURODEVELOPMENTAL OUTCOMES HAVE BEEN OBSERVED; HOWEVER, THE UNDERLYING MECHANISMS ARE NOT FULLY UNDERSTOOD. TO ADDRESS THIS ISSUE, WE INVESTIGATED WHETHER THERE ARE SEX DIFFERENCES IN EPIGENETIC REPROGRAMMING IN RATS EXPOSED TO PS. PREGNANT FEMALE RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS FROM GESTATIONAL DAY (G)12 TO G18. FROM POSTNATAL DAY (P)38 TO P45, SUBGROUPS OF OFFSPRING INCLUDING BOTH MALES AND FEMALES WERE SUBJECTED TO BEHAVIORAL TESTING AND BRAIN TISSUE SPECIMENS WERE ANALYZED BY DNA PYROSEQUENCING, WESTERN BLOTTING, AND GOLGI STAINING TO ASSESS CHANGES IN METHYLATION PATTERN OF GLUCOCORTICOID RECEPTOR (GR) GENE, EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) AND DNA DEMETHYLASE, AND DENDRITE MORPHOLOGY, RESPECTIVELY. THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE WAS ADMINISTERED TO RATS PRIOR TO PS TO FURTHER EVALUATE THE ROLE OF METHYLATION IN THE SEXUALLY DIMORPHIC EFFECTS OF PS. THE RESULTS SHOWED THAT PS INCREASED ANXIETY-LIKE BEHAVIOR IN OFFSPRING, ESPECIALLY IN FEMALES, WHILE DEPRESSION-LIKE BEHAVIOR WAS INCREASED IN MALE OFFSPRING COMPARED TO CONTROL LITTERMATES. THE METHYLATION PATTERN IN THE PROMOTER REGION OF THE GR GENE DIFFERED BETWEEN MALES AND FEMALES. SEX-SPECIFIC CHANGES IN THE EXPRESSION OF DNMTS (DNMT1 AND DNMT3A) AND DNA DEMETHYLASE (TET METHYLCYTOSINE DIOXYGENASE 2) WERE ALSO OBSERVED. INTERESTINGLY, DECITABINE ALLEVIATED THE BEHAVIORAL DISORDER CAUSED BY PS AND RESTORED DENDRITE DENSITY AND MORPHOLOGY IN FEMALE BUT NOT MALE RATS. THESE FINDINGS SUGGEST THAT DIFFERENT CHANGE PATTERNS OF DNMT AND DEMETHYLASE IN THE TWO SEXES AFTER PS ARE RESPONSIBLE FOR THE SEXUALLY DIMORPHISM, WHICH COULD HAVE IMPLICATIONS FOR THE CLINICAL MANAGEMENT OF STRESS-RELATED DISORDERS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4 1820  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5 3991  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6 1579  37 DNA METHYLATION PROFILE OF LIVER OF MICE CONCEIVED BY IN VITRO FERTILIZATION. OFFSPRING GENERATED BY IN VITRO FERTILIZATION (IVF) ARE BELIEVED TO BE HEALTHY BUT DISPLAY A POSSIBLE PREDISPOSITION TO CHRONIC DISEASES, LIKE HYPERTENSION AND GLUCOSE INTOLERANCE. SINCE EPIGENETIC CHANGES ARE BELIEVED TO UNDERLIE SUCH PHENOTYPE, THIS STUDY AIMED AT DESCRIBING GLOBAL DNA METHYLATION CHANGES IN THE LIVER OF ADULT MICE GENERATED BY NATURAL MATING (FB GROUP) OR BY IVF. EMBRYOS WERE GENERATED BY IVF OR NATURAL MATING. AT 30 WEEKS OF AGE, MICE WERE SACRIFICED. THE LIVER WAS REMOVED, AND GLOBAL DNA METHYLATION WAS ASSESSED USING WHOLE-GENOME BISULFITE SEQUENCING (WGBS). GENOMIC REGIONS FOR ENRICHMENT ANALYSIS TOOL (GREAT) AND G:PROFILERBETA WERE USED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) AND FOR FUNCTIONAL ENRICHMENT ANALYSIS. OVERREPRESENTED GENE ONTOLOGY TERMS WERE SUMMARIZED WITH REVIGO, WHILE CANONICAL PATHWAYS (CPS) WERE IDENTIFIED WITH INGENUITY(R) PATHWAY ANALYSIS. OVERALL, 2692 DMRS (4.91%) WERE DIFFERENT BETWEEN THE GROUPS. THE MAJORITY OF DMRS (84.92%) WERE HYPOMETHYLATED IN THE IVF GROUP. SURPRISINGLY, ONLY 0.16% OF CPG ISLANDS WERE DIFFERENTIALLY METHYLATED AND ONLY A FEW DMRS WERE LOCATED ON KNOWN GENE PROMOTERS (N = 283) OR ENHANCERS (N = 190). NOTABLY, THE LONG-INTERSPERSED ELEMENT (LINE), SHORT-INTERSPERSED ELEMENT (SINE), AND LONG TERMINAL REPEAT (LTR1) TRANSPOSABLE ELEMENTS SHOWED REDUCED METHYLATION (P < 0.05) IN IVF LIVERS. CELLULAR METABOLIC PROCESS, HEPATIC FIBROSIS, AND INSULIN RECEPTOR SIGNALING WERE SOME OF THE PRINCIPAL BIOLOGICAL PROCESSES AND CPS MODIFIED BY IVF. IN SUMMARY, IVF MODIFIES THE DNA METHYLATION SIGNATURE IN THE ADULT LIVER, RESULTING IN HYPOMETHYLATION OF GENES INVOLVED IN METABOLISM AND GENE TRANSCRIPTION REGULATION. THESE FINDINGS MAY SHED LIGHT ON THE MECHANISMS UNDERLYING THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7 1537  30 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
8 6551  50 TRANSGENERATIONAL BLUNTING OF MORPHINE-INDUCED CORTICOSTERONE SECRETION IS ASSOCIATED WITH DYSREGULATED GENE EXPRESSION IN MALE OFFSPRING. A NUMBER OF PARENTAL EXPERIENCES, EVEN WHEN OCCURRING PRIOR TO CONCEPTION, HAVE BEEN SHOWN TO INDUCE TRANSGENERATIONAL EFFECTS BEYOND THE FIRST GENERATION. IN THE CASE OF EXPOSURE TO DRUGS OF ABUSE, STUDIES IN RODENTS SUGGEST THAT OFFSPRING DEMONSTRATE SIGNIFICANT DIFFERENCES IN HOW THEY RESPOND TO THE DRUG TO WHICH THEIR PARENT WAS EXPOSED. WE HAVE PREVIOUSLY OBSERVED SIGNIFICANT ALTERATIONS IN MORPHINE ANALGESIA, CONDITIONED PLACE PREFERENCE AND SELF-ADMINISTRATION IN THE OFFSPRING OF FEMALES EXPOSED TO MORPHINE DURING ADOLESCENT DEVELOPMENT. IN ADDITION TO EFFECTS ON PAIN PERCEPTION AND REWARD, MORPHINE ALSO MODULATES THE HYPOTHALAMIC PITUITARY ADRENAL (HPA) AXIS. THE PURPOSE OF THE CURRENT STUDY WAS TO DETERMINE WHETHER FEMALE ADOLESCENT MORPHINE EXPOSURE RESULTS IN TRANSGENERATIONAL EFFECTS ON REGULATION OF THE HPA AXIS BY MORPHINE IN FUTURE GENERATIONS. ADOLESCENT MORPHINE WAS ADMINISTERED TO FEMALE SPRAGUE DAWLEY RATS USING A 10 DAY, ESCALATING DOSE REGIMEN OF MORPHINE (5-25 MG/KG; FROM 30 TO 39 DAYS OF AGE). CONTROL ANIMALS RECEIVED SALINE. BOTH SALINE AND MORPHINE EXPOSED FEMALES (SAL-F0 AND MOR-F0, RESPECTIVELY) WERE MATED WITH DRUG NAIVE MALES BEGINNING AT LEAST 3 WEEKS AFTER THE FINAL INJECTION. PLASMA CORTICOSTERONE LEVELS WERE MEASURED IN MALE AND FEMALE OFFSPRING (F1) DURING ADULTHOOD FOLLOWING 0, 0.1, OR 10 MG/KG MORPHINE. IN ADDITION, EXPRESSION OF CORTICOTROPIN RELEASING HORMONE (CRH) AND MU OPIOID RECEPTOR (OPRM1) IN THE PARAVENTRICULAR NUCLEUS (PVN) WERE MEASURED USING QUANTITATIVE PCR. MOR-F1 MALES, BUT NOT FEMALES, HAD BLUNTED MORPHINE-INDUCED CORTICOSTERONE SECRETION. THIS EFFECT WAS SPECIFIC TO OFFSPRING FROM FEMALES EXPOSED TO MORPHINE DURING ADOLESCENCE AS THOSE EXPOSED DURING ADULTHOOD PRODUCED OFFSPRING IN WHICH THE EFFECT WAS ABSENT. IN ADDITION, MOR-F1 MALES HAD SIGNIFICANTLY LOWER LEVELS OF PVN CRH FOLLOWING SALINE. THESE EFFECTS WERE NOT DRIVEN BY PVN OPRM1 IN THE F1 MALES AS THERE WERE NO DIFFERENCES BASED ON MATERNAL ADOLESCENT EXPOSURE. TO DETERMINE THE PERSISTENCE OF THE BLUNTED MORPHINE-INDUCED CORTICOSTERONE EFFECT, SAL-F2 AND MOR-F2 MALES WERE EXAMINED. BLUNTED MORPHINE-INDUCED CORTICOSTERONE SECRETION EXTENDED INTO THE MOR-F2 GENERATION, AS WELL AS EFFECTS ON CRH. IN ADDITION, THERE WAS ADDITIONAL DYSREGULATION OFOPRM1 EXPRESSION IN THE PVN IN MOR-F2 COMPARED WITH SAL-F2 MALES. THESE FINDINGS SUGGEST THAT SEX-SPECIFIC ALTERATIONS IN OPIOID-MEDIATED REGULATION OF THE HPA AXIS ARE TRANSGENERATIONALLY TRANSMITTED FOR AT LEAST TWO GENERATIONS FOLLOWING FEMALE ADOLESCENT MORPHINE EXPOSURE. THESE EFFECTS MAY PLAY A ROLE IN THE PREVIOUSLY OBSERVED CHANGES IN MORPHINE ANALGESIA AND REWARD-RELATED BEHAVIORS OBSERVED IN THIS PHENOTYPE. IN ADDITION, ALTERATIONS IN HPA FUNCTIONING SUCH AS THESE MAY PLAY A BROAD ROLE IN TRANSGENERATIONAL EPIGENETIC TRANSMISSION.	2018	

9 4528  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
10 3652  39 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11 5628  39 SEMEN ABNORMALITIES, SPERM DNA DAMAGE AND GLOBAL HYPERMETHYLATION IN HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION. BACKGROUND: CYTOGENETIC STUDIES HAVE DEMONSTRATED THAT LOW LEVELS OF CHRONIC RADIATION EXPOSURE CAN POTENTIALLY INCREASE THE FREQUENCY OF CHROMOSOMAL ABERRATIONS AND ANEUPLOIDY IN SOMATIC CELLS. EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION BEAR AN INCREASED RISK OF HEMATOLOGICAL MALIGNANCIES. OBJECTIVES: TO FIND THE INFLUENCE OF OCCUPATIONAL RADIATION EXPOSURE ON SEMEN CHARACTERISTICS, INCLUDING GENETIC AND EPIGENETIC INTEGRITY OF SPERMATOZOA IN A CHRONICALLY EXPOSED POPULATION. METHODS: THIS CROSS SECTIONAL STUDY INCLUDED 134 MALE VOLUNTEERS OF WHICH 83 WERE OCCUPATIONALLY EXPOSED TO IONIZING RADIATION AND 51 WERE NON-EXPOSED CONTROL SUBJECTS. SEMEN CHARACTERISTICS, SPERM DNA FRAGMENTATION, ANEUPLOIDY AND INCIDENCE OF GLOBAL HYPERMETHYLATION IN THE SPERMATOZOA WERE DETERMINED AND COMPARED BETWEEN THE NON-EXPOSED AND THE EXPOSED GROUP. RESULTS: DIRECT COMPARISON OF THE SEMEN CHARACTERISTICS BETWEEN THE NON-EXPOSED AND THE EXPOSED POPULATION REVEALED SIGNIFICANT DIFFERENCES IN MOTILITY CHARACTERISTICS, VIABILITY, AND MORPHOLOGICAL ABNORMALITIES (P<0.05-0.0001). ALTHOUGH, THE LEVEL OF SPERM DNA FRAGMENTATION WAS SIGNIFICANTLY HIGHER IN THE EXPOSED GROUP AS COMPARED TO THE NON-EXPOSED GROUP (P<0.05-0.0001), THE INCIDENCE OF SPERM ANEUPLOIDY WAS NOT STATISTICALLY DIFFERENT BETWEEN THE TWO GROUPS. HOWEVER, A SIGNIFICANT NUMBER OF HYPERMETHYLATED SPERMATOZOA WERE OBSERVED IN THE EXPOSED GROUP IN COMPARISON TO NON-EXPOSED GROUP (P<0.05). CONCLUSIONS: WE PROVIDE THE FIRST EVIDENCE ON THE DETRIMENTAL EFFECTS OF OCCUPATIONAL RADIATION EXPOSURE ON FUNCTIONAL, GENETIC AND EPIGENETIC INTEGRITY OF SPERM IN HEALTH WORKERS. HOWEVER, FURTHER STUDIES ARE REQUIRED TO CONFIRM THE POTENTIAL DETRIMENTAL EFFECTS OF IONIZING RADIATION IN THESE SUBJECTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12 5722  33 SISTER CHROMATID EXCHANGE AND PROLIFERATIVE RATE INDEX IN THE LONGITUDINAL RISK ASSESSMENT OF OCCUPATIONAL EXPOSURE TO PESTICIDES. AT PRESENT, THERE ARE MORE THAN 1,000 CHEMICALS CLASSIFIED AS PESTICIDES AND MANY REPORTS HAVE SHOWN THAT SOME OF THEM HAVE GENOTOXIC PROPERTIES. IN THE PRESENT LONGITUDINAL STUDY, POSSIBLE GENETIC DAMAGE ON A POPULATION OF WORKERS OCCUPATIONALLY EXPOSED TO A MIXTURE OF PESTICIDES BY USING SISTER CHROMATID EXCHANGE (SCE) ANALYSIS HAS BEEN EVALUATED. AS AN ADDITIONAL CYTOGENETIC PARAMETER, THE PROPORTION OF LYMPHOCYTES THAT UNDERGO ONE, TWO OR THREE CELL DIVISIONS AS WELL AS PROLIFERATIVE RATE INDEX HAVE BEEN DETERMINED. THIS STUDY WAS PERFORMED ON THE EXPOSED GROUP OF WORKERS EMPLOYED IN PESTICIDE PRODUCTION, SIMULTANEOUSLY EXPOSED TO A COMPLEX MIXTURE OF PESTICIDES (ATRAZINE, ALACHLOR, CYANAZINE, 2,4-DICHLOROPHENOXYACETIC ACID, AND MALATHION). THE BLOOD SAMPLES OF THE EXPOSED SUBJECTS WERE COLLECTED IN THREE DIFFERENT PERIODS: BEFORE THE BEGINNING OF THE NEW PESTICIDE PRODUCTION PERIOD, AFTER 8 MONTHS OF EVERYDAY WORK IN THE PESTICIDE PRODUCTION, AND 8 MONTHS AFTER THE REMOVAL OF SUBJECTS OUT OF THE PRODUCTION. IN ALL THREE SAMPLINGS, THE MEAN VALUE OF SCE AND NUMBER OF CELLS WITH HIGH SISTER CHROMATID EXCHANGE FREQUENCY (HFC) IN THE EXPOSED GROUP WAS SIGNIFICANTLY HIGHER IN THE COMPARISON WITH THE CONTROL GROUP. THERE WERE NO DIFFERENCES IN THE PROLIFERATIVE RATE INDEX (PRI) BETWEEN THE CONTROL AND EXPOSED GROUP, REGARDLESS OF THE SAMPLING PERIOD. IN BOTH GROUPS EXAMINED, THE MAJORITY OF LYMPHOCYTES WERE FOUND IN THE SECOND CELL DIVISION, FOLLOWING CULTIVATION. THESE RESULTS SUGGEST THAT THE INCREASE IN THE NUMBER OF SCE FOUND IN THE EXPOSED SUBJECTS IS NOT THE RESULT OF EITHER CYTOTOXIC OR EPIGENETIC ACTION OF PESTICIDE MIXTURE, BUT CHRONIC OCCUPATIONAL EXPOSURE TO MIXTURE OF PESTICIDES.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  891  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14 1503  29 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15 1795  31 EFFECT OF DIFFERENT COMBINATION OF MATERNAL AND POSTNATAL DIET ON ADIPOSE TISSUE MORPHOLOGY IN MALE RAT OFFSPRING. PURPOSE: ADIPOSE TISSUE EXPANSION CAN OCCUR THROUGH SEVERAL DIFFERENT WAYS AND, UNDER CERTAIN CONDITIONS, CAN BE CONNECTED WITH CHRONIC INFLAMMATION. TNF-ALPHA IS ONE OF THE IMPORTANT CYTOKINES INVOLVED IN THIS PROCESS. PROLONGED INFLAMMATION IN OBESITY CAN LEAD TO OBESITY-RELATED INSULIN RESISTANCE AND TISSUE DYSFUNCTION. THE AIM OF OUR STUDY WAS TO INVESTIGATE HOW DIFFERENT COMBINATION OF MATERNAL AND POSTNATAL DIET AFFECTS OFFSPRING ADIPOSE TISSUE MORPHOLOGY AND ADIPOSE TISSUE TNF-ALPHA EXPRESSION. METHODS: TEN FEMALE SPRAGUE DAWLEY RATS, 9 WEEKS OLD, WERE RANDOMLY DIVIDED INTO TWO GROUPS AND FED EITHER STANDARD LABORATORY CHOW OR FOOD RICH IN SATURATED FATTY ACIDS DURING 6 WEEKS AND THEN MATED WITH THE SAME MALE RAT. AFTER BIRTH AND LACTATION MALE RAT OFFSPRING FROM BOTH GROUPS WERE DIVIDED INTO FOUR SUBGROUPS DEPENDING ON THE DIET THEY WERE FED UNTIL 22 WEEKS OLD. SAMPLES OF WHITE ADIPOSE TISSUE WERE TAKEN FROM THE SUBCUTANEOUS, EPIDIDYMAL, AND PERIRENAL FAT PAD. ON TISSUE SECTIONS, HISTOMORPHOMETRIC ANALYSIS WAS CONDUCTED USING CELLPROFILER PROGRAM V 2.1.1, AND IMMUNOHISTOCHEMICAL STAINING FOR TNF-ALPHA WAS PERFORMED. RESULTS: GREATER MEAN SURFACE AREA OF SUBCUTANEOUS AND EPIDIDYMAL ADIPOCYTES WAS FOUND IN GROUPS OF MALE RAT OFFSPRING WITH ALTERED DIET. IN PERIRENAL ADIPOSE TISSUE, THE HIGHEST NUMBER OF ADIPOCYTES WAS MEASURED IN THE GROUP WHERE BOTH MOTHER AND OFFSPRING WERE FED A HIGH-FAT DIET. ADIPOCYTE STAINING INTENSITY FOR TNF-ALPHA DID NOT DIFFER SIGNIFICANTLY BETWEEN THE GROUPS. CONCLUSIONS: TOGETHER WITH OUR PREVIOUSLY PUBLISHED DATA, OUR RESULTS LEAD TO THE CONCLUSION THAT ALTERATION OF POSTNATAL DIET CAN LEAD TO TNF-ALPHA AND ADIPOCYTE MORPHOLOGY CHANGES.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16 3077  36 GENOME-WIDE METHYL-SEQ ANALYSIS OF BLOOD-BRAIN TARGETS OF GLUCOCORTICOID EXPOSURE. CHRONIC EXPOSURE TO GLUCOCORTICOIDS (GCS) CAN LEAD TO PSYCHIATRIC COMPLICATIONS THROUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION (DNAM). WE SOUGHT TO DETERMINE WHETHER EPIGENETIC CHANGES IN A PERIPHERAL TISSUE CAN SERVE AS A SURROGATE FOR THOSE IN A RELATIVELY INACCESSIBLE TISSUE SUCH AS THE BRAIN. DNA EXTRACTED FROM THE HIPPOCAMPUS AND BLOOD OF MICE TREATED WITH GCS OR VEHICLE SOLUTION WAS ASSAYED USING A GENOME-WIDE DNAM PLATFORM (METHYL-SEQ) TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) INDUCED BY GC TREATMENT. WE OBSERVED THAT APPROXIMATELY 70% OF THE DMRS IN BOTH TISSUES LOST METHYLATION FOLLOWING GC TREATMENT. OF THE 3,095 DMRS THAT MAPPED TO THE SAME GENES IN BOTH TISSUES, 1,853 DMRS UNDERWENT DNAM CHANGES IN THE SAME DIRECTION. INTERESTINGLY, ONLY 209 DMRS (<7%) OVERLAPPED IN GENOMIC COORDINATES BETWEEN THE 2 TISSUES, SUGGESTING TISSUE-SPECIFIC DIFFERENCES IN GC-TARGETED LOCI. PATHWAY ANALYSIS SHOWED THAT THE DMR-ASSOCIATED GENES WERE MEMBERS OF PATHWAYS INVOLVED IN METABOLISM, IMMUNE FUNCTION, AND NEURODEVELOPMENT. ALSO, CHANGES IN CELL TYPE COMPOSITION OF BLOOD AND BRAIN WERE EXAMINED BY FLUORESCENCE-ACTIVATED CELL SORTING. SEPARATION OF THE CORTEX INTO NEURONAL AND NON-NEURONAL FRACTIONS AND THE LEUKOCYTES INTO T-CELLS, B-CELLS, AND NEUTROPHILS SHOWED THAT GC-INDUCED METHYLATION CHANGES PRIMARILY OCCURRED IN NEURONS AND T-CELLS, WITH THE BLOOD TISSUE ALSO UNDERGOING A SHIFT IN THE PROPORTION OF CONSTITUENT CELL TYPES WHILE THE PROPORTION OF NEURONS AND GLIA IN THE BRAIN REMAINED STABLE. FROM THE CURRENT PILOT STUDY, WE FOUND THAT DESPITE TISSUE-SPECIFIC EPIGENETIC CHANGES AND CELLULAR HETEROGENEITY, BLOOD CAN SERVE AS A SURROGATE FOR GC-INDUCED CHANGES IN THE BRAIN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 3714  38 INHERITANCE OF SOCIAL DOMINANCE IS ASSOCIATED WITH GLOBAL SPERM DNA METHYLATION IN INBRED MALE MICE. DOMINANCE RELATIONSHIPS BETWEEN MALES AND THEIR ASSOCIATED TRAITS ARE USUALLY HERITABLE AND HAVE IMPLICATIONS FOR SEXUAL SELECTION IN ANIMALS. IN PARTICULAR, SOCIAL DOMINANCE AND ITS RELATED MALE PHEROMONES ARE HERITABLE IN INBRED MICE; THUS, WE WONDERED WHETHER EPIGENETIC CHANGES DUE TO ALTERED LEVELS OF DNA METHYLATION DETERMINE INHERITANCE. HERE, WE USED C57BL/6 MALE MICE TO ESTABLISH A SOCIAL DOMINANCE-SUBORDINATION RELATIONSHIP THROUGH CHRONIC DYADIC ENCOUNTERS, AND THIS RELATIONSHIP AND PHEROMONE COVARIATION OCCURRED IN THEIR OFFSPRING, INDICATIVE OF HERITABILITY. THROUGH TRANSCRIPTOME SEQUENCING AND WHOLE-GENOME DNA METHYLATION PROFILING OF THE SPERM OF BOTH GENERATIONS, WE FOUND THAT DIFFERENTIAL METHYLATION OF MANY GENES WAS INDUCED BY SOCIAL DOMINANCE-SUBORDINATION IN SIRES AND COULD BE PASSED ON TO THE OFFSPRING. THESE METHYLATED GENES WERE MAINLY RELATED TO GROWTH AND DEVELOPMENT PROCESSES, NEURODEVELOPMENT, AND CELLULAR TRANSPORTATION. THE EXPRESSION OF THE GENES WITH SIMILAR FUNCTIONS IN WHOLE-GENOME METHYLATION/BISULFITE SEQUENCING WAS ALSO DIFFERENTIATED BY SOCIAL DOMINANCE-SUBORDINATION, AS REVEALED BY RNA-SEQ. IN PARTICULAR, THE GENE DENND1A, WHICH REGULATES NEURAL SIGNALING, WAS DIFFERENTIALLY METHYLATED AND EXPRESSED IN THE SPERM AND MEDIAL PREFRONTAL CORTEX IN PAIRED MALES BEFORE AND AFTER DOMINANCE-SUBORDINATION ESTABLISHMENT, SUGGESTING THE POTENTIAL EPIGENETIC CONTROL AND INHERITANCE OF SOCIAL DOMINANCE-RELATED AGGRESSION. WE SUGGEST THAT SOCIAL DOMINANCE MIGHT BE PASSED ON TO MALE OFFSPRING THROUGH SPERM DNA METHYLATION AND THAT THE DIFFERENCES COULD POTENTIALLY AFFECT MALE COMPETITION IN OFFSPRING BY AFFECTING THE DEVELOPMENT OF THE NERVOUS SYSTEM.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
18 3914  32 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19 6794  35 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20 5188  39 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