1  2467 143 EPIGENETIC TOXICITY OF TRICHLOROETHYLENE: A SINGLE-MOLECULE PERSPECTIVE. THE VOLATILE, WATER SOLUBLE TRICHLOROETHYLENE (TCE) IS A HAZARDOUS INDUSTRIAL WASTE AND COULD LEAD TO VARIOUS HEALTH PROBLEMS, INCLUDING CANCER, NEUROPATHY, CARDIOVASCULAR DEFECTS, AND IMMUNE DISEASES. TOXICOLOGICAL STUDIES TAKING USE OF IN VITRO AND IN VIVO MODELS HAVE BEEN CONDUCTED TO UNDERSTAND THE BIOLOGICAL IMPACTS OF TCE AT THE GENETIC, TRANSCRIPTOMIC, METABOLOMIC, AND SIGNALING LEVELS. THE EPIGENETIC ABERRATIONS INDUCED BY TCE HAVE ALSO BEEN REPORTED IN A NUMBER OF MODEL ORGANISMS, WHILE A DETAILED MECHANISTIC ELUCIDATION IS LACKING. IN THIS STUDY WE UNCOVER AN UNREPORTED MECHANISM ACCOUNTING FOR THE EPIGENETIC TOXICITY DUE TO TCE EXPOSURE BY MONITORING THE SINGLE-MOLECULE DYNAMICS OF DNA METHYLTRANSFERASE 3A (DNMT3A) IN LIVING CELLS. TCE-INDUCED GLOBAL DNA HYPOMETHYLATION COULD BE PARTLY ATTRIBUTED TO THE DISRUPTED DNMT3A-DNA ASSOCIATION. BY ANALYZING THE COMPONENTS OF DETACHED DNMT3A, WE FOUND THAT THE DNMT3A OLIGOMERS (E.G., DIMER, TRIMER, AND HIGH-ORDER OLIGOMERS) DISSOCIATED FROM HETEROCHROMATIN IN A DOSE-DEPENDENT MANNER UPON EXPOSURE. THEREAFTER THE DIMINISHED DNA-BINDING AFFINITY OF DNMT3A RESULTED IN A SIGNIFICANT DECREASE IN 5-METHYLCYTOSINE (5MC) UNDER BOTH ACUTE HIGH-DOSAGE AND CHRONIC LOW-DOSAGE TCE EXPOSURE. THE RESULTING DNA DEMETHYLATION MIGHT ALSO BE CONTRIBUTED BY THE ELEVATED EXPRESSION OF TEN-ELEVEN-TRANSLOCATION (TET) ENZYMES AND REFORMED CYSTEINE CYCLE. BESIDES THE GLOBAL EFFECT, WE FURTHER IDENTIFIED THAT A GROUP OF HETEROCHROMATIN-LOCATED, CANCER-RELATED MICRORNAS (MIRNAS) EXPERIENCED PROMOTER DEMETHYLATION UPON TCE EXPOSURE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2   118  23 A SUBSET OF METHYLATED CPG SITES DIFFERENTIATE PSORIATIC FROM NORMAL SKIN. PSORIASIS IS A CHRONIC INFLAMMATORY IMMUNE-MEDIATED DISORDER AFFECTING THE SKIN AND OTHER ORGANS INCLUDING JOINTS. OVER 1,300 TRANSCRIPTS ARE ALTERED IN PSORIATIC INVOLVED SKIN COMPARED WITH NORMAL SKIN. HOWEVER, TO OUR KNOWLEDGE, GLOBAL EPIGENETIC PROFILING OF PSORIATIC SKIN IS PREVIOUSLY UNREPORTED. HERE, WE DESCRIBE A GENOME-WIDE STUDY OF ALTERED CPG METHYLATION IN PSORIATIC SKIN. WE DETERMINED THE METHYLATION LEVELS AT 27,578 CPG SITES IN SKIN SAMPLES FROM INDIVIDUALS WITH PSORIASIS (12 INVOLVED, 8 UNINVOLVED) AND 10 UNAFFECTED INDIVIDUALS. CPG METHYLATION OF INVOLVED SKIN DIFFERED FROM NORMAL SKIN AT 1,108 SITES. TWELVE MAPPED TO THE EPIDERMAL DIFFERENTIATION COMPLEX, UPSTREAM OR WITHIN GENES THAT ARE HIGHLY UPREGULATED IN PSORIASIS. HIERARCHICAL CLUSTERING OF 50 OF THE TOP DIFFERENTIALLY METHYLATED (DM) SITES SEPARATED PSORIATIC FROM NORMAL SKIN SAMPLES WITH UNINVOLVED SKIN EXHIBITING INTERMEDIATE METHYLATION. CPG SITES WHERE METHYLATION WAS CORRELATED WITH GENE EXPRESSION ARE REPORTED. SITES WITH INVERSE CORRELATIONS BETWEEN METHYLATION AND NEARBY GENE EXPRESSION INCLUDE THOSE OF KYNU, OAS2, S100A12, AND SERPINB3, WHOSE STRONG TRANSCRIPTIONAL UPREGULATION IS AN IMPORTANT DISCRIMINATOR OF PSORIASIS. PYROSEQUENCING OF BISULFITE-TREATED DNA FROM SKIN BIOPSIES AT THREE DM LOCI CONFIRMED EARLIER FINDINGS AND REVEALED REVERSION OF METHYLATION LEVELS TOWARD THE NON-PSORIATIC STATE AFTER 1 MONTH OF ANTI-TNF-ALPHA THERAPY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3   912  24 CHRONIC EXPOSURE TO WATER POLLUTANT TRICHLOROETHYLENE INCREASED EPIGENETIC DRIFT IN CD4(+) T CELLS. AIM: AUTOIMMUNE DISEASE AND CD4(+) T-CELL ALTERATIONS ARE INDUCED IN MICE EXPOSED TO THE WATER POLLUTANT TRICHLOROETHYLENE (TCE). WE EXAMINED HERE WHETHER TCE ALTERED GENE-SPECIFIC DNA METHYLATION IN CD4(+) T CELLS AS A POSSIBLE MECHANISM OF IMMUNOTOXICITY. MATERIALS & METHODS: NAIVE AND EFFECTOR/MEMORY CD4(+) T CELLS FROM MICE EXPOSED TO TCE (0.5 MG/ML IN DRINKING WATER) FOR 40 WEEKS WERE EXAMINED BY BISULFITE NEXT-GENERATION DNA SEQUENCING. RESULTS: A PROBABILISTIC MODEL CALCULATED FROM MULTIPLE GENES SHOWED THAT TCE DECREASED METHYLATION CONTROL IN CD4(+) T CELLS. DATA FROM INDIVIDUAL GENES FITTED TO A QUADRATIC REGRESSION MODEL SHOWED THAT TCE INCREASED GENE-SPECIFIC METHYLATION VARIANCE IN BOTH CD4 SUBSETS. CONCLUSION: TCE INCREASED EPIGENETIC DRIFT OF SPECIFIC CPG SITES IN CD4(+) T CELLS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4   406  23 ANALYSIS OF FIVE CHRONIC INFLAMMATORY DISEASES IDENTIFIES 27 NEW ASSOCIATIONS AND HIGHLIGHTS DISEASE-SPECIFIC PATTERNS AT SHARED LOCI. WE SIMULTANEOUSLY INVESTIGATED THE GENETIC LANDSCAPE OF ANKYLOSING SPONDYLITIS, CROHN'S DISEASE, PSORIASIS, PRIMARY SCLEROSING CHOLANGITIS AND ULCERATIVE COLITIS TO INVESTIGATE PLEIOTROPY AND THE RELATIONSHIP BETWEEN THESE CLINICALLY RELATED DISEASES. USING HIGH-DENSITY GENOTYPE DATA FROM MORE THAN 86,000 INDIVIDUALS OF EUROPEAN ANCESTRY, WE IDENTIFIED 244 INDEPENDENT MULTIDISEASE SIGNALS, INCLUDING 27 NEW GENOME-WIDE SIGNIFICANT SUSCEPTIBILITY LOCI AND 3 UNREPORTED SHARED RISK LOCI. COMPLEX PLEIOTROPY WAS SUPPORTED WHEN CONTRASTING MULTIDISEASE SIGNALS WITH EXPRESSION DATA SETS FROM HUMAN, RAT AND MOUSE TOGETHER WITH EPIGENETIC AND EXPRESSED ENHANCER PROFILES. THE COMORBIDITIES AMONG THE FIVE IMMUNE DISEASES WERE BEST EXPLAINED BY BIOLOGICAL PLEIOTROPY RATHER THAN HETEROGENEITY (A SUBGROUP OF CASES GENETICALLY IDENTICAL TO THOSE WITH ANOTHER DISEASE, POSSIBLY OWING TO DIAGNOSTIC MISCLASSIFICATION, MOLECULAR SUBTYPES OR EXCESSIVE COMORBIDITY). IN PARTICULAR, THE STRONG COMORBIDITY BETWEEN PRIMARY SCLEROSING CHOLANGITIS AND INFLAMMATORY BOWEL DISEASE IS LIKELY THE RESULT OF A UNIQUE DISEASE, WHICH IS GENETICALLY DISTINCT FROM CLASSICAL INFLAMMATORY BOWEL DISEASE PHENOTYPES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  1161  39 CONTINUOUS DEVELOPMENTAL AND EARLY LIFE TRICHLOROETHYLENE EXPOSURE PROMOTED DNA METHYLATION ALTERATIONS IN POLYCOMB PROTEIN BINDING SITES IN EFFECTOR/MEMORY CD4(+) T CELLS. TRICHLOROETHYLENE (TCE) IS AN INDUSTRIAL SOLVENT AND DRINKING WATER POLLUTANT ASSOCIATED WITH CD4(+) T CELL-MEDIATED AUTOIMMUNITY. IN OUR MOUSE MODEL, DISCONTINUATION OF TCE EXPOSURE DURING ADULTHOOD AFTER DEVELOPMENTAL EXPOSURE DID NOT PREVENT IMMUNOTOXICITY. TO DETERMINE WHETHER PERSISTENT EFFECTS WERE LINKED TO EPIGENETIC CHANGES WE CONDUCTED WHOLE GENOME REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TO EVALUATE METHYLATION OF CPG SITES IN AUTOSOMAL CHROMOSOMES IN ACTIVATED EFFECTOR/MEMORY CD4(+) T CELLS. FEMALE MRL+/+ MICE WERE EXPOSED TO VEHICLE CONTROL OR TCE IN THE DRINKING WATER FROM GESTATION UNTIL ~37 WEEKS OF AGE [POSTNATAL DAY (PND) 259]. IN A SUBSET OF MICE, TCE EXPOSURE WAS DISCONTINUED AT ~22 WEEKS OF AGE (PND 154). AT PND 259, RRBS ASSESSMENT REVEALED MORE GLOBAL METHYLATION CHANGES IN THE CONTINUOUS EXPOSURE GROUP VS. THE DISCONTINUOUS EXPOSURE GROUP. A MAJORITY OF THE DIFFERENTIALLY METHYLATED CPG REGIONS (DMRS) ACROSS PROMOTERS, ISLANDS, AND REGULATORY ELEMENTS WERE HYPERMETHYLATED (~90%). HOWEVER, CONTINUOUS DEVELOPMENTAL TCE EXPOSURE ALTERED THE METHYLATION OF 274 CPG SITES IN PROMOTERS AND CPG ISLANDS. IN CONTRAST, ONLY 4 CPG ISLAND REGIONS WERE DIFFERENTIALLY METHYLATED (HYPERMETHYLATED) IN THE DISCONTINUOUS GROUP. INTERESTINGLY, 2 OF THESE 4 SITES WERE ALSO HYPERMETHYLATED IN THE CONTINUOUS EXPOSURE GROUP, AND BOTH OF THESE ISLAND REGIONS ARE ASSOCIATED WITH LYSINE 27 ON HISTONE H3 (H3K27) INVOLVED IN POLYCOMB COMPLEX-DEPENDENT TRANSCRIPTIONAL REPRESSION VIA H3K27 TRI-METHYLATION. CPG SITES WERE OVERLAPPED WITH THE OPEN REGULATORY ANNOTATION DATABASE. UNLIKE THE DISCONTINUOUS GROUP, CONTINUOUS TCE TREATMENT RESULTED IN 129 DMRS INCLUDING 12 UNIQUE TRANSCRIPTION FACTORS AND REGULATORY ELEMENTS; 80% OF WHICH WERE ENRICHED FOR ONE OR MORE POLYCOMB GROUP (PCG) PROTEIN BINDING REGIONS (I.E., SUZ12, EZH2, JARID2, AND MTF2). PATHWAY ANALYSIS OF THE DMRS INDICATED THAT TCE PRIMARILY ALTERED THE METHYLATION OF GENES ASSOCIATED WITH REGULATION OF CELLULAR METABOLISM AND CELL SIGNALING. THE RESULTS DEMONSTRATED THAT CONTINUOUS DEVELOPMENTAL EXPOSURE TO TCE DIFFERENTIALLY METHYLATED BINDING SITES OF PCG PROTEINS IN EFFECTOR/MEMORY CD4(+) CELLS. THERE WERE MINIMAL YET POTENTIALLY BIOLOGICALLY SIGNIFICANT EFFECTS THAT OCCURRED WHEN EXPOSURE WAS DISCONTINUED. THESE RESULTS POINT TOWARD A NOVEL MECHANISM BY WHICH CHRONIC DEVELOPMENTAL TCE EXPOSURE MAY ALTER TERMINALLY DIFFERENTIATED CD4(+) T CELL FUNCTION IN ADULTHOOD.	2019	

6  5193  32 PRENATAL EXPOSURE TO ENVIRONMENTAL PRO-OXIDANTS INDUCES MITOCHONDRIA-MEDIATED EPIGENETIC CHANGES: A CROSS-SECTIONAL PILOT STUDY. MITOCHONDRIA PLAY A CENTRAL ROLE IN MAINTAINING CELLULAR AND METABOLIC HOMEOSTASIS DURING VITAL DEVELOPMENT CYCLES OF FOETAL GROWTH. OPTIMAL MITOCHONDRIAL FUNCTIONS ARE IMPORTANT NOT ONLY TO SUSTAIN ADEQUATE ENERGY PRODUCTION BUT ALSO FOR REGULATED EPIGENETIC PROGRAMMING. HOWEVER, THESE ORGANELLES ARE SUBTLE TARGETS OF ENVIRONMENTAL EXPOSURES, AND ANY PERTURBANCE IN THE DEFINED MITOCHONDRIAL MACHINERY DURING THE DEVELOPMENTAL STAGE CAN LEAD TO THE RE-PROGRAMMING OF THE FOETAL EPIGENETIC LANDSCAPE. AS THESE MODIFICATIONS CAN BE TRANSFERRED TO SUBSEQUENT GENERATIONS, WE HEREIN PERFORMED A CROSS-SECTIONAL STUDY TO HAVE AN IN-DEPTH UNDERSTANDING OF THIS INTRICATE PHENOMENON. THE STUDY WAS CONDUCTED WITH TWO ARMS: WHEREAS THE FIRST GROUP CONSISTED OF IN UTERO PRO-OXIDANT EXPOSED INDIVIDUALS AND THE SECOND GROUP INCLUDED CONTROLS. OUR RESULTS SHOWED HIGHER LEVELS OF OXIDATIVE MTDNA DAMAGE AND ASSOCIATED INTEGRATED STRESS RESPONSE AMONG THE EXPOSED INDIVIDUALS. THESE DISTURBANCES WERE FOUND TO BE CLOSELY RELATED TO THE OBSERVED DISCREPANCIES IN MITOCHONDRIAL BIOGENESIS. THE EXPOSED GROUP SHOWED MTDNA HYPERMETHYLATION AND CHANGES IN ALLIED MITOCHONDRIAL FUNCTIONING. ALTERED EXPRESSION OF MITOMIRS AND THEIR RESPECTIVE TARGET GENES IN THE EXPOSED GROUP INDICATED THE POSSIBILITIES OF A DISTURBED MITOCHONDRIAL-NUCLEAR CROSS TALK. THIS WAS FURTHER CONFIRMED BY THE MODIFIED ACTIVITY OF THE MITOCHONDRIAL STRESS REGULATORS AND PRO-INFLAMMATORY MEDIATORS AMONG THE EXPOSED GROUP. IMPORTANTLY, THE DISTURBED DNMT FUNCTIONING, HYPERMETHYLATION OF NUCLEAR DNA, AND HIGHER DEGREE OF POST-TRANSLATIONAL HISTONE MODIFICATIONS ESTABLISHED THE EXISTENCE OF ABERRANT EPIGENETIC MODIFICATIONS IN THE EXPOSED INDIVIDUALS. OVERALL, OUR RESULTS DEMONSTRATE THE FIRST MOLECULAR INSIGHTS OF IN UTERO PRO-OXIDANT EXPOSURE ASSOCIATED CHANGES IN THE MITOCHONDRIAL-EPIGENETIC AXIS. ALTHOUGH, OUR STUDY MIGHT NOT CEMENT AN EXPOSURE-RESPONSE RELATIONSHIP FOR ANY PARTICULAR ENVIRONMENTAL PRO-OXIDANT, BUT SUFFICE TO ESTABLISH A DOGMA OF MITO-EPIGENETIC REPROGRAMMING AT INTRAUTERINE MILIEU WITH CHRONIC ILLNESS, A HITHERTO UNREPORTED INTERACTION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                   
7  1986  34 EPIGENETIC ALTERATIONS MAY REGULATE TEMPORARY REVERSAL OF CD4(+) T CELL ACTIVATION CAUSED BY TRICHLOROETHYLENE EXPOSURE. PREVIOUS STUDIES HAVE SHOWN THAT SHORT-TERM (4 WEEKS) OR CHRONIC (32 WEEKS) EXPOSURE TO TRICHLOROETHYLENE (TCE) IN DRINKING WATER OF FEMALE MRL+/+ MICE GENERATED CD4(+) T CELLS THAT SECRETED INCREASED LEVELS OF INTERFERON (IFN)-GAMMA AND EXPRESSED AN ACTIVATED (CD44(HI)CD62L(LO)) PHENOTYPE. IN CONTRAST, THE CURRENT STUDY OF SUBCHRONIC TCE EXPOSURE SHOWED THAT MIDWAY IN THE DISEASE PROCESS BOTH OF THESE PARAMETERS OF CD4(+) T CELL ACTIVATION WERE REVERSED. THIS PHASE OF THE DISEASE PROCESS MAY REPRESENT AN ATTEMPT BY THE BODY TO COUNTERACT THE INFLAMMATORY EFFECTS OF TCE. THE DECREASE IN CD4(+) T CELL PRODUCTION OF IFN-GAMMA FOLLOWING SUBCHRONIC TCE EXPOSURE COULD NOT BE ATTRIBUTED TO SKEWING TOWARD A TH2 OR TH17 PHENOTYPE OR TO AN INCREASE IN TREG CELLS. INSTEAD, THE SUPPRESSION CORRESPONDED TO ALTERATIONS IN MARKERS USED TO ASSESS DNA METHYLATION, NAMELY INCREASED EXPRESSION OF RETROTRANSPOSONS IAP (INTRACISTERNAL A PARTICLE) AND MUERV (MURINE ENDOGENOUS RETROVIRUS). ALSO OBSERVED WAS AN INCREASE IN THE EXPRESSION OF DNMT1 (DNA METHYLTRANSFERASE-1) AND DECREASED EXPRESSION OF SEVERAL GENES KNOWN TO BE DOWNREGULATED BY DNA METHYLATION, NAMELY IFNG, IL2, AND CDKN1A. CD4(+) T CELLS FROM A SECOND STUDY IN WHICH MRL+/+ MICE WERE TREATED FOR 17 WEEKS WITH TCE SHOWED A SIMILAR INCREASE IN IAP AND DECREASE IN CDKN1A. IN ADDITION, DNA COLLECTED FROM THE CD4(+) T CELLS IN THE SECOND STUDY SHOWED TCE-DECREASED GLOBAL DNA METHYLATION. THUS, THESE RESULTS DESCRIBED THE BIPHASIC NATURE OF TCE-INDUCED ALTERATIONS IN CD4(+) T CELL FUNCTION AND SUGGESTED THAT THESE CHANGES REPRESENTED POTENTIALLY REVERSIBLE ALTERATIONS IN EPIGENETIC PROCESSES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8  3068  24 GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIES DIFFERENTIAL METHYLATION IN UNINVOLVED PSORIATIC EPIDERMIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH BOTH LOCAL AND SYSTEMIC COMPONENTS. GENOME-WIDE APPROACHES HAVE IDENTIFIED MORE THAN 60 PSORIASIS-SUSCEPTIBILITY LOCI, BUT GENES ARE ESTIMATED TO EXPLAIN ONLY ONE-THIRD OF THE HERITABILITY IN PSORIASIS, SUGGESTING ADDITIONAL, YET UNIDENTIFIED, SOURCES OF HERITABILITY. EPIGENETIC MODIFICATIONS HAVE BEEN LINKED TO PSORIASIS AND ALTERED DNA METHYLATION PATTERNS IN PSORIATIC VERSUS HEALTHY SKIN HAVE BEEN REPORTED IN WHOLE-SKIN BIOPSIES. IN THIS STUDY, FOCUSING ON EPIGENETIC MODIFICATIONS IN THE PSORIATIC UNINVOLVED SKIN, WE COMPARED THE LESIONAL AND NON-LESIONAL EPIDERMIS FROM PSORIASIS PATIENTS WITH EPIDERMIS FROM HEALTHY CONTROLS. WE PERFORMED AN EXHAUSTIVE GENOME-WIDE DNA METHYLATION PROFILING USING REDUCED REPRESENTATION BISULFITE SEQUENCING, WHICH INTERROGATES THE METHYLATION STATUS OF APPROXIMATELY 3-4 MILLION CPG SITES. MORE THAN 2,000 STRONGLY DIFFERENTIALLY METHYLATED SITES WERE IDENTIFIED AND A STRIKING OVERREPRESENTATION OF THE WNT AND CADHERIN PATHWAYS AMONG THE DIFFERENTIALLY METHYLATED SITES WAS FOUND. IN PARTICULAR, WE OBSERVE A STRONG DIFFERENTIAL METHYLATION IN SEVERAL PSORIASIS CANDIDATE GENES. A SUBSTANTIAL NUMBER OF DIFFERENTIALLY METHYLATED SITES PRESENT IN THE UNINVOLVED VERSUS HEALTHY EPIDERMIS SUGGESTS THE PRESENCE OF A PRE-PSORIATIC STATE IN THE CLINICALLY HEALTHY SKIN TYPE. OUR EXPLORATORY STUDY REPRESENTS A STARTING POINT FOR IDENTIFYING BIOMARKERS FOR PSORIASIS-PRONE SKIN BEFORE DISEASE ONSET.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9  2743  35 EXPOSURE TO ULTRAFINE PARTICULATE MATTER INDUCES NF-KAPPABETA MEDIATED EPIGENETIC MODIFICATIONS. EXPOSURE TO ULTRAFINE PARTICULATE MATTER (PM0.1) IS POSITIVELY ASSOCIATED WITH THE ETIOLOGY OF DIFFERENT ACUTE AND CHRONIC DISORDERS; HOWEVER, THE IN-DEPTH BIOLOGICAL IMPRINTS THAT LINK THESE SUBMICRON PARTICLES WITH THE DISTURBANCES IN THE EPIGENOMIC MACHINERY ARE NOT WELL DEFINED. EARLIER, WE SHOWED THAT EXPOSURE TO THESE PARTICLES CAUSES SIGNIFICANT DISTURBANCES IN THE MITOCHONDRIAL MACHINERY AND TRIGGERS PI-3-KINASE MEDIATED DNA DAMAGE RESPONSES. IN THE PRESENT STUDY, WE AIMED TO FURTHER UNDERSTAND THE EPIGENOMIC INSIGHTS OF THE ULTRAFINE PM EXPOSURE. THE HIGHER LEVELS OF INTRACELLULAR REACTIVE OXYGEN SPECIES AND DEPLETED NRF-2 IN ULTRAFINE PM EXPOSED CELLS RECONFIRMED ITS POTENTIAL TO INDUCE OXIDATIVE STRESS. IMPORTANTLY, THE OBSERVED INCREASE IN THE LEVELS OF NF-KAPPABETA AND ASSOCIATED CYTOKINES AMONG EXPOSED CELLS SUGGESTED THE ACTIVATION OF NF-KAPPABETA MEDIATED INFLAMMATORY LOOP WHICH POTENTIALLY SERVES AS A PLATFORM FOR INITIATING EPIGENETIC INSINUATIONS. THIS FACT WAS STRONGLY SUPPORTED BY THE ALTERED MIRNA EXPRESSION PROFILE OF THE ULTRAFINE PM EXPOSED CELLS. THESE NF-KAPPABETA INDUCED MIRNA ALTERATIONS WERE ALSO FOUND TO BE ASSOCIATED WITH OTHER EPIGENETIC TARGETS AS THE EXPOSED CELLS SHOWED HIGHER EXPRESSION LEVELS OF DNA METHYLTRANSFERASES WHICH POSITIVELY CORRESPONDED WITH THE GLOBAL CHANGES IN DNA METHYLATION LEVELS. UPON FURTHER ANALYSIS, SIGNIFICANT ALTERATIONS IN HISTONE CODE WERE ALSO REPORTED IN ULTRAFINE PM EXPOSED CELLS. CONCLUSIVELY OUR RESULTS SUGGESTED THAT NF-KAPPABETA ACTS AS AN INFLAMMATORY SWITCH THAT POSSESSES THE POTENTIAL TO INDUCE GENOME-WIDE EPIGENETIC MODIFICATION UPON ULTRAFINE PM EXPOSURE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  3046  20 GENOME-WIDE ANALYSIS OF DNA METHYLATION IDENTIFIES S100A13 AS AN EPIGENETIC BIOMARKER IN INDIVIDUALS WITH CHRONIC (>/= 30 YEARS) TYPE 2 DIABETES WITHOUT DIABETIC RETINOPATHY. BACKGROUND: THIS STUDY AIMED TO DETERMINE THE EPIGENETIC BIOMARKERS OF DIABETIC RETINOPATHY (DR) IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS (T2DM). THIS RETROSPECTIVE STUDY IS BASED ON THE SHANGHAI XINJING COMMUNITY PREVENTION AND TREATMENT ADMINISTRATIVE SYSTEM OF CHRONIC DISEASES. THE SUBJECTS ENROLLED HEREIN WERE T2DM PATIENTS WHO HAD UNDERGONE LONG-TERM FOLLOW-UP EVALUATION IN THE SYSTEM. TWO CONSECUTIVE STUDIES WERE CONDUCTED. IN THE DISCOVERY COHORT, AMONG 19 SUBJECTS WHO HAD DEVELOPED DR WITH A DM DURATION < 3 YEARS AND 21 SUBJECTS WITHOUT DR > 30 YEARS AFTER BEING DIAGNOSED WITH DM, AN INFINIUM HUMAN METHYLATION 850 BEADCHIP WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS (DMRS) AND DIFFERENTIAL METHYLATION SITES (DMSS). THE FUNCTION OF THE GENES WAS ASSESSED THROUGH KEGG ENRICHMENT ANALYSIS, GENE ONTOLOGY (GO) ANALYSIS, AND PATHWAY NETWORK ANALYSIS. IN THE REPLICATION COHORT, 87 DR PATIENTS WITH A SHORT DM DURATION AND 89 PATIENTS WITHOUT DR OVER A DM DURATION > 20 YEARS WERE COMPARED TO ASSESS THE ASSOCIATION BETWEEN DMSS AND DR UPON PYROSEQUENCING. RESULTS: A TOTAL OF 34 DMRS WERE IDENTIFIED. GENES CONTAINING DMSS WITH THE TOP 5 HIGHEST BETA VALUE DIFFERENCES BETWEEN DR AND NON-DR PARTICIPANTS WERE LOCATED ON CHROMOSOME 1 AND WERE PRESENT IN THE S100A13 GENE, WHICH WAS ASSOCIATED WITH 71 GO TERMS. TWO S100A13 GENE SITES, I.E., CG02873163 AND CG11343894, DISPLAYED A GOOD CORRELATION WITH DR ON PYROSEQUENCING. CONCLUSIONS: DMSS IN THE S100A13 GENE MAY BE POTENTIAL BIOMARKERS OF DR.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11  2940  41 GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL AND SENSITIVE COPD-DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5). EVEN THOUGH CLINICAL, EPIDEMIOLOGICAL AND TOXICOLOGICAL STUDIES HAVE PROGRESSIVELY PROVIDED A BETTER KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS, FURTHER IN VITRO STUDIES ON RELEVANT CELL SYSTEMS ARE STILL NEEDED. HENCE, AIMING OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS, PRIMARY HUMAN BRONCHIAL EPITHELIAL CELLS DERIVED FROM NORMAL SUBJECTS (NHBE) OR SENSITIVE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED PATIENTS (DHBE) WERE DIFFERENTIATED AT THE AIR-LIQUID INTERFACE. THEREAFTER, THEY WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) TO STUDY THE OCCURRENCE OF SOME RELEVANT GENETIC AND/OR EPIGENETIC ENDPOINTS. CONCENTRATION-, EXPOSURE- AND SEASON-DEPENDENT INCREASES OF OH-B[A]P METABOLITES IN NHBE, AND TO A LESSER EXTENT, COPD-DHBE CELLS WERE REPORTED; HOWEVER, THERE WERE MORE TETRA-OH-B[A]P AND 8-OHDG DNA ADDUCTS IN COPD-DHBE CELLS. NO INCREASE IN PRIMARY DNA STRAND BREAK NOR CHROMOSOMAL ABERRATION WAS OBSERVED IN REPEATEDLY EXPOSED CELLS. TELOMERE LENGTH AND TELOMERASE ACTIVITY WERE MODIFIED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN NHBE AND PARTICULARLY COPD-DHBE CELLS. THERE WERE A GLOBAL DNA HYPOMETHYLATION, A P16 GENE PROMOTER HYPERMETHYLATION, AND A DECREASING DNA METHYLTRANSFERASE ACTIVITY IN NHBE AND NOTABLY COPD-DHBE CELLS REPEATEDLY EXPOSED. CHANGES IN SITE-SPECIFIC METHYLATION, ACETYLATION, AND PHOSPHORYLATION OF HISTONE H3 (I.E., H3K4ME3, H3K9AC, H3K27AC, AND H3S10PH) AND RELATED ENZYME ACTIVITIES OCCURRED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN ALL THE REPEATEDLY EXPOSED CELLS. COLLECTIVELY, THESE RESULTS HIGHLIGHTED THE KEY ROLE PLAYED BY GENETIC AND EVEN EPIGENETIC EVENTS IN NHBE AND PARTICULARLY SENSITIVE COPD-DHBE CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) AND THEIR DIFFERENT RESPONSIVENESS. WHILE THESE SPECIFIC EPIGENETIC CHANGES HAVE BEEN ALREADY DESCRIBED IN COPD AND EVEN LUNG CANCER PHENOTYPES, OUR FINDINGS SUPPORTED THAT, TOGETHER WITH GENETIC EVENTS, THESE EPIGENETIC EVENTS COULD DRAMATICALLY CONTRIBUTE TO THE SHIFT FROM HEALTHY TO DISEASED PHENOTYPES FOLLOWING REPEATED EXPOSURE TO RELATIVELY LOW DOSES OF AIR POLLUTION-DERIVED PM(2.5).	2017	
                                                                                                                                                                                                                                                        
12  3063  33 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  2101  33 EPIGENETIC EFFECTS OF PRENATAL STRESS ON 11BETA-HYDROXYSTEROID DEHYDROGENASE-2 IN THE PLACENTA AND FETAL BRAIN. MATERNAL EXPOSURE TO STRESS DURING PREGNANCY IS ASSOCIATED WITH SIGNIFICANT ALTERATIONS IN OFFSPRING NEURODEVELOPMENT AND ELEVATED MATERNAL GLUCOCORTICOIDS LIKELY PLAY A CENTRAL ROLE IN MEDIATING THESE EFFECTS. PLACENTAL 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 2 (HSD11B2) BUFFERS THE IMPACT OF MATERNAL GLUCOCORTICOID EXPOSURE BY CONVERTING CORTISOL/CORTICOSTERONE INTO INACTIVE METABOLITES. HOWEVER, PREVIOUS STUDIES INDICATE THAT MATERNAL ADVERSITY DURING THE PRENATAL PERIOD CAN LEAD TO A DOWN-REGULATION OF THIS ENZYME. IN THE CURRENT STUDY, WE EXAMINED THE IMPACT OF PRENATAL STRESS (CHRONIC RESTRAINT STRESS DURING GESTATIONAL DAYS 14-20) IN LONG EVANS RATS ON HSD11B2 MRNA IN THE PLACENTA AND FETAL BRAIN (E20) AND ASSESSED THE ROLE OF EPIGENETIC MECHANISMS IN THESE STRESS-INDUCED EFFECTS. IN THE PLACENTA, PRENATAL STRESS WAS ASSOCIATED WITH A SIGNIFICANT DECREASE IN HSD11B2 MRNA, INCREASED MRNA LEVELS OF THE DNA METHYLTRANSFERASE DNMT3A, AND INCREASED DNA METHYLATION AT SPECIFIC CPG SITES WITHIN THE HSD11B2 GENE PROMOTER. WITHIN THE FETAL HYPOTHALAMUS, THOUGH WE FIND NO STRESS-INDUCED EFFECTS ON HSD11B2 MRNA LEVELS, PRENATAL STRESS INDUCED DECREASED CPG METHYLATION WITHIN THE HSD11B2 PROMOTER AND INCREASED METHYLATION AT SITES WITHIN EXON 1. WITHIN THE FETAL CORTEX, HSD11B2 MRNA AND DNA METHYLATION LEVELS WERE NOT ALTERED BY PRENATAL STRESS, THOUGH WE DID FIND STRESS-INDUCED ELEVATIONS IN DNMT1 MRNA IN THIS BRAIN REGION. WITHIN INDIVIDUALS, WE IDENTIFIED CPG SITES WITHIN THE HSD11B2 GENE PROMOTER AND EXON 1 AT WHICH DNA METHYLATION LEVELS WERE HIGHLY CORRELATED BETWEEN THE PLACENTA AND FETAL CORTEX. OVERALL, OUR FINDINGS IMPLICATE DNA METHYLATION AS A MECHANISM BY WHICH PRENATAL STRESS ALTERS HSD11B2 GENE EXPRESSION. THESE FINDINGS HIGHLIGHT THE TISSUE SPECIFICITY OF EPIGENETIC EFFECTS, BUT ALSO RAISE THE INTRIGUING POSSIBILITY OF USING THE EPIGENETIC STATUS OF PLACENTA TO PREDICT CORRESPONDING CHANGES IN THE BRAIN.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
14  3056  28 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                       
15   502  39 ASSOCIATION OF ARSENIC EXPOSURE WITH WHOLE BLOOD DNA METHYLATION: AN EPIGENOME-WIDE STUDY OF BANGLADESHI ADULTS. BACKGROUND: ARSENIC EXPOSURE AFFECTS [FORMULA: SEE TEXT] PEOPLE WORLDWIDE, INCLUDING [FORMULA: SEE TEXT] IN BANGLADESH. ARSENIC EXPOSURE INCREASES THE RISK OF CANCER AND OTHER CHRONIC DISEASES, AND ONE POTENTIAL MECHANISM OF ARSENIC TOXICITY IS EPIGENETIC DYSREGULATION. OBJECTIVE: WE ASSESSED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENOME-WIDE DNA METHYLATION MEASURED AT BASELINE AMONG 396 BANGLADESHI ADULTS PARTICIPATING IN THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (HEALS) WHO WERE EXPOSED BY DRINKING NATURALLY CONTAMINATED WELL WATER. METHODS: METHYLATION IN WHOLE BLOOD DNA WAS MEASURED AT [FORMULA: SEE TEXT] USING THE ILLUMINA INFINIUMMETHYLATIONEPIC (EPIC) ARRAY. TO ASSESS ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG METHYLATION, WE USED LINEAR REGRESSION MODELS ADJUSTED FOR COVARIATES AND SURROGATE VARIABLES (SVS) (CAPTURING UNKNOWN TECHNICAL AND BIOLOGIC FACTORS). WE ATTEMPTED REPLICATION AND CONDUCTED A META-ANALYSIS USING AN INDEPENDENT DATASET OF [FORMULA: SEE TEXT] FROM 400 BANGLADESHI INDIVIDUALS WITH ARSENICAL SKIN LESIONS. RESULTS: WE IDENTIFIED 34 CPGS ASSOCIATED WITH [FORMULA: SEE TEXT] CREATININE-ADJUSTED URINARY ARSENIC [[FORMULA: SEE TEXT]]. SIXTEEN OF THESE CPGS ANNOTATED TO THE [FORMULA: SEE TEXT] ARRAY, AND 10 ASSOCIATIONS WERE REPLICATED ([FORMULA: SEE TEXT]). THE TOP TWO CPGS ANNOTATED UPSTREAM OF THE ABR GENE (CG01912040, CG10003262 ). ALL URINARY ARSENIC-ASSOCIATED CPGS WERE ALSO ASSOCIATED WITH ARSENIC CONCENTRATION MEASURED IN DRINKING WATER ([FORMULA: SEE TEXT]). META-ANALYSIS ([FORMULA: SEE TEXT] SAMPLES) IDENTIFIED 221 URINARY ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]). THE ARSENIC-ASSOCIATED CPGS FROM THE META-ANALYSIS WERE ENRICHED IN NON-CPG ISLANDS AND SHORES ([FORMULA: SEE TEXT]) AND DEPLETED IN PROMOTER REGIONS ([FORMULA: SEE TEXT]). AMONG THE ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]), WE OBSERVED SIGNIFICANT ENRICHMENT OF GENES ANNOTATING TO THE REACTIVE OXYGEN SPECIES PATHWAY, INFLAMMATORY RESPONSE, AND TUMOR NECROSIS FACTOR [FORMULA: SEE TEXT] ([FORMULA: SEE TEXT]) SIGNALING VIA NUCLEAR FACTOR KAPPA-B ([FORMULA: SEE TEXT]) HALLMARKS ([FORMULA: SEE TEXT]). CONCLUSIONS: THE NOVEL AND REPLICABLE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND DNA METHYLATION AT SPECIFIC CPGS OBSERVED IN THIS WORK SUGGEST THAT EPIGENETIC ALTERATIONS SHOULD BE FURTHER INVESTIGATED AS POTENTIAL MEDIATORS IN ARSENIC TOXICITY AND AS BIOMARKERS OF EXPOSURE AND EFFECT IN EXPOSED POPULATIONS. HTTPS://DOI.ORG/10.1289/EHP3849.	2019	
                                            
16  5682  22 SHORT-TERM CHANGES IN GLOBAL METHYLATION AND HYDROXYMETHYLATION DURING ALCOHOL DETOXIFICATION. ALCOHOL DEPENDENCE IS A COMMON PUBLIC HEALTH PROBLEM AND EPIGENETICS MAY OFFER NEW ASPECTS IN UNDERSTANDING THE BIOLOGICAL AND GENETIC UNDERPINNINGS AND IMPROVE TREATMENT OF THIS COMPLEX DISEASE. SUPPOSEDLY, METHYLATION AND HYDROXYMETHYLATION ARE ALTERED IN BRAIN TISSUES AND IN SYNAPSE-RELATED GENES DUE TO CHRONIC ALCOHOL INTAKE AND DURING WITHDRAWAL. TO ASSESS POTENTIAL EPIGENETIC CHANGES AFTER CESSATION OF CHRONIC ALCOHOL INTAKE, WE COMPARED 23 ALCOHOL-DEPENDENT INDIVIDUALS DURING INPATIENT ALCOHOL DETOXIFICATION WITH 13 CAREFULLY MATCHED CONTROLS. BLOOD SAMPLES WERE TAKEN ON THE DAY OF ADMISSION, AFTER ONE AND AFTER TWO WEEKS AT THE END OF INPATIENT TREATMENT. GENOME-WIDE GLOBAL METHYLATION AND GLOBAL DNA HYDROXYMETHYLATION WERE COMPARED ACROSS GROUPS. THERE WERE SIGNIFICANT DIFFERENCES IN GLOBAL METHYLATION ACROSS TIME FROM ADMISSION TO ONE AND TWO WEEKS OF INPATIENT WITHDRAWAL (P < 0.001). THESE FINDINGS WERE PARALLELED TO CHANGES IN GLOBAL DNA HYDROXYMETHYLATION ACROSS TIME WHEN AGE WAS EMPLOYED AS A COFACTOR (P < 0.001). SEVERAL POTENTIALLY INFLUENCING VARIABLES LIKE SEVERITY OF WITHDRAWAL, DOSE OF WITHDRAWAL MEDICATION AND ALCOHOL INTAKE BEFORE ADMISSION DID NOT YIELD SIGNIFICANT INFLUENCE ON EPIGENETIC CHANGES. THE RESULTS CONFIRM PREVIOUS FINDINGS OF SIGNIFICANT ALTERATIONS OF EPIGENETIC PATTERNS DURING ALCOHOL INTOXICATION AND PRESENT FOR THE FIRST TIME HYDROXYMETHYLATION CHANGES IN THESE INDIVIDUALS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  3099  29 GENOMIC DNA METHYLATION SIGNATURES IN DIFFERENT TISSUES AFTER AMBIENT AIR PARTICULATE MATTER EXPOSURE. DNA METHYLATION (5-MC) IS ONE OF THE SEVERAL EPIGENETIC MARKERS, AND IS GENERALLY ASSOCIATED WITH THE INHIBITION OF GENE EXPRESSION. BOTH HYPER AND HYPO DNA METHYLATION ARE ASSOCIATED WITH THE DISEASES. EXPOSURE TO FINE PARTICLES WITH A DIAMETER OF 2.5 MUM OR LESS (PM(2.5)) IS A PERVASIVE RISK FACTOR FOR CARDIOPULMONARY MORTALITY, METABOLIC DISORDERS, COGNITION DAMAGE, AND ETC.. RECENT REPORTS POINTED TOWARD THAT THESE DISEASES WERE ASSOCIATED WITH THE ALTERED DNA METHYLATION LEVEL OF SOME SPECIFIC-GENE, POTENTIALLY SUGGESTING THAT THE DNA METHYLATION ALTERATION WAS INVOLVED IN THE HEALTH HAZARD DERIVED FROM THE PM(2.5) EXPOSURE. IN THIS STUDY, WE SYSTEMATICALLY INVESTIGATED THE GLOBAL DNA METHYLATION LEVEL OF MOST TISSUES, INCLUDING LUNG, HEART, TESTIS, THYMUS, SPLEEN, EPIDIDYMAL FAT, HIPPOCAMPUS, KIDNEY, LIVE, AFTER SHORT AND LONG TERM PM(2.5) EXPOSURE. AFTER ACUTE PM(2.5) EXPOSURE, THE GLOBAL HYPO-METHYLATION IN DNA WAS OBSERVED IN LUNG AND HEART. NOTABLY, AFTER CHRONIC PM(2.5) EXPOSURE, LEVEL OF GLOBAL DNA METHYLATION DECREASED IN MOST ORGANS WHICH INCLUDED LUNG, TESTIS, THYMUS, SPLEEN, EPIDIDYMAL FAT, HIPPOCAMPUS AND BLOOD. THE PRESENT STUDY SYSTEMATICALLY DEMONSTRATED THE GLOBAL DNA METHYLATION CHANGES BY PM(2.5) EXPOSURE, AND PUT FORWARD A POSSIBLE ORIENTATION FOR FURTHER EXPLORING THE EFFECTS OF AMBIENT AIR PARTICLES EXPOSURE ON THE SPECIFIC ORGANS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  1443  38 DIFFERENTIAL RESPONSES OF HEALTHY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4). WHILE THE KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS IS STILL INCOMPLETE, DETAILED IN VITRO STUDIES ARE HIGHLY NEEDED. WITH THE AIM OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS AND BETTER INTEGRATING A NUMBER OF FACTORS RELATED TO PRE-EXISTING CHRONIC PULMONARY INFLAMMATORY, WE SOUGHT TO DEVELOP PRIMARY CULTURES OF NORMAL HUMAN BRONCHIAL EPITHELIAL (NHBE) CELLS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED HUMAN BRONCHIAL EPITHELIAL (DHBE) CELLS, GROWN AT THE AIR-LIQUID INTERFACE. PAN-CYTOKERATIN AND MUC5AC IMMUNOSTAINING CONFIRMED THE SPECIFIC CELL-TYPES OF BOTH THESE HEALTHY AND DISEASED CELL MODELS AND SHOWED THEY ARE CLOSED TO HUMAN BRONCHIAL EPITHELIA. THEREAFTER, HEALTHY AND DISEASED CELLS WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4) AT THE NON-CYTOTOXIC CONCENTRATION OF 5 MUG/CM(2). THE DIFFERENCES BETWEEN THE OXIDATIVE AND INFLAMMATORY STATES IN NON-EXPOSED NHBE AND COPD-DHBE CELLS INDICATED THAT DISEASED CELLS CONSERVED THEIR SPECIFIC PHYSIOPATHOLOGICAL CHARACTERISTICS. INCREASES IN BOTH OXIDATIVE DAMAGE AND CYTOKINE SECRETION WERE REPORTED IN REPEATEDLY EXPOSED NHBE CELLS AND PARTICULARLY IN COPD-DHBE CELLS. DISEASED CELLS REPEATEDLY EXPOSED HAD LOWER CAPACITIES TO METABOLIZE THE ORGANIC CHEMICALS-COATED ONTO THE AIR-POLLUTION-DERIVED PM(4), SUCH AS BENZO[A]PYRENE (B[A]P), BUT SHOWED HIGHER SENSIBILITY TO THE FORMATION OF OH-B[A]P DNA ADDUCTS, BECAUSE THEIR DISEASED STATE POSSIBLY AFFECTED THEIR DEFENSES. DIFFERENTIAL PROFILES OF EPIGENETIC HALLMARKS (I.E., GLOBAL DNA HYPOMETHYLATION, P16 PROMOTER HYPERMETHYLATION, TELOMERE LENGTH SHORTENING, TELOMERASE ACTIVATION, AND HISTONE H3 MODIFICATIONS) OCCURRED IN REPEATEDLY EXPOSED NHBE AND PARTICULARLY IN COPD-DHBE CELLS. TAKEN TOGETHER, THESE RESULTS CLOSELY SUPPORTED THE HIGHEST RESPONSIVENESS OF COPD-DHBE CELLS TO A REPEATED EXPOSURE TO AIR POLLUTION-DERIVED PM(4). THE USE OF THESE INNOVATIVE IN VITRO EXPOSURE SYSTEMS SUCH AS NHBE AND COPD-DHBE CELLS COULD THEREFORE BE CONSIDER AS A VERY USEFUL AND POWERFUL PROMISING TOOL IN THE FIELD OF THE RESPIRATORY TOXICOLOGY, TAKING INTO ACCOUNT SENSITIVE INDIVIDUALS.	2016	
                                                                                                                                                                                                                                                                                  
19  5628  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20  4252  29 METHYLOME CHANGES ASSOCIATED WITH FUNCTIONAL MOVEMENT/CONVERSION DISORDER: INFLUENCE OF BIOLOGICAL SEX AND CHILDHOOD ABUSE EXPOSURE. EPIGENETIC CHANGES, SUCH AS DNA METHYLATION (DNAM), MAY REPRESENT AN IMPORTANT MECHANISM IMPLICATED IN THE ETIOPATHOGENESIS OF FUNCTIONAL MOVEMENT/CONVERSION DISORDER (FMD). HERE, WE AIMED TO IDENTIFY METHYLOMIC VARIATIONS IN A CASE-CONTROL COHORT OF FMD AND TO UNCOVER SPECIFIC EPIGENETIC SIGNATURES ASSOCIATED WITH FEMALE SEX AND CHILDHOOD ABUSE, TWO KEY RISK FACTORS FOR FMD AND OTHER FUNCTIONAL NEUROLOGICAL DISORDERS. GENOME-WIDE DNAM ANALYSIS WAS PERFORMED FROM PERIPHERAL BLOOD IN 57 PATIENTS WITH FMD AND 47 HEALTHY CONTROLS WITH AND WITHOUT CHILDHOOD ABUSE. USING PRINCIPAL COMPONENT ANALYSIS, WE EXAMINED THE ASSOCIATION OF PRINCIPAL COMPONENTS WITH FMD STATUS IN ABUSED AND NON-ABUSED INDIVIDUALS, IN THE ENTIRE STUDY SAMPLE AND IN FEMALE SUBJECTS ONLY. NEXT, WE USED ENRICHMENT PATHWAY ANALYSIS TO INVESTIGATE THE BIOLOGICAL SIGNIFICANCE OF DNAM CHANGES AND EXPLORED DIFFERENCES IN METHYLATION LEVELS OF GENES ANNOTATED TO THE TOP ENRICHED BIOLOGICAL PATHWAYS SHARED ACROSS COMPARISONS. WE FOUND THAT FMD WAS ASSOCIATED WITH DNAM VARIATION ACROSS THE GENOME AND IDENTIFIED A COMMON EPIGENETIC 'SIGNATURE' ENRICHED FOR BIOLOGICAL PATHWAYS IMPLICATED IN CHRONIC STRESS AND CHRONIC PAIN. HOWEVER, METHYLATION LEVELS OF GENES INCLUDED IN THE TOP TWO SHARED PATHWAYS HARDLY OVERLAPPED, SUGGESTING THAT TRANSCRIPTIONAL PROFILES MAY DIFFER AS A FUNCTION OF CHILDHOOD ABUSE EXPOSURE AND SEX AMONG SUBJECTS WITH FMD. THIS STUDY IS UNIQUE IN PROVIDING GENOME-WIDE EVIDENCE OF DNAM CHANGES IN FMD AND IN INDICATING A POTENTIAL MECHANISM LINKING CHILDHOOD ABUSE EXPOSURE AND FEMALE SEX TO DIFFERENCES IN FMD PATHOPHYSIOLOGY. FUTURE STUDIES ARE NEEDED TO REPLICATE OUR FINDINGS IN INDEPENDENT COHORTS.	2023