1   884 147 CHRONIC COEXPOSURE TO ARSENIC AND ESTROGEN POTENTIATES GENOTOXIC ESTROGEN METABOLIC PATHWAY AND HYPERMETHYLATION OF DNA GLYCOSYLASE MBD4 IN HUMAN PROSTATE EPITHELIAL CELLS. BACKGROUND: PREVIOUSLY WE REPORTED THAT ARSENIC AND ESTROGEN CAUSE SYNERGISTIC EFFECTS IN THE NEOPLASTIC TRANSFORMATION OF HUMAN PROSTATE EPITHELIAL CELLS. IN ADDITION TO RECEPTOR-MEDIATED PATHWAYS, DNA-REACTIVE ESTROGEN METABOLITES HAVE ALSO BEEN SHOWN TO PLAY A CRITICAL ROLE IN MUTAGENICITY AND CARCINOGENICITY. BOTH ESTROGEN AND ARSENIC ARE KNOWN PROSTATE CARCINOGENS, HOWEVER, THE EFFECT OF COEXPOSURE TO THESE TWO CHEMICALS ON GENES INVOLVED IN ESTROGEN METABOLISM IS NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE ROLE OF ARSENIC AND ESTROGEN COEXPOSURE ON THE EXPRESSION OF ESTROGEN RECEPTORS AND ESTROGEN METABOLISM-ASSOCIATED GENES. EARLIER, WE ALSO REPORTED THE SYNERGISTIC EFFECT OF ARSENIC AND ESTROGEN ON DECREASED EXPRESSION OF MBD4 GENES THAT PLAY AN IMPORTANT ROLE IN DNA REPAIR THROUGH ITS DNA GLYCOSYLASE ACTIVITY. TO FURTHER UNDERSTAND THE MECHANISM, THE PROMOTER METHYLATION OF THIS GENE WAS ALSO ANALYZED. METHODS: TOTAL RNA AND PROTEIN WERE ISOLATED FROM RWPE-1 HUMAN PROSTATE EPITHELIAL CELLS THAT WERE COEXPOSED TO ARSENIC AND ESTROGEN FOR A CHRONIC DURATION (6 MONTHS). THE EXPRESSION OF ESTROGEN RECEPTORS, ESTROGEN METABOLISM ASSOCIATED PHASE I GENES (CYP 1A1, 1A2, 3A4, AND 1B1) AND PHASE II GENE CATECHOL-O-METHYLTRANSFERASE (COMT), AS WELL AS ANTIOXIDANT MNSOD, WERE ANALYZED EITHER AT THE RNA LEVEL BY QUANTITATIVE REVERSE TRANSCRIPTASE-POLYMERASE CHAIN REACTION OR AT THE PROTEIN LEVEL BY WESTERN BLOT. PROMOTER METHYLATION OF MBD4 WAS ANALYZED BY PYROSEQUENCING. RESULTS: EXPRESSION OF MNSOD AND PHASE I GENES THAT CONVERT E(2) INTO GENOTOXIC METABOLITES 2-OH-E(2) AND 4-OH-E(2) WERE SIGNIFICANTLY INCREASED, WHEREAS THE EXPRESSION OF PHASE II GENE COMT THAT DETOXIFIES ESTROGEN METABOLITES WAS SIGNIFICANTLY DECREASED IN ARSENIC AND ESTROGEN COEXPOSED CELLS. MBD4 PROMOTER WAS HYPERMETHYLATED IN ARSENIC AND ESTROGEN COEXPOSED CELLS. COEXPOSURE TO ARSENIC AND ESTROGEN HAS SYNERGISTIC EFFECTS ON THE EXPRESSION OF THESE GENES AS WELL AS IN MBD4 PROMOTER HYPERMETHYLATION. CONCLUSIONS: THESE NOVEL FINDINGS SUGGEST THAT COEXPOSURE TO ARSENIC AND ESTROGEN ACTS SYNERGISTICALLY IN THE ACTIVATION OF NOT ONLY THE ESTROGEN RECEPTORS BUT ALSO THE GENES ASSOCIATED WITH GENOTOXIC ESTROGEN METABOLISM AND EPIGENETIC INACTIVATION OF DNA GLYCOSYLASE MBD4. TOGETHER, THESE GENETIC AND EPIGENETIC ABERRATIONS PROVIDE THE MOLECULAR BASIS FOR THE POTENTIATION OF CARCINOGENICITY OF ARSENIC AND ESTROGEN COEXPOSURE IN PROSTATE EPITHELIAL CELLS.	2022	
                                                                                
2  1875  55 EMERGING ROLE OF ONE-CARBON METABOLISM AND DNA METHYLATION ENRICHMENT ON DELTA-CONTAINING GABAA RECEPTOR EXPRESSION IN THE CEREBELLUM OF SUBJECTS WITH ALCOHOL USE DISORDERS (AUD). BACKGROUND: CEREBELLUM IS AN AREA OF THE BRAIN PARTICULARLY SENSITIVE TO THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL CONSUMPTION. ALCOHOL EXPOSURE DECREASES CEREBELLAR PURKINJE CELL OUTPUT BY INCREASING GABA RELEASE FROM GOLGI CELLS ONTO EXTRASYNAPTIC ALPHA6/DELTA-CONTAINING GABAA RECEPTORS LOCATED ON GLUTAMATERGIC GRANULE CELLS. HERE, WE STUDIED WHETHER CHRONIC ALCOHOL CONSUMPTION INDUCES CHANGES IN GABAA RECEPTOR SUBUNIT EXPRESSION AND WHETHER THESE CHANGES ARE ASSOCIATED WITH ALTERATIONS IN EPIGENETIC MECHANISMS VIA DNA METHYLATION. METHODS: WE USED A COHORT OF POSTMORTEM CEREBELLUM FROM CONTROL AND CHRONIC ALCOHOLICS, HERE DEFINED AS ALCOHOL USE DISORDERS SUBJECTS (N=25/GROUP). S-ADENOSYL-METHIONINE/S-ADENOSYL-HOMOCYSTEINE WERE MEASURED BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY. MRNA LEVELS OF VARIOUS GENES WERE ASSESSED BY REVERSE TRANSCRIPTASE-QUANTITATIVE POLYMERASE CHAIN REACTION. PROMOTER METHYLATION ENRICHMENT WAS ASSESSED USING METHYLATED DNA IMMUNOPRECIPITATION AND HYDROXY-METHYLATED DNA IMMUNOPRECIPITATION ASSAYS. RESULTS: MRNAS ENCODING KEY ENZYMES OF 1-CARBON METABOLISM THAT DETERMINE THE S-ADENOSYL-METHIONINE/S-ADENOSYL-HOMOCYSTEINE RATIO WERE INCREASED, INDICATING HIGHER "METHYLATION INDEX" IN ALCOHOL USE DISORDER SUBJECTS. WE FOUND THAT INCREASED METHYLATION OF THE PROMOTER OF THE DELTA SUBUNIT GABAA RECEPTOR WAS ASSOCIATED WITH REDUCED MRNA AND PROTEIN LEVELS IN THE CEREBELLUM OF ALCOHOL USE DISORDER SUBJECTS. NO CHANGES WERE OBSERVED IN ALPHA1- OR ALPHA6-CONTAINING GABAA RECEPTOR SUBUNITS. THE EXPRESSION OF DNA-METHYLTRANSFERASES (1, 3A, AND 3B) WAS UNALTERED, WHEREAS THE MRNA LEVEL OF TET1, WHICH PARTICIPATES IN THE DNA DEMETHYLATION PATHWAY, WAS DECREASED. HENCE, INCREASED METHYLATION OF THE DELTA SUBUNIT GABAA RECEPTOR PROMOTER MAY RESULT FROM ALCOHOL-INDUCED REDUCTION OF DNA DEMETHYLATION. CONCLUSION: TOGETHER, THESE RESULTS SUPPORT THE HYPOTHESIS THAT ABERRANT DNA METHYLATION PATHWAYS MAY BE INVOLVED IN CEREBELLAR PATHOPHYSIOLOGY OF ALCOHOLISM. FURTHERMORE, THIS WORK PROVIDES NOVEL EVIDENCE FOR A CENTRAL ROLE OF DNA METHYLATION MECHANISMS IN THE ALCOHOL-INDUCED NEUROADAPTIVE CHANGES OF HUMAN CEREBELLAR GABAA RECEPTOR FUNCTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                      
3  5468  38 RESISTANCE TRAINING AND REDOX HOMEOSTASIS: CORRELATION WITH AGE-ASSOCIATED GENOMIC CHANGES. REGULAR PHYSICAL ACTIVITY IS EFFECTIVE AS PREVENTION AND TREATMENT FOR DIFFERENT CHRONIC CONDITIONS RELATED TO THE AGEING PROCESSES. IN FACT, A SEDENTARY LIFESTYLE HAS BEEN LINKED TO A WORSENING OF CELLULAR AGEING BIOMARKERS SUCH AS TELOMERE LENGTH (TL) AND/OR SPECIFIC EPIGENETIC CHANGES (E.G. DNA METHYLATION), WITH INCREASE OF THE PROPENSITY TO AGING-RELATED DISEASES AND PREMATURE DEATH. EXTENDING OUR PREVIOUS FINDINGS, WE AIMED TO TEST THE HYPOTHESIS THAT 12 WEEKS OF LOW FREQUENCY, MODERATE INTENSITY, EXPLOSIVE-TYPE RESISTANCE TRAINING (EMRT) MAY ATTENUATE AGE-ASSOCIATED GENOMIC CHANGES. TO THIS AIM, TL, GLOBAL DNA METHYLATION, TRF2, KU80, SIRT1, SIRT2 AND GLOBAL PROTEIN ACETYLATION, AS WELL AS OTHER PROTEINS INVOLVED IN APOPTOTIC PATHWAY (BCL-2, BAX AND CASPASE-3), ANTIOXIDANT RESPONSE (TRXR1 AND MNSOD) AND OXIDATIVE DAMAGE (MYELOPEROXIDASE) WERE EVALUATED BEFORE AND AFTER EMRT IN WHOLE BLOOD OR PERIPHERAL MONONUCLEAR CELLS (PBMCS) OF ELDERLY SUBJECTS. OUR FINDINGS CONFIRM THE POTENTIAL OF EMRT TO INDUCE AN ADAPTIVE CHANGE IN THE ANTIOXIDANT PROTEIN SYSTEMS AT SYSTEMIC LEVEL AND SUGGEST A PUTATIVE ROLE OF RESISTANCE TRAINING IN THE REDUCTION OF GLOBAL DNA METHYLATION. MOREOVER, WE OBSERVED THAT EMRT COUNTERACTS THE TELOMERES' SHORTENING IN A MANNER THAT PROVED TO BE DIRECTLY CORRELATED WITH THE AMELIORATION OF REDOX HOMEOSTASIS AND EFFICACY OF TRAINING REGIME, EVALUATED AS IMPROVEMENT OF BOTH MUSCLE'S POWER/STRENGTH AND FUNCTIONAL PARAMETERS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4   902  68 CHRONIC EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION CAUSES INCREASED GROWTH AND TRANSFORMATION IN HUMAN PROSTATE EPITHELIAL CELLS POTENTIALLY BY HYPERMETHYLATION-MEDIATED SILENCING OF MLH1. BACKGROUND: CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN IS ASSOCIATED WITH RISK OF PROSTATE CANCER, BUT THEIR MECHANISM IS NOT FULLY UNDERSTOOD. ADDITIONALLY, THE CARCINOGENIC EFFECTS OF THEIR CO-EXPOSURE ARE NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF CHRONIC EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION, ON CELL GROWTH AND TRANSFORMATION, AND IDENTIFY THE MECHANISM BEHIND THESE EFFECTS. METHODS: RWPE-1 HUMAN PROSTATE EPITHELIAL CELLS WERE CHRONICALLY EXPOSED TO ARSENIC AND ESTROGEN ALONE AND IN COMBINATION. CELL GROWTH WAS MEASURED BY CELL COUNT AND CELL CYCLE, WHEREAS CELL TRANSFORMATION WAS EVALUATED BY COLONY FORMATION ASSAY. GENE EXPRESSION WAS MEASURED BY QUANTITATIVE REAL-TIME PCR AND CONFIRMED AT PROTEIN LEVEL BY WESTERN BLOT ANALYSIS. MLH1 PROMOTER METHYLATION WAS DETERMINED BY PYROSEQUENCING METHOD. RESULTS: EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATIONS INCREASES CELL GROWTH AND TRANSFORMATION IN RWPE-1 CELLS. INCREASED EXPRESSION OF CYCLIN D1 AND BCL2, WHEREAS DECREASED EXPRESSION OF MISMATCH REPAIR GENES MSH4, MSH6, AND MLH1 WAS ALSO OBSERVED. HYPERMETHYLATION OF MLH1 PROMOTER FURTHER SUGGESTED THE EPIGENETIC INACTIVATION OF MLH1 EXPRESSION IN ARSENIC AND ESTROGEN TREATED CELLS. ARSENIC AND ESTROGEN COMBINATION CAUSED GREATER CHANGES THAN THEIR INDIVIDUAL TREATMENTS. CONCLUSIONS: FINDINGS OF THIS STUDY FOR THE FIRST TIME SUGGEST THAT ARSENIC AND ESTROGEN EXPOSURES CAUSE INCREASED CELL GROWTH AND SURVIVAL POTENTIALLY THROUGH EPIGENETIC INACTIVATION OF MLH1 RESULTING IN DECREASED MLH1-MEDIATED APOPTOTIC RESPONSE, AND CONSEQUENTLY INCREASED CELLULAR TRANSFORMATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  3460  44 HYPOMETHYLATION OF THE IL8 PROMOTER IN NASAL EPITHELIAL CELLS OF PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND: IL-8 IS AN IMPORTANT CHEMOKINE IMPLICATED IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS (CRS), BUT LITTLE IS KNOWN ABOUT EPIGENETIC REGULATION OF IL8 IN THE PATHOGENESIS OF CRS. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE RELATIONSHIP BETWEEN THE DNA METHYLATION LEVEL IN THE IL8 PROXIMAL PROMOTER AND CRS IN HAN CHINESE SUBJECTS. METHODS: PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP; N = 187), PATIENTS WITH CHRONIC RHINOSINUSITIS WITHOUT NASAL POLYPS (CRSSNP; N = 89), AND CONTROL SUBJECTS (N = 57) WERE ENROLLED IN 2 INDEPENDENT COHORTS. PURIFIED HUMAN NASAL EPITHELIAL CELLS FROM EACH PARTICIPANT WERE ASSESSED FOR PERCENTAGE DNA METHYLATION OF CPG SITES IN THE IL8 PROXIMAL PROMOTER BY USING BISULFITE PYROSEQUENCING AND FOR FUNCTIONAL ASPECTS OF METHYLATION STATUS BY USING IN VITRO ASSAYS. RESULTS: DNA METHYLATION OF CPG SITES 1, 2, AND 3, RESPECTIVELY, IN THE IL8 PROXIMAL PROMOTER WAS SIGNIFICANTLY DECREASED IN HUMAN NASAL EPITHELIAL CELLS OF PATIENTS WITH CRSWNP COMPARED WITH THAT IN PATIENTS WITH CRSSNP (P < .001) AND CONTROL SUBJECTS (P < .001). PERCENTAGE OF DNA METHYLATION OF THE CPG3 SITE WAS CORRELATED NEGATIVELY WITH BOTH TISSUE EOSINOPHILIC CATIONIC PROTEIN (P < .01) AND MYELOPEROXIDASE (P < .05) LEVELS. IL-1BETA (P < .001) AND TNF-ALPHA (P < .01) SIGNIFICANTLY INCREASED IL8 EXPRESSION ACCOMPANIED BY A REDUCTION IN METHYLATION AT THE CPG3 SITE (P < .001). ELECTROPHORETIC MOBILITY SHIFT ASSAYS DEMONSTRATED THAT METHYLATION STATUS OF CPG3 CHANGED THE BINDING OF OCTAMER-BINDING TRANSCRIPTION FACTOR 1 AND NUCLEAR FACTOR KAPPAB. CONCLUSION: DECREASED DNA METHYLATION OF PARTICULARLY CPG SITES IN THE IL8 PROXIMAL PROMOTER MIGHT PLAY A ROLE IN THE PATHOGENESIS OF CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  5683  41 SHORTER TELOMERE LENGTH IN PERIPHERAL BLOOD LYMPHOCYTES OF WORKERS EXPOSED TO POLYCYCLIC AROMATIC HYDROCARBONS. SHORTER TELOMERE LENGTH (TL) IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) IS PREDICTIVE OF LUNG CANCER RISK. POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) ARE ESTABLISHED LUNG CARCINOGENS THAT CAUSE CHROMOSOME INSTABILITY. WHETHER PAH EXPOSURE AND ITS MOLECULAR EFFECTS ARE LINKED WITH SHORTER TL HAS NEVER BEEN EVALUATED. IN THE PRESENT STUDY, WE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO PAHS ON TL MEASURED IN PBLS OF POLISH MALE NON-CURRENT SMOKING COKEOVEN WORKERS AND MATCHED CONTROLS. PAH EXPOSURE AND MOLECULAR EFFECTS WERE CHARACTERIZED USING MEASURES OF INTERNAL DOSE (URINARY 1-PYRENOL), EFFECTIVE DOSE [ANTI-BENZO[A]PYRENE DIOLEPOXIDE (ANTI-BPDE)-DNA ADDUCT], GENETIC INSTABILITY (MICRONUCLEI, MN) AND DNA METHYLATION [P53 PROMOTER AND ALU AND LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) REPETITIVE ELEMENTS, AS SURROGATE MEASURES OF GLOBAL METHYLATION] IN PBLS. TL WAS MEASURED BY REAL-TIME POLYMERASE CHAIN REACTION. COKEOVEN WORKERS WERE HEAVILY EXPOSED TO PAHS (79% EXCEEDED THE URINARY 1-PYRENOL BIOLOGICAL EXPOSURE INDEX) AND EXHIBITED LOWER TL (P = 0.038) THAN CONTROLS, AS WELL AS HIGHER LEVELS OF GENETIC AND CHROMOSOMAL ALTERATIONS [I.E. ANTI-BPDE-DNA ADDUCT AND MN (P < 0.0001)] AND EPIGENETIC CHANGES [I.E. P53 GENE-SPECIFIC PROMOTER AND GLOBAL METHYLATION (P <OR= 0.001)]. TL DECREASED WITH LONGER DURATION OF WORK AS COKEOVEN WORKER (P = 0.039) AND IN ALL SUBJECTS WITH HIGHER LEVELS OF ANTI-BPDE-DNA ADDUCT (P = 0.042), P53 HYPOMETHYLATION (P = 0.005) AND MN (P = 0.009). IN MULTIVARIATE ANALYSIS, YEARS OF WORK IN COKERY (P = 0.008) AND P53 HYPOMETHYLATION (P = 0.001) WERE THE PRINCIPAL DETERMINANTS OF SHORTER TL. OUR RESULTS INDICATE THAT SHORTER TL IS ASSOCIATED WITH CHRONIC PAH EXPOSURE. THE INTERRELATIONS WITH OTHER GENETIC AND EPIGENETIC MECHANISMS IN OUR DATA SUGGEST THAT SHORTER TL COULD BE A CENTRAL EVENT IN PAH CARCINOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7  1815  46 EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN ON EPIGENETIC REGULATORY GENES EXPRESSION AND EPIGENETIC CODE IN HUMAN PROSTATE EPITHELIAL CELLS. CHRONIC EXPOSURES TO ARSENIC AND ESTROGEN ARE KNOWN RISK FACTORS FOR PROSTATE CANCER. THOUGH THE EVIDENCE SUGGESTS THAT EXPOSURE TO ARSENIC OR ESTROGENS CAN DISRUPT NORMAL DNA METHYLATION PATTERNS AND HISTONE MODIFICATIONS, THE MECHANISMS BY WHICH THESE CHEMICALS INDUCE EPIGENETIC CHANGES ARE NOT FULLY UNDERSTOOD. MOREOVER, THE EPIGENETIC EFFECTS OF CO-EXPOSURE TO THESE TWO CHEMICALS ARE NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN, BOTH ALONE AND IN COMBINATION, ON THE EXPRESSION OF EPIGENETIC REGULATORY GENES, THEIR CONSEQUENCES ON DNA METHYLATION, AND HISTONE MODIFICATIONS. HUMAN PROSTATE EPITHELIAL CELLS, RWPE-1, CHRONICALLY EXPOSED TO ARSENIC AND ESTROGEN ALONE AND IN COMBINATION WERE USED FOR ANALYSIS OF EPIGENETIC REGULATORY GENES EXPRESSION, GLOBAL DNA METHYLATION CHANGES, AND HISTONE MODIFICATIONS AT PROTEIN LEVEL. THE RESULT OF THIS STUDY REVEALED THAT EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION ALTERS THE EXPRESSION OF EPIGENETIC REGULATORY GENES AND CHANGES GLOBAL DNA METHYLATION AND HISTONE MODIFICATION PATTERNS IN RWPE-1 CELLS. THESE CHANGES WERE SIGNIFICANTLY GREATER IN ARSENIC AND ESTROGEN COMBINATION TREATED GROUP THAN INDIVIDUALLY TREATED GROUP. THE FINDINGS OF THIS STUDY WILL HELP EXPLAIN THE EPIGENETIC MECHANISM OF ARSENIC- AND/OR ESTROGEN-INDUCED PROSTATE CARCINOGENESIS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8  1189  45 CORRELATION BETWEEN GLOBAL METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES AND SERUM C REACTIVE PROTEIN LEVEL MODIFIED BY MTHFR POLYMORPHISM: A CROSS-SECTIONAL STUDY. BACKGROUND: CHRONIC INFLAMMATORY CONDITIONS ARE ASSOCIATED WITH HIGHER TUMOR INCIDENCE THROUGH EPIGENETIC AND GENETIC ALTERATIONS. HERE, WE FOCUSED ON AN ASSOCIATION BETWEEN AN INFLAMMATION MARKER, C-REACTIVE-PROTEIN (CRP), AND GLOBAL DNA METHYLATION LEVELS OF PERIPHERAL BLOOD LEUKOCYTES. METHODS: THE SUBJECTS WERE 384 HEALTHY JAPANESE WOMEN ENROLLED AS THE CONTROL GROUP OF A CASE-CONTROL STUDY FOR BREAST CANCER CONDUCTED FROM 2001 TO 2005. GLOBAL DNA METHYLATION WAS QUANTIFIED BY LUMINOMETRIC METHYLATION ASSAY (LUMA). RESULTS: WITH ADJUSTMENT FOR LIFESTYLE-RELATED FACTORS, INCLUDING FOLATE INTAKE, THE GLOBAL DNA METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES WAS SIGNIFICANTLY BUT WEAKLY INCREASED BY 0.43% PER QUARTILE CATEGORY FOR CRP (P FOR TREND = 0.010). ESTIMATED METHYLATION LEVELS STRATIFIED BY CRP QUARTILE WERE 70.0%, 70.8%, 71.4%, AND 71.3%, RESPECTIVELY. IN ADDITION, INTERACTION BETWEEN POLYMORPHISM OF MTHFR (RS1801133, KNOWN AS C677T) AND CRP WAS SIGNIFICANT (P FOR INTERACTION = 0.046); THE GLOBAL METHYLATION LEVEL WAS SIGNIFICANTLY INCREASED BY 0.61% PER QUARTILE CATEGORY FOR CRP IN THE CT/TT GROUP (THOSE WITH THE MINOR ALLELE T, P FOR TREND = 0.001), WHEREAS NO ASSOCIATION WAS OBSERVED IN THE CC GROUP (WILD TYPE). CONCLUSIONS: OUR STUDY SUGGESTS THAT CRP CONCENTRATION IS WEAKLY ASSOCIATED WITH GLOBAL DNA METHYLATION LEVEL. HOWEVER, THIS ASSOCIATION WAS OBSERVED MORE CLEARLY IN INDIVIDUALS WITH THE MINOR ALLELE OF THE MTHFR MISSENSE SNP RS1801133. BY ELUCIDATING THE COMPLEX MECHANISM OF THE REGULATION OF DNA METHYLATION BY BOTH ACQUIRED AND GENETIC FACTORS, OUR RESULTS MAY BE IMPORTANT FOR CANCER PREVENTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9  5116  31 POSITIVE REGULATION OF HUMAN TELOMERASE REVERSE TRANSCRIPTASE GENE EXPRESSION AND TELOMERASE ACTIVITY BY DNA METHYLATION IN PANCREATIC CANCER. AIM: WE SOUGHT TO DETERMINE THE ROLE OF TELOMERASE AND ITS CATALYTIC SUBUNIT HTERT IN PANCREATIC CANCER AND EVALUATE THE EPIGENETIC REGULATION OF HTERT BY PROMOTER METHYLATION. METHODS: THIRTY PAIRED SAMPLES OF PANCREATIC DUCTAL ADENOCARCINOMAS AND ADJACENT NORMAL TISSUE AND 12 CHRONIC PANCREATITIS SAMPLES WERE STUDIED. REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION, TELOMERIC REPEAT AMPLIFICATION PROTOCOL ASSAY, AND METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION WERE PERFORMED TO ANALYZE HTERT EXPRESSION, TELOMERASE ACTIVITY, AND METHYLATION STATUS OF GENE PROMOTERS, RESPECTIVELY. RESULT: HTERT AND TELOMERASE ACTIVITY WERE UPREGULATED IN PANCREATIC CANCER COMPARED WITH PAIRED NORMAL TISSUES AND SAMPLES OF PANCREATITIS. HTERT EXPRESSION CORRELATED WITH TELOMERASE ACTIVITY (P \ .05) AND IN TURN CORRELATED POSITIVELY WITH HTERT PROMOTER METHYLATION (P \ .001) AND P16 PROMOTER METHYLATION. HTERT TRANSCRIPT EXPRESSION AND TELOMERASE ACTIVITY BOTH CONFERRED A WORSE OUTCOME BY UNIVARIATE AND MULTIVARIATE ANALYSIS (P \ .05). CONCLUSION: HTERT EXPRESSION AND TELOMERASE ACTIVITY ARE PREDICTORS OF POOR OUTCOME IN PANCREATIC CANCER. HTERT GENE EXPRESSION IS POSITIVELY REGULATED BY PROMOTER METHYLATION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10   974  42 CHRONIC OCCUPATIONAL EXPOSURE ENDURED BY TOBACCO FARMERS FROM BRAZIL AND ASSOCIATION WITH DNA DAMAGE. TOBACCO FARMING IS AN IMPORTANT ECONOMIC INCOME IN BRAZIL, ALTHOUGH IT HAS BEEN CHALLENGED AS REGARD THE OCCUPATIONAL EXPOSURE TO BOTH PESTICIDES AND NICOTINE ENDURED BY FARMERS. CHRONIC OCCUPATIONAL EXPOSURE TO COMPLEX MIXTURES CAN LEAD TO HEALTH HAZARDOUS. WE EXAMINED GENOMIC INSTABILITY AND EPIGENETIC CHANGES IN TOBACCO FARMERS OCCUPATIONALLY EXPOSED TO PESTICIDE MIXTURES AND NICOTINE AT TOBACCO FIELDS. DNA DAMAGE WAS ASSESSED BY ALKALINE COMET ASSAY IN BLOOD CELLS. GENOMIC DNA WAS ISOLATED, AND TELOMERE LENGTH WAS MEASURED USING QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY. WE MEASURED 5-METHYL-2'-DEOXYCYTIDINE, A MARKER OF GLOBAL DNA METHYLATION, AND P16 PROMOTER METHYLATION. THE OXIDATIVE PROFILE WAS EVALUATED BY TROLOX EQUIVALENT ANTIOXIDANT CAPACITY AND LIPID PEROXIDATION (THIOBARBITURIC ACID REACTIVE SUBSTANCES) IN SERUM. EXPOSURE PARAMETERS, PLASMA COTININE AND INORGANIC ELEMENT LEVELS, WERE ALSO MEASURED. DNA DAMAGE WAS SIGNIFICANTLY ELEVATED FOR FARMERS IN RELATION TO UNEXPOSED GROUP (P < 0.001; MANN-WHITNEY TEST) AND POSITIVELY ASSOCIATED WITH YEARS OF EXPOSURE. INVERSE RELATIONSHIP BETWEEN DNA DAMAGE AND TOTAL EQUIVALENT ANTIOXIDANT ACTIVITY WAS DEMONSTRATED FOR EXPOSED AND UNEXPOSED GROUPS. EXPOSED GROUP SHOWED SIGNIFICANTLY SHORTER TELOMERES (P < 0.001; UNPAIRED T-TEST) AND DNA HYPOMETHYLATION (P < 0.001; UNPAIRED T-TEST), AS WELL AS P16 HYPERMETHYLATION (P = 0.003; MANN-WHITNEY TEST). LIPID PEROXIDATION WAS INCREASED FOR EXPOSED GROUP IN RELATION TO UNEXPOSED ONE (P = 0.02; MANN-WHITNEY TEST) AND PRESENTED A POSITIVE CORRELATION WITH GLOBAL DNA METHYLATION (P = 0.0264). FARMERS HAVE INCREASED PLASMA COTININE LEVELS (P < 0.001) AND INORGANIC ELEMENTS (PHOSPHORUS, SULPHUR AND CHLORINE) IN RELATION TO UNEXPOSED GROUP. ELEVATED OXIDATIVE STRESS LEVELS DUE TO CHRONIC OCCUPATIONAL PESTICIDE MIXTURES AND NICOTINE EXPOSURE IN TOBACCO FARMERS WERE ASSOCIATED WITH HIGHER DNA DAMAGE, SHORTER TELOMERES AND ALTERED DNA METHYLATION. TELOMERE-ACCELERATED ATTRITION DUE TO EXPOSURE MAY BE POTENTIAL INTERMEDIATE STEP BEFORE A DISEASE STATE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11   364  47 AMELIORATION OF UREMIC TOXIN INDOXYL SULFATE-INDUCED OSTEOBLASTIC CALCIFICATION BY SET DOMAIN CONTAINING LYSINE METHYLTRANSFERASE 7/9 PROTEIN. BACKGROUND: VASCULAR CALCIFICATION (VC) IS A VERY COMMON PHENOMENON IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). IT HAS BEEN REPORTED THAT SOME HISTONE METHYLATION PLAY A ROLE IN VC AS AN EPIGENETIC REGULATOR. INDOXYL SULFATE (IS) IS A PROTEIN-BOUND UREMIC TOXIN THAT HAS BEEN PROVEN AS ONE OF THE MAJOR RISK FACTORS OF CARDIOVASCULAR DISEASE IN CKD. SET DOMAIN CONTAINING LYSINE METHYLTRANSFERASE 7/9 (SET7/9) IS ONE OF THE IMPORTANT HISTONE METHYLTRANSFERASES. OBJECTIVES: THIS STUDY AIMED TO DETERMINE THE EFFECT OF IS ON THE EXPRESSION OF SET7/9 AND THE ROLE OF SET7/9 IN IS-INDUCED OSTEOBLASTIC DIFFERENTIATION AND CALCIFICATION OF VASCULAR SMOOTH MUSCLE CELLS (VSMCS). METHODS: VSMCS WERE INCUBATED WITH VARIOUS CONCENTRATIONS OF IS FOR DIFFERENT DURATIONS TO ASSESS OSTEOBLASTIC DIFFERENTIATION AND EXPRESSION OF SET7/9. WESTERN BLOT ANALYSIS AND QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION WERE PERFORMED TO ASSESS THE PROTEIN AND MRNA LEVELS OF SET7/9 RESPECTIVELY. THE CALCIUM CONTENT WAS MEASURED TO EVALUATE CALCIFICATION. RESULTS: OSTEOBLASTIC DIFFERENTIATION AND CALCIFICATION OF VSMCS AND DOWNREGULATION OF THE EXPRESSION OF SET7/9 WERE OBSERVED AFTER IS TREATMENT. THE AUTOPHAGY WAS ACTIVATED AFTER TREATMENT WITH IS, WHEREAS THE INHIBITION OF THE AUTOPHAGY PARTIALLY ATTENUATED THE EFFECT OF IS ON BOTH THE STIMULATION OF THE EXPRESSION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 AND CALCIUM DEPOSITION. CONCLUSIONS: OUR DATA DEMONSTRATED THAT SET7/9 DOWNREGULATION AND AUTOPHAGY ACTIVATION MAY BE THE KEY MECHANISM OF IS-INDUCED VC IN CKD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12   871  48 CHRONIC ALCOHOL EXPOSURE AFFECTS PANCREATIC ACINAR MITOCHONDRIAL THIAMIN PYROPHOSPHATE UPTAKE: STUDIES WITH MOUSE 266-6 CELL LINE AND PRIMARY CELLS. THIAMIN IS ESSENTIAL FOR NORMAL METABOLIC ACTIVITY OF ALL MAMMALIAN CELLS, INCLUDING THOSE OF THE PANCREAS. CELLS OBTAIN THIAMIN FROM THEIR SURROUNDINGS AND ENZYMATICALLY CONVERT IT INTO THIAMIN PYROPHOSPHATE (TPP) IN THE CYTOPLASM; TPP IS THEN TAKEN UP BY MITOCHONDRIA VIA A SPECIFIC CARRIER THE MITOCHONDRIAL TPP TRANSPORTER (MTPPT; PRODUCT OF THE SLC25A19 GENE). CHRONIC ALCOHOL EXPOSURE NEGATIVELY IMPACTS THE HEALTH OF PANCREATIC ACINAR CELLS (PAC), BUT ITS EFFECT ON PHYSIOLOGICAL/MOLECULAR PARAMETERS OF MTPPT IS NOT KNOWN. WE ADDRESSED THIS ISSUE USING MOUSE PANCREATIC ACINAR TUMOR CELL LINE 266-6 AND PRIMARY PAC OF WILD-TYPE AND TRANSGENIC MICE CARRYING THE SLC25A19 PROMOTER THAT WERE FED ALCOHOL CHRONICALLY. CHRONIC ALCOHOL EXPOSURE OF 266-6 CELLS (BUT NOT TO ITS NONOXIDATIVE METABOLITES ETHYL PALMITATE AND ETHYL OLEATE) LED TO A SIGNIFICANT INHIBITION IN MITOCHONDRIAL TPP UPTAKE, WHICH WAS ASSOCIATED WITH A DECREASED EXPRESSION OF MTPPT PROTEIN, MRNA, AND ACTIVITY OF THE SLC25A19 PROMOTER. SIMILARLY, CHRONIC ALCOHOL FEEDING OF MICE LED TO A SIGNIFICANT INHIBITION IN EXPRESSION OF MTPPT PROTEIN, MRNA, HETEROGENEOUS NUCLEAR RNA, AS WELL AS IN ACTIVITY OF SLC25A19 PROMOTER IN PAC. WHILE CHRONIC ALCOHOL EXPOSURE DID NOT AFFECT DNA METHYLATION OF THE SLC25A19 PROMOTER, A SIGNIFICANT DECREASE IN HISTONE H3 EUCHROMATIN MARKERS AND AN INCREASE IN H3 HETEROCHROMATIN MARKER WERE OBSERVED. THESE FINDINGS SHOW, FOR THE FIRST TIME, THAT CHRONIC ALCOHOL EXPOSURE NEGATIVELY IMPACTS PANCREATIC MTPPT, AND THAT THIS EFFECT IS EXERTED, AT LEAST IN PART, AT THE LEVEL OF SLC25A19 TRANSCRIPTION AND APPEARS TO INVOLVE EPIGENETIC MECHANISM(S).	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
13  3841  43 IRON SUPPLEMENTATION REVERSES THE REDUCTION OF HYDROXYMETHYLCYTOSINE IN HEPATIC DNA ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION IN RATS. BACKGROUND: ALCOHOL IS KNOWN TO AFFECT TWO EPIGENETIC PHENOMENA, DNA METHYLATION AND DNA HYDROXYMETHYLATION, AND IRON IS A COFACTOR OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES THAT CATALYZE THE CONVERSION FROM METHYLCYTOSINE TO HYDROXYMETHYLCYTOSINE. IN THE PRESENT STUDY WE AIMED TO DETERMINE THE EFFECTS OF ALCOHOL ON DNA HYDROXYMETHYLATION AND FURTHER EFFECTS OF IRON ON ALCOHOL ASSOCIATED EPIGENETIC CHANGES. METHODS: TWENTY-FOUR MALE SPRAGUE-DAWLEY RATS WERE FED EITHER LIEBER-DECARLI ALCOHOL DIET (36% CALORIES FROM ETHANOL) OR LIEBER-DECARLI CONTROL DIET ALONG WITH OR WITHOUT IRON SUPPLEMENTATION (0.6% CARBONYL IRON) FOR 8 WEEKS. HEPATIC NON-HEME IRON CONCENTRATIONS WERE MEASURED BY COLORIMETRIC ASSAYS. PROTEIN LEVELS OF HEPATIC FERRITIN AND TRANSFERRIN RECEPTOR WERE DETERMINED BY WESTERN BLOTTING. METHYLCYTOSINE, HYDROXYMETHYLCYTOSINE AND UNMODIFIED CYTOSINE IN DNA WERE SIMULTANEOUSLY MEASURED BY LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY METHOD. RESULTS: IRON SUPPLEMENTATION SIGNIFICANTLY INCREASED HEPATIC NON-HEME IRON CONTENTS (P < 0.05) BUT ALCOHOL ALONE DID NOT. HOWEVER, BOTH ALCOHOL AND IRON SIGNIFICANTLY INCREASED HEPATIC FERRITIN LEVELS AND DECREASED HEPATIC TRANSFERRIN RECEPTOR LEVELS (P < 0.05). ALCOHOL REDUCED HEPATIC DNA HYDROXYMETHYLATION (0.21% +/- 0.04% VS. 0.33% +/- 0.04%, P = 0.01) COMPARED TO CONTROL, WHILE IRON SUPPLEMENTATION TO ALCOHOL DIET DID NOT CHANGE DNA HYDROXYMETHYLATION. THERE WAS NO SIGNIFICANT DIFFERENCE IN METHYLCYTOSINE LEVELS, WHILE UNMODIFIED CYTOSINE LEVELS WERE SIGNIFICANTLY INCREASED IN ALCOHOL-FED GROUPS COMPARED TO CONTROL (95.61% +/- 0.08% VS. 95.26% +/- 0.12%, P = 0.03), SUGGESTING THAT ALCOHOL FURTHER INCREASES THE CONVERSION FROM HYDROXYMETHYLCYTOSINE TO UNMODIFIED CYTOSINE. CONCLUSIONS: CHRONIC ALCOHOL CONSUMPTION ALTERS GLOBAL DNA HYDROXYMETHYLATION IN THE LIVER BUT IRON SUPPLEMENTATION REVERSES THE EPIGENETIC EFFECT OF ALCOHOL.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  1610  50 DNA METHYLATION/DEMETHYLATION NETWORK EXPRESSION IN PSYCHOTIC PATIENTS WITH A HISTORY OF ALCOHOL ABUSE. BACKGROUND: RECENT STUDIES SUGGEST THAT PROTRACTED AND EXCESSIVE ALCOHOL USE INDUCES AN EPIGENETIC DYSREGULATION IN HUMAN AND RODENT BRAINS. WE RECENTLY REPORTED THAT DNA METHYLATION DYNAMICS ARE ALTERED IN BRAINS OF PSYCHOTIC (PS) PATIENTS, INCLUDING SCHIZOPHRENIA AND BIPOLAR DISORDER PATIENTS. BECAUSE PS PATIENTS ARE OFTEN COMORBID WITH CHRONIC ALCOHOL ABUSE, WE EXAMINED WHETHER THE ALTERED EXPRESSION OF MULTIPLE MEMBERS OF THE DNA METHYLATION/DEMETHYLATION NETWORK OBSERVED IN POSTMORTEM BRAINS OF PS PATIENTS WAS MODIFIED IN PS PATIENTS WITH A HISTORY OF CHRONIC ALCOHOL ABUSE. METHODS: DNA-METHYLTRANSFERASE-1 (DNMT1) MRNA-POSITIVE NEURONS WERE COUNTED IN SITU IN PREFRONTAL CORTEX SAMPLES OBTAINED FROM THE HARVARD BRAIN TISSUE RESOURCE CENTER, BELMONT, MA. 10-11-TRANSLOCATION (TETS 1, 2, 3), APOLIPOPROTEIN B EDITING COMPLEX ENZYME (APOBEC-3C), GROWTH AND DNA-DAMAGE-INDUCIBLE PROTEIN 45BETA (GADD45BETA), AND METHYL-BINDING DOMAIN PROTEIN-4 (MBD4) MRNAS WERE MEASURED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION IN INFERIOR PARIETAL CORTICAL LOBULE SAMPLES OBTAINED FROM THE STANLEY FOUNDATION NEUROPATHOLOGY CONSORTIUM, BETHESDA, MD. RESULTS: WE OBSERVED AN INCREASE IN DNMT1 MRNA-POSITIVE NEURONS IN PS PATIENTS COMPARED WITH NON-PS SUBJECTS. IN ADDITION, THERE WAS A PRONOUNCED DECREASE IN APOBEC-3C AND A PRONOUNCED INCREASE IN GADD45BETA AND TET1 MRNAS IN PS PATIENTS WITH NO HISTORY OF ALCOHOL ABUSE. IN PS PATIENTS WITH A HISTORY OF CHRONIC ALCOHOL ABUSE, THE NUMBERS OF DNMT1-POSITIVE NEURONS WERE NOT INCREASED SIGNIFICANTLY. FURTHERMORE, THE DECREASE IN APOBEC-3C MRNA WAS LESS PRONOUNCED, WHILE THE INCREASE IN TET1 MRNA HAD A TENDENCY TO BE POTENTIATED IN THOSE PS PATIENTS THAT WERE CHRONIC ALCOHOL ABUSERS. GADD45BETA AND MBD4 MRNAS WERE NOT INFLUENCED BY ALCOHOL ABUSE. THE EFFECT OF CHRONIC ALCOHOL ABUSE ON DNA METHYLATION/DEMETHYLATION NETWORK ENZYMES CANNOT BE ATTRIBUTED TO CONFOUNDING DEMOGRAPHIC VARIABLES OR TO THE TYPE AND DOSE OF MEDICATION USED. CONCLUSIONS: BASED ON THESE RESULTS, WE HYPOTHESIZE THAT PS PATIENTS MAY ABUSE ALCOHOL AS A POTENTIAL ATTEMPT AT SELF-MEDICATION TO NORMALIZE ALTERED DNA METHYLATION/DEMETHYLATION NETWORK PATHWAYS. HOWEVER, BEFORE ACCEPTING THIS CONCLUSION, WE NEED TO STUDY ALTERATIONS IN THE DNA METHYLATION/DEMETHYLATION PATHWAYS AND THE DNA METHYLATION DYNAMICS IN A SUBSTANTIAL NUMBER OF ALCOHOLIC PS AND NON-PS PATIENTS. ADDITIONAL INVESTIGATION MAY ALSO BE NECESSARY TO DETERMINE WHETHER THE ALTERED DNA METHYLATION DYNAMICS ARE DIRECT OR THE CONSEQUENCE OF AN INDIRECT INTERACTION OF ALCOHOL WITH THE NEUROPATHOGENETIC MECHANISMS UNDERLYING PSYCHOSIS.	2013	

15   502  49 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   286  47 AGING AND ALCOHOL INTERACT TO ALTER HEPATIC DNA HYDROXYMETHYLATION. BACKGROUND: AGING AND CHRONIC ALCOHOL CONSUMPTION ARE BOTH MODIFIERS OF DNA METHYLATION, BUT IT IS NOT YET KNOWN WHETHER CHRONIC ALCOHOL CONSUMPTION ALSO ALTERS DNA HYDROXYMETHYLATION, A NEWLY DISCOVERED EPIGENETIC MARK PRODUCED BY OXIDATION OF METHYLCYTOSINE. FURTHERMORE, IT HAS NOT BEEN TESTED WHETHER AGING AND ALCOHOL INTERACT TO MODIFY THIS EPIGENETIC PHENOMENON, THEREBY HAVING AN INDEPENDENT EFFECT ON GENE EXPRESSION. METHODS: OLD (18 MONTHS) AND YOUNG (4 MONTHS) MALE C57BL/6 MICE WERE PAIR-FED EITHER A LIEBER-DECARLI LIQUID DIET WITH ALCOHOL (18% OF ENERGY) OR AN ISOCALORIC LIEBER-DECARLI CONTROL DIET FOR 5 WEEKS. GLOBAL DNA HYDROXYMETHYLATION AND DNA METHYLATION WERE ANALYZED FROM HEPATIC DNA USING A NEW LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY METHOD. HEPATIC MRNA EXPRESSION OF THE TET ENZYMES WERE MEASURED VIA QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION. RESULTS: IN YOUNG MICE, MILD CHRONIC ALCOHOL EXPOSURE SIGNIFICANTLY REDUCED GLOBAL DNA HYDROXYMETHYLATION COMPARED WITH CONTROL MICE (0.22 +/- 0.01 VS. 0.29 +/- 0.06%, P = 0.004). ALCOHOL DID NOT SIGNIFICANTLY ALTER HYDROXYMETHYLCYTOSINE LEVELS IN OLD MICE. OLD MICE FED THE CONTROL DIET SHOWED DECREASED GLOBAL DNA HYDROXYMETHYLATION COMPARED WITH YOUNG MICE FED THE CONTROL DIET (0.24 +/- 0.02 VS. 0.29 +/- 0.06%, P = 0.04). THIS MODEL SUGGESTS AN INTERACTION BETWEEN AGING AND ALCOHOL IN DETERMINING DNA HYDROXYMETHYLATION (PINTERACTION = 0.009). EXPRESSION OF TET2 AND TET3 WAS DECREASED IN THE OLD MICE RELATIVE TO THE YOUNG (P < 0.005). CONCLUSIONS: THE OBSERVATION THAT ALCOHOL ALTERS DNA HYDROXYMETHYLATION INDICATES A NEW EPIGENETIC EFFECT OF ALCOHOL. THIS IS THE FIRST STUDY DEMONSTRATING THE INTERACTIVE EFFECTS OF CHRONIC ALCOHOL CONSUMPTION AND AGING ON DNA HYDROXYMETHYLATION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
17  5010  41 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID.	1994	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  3456  41 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  5860  39 SULFORAPHANE PREVENTS ANGIOTENSIN II-INDUCED CARDIOMYOPATHY BY ACTIVATION OF NRF2 THROUGH EPIGENETIC MODIFICATION. NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR (NRF2) IS AN IMPORTANT REGULATOR OF CELLULAR ANTIOXIDANT DEFENCE. WE PREVIOUSLY SHOWED THAT SFN PREVENTED ANG II-INDUCED CARDIAC DAMAGE VIA ACTIVATION OF NRF2. HOWEVER, THE UNDERLYING MECHANISM OF SFN'S PERSISTENT CARDIAC PROTECTION REMAINS UNCLEAR. THIS STUDY AIMED TO EXPLORE THE POTENTIAL OF SFN IN ACTIVATING CARDIAC NRF2 THROUGH EPIGENETIC MECHANISMS. WILD-TYPE MICE WERE INJECTED SUBCUTANEOUSLY WITH ANG II, WITH OR WITHOUT SFN. ADMINISTRATION OF CHRONIC ANG II-INDUCED CARDIAC INFLAMMATORY FACTOR EXPRESSION, OXIDATIVE DAMAGE, FIBROSIS AND CARDIAC REMODELLING AND DYSFUNCTION, ALL OF WHICH WERE EFFECTIVELY IMPROVED BY SFN TREATMENT, COUPLED WITH AN UP-REGULATION OF NRF2 AND DOWNSTREAM GENES. BISULFITE GENOME SEQUENCING AND CHROMATIN IMMUNOPRECIPITATION (CHIP) WERE PERFORMED TO DETECT THE METHYLATION LEVEL OF THE FIRST 15 CPGS AND HISTONE H3 ACETYLATION (AC-H3) STATUS IN THE NRF2 PROMOTER REGION, RESPECTIVELY. THE RESULTS SHOWED THAT SFN REDUCED ANG II-INDUCED CPG HYPERMETHYLATION AND PROMOTED AC-H3 ACCUMULATION IN THE NRF2 PROMOTER REGION, ACCOMPANIED BY THE INHIBITION OF GLOBAL DNMT AND HDAC ACTIVITY, AND A DECREASED PROTEIN EXPRESSION OF KEY DNMT AND HDAC ENZYMES. TAKEN TOGETHER, SFN EXERTS ITS CARDIOPROTECTIVE EFFECT THROUGH EPIGENETIC MODIFICATION OF NRF2, WHICH MAY PARTIALLY CONTRIBUTE TO LONG-TERM ACTIVATION OF CARDIAC NRF2.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20  4899  36 OXIDATIVE STRESS MEDIATES THE APOPTOSIS AND EPIGENETIC MODIFICATION OF THE BCL-2 PROMOTER VIA DNMT1 IN A CIGARETTE SMOKE-INDUCED EMPHYSEMA MODEL. BACKGROUND: EMPHYSEMA IS A CRUCIAL PATHOLOGICAL CHARACTERISTIC OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). OXIDATIVE STRESS, APOPTOSIS AND EPIGENETIC MECHANISMS CONTRIBUTE TO THE PATHOGENESIS OF EMPHYSEMA. HOWEVER, AN ATTEMPT TO ACCURATELY IDENTIFY WHETHER THESE MECHANISMS INTERACT WITH EACH OTHER AND HOW THEY ARE TRIGGERED HAS NEVER BEEN CONDUCTED. METHOD: THE TOTAL REACTIVE OXYGEN SPECIES (ROS) LEVEL, PULMONARY APOPTOSIS AND B-CELL LYMPHOMA/LEUKEMIA-2 (BCL-2) EXPRESSION, AN APOPTOSIS REGULATOR, WERE DETECTED IN SAMPLES FROM COPD PATIENTS. BISULFITE SEQUENCING PCR (BSP) WAS CONDUCTED TO OBSERVE THE ALTERATIONS IN THE METHYLATION OF THE BCL-2 PROMOTER IN SPECIMENS. THE DYSREGULATION OF DNA METHYLTRANSFERASE ENZYME 1 (DNMT1), A VITAL DNA METHYLTRANSFERASE ENZYME, IN THE LUNGS OF PATIENTS WAS CONFIRMED THROUGH WESTERN BLOTTING. TO FIND OUT INTERACTIONS BETWEEN OXIDATIVE STRESS AND DNA METHYLATION IN EMPHYSEMA, MOUSE MODELS WERE BUILT WITH ANTIOXIDANT TREATMENT AND DNMT1 SILENCING, AND WERE EXAMINED WITH THE PULMONARY APOPTOSIS, BCL-2 AND DNMT1 LEVELS, AND EPIGENETIC ALTERATIONS OF BCL-2. RESULTS: HIGHER ROS LEVELS AND PULMONARY APOPTOSIS WERE OBSERVED IN COPD PATIENTS THAN IN HEALTHY CONTROLS. DOWNREGULATED BCL-2 EXPRESSION WITH INCREASED PROMOTER METHYLATION AND DNMT1 PROTEIN EXPRESSION WAS FOUND IN COPD PATIENTS. ANTIOXIDANT TREATMENT REDUCED THE LEVEL OF ROS, DNMT1 PROTEIN AND EMPHYSEMATOUS PROGRESSION IN THE SMOKING MODELS. FOLLOWING DNMT1 BLOCKADE, SMOKING MODELS SHOWED IMPROVED LUNG FUNCTION, PULMONARY APOPTOSIS, EMPHYSEMATOUS PROGRESSION, AND INCREASED BCL-2 PROTEIN LEVEL WITH LESS PROMOTER METHYLATION THAN EMPHYSEMA MICE. CONCLUSION: CIGARETTE-INDUCED OXIDATIVE STRESS MEDIATES PULMONARY APOPTOSIS AND HYPERMETHYLATION OF THE BCL-2 PROMOTER IN EMPHYSEMA MODELS THROUGH DNMT1.	2020