1  4378 154 MITOCHONDRIAL DNA COPY NUMBER AND EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS. BACKGROUND: INCREASED MITOCHONDRIAL DNA COPY NUMBER (MTDNACN) IS A BIOLOGIC RESPONSE TO MTDNA DAMAGE AND DYSFUNCTION, PREDICTIVE OF LUNG CANCER RISK. POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) ARE ESTABLISHED LUNG CARCINOGENS AND MAY CAUSE MITOCHONDRIAL TOXICITY. WHETHER PAH EXPOSURE AND PAH-RELATED NUCLEAR DNA (NDNA) GENOTOXIC EFFECTS ARE LINKED WITH INCREASED MTDNACN HAS NEVER BEEN EVALUATED. METHODS: WE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO PAHS ON MTDNACN IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) OF 46 POLISH MALE NONCURRENT SMOKING COKE-OVEN WORKERS AND 44 MATCHED CONTROLS, WHO WERE PART OF A GROUP OF 94 STUDY INDIVIDUALS EXAMINED IN OUR PREVIOUS WORK. SUBJECTS' PAH EXPOSURE AND GENETIC ALTERATIONS WERE CHARACTERIZED THROUGH MEASURES OF INTERNAL DOSE (URINARY 1-PYRENOL), TARGET DOSE [ANTI-BENZO[A]PYRENE DIOLEPOXIDE (ANTI-BPDE)-DNA ADDUCT], GENETIC INSTABILITY (MICRONUCLEI AND TELOMERE LENGTH), AND DNA METHYLATION (P53 PROMOTER) IN PBLS. MTDNACN (MT/S) WAS MEASURED USING A VALIDATED REAL-TIME PCR METHOD. RESULTS: WORKERS WITH PAH EXPOSURE ABOVE THE MEDIAN VALUE (>3 MUMOL 1-PYRENOL/MOL CREATININE) SHOWED HIGHER MTDNACN [GEOMETRIC MEANS (GM) OF 1.06 (UNADJUSTED) AND 1.07 (AGE-ADJUSTED)] COMPARED WITH CONTROLS [GM 0.89 (UNADJUSTED); 0.89 (AGE-ADJUSTED); (P = 0.029 AND 0.016)], AS WELL AS HIGHER LEVELS OF GENETIC AND CHROMOSOMAL [I.E., ANTI-BPDE-DNA ADDUCTS (P < 0.001), MICRONUCLEI (P < 0.001), AND TELOMERE LENGTH (P = 0.053)] AND EPIGENETIC [I.E., P53 GENE-SPECIFIC PROMOTER METHYLATION (P < 0.001)] ALTERATIONS IN THE NDNA. IN THE WHOLE STUDY POPULATION, UNADJUSTED AND AGE-ADJUSTED MTDNACN WAS POSITIVELY CORRELATED WITH 1-PYRENOL (P = 0.043 AND 0.032) AND ANTI-BPDE-DNA ADDUCTS (P = 0.046 AND 0.049). CONCLUSIONS: PAH EXPOSURE AND PAH-RELATED NDNA GENOTOXICITY ARE ASSOCIATED WITH INCREASED MTDNACN. IMPACT: THE PRESENT STUDY IS SUGGESTIVE OF POTENTIAL ROLES OF MTDNACN IN PAH-INDUCED CARCINOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  5683  87 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3  3916  33 LINE1 CPG-DNA HYPOMETHYLATION IN GRANULOSA CELLS AND BLOOD LEUKOCYTES IS ASSOCIATED WITH PCOS AND RELATED TRAITS. CONTEXT: ALTERED GLOBAL DNA METHYLATION IS INDICATIVE OF EPIGENOMIC INSTABILITY CONCERNING CHRONIC DISEASES. INVESTIGATING ITS INCIDENCE AND ASSOCIATION WITH POLYCYSTIC OVARY SYNDROME (PCOS) IS ESSENTIAL TO UNDERSTAND THE ETIOPATHOGENESIS OF THIS DISORDER. OBJECTIVES: WE ASSESSED GLOBAL DNA METHYLATION DIFFERENCES IN PERIPHERAL BLOOD LEUKOCYTES (PBLS) AND CUMULUS GRANULOSA CELLS (CGCS) OF CONTROLS AND WOMEN WITH PCOS; AND THEIR ASSOCIATION WITH PCOS AND ITS TRAITS. DESIGN, SETTING, PARTICIPANTS, MAIN OUTCOME MEASURE: THIS STUDY INCLUDED A TOTAL OF 102 CONTROLS AND WOMEN WITH PCOS. FORTY-ONE WOMEN UNDERGOING CONTROLLED OVARIAN HYPERSTIMULATION (COH) AND 61 WOMEN NOT UNDERGOING COH WERE RECRUITED FROM IN VITRO FERTILIZATION (IVF) AND INFERTILITY CLINICS. DNA METHYLATION WAS MEASURED BY ELISA FOR 5'-METHYL-CYTOSINE CONTENT AND BISULFITE SEQUENCING OF 5'-UNTRANSLATED REGION (5'-UTR) OF LONG INTERSPERSED NUCLEOTIDE ELEMENT-1 (LINE1/L1). RESULTS: TOTAL 5'-METHYL-CYTOSINE AND L1 METHYLATION LEVELS IN PBLS AND CGCS WERE SIMILAR BETWEEN CONTROLS AND WOMEN WITH PCOS. METHYLATION ASSESSED AT CPG SITES OF L1 5'-UTR REVEALED A SINGLE CPG-SITE (CPG-4) TO BE CONSISTENTLY HYPOMETHYLATED IN PBLS OF BOTH PCOS GROUPS AND CGCS OF STIMULATED PCOS GROUP. IN UNSTIMULATED WOMEN, HYPOMETHYLATION AT CPG-4 WAS STRONGLY ASSOCIATED WITH PCOS SUSCEPTIBILITY, WHEREAS IN STIMULATED GROUP IT SHOWED STRONG ASSOCIATIONS WITH PCOS AND ITS HORMONAL TRAITS. FURTHERMORE, CGCS DEMONSTRATED CONSISTENT GLOBAL AND CPG-DNA HYPOMETHYLATION RELATIVE TO PBLS, IRRESPECTIVE OF NORMAL OR DISEASE STATES. CONCLUSION: OUR STUDY REVEALED STRONG ASSOCIATION OF SINGLE HYPOMETHYLATED CPG-SITE WITH PCOS. IDENTIFICATION AND CHARACTERIZATION OF MORE SUCH METHYL-CPG SIGNATURES IN REPETITIVE ELEMENTS IN LARGER STUDY POPULATIONS WOULD PROVIDE VALUABLE EPIGENETIC INSIGHTS INTO PCOS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4   766  31 CCL5 SUPPRESSES KLOTHO EXPRESSION VIA P-STAT3/DNA METHYLTRANSFERASE1-MEDIATED PROMOTER HYPERMETHYLATION. BACKGROUND: ENHANCED INFLAMMATION AND REDUCED KLOTHO ARE COMMON FEATURES IN CHRONIC KIDNEY DISEASE (CKD). INFLAMMATION INDUCES DNA HYPERMETHYLATION. THIS STUDY ASSESSED THE PERFORMANCE OF INFLAMMATORY MARKER C-C MOTIF CHEMOKINE 5 (CCL5) IN EPIGENETIC REGULATION OF KLOTHO EXPRESSION. METHODS: FIFTY CKD PATIENTS AND 25 MATCHED CONTROLS WERE ENROLLED, AND SERUM CCL5 LEVEL, SKLOTHO LEVEL, AND DNA METHYLATION WERE EVALUATED IN THESE SUBJECTS. A RENAL INTERSTITIAL FIBROSIS (RIF) MODEL WITH CKD WAS INDUCED IN MICE VIA UNILATERAL URETERAL OBSTRUCTION (UUO) IN VIVO AND HUMAN PROXIMAL TUBULAR EPITHELIAL (HK-2) CELLS TREATED WITH CCL5 IN VITRO. 5-AZA-2'-DEOXYCYTIDINE (5-AZA), A DNA METHYLTRANSFERASE INHIBITOR WAS GIVEN TO UUO MICE. HEMATOXYLIN AND EOSIN (HE) AND MASSON TRICHROME STAINING WERE ADOPTED TO EVALUATE RENAL PATHOLOGICAL CHANGES. METHYLATION-SPECIFIC PCR WAS PERFORMED TO ASSESS DNA METHYLATION OF KLOTHO PROMOTER IN THE PERIPHERAL BLOOD LEUCOCYTES (PBLS) FROM CKD PATIENTS AND OBSTRUCTIVE KIDNEY FROM UUO MICE. CCL5, KLOTHO, AND DNA METHYLTRANSFERASES (DNMTS) WERE DETERMINED BY ELISAS, IMMUNOFLUORESCENCE, OR WESTERN BLOTTING. HK-2 CELLS WERE EXPOSED TO CCL5 WITH OR WITHOUT 5-AZA AND STATTIC, A P-SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) INHIBITOR, AND EXPRESSIONS OF P-STAT3, DNMT1, AND KLOTHO WERE DETERMINED BY WESTERN BLOTTING. RESULTS: CCL5 UPREGULATION CONCOMITANT WITH KLOTHO DOWNREGULATION IN SERUM AND GLOBAL DNA METHYLATION IN PBLS WERE OBSERVED IN CKD SAMPLES. UUO CONTRIBUTED TO SEVERE RENAL INTERSTITIAL FIBROSIS AND ENHANCED EXPRESSIONS OF FIBROTIC MARKERS. MOREOVER, UUO INCREASED THE CCL5 LEVEL, INDUCED KLOTHO PROMOTER METHYLATION, SUPPRESSED KLOTHO LEVEL, ACTIVATED P-STAT3 SIGNALING, AND UPREGULATED DNMT1 LEVEL. A SIMILAR OBSERVATION WAS MADE IN HK-2 CELLS TREATED WITH CCL5. MORE IMPORTANTLY, 5-AZA INHIBITED UUO-INDUCED KLOTHO HYPERMETHYLATION, REVERSED KLOTHO, DOWNREGULATED P-STAT3 EXPRESSIONS, AND AMELIORATED RIF IN VIVO. THE CONSISTENT FINDINGS IN VITRO WERE ALSO OBTAINED IN HK-2 CELLS EXPOSED TO 5-AZA AND STATTIC. CONCLUSION: THE CCL5/P-STAT3/DNMT1 AXIS IS IMPLICATED IN EPIGENETIC REGULATION OF KLOTHO EXPRESSION IN CKD. THIS STUDY PROVIDES NOVEL THERAPEUTIC POSSIBILITIES FOR REVERSAL OF KLOTHO SUPPRESSION BY CKD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5  4601  32 NDRG2 MRNA LEVELS AND MIR-28-5P AND MIR-650 ACTIVITY IN CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: NDRG2 IS IDENTIFIED AS A TUMOR SUPPRESSOR GENE IN MANY TUMORS, AND FUNCTIONS IN CELL PROLIFERATION, DIFFERENTIATION AND APOPTOSIS. RECENT DATA INDICATE THAT NDRG2 EXPRESSION IS UP-REGULATED BY TP53. MOREOVER, PROPOSED MECHANISMS OF NDRG2 INACTIVATION INCLUDE EPIGENETIC SILENCING OF THE NDRG2 PROMOTER AND DOWN-REGULATION BY MICRORNAS (MIRNAS). HOWEVER, FEW STUDIES HAVE EVER BEEN DONE ON THE ROLE OF NDRG2 AND THE NDRG2-REGULATING MIRNAS INTERFERENCE IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). METHODS: NDRG2 AND MICRORNAS MRNA LEVELS IN CLL SUBJECTS WERE ASSESSED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR). THE DUAL-LUCIFERASE REPORTER ASSAY WAS PERFORMED TO DETERMINE NDRG2-RELATED MIRNAS. LOW EXPRESSION OF MATURE EXOGENOUS MIRNAS IN CLL CELLS WAS ESTABLISHED BY TRANSIENT TRANSFECTION. NDRG2 PROTEIN LEVELS IN CLL CELLS WERE DETECTED BY WESTERN BLOT. IN ADDITION, FLOW CYTOMETRY WAS CONDUCTED TO EXAMINE THE APOPTOSIS OF CLL CELLS. RESULTS: LOWER EXPRESSION OF NDRG2 WAS FOUND IN THE B-CELLS FROM 102 CLL PATIENTS COMPARED THE 40 NORMAL SUBJECTS (P < 0.001). PATIENTS WITH ADVANCED BINET STAGE (P = 0.001), HIGH LACTATE DEHYDROGENASE (LDH) LEVEL (P = 0.036), UN-MUTATED IMMUNOGLOBULIN HEAVY CHAIN VARIABLE REGION GENE (IGHV) (P = 0.004) AND THOSE WITH P53 ABERRATIONS (P < 0.001) HAD A MARKEDLY LOWER LEVELS OF NDRG2 MRNA. THIS DECREASE WAS ASSOCIATED WITH BRIEFER TIME-TO-TREATMENT (P = 0.001) AND POORER SURVIVAL (P < 0.001). HIGH EXPRESSION OF MIR-28-5P AND MIR-650 WAS ASSOCIATED WITH BINET B/C STAGE (P = 0.044) AND IGHV UN-MUTATED (P = 0.011), AS WELL AS BINET B/C STAGE (P = 0.013) AND P53 ABERRATIONS (P = 0.037), RESPECTIVELY. INHIBITION OF MIR-28-5P OR MIR-650 COULD INDUCE MORE APOPTOSIS IN CLL CELLS WITH GERMLINE TP53. CONCLUSIONS: NDRG2 MRNA LEVELS MIGHT BE A USEFUL PROGNOSTIC VARIABLE FOR PATIENTS OF CLL AND UP-REGULATING NDRG2 TRANSCRIPTION MAY BE A THERAPY APPROACH IN CLL WITHOUT P53 ABERRATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6  1189  43 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7  3448  32 HYPERMETHYLATION OF THE N-MYC DOWNSTREAM-REGULATED GENE 2 PROMOTER IN PERIPHERAL BLOOD MONONUCLEAR CELLS IS ASSOCIATED WITH LIVER FIBROSIS IN CHRONIC HEPATITIS B. DNA METHYLATION IS A FUNDAMENTAL EPIGENETIC MODIFICATION TO REGULATE GENE EXPRESSION. N-MYC DOWNSTREAM-REGULATED GENE (NDRG) 2 IS A CYTOPLASMIC PROTEIN AND PARTICIPATES IN THE PATHOGENESIS OF LIVER FIBROSIS. IN THIS STUDY, THE MRNA EXPRESSION AND METHYLATION STATUS OF NDRG2 WAS EVALUATED IN PATIENTS WITH CHRONIC HEPATITIS B (CHB). THE STUDY INCLUDED 143 CHB PATIENTS AND 65 NORMAL CONTROLS (NC). THE MRNA EXPRESSION OF NDRG2 IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WAS DETECTED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION. THE METHYLATION STATUS OF THE NDRG2 PROMOTER IN PBMCS WAS DETECTED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. THE NDRG2 MRNA LEVEL WAS LOWER IN THE CHB GROUP THAN IN THE NC GROUP (P < 0.001). METHYLATION FREQUENCY OF THE NDRG2 PROMOTER WAS SIGNIFICANTLY HIGHER IN CHB PATIENTS THAN IN THE NC GROUP (52.44% VS. 26.15%, P < 0.001). IMPORTANTLY, THE RELATIVE EXPRESSION LEVELS OF NDRG2 MRNA WERE SIGNIFICANTLY LOWER IN THE METHYLATED GROUP THAN IN THE UNMETHYLATED GROUP IN BOTH CHB PATIENTS AND NC (P < 0.001). FURTHERMORE, A LOWER MRNA LEVEL AND HYPERMETHYLATION OF NDRG2 WERE ASSOCIATED WITH LIVER FIBROSIS AND INFLAMMATION GRADE IN CHB. THE ASPARTATE AMINOTRANSFERASE-TO-PLATELET RATIO INDEX (APRI) SCORE IS WIDELY USED TO PREDICT LIVER FIBROSIS. THE MRNA EXPRESSION LEVELS AND METHYLATION STATUS OF NDRG2 SHOWED A BETTER SCORE COMPARED TO APRI FOR DISCRIMINATING THE SEVERITY OF LIVER FIBROSIS. IN CONCLUSION, HYPERMETHYLATION OF NDRG2 IN PBMCS WAS CORRELATED WITH DECREASED MRNA EXPRESSION AND WITH LIVER FIBROSIS. THE METHYLATION STATUS OF THE NDRG2 PROMOTER IN PBMCS IS A POTENTIAL NONINVASIVE BIOMARKER TO PREDICT THE SEVERITY OF LIVER FIBROSIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8   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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9   659  30 BLOOD GLOBAL DNA METHYLATION IS DECREASED IN NON-SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS. BACKGROUND: ALTERATIONS IN GLOBAL DNA METHYLATION HAVE BEEN ASSOCIATED WITH OXIDATIVE STRESS (OS). SINCE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY INCREASED OXIDATIVE STRESS WE AIMED TO EVALUATE THE LEVELS OF GLOBAL DNA METHYLATION IN THIS PATIENT GROUP. METHODS: WE ASSESSED METHYLCYTOSINE (MCYT) LEVELS IN DNA FROM BLOOD COLLECTED IN 43 COPD PATIENTS (29 WITH MILD AND 14 WITH MODERATE DISEASE) AND 43 AGE- AND SEX-MATCHED HEALTHY CONTROLS. RESULTS: DNA METHYLATION WAS SIGNIFICANTLY LOWER IN COPD PATIENTS VS. CONTROLS (4.20 +/- 0.18% MCYT VS. 4.29 +/- 0.18% MCYT, P = 0.02). FURTHERMORE, DNA METHYLATION IN COPD PATIENTS WITH MODERATE DISEASE WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH MILD DISEASE (4.14 +/- 0.15% MCYT VS. 4.23 +/- 0.19% MCYT, P < 0.05). UNIVARIATE LOGISTIC REGRESSION ANALYSIS SHOWED THAT LOWER DNA METHYLATION LEVELS WERE ASSOCIATED WITH PRESENCE OF COPD (CRUDE OR = 0.06, 95% CI 0.00 TO 0.67, P = 0.023). THIS RELATIONSHIP REMAINED SIGNIFICANT AFTER ADJUSTING FOR SEVERAL CONFOUNDERS (OR 0.03, 95% CI 0.00 TO 0.67; P = 0.028). RECEIVER OPERATING CHARACTERISTICS (ROC) CURVE ANALYSIS DEMONSTRATED THE AREA UNDER THE CURVE OF MCYT WAS 0.646, WITH 46.6% SENSITIVITY AND 79.1% SPECIFICITY FOR PRESENCE OF COPD. CONCLUSIONS: THERE WERE NO SIGNIFICANT CORRELATIONS BETWEEN METHYLATION AND OS INDICES. THE PRESENCE AND SEVERITY OF COPD IS ASSOCIATED WITH PROGRESSIVELY LOWER DNA METHYLATION IN BLOOD. HOWEVER, THIS EPIGENETIC ALTERATION SEEMS INDEPENDENT OF OXIDATIVE STRESS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
10  3460  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  1140  29 CONCENTRATION OF FOLIC ACID (FA) IN SERUM OF JAPANESE PREGNANT WOMEN. OBJECTIVES EXPOSURE TO INORGANIC ARSENIC (IAS) IS A WORLD-WIDE HEALTH CONCERN. WE REPORTED THAT JAPANESE CHILDREN AND PREGNANT WOMEN ARE EXPOSED TO MODERATE LEVELS OF IAS THROUGH FOOD. REDUCING IAS CONTAMINATION FROM FOODS OF HIGH IAS IS AN IMPORTANT ISSUE UNIQUE IN JAPAN. INTEGRATED IAS IS METHYLATED TO LESS TOXIC ORGANIC FORMS, AND S-ADENOSYL-L-METHYONINE (SAM), A COMMON METHYL-DONOR OF DNA AND HISTONES, IS UTILIZED IN THIS PROCESS. CHRONIC CONSUMPTION OF SAM BY IAS METABOLISM DUE TO EXPOSURE TO IAS MIGHT ALTER THE EPIGENETIC MODIFICATION OF GENOME. THE SAM BIOSYNTHESIS PATHWAY IS DEPENDENT ON FOLATE CYCLE, AND IT IS POSSIBLE THAT INGESTION OF SUFFICIENT FOLIC ACID (FA) IS PROTECTIVE TO IAS INDUCED TOXICITY. METHODS IN THE COURSE OF OUR CROSS-SECTIONAL BODY BURDEN ANALYSES OF PB AND IAS IN JAPANESE CHILDREN AND PREGNANT WOMEN, TERMED "PBAS STUDY", FA CONCENTRATION IN SERUM OF 104 PREGNANT WOMEN WAS MEASURED. RESULTS MEAN (+/-SEM) OF SERUM FA CONCENTRATION WAS 15.8 +/- 1.3 (NG/ML). THERE ARE SIGNIFICANT NUMBER OF PEOPLE SHOWING VERY HIGH FA (>30 NG/ ML), AND LARGE FRACTION OF THEM WERE TAKING SUPPLEMENTS DAILY. CONCLUSIONS THESE RESULTS SUGGESTED THAT LEVEL OF FA INGESTION OF JAPANESE PREGNANT WOMEN IS HIGH FOR SUPPORTING NORMAL FETAL DEVELOPMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12  3558  36 IMPACT OF CHRONIC BENZENE POISONING ON ABERRANT MITOCHONDRIAL DNA METHYLATION: A PROSPECTIVE OBSERVATIONAL STUDY. BENZENE IS USED AS AN INDUSTRIAL SOLVENT, WHICH MAY RESULT IN CHRONIC BENZENE POISONING (CBP). SEVERAL STUDIES SUGGESTED THAT CBP WAS ASSOCIATED WITH MITOCHONDRIAL EPIGENETIC REGULATION. THIS STUDY AIMED TO EXPLORE THE POTENTIAL RELATION BETWEEN CBP AND MITOCHONDRIAL DNA (MTDNA) METHYLATION. THIS PROSPECTIVE OBSERVATIONAL STUDY ENROLLED CBP PATIENTS ADMITTED TO SHENZHEN PREVENTION AND TREATMENT CENTER FOR OCCUPATIONAL DISEASES HOSPITAL AND HEALTHY INDIVIDUALS BETWEEN 2018 AND 2021. THE WHITE BLOOD CELL (WBC), RED BLOOD CELL (RBC), HEMOGLOBIN (HB), AND PLATELET (PLT) COUNTS AND MTDNA METHYLATION LEVELS WERE MEASURED USING BLOOD FLOW CYTOMETRY AND TARGETED BISULFITE SEQUENCING, RESPECTIVELY. A TOTAL OF 90 PARTICIPANTS WERE RECRUITED, INCLUDING 30 CASES OF CBP (20 FEMALES, MEAN AGE 43.0 +/- 8.0 YEARS) AND 60 HEALTHY INDIVIDUALS (42 FEMALES, MEAN AGE 43.5 +/- 11.5 YEARS). THIS STUDY DETECTED 168 MITOCHONDRIAL METHYLATION SITES >0 IN ALL STUDY SUBJECTS. THE MTDNA METHYLATION LEVELS IN THE CBP CASES WERE LOWER THAN THE HEALTHY INDIVIDUALS [MEDIAN +/- INTERQUARTILE-RANGE (IQR), 25TH PERCENTILE, 75TH PERCENTILE: (1.140 +/- 0.570, 0.965, 1.535)% VS. MEDIAN +/- IQR, 25TH PERCENTILE, 75TH PERCENTILE: (1.705 +/- 0.205,1.240,2.445)%, P < 0.05]. ADDITIONALLY, THE SPEARMAN CORRELATION ANALYSIS SHOWED THAT THE MTDNA METHYLATION LEVELS WERE POSITIVELY CORRELATED WITH THE COUNTS OF CIRCULATING LEUKOCYTES [WBC (R = 0.048, P = 0.036)] AND PLATELETS [PLT (R = 0.129, P < 0.01)]. WE PROVIDED SOLID EVIDENCE OF ASSOCIATION BETWEEN CBP AND ABERRANT MTDNA METHYLATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13  4249  39 METHYLATION-BASED BIOLOGICAL AGE AND BREAST CANCER RISK. BACKGROUND: AGE IS ONE OF THE STRONGEST PREDICTORS OF CANCER, CHRONIC DISEASE, AND MORTALITY, BUT BIOLOGICAL RESPONSES TO AGING DIFFER AMONG PEOPLE. EPIGENETIC DNA MODIFICATIONS HAVE BEEN USED TO ESTIMATE "BIOLOGICAL AGE," WHICH MAY BE A USEFUL PREDICTOR OF DISEASE RISK. WE TESTED THIS HYPOTHESIS FOR BREAST CANCER. METHODS: USING A CASE-COHORT APPROACH, WE MEASURED BASELINE BLOOD DNA METHYLATION OF 2764 WOMEN ENROLLED IN THE SISTER STUDY, 1566 OF WHOM SUBSEQUENTLY DEVELOPED BREAST CANCER AFTER AN AVERAGE OF 6 YEARS. USING THREE PREVIOUSLY ESTABLISHED METHYLATION-BASED "CLOCKS" (HANNUM, HORVATH, AND LEVINE), WE DEFINED BIOLOGICAL AGE ACCELERATION FOR EACH WOMAN BY COMPARING HER ESTIMATED BIOLOGICAL AGE WITH HER CHRONOLOGICAL AGE. HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR BREAST CANCER RISK WERE ESTIMATED USING COX REGRESSION MODELS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: EACH OF THE THREE CLOCKS SHOWED THAT BIOLOGICAL AGE ACCELERATION WAS STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH INCREASED RISK OF DEVELOPING BREAST CANCER (5-YEAR AGE ACCELERATION, HANNUM'S CLOCK: HAZARD RATIO [HR] = 1.10, 95% CONFIDENCE INTERVAL [CI] = 1.00 TO 1.21, P = .04; HORVATH'S CLOCK: HR = 1.08, 95% CI = 1.00 TO 1.17, P = .04; LEVINE'S CLOCK: HR = 1.15, 95% CI = 1.07 TO 1.23, P < .001). FOR LEVINE'S CLOCK, EACH 5-YEAR ACCELERATION IN BIOLOGICAL AGE CORRESPONDED WITH A 15% INCREASE IN BREAST CANCER RISK. ALTHOUGH BIOLOGICAL AGE MAY ACCELERATE WITH MENOPAUSAL TRANSITION, AGE ACCELERATION IN PREMENOPAUSAL WOMEN INDEPENDENTLY PREDICTED BREAST CANCER. CASE-ONLY ANALYSIS SUGGESTED THAT, AMONG WOMEN WHO DEVELOP BREAST CANCER, INCREASED AGE ACCELERATION IS ASSOCIATED WITH INVASIVE CANCER (ODDS RATIO FOR INVASIVE = 1.09, 95% CI = 0.98 TO 1.22, P = .10). CONCLUSIONS: DNA METHYLATION-BASED MEASURES OF BIOLOGICAL AGE MAY BE IMPORTANT PREDICTORS OF BREAST CANCER RISK.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14  3458  31 HYPOMETHYLATION OF LINE-1 REPEAT ELEMENTS AND GLOBAL LOSS OF DNA HYDROXYMETHYLATION IN VAPERS AND SMOKERS. THE OUTBREAK OF VAPING-RELATED SEVERE LUNG INJURIES AND DEATHS AND THE EPIDEMIC OF TEEN VAPING IN THE U.S. UNDERSCORE THE URGENT NEED FOR DETERMINING THE BIOLOGICAL CONSEQUENCES OF ELECTRONIC CIGARETTE (E-CIG) USE. WE HAVE INVESTIGATED THE ASSOCIATION BETWEEN VAPING AND EPIGENETIC CHANGES BY QUANTIFYING DNA METHYLATION LEVELS IN LONG INTERSPERSED NUCLEOTIDE ELEMENT 1 (LINE-1) AND GLOBAL DNA HYDROXYMETHYLATION (5-HMC) LEVELS AND MEASURING THE EXPRESSION LEVEL OF ENZYMES CATALYSING THE RESPECTIVE PROCESSES IN PERIPHERAL BLOOD OF EXCLUSIVE VAPERS, SMOKERS, AND CONTROLS, MATCHED FOR AGE, GENDER, AND RACE (N = 45). BOTH VAPERS AND SMOKERS SHOWED SIGNIFICANT LOSS OF METHYLATION IN LINE-1 REPEAT ELEMENTS IN COMPARISON TO CONTROLS (P = 0.00854 AND P = 0.03078, RESPECTIVELY). SIMILARLY, VAPERS AND SMOKERS HAD SIGNIFICANT REDUCTIONS IN 5-HMC LEVELS RELATIVE TO CONTROLS (P = 0.04884 AND P = 0.0035, RESPECTIVELY). NEITHER THE LINE-1 METHYLATION LEVELS NOR THE GLOBAL 5-HMC LEVELS WERE DIFFERENT BETWEEN VAPERS AND SMOKERS. THERE WAS A DIRECT CORRELATION BETWEEN METHYLATION LEVELS IN THE LINE-1 ELEMENTS AND GLOBAL 5-HMC LEVELS IN THE STUDY SUBJECTS (R = 0.31696, P = 0.03389). INVERSE AND STATISTICALLY SIGNIFICANT CORRELATIONS WERE FOUND BETWEEN BOTH THE LINE-1 METHYLATION LEVELS AND THE GLOBAL 5-HMC LEVELS AND VARIOUS VAPING/SMOKING METRICS IN THE STUDY SUBJECTS. THERE WERE MODEST BUT NOT STATISTICALLY SIGNIFICANT CHANGES IN TRANSCRIPTION OF DNA METHYLTRANSFERASES AND TEN-ELEVEN TRANSLOCATION ENZYMES IN BOTH VAPERS AND SMOKERS RELATIVE TO CONTROLS. OUR FINDINGS SUPPORT FOLLOW-UP GENOME-WIDE INVESTIGATIONS INTO THE EPIGENETIC EFFECTS OF VAPING, WHICH MAY FURTHER CLARIFY THE HEALTH CONSEQUENCES OF E-CIG USE. ABBREVIATIONS: 5-MC: 5-METHYLCYTOSINE; 5-HMC: 5-HYDROXYMETHYLCYTOSINE; 8-OHDG: 8-HYDROXY-2'-DEOXYGUANOSINE; ACTIN: ACTIN BETA; ANOVA: ANALYSIS OF VARIANCE; BER: BASE EXCISION REPAIR; BMI: BODY MASS INDEX; CO: CARBON MONOXIDE; COHB: CARBOXYHAEMOGLOBIN; COBRA: COMBINED BISULPHITE RESTRICTION ANALYSIS; COPD: CHRONIC OBSTRUCTIVE PULMONARY DISEASE; DNMT1: DNA METHYLTRANSFERASE 1; DNMT3A: DNA METHYLTRANSFERASE 3A; DNMT3B: DNA METHYLTRANSFERASE 3B; E-CIGS: ELECTRONIC CIGARETTES; ELISA: ENZYME-LINKED IMMUNOSORBENT ASSAY; ENDS: ELECTRONIC NICOTINE DELIVERY SYSTEMS; FDA: FOOD AND DRUG ADMINISTRATION; GAPDH; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; HPLC: HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; LINE-1: LONG INTERSPERSED NUCLEOTIDE ELEMENT 1; PBS: PHOSPHATE-BUFFERED SALINE; RFU: RELATIVE FLUORESCENCE UNITS; RT-QPCR: QUANTITATIVE REVERSE-TRANSCRIPTION POLYMERASE CHAIN REACTION; ROS: REACTIVE OXYGEN SPECIES; SAM, S-ADENOSYLMETHIONINE; SE: STANDARD ERROR; TET1: TEN-ELEVEN TRANSLOCATION 1; TET2: TEN-ELEVEN TRANSLOCATION 2; TET3: TEN-ELEVEN TRANSLOCATION 3.	2020	

15  4244  37 METHYLATION STATUS OF COX-2 IN BLOOD LEUKOCYTE DNA AND RISK OF GASTRIC CANCER IN A HIGH-RISK CHINESE POPULATION. BACKGROUND: METHYLATION IS A COMMON EPIGENETIC MODIFICATION WHICH MAY PLAY A CRUCIAL ROLE IN CANCER DEVELOPMENT. TO INVESTIGATE THE ASSOCIATION BETWEEN METHYLATION OF COX-2 IN BLOOD LEUKOCYTE DNA AND RISK OF GASTRIC CANCER (GC), A NESTED CASE-CONTROL STUDY WAS CONDUCTED IN LINQU COUNTY, SHANDONG PROVINCE, A HIGH RISK AREA OF GC IN CHINA. METHODS: ASSOCIATION BETWEEN BLOOD LEUKOCYTE DNA METHYLATION OF COX-2 AND RISK OF GC WAS INVESTIGATED IN 133 GCS AND 285 SUPERFICIAL GASTRITIS (SG)/ CHRONIC ATROPHIC GASTRITIS (CAG). THE TEMPORAL TREND OF COX-2 METHYLATION LEVEL DURING GC DEVELOPMENT WAS FURTHER EXPLORED IN 74 PRE-GC AND 95 POST-GC SAMPLES (INCLUDING 31 CASES WITH BOTH PRE- AND POST-GC SAMPLES). IN ADDITION, THE ASSOCIATION OF DNA METHYLATION AND RISK OF PROGRESSION TO GC WAS EVALUATED IN 74 PRE-GC SAMPLES AND THEIR RELEVANT INTESTINAL METAPLASIA (IM)/DYSPLASIA (DYS) CONTROLS. METHYLATION LEVEL WAS DETERMINED BY QUANTITATIVE METHYLATION-SPECIFIC PCR (QMSP). ODDS RATIOS (ORS) AND 95% CONFIDENCE INTERVALS (CIS) WERE CALCULATED BY UNCONDITIONAL LOGISTIC REGRESSION ANALYSIS. RESULTS: THE MEDIANS OF COX-2 METHYLATION LEVELS WERE 2.3% AND 2.2% IN GC CASES AND CONTROLS, RESPECTIVELY. NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN COX-2 METHYLATION AND RISK OF GC (OR, 1.15; 95% CI: 0.70-1.88). HOWEVER, THE TEMPORAL TREND ANALYSIS SHOWED THAT COX-2 METHYLATION LEVELS WERE ELEVATED AT 1-4 YEARS AHEAD OF CLINICAL GC DIAGNOSIS COMPARED WITH THE YEAR OF GC DIAGNOSIS (3.0% VS. 2.2%, P=0.01). FURTHER VALIDATION IN 31 GCS WITH BOTH PRE- AND POST-GC SAMPLES INDICATED THAT COX-2 METHYLATION LEVELS WERE SIGNIFICANTLY DECREASED AT THE YEAR OF GC DIAGNOSIS COMPARED WITH PRE-GC SAMPLES (1.5% VS. 2.5%, P=0.02). NO SIGNIFICANT ASSOCIATION BETWEEN COX-2 METHYLATION AND RISK OF PROGRESSION TO GC WAS FOUND IN SUBJECTS WITH IM (OR, 0.50; 95% CI: 0.18-1.42) OR DYS (OR, 0.70; 95% CI: 0.23-2.18). ADDITIONALLY, WE FOUND THAT ELDER PEOPLE HAD INCREASED RISK OF COX-2 HYPERMETHYLATION (OR, 1.55; 95% CI: 1.02-2.36) AND SUBJECTS WHO EVER INFECTED WITH H. PYLORI HAD DECREASED RISK OF COX-2 HYPERMETHYLATION (OR, 0.54; 95% CI: 0.34-0.88). CONCLUSIONS: COX-2 METHYLATION EXISTS IN BLOOD LEUKOCYTE DNA BUT AT A LOW LEVEL. COX-2 METHYLATION LEVELS IN BLOOD LEUKOCYTE DNA MAY CHANGE DURING GC DEVELOPMENT.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16  4349  34 MIR-155 AND MIR-122 EXPRESSION OF SPERMATOZOA IN OBESE SUBJECTS. OBESITY IS CHARACTERIZED BY MILD CHRONIC INFLAMMATION THAT IS LINKED WITH IMPAIRED IRON HOMEOSTASIS. STUDIES IN HUMAN AND MURINE SHOW THAT THERE IS A TRANSGENERATIONAL EPIGENETIC INHERITANCE VIA THE GAMETES IN OBESITY; HOWEVER, THERE IS LITTLE INFORMATION ON CHANGES IN THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION AND IRON HOMEOSTASIS IN SPERMATOZOA FROM OBESE SUBJECTS. THE PRESENT STUDY INVESTIGATED THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION (MIR-21 Y MIR-155) AND IRON NUTRITION (MIR-122 AND MIR-200B) IN PLASMA, PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND SPERMATOZOA FROM NORMOZOOSPERMIC CONTROLS (CN; N = 17; BMI: 24.6 +/- 2.0) AND OBESE (OB; N = 17; BMI: 32.6 +/- 4.4) MEN. TO DETERMINE THE INFLAMMATION LEVELS, WE MEASURED IL-6, TNF-ALPHA, AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP1) BY MAGNETIC LUMINEX((R)) ASSAY. MRNA EXPRESSION OF IL6, TNF-ALPHA, AND HEPCIDIN (HAMP) IN PBMC WERE EVALUATED BY RT-QPCR. THE ANALYSIS OF MICRORNAS WAS PERFORMED USING THE TAQMAN((R)) ASSAYS. THE IRON CONTENT IN PBMC, SEMINAL PLASMA, AND SPERMATOZOA WAS DETERMINED BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS). HIGH SERUM IL6, TNF-ALPHA, AND MCP1 LEVELS WERE OBSERVED IN OB GROUP (P < 0.05). GENE EXPRESSION ANALYSIS SHOWED AN INCREASED ABUNDANCE RELATIVE OF TNF-ALPHA (P = 0.018), HAMP (P = 0.03), AND IL6 (P = 0.02) IN PBMC FROM OBESE SUBJECTS. ALSO, WE OBSERVED HIGH LEVELS OF SERUM FERRITIN (P = 0.03), IRON CONTENT IN SEMINAL PLASMA (P = 0.04), AND SPERMATOZOA (P = 0.002), BUT LOWER SERUM FE (P = 0.007) IN OBESE SUBJECTS. IN THE OB GROUP, A HIGH EXPRESSION OF MIR-155 (P = 0.02) AND MIR-21 (P = 0.03) WAS OBSERVED IN PBMC AND MIR-122 (P = 0.03) IN PLASMA. IN SPERM, BOTH MIR-155 (P = 0.004) AND MIR-122 (P = 0.028) WERE HIGH IN THE OB GROUP. OUR RESULTS SHOWED THAT OBESE SUBJECTS HAVE INCREASED EXPRESSIONS OF MIR-155 AND MIR-122, TWO MICRORNAS THAT WERE PREVIOUSLY RELATED WITH INFLAMMATION AND IRON METABOLISM, RESPECTIVELY, AT BOTH THE SYSTEMIC AND SPERM LEVELS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17   525  28 ASSOCIATIONS OF BODY COMPOSITION AND PHYSICAL ACTIVITY LEVEL WITH MULTIPLE MEASURES OF EPIGENETIC AGE ACCELERATION. EPIGENETIC CLOCKS USE DNA METHYLATION TO ESTIMATE BIOLOGICAL AGE. WHETHER BODY COMPOSITION AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH THESE CLOCKS IS NOT WELL UNDERSTOOD. USING BLOOD SAMPLES COLLECTED AT ENROLLMENT (2003-2009) FROM 2,758 WOMEN IN THE US NATIONWIDE SISTER STUDY, WE CALCULATED 6 EPIGENETIC AGE ACCELERATION METRICS USING 4 EPIGENETIC CLOCKS (HANNUM, HORVATH, PHENOAGE, GRIMAGE). RECREATIONAL PHYSICAL ACTIVITY WAS SELF-REPORTED, AND ADIPOSITY MEASURES WERE ASSESSED BY TRAINED MEDICAL EXAMINERS (BODY MASS INDEX (BMI), WAIST-TO-HIP RATIO (WTH), WAIST CIRCUMFERENCE). IN CROSS-SECTIONAL ANALYSES, ALL ADIPOSITY MEASURES WERE ASSOCIATED WITH EPIGENETIC AGE ACCELERATION. THE STRONGEST ASSOCIATION WAS FOR BMI AND PHENOAGE, A MEASURE OF BIOLOGICAL AGE THAT CORRELATES WITH CHRONIC DISEASE (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 3.15 YEARS, 95% CONFIDENCE INTERVAL (CI): 2.41, 3.90; P FOR TREND < 0.001). IN A MUTUAL-ADJUSTMENT MODEL, BOTH WERE ASSOCIATED WITH PHENOAGE AGE ACCELERATION (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 2.69 YEARS, 95% CI: 1.90, 3.48; P FOR TREND < 0.001; QUARTILE 4 VS.1 WTH, BETA = 1.00 YEARS, 95% CI: 0.34, 1.65; P FOR TREND < 0.008). AFTER ADJUSTMENT, PHYSICAL ACTIVITY WAS ASSOCIATED ONLY WITH GRIMAGE (QUARTILE 4 VS. 1, BETA = -0.42 YEARS, 95% CI: -0.70, -0.14; P FOR TREND = 0.001). PHYSICAL ACTIVITY ATTENUATED THE WAIST CIRCUMFERENCE ASSOCIATIONS WITH PHENOAGE AND GRIMAGE. EXCESS ADIPOSITY WAS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION; PHYSICAL ACTIVITY MIGHT ATTENUATE ASSOCIATIONS WITH WAIST CIRCUMFERENCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  1953  35 EPIGENETIC AGE ACCELERATION AND CHRONIC HEALTH CONDITIONS AMONG ADULT SURVIVORS OF CHILDHOOD CANCER. BACKGROUND: MOUNTING EVIDENCE SUPPORTS THE OCCURRENCE OF ACCELERATING AGING AMONG LONG-TERM SURVIVORS OF CHILDHOOD CANCER. WE AIMED TO INVESTIGATE EPIGENETIC AGE ACCELERATION (EAA) IN SURVIVORS AND EVALUATE ASSOCIATIONS BETWEEN EAA, TREATMENT EXPOSURES, HEALTH BEHAVIORS, AND CHRONIC HEALTH CONDITIONS (CHCS). METHODS: GENOME-WIDE METHYLATION DATA WERE GENERATED WITH INFINIUM EPIC BEADCHIP ON BLOOD-DERIVED DNA FROM 2139 SURVIVORS AND 282 FREQUENCY MATCHED CONTROLS FROM THE ST JUDE LIFETIME COHORT STUDY. EAAS WERE ESTIMATED AS RESIDUALS FROM A LINEAR REGRESSION OF EPIGENETIC AGE (LEVINE'S CLOCK) AGAINST CHRONOLOGICAL AGE. ADJUSTED LEAST SQUARE MEAN (ALSM) OF EAA WAS CALCULATED AND COMPARED BETWEEN SURVIVORS AND CONTROLS, ACROSS TREATMENT EXPOSURES AND HEALTH BEHAVIORS. ASSOCIATIONS OF EAA WITH 20 CLINICALLY ASSESSED CHCS WERE EVALUATED WITH MULTIVARIABLE PIECEWISE-EXPONENTIAL MODELS. ALL STATISTICAL TESTS FOR P VALUES BELOW WERE 2-SIDED. RESULTS: EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS THAN CONTROLS (ALSM = 0.63, 95% CONFIDENCE INTERVAL [CI] = 0.26 TO 1.01 VS -3.61, 95% CI = -4.43 TO 2.80). IN A MULTIVARIABLE MODEL AMONG SURVIVORS, STATISTICALLY SIGNIFICANTLY HIGHER EAA (P < .05) WAS OBSERVED IN THOSE EXPOSED TO CHEST RADIOTHERAPY, ABDOMEN OR PELVIC RADIOTHERAPY, ALKYLATING AGENTS, GLUCOCORTICOIDS, OR EPIPODOPHYLLOTOXINS. COMPARED WITH SURVIVORS WITH FAVORABLE HEALTH BEHAVIORS (ALSM = 0.26, 95% CI=-0.36 TO 0.87), EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER AMONG SURVIVORS WITH INTERMEDIATE (ALSM = 1.07, 95% CI = 0.59 TO 1.54) OR UNFAVORABLE HEALTH BEHAVIORS (ALSM = 1.45, 95% CI = 0.60 TO 2.30). IN TIME-TO-EVENT ANALYSES, STATISTICALLY SIGNIFICANT ASSOCIATIONS WERE IDENTIFIED BETWEEN EAA TERTILES AND INCIDENCE OF 7 CHCS: HYPERTENSION (3RD VS 1ST TERTILE, RELATIVE RATE [RR] = 1.83, 95% CI = 1.17 TO 2.83), MYOCARDIAL INFARCTION (RR = 2.91, 95% CI = 1.27 TO 7.21), OBESITY (RR = 1.39, 95% CI = 1.17 TO 1.66), OBSTRUCTIVE PULMONARY DEFICIT (RR = 1.86, 95% CI = 0.95 TO 3.77), PERIPHERAL MOTOR NEUROPATHY (RR = 2.89, 95% CI = 1.24 TO 6.97), PERIPHERAL SENSORY NEUROPATHY (RR = 2.04, 95% CI = 0.99 TO 4.26), AND PULMONARY DIFFUSION DEFICITS (RR = 2.75, 95% CI = 0.95 TO 7.63). CONCLUSIONS: EAA IS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS OF CHILDHOOD CANCER THAN IN NONCANCER CONTROLS AND IS ASSOCIATED WITH SPECIFIC TREATMENT EXPOSURES, UNFAVORABLE HEALTH BEHAVIORS, AND PRESENCE OF SPECIFIC CHCS.	2021	
                                                                                                                                                                                                                                                                                                                                                     
19  3995  36 LONGITUDINAL STUDY OF DNA METHYLATION OF INFLAMMATORY GENES AND CANCER RISK. BACKGROUND: CHRONIC INFLAMMATION PLAYS A KEY ROLE IN CANCER ETIOLOGY. DNA METHYLATION MODIFICATION, ONE OF THE EPIGENETIC MECHANISMS REGULATING GENE EXPRESSION, IS CONSIDERED A HALLMARK OF CANCER. HUMAN AND ANIMAL MODELS HAVE IDENTIFIED NUMEROUS LINKS BETWEEN DNA METHYLATION AND INFLAMMATORY BIOMARKERS. OUR OBJECTIVE WAS TO PROSPECTIVELY AND LONGITUDINALLY EXAMINE ASSOCIATIONS BETWEEN METHYLATION OF FOUR INFLAMMATORY GENES AND CANCER RISK. METHODS: WE INCLUDED 795 NORMATIVE AGING STUDY PARTICIPANTS WITH BLOOD DRAWN ONE TO FOUR TIMES FROM 1999 TO 2012 (MEDIAN FOLLOW-UP, 10.6 YEARS). PROMOTER DNA METHYLATION OF IL6, ICAM-1, IFN, AND TLR2 IN BLOOD LEUKOCYTES WAS MEASURED USING PYROSEQUENCING AT MULTIPLE CPG SITES AND AVERAGED BY GENE FOR DATA ANALYSIS. WE USED COX REGRESSION MODELS TO EXAMINE PROSPECTIVE ASSOCIATIONS OF BASELINE AND TIME-DEPENDENT METHYLATION WITH CANCER RISK AND COMPARED MEAN METHYLATION DIFFERENCES OVER TIME BETWEEN CANCER CASES AND CANCER-FREE PARTICIPANTS. RESULTS: BASELINE IFN HYPERMETHYLATION WAS ASSOCIATED WITH ALL-CANCER (HR, 1.49; P = 0.04) AND PROSTATE CANCER INCIDENCE (HR, 1.69; P = 0.02). BASELINE ICAM-1 AND IL6 HYPERMETHYLATION WERE ASSOCIATED WITH PROSTATE CANCER INCIDENCE (HR, 1.43; P = 0.02; HR, 0.70; P = 0.03, RESPECTIVELY). IN OUR TIME-DEPENDENT ANALYSES, IFN HYPERMETHYLATION WAS ASSOCIATED WITH ALL-CANCER (HR, 1.79; P = 0.007) AND PROSTATE CANCER (HR, 1.57; P = 0.03) INCIDENCE; AND ICAM-1 AND IL6 HYPERMETHYLATION WERE ASSOCIATED WITH PROSTATE CANCER INCIDENCE (HR, 1.39; P = 0.02; HR, 0.69; P = 0.03, RESPECTIVELY). WE DETECTED SIGNIFICANT ICAM-1 HYPERMETHYLATION IN CANCER CASES (P = 0.0003) 10 TO 13 YEARS PREDIAGNOSIS. CONCLUSION: HYPERMETHYLATION OF IFN AND ICAM-1 MAY PLAY IMPORTANT ROLES IN EARLY CARCINOGENESIS, PARTICULARLY THAT OF PROSTATE CANCER. IMPACT: THESE METHYLATION CHANGES COULD INFORM THE DEVELOPMENT OF EARLY DETECTION BIOMARKERS AND POTENTIAL TREATMENTS OF INFLAMMATION-RELATED CARCINOGENESIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20  2759  33 EXPRESSION OF IL-17 AND ITS GENE PROMOTER METHYLATION STATUS ARE ASSOCIATED WITH THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS INFECTION. TO EXPLORE INTERLEUKIN-17 (IL-17) AND ITS EPIGENETIC REGULATION DURING THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION.A TOTAL OF 162 PATIENTS WITH CHRONIC HBV INFECTION, INCLUDING 75 WITH CHRONIC HEPATITIS B (CHB), 54 WITH HEPATITIS B-ASSOCIATED LIVER CIRRHOSIS AND 33 WITH HEPATITIS B-ASSOCIATED HEPATOCELLULAR CARCINOMA (HBV-HCC), WERE ENROLLED IN THIS STUDY. THIRTY HEALTHY ADULTS OF THE SAME ETHNICITY WERE ENROLLED IN THE CONTROL GROUP. WHOLE VENOUS BLOOD WAS OBTAINED FROM THE PATIENTS AND NORMAL CONTROLS (N = 30). CLINICAL AND LABORATORY PARAMETERS WERE ASSESSED, AND WE PERFORMED ENZYME-LINKED IMMUNOSORBENT ASSAY AND QUANTITATIVE REAL-TIME PCR TO MEASURE THE SERUM LEVELS AND RELATIVE MRNA EXPRESSION OF IL-17, RESPECTIVELY. IL-17 PROMOTER METHYLATION IN PERIPHERAL BLOOD MONONUCLEAR CELLS WAS ASSESSED BY METHYLATION-SPECIFIC PCR. WE ANALYZED THE SERUM AND MRNA LEVELS OF IL-17 AND IL-17 PROMOTER METHYLATION IN THE 4 GROUPS AS WELL AS THE EFFECT OF METHYLATION ON SERUM IL-17 LEVELS. CORRELATIONS BETWEEN THE IL-17 PROMOTER METHYLATION STATUS AND CLINICAL PARAMETERS WERE ANALYZED BY SPEARMAN CORRELATION ANALYSIS.COMPARED TO THE NORMAL CONTROL GROUP, THE PATIENT GROUPS EXHIBITED SIGNIFICANTLY HIGHER SERUM AND RELATIVE MRNA LEVELS OF IL-17. THE METHYLATION DISTRIBUTION AMONG THE PATIENTS WAS SIGNIFICANTLY LOWER THAN THAT AMONG THE NORMAL CONTROLS (P < .05), WITH THE HBV-HCC GROUP SHOWING THE LOWEST IL-17 GENE METHYLATION FREQUENCY. THE AVERAGE IL-17 PROMOTER CG METHYLATION LEVEL WAS NEGATIVELY CORRELATED WITH IL-17 MRNA EXPRESSION (R = -0.39, P = .03), AND NEGATIVE CORRELATIONS BETWEEN IL-17 PROMOTER METHYLATION AND PROTHROMBIN TIME ACTIVITY (R = -0.585, P = .035), ALANINE AMINOTRANSFERASE (R = -0.522, P < .01), ASPARTATE AMINOTRANSFERASE (R = -0.315, P < .05), AND THE MODEL FOR END-STAGE LIVER DISEASE SCORE (R = -0.461, P < .05) WERE OBSERVED. IL-17 SERUM LEVELS IN THE METHYLATED-PROMOTER GROUPS WERE SIGNIFICANTLY LOWER THAN THOSE IN THE UNMETHYLATED-PROMOTER GROUPS.IL-17 EXPRESSION AND PROMOTER METHYLATION WERE ASSOCIATED WITH CHRONIC HBV INFECTION PROGRESSION, ESPECIALLY IN THE HBV-HCC GROUP. THE IL-17 PROMOTER STATUS MAY HELP CLINICIANS INITIATE THE CORRECT TREATMENT STRATEGY AT THE CHB STAGE.	2019