1 6492 162 TRAFFIC-RELATED AIR POLLUTION AND GROUND-LEVEL OZONE ASSOCIATED GLOBAL DNA HYPOMETHYLATION AND BULKY DNA ADDUCT FORMATION. STUDIES HAVE INDICATED THAT AIR POLLUTION, INCLUDING SURFACE-LEVEL OZONE (O(3)), CAN SIGNIFICANTLY INFLUENCE THE RISK OF CHRONIC DISEASES. TO BETTER UNDERSTAND THE CARCINOGENIC MECHANISMS OF AIR POLLUTANTS AND IDENTIFY PREDICTIVE DISEASE BIOMARKERS, WE EXAMINED THE ASSOCIATION BETWEEN TRAFFIC-RELATED POLLUTANTS WITH DNA METHYLATION ALTERATIONS AND BULKY DNA ADDUCTS, TWO BIOMARKERS OF CARCINOGEN EXPOSURE AND CANCER RISK, IN THE PERIPHERAL BLOOD OF 140 VOLUNTEERS-95 TRAFFIC POLICE OFFICERS, AND 45 UNEXPOSED SUBJECTS. THE DNA METHYLATION AND ADDUCT MEASUREMENTS WERE PERFORMED BY BISULFITE-PCR AND PYROSEQUENCING AND (32)P-POSTLABELING ASSAY. AIRBORNE LEVELS OF BENZO(A)PYRENE [B(A)P], CARBON MONOXIDE, AND TROPOSPHERIC O(3) WERE DETERMINED BY PERSONAL EXPOSURE BIOMONITORING OR BY FIXED MONITORING STATIONS. OVERALL, AIR POLLUTION EXPOSURE WAS ASSOCIATED WITH A SIGNIFICANT REDUCTION (1.41 UNITS) IN GLOBAL DNA METHYLATION (95% C.I. -2.65-0.04, P = 0.026). THE DECREMENT IN ALU REPETITIVE ELEMENTS WAS GREATEST IN THE POLICEMEN WORKING DOWNTOWN (95% C.I. -3.23--0.49, P = 0.008). THE DNA ADDUCTS WERE FOUND TO BE SIGNIFICANTLY INCREASED (0.45 UNITS) IN THE MUNICIPAL OFFICERS WITH RESPECT TO UNEXPOSED SUBJECTS (95% C.I. 0.02-0.88, P = 0.039), MAINLY IN THOSE WHO WERE CONTROLLING TRAFFIC IN DOWNTOWN AREAS (95% C.I. 0.39-1.29, P < 0.001). REGRESSION MODELS INDICATED AN INCREMENT OF ALU METHYLATION AT HIGHER B(A)P CONCENTRATIONS (95% C.I. 0.03-0.60, P = 0.032). MOREOVER, STATISTICAL MODELS SHOWED A DECREMENT IN ALU METHYLATION AND AN INCREMENT OF DNA DAMAGE ONLY ABOVE THE CUT-OFF VALUE OF 30 MICROG/M(3) O(3). A SIGNIFICANT INCREMENT OF 0.73 UNITS OF IL-6 GENE METHYLATION WAS ALSO FOUND IN SMOKERS WITH RESPECT TO NON-SMOKERS. OUR RESULTS HIGHLIGHTED THE ROLE OF AIR POLLUTION ON EPIGENETIC ALTERATIONS AND GENOTOXIC EFFECTS, ESPECIALLY ABOVE THE TARGET VALUE OF 30 MICROG/M(3) SURFACE-LEVEL O(3), SUPPORTING THE NECESSITY FOR DEVELOPING PUBLIC HEALTH STRATEGIES AIMED TO REDUCE TRAFFIC-RELATED AIR POLLUTION MOLECULAR ALTERATIONS.	2023	
                                                                                                                                                                                
2 1847  45 EFFECTS OF VARIOUS ENVIRONMENTS ON EPIGENETIC SETTINGS AND CHROMOSOMAL DAMAGE. AIR POLLUTION IS A DOMINANT ENVIRONMENTAL EXPOSURE FACTOR WITH SIGNIFICANT HEALTH CONSEQUENCES. UNEXPECTEDLY, RESEARCH IN A HEAVILY POLLUTED REGION OF THE CZECH REPUBLIC, WITH TRADITIONAL HEAVY INDUSTRY, REVEALED REPEATEDLY THE LOWEST FREQUENCY OF MICRONUCLEI IN THE SEASON WITH THE HIGHEST CONCENTRATIONS OF AIR POLLUTANTS INCLUDING CARCINOGENIC BENZO[A]PYRENE (B[A]P). MOLECULAR FINDINGS HAVE BEEN COLLECTED FOR MORE THAN 10 YEARS FROM VARIOUS LOCATIONS OF THE CZECH REPUBLIC, WITH DIFFERING QUALITY OF AMBIENT AIR. PRELIMINARY CONCLUSIONS HAVE SUGGESTED ADAPTATION OF THE POPULATION FROM THE POLLUTED LOCALITY (OSTRAVA, MORAVIAN-SILESIAN REGION (MSR)) TO CHRONIC AIR POLLUTION EXPOSURE. IN THIS STUDY WE UTILIZE THE PREVIOUS FINDINGS AND, FOR THE FIRST TIME, INVESTIGATE MICRONUCLEI (MN) FREQUENCY BY TYPE: (I) CENTROMERE POSITIVE (CEN+) MN, REPRESENTING CHROMOSOMAL LOSSES, AND (II) CENTROMERE NEGATIVE (CEN-) MN REPRESENTING CHROMOSOMAL BREAKS. AS PREVIOUS RESULTS INDICATED DIFFERENCES BETWEEN POPULATIONS IN THE EXPRESSION OF XRCC5, A GENE INVOLVED IN THE NON-HOMOLOGOUS END-JOINING (NHEJ) REPAIR PATHWAY, POSSIBLE VARIATIONS IN EPIGENETIC SETTINGS IN THIS GENE WERE ALSO INVESTIGATED. THIS NEW RESEARCH WAS CONDUCTED IN TWO SEASONS IN THE GROUPS FROM TWO LOCALITIES WITH DIFFERENT AIR QUALITY LEVELS (OSTRAVA (OS) AND PRAGUE (PG)). THE OBTAINED NEW RESULTS SHOW SIGNIFICANTLY LOWER FREQUENCIES OF CHROMOSOMAL BREAKS IN THE OS SUBJECTS, RELATED TO THE HIGHEST AIR POLLUTION LEVELS (P < 0.001). IN CONTRAST, CHROMOSOMAL LOSSES WERE COMPARABLE BETWEEN BOTH GROUPS. IN ADDITION, SIGNIFICANTLY LOWER DNA METHYLATION WAS FOUND IN 14.3% OF THE ANALYZED CPG LOCI OF XRCC5 IN THE POPULATION FROM OS. IN CONCLUSION, THE EPIGENETIC ADAPTATION (HYPOMETHYLATION) IN XRCC5 INVOLVED IN THE NHEJ REPAIR PATHWAY IN THE POPULATION FROM THE POLLUTED REGION, WAS SUGGESTED AS A REASON FOR THE REDUCED LEVEL OF CHROMOSOMAL BREAKS. FURTHER RESEARCH IS NEEDED TO EXPLORE THE ADDITIONAL MECHANISMS, INCLUDING GENETIC ADAPTATION.	2023	
                                                                                                                                                                                                                                                         
3 2921  38 GENE-SPECIFIC DIFFERENTIAL DNA METHYLATION AND CHRONIC ARSENIC EXPOSURE IN AN EPIGENOME-WIDE ASSOCIATION STUDY OF ADULTS IN BANGLADESH. BACKGROUND: INORGANIC ARSENIC IS ONE OF THE MOST COMMON NATURALLY OCCURRING CONTAMINANTS FOUND IN THE ENVIRONMENT. ARSENIC IS ASSOCIATED WITH A NUMBER OF HEALTH OUTCOMES, WITH EPIGENETIC MODIFICATION SUGGESTED AS A POTENTIAL MECHANISM OF TOXICITY. OBJECTIVE: AMONG A SAMPLE OF 400 ADULT PARTICIPANTS, WE EVALUATED THE ASSOCIATION BETWEEN ARSENIC EXPOSURE, AS MEASURED BY BLOOD AND URINARY TOTAL ARSENIC CONCENTRATIONS, AND EPIGENOME-WIDE WHITE BLOOD CELL DNA METHYLATION. METHODS: WE USED LINEAR REGRESSION MODELS TO EXAMINE THE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND METHYLATION AT EACH CPG SITE, ADJUSTED FOR SEX, AGE, AND BATCH. DIFFERENTIALLY METHYLATED LOCI WERE SUBSEQUENTLY EXAMINED IN RELATION TO CORRESPONDING GENE EXPRESSION FOR FUNCTIONAL EVIDENCE OF GENE REGULATION. RESULTS: IN ADJUSTED ANALYSES, WE OBSERVED FOUR DIFFERENTIALLY METHYLATED CPG SITES WITH URINARY TOTAL ARSENIC CONCENTRATION AND THREE DIFFERENTIALLY METHYLATED CPG SITES WITH BLOOD ARSENIC CONCENTRATION, BASED ON THE BONFERRONI-CORRECTED SIGNIFICANCE THRESHOLD OF P < 1 X 10(-7). METHYLATION OF PLA2G2C (PROBE CG04605617) WAS THE MOST SIGNIFICANTLY ASSOCIATED LOCUS IN RELATION TO BOTH URINARY (P = 3.40 X 10(-11)) AND BLOOD ARSENIC CONCENTRATIONS (P = 1.48 X 10(-11)). THREE ADDITIONAL NOVEL METHYLATION LOCI-SQSTM1 (CG01225779), SLC4A4 (CG06121226), AND IGH (CG13651690)--WERE ALSO SIGNIFICANTLY ASSOCIATED WITH ARSENIC EXPOSURE. FURTHER, THERE WAS EVIDENCE OF METHYLATION-RELATED GENE REGULATION BASED ON GENE EXPRESSION FOR A SUBSET OF DIFFERENTIALLY METHYLATED LOCI. CONCLUSIONS: WE OBSERVED SIGNIFICANT ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENE-SPECIFIC DIFFERENTIAL WHITE BLOOD CELL DNA METHYLATION, SUGGESTING THAT EPIGENETIC MODIFICATIONS MAY BE AN IMPORTANT PATHWAY UNDERLYING ARSENIC TOXICITY. THE SPECIFIC DIFFERENTIALLY METHYLATED LOCI IDENTIFIED MAY INFORM POTENTIAL PATHWAYS FOR FUTURE INTERVENTIONS.	2015	
                                                                                                                                                                                                                                                                                                             
4 5964  36 TEMPORAL VARIABILITY OF GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION IN BUCCAL CELLS OF HEALTHY ADULTS: ASSOCIATION WITH AIR POLLUTION. BACKGROUND: EPIGENETIC CHANGES, SUCH AS DNA METHYLATION, ARE OBSERVED IN RESPONSE TO ENVIRONMENTAL EXPOSURE AND IN THE DEVELOPMENT OF SEVERAL CHRONIC DISEASES. CONSEQUENTLY, DNA METHYLATION ALTERATIONS MIGHT SERVE AS INDICATORS OF EARLY EFFECTS. IN THIS CONTEXT, THE AIM OF THIS STUDY WAS TO ASSESS THE TEMPORAL VARIABILITY OF GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION LEVELS IN BUCCAL CELLS FROM HEALTHY ADULT VOLUNTEERS. METHODS: GLOBAL DNA METHYLATION (%5MDC) AND HYDROXYMETHYLATION (%5HMDC) LEVELS IN HUMAN BUCCAL CELLS, COLLECTED FROM 26 HEALTHY ADULTS AT DIFFERENT TIME POINTS, WERE QUANTIFIED BY UPLC-MS/MS. ASSOCIATIONS BETWEEN %5MDC AND %5HMDC, RESPECTIVELY, AND SHORT-TERM EXPOSURE (1-7DAYS) TO AIR POLLUTANTS PM(2.5) AND PM(10) WERE TESTED WITH MIXED-EFFECTS MODELS INCLUDING VARIOUS COVARIATES. RESULTS/DISCUSSION: DYNAMIC SHORT-TERM CHANGES IN DNA METHYLATION AND HYDROXYMETHYLATION LEVELS IN BUCCAL CELLS WERE OBSERVED, WHICH WERE INVERSELY ASSOCIATED WITH EXPOSURE TO PM(2.5) AND PM(10). AN IQR INCREASE IN PM(2.5) OVER A 7-DAY MOVING AVERAGE PERIOD WAS SIGNIFICANTLY ASSOCIATED WITH A DECREASE OF -1.47% (-1.74%, -1.20%) AND -0.043% (-0.054%, -0.032%) IN %5MDC AND %5HMDC, RESPECTIVELY. LIKEWISE, FOR PM(10), A DECREASE OF -1.42% (-1.70, -1.13) AND -0.040% (-0.051%, -0.028%) WAS OBSERVED. CONCLUSION: GLOBAL DNA METHYLATION AND HYDROXYMETHYLATATION VARIED OVER A TIME PERIOD OF THREE WEEKS. THE OBSERVED TEMPORAL VARIABILITY WAS ASSOCIATED WITH EXPOSURE TO AMBIENT PM(2.5) AND PM(10) LEVELS. THIS SHOULD BE TAKEN INTO ACCOUNT WHEN INTERPRETING EPIGENETIC ALTERATIONS IN BUCCAL CELLS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5 5722  34 SISTER CHROMATID EXCHANGE AND PROLIFERATIVE RATE INDEX IN THE LONGITUDINAL RISK ASSESSMENT OF OCCUPATIONAL EXPOSURE TO PESTICIDES. AT PRESENT, THERE ARE MORE THAN 1,000 CHEMICALS CLASSIFIED AS PESTICIDES AND MANY REPORTS HAVE SHOWN THAT SOME OF THEM HAVE GENOTOXIC PROPERTIES. IN THE PRESENT LONGITUDINAL STUDY, POSSIBLE GENETIC DAMAGE ON A POPULATION OF WORKERS OCCUPATIONALLY EXPOSED TO A MIXTURE OF PESTICIDES BY USING SISTER CHROMATID EXCHANGE (SCE) ANALYSIS HAS BEEN EVALUATED. AS AN ADDITIONAL CYTOGENETIC PARAMETER, THE PROPORTION OF LYMPHOCYTES THAT UNDERGO ONE, TWO OR THREE CELL DIVISIONS AS WELL AS PROLIFERATIVE RATE INDEX HAVE BEEN DETERMINED. THIS STUDY WAS PERFORMED ON THE EXPOSED GROUP OF WORKERS EMPLOYED IN PESTICIDE PRODUCTION, SIMULTANEOUSLY EXPOSED TO A COMPLEX MIXTURE OF PESTICIDES (ATRAZINE, ALACHLOR, CYANAZINE, 2,4-DICHLOROPHENOXYACETIC ACID, AND MALATHION). THE BLOOD SAMPLES OF THE EXPOSED SUBJECTS WERE COLLECTED IN THREE DIFFERENT PERIODS: BEFORE THE BEGINNING OF THE NEW PESTICIDE PRODUCTION PERIOD, AFTER 8 MONTHS OF EVERYDAY WORK IN THE PESTICIDE PRODUCTION, AND 8 MONTHS AFTER THE REMOVAL OF SUBJECTS OUT OF THE PRODUCTION. IN ALL THREE SAMPLINGS, THE MEAN VALUE OF SCE AND NUMBER OF CELLS WITH HIGH SISTER CHROMATID EXCHANGE FREQUENCY (HFC) IN THE EXPOSED GROUP WAS SIGNIFICANTLY HIGHER IN THE COMPARISON WITH THE CONTROL GROUP. THERE WERE NO DIFFERENCES IN THE PROLIFERATIVE RATE INDEX (PRI) BETWEEN THE CONTROL AND EXPOSED GROUP, REGARDLESS OF THE SAMPLING PERIOD. IN BOTH GROUPS EXAMINED, THE MAJORITY OF LYMPHOCYTES WERE FOUND IN THE SECOND CELL DIVISION, FOLLOWING CULTIVATION. THESE RESULTS SUGGEST THAT THE INCREASE IN THE NUMBER OF SCE FOUND IN THE EXPOSED SUBJECTS IS NOT THE RESULT OF EITHER CYTOTOXIC OR EPIGENETIC ACTION OF PESTICIDE MIXTURE, BUT CHRONIC OCCUPATIONAL EXPOSURE TO MIXTURE OF PESTICIDES.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6 4602  28 NECESSITY OF EPIGENETIC EPIDEMIOLOGY STUDIES ON THE CARCINOGENESIS OF LUNG CANCER IN NEVER SMOKERS. BASED ON EPIDEMIOLOGICAL AND GENOMIC CHARACTERISTICS, LUNG CANCER IN NEVER SMOKERS (LCNS) IS A DIFFERENT DISEASE FROM LUNG CANCER IN SMOKERS. BASED ON CURRENT RESEARCH, THE MAIN RISK FACTOR FOR LCNS MAY BE AIR POLLUTION. A RECENT CASE-CONTROL STUDY IN KOREANS REPORTED THAT NITROGEN DIOXIDE (NO2) MAY BE A RISK FACTOR FOR LCNS. ADDITIONALLY, A COHORT STUDY SHOWED THAT EXPOSURE TO NO2 WAS ASSOCIATED WITH SIGNIFICANT HYPOMETHYLATION. THUS, EPIGENETIC EPIDEMIOLOGY STUDIES ARE NEEDED IN THE NEAR FUTURE TO EVALUATE THE CARCINOGENESIS OF LCNS ACCORDING TO CHRONIC EXPOSURE TO AIR POLLUTION AND/OR VIRAL INFECTIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  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	
                                                                                                                                                                   
8 3991  36 LONGITUDINAL EFFECTS OF DEVELOPMENTAL BISPHENOL A, VARIABLE DIET, AND PHYSICAL ACTIVITY ON AGE-RELATED METHYLATION IN BLOOD. RESEARCH INDICATES THAT ENVIRONMENTAL FACTORS CAN ALTER DNA METHYLATION, BUT THE SPECIFIC EFFECTS OF ENVIRONMENTAL EXPOSURES ON EPIGENETIC AGING REMAIN UNCLEAR. HERE, USING A MOUSE MODEL OF HUMAN-RELEVANT EXPOSURES, WE TESTED THE HYPOTHESIS THAT EARLY-LIFE EXPOSURE TO BISPHENOL A (BPA), VARIABLE DIET, AND/OR CHANGES IN PHYSICAL ACTIVITY WOULD MODIFY RATES OF AGE-RELATED METHYLATION AT SEVERAL TARGET REGIONS, AS MEASURED FROM LONGITUDINAL BLOOD SAMPLES (2, 4, AND 10 MONTHS OLD). DNA METHYLATION WAS QUANTIFIED AT TWO REPETITIVE ELEMENTS (LINE-1, IAP), TWO IMPRINTED GENES (IGF2, H19), AND ONE NON-IMPRINTED GENE (ESR1) IN ISOGENIC MICE DEVELOPMENTALLY EXPOSED TO CONTROL, CONTROL + BPA (50 MICROG/KG DIET), WESTERN HIGH-FAT DIET (WHFD), OR WESTERN + BPA DIETS. IN BLOOD SAMPLES, ESR1 DNA METHYLATION INCREASED SIGNIFICANTLY WITH AGE, BUT NO OTHER INVESTIGATED LOCI SHOWED SIGNIFICANT AGE-RELATED METHYLATION. LINE-1 AND IAP BOTH SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE (P < 0.05). ESR1ALSO SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE IN FEMALE MICE (P = 0.02), BUT NOT MALE MICE. PHYSICAL ACTIVITY HAD A NON-SIGNIFICANT POSITIVE EFFECT ON AGE-RELATED ESR1 METHYLATION IN FEMALE BLOOD, SUGGESTING THAT IT MAY PARTIALLY ABROGATE THE EFFECTS OF WHFD ON THE AGING EPIGENOME. THESE RESULTS SUGGEST THAT DEVELOPMENTAL NUTRITIONAL EXPOSURES CAN MODIFY AGE-RELATED DNA METHYLATION PATTERNS AT A GENE RELATED TO GROWTH AND DEVELOPMENT. AS SUCH, ENVIRONMENTAL DEFLECTION OF THE AGING EPIGENOME MAY HELP TO EXPLAIN THE GROWING PREVALENCE OF CHRONIC DISEASES IN HUMAN POPULATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9 3441  37 HYPERMETHYLATION IN GENE PROMOTERS ARE INDUCED BY CHRONIC EXPOSURE TO BENZENE, TOLUENE, ETHYLBENZENE AND XYLENES. BACKGROUND AND OBJECTIVE: GAS STATION ATTENDANTS ARE OCCUPATIONALLY EXPOSED TO BENZENE, TOLUENE, ETHYLBENZENE AND XYLENE (BTEX) COMPOUNDS AND THUS MORE SUSCEPTIBLE TO THE BIOLOGICAL EFFECTS OF THIS MIXTURE PRESENT IN GASOLINE, ESPECIALLY DUE TO THE CARCINOGENICITY OF BENZENE. FURTHERMORE, THE HARMFUL EFFECTS OF BTEX EXPOSURE MAY BE POTENTIATED BY GENETIC AND EPIGENETIC INACTIVATION OF CRITICAL GENES. THE OBJECTIVE WAS TO EVALUATE SUCH GENE-BTEX INTERACTIONS ACCESSING THE PROMOTER METHYLATION STATUS OF P14ARF, P16INK4A AND GSTP1 IN PERIPHERAL BLOOD LEUKOCYTE SAMPLES. MATERIALS AND METHODS: THE 59 EXPOSED AND 68 UNEXPOSED PARTICIPANTS FROM RIO DE JANEIRO, BRAZIL, WERE INCLUDED. THE PROMOTER METHYLATION STATUS WAS ACCESSED BY METHYLATION-SPECIFIC PCR (MSP) AND GSTP1 ILE105VAL POLYMORPHISM WAS INVESTIGATED BY PCR-RESTRICTION FRAGMENT LENGTH POLYMORPHISM (PCR-RFLP) TECHNIQUE. RESULTS: BOTH P14ARF AND P16INK4A WERE SIGNIFICANTLY HYPERMETHYLATED IN EXPOSED SUBJECTS COMPARED TO UNEXPOSED (P = 0.004 AND P<0.001, RESPECTIVELY). ADDITIONALLY, P16INK4A HYPERMETHYLATION IN THE EXPOSED GROUP WAS CORRELATED WITH CHROMOSOMAL ABNORMALITIES (CAS) (P = 0.018), THUS HIGHLIGHTING THE INFLUENCE OF THE GENE-ENVIRONMENT INTERACTIONS ON GENOME INSTABILITY. NOTEWORTHY, P16INK4A METHYLATION WAS SIGNIFICANTLY ASSOCIATED WITH MISCARRIAGE AMONG FEMALE ATTENDANTS (P = 0.047), IN WHICH THOSE WHO REPORTED MISCARRIAGE EXHIBITED HYPERMETHYLATION IN AT LEAST 2 OF THE 3 GENES ANALYZED. THE GSTP1 HETEROZYGOTE GENOTYPE, WHICH COULD AFFECT THE METABOLISM OF BENZENE DETOXIFICATION, WAS FOUND IN BOTH GROUPS BUT WAS MORE FREQUENT IN THOSE OCCUPATIONALLY EXPOSED. NO SIGNIFICANT ASSOCIATION WAS OBSERVED BETWEEN GSTP1 GENOTYPES AND METHYLATION STATUS. CONCLUSION: TOGETHER, THESE FINDINGS INDICATE THAT GAS STATION ATTENDANTS WITH THE AFOREMENTIONED EPIGENETIC AND GENETIC PROFILES MAY BE AT GREATER RISK OF OCCUPATIONAL BTEX EXPOSURE-INDUCED GENOME INSTABILITY, WHICH COULD REQUIRE CONCERTED EFFORTS TO ESTABLISH MORE PREVENTIVE ACTIONS AND CONSTANT BIOMONITORING IN GAS STATION ATTENDANTS.	2020	
                                                                                                                                                       
10 4242  35 METHYLATION STATUS OF ALU AND LINE-1 INTERSPERSED REPETITIVE SEQUENCES IN BEHCET'S DISEASE PATIENTS. BEHCET'S DISEASE (BD) IS A MULTISYSTEM CHRONIC INFLAMMATORY DISEASE. THE PATHOLOGY IS BELIEVED TO INVOLVE BOTH GENETIC SUSCEPTIBILITY AND ENVIRONMENTAL FACTORS. HYPOMETHYLATION LEADING TO ACTIVATION OF INTERSPERSED REPETITIVE SEQUENCES (IRSS) SUCH AS LINE-1 AND ALU CONTRIBUTES TO THE PATHOLOGIES OF AUTOIMMUNE DISEASES AND CANCER. HEREIN, THE EPIGENETIC CHANGES OF IRSS IN BD WERE EVALUATED USING COMBINED BISULFITE RESTRICTION ANALYSIS-INTERSPERSED REPETITIVE SEQUENCES (COBRA-IRS). DNA FROM NEUTROPHILS AND PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF BD PATIENTS WITH OCULAR INVOLVEMENT THAT WERE IN ACTIVE OR INACTIVE STATES AND HEALTHY CONTROLS WERE USED TO ANALYZE LINE-1 AND ALU METHYLATION LEVELS. FOR ALU SEQUENCES, SIGNIFICANT DIFFERENCES WERE OBSERVED IN THE FREQUENCY OF (U)C(U)C ALLELES BETWEEN PBMCS OF PATIENTS AND CONTROLS (P = 0.03), AND BETWEEN INACTIVE PATIENTS AND CONTROLS (P = 0.03). FOR NEUTROPHILS, THE FREQUENCY OF (U)C(U)C WAS SIGNIFICANTLY HIGHER BETWEEN PATIENTS AND CONTROLS (P = 0.006) AND BETWEEN INACTIVE PATIENTS AND CONTROLS (P = 0.002). THE PARTIAL METHYLATION ((U)C(M)C + (M)C(U)C) FREQUENCIES OF ALU BETWEEN INACTIVE PATIENTS AND CONTROL SAMPLES ALSO DIFFERED (P = 0.02). NO STATISTICALLY SIGNIFICANT DIFFERENCES FOR LINE-1 WERE DETECTED. THUS, CHANGES IN THE METHYLATION LEVEL OF IRS ELEMENTS MIGHT CONTRIBUTE TO THE PATHOGENESIS OF BD. THE ROLE OF ALU TRANSCRIPTS IN BD SHOULD BE INVESTIGATED FURTHER.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11 4024  35 LUNG ALLOGRAFT EPITHELIUM DNA METHYLATION AGE IS ASSOCIATED WITH GRAFT CHRONOLOGIC AGE AND PRIMARY GRAFT DYSFUNCTION. ADVANCED DONOR AGE IS A RISK FACTOR FOR POOR SURVIVAL FOLLOWING LUNG TRANSPLANTATION. HOWEVER, RECENT WORK IDENTIFYING EPIGENETIC DETERMINANTS OF AGING HAS SHOWN THAT BIOLOGIC AGE MAY NOT ALWAYS REFLECT CHRONOLOGIC AGE AND THAT STRESSORS CAN ACCELERATE BIOLOGIC AGING. WE HYPOTHESIZED THAT LUNG ALLOGRAFTS THAT EXPERIENCED PRIMARY GRAFT DYSFUNCTION (PGD), CHARACTERIZED BY POOR OXYGENATION IN THE FIRST THREE POST-TRANSPLANT DAYS, WOULD HAVE INCREASED BIOLOGIC AGE. WE CULTURED AIRWAY EPITHELIAL CELLS ISOLATED BY TRANSBRONCHIAL BRUSH AT 1-YEAR BRONCHOSCOPIES FROM 13 SUBJECTS WITH SEVERE PGD AND 15 CONTROLS MATCHED ON AGE AND TRANSPLANT INDICATION. WE MEASURED EPIGENETIC AGE USING THE HORVATH EPIGENETIC CLOCK. LINEAR MODELS WERE USED TO DETERMINE THE ASSOCIATION OF AIRWAY EPIGENETIC AGE WITH CHRONOLOGIC AGES AND PGD STATUS, ADJUSTED FOR RECIPIENT PGD RISK FACTORS. SURVIVAL MODELS ASSESSED THE ASSOCIATION WITH CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) OR DEATH. DISTRIBUTIONS OF PROMOTER METHYLATION WITHIN PATHWAYS WERE COMPARED BETWEEN GROUPS. DNA METHYLTRANSFERASE (DNMT) ACTIVITY WAS QUANTIFIED IN AIRWAY EPITHELIAL CELLS UNDER HYPOXIC OR NORMOXIC CONDITIONS. AIRWAY EPIGENETIC AGE APPEARED YOUNGER BUT WAS STRONGLY ASSOCIATED WITH THE AGE OF THE ALLOGRAFT (SLOPE 0.38 PER YEAR, 95% CI 0.27-0.48). THERE WAS NO CORRELATION BETWEEN EPIGENETIC AGE AND RECIPIENT AGE (P = 0.96). EPIGENETIC AGE WAS 6.5 YEARS GREATER (95% CI 1.7-11.2) IN SUBJECTS WHO HAD EXPERIENCED PGD, AND THIS EFFECT REMAINED SIGNIFICANT AFTER ADJUSTING FOR DONOR AND RECIPIENT CHARACTERISTICS (P = 0.03). EPIGENETIC AGE WAS NOT ASSOCIATED WITH CLAD-FREE SURVIVAL RISK (P = 0.11). ANALYSIS OF DIFFERENTIAL METHYLATION OF PROMOTERS OF KEY BIOLOGIC PATHWAYS REVEALED HYPOMETHYLATION IN REGIONS RELATED TO HYPOXIA, INFLAMMATION, AND METABOLISM-ASSOCIATED PATHWAYS. ACCORDINGLY, AIRWAY EPITHELIAL CELLS CULTURED IN HYPOXIC CONDITIONS SHOWED SUPPRESSED DNMT ACTIVITY. WHILE AIRWAY METHYLATION AGE WAS PRIMARILY DETERMINED BY DONOR CHRONOLOGIC AGE, EARLY INJURY IN THE FORM OF PGD WAS ASSOCIATED WITH INCREASED ALLOGRAFT EPIGENETIC AGE. THESE DATA SHOW HOW PGD MIGHT SUPPRESS KEY PROMOTER METHYLATION RESULTING IN LONG-TERM IMPACTS ON THE ALLOGRAFT.	2021	

12 1607  36 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13 1193  37 CORRELATION OF CYP2R1 GENE PROMOTER METHYLATION WITH CIRCULATING VITAMIN D LEVELS AMONG HEALTHY ADULTS. BACKGROUND & OBJECTIVES: DESPITE BEING A TROPICAL COUNTRY, VITAMIN D DEFICIENCY IS HIGHLY PREVALENT IN INDIA WITH STUDIES INDICATING 40-99 PER CENT PREVALENCE. APART FROM CALCIUM AND PHOSPHATE METABOLISM, VITAMIN D IS INVOLVED IN CELL CYCLE REGULATION, CARDIOVASCULAR, HEPATOPROTECTION. THE METABOLISM OF VITAMIN D IS REGULATED BY VITAMIN D TOOL GENES (CYP2R1/CYP27B1/CYP24A1/VDR). THE PROMOTER REGIONS OF SOME OF THESE GENES HAVE CPG ISLANDS, MAKING THEM PRONE TO METHYLATION INDUCED GENE SILENCING, WHICH MAY CAUSE A REDUCTION IN CIRCULATING VITAMIN D LEVELS. EPIGENETIC BASIS OF VITAMIN D DEFICIENCY IS YET TO BE STUDIED IN INDIA, AND HENCE, THIS PILOT STUDY WAS AIMED TO ANALYZE WHETHER METHYLATION LEVELS OF CYP2R1 GENE WERE CORRELATED WITH THE LEVELS OF 25(OH)D IN HEALTHY, ADULT INDIVIDUALS IN INDIAN POPULATION. METHODS: IN THIS CROSS-SECTIONAL STUDY, HEALTHY ADULTS OF 18-45 YR OF AGE WITH NO HISTORY OF MALABSORPTION, THYROIDECTOMY, CHRONIC ILLNESS OR THERAPEUTIC VITAMIN D SUPPLEMENTATION WERE RECRUITED. DNA METHYLATION ANALYSIS WAS CARRIED OUT BY METHYLATION SPECIFIC QUANTITATIVE PCR. SERUM CALCIUM, PHOSPHATE AND VITAMIN D LEVELS WERE ALSO QUANTIFIED. STATISTICAL ANALYSIS WAS DONE BY R 4.0.5 SOFTWARE. RESULTS: A TOTAL OF 61 APPARENTLY HEALTHY ADULTS WERE ANALYZED. THE SERUM VITAMIN D LEVELS DID NOT CORRELATE WITH CYP2R1 METHYLATION LEVELS IN OUR STUDY POPULATION. SIGNIFICANT POSITIVE CORRELATION WAS OBSERVED BETWEEN AGE AND SERUM VITAMIN D LEVELS. SIGNIFICANT ASSOCIATION OF GENDER WAS FOUND WITH CYP2R1 METHYLATION LEVELS. INTERPRETATION & CONCLUSIONS: THIS STUDY FOUND NO SIGNIFICANT CORRELATION BETWEEN LEVELS OF CYP2R1 METHYLATION AND CIRCULATING 25(OH)D DEFICIENCY. FURTHER STUDIES ON THE INDIAN POPULATION HAVING A LARGER SAMPLE SIZE INCLUDING ENTIRE VITAMIN D TOOL GENES, AMONG DIFFERENT ETHNIC GROUPS MAY BE CONDUCTED TO ELUCIDATE MOLECULAR ETIOLOGY OF CIRCULATING 25(OH)D DEFICIENCY. THE HIGH PREVALENCE OF NORMAL SERUM CALCIUM AND PHOSPHATE LEVELS AMONG VITAMIN D DEFICIENT SUBJECTS IN THIS STUDY COUPLED WITH THE STRIKINGLY HIGH PREVALENCE OF THE DEFICIENCY AT THE NATIONAL LEVEL, MAY SUGGEST THE NEED TO REVISE THE CUT-OFF CRITERIA FOR VITAMIN D DEFICIENCY IN THE INDIAN POPULATION.	2023	
                    
14 1553  35 DNA METHYLATION LEVELS ASSOCIATED WITH RACE AND CHILDHOOD ASTHMA SEVERITY. OBJECTIVE: ASTHMA IS A COMMON CHRONIC CHILDHOOD DISEASE WORLDWIDE. SOCIOECONOMIC STATUS, GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS CONTRIBUTE TO ITS INCIDENCE AND SEVERITY. A DISPROPORTIONATE NUMBER OF CHILDREN WITH ASTHMA ARE ECONOMICALLY DISADVANTAGED AND LIVE IN SUBSTANDARD HOUSING WITH POTENTIAL INDOOR ENVIRONMENTAL EXPOSURES SUCH AS COCKROACHES, DUST MITES, RODENTS AND MOLDS. THESE EXPOSURES MAY MANIFEST THROUGH EPIGENETIC MECHANISMS THAT CAN LEAD TO CHANGES IN RELEVANT GENE EXPRESSION. WE EXAMINED THE ASSOCIATION OF GLOBAL DNA METHYLATION LEVELS WITH SOCIOECONOMIC STATUS, ASTHMA SEVERITY AND RACE/ETHNICITY. METHODS: WE MEASURED GLOBAL DNA METHYLATION IN PERIPHERAL BLOOD OF CHILDREN WITH ASTHMA ENROLLED IN THE KANSAS CITY SAFE AND HEALTHY HOMES PROGRAM. INCLUSION CRITERIA INCLUDED RESIDING IN THE SAME HOME FOR A MINIMUM OF 4 DAYS PER WEEK AND TOTAL FAMILY INCOME OF LESS THAN 80% OF THE KANSAS CITY MEDIAN FAMILY INCOME. DNA METHYLATION LEVELS WERE QUANTIFIED BY AN IMMUNOASSAY THAT ASSESSED THE PERCENTAGE OF 5-METHYLCYTOSINE. RESULTS: OUR RESULTS INDICATE THAT OVERALL, AFRICAN AMERICAN CHILDREN HAD HIGHER LEVELS OF GLOBAL DNA METHYLATION THAN CHILDREN OF OTHER RACES/ETHNICITIES (P = 0.029). THIS DIFFERENCE WAS MORE PRONOUNCED WHEN SOCIOECONOMIC STATUS AND ASTHMA SEVERITY WERE COUPLED WITH RACE/ETHNICITY (P = 0.042) WHERE LOW-INCOME, AFRICAN AMERICAN CHILDREN WITH PERSISTENT ASTHMA HAD SIGNIFICANTLY ELEVATED METHYLATION LEVELS RELATIVE TO OTHER RACES/ETHNICITIES IN THE SAME CONTEXT (P = 0.006, HEDGES G = 1.14). CONCLUSION: OUR STUDY DEMONSTRATES A SIGNIFICANT INTERACTION EFFECT AMONG GLOBAL DNA METHYLATION LEVELS, ASTHMA SEVERITY, RACE/ETHNICITY, AND SOCIOECONOMIC STATUS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15 2627  40 EPIGENOME-WIDE ASSOCIATION STUDY OF ADIPOSITY AND FUTURE RISK OF OBESITY-RELATED DISEASES. BACKGROUND: OBESITY IS AN ESTABLISHED RISK FACTOR FOR SEVERAL COMMON CHRONIC DISEASES SUCH AS BREAST AND COLORECTAL CANCER, METABOLIC AND CARDIOVASCULAR DISEASES; HOWEVER, THE BIOLOGICAL BASIS FOR THESE RELATIONSHIPS IS NOT FULLY UNDERSTOOD. TO EXPLORE THE ASSOCIATION OF OBESITY WITH THESE CONDITIONS, WE INVESTIGATED PERIPHERAL BLOOD LEUCOCYTE (PBL) DNA METHYLATION MARKERS FOR ADIPOSITY AND THEIR CONTRIBUTION TO RISK OF INCIDENT BREAST AND COLORECTAL CANCER AND MYOCARDIAL INFARCTION. METHODS: DNA METHYLATION PROFILES (ILLUMINA INFINIUM((R)) HUMANMETHYLATION450 BEADCHIP) FROM 1941 INDIVIDUALS FROM FOUR POPULATION-BASED EUROPEAN COHORTS WERE ANALYSED IN RELATION TO BODY MASS INDEX, WAIST CIRCUMFERENCE, WAIST-HIP AND WAIST-HEIGHT RATIO WITHIN A META-ANALYTICAL FRAMEWORK. IN A SUBSET OF THESE INDIVIDUALS, DATA ON GENOME-WIDE GENE EXPRESSION LEVEL, BIOMARKERS OF GLUCOSE AND LIPID METABOLISM WERE ALSO AVAILABLE. VALIDATION OF METHYLATION MARKERS ASSOCIATED WITH ALL ADIPOSITY MEASURES WAS PERFORMED IN 358 INDIVIDUALS. FINALLY, WE INVESTIGATED THE ASSOCIATION OF OBESITY-RELATED METHYLATION MARKS WITH BREAST, COLORECTAL CANCER AND MYOCARDIAL INFARCTION WITHIN RELEVANT SUBSETS OF THE DISCOVERY POPULATION. RESULTS: WE IDENTIFIED 40 CPG LOCI WITH METHYLATION LEVELS ASSOCIATED WITH AT LEAST ONE ADIPOSITY MEASURE. OF THESE, ONE CPG LOCUS (CG06500161) IN ABCG1 WAS ASSOCIATED WITH ALL FOUR ADIPOSITY MEASURES (P = 9.07X10(-)(8) TO 3.27X10(-18)) AND LOWER TRANSCRIPTIONAL ACTIVITY OF THE FULL-LENGTH ISOFORM OF ABCG1 (P = 6.00X10(-7)), HIGHER TRIGLYCERIDE LEVELS (P = 5.37X10(-)(9)) AND HIGHER TRIGLYCERIDES-TO-HDL CHOLESTEROL RATIO (P = 1.03X10(-10)). OF THE 40 INFORMATIVE AND OBESITY-RELATED CPG LOCI, TWO (IN IL2RB AND FGF18) WERE SIGNIFICANTLY ASSOCIATED WITH COLORECTAL CANCER (INVERSELY, P < 1.6X10(-3)) AND ONE INTERGENIC LOCUS ON CHROMOSOME 1 WAS INVERSELY ASSOCIATED WITH MYOCARDIAL INFARCTION (P < 1.25X10(-3)), INDEPENDENTLY OF OBESITY AND ESTABLISHED RISK FACTORS. CONCLUSION: OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES, IN PARTICULAR ALTERED DNA METHYLATION PATTERNS, MAY BE AN INTERMEDIATE BIOMARKER AT THE INTERSECTION OF OBESITY AND OBESITY-RELATED DISEASES, AND COULD OFFER CLUES AS TO UNDERLYING BIOLOGICAL MECHANISMS.	2018	
    
16 1408  37 DIETARY INTAKE IS ASSOCIATED WITH RESPIRATORY HEALTH OUTCOMES AND DNA METHYLATION IN CHILDREN WITH ASTHMA. BACKGROUND: ASTHMA IS AN INCREASINGLY COMMON CHRONIC DISEASE AMONG CHILDREN, AND DATA POINT TOWARD A COMPLEX MECHANISM INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. EPIGENETIC MODIFICATIONS SUCH AS DNA HYPO- OR HYPER-METHYLATION HAVE BEEN SHOWN TO OCCUR IN RESPONSE TO ENVIRONMENTAL EXPOSURES INCLUDING DIETARY NUTRIENTS. METHODS: WITHIN THE CONTEXT OF THE ASTHMA RANDOMIZED TRIAL OF INDOOR WOOD SMOKE (ARTIS) STUDY, WE INVESTIGATED RELATIONSHIPS BETWEEN DIET, ASTHMA HEALTH MEASURES, AND DNA METHYLATION. ASTHMA HEALTH MEASURES INCLUDED A QUALITY OF LIFE INSTRUMENT, DIURNAL PEAK FLOW VARIABILITY (DPFV) AND FORCED EXPIRATORY VOLUME IN THE FIRST SECOND (FEV(1)). DIETARY INTAKE WAS ASSESSED WITH A FOOD FREQUENCY QUESTIONNAIRE. METHYLATION LEVELS OF LINE-1 REPETITIVE ELEMENT AND TWO PROMOTER CPG SITES FOR INTERFERON GAMMA (IFNGAMMA, -186 AND -54) FROM BUCCAL CELL DNA WERE MEASURED USING PYROSEQUENCING ASSAYS. RESULTS: DATA WERE COLLECTED ON 32 CHILDREN WITH ASTHMA LIVING IN WESTERN MONTANA WHO WERE RECRUITED TO THE ARTIS STUDY. SELENIUM AND SEVERAL METHYL DONOR DIETARY NUTRIENTS WERE POSITIVELY ASSOCIATED WITH THE ASTHMA QUALITY OF LIFE MEASURE. INTAKE OF METHYL DONATING NUTRIENTS INCLUDING FOLATE WAS POSITIVELY ASSOCIATED LINE-1 METHYLATION AND NEGATIVELY ASSOCIATED WITH IFNGAMMA CPG-186. HIGHER LEVELS OF LINE-1 METHYLATION WERE ASSOCIATED WITH GREATER DPFV. CONCLUSION: WE IDENTIFIED SEVERAL NUTRIENTS THAT WERE ASSOCIATED WITH IMPROVED QUALITY OF LIFE MEASURES AMONG CHILDREN WITH ASTHMA. THE IFNGAMMA PROMOTER CPG SITE -186 BUT NOT -54 WAS ASSOCIATED WITH THE INTAKE OF SELECTED DIETARY NUTRIENTS. HOWEVER, IN THIS SMALL POPULATION OF CHILDREN WITH ASTHMA, THE IFNGAMMA PROMOTER CPG SITES WERE NOT ASSOCIATED WITH RESPIRATORY HEALTH MEASURES SO IT REMAINS UNCLEAR THROUGH WHICH EPIGENETIC MECHANISM THESE NUTRIENTS ARE IMPACTING THE QUALITY OF LIFE MEASURE. THESE FINDINGS ADD TO THE EVIDENCE THAT DIETARY NUTRIENTS, PARTICULARLY FOODS CONTAINING METHYL DONORS, MAY BE IMPORTANT FOR EPIGENETIC REGULATION AS IT PERTAINS TO THE CONTROL OF ASTHMA. TRIAL REGISTRATION CLINCIALTRIALS.GOV NCT00807183. REGISTERED 10 DECEMBER 2008.	2017	
                                                                               
17 3378  35 HIV INDUCED NITRIC OXIDE AND LIPID PEROXIDATION, INFLUENCES NEONATAL BIRTHWEIGHT IN A SOUTH AFRICAN POPULATION. HIV HAS BEEN IMPLICATED IN ADVERSE BIRTH OUTCOMES, DUE TO INCREASED OXIDATIVE STRESS AND INFLAMMATION. IN ADDITION, HIV HAS BEEN REPORTED TO INCREASE NITRIC OXIDE LEVELS. THEREFORE THE COMBINED EXPOSURES TO HIV AND TRAFFIC-RELATED AIR POLLUTION, WITHIN SOUTH DURBAN, SOUTH AFRICA (SA), MAY LEAD TO ADVERSE BIRTH OUTCOMES. HOWEVER, THE EXACT MECHANISM IS STILL UNKNOWN; THIS STUDY AIMED TO IDENTIFY A POTENTIAL MECHANISM. FIRST, THE INFLUENCE OF HIV ON OXIDATIVE AND NITROSATIVE STRESS MARKERS IN PREGNANT WOMEN WAS ASSESSED. SECONDLY, THE EFFECT OF THESE STRESS MAKERS AND EXPOSURE TO OXIDES OF NITROGEN (NOX) ON NEONATAL BIRTHWEIGHT (BW) WAS EVALUATED. FINALLY, THE EFFECT HIV AND TRAFFIC-RELATED POLLUTION EXPOSURE HAS ON THE OXIDATIVE AND ENDOPLASMIC PROFILE AND EPIGENETIC REGULATION OF NRF2-KEAP1 PATHWAY BY MIR-144 AND MIR-28 IN PREGNANT WOMEN WAS DETERMINED. WOMEN, IN THEIR THIRD TRIMESTER WITH SINGLETON PREGNANCIES, WHO WERE HIV+ AND HIV-, WERE RECRUITED FROM DURBAN, SA. BIOMARKER LEVELS OF SERUM NITRITES/NITRATES (NO) AND MALONDIALDEHYDE (MDA) WERE ANALYSED AND MRNA EXPRESSION LEVELS OF OXIDATIVE AND ENDOPLASMIC STRESS RESPONSE GENES WERE ASSESSED. LAND REGRESSION MODELLING WAS PERFORMED TO DETERMINE NOX EXPOSURE LEVELS. HIV EXPOSURE DURING PREGNANCY WAS ASSOCIATED WITH INCREASED NO LEVELS. NO WAS SHOWN TO REDUCE NEONATAL BW. NO AND MDA WAS FOUND TO RECIPROCALLY INCREASE EACH OTHER, WITH HIV DIFFERENTIALLY INFLUENCING MDA'S EFFECT ON BW. HIV DOWN-REGULATED MIR-144 WHICH WAS NEGATIVELY ASSOCIATED WITH NRF2, SUGGESTING A POTENTIAL MECHANISM FOR HIV ASSOCIATED CHRONIC OXIDATIVE STRESS. THIS STUDY PROPOSES THAT NO PLAYS A KEY ROLE IN NEONATAL BW REDUCTION IN RESPONSE TO HIV AND TRAFFIC-RELATED AIR POLLUTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18 1849  30 EIGHT WEEKS OF PHYSICAL TRAINING DECREASES 2 YEARS OF DNA METHYLATION AGE OF SEDENTARY WOMEN. PURPOSE: THE ACCELERATION OF EPIGENETIC AGE IS A PREDICTOR OF MORTALITY AND CONTRIBUTES TO THE INCREASE IN CHRONIC DISEASES. ADHERENCE TO A HEALTHY LIFESTYLE IS A STRATEGY TO REDUCE EPIGENETIC AGE. THE PRESENT STUDY AIMED TO DETERMINE WHETHER EIGHT WEEKS OF COMBINED (AEROBIC AND STRENGTH) TRAINING (CT) CAN INFLUENCE THE EPIGENETIC AGE OF WOMEN BETWEEN 50 AND 70 YEARS OLD AND THE DIFFERENCES IN SITES AND METHYLATED REGIONS. METHODS: EIGHTEEN WOMEN (AAR(LOW): LOWER AGE ACCELERATION RESIDUAL, N = 10; AAR(HIGH): HIGHER AGE ACCELERATION RESIDUAL, N = 8) PARTICIPATED IN A COMBINED EXERCISE TRAINING PROGRAM (60 MINUTES, 3X A WEEK) FOR EIGHT WEEKS. DNA WAS EXTRACTED FROM WHOLE BLOOD USING THE SALTING OUT TECHNIQUE. DNA METHYLATION WAS PERFORMED USING THE ARRAY TECHNIQUE (ILLUMINA'S INFINIUM METHYLATION BEADCHIP 850K). WE USED THE DNA METHYLATION AGE CALCULATOR PLATFORM TO CALCULATE THE BIOLOGICAL EPIGENETIC AGE. TWO-WAY ANOVA FOLLOWED BY FISHER LSD POSTHOC WAS APPLIED, ADOPTING P < .05. RESULTS: AFTER EIGHT WEEKS OF CT, THERE WERE NO CHANGES TO THE EPIGENETIC AGE ACCELERATION FOR THE AAR(LOW) GROUP (PRE: -2.3 +/- 3.2 TO POST: -2.3 +/- 3.6). HOWEVER, THE AAR(HIGH) GROUP SIGNIFICANTLY DECREASED THE AGE ACCELERATION (PRE: 3.6 +/- 2.6 TO POST: 2.2 +/- 2.7) (GROUP EFFECT, P = .01; TIME EFFECT, P = .31; GROUP VS. TIME EFFECT, P = .005). CONCLUSION: CT FOR EIGHT WEEKS BENEFITS THE EPIGENETIC CLOCK OF WOMEN WITH THE MOST ACCELERATED AGE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 3568  36 IMPACT OF INFLAMMATION ON EPIGENETIC DNA METHYLATION - A NOVEL RISK FACTOR FOR CARDIOVASCULAR DISEASE? OBJECTIVE: THE LIFESPAN OF DIALYSIS PATIENTS IS AS SHORT AS IN PATIENTS WITH METASTATIC CANCER DISEASE, MAINLY DUE TO CARDIOVASCULAR DISEASE (CVD). DNA METHYLATION IS AN IMPORTANT CELLULAR MECHANISM MODULATING GENE EXPRESSION ASSOCIATED WITH AGEING, INFLAMMATION AND ATHEROSCLEROTIC PROCESSES. DESIGN: DNA METHYLATION WAS ANALYSED IN PERIPHERAL BLOOD LEUCOCYTES FROM THREE DIFFERENT GROUPS OF CHRONIC KIDNEY DISEASE (CKD) POPULATIONS (37 CKD STAGES 3 AND 4 PATIENTS, 98 CKD STAGE 5 PATIENTS AND 20 PREVALENT HAEMODIALYSIS PATIENTS). THIRTY-SIX HEALTHY SUBJECTS SERVED AS CONTROLS. CLINICAL CHARACTERISTICS (DIABETES MELLITUS, NUTRITIONAL STATUS AND PRESENCE OF CLINICAL CVD), INFLAMMATION AND OXIDATIVE STRESS BIOMARKERS, HOMOCYSTEINE AND GLOBAL DNA METHYLATION IN PERIPHERAL BLOOD LEUCOCYTES (DEFINED AS HPAII/MSPI RATIO BY THE LUMINOMETRIC METHYLATION ASSAY METHOD) WERE EVALUATED. CKD STAGE 5 PATIENTS (N=98) STARTING DIALYSIS TREATMENT WERE FOLLOWED FOR A PERIOD OF 36 +/- 2 MONTHS. RESULTS: INFLAMED PATIENTS HAD LOWER RATIOS OF HPAII/MSPI, INDICATING GLOBAL DNA HYPERMETHYLATION. ANALYSIS BY THE COX REGRESSION MODEL DEMONSTRATED THAT DNA HYPERMETHYLATION (HPAII/MSPI RATIO <MEDIAN) WAS SIGNIFICANTLY ASSOCIATED WITH BOTH ALL-CAUSE (RR 5.0; 95% CI: 1.7-14.8; P<0.01) AND CARDIOVASCULAR (RR 13.9; 95% CI: 1.8-109.3; P<0.05) MORTALITY, EVEN FOLLOWING THE ADJUSTMENT FOR AGE, CVD, DIABETES MELLITUS AND INFLAMMATION. CONCLUSION: THE PRESENT STUDY DEMONSTRATES THAT GLOBAL DNA HYPERMETHYLATION IS ASSOCIATED WITH INFLAMMATION AND INCREASED MORTALITY IN CKD.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20 3414  32 HSD11B2, RUNX3, AND LINE-1 METHYLATION IN PLACENTAL DNA OF HYPERTENSIVE DISORDERS OF PREGNANCY PATIENTS. HYPERTENSIVE DISORDERS OF PREGNANCY (HDSP) REMAIN LEADING CAUSES OF MATERNAL AND PERINATAL MORBIDITY AND MORTALITY. GROWING EVIDENCE SUGGESTS THE INVOLVEMENT OF EPIGENETIC FACTORS, SUCH AS GENE-SPECIFIC AND GLOBAL DNA METHYLATION CHANGES, BOTH IN THE ETIOLOGY AND AS AN EFFECT OF HDSP. IN THIS STUDY, WE INVESTIGATED THE POTENTIAL ASSOCIATION BETWEEN PLACENTAL DNA METHYLATION STATUS IN SELECTED CPGS OF HSD11B2 CORTISOL LEVEL CONTROLLING GENE, RUNX3 TUMOR SUPPRESSOR GENE, AND LONG INTERSPERSED NUCLEOTIDE ELEMENT-1 (LINE-1) REPETITIVE ELEMENTS AND HDSP-PREECLAMPSIA (PE), GESTATIONAL HYPERTENSION (GH), AND CHRONIC HYPERTENSION (CH). METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND PYROSEQUENCING (PSQ) WERE USED TO ANALYZE PLACENTAL DNA METHYLATION. PLASMA AND URINE CORTISOL AND CORTISONE LEVELS WERE MEASURED USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY WITH FLUORESCENCE DETECTION (HPLC-FLD), WHEREAS SERUM PROGESTERONE LEVEL WAS DETERMINED BY ELECTROCHEMILUMINESCENCE IMMUNOASSAY. THE MEAN PERCENTAGE OF HSD11B2, RUNX3, AND LINE-1 METHYLATION WAS NOT ALTERED IN THE PLACENTAS OF PATIENTS WITH HDSP, AS COMPARED TO THE CONTROLS. HOWEVER, AMONG PATIENTS FROM PE, GH, AND CH GROUPS, SEVERAL SIGNIFICANT CORRELATIONS WERE OBSERVED BETWEEN THE METHYLATION STATUS OF HSD11B2, RUNX3, OR LINE-1 AND CHILDREN'S BIRTH WEIGHT, GESTATIONAL AGE AT DELIVERY, MOTHER'S AGE, AND BODY MASS INDEX AS WELL AS HORMONES LEVELS. THESE RESULTS INDICATE LACK OF ASSOCIATION BETWEEN METHYLATION STATUS OF HSD11B2, RUNX3, OR LINE-1 REPETITIVE ELEMENTS AND HDSP. HOWEVER, ASSOCIATION OF THESE PARAMETERS WITH SOME CLINICAL VARIABLES MAY SUGGEST THE ROLE OF PLACENTAL DNA METHYLATION IN FETAL DEVELOPMENT AND SHOULD BE FURTHER EXPLORED.	2017