1 813 157 CHANGES IN POLY(ADP-RIBOSYL)ATION PATTERNS IN WORKERS EXPOSED TO BTX. OCCUPATIONAL EXPOSURE TO (BENZENE, TOLUENE AND XYLENE, BTX IS COMMON IN THE CHINESE WORKPLACE. CHRONIC OCCUPATIONAL EXPOSURE TO BENZENE IS ASSOCIATED WITH AN INCREASED RISK OF HEMATOLOGICAL MALIGNANCIES SUCH AS ACUTE MYELOID LEUKEMIA (AML), BUT THE UNDERLYING MECHANISMS ARE STILL UNCLEAR. THIS STUDY INVESTIGATES CHANGES IN POLY(ADP-RIBOSYL)ATION AND DNA METHYLATION IN SUBJECTS OCCUPATIONALLY EXPOSED TO A BTX. BLOOD DNA SAMPLES AND EXPOSURE DATA WERE OBTAINED FROM SUBJECTS WITH DIFFERENT LEVELS OF EXPOSURE, INCLUDING 132 DECORATORS, 129 PAINTERS, AND 130 UNEXPOSED REFERENTS IN A CONTAINER-MANUFACTURING FACTORY IN SHENZHEN, CHINA. OCCUPATIONAL EXPOSURE ASSESSMENT INCLUDED PERSONAL MONITORING OF AIRBORNE BENZENE, TOLUENE AND XYLENE. HEMATOLOGICAL PARAMETERS WERE MEASURED AND THE CYTOKINESIS-BLOCK MICRONUCLEUS (CBMN) ASSAY WAS USED TO DETECT DNA DAMAGE IN PERIPHERAL LYMPHOCYTES. QUANTITATIVE REAL-TIME PCR WAS USED TO DETECT THE MRNA EXPRESSION OF POLY(ADP-RIBOSE) POLYMERASE 1 (PARP1) AND POLY(ADP-RIBOSE) GLYCOHYDROLASE (PARG), DNA METHYLTRANSFERASES (DNMTS) INCLUDING DNMT1, DNMT3A AND DNMT3B, METHYL-CPG-BINDING DOMAIN PROTEIN 2(MBD2). PARP1 ASSAY WAS USED TO MEASURE PARP ACTIVITY. AIRBORNE LEVELS OF BENZENE, TOLUENE AND XYLENE IN THE TWO EXPOSED GROUPS WERE SIGNIFICANTLY HIGHER THAN THOSE OF CONTROLS (P<0.001). THE TWO EXPOSED GROUPS (DECORATORS, PAINTERS) SHOWED DECREASED PARP1, DNMTS AND MBD2 EXPRESSION RELATIVE TO CONTROLS (P<0.05), AND PARP ACTIVITY WAS ALSO DECREASED (P<0.05). DECREASED PARP1, DNMT1, DNMT3A, DNMT3B AND MBD2 MRNA EXPRESSION WAS CORRELATED WITH INCREASED AIRBORNE BTX (PEARSON'S R: -0.587, -0.314, -0.636, -0.567 AND -0.592 RESPECTIVELY, P<0.001). NO SIGNIFICANT DIFFERENCES IN HEMATOLOGICAL PARAMETERS AND CBMN WERE FOUND AMONG THE THREE GROUPS. TOGETHER, THESE RESULTS SUGGEST THAT DECREASED DNMTS, MBD2 AND PARP1 MIGHT BE INVOLVED IN THE GLOBAL HYPOMETHYLATION ASSOCIATED WITH BTX EXPOSURE, AND THE IMBALANCE OF PARP/PARG MIGHT PARTICIPATE IN THE DOWN-REGULATION OF DNMTS. THIS IS THE FIRST HUMAN STUDY TO LINK ALTERED POLY(ADP-RIBOSYL)ATION PATTERNS, WHICH REPRODUCE THE ABERRANT EPIGENETIC PATTERNS FOUND IN BENZENE-TREATED CELLS, TO CHRONIC OCCUPATIONAL EXPOSURE TO BTX. 2014 2 6898 19 [THE ADVANCE OF MODEL OF ACTION IN LOW-DOSE CHRONIC BENZENE EXPOSURE INDUCED HEMATOTOXICITY]. BENZENE IS CLASSIFIED AS GROUP 1 CARCINOGEN BY IARC. IT HAS BEEN FOUND THAT BENZENE INDUCES HEMATOTOXICITY EVEN IN LOW DOSE EXPOSURE. THE IDENTIFICATION OF KEY EVENTS DURING BENZENE INDUCED HEMATOTOXICTY LEADS TO ADJUSTMENT OF OCCUPATIONAL EXPOSURE LIMITS OF BENZENE. IN THIS REVIEW, WE FOCUS ON THE EXPOSURE, METABOLISM, TARGET ORGANS, KEY EPIGENETIC CHANGES, TOXICTY EFFECTS AND END POINTS OF LOW-DOSE CHRONIC BENZENE EXPOSURE INDUCED HEMATOTOXICITY AND FINALLY DISCUSS THE PERSPECTIVES ON THE FUTURE STUDY OF THIS AREA. 2015 3 3558 37 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 4 143 40 ABERRANT DNA METHYLATION OF TWO TUMOR SUPPRESSOR GENES, P14(ARF) AND P15(INK4B), AFTER CHRONIC OCCUPATIONAL EXPOSURE TO LOW LEVEL OF BENZENE. BACKGROUND: EXPOSURE TO BENZENE WOULD BE ASSOCIATED WITH MANY DISEASES INCLUDING LEUKEMIA. EPIGENETIC ALTERATIONS SEEM TO BE AMONG THE MAIN MECHANISMS INVOLVED. OBJECTIVE: TO DETERMINE IF CHRONIC OCCUPATIONAL EXPOSURE TO LOW LEVEL OF BENZENE WOULD BE ASSOCIATED WITH DNA METHYLATION. METHODS: GLOBAL DNA METHYLATION AND PROMOTER-SPECIFIC METHYLATION OF THE TWO TUMOR SUPPRESSOR GENES, P14(ARF) AND P15(INK4B), WERE ASSESSED EMPLOYING METHYLATION-SPECIFIC PCR USING THE DNA EXTRACTED FROM 40 PETROCHEMICAL WORKERS EXPOSED TO AMBIENT BENZENE LEVELS OF <1 PPM, AND 31 OFFICE WORKERS NOT EXPOSED TO BENZENE OR ITS DERIVATIVES. RESULTS: WHILE AN INCREASE IN GLOBAL DNA METHYLATION OF 5% IN P14(ARF) (P=0.501) AND 28% IN P15(INK4B) (P=0.02) GENES WAS OBSERVED IN THE EXPOSED GROUP, NO HYPERMETHYLATION IN EITHER OF THE STUDIED GENES WAS OBSERVED IN THE UNEXPOSED GROUP. NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN THE FREQUENCY OF ABERRANT METHYLATION AND EITHER OF AGE, WORK EXPERIENCE, AND SMOKING HABIT IN THE EXPOSED GROUP. CONCLUSION: CHRONIC OCCUPATIONAL EXPOSURE TO LOWER THAN THE PERMISSIBLE EXPOSURE LIMIT OF BENZENE MAY STILL RESULT IN DNA METHYLATION OF TUMOR SUPPRESSOR GENES THAT MAY ULTIMATELY LEAD TO DEVELOPMENT OF CANCER. 2018 5 3441 48 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 6 588 35 BENZENE EXPOSURE IS ASSOCIATED WITH EPIGENETIC CHANGES (REVIEW). BENZENE IS A VOLATILE AROMATIC HYDROCARBON SOLVENT AND IS KNOWN AS ONE OF THE PREDOMINANT AIR POLLUTANTS IN THE ENVIRONMENT. CHRONIC EXPOSURE TO BENZENE IS KNOWN TO CAUSE APLASTIC ANEMIA AND INCREASED RISK OF ACUTE MYELOGENOUS LEUKEMIA IN HUMANS. ALTHOUGH THE MECHANISMS BY WHICH BENZENE CAUSES TOXICITY REMAIN TO BE FULLY ELUCIDATED, IT IS WIDELY ACCEPTED THAT ITS METABOLISM IS CRUCIAL TO ITS TOXICITY, WITH INVOLVEMENT OF ONE OR MORE REACTIVE METABOLITES. NOVEL APPROACHES AIMED AT EVALUATING DIFFERENT MECHANISMS BY WHICH BENZENE CAN IMPACT ON HUMAN HEALTH BY ALTERING GENE REGULATION HAVE BEEN DEVELOPED. AMONG THESE NOVEL APPROACHES, EPIGENETICS APPEARS TO BE PROMISING. THE PRESENT REVIEW ARTICLE SUMMARIZES THE MOST IMPORTANT FINDINGS, REPORTED FROM THE LITERATURE, ON EPIGENETIC MODIFICATIONS CORRELATED TO BENZENE EXPOSURE. A COMPUTERIZED SEARCH IN PUBMED WAS PERFORMED IN NOVEMBER 2014, USING SEARCH TERMS, INCLUDING 'BENZENE', 'EPIGENETIC', 'HISTONE MODIFICATIONS', 'DNA METHYLATION' AND 'MICRORNA'. EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES HAVE DEMONSTRATED THE POTENTIAL EPIGENETIC EFFECTS OF BENZENE EXPOSURE. SEVERAL OF THE EPIGENOMIC CHANGES OBSERVED IN RESPONSE TO ENVIRONMENTAL EXPOSURES MAY BE MECHANISTICALLY ASSOCIATED WITH SUSCEPTIBILITY TO DISEASES. HOWEVER, FURTHER ELUCIDATION OF THE MECHANISMS BY WHICH BENZENE ALTERS GENE EXPRESSION MAY IMPROVE PREDICTION OF THE TOXIC POTENTIAL OF NOVEL COMPOUNDS INTRODUCED INTO THE ENVIRONMENT, AND ALLOW FOR MORE TARGETED AND APPROPRIATE DISEASE PREVENTION STRATEGIES. 2016 7 2095 33 EPIGENETIC EFFECTS OF BENZENE IN HEMATOLOGIC NEOPLASMS: THE ALTERED GENE EXPRESSION. BENZENE CARCINOGENIC ABILITY HAS BEEN REPORTED, AND CHRONIC EXPOSURE TO BENZENE CAN BE ONE OF THE RISK ELEMENTS FOR SOLID CANCERS AND HEMATOLOGICAL NEOPLASMS. BENZENE IS ACKNOWLEDGED AS A MYELOTOXIN, AND IT IS ABLE TO AUGMENT THE RISK FOR THE ONSET OF ACUTE MYELOID LEUKEMIA, MYELODYSPLASTIC SYNDROMES, APLASTIC ANEMIA, AND LYMPHOMAS. POSSIBLE MECHANISMS OF BENZENE INITIATION OF HEMATOLOGICAL TUMORS HAVE BEEN IDENTIFIED, AS A GENOTOXIC EFFECT, AN ACTION ON OXIDATIVE STRESS AND INFLAMMATION AND THE PROVOCATION OF IMMUNOSUPPRESSION. HOWEVER, IT IS BECOMING EVIDENT THAT GENETIC ALTERATIONS AND THE OTHER CAUSES ARE INSUFFICIENT TO FULLY JUSTIFY SEVERAL PHENOMENA THAT INFLUENCE THE ONSET OF HEMATOLOGIC MALIGNANCIES. ACQUIRED EPIGENETIC ALTERATIONS MAY PARTICIPATE WITH BENZENE LEUKEMOGENESIS, AS BENZENE MAY AFFECT NUCLEAR RECEPTORS, AND PROVOKE POST-TRANSLATIONAL ALTERATIONS AT THE PROTEIN LEVEL, THEREBY TOUCHING THE FUNCTION OF REGULATORY PROTEINS, COMPRISING ONCOPROTEINS AND TUMOR SUPPRESSOR PROTEINS. DNA HYPOMETHYLATION CORRELATES WITH STIMULATION OF ONCOGENES, WHILE THE HYPERMETHYLATION OF CPG ISLANDS IN PROMOTER REGIONS OF SPECIFIC TUMOR SUPPRESSOR GENES INHIBITS THEIR TRANSCRIPTION AND STIMULATES THE ONSET OF TUMORS. THE DISCOVERY OF THE SYSTEMS OF EPIGENETIC INDUCTION OF BENZENE-CAUSED HEMATOLOGICAL TUMORS HAS ALLOWED THE POSSIBILITY TO OPERATE WITH PHARMACOLOGICAL INTERVENTIONS ABLE OF STOPPING OR OVERTURNING THE NEGATIVE EFFECTS OF BENZENE. 2021 8 5683 45 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 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 14 508 38 ASSOCIATION OF LOW-DOSE EXPOSURE TO PERSISTENT ORGANIC POLLUTANTS WITH E-CADHERIN PROMOTER METHYLATION IN HEALTHY KOREANS. BACKGROUND: PERSISTENT ORGANIC POLLUTANTS (POPS), DESPITE THEIR CONSIDERABLY LOW LEVELS IN HUMANS, ARE AN INCREASING CONCERN FOR THE GENERAL POPULATIONS GIVEN THEIR VARIOUS ADVERSE HEALTH PROBLEMS, INCLUDING METABOLIC AND CARCINOGENIC EFFECTS. DNA METHYLATION DEREGULATION IS THOUGHT TO BE A KEY MECHANISM IN THE DEVELOPMENT OF HUMAN CHRONIC DISEASES INCLUDING CANCER. METHODS: IN AN ATTEMPT TO IDENTIFY BIOMARKERS MONITORING LOW-DOSE EXPOSURE AND HAZARD, WE EXPLORED WHETHER ORGANOCHLORINE PESTICIDES (OCPS) AND POLYCHLORINATED BIPHENYLS (PCBS) MAY INFLUENCE THE METHYLATION OF TUMOUR SUPPRESSOR GENE E-CADHERIN (CDH1) USING PERIPHERAL BLOOD CELLS FROM 364 HEALTHY KOREAN SUBJECTS. RESULTS: CDH1 METHYLATION WAS OBSERVED IN 78.3% OF STUDY SUBJECTS. SERUM CONCENTRATIONS OF OCPS OR PCBS COMPOUNDS WERE HIGHER IN CDH1 METHYLATION-POSITIVE SUBJECTS THAN IN METHYLATION-NEGATIVE ONES. AFTER ADJUSTING FOR VARIOUS COVARIATES, THE ODDS RATIO OF CDH1 METHYLATION OF THE SUMMARY MEASURE OF PCBS WERE 1.0, 2.5 (95% CONFIDENCE INTERVAL: 1.2-5.3), 3.6 (1.6-8.1), 3.6 (1.4-8.6), AND 2.5 (1.1-5.7) ACROSS QUINTILES OF PCBS (P(TREND) = 0.01). THE VALUES OF OCPS WERE 1.0, 0.9, 1.2, 2.4 (1.0-5.9), AND 1.7 (P(TREND) = 0.05). CONCLUSIONS: IN THIS EXPLORATORY STUDY WITH A SMALL SAMPLE, CDH1 METHYLATION MIGHT BE SERVED AS THE EPIGENETIC BIOMARKER ASSOCIATED WITH POPS EXPOSURE AND ADVERSE HEALTH EFFECT. 2018 15 1264 45 CYP2E1 EPIGENETIC REGULATION IN CHRONIC, LOW-LEVEL TOLUENE EXPOSURE: RELATIONSHIP WITH OXIDATIVE STRESS AND SMOKING HABIT. BACKGROUND: CYP2E1 IS A VERSATILE PHASE I DRUG-METABOLIZING ENZYME RESPONSIBLE FOR THE BIOTRANSFORMATION OF MOST VOLATILE ORGANIC COMPOUNDS, INCLUDING TOLUENE. HUMAN TOLUENE EXPOSURE INCREASES CYP2E1 MRNA AND MODIFIES ITS ACTIVITY IN LEUCOCYTES; HOWEVER, EPIGENETIC IMPLICATIONS OF THIS INTERACTION HAVE NOT BEEN INVESTIGATED. GOAL: TO DETERMINE PROMOTER METHYLATION OF CYP2E1 AND OTHER GENES KNOWN TO BE AFFECTED BY TOLUENE EXPOSURE. METHODS: WE OBTAINED VENOUS BLOOD FROM 24 TANNERY WORKERS EXPOSED TO TOLUENE (MEAN LEVELS: 10.86+/-7MG/M(3)) AND 24 ADMINISTRATIVE WORKERS (REFERENCE GROUP, MEAN LEVELS 0.21+/-0.02MG/M(3)) ALL OF THEM FROM THE CITY OF LEON, GUANAJUATO, MEXICO. AFTER DNA EXTRACTION AND BISULFITE TREATMENT, WE PERFORMED PCR-PYROSEQUENCING IN ORDER TO MEASURE METHYLATION LEVELS AT PROMOTER REGION OF 13 GENES. RESULTS: IN EXPOSED GROUP WE FOUND SIGNIFICANT CORRELATIONS BETWEEN TOLUENE AIRBORNE LEVELS AND CYP2E1 PROMOTER METHYLATION (R=-.36, P<0.05), AS WELL AS FOR IL6 PROMOTER METHYLATION LEVELS (R=.44, P<0.05). MOREOVER, CYP2E1 PROMOTER METHYLATION LEVELS WHERE HIGHER IN TOLUENE-EXPOSED SMOKERS COMPARED TO NONSMOKERS (P=0.009). WE ALSO OBSERVED SIGNIFICANT CORRELATIONS FOR CYP2E1 PROMOTER METHYLATION WITH GSTP1 AND SOD1 PROMOTER METHYLATION LEVELS (R=-.37, P<0.05 AND R=-.34, P<0.05 RESPECTIVELY). CONCLUSION: THESE RESULTS HIGHLIGHT THE IMPORTANCE OF CONSIDERING CYP2E1 EPIGENETIC MODIFICATIONS, AS WELL AS ITS INTERACTIONS WITH OTHER GENES, AS KEY FACTORS FOR UNRAVELING THE SUB CELLULAR MECHANISMS OF TOXICITY EXERTED BY OXIDATIVE STRESS, WHICH CAN INITIATE DISEASE PROCESS IN CHRONIC, LOW-LEVEL TOLUENE EXPOSURE. PEOPLE CO-EXPOSED TO TOLUENE AND TOBACCO SMOKE ARE IN HIGHER RISK DUE TO A POSSIBLE CYP2E1 REPRESSION. 2015 16 6491 42 TRAFFIC-DERIVED PARTICULATE MATTER EXPOSURE AND HISTONE H3 MODIFICATION: A REPEATED MEASURES STUDY. BACKGROUND: AIRBORNE PARTICULATE MATTER (PM) MAY INDUCE EPIGENETIC CHANGES THAT POTENTIALLY LEAD TO CHRONIC DISEASES. HISTONE MODIFICATIONS REGULATE GENE EXPRESSION BY INFLUENCING CHROMATIN STRUCTURE THAT CAN CHANGE GENE EXPRESSION STATUS. WE EVALUATED WHETHER TRAFFIC-DERIVED PM EXPOSURE IS ASSOCIATED WITH FOUR TYPES OF ENVIRONMENTALLY INDUCIBLE GLOBAL HISTONE H3 MODIFICATIONS. METHODS: THE BEIJING TRUCK DRIVER AIR POLLUTION STUDY INCLUDED 60 TRUCK DRIVERS AND 60 OFFICE WORKERS EXAMINED TWICE, 1-2 WEEKS APART, FOR AMBIENT PM(10) (BOTH DAY-OF AND 14-DAY AVERAGE EXPOSURES), PERSONAL PM(2.5), BLACK CARBON (BC), AND ELEMENTAL COMPONENTS (POTASSIUM, SULFUR, IRON, SILICON, ALUMINUM, ZINC, CALCIUM, AND TITANIUM). FOR BOTH PM(10) MEASURES, WE OBTAINED HOURLY AMBIENT PM(10) DATA FOR THE STUDY PERIOD FROM THE BEIJING MUNICIPAL ENVIRONMENTAL BUREAU'S 27 REPRESENTATIVELY DISTRIBUTED MONITORING STATIONS. WE THEN CALCULATED A 24H AVERAGE FOR EACH EXAMINATION DAY AND A MOVING AVERAGE OF AMBIENT PM(10) MEASURED IN THE 14 DAYS PRIOR TO EACH EXAMINATION. EXAMINATIONS MEASURED GLOBAL LEVELS OF H3 LYSINE 9 ACETYLATION (H3K9AC), H3 LYSINE 9 TRI-METHYLATION (H3K9ME3), H3 LYSINE 27 TRI-METHYLATION (H3K27ME3), AND H3 LYSINE 36 TRI-METHYLATION (H3K36ME3) IN BLOOD LEUKOCYTES COLLECTED AFTER WORK. WE USED ADJUSTED LINEAR MIXED-EFFECT MODELS TO EXAMINE PERCENT CHANGES IN HISTONE MODIFICATIONS PER EACH MUG/M(3) INCREASE IN PM EXPOSURE. RESULTS: IN ALL PARTICIPANTS EACH MUG/M(3) INCREASE IN 14-DAY AVERAGE AMBIENT PM(10) EXPOSURE WAS ASSOCIATED WITH LOWER H3K27ME3 (BETA=-1.1%, 95% CI: -1.6, -0.6) AND H3K36ME3 LEVELS (BETA=-0.8%, 95% CI: -1.4, -0.1). OCCUPATION-STRATIFIED ANALYSES SHOWED ASSOCIATIONS BETWEEN BC AND BOTH H3K9AC AND H3K36ME3 THAT WERE STRONGER IN OFFICE WORKERS (BETA=4.6%, 95% CI: 0.9, 8.4; AND BETA=4.1%, 95% CI: 1.3; 7.0 RESPECTIVELY) THAN IN TRUCK DRIVERS (BETA=0.1%, 95% CI: -1.3, 1.5; AND BETA=0.9%, 95% CI: -0.9, 2.7, RESPECTIVELY; BOTH P(INTERACTION) <0.05). SEX-STRATIFIED ANALYSES SHOWED ASSOCIATIONS BETWEEN EXAMINATION-DAY PM(10) AND H3K9AC, AND BETWEEN BC AND H3K9ME3, WERE STRONGER IN WOMEN (BETA=10.7%, 95% CI: 5.4, 16.2; AND BETA=7.5%, 95% CI: 1.2, 14.2, RESPECTIVELY) THAN IN MEN (BETA=1.4%, 95% CI: -0.9, 3.7; AND BETA=0.9%, 95% CI: -0.9, 2.7, RESPECTIVELY; BOTH P(INTERACTION) <0.05). WE OBSERVED NO ASSOCIATIONS BETWEEN PERSONAL PM(2.5) OR ELEMENTAL COMPONENTS AND HISTONE MODIFICATIONS. CONCLUSIONS: OUR RESULTS SUGGEST A POSSIBLE ROLE OF GLOBAL HISTONE H3 MODIFICATIONS IN EFFECTS OF TRAFFIC-DERIVED PM EXPOSURES, PARTICULARLY BC EXPOSURE. FUTURE STUDIES SHOULD ASSESS THE ROLES OF THESE MODIFICATIONS IN HUMAN DISEASES AND AS POTENTIAL MEDIATORS OF AIR POLLUTION-INDUCED DISEASE, IN PARTICULAR BC EXPOSURE. 2017 17 1970 23 EPIGENETIC ALTERATIONS AND OCCUPATIONAL EXPOSURE TO BENZENE, FIBERS, AND HEAVY METALS ASSOCIATED WITH TUMOR DEVELOPMENT (REVIEW). THE CHRONIC OCCUPATIONAL EXPOSURE TO CONTAMINANTS AND CARCINOGENS LEADS TO THE DEVELOPMENT OF CANCER. OVER THE PAST DECADES, MANY CARCINOGENS HAVE BEEN FOUND IN THE OCCUPATIONAL ENVIRONMENT AND THEIR PRESENCE IS OFTEN ASSOCIATED WITH AN INCREASED INCIDENCE OF CANCER. ACCORDING TO THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC), THE MAJORITY OF CARCINOGENS ARE CLASSIFIED AS 'PROBABLE' AND 'POSSIBLE' HUMAN CARCINOGENS, WHILE, DIRECT EVIDENCE OF CARCINOGENICITY IS PROVIDED IN EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES. ADDITIONALLY, ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS MAY BE EARLY INDICATORS OF GENOTOXIC AND NON-GENOTOXIC CARCINOGEN EXPOSURE. IN THE PRESENT REVIEW, THE RELATIONSHIP BETWEEN EXPOSURES TO BENZENE, MINERAL FIBERS, METALS AND EPIGENETIC ALTERATIONS ARE DISCUSSED AS THE MOST IMPORTANT CANCER RISK FACTORS DURING WORK ACTIVITIES. 2017 18 3712 31 INHALED POLLUTANTS: THE MOLECULAR SCENE BEHIND RESPIRATORY AND SYSTEMIC DISEASES ASSOCIATED WITH ULTRAFINE PARTICULATE MATTER. AIR POLLUTION OF ANTHROPOGENIC ORIGIN IS LARGELY FROM THE COMBUSTION OF BIOMASS (E.G., WOOD), FOSSIL FUELS (E.G., CARS AND TRUCKS), INCINERATORS, LANDFILLS, AGRICULTURAL ACTIVITIES AND TOBACCO SMOKE. AIR POLLUTION IS A COMPLEX MIXTURE THAT VARIES IN SPACE AND TIME, AND CONTAINS HUNDREDS OF COMPOUNDS INCLUDING VOLATILE ORGANIC COMPOUNDS (E.G., BENZENE), METALS, SULPHUR AND NITROGEN OXIDES, OZONE AND PARTICULATE MATTER (PM). PM(0.1) (ULTRAFINE PARTICLES (UFP)), THOSE PARTICLES WITH A DIAMETER LESS THAN 100 NM (INCLUDES NANOPARTICLES (NP)) ARE CONSIDERED ESPECIALLY DANGEROUS TO HUMAN HEALTH AND MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF NUMEROUS RESPIRATORY AND CARDIOVASCULAR DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND ATHEROSCLEROSIS. SOME OF THE PATHOGENIC MECHANISMS THROUGH WHICH PM(0.1) MAY CONTRIBUTE TO CHRONIC DISEASE IS THEIR ABILITY TO INDUCE INFLAMMATION, OXIDATIVE STRESS AND CELL DEATH BY MOLECULAR MECHANISMS THAT INCLUDE TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR KAPPAB (NF-KAPPAB) AND NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2 (NRF2). EPIGENETIC MECHANISMS INCLUDING NON-CODING RNA (NCRNA) MAY ALSO CONTRIBUTE TOWARDS THE DEVELOPMENT OF CHRONIC DISEASE ASSOCIATED WITH EXPOSURE TO PM(0.1). THIS PAPER HIGHLIGHTS EMERGING MOLECULAR CONCEPTS ASSOCIATED WITH INHALATIONAL EXPOSURE TO PM(0.1) AND THEIR ABILITY TO CONTRIBUTE TO CHRONIC RESPIRATORY AND SYSTEMIC DISEASE. 2017 19 3629 34 INACTIVATION OF P15(INK4B) IN CHRONIC ARSENIC POISONING CASES. ARSENIC EXPOSURE FROM BURNING HIGH ARSENIC-CONTAINING COAL HAS BEEN ASSOCIATED WITH HUMAN SKIN LESION AND CANCER. HOWEVER, THE MECHANISMS OF ARSENIC-RELATED CARCINOGENESIS ARE NOT FULLY UNDERSTOOD. INACTIVATION OF CRITICAL TUMOR SUPPRESSION GENES BY EPIGENETIC REGULATION OR GENETIC MODIFICATION MIGHT CONTRIBUTE TO ARSENIC-INDUCED CARCINOGENICITY. THIS STUDY AIMS TO CLARIFY THE CORRELATION BETWEEN ARSENIC POLLUTION AND FUNCTIONAL DEFECT OF P15(INK4B) GENE IN ARSENIC EXPOSURE RESIDENTS FROM A REGION OF GUIZHOU PROVINCE, CHINA. TO THIS END, 103 ARSENIC EXPOSURE RESIDENTS AND 105 CONTROL SUBJECTS WERE RECRUITED IN THIS STUDY. THE RESULTS SHOWED THAT THE EXPOSURE GROUP EXHIBITED HIGHER LEVELS OF URINARY AND HAIR ARSENIC COMPARED WITH THE CONTROL GROUP (55.28 VS 28.87 MUG/L, 5.16 VS 1.36 MUG/G). SUBJECTS WITH HIGHER ARSENIC CONCENTRATIONS ARE MORE LIKELY TO HAVE P15(INK4B) METHYLATION AND GENE DELETION (CHI(2) = 4.28, P = 0.04 AND CHI(2) = 4.31, P = 0.04). WE ALSO FOUND THAT THE DEGREE OF P15(INK4B) HYPERMETHYLATION AND GENE DELETION OCCURRED AT HIGHER INCIDENCE IN THE POISONING CASES WITH SKIN CANCER (3.7% AND 14.81% IN NON-SKIN CANCER GROUP, 41.18% AND 47.06 IN SKIN CANCER GROUP), AND WERE SIGNIFICANTLY ASSOCIATED WITH THE STAGE OF SKIN LESIONS (CHI(2) = 12.82, P < 0.01 AND CHI(2) = 7.835, P = 0.005). THESE OBSERVATIONS INDICATE THAT INACTIVATION OF P15(INK4B) THROUGH GENETIC ALTERATION OR EPIGENETIC MODIFICATION IS A COMMON EVENT THAT IS ASSOCIATED WITH ARSENIC EXPOSURE AND THE DEVELOPMENT OF ARSENICOSIS. 2014 20 1786 44 EFFECT OF ARSENIC EXPOSURE ON NRF2-KEAP1 PATHWAY AND EPIGENETIC MODIFICATION. ARSENIC (AS) IS A KNOWN TOXIC ELEMENT AND CARCINOGEN. TRANSCRIPTION FACTOR NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) CONTROLS CELLULAR ADAPTATION TO OXIDANTS AND ELECTROPHILES BY INDUCING ANTIOXIDANT GENES IN RESPONSE TO REDOX STRESS. TO EXPLORE ASSOCIATIONS BETWEEN AS LEVEL AND NRF2-REGULATED CYTOPROTECTIVE GENES EXPRESSION, AN OBSERVATIONAL STUDY WAS CONDUCTED IN A POPULATION OF 61 OCCUPATIONALLY EXPOSED MEN WITH MEDIAN (ME) AGE 50 YEARS (INTERQUARTILE RANGE (IQR) 42-54) AND IN A CONTROL GROUP OF 52 MEN AGED 40 (IQR 31-51.5) WITHOUT OCCUPATIONAL EXPOSURE. NRF2, KEAP1, GSTP1, HMOX1, NQO1, PRDX1, AND TXNRD1 TRANSCRIPT LEVELS WERE DETERMINED BY MEANS OF QUANTITATIVE REAL-TIME PCR ALONG WITH THE GENE EXPRESSION, METHYLATION OF NRF2 AND KEAP1, AS WELL AS GLOBAL DNA METHYLATION WERE ASSESSED. THE MEDIAN URINE AS (TOT.) LEVEL IN THE EXPOSED AND CONTROL GROUP WAS FOUND TO BE 21.8 MUG/G CREAT. (IQR 15.5-39.8 MUG/G CREAT.) AND 3.8 MUG/G CREAT. (IQR 2.5-9.3) (P < 0.001). GLOBAL DNA METHYLATION WAS SIGNIFICANTLY HIGHER IN OCCUPATIONALLY EXPOSED WORKERS THAN IN CONTROLS (ME 14.1 (IQR 9.5-18.1) VS ME 8.5 (IQR 5.9-12.6) P < 0.0001). NRF2 MRNA LEVEL WAS POSITIVELY CORRELATED WITH EXPRESSION OF ALL INVESTIGATED NRF2-TARGET GENES IN BOTH GROUPS (0.37 > R < 0.76, ALL P VALUES < 0.0001). THE MULTIVARIATE LINEAR REGRESSION ADJUSTING FOR GLOBAL METHYLATION SHOWED THAT AS(III) LEVEL WAS SIGNIFICANTLY ASSOCIATED WITH EXPRESSION OF TXNRD1, GSTP1, HMOX1, AND PRDX1. THE RESULTS OF THIS STUDY INDICATE THAT ARSENIC OCCUPATIONAL EXPOSURE IS POSITIVELY ASSOCIATED WITH GLOBAL DNA METHYLATION. THE FINDINGS PROVIDE EVIDENCE FOR RATHER INACTIVATION OF NRF2-KEAP1 PATHWAY IN RESPONSE TO CHRONIC ARSENIC EXPOSURE. 2018