1 1115 122 COMPARATIVE ANALYSIS OF EPIGENETIC VARIABILITY IN TWO PINE SPECIES EXPOSED TO CHRONIC RADIATION IN THE CHERNOBYL AND FUKUSHIMA AFFECTED ZONES. COMPARATIVE ANALYSIS OF EPIGENETIC VARIABILITY IN TWO PINE SPECIES AFFECTED AS A RESULT OF THE CHERNOBYL AND FUKUSHIMA ACCIDENTS IS PRESENTED. THE ABSORBED DOSE RATE WITHIN THE AFFECTED CHERNOBYL SITES VARIES OVER A WIDER RANGE (1.5-24.6 MUGY/H) THAN WITHIN THE FUKUSHIMA SITES (3.5-6.5 MUGY/H). IT WAS SHOWN THAT CHRONIC IRRADIATION CAN CHANGE THE LEVEL OF WHOLE GENOME METHYLATION IN PINE POPULATIONS, BUT IN DIFFERENT WAYS. THE GENOMES OF JAPANESE RED PINES ARE HYPOMETHYLATED, AND THE DEGREE OF METHYLATION AND HYDROXYMETHYLATION DECREASES WITH AN INCREASE IN THE LEVEL OF RADIATION EXPOSURE. IN CONTRAST, THE PERCENTAGES OF GENOME METHYLATION AND HYDROXYMETHYLATION IN SCOTS PINE POPULATIONS EXCEED THE REFERENCE LEVELS. THE OBSERVED DISCREPANCY IN THE PATTERNS OF GENOME-WIDE DNA METHYLATION CAN BE ATTRIBUTED PARTLY TO THE DESIGN OF THE STUDY (DIFFERENCES IN THE CLIMATE, RADIATION DOSE, AGE AND SPECIES OF THE PINES) WHICH COULD AFFECT THE RESULTS. IN THE FRAME OF IRAP ANALYSIS, A LARGER NUMBER OF DIFFERENT BANDS WAS OBSERVED IN THE CHERNOBYL POPULATIONS COMPARED TO THE JAPANESE POPULATIONS. BOTH THE JAPANESE AND CHERNOBYL POPULATIONS ARE CHARACTERIZED BY SIGNIFICANT GENETIC VARIABILITY. HOWEVER, THE MAIN PART OF THIS VARIABILITY IS OBSERVED WITHIN POPULATIONS. THE DENDROGRAMS, BASED ON PRESENCE/ABSENCE OF IRAP FRAGMENTS AND NEI'S GENETIC DISTANCES, REVEALED SUBDIVISIONS OF THE CHERNOBYL AND JAPANESE POPULATIONS ACCORDING TO THE LEVEL OF RADIOACTIVE CONTAMINATION. ANALYSIS OF THE RESULTS PRESENTED WILL IMPROVE OUR UNDERSTANDING OF THE MECHANISMS UNDERLYING THE RESPONSES OF PINE TREES TO CHRONIC RADIATION EXPOSURE. 2023 2 985 33 CHRONIC RADIATION EXPOSURE AS AN ECOLOGICAL FACTOR: HYPERMETHYLATION AND GENETIC DIFFERENTIATION IN IRRADIATED SCOTS PINE POPULATIONS. GENETIC AND EPIGENETIC CHANGES WERE INVESTIGATED IN CHRONICALLY IRRADIATED SCOTS PINE (PINUS SYLVESTRIS L.) POPULATIONS FROM TERRITORIES THAT WERE HEAVILY CONTAMINATED BY RADIONUCLIDES AS RESULT OF THE CHERNOBYL NUCLEAR POWER PLANT ACCIDENT. IN COMPARISON TO THE REFERENCE SITE, THE GENETIC DIVERSITY REVEALED BY ELECTROPHORETIC MOBILITY OF AFLPS WAS FOUND TO BE SIGNIFICANTLY HIGHER AT THE RADIOACTIVELY CONTAMINATED AREAS. IN ADDITION, THE GENOME OF PINE TREES WAS SIGNIFICANTLY HYPERMETHYLATED AT 4 OF THE 7 AFFECTED SITES. 2018 3 1456 29 DISCRIMINATING THE MOLECULAR BASIS OF HEPATOTOXICITY USING THE LARGE-SCALE CHARACTERISTIC MOLECULAR SIGNATURES OF TOXICANTS BY EXPRESSION PROFILING ANALYSIS. PREDICTING THE POTENTIAL HUMAN HEALTH RISK POSED BY CHEMICAL STRESSORS HAS LONG BEEN A MAJOR CHALLENGE FOR TOXICOLOGISTS, AND THE USE OF MICROARRAYS TO MEASURE RESPONSES TO TOXICOLOGICALLY RELEVANT GENES, AND TO IDENTIFY SELECTIVE, SENSITIVE BIOMARKERS OF TOXICITY IS A MAJOR APPLICATION OF PREDICTIVE AND DISCOVERY TOXICOLOGY. TO INVESTIGATE THIS POSSIBILITY, WE INVESTIGATED WHETHER CARCINOGENS (AT DOSES KNOWN TO INDUCE LIVER TUMORS IN CHRONIC EXPOSURE BIOASSAYS) DEREGULATE CHARACTERISTIC SETS OF GENES IN MICE. MALE C3H/HE MICE WERE DOSED WITH TWO HEPATOCARCINOGENS (VINYL CHLORIDE (VC, 50-25 MG/KG), ALDRIN (AD, 0.8-0.4 MG/KG)), OR TWO NON-HEPATOCARCINOGENS (COPPER SULFATE (CS, 150-60 MG/KG), 2,4,5-TRICHLOROPHENOXYACETIC ACID (2,4,5-T, 150-60 MG/KG)). LARGE-SCALE MOLECULAR CHANGES ELICITED BY THESE FOUR HEPATOTOXICANTS IN LIVER TISSUES WERE ANALYZED USING DNA MICROARRAY. THREE DAYS AFTER ADMINISTRATION, NO SIGNIFICANT PHENOTYPIC CHANGES WERE INDUCED BY THESE FOUR DIFFERENT HEPATOTOXICANTS IN TERMS OF HISTOLOGICAL EXAMINATION OR BLOOD BIOCHEMICAL ASSAY. HOWEVER, UNSUPERVISED HIERARCHICAL ANALYSIS OF GENE EXPRESSIONAL CHANGES INDUCED BY HEPATOTOXICANTS RESULTED IN TWO MAJOR GENE SUBCLUSTERS ON DENDROGRAM, I.E., A CARCINOGEN (VN, AD) AND NON-CARCINOGEN GROUP (CS, 2,4,5-T), AND ALSO REVEALED THAT DISTINCT MOLECULAR SIGNATURES EXIST. THESE SIGNATURES WERE FOUNDED ON WELL-DEFINED FUNCTIONAL GENE CATEGORIES AND MAY DIFFERENTIATE GENOTOXIC AND NON-GENOTOXIC CARCINOGENS. FURTHERMORE, VENN DIAGRAM ANALYSIS ALLOWED US TO IDENTIFY CARCINOGEN AND NON-CARCINOGEN-ASSOCIATED MOLECULAR SIGNATURES. USING STATISTICAL METHODS, WE ANALYZED OUTLIER GENES FOR FOUR DIFFERENT CLASSES (GENOTOXIC-, NON-GENOTOXIC-CARCINOGEN, GENOTOXIC-, NON-GENOTOXIC NON-CARCINOGEN) IN TERMS OF THEIR POTENTIAL TO PREDICT DIFFERENT MODES-OF-ACTION. IN CONCLUSION, THE IDENTIFICATION OF LARGE-SCALE MOLECULAR CHANGES IN DIFFERENT HEPATOCARCINOGEN EXPOSURE MODELS REVEALED THAT DIFFERENT TYPES OF HEPATOTOXICANTS ARE ASSOCIATED WITH DIFFERENT EPIGENETIC CHANGES AND MOLECULAR PATHWAYS AND THAT THESE LARGE-SCALE CHARACTERISTIC MOLECULAR CHANGES COULD BE USED AS PREDICTABLE TOXICITY MARKERS. 2008 4 3040 37 GENOME HYPERMETHYLATION IN PINUS SILVESTRIS OF CHERNOBYL--A MECHANISM FOR RADIATION ADAPTATION? ADAPTATION IS A COMPLEX PROCESS BY WHICH POPULATIONS OF ORGANISMS RESPOND TO LONG-TERM ENVIRONMENTAL STRESSES BY PERMANENT GENETIC CHANGE. HERE WE PRESENT DATA FROM THE NATURAL "OPEN-FIELD" RADIATION ADAPTATION EXPERIMENT AFTER THE CHERNOBYL ACCIDENT AND PROVIDE THE FIRST EVIDENCE OF THE INVOLVEMENT OF EPIGENETIC CHANGES IN ADAPTATION OF A EUKARYOTE-SCOTS PINE (PINUS SILVESTRIS), TO CHRONIC RADIATION EXPOSURE. WE HAVE EVALUATED GLOBAL GENOME METHYLATION OF CONTROL AND RADIATION-EXPOSED PINE TREES USING A METHOD BASED ON CLEAVAGE BY A METHYLATION-SENSITIVE HPAII RESTRICTION ENDONUCLEASE THAT LEAVES A 5' GUANINE OVERHANG AND SUBSEQUENT SINGLE NUCLEOTIDE EXTENSION WITH LABELED [3H] DCTP. WE HAVE FOUND THAT GENOMIC DNA OF EXPOSED PINE TREES WAS CONSIDERABLY HYPERMETHYLATED. MOREOVER, HYPERMETHYLATION APPEARED TO BE DEPENDENT UPON THE RADIATION DOSE ABSORBED BY THE TREES. SUCH HYPERMETHYLATION MAY BE VIEWED AS A DEFENSE STRATEGY OF PLANTS THAT PREVENTS GENOME INSTABILITY AND RESHUFFLING OF THE HEREDITARY MATERIAL, ALLOWING SURVIVAL IN AN EXTREME ENVIRONMENT. FURTHER STUDIES ARE CLEARLY NEEDED TO ANALYZE IN DETAIL THE INVOLVEMENT OF DNA METHYLATION AND OTHER EPIGENETIC MECHANISMS IN THE COMPLEX PROCESS OF RADIATION STRESS AND ADAPTIVE RESPONSE. 2003 5 502 33 ASSOCIATION OF ARSENIC EXPOSURE WITH WHOLE BLOOD DNA METHYLATION: AN EPIGENOME-WIDE STUDY OF BANGLADESHI ADULTS. BACKGROUND: ARSENIC EXPOSURE AFFECTS [FORMULA: SEE TEXT] PEOPLE WORLDWIDE, INCLUDING [FORMULA: SEE TEXT] IN BANGLADESH. ARSENIC EXPOSURE INCREASES THE RISK OF CANCER AND OTHER CHRONIC DISEASES, AND ONE POTENTIAL MECHANISM OF ARSENIC TOXICITY IS EPIGENETIC DYSREGULATION. OBJECTIVE: WE ASSESSED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENOME-WIDE DNA METHYLATION MEASURED AT BASELINE AMONG 396 BANGLADESHI ADULTS PARTICIPATING IN THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (HEALS) WHO WERE EXPOSED BY DRINKING NATURALLY CONTAMINATED WELL WATER. METHODS: METHYLATION IN WHOLE BLOOD DNA WAS MEASURED AT [FORMULA: SEE TEXT] USING THE ILLUMINA INFINIUMMETHYLATIONEPIC (EPIC) ARRAY. TO ASSESS ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG METHYLATION, WE USED LINEAR REGRESSION MODELS ADJUSTED FOR COVARIATES AND SURROGATE VARIABLES (SVS) (CAPTURING UNKNOWN TECHNICAL AND BIOLOGIC FACTORS). WE ATTEMPTED REPLICATION AND CONDUCTED A META-ANALYSIS USING AN INDEPENDENT DATASET OF [FORMULA: SEE TEXT] FROM 400 BANGLADESHI INDIVIDUALS WITH ARSENICAL SKIN LESIONS. RESULTS: WE IDENTIFIED 34 CPGS ASSOCIATED WITH [FORMULA: SEE TEXT] CREATININE-ADJUSTED URINARY ARSENIC [[FORMULA: SEE TEXT]]. SIXTEEN OF THESE CPGS ANNOTATED TO THE [FORMULA: SEE TEXT] ARRAY, AND 10 ASSOCIATIONS WERE REPLICATED ([FORMULA: SEE TEXT]). THE TOP TWO CPGS ANNOTATED UPSTREAM OF THE ABR GENE (CG01912040, CG10003262 ). ALL URINARY ARSENIC-ASSOCIATED CPGS WERE ALSO ASSOCIATED WITH ARSENIC CONCENTRATION MEASURED IN DRINKING WATER ([FORMULA: SEE TEXT]). META-ANALYSIS ([FORMULA: SEE TEXT] SAMPLES) IDENTIFIED 221 URINARY ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]). THE ARSENIC-ASSOCIATED CPGS FROM THE META-ANALYSIS WERE ENRICHED IN NON-CPG ISLANDS AND SHORES ([FORMULA: SEE TEXT]) AND DEPLETED IN PROMOTER REGIONS ([FORMULA: SEE TEXT]). AMONG THE ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]), WE OBSERVED SIGNIFICANT ENRICHMENT OF GENES ANNOTATING TO THE REACTIVE OXYGEN SPECIES PATHWAY, INFLAMMATORY RESPONSE, AND TUMOR NECROSIS FACTOR [FORMULA: SEE TEXT] ([FORMULA: SEE TEXT]) SIGNALING VIA NUCLEAR FACTOR KAPPA-B ([FORMULA: SEE TEXT]) HALLMARKS ([FORMULA: SEE TEXT]). CONCLUSIONS: THE NOVEL AND REPLICABLE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND DNA METHYLATION AT SPECIFIC CPGS OBSERVED IN THIS WORK SUGGEST THAT EPIGENETIC ALTERATIONS SHOULD BE FURTHER INVESTIGATED AS POTENTIAL MEDIATORS IN ARSENIC TOXICITY AND AS BIOMARKERS OF EXPOSURE AND EFFECT IN EXPOSED POPULATIONS. HTTPS://DOI.ORG/10.1289/EHP3849. 2019 6 3081 27 GENOME-WIDE PROMOTER DNA METHYLATION PROFILING OF HEPATOCELLULAR CARCINOMAS ARISING EITHER SPONTANEOUSLY OR DUE TO CHRONIC EXPOSURE TO GINKGO BILOBA EXTRACT (GBE) IN B6C3F1/N MICE. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, PLAY AN IMPORTANT ROLE IN CARCINOGENESIS. IN A RECENT NTP STUDY, CHRONIC EXPOSURE OF B6C3F1/N MICE TO GINKGO BILOBA EXTRACT (GBE) RESULTED IN A HIGH INCIDENCE OF HEPATOCELLULAR CARCINOMAS (HCC). GENOME-WIDE PROMOTER METHYLATION PROFILING ON GBE-EXPOSED HCC (2000 MG/KG GROUP), SPONTANEOUS HCC (VEHICLE-CONTROL GROUP), AND AGE-MATCHED VEHICLE CONTROL LIVER WAS PERFORMED TO IDENTIFY DIFFERENTIALLY METHYLATED GENES IN GBE-EXPOSED HCC AND SPONTANEOUS HCC. DNA METHYLATION ALTERATIONS WERE CORRELATED TO THE CORRESPONDING GLOBAL GENE EXPRESSION CHANGES. COMPARED TO CONTROL LIVER, 1296 GENE PROMOTERS (719 HYPERMETHYLATED, 577 HYPOMETHYLATED) IN GBE-EXPOSED HCC AND 738 (427 HYPERMETHYLATED, 311 HYPOMETHYLATED) GENE PROMOTERS IN SPONTANEOUS HCC WERE SIGNIFICANTLY DIFFERENTIALLY METHYLATED, SUGGESTING AN IMPACT OF METHYLATION ON GBE-EXPOSED HCC. DIFFERENTIAL METHYLATION OF PROMOTER REGIONS IN RELEVANT CANCER GENES (CMYC, SPRY2, DUSP5) AND THEIR CORRESPONDING DIFFERENTIAL GENE EXPRESSION WAS VALIDATED BY QUANTITATIVE PYROSEQUENCING AND QRT-PCR, RESPECTIVELY. IN CONCLUSION, WE HAVE IDENTIFIED DIFFERENTIALLY METHYLATED PROMOTER REGIONS OF RELEVANT CANCER GENES ALTERED IN GBE-EXPOSED HCC COMPARED TO SPONTANEOUS HCC. FURTHER STUDY OF UNIQUE SETS OF DIFFERENTIALLY METHYLATED GENES IN CHEMICAL-EXPOSED MOUSE HCC COULD POTENTIALLY BE USED TO DIFFERENTIATE TREATMENT-RELATED TUMORS FROM SPONTANEOUS-TUMORS IN CANCER BIOASSAYS AND PROVIDE ADDITIONAL UNDERSTANDING OF THE UNDERLYING EPIGENETIC MECHANISMS OF CHEMICAL CARCINOGENESIS. 2019 7 5338 28 QUANTITATIVE EVALUATION OF RASSF1A METHYLATION IN THE NON-LESIONAL, REGENERATIVE AND NEOPLASTIC LIVER. BACKGROUND: EPIGENETIC CHANGES DURING AGEING AND THEIR RELATIONSHIP WITH CANCER ARE UNDER THE FOCUS OF INTENSE RESEARCH. RASSF1A AND NORE1A ARE NOVEL GENES ACTING IN CONCERT IN THE PROAPOPTOTIC PATHWAY OF THE RAS SIGNALLING. WHILE NORE1A HAS NOT BEEN PREVIOUSLY INVESTIGATED IN THE HUMAN LIVER, RECENT REPORTS HAVE SUGGESTED THAT RASSF1A IS FREQUENTLY EPIGENETICALLY METHYLATED NOT ONLY IN HCC BUT ALSO IN THE CIRRHOTIC LIVER. METHODS: TO ADDRESS WHETHER EPIGENETIC CHANGES TAKE PLACE IN CONNECTION TO AGE AND/OR TO THE UNDERLYING DISEASE, WE INVESTIGATED RASSF1A AND NORE1A GENE PROMOTER METHYLATION BY CONVENTIONAL METHYLATION SPECIFIC PCR AND REAL-TIME MSP IN A SERIES OF HEPATITIC AND NON-HEPATITIC LIVERS HARBORING REGENERATIVE/HYPERPLASTIC (CIRRHOSIS/FOCAL NODULAR HYPERPLASIA), DYSPLASTIC (LARGE REGENERATIVE, LOW AND HIGH GRADE DYSPLASTIC NODULES) AND NEOPLASTIC (HEPATOCELLULAR ADENOMA AND CARCINOMA) GROWTHS. RESULTS: IN THE HEPATITIC LIVER (CHRONIC HEPATITIC/CIRRHOSIS, HEPATOCELLULAR NODULES AND HCC) WE FOUND WIDESPREAD RASSF1A GENE PROMOTER METHYLATION WITH A METHYLATION INDEX THAT INCREASED FROM REGENERATIVE CONDITIONS (CIRRHOSIS) TO HEPATOCELLULAR NODULES (P < 0.01) TO HCC (P < 0.001). IN THE NON-HEPATITIC LIVER A CONSISTENT PATTERN OF GENE METHYLATION WAS ALSO FOUND IN BOTH LESIONAL (FOCAL NODULAR HYPERPLASIA AND HEPATOCELLULAR ADENOMA) AND NON-LESIONAL TISSUE. SPECIFICALLY, HEPATOCELLULAR ADENOMAS (HA) SHOWED A METHYLATION INDEX SIGNIFICANTLY HIGHER THAN THAT DETECTED IN FOCAL NODULAR HYPERPLASIA (FNH) (P < 0.01) AND IN NON-LESIONAL TISSUE (P < 0.001). IN NON-LESIONAL LIVER ALSO THE METHYLATION INDEX GRADUALLY INCREASED BY AGEING (P = 0.002), SUGGESTING A PROGRESSIVE SPREADING OF METHYLATED CELLS OVER TIME. AS OPPOSED TO RASSF1A GENE PROMOTER METHYLATION, NORE1A GENE WAS NEVER FOUND EPIGENETICALLY ALTERATED IN BOTH HEPATITIC AND NON-HEPATITIC LIVER. CONCLUSION: WE HAVE SHOWN THAT IN NON-LESIONAL, REGENERATIVE AND NEOPLASTIC LIVER THE RASSF1A GENE IS INCREASINGLY METHYLATED, THAT THIS CONDITION TAKES PLACE AS AN AGE-RELATED PHENOMENON AND THAT THE EARLY SETTING AND SPREADING OVER TIME OF AN EPIGENETICALLY METHYLATED HEPATOCYTE SUBPOPULATION, MIGHT BE RELATED TO LIVER TUMORIGENESIS. 2006 8 1835 38 EFFECTS OF NON-HUMAN SPECIES IRRADIATION AFTER THE CHERNOBYL NPP ACCIDENT. THE AREA AFFECTED BY THE CHERNOBYL NUCLEAR POWER PLANT ACCIDENT IN 1986 HAS BECOME A UNIQUE TEST SITE WHERE LONG-TERM ECOLOGICAL AND BIOLOGICAL CONSEQUENCES OF A DRASTIC CHANGE IN A RANGE OF ENVIRONMENTAL FACTORS AS WELL AS TRENDS AND INTENSITY OF SELECTION ARE STUDIED IN NATURAL SETTINGS. THE CONSEQUENCES OF THE CHERNOBYL ACCIDENT FOR BIOTA VARIED FROM AN ENHANCED RATE OF MUTAGENESIS TO DAMAGE AT THE ECOSYSTEM LEVEL. THE REVIEW COMPREHENSIVELY BRINGS TOGETHER KEY DATA OF THE LONG-TERM STUDIES OF BIOLOGICAL EFFECTS IN PLANTS AND ANIMALS INHABITING OVER 20 YEARS THE CHERNOBYL NPP ZONE. THE SEVERITY OF RADIATION EFFECTS WAS STRONGLY DEPENDENT ON THE DOSE RECEIVED IN THE EARLY PERIOD AFTER THE ACCIDENT. THE MOST EXPOSED PHYTOCENOSES AND SOIL ANIMALS' COMMUNITIES EXHIBITED DOSE DEPENDENT ALTERATIONS IN THE SPECIES COMPOSITION AND REDUCTION IN BIOLOGICAL DIVERSITY. ON THE OTHER HAND, NO DECREASE IN NUMBERS OR TAXONOMIC DIVERSITY OF SMALL MAMMALS EVEN IN THE MOST RADIOACTIVE HABITAT WAS SHOWN. IN A MAJORITY OF THE STUDIES, IN BOTH PLANT AND ANIMAL POPULATIONS FROM THE CHERNOBYL ZONE, IN THE FIRST YEARS AFTER THE ACCIDENT HIGH INCREASES IN MUTATION RATES WERE DOCUMENTED. IN MOST CASES THE DOSE-EFFECT RELATIONSHIPS WERE NONLINEAR AND THE MUTATION RATES PER UNIT DOSE WERE HIGHER AT LOW DOSES AND DOSE RATES. IN SUBSEQUENT YEARS A DECLINE IN THE RADIATION BACKGROUND RATE OCCURRED FASTER THAN REDUCTION IN THE MUTATION RATE. PLANT AND ANIMAL POPULATIONS HAVE SHOWN SIGNS OF ADAPTATION TO CHRONIC EXPOSURE. IN ADAPTATION TO THE ENHANCED LEVEL OF EXPOSURE AN ESSENTIAL ROLE OF EPIGENETIC MECHANISMS OF GENE EXPRESSION REGULATION WAS SHOWN. BASED ON THE CHERNOBYL NPP ACCIDENT STUDIES, IN THE PRESENT REVIEW ATTEMPTS WERE MADE TO ASSESS MINIMUM DOSES AT WHICH ECOLOGICAL AND BIOLOGICAL EFFECTS WERE OBSERVED. 2008 9 1140 32 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 10 6216 20 THE INVOLVEMENT OF COPPER, CIRCULAR RNAS, AND INFLAMMATORY CYTOKINES IN CHRONIC RESPIRATORY DISEASE. EXPOSURE TO HIGH CONCENTRATIONS OF COPPER IS ASSOCIATED WITH PULMONARY INFLAMMATION AND CHRONIC RESPIRATORY DISEASE (CRD). EPIGENETIC MODULATION OF NONCODING RNAS CONTRIBUTES TO THE DEVELOPMENT OF SEVERAL CRDS. IT IS UNKNOWN WHETHER EPIGENETIC MODULATION IS INVOLVED IN COPPER MEDIATED PULMONARY INFLAMMATION AND CRD. WE CONDUCTED A CASE-CONTROL STUDY OF 101 CRD CASES AND 161 CONTROL SUBJECTS IN SHIJIAZHUANG, CHINA, AND EVALUATED CIRCRNAS AND CYTOKINE LEVELS (IL-6 AND IL-8) BY QPCR AND ELISA. URINARY COPPER CONCENTRATION WAS DETERMINED BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY. LINEAR MIXED MODELS AND GENERALIZED LINEAR MIXED MODELS WERE USED TO ASSESS THE ASSOCIATIONS OF CIRCRNAS WITH CRD, URINARY COPPER, AND CYTOKINES. WE EXPOSED THE HUMAN BRONCHIAL EPITHELIAL CELL LINE, 16HBE, TO COPPER AND ASSESSED THE FUNCTIONAL ROLE OF A CIRCRNA, CIRC_0008882, BY RNA OVEREXPRESSION. CELLULAR LOCATION OF CIRC_0008882 WAS ASSESSED BY SEPARATION OF NUCLEAR AND CYTOPLASMIC RNAS. NINE CIRCRNAS WERE ASSOCIATED WITH AN INCREASED RISK FOR CRDS, WHILE THE RELATIVE EXPRESSION OF CIRC_0008882 WAS DECREASED AFTER COPPER EXPOSURE IN VITRO AND IN VIVO. COPPER EXPOSURE STIMULATED 16HBE CELLS TO RELEASE PROINFLAMMATORY IL-6 AND IL-8. THE RELEASE OF THE CYTOKINES WAS INHIBITED BY OVEREXPRESSION OF CIRC_0008882. THESE RESULTS SUGGEST A ROLE FOR CIRC_0008882 IN THE REGULATION OF CRD ASSOCIATED INFLAMMATION FOLLOWING COPPER EXPOSURE. 2022 11 401 28 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160. 2012 12 5683 34 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 13) TO DISTINGUISH GENOTOXIC CARCINOGENS FROM EPIGENETIC CARCINOGENS WHEN PERFORMED ON FRESHLY ISOLATED KIDNEY CELLS AND TO DETERMINE THE POSSIBLE INTERFERENCE OF CYTOTOXICITY BY ASSESSING DNA DAMAGE INDUCED BY RENAL GENOTOXIC, EPIGENETIC OR TOXIC COMPOUNDS AFTER ENZYMATIC ISOLATION OF KIDNEY CELLS FROM OFA SPRAGUE-DAWLEY MALE RATS. THE ABILITY OF THE COMET ASSAY TO DISTINGUISH (1) GENOTOXICITY VERSUS CYTOTOXICITY AND (2) GENOTOXIC VERSUS NON-GENOTOXIC (EPIGENETIC) CARCINOGENS, WAS THUS INVESTIGATED BY STUDYING FIVE KNOWN GENOTOXIC RENAL CARCINOGENS ACTING THROUGH DIVERSE MECHANISMS OF ACTION, I.E. STREPTOZOTOCIN, ARISTOLOCHIC ACIDS, 2-NITROANISOLE, POTASSIUM BROMATE AND CISPLATIN, TWO RODENT RENAL EPIGENETIC CARCINOGENS: D-LIMONENE AND CICLOSPORINE AND TWO NEPHROTOXIC COMPOUNDS: STREPTOMYCIN AND INDOMETHACIN. ANIMALS WERE TREATED ONCE WITH THE TEST COMPOUND BY THE APPROPRIATE ROUTE OF ADMINISTRATION AND GENOTOXIC EFFECTS WERE MEASURED AT THE TWO SAMPLING TIMES OF 3-6 AND 22-26H AFTER TREATMENT. REGARDING THE TISSUE PROCESSING, THE LIMITED BACKGROUND LEVEL OF DNA MIGRATION OBSERVED IN THE NEGATIVE CONTROL GROUPS THROUGHOUT ALL EXPERIMENTS DEMONSTRATED THAT THE ENZYMATIC ISOLATION METHOD IMPLEMENTED IN THE CURRENT STUDY IS APPROPRIATE. ON THE OTHER HAND, STREPTOZOTOCIN, 20MG/KG, USED AS POSITIVE REFERENCE CONTROL CONCURRENTLY TO EACH ASSAY, CAUSED A CLEAR INCREASE IN THE MEAN OLIVE TAIL MOMENT MEDIAN VALUE, WHICH ALLOWS VALIDATING THE CURRENT METHODOLOGY. UNDER THESE EXPERIMENTAL CONDITIONS, THE IN VIVO RODENT COMET ASSAY DEMONSTRATED GOOD SENSITIVITY AND GOOD SPECIFICITY: ALL THE FIVE RENAL GENOTOXIC CARCINOGENS WERE CLEARLY DETECTED IN AT LEAST ONE EXPRESSION PERIOD EITHER DIRECTLY OR INDIRECTLY, AS IN THE CASE OF CISPLATIN: FOR THIS CROSS-LINKING AGENT, THE SIGNIFICANT DECREASE IN DNA MIGRATION OBSERVED UNDER STANDARD ELECTROPHORESIS CONDITIONS WAS CLEARLY AMPLIFIED WHEN THE DURATION OF ELECTROPHORESIS WAS INCREASED UP TO 40MIN. IN CONTRAST, EPIGENETIC AND NEPHROTOXIC COMPOUNDS FAILED TO INDUCE ANY SIGNIFCANT INCREASE IN DNA MIGRATION. IN CONCLUSION, THE IN VIVO RODENT COMET ASSAY PERFORMED ON ISOLATED KIDNEY CELLS COULD BE USED AS A TOOL TO INVESTIGATE THE GENOTOXIC POTENTIAL OF A TEST COMPOUND IF NEOPLASIC/PRENEOPLASIC CHANGES OCCUR AFTER SUBCHRONIC OR CHRONIC TREATMENTS, IN ORDER TO DETERMINE THE ROLE OF GENOTOXICITY IN TUMOR INDUCTION. MOREOVER, THE EPIGENETIC CARCINOGENS AND CYTOTOXIC COMPOUNDS DISPLAYED CLEARLY NEGATIVE RESPONSES IN THIS STUDY. THESE RESULTS ALLOW EXCLUDING A DNA DIRECT-ACTING MECHANISM OF ACTION AND CAN THUS SUGGEST THAT A THRESHOLD EXISTS. THEREFORE, THE CURRENT IN VIVO RODENT COMET ASSAY COULD CONTRIBUTE TO ELUCIDATE AN EPIGENETIC MECHANISM AND THUS, TO UNDERTAKE A RISK ASSESSMENT ASSOCIATED WITH HUMAN USE, DEPENDING ON THE EXPOSURE LEVEL. 2007 16 2031 26 EPIGENETIC CHANGES IN LYMPHOCYTES OF SOLVENT-EXPOSED INDIVIDUALS. AIM: WE INVESTIGATED GLOBAL DNA METHYLATION ALTERATIONS IN LYMPHOCYTES OF SOLVENT WORKERS AND CHRONIC TOXIC ENCEPHALOPATHY (CTE) PATIENTS AND EXPLORED POTENTIAL GENE-ENVIRONMENT INTERACTIONS FOR GST. POPULATION & METHODS: A CROSS-SECTIONAL STUDY WAS SET UP IN 41 REFERENTS, 128 SOLVENT WORKERS AND 23 CTE PATIENTS. RESULTS: WE FOUND A GLOBAL DNA HYPERMETHYLATION IN THE SOLVENT-EXPOSED POPULATION COMPARED WITH THE REFERENTS (P = 0.001, R = -0.544). GLOBAL DNA METHYLATION WAS NEGATIVELY ASSOCIATED WITH EXPOSURE. FURTHERMORE, GSTP1 GENOTYPIC POLYMORPHISM WAS FOUND TO BE SIGNIFICANTLY ASSOCIATED (P = 0.033) WITH GLOBAL DNA HYPOMETHYLATION, WHICH INDICATES A POTENTIAL ROLE FOR GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF SOLVENT-INDUCED NEUROBEHAVIORAL DISORDERS. CONCLUSION: THIS STUDY INDICATES THAT SOLVENT-INDUCED DNA METHYLATION ALTERATIONS HAVE AN IMPACT ON NEUROTOXICITY AND DEVELOPMENT OF CTE. 2012 17 6748 33 WHOLE GENOME METHYLATION ARRAY ANALYSIS REVEALS NEW ASPECTS IN BALKAN ENDEMIC NEPHROPATHY ETIOLOGY. BACKGROUND: BALKAN ENDEMIC NEPHROPATHY (BEN) REPRESENTS A CHRONIC PROGRESSIVE INTERSTITIAL NEPHRITIS IN STRIKING CORRELATION WITH UROEPITHELIAL TUMOURS OF THE UPPER URINARY TRACT. THE DISEASE HAS ENDEMIC DISTRIBUTION IN THE DANUBE RIVER REGIONS IN SEVERAL BALKAN COUNTRIES.DNA METHYLATION IS A PRIMARY EPIGENETIC MODIFICATION THAT IS INVOLVED IN MAJOR PROCESSES SUCH AS CANCER, GENOMIC IMPRINTING, GENE SILENCING, ETC. THE SIGNIFICANCE OF CPG ISLAND METHYLATION STATUS IN NORMAL DEVELOPMENT, CELL DIFFERENTIATION AND GENE EXPRESSION IS WIDELY RECOGNIZED, ALTHOUGH STILL STAYS POORLY UNDERSTOOD. METHODS: WE PERFORMED WHOLE GENOME DNA METHYLATION ARRAY ANALYSIS ON DNA POOL SAMPLES FROM PERIPHERAL BLOOD FROM 159 AFFECTED INDIVIDUALS AND 170 HEALTHY INDIVIDUALS. THIS TECHNIQUE ALLOWED US TO DETERMINE THE METHYLATION STATUS OF 27 627 CPG ISLANDS THROUGHOUT THE WHOLE GENOME IN HEALTHY CONTROLS AND BEN PATIENTS. THUS WE OBTAINED THE METHYLATION PROFILE OF BEN PATIENTS FROM BULGARIAN AND SERBIAN ENDEMIC REGIONS. RESULTS: USING SPECIFICALLY DEVELOPED SOFTWARE WE COMPARED THE METHYLATION PROFILES OF BEN PATIENTS AND CORRESPONDING CONTROLS AND REVEALED THE DIFFERENTLY METHYLATED REGIONS. WE THEN COMPARED THE DMRS BETWEEN ALL PATIENT-CONTROL PAIRS TO DETERMINE COMMON CHANGES IN THE EPIGENETIC PROFILES.SEC61G, IL17RA, HDAC11 PROVED TO BE DIFFERENTLY METHYLATED THROUGHOUT ALL PATIENT-CONTROL PAIRS. THE CPG ISLANDS OF ALL 3 GENES WERE HYPOMETHYLATED COMPARED TO CONTROLS. THIS SUGGESTS THAT DYSREGULATION OF THESE GENES INVOLVED IN IMMUNOLOGICAL RESPONSE COULD BE A COMMON MECHANISM IN BEN PATHOGENESIS IN BOTH ENDEMIC REGIONS AND IN BOTH GENDERS. CONCLUSION: OUR DATA PROPOSE A NEW HYPOTHESIS THAT IMMUNOLOGIC DYSREGULATION HAS A PLACE IN BEN ETIOPATHOGENESIS. 2013 18 3063 34 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER