1   936 116 CHRONIC LOW-LEVEL PERFLUOROOCTANE SULFONATE (PFOS) EXPOSURE PROMOTES TESTICULAR STEROIDOGENESIS THROUGH ENHANCED HISTONE ACETYLATION. PERFLUOROOCTANE SULFONATE (PFOS), AN ARTIFICIAL PERFLUORINATED COMPOUND, HAS BEEN ASSOCIATED WITH MALE REPRODUCTIVE DISORDERS. HISTONE MODIFICATIONS ARE IMPORTANT EPIGENETIC MEDIATORS; HOWEVER, THE IMPACT OF PFOS EXPOSURE ON TESTICULAR STEROIDOGENESIS THROUGH HISTONE MODIFICATION REGULATIONS REMAINS TO BE ELUCIDATED. IN THIS STUDY, WE EXAMINED THE ROLES OF HISTONE MODIFICATIONS IN REGULATING STEROID HORMONE PRODUCTION IN MALE RATS CHRONICALLY EXPOSED TO LOW-LEVEL PFOS. THE RESULTS INDICATE THAT PFOS EXPOSURE SIGNIFICANTLY UP-REGULATED THE EXPRESSIONS OF STAR, CYP11A1 AND 3BETA-HSD, WHILE CYP17A1 AND 17BETA-HSD WERE DOWN-REGULATED, THUS CONTRIBUTING TO THE ELEVATED PROGESTERONE AND TESTOSTERONE LEVELS. FURTHERMORE, PFOS SIGNIFICANTLY INCREASED THE HISTONES H3K9ME2, H3K9AC AND H3K18AC WHILE REDUCED H3K9ME3 IN RAT TESTIS. IT IS KNOWN THAT HISTONE MODIFICATIONS ARE CLOSELY INVOLVED IN GENE TRANSCRIPTION. THEREFORE, TO INVESTIGATE THE ASSOCIATION BETWEEN HISTONE MODIFICATIONS AND STEROIDOGENIC GENE REGULATION, THE LEVELS OF THESE HISTONE MARKS WERE FURTHER MEASURED IN STEROIDOGENIC GENE PROMOTER REGIONS BY CHIP. IT WAS FOUND THAT H3K18AC WAS AUGMENTED IN CYP11A1 PROMOTER, AND H3K9AC WAS INCREASED IN HSD3B AFTER PFOS EXPOSURE, WHICH IS PROPOSED TO RESULT IN THE ACTIVATION OF CYP11A1 AND 3BETA-HSD, RESPECTIVELY. TO SUM UP, CHRONIC LOW-LEVEL PFOS EXPOSURE ACTIVATED KEY STEROIDOGENIC GENE EXPRESSION THROUGH ENHANCING HISTONE ACETYLATION (H3K9AC AND H3K18AC), ULTIMATELY STIMULATING STEROID HORMONE BIOSYNTHESIS IN RAT TESTIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2  3505  25 IDENTIFICATION OF SEX-SPECIFIC DNA METHYLATION CHANGES DRIVEN BY SPECIFIC CHEMICALS IN CORD BLOOD IN A FAROESE BIRTH COHORT. FAROE ISLANDERS CONSUME MARINE FOODS CONTAMINATED WITH METHYLMERCURY (MEHG), POLYCHLORINATED BIPHENYLS (PCBS), AND OTHER TOXICANTS ASSOCIATED WITH CHRONIC DISEASE RISKS. DIFFERENTIAL DNA METHYLATION AT SPECIFIC CPG SITES IN CORD BLOOD MAY SERVE AS A SURROGATE BIOMARKER OF HEALTH IMPACTS FROM CHEMICAL EXPOSURES. WE AIMED TO IDENTIFY KEY ENVIRONMENTAL CHEMICALS IN CORD BLOOD ASSOCIATED WITH DNA METHYLATION CHANGES IN A POPULATION WITH ELEVATED EXPOSURE TO CHEMICAL MIXTURES. WE STUDIED 72 PARTICIPANTS OF A FAROESE BIRTH COHORT RECRUITED BETWEEN 1986 AND 1987 AND FOLLOWED UNTIL ADULTHOOD. THE CORD BLOOD DNA METHYLOME WAS PROFILED USING INFINIUM HUMANMETHYLATION450 BEADCHIPS. WE DETERMINED THE ASSOCIATIONS OF CPG SITE CHANGES WITH CONCENTRATIONS OF MEHG, MAJOR PCBS, OTHER ORGANOCHLORINE COMPOUNDS [HEXACHLOROBENZENE (HCB), P,P'-DICHLORODIPHENYLDICHLOROETHYLENE (P,P'-DDE) AND P,P'-DICHLORODIPHENYLTRICHLOROETHANE], AND PERFLUOROALKYL SUBSTANCES. IN A COMBINED SEX ANALYSIS, AMONG THE 16 CHEMICALS STUDIED, PCB CONGENER 105 (CB-105) EXPOSURE WAS ASSOCIATED WITH THE MAJORITY OF DIFFERENTIALLY METHYLATED CPG SITES (214 OUT OF A TOTAL OF 250). IN FEMALE-ONLY ANALYSIS, ONLY 73 CB-105 ASSOCIATED CPG SITES WERE DETECTED, 44 OF WHICH WERE MAPPED TO GENES IN THE ELAV1-ASSOCIATED CANCER NETWORK. IN MALES-ONLY, METHYLATION CHANGES WERE SEEN FOR PERFLUOROOCTANE SULFONATE, HCB, AND P,P'-DDE IN 10,598, 1,238, AND 1,473 CPG SITES, RESPECTIVELY, 15% OF WHICH WERE ENRICHED IN CYTOBANDS OF THE X-CHROMOSOME ASSOCIATED WITH NEUROLOGICAL DISORDERS. IN THIS MULTIPLE-POLLUTANT AND GENOME-WIDE STUDY, WE IDENTIFIED KEY EPIGENETIC TOXICANTS. THE SIGNIFICANT ENRICHMENT OF SPECIFIC X-CHROMOSOME SITES IN MALES IMPLIES POTENTIAL SEX-SPECIFIC EPIGENOME RESPONSES TO PRENATAL CHEMICAL EXPOSURES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  6491  35 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	

4  4180  35 MERCURY EXPOSURE INDUCES CYTOSKELETON DISRUPTION AND LOSS OF RENAL FUNCTION THROUGH EPIGENETIC MODULATION OF MMP9 EXPRESSION. MERCURY IS ONE OF THE MAJOR HEAVY METAL POLLUTANTS OCCURRING IN ELEMENTAL, INORGANIC AND ORGANIC FORMS. DUE TO BAN ON MOST INORGANIC MERCURY CONTAINING PRODUCTS, HUMAN EXPOSURE TO MERCURY GENERALLY OCCURS AS METHYLMERCURY (MEHG) BY CONSUMPTION OF CONTAMINATED FISH AND OTHER SEA FOOD. ANIMAL AND EPIDEMIOLOGICAL STUDIES INDICATE THAT MEHG AFFECTS NEURAL AND RENAL FUNCTION. OUR STUDY IS FOCUSED ON NEPHROTOXIC POTENTIAL OF MEHG. IN THIS STUDY, WE HAVE SHOWN FOR THE FIRST TIME HOW MEHG COULD EPIGENETICALLY MODULATE MATRIX METALLOPROTEINASE 9(MMP9) TO PROMOTE NEPHROTOXICITY USING AN ANIMAL MODEL OF SUB CHRONIC MEHG EXPOSURE. MEHG CAUSED RENAL TOXICITY AS WAS SEEN BY INCREASED LEVELS OF SERUM CREATININE AND EXPRESSION OF EARLY NEPHROTOXICITY MARKERS (KIM-1, CLUSTERIN, IP-10, AND TIMP). MEHG EXPOSURE ALSO CORRELATED STRONGLY WITH INDUCTION OF MMP9 MRNA AND PROTEIN IN A DOSE DEPENDENT MANNER. FURTHER, WHILE INDUCTION OF MMP9 PROMOTED CYTOSKELETON DISRUPTION AND LOSS OF CELL-CELL ADHESION (LOSS OF F-ACTIN, VIMENTIN AND FIBRONECTIN), INHIBITION OF MMP9 WAS FOUND TO REDUCE THESE DISRUPTIONS. MECHANISTIC STUDIES BY CHIP ANALYSIS SHOWED THAT MEHG MODULATED MMP9 BY PROMOTING DEMETHYLATION OF ITS REGULATORY REGION TO INCREASE ITS EXPRESSION. BISULFITE SEQUENCING IDENTIFIED CRITICAL CPGS IN THE FIRST EXON OF MMP9 WHICH WERE DEMETHYLATED FOLLOWING MEHG EXPOSURE. CHIP STUDIES ALSO SHOWED LOSS OF METHYL BINDING PROTEIN, MECP2 AND TRANSCRIPTION FACTOR PEA3 AT THE DEMETHYLATED SITE CONFIRMING DECREASED CPG METHYLATION. OUR STUDIES THUS SHOW HOW MEHG COULD EPIGENETICALLY MODULATE MMP9 TO PROMOTE CYTOSKELETON DISRUPTION LEADING TO LOSS OF RENAL FUNCTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5   508  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6   947  35 CHRONIC MEHG EXPOSURE MODIFIES THE HISTONE H3K4ME3 EPIGENETIC LANDSCAPE IN CAENORHABDITIS ELEGANS. METHYLMERCURY (MEHG) IS A PERSISTENT ENVIRONMENTAL POLLUTANT THAT OCCURS IN THE FOOD CHAIN, AT OCCUPATIONAL SITES, AND VIA MEDICAL PROCEDURES. EXPOSURE IN HUMANS AND ANIMAL MODELS RESULTS IN RENAL, NEURO, AND REPRODUCTIVE TOXICITIES. IN THIS STUDY, WE DEMONSTRATE THAT CHRONIC EXPOSURE TO MEHG (10MUM) CAUSES EPIGENETIC LANDSCAPE MODIFICATIONS OF HISTONE H3K4 TRIMETHYLATION (H3K4ME3) MARKS IN CAENORHABDITIS ELEGANS USING CHROMATIN IMMUNO-PRECIPITATION SEQUENCING (CHIP-SEQ). THE MODIFICATIONS CORRESPOND TO THE LOCATIONS OF 1467 GENES WITH ENHANCED AND 508 GENES WITH REDUCED SIGNALS. AMONG ENHANCED GENES ARE THOSE ENCODING GLUTATHIONE-S-TRANSFERASES, LIPOCALIN-RELATED PROTEIN AND A CUTICULAR COLLAGEN. CHIP-SEQ ENHANCEMENT OF THESE GENES WAS CONFIRMED WITH INCREASED MRNA EXPRESSION LEVELS REVEALED BY QRT-PCR. FURTHERMORE, WE OBSERVED ENHANCEMENT OF H3K4ME3 MARKS IN THESE GENES IN ANIMALS EXPOSED TO MEHG IN UTERO AND ASSAYED AT L4 STAGE. IN UTERO EXPOSURE ENHANCED MARKS WITHOUT ALTERATIONS IN MRNA EXPRESSION EXCEPT FOR THE LPR-5 GENE. FINALLY, KNOCKDOWN OF LIPOCALIN-RELATED PROTEIN GENE LPR-5, WHICH IS INVOLVED IN INTERCELLULAR SIGNALING, AND CUTICULAR COLLAGEN GENE DPY-7, STRUCTURAL COMPONENT OF THE CUTICLE, BY RNA INTERFERENCE (RNAI) RESULTED IN INCREASED LETHALITY OF ANIMALS AFTER MEHG EXPOSURE. OUR RESULTS PROVIDE NEW DATA ON THE EPIGENETIC LANDSCAPE CHANGES ELICITED BY MEHG EXPOSURE, AS WELL AS DESCRIBE A UNIQUE MODEL FOR STUDYING IN UTERO EFFECTS OF HEAVY METALS. TOGETHER, THESE FINDINGS MAY HELP TO UNDERSTAND THE TOXICOLOGICAL EFFECTS OF MEHG AT THE MOLECULAR LEVEL.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7   308  25 ALCOHOL AND DNA METHYLATION: AN EPIGENOME-WIDE ASSOCIATION STUDY IN BLOOD AND NORMAL BREAST TISSUE. THE BIOLOGICAL MECHANISMS DRIVING ASSOCIATIONS BETWEEN ALCOHOL CONSUMPTION AND CHRONIC DISEASES MIGHT INCLUDE EPIGENETIC MODIFICATION OF DNA METHYLATION. WE EXPLORED THE HYPOTHESIS THAT ALCOHOL CONSUMPTION IS ASSOCIATED WITH METHYLATION IN AN EPIGENOME-WIDE ASSOCIATION STUDY OF BLOOD AND NORMAL BREAST TISSUE DNA. INFINIUM HUMANMETHYLATION450 BEADCHIP (ILLUMINA INC., SAN DIEGO, CALIFORNIA) ARRAY DATA ON BLOOD DNA METHYLATION WAS EXAMINED IN A DISCOVERY SET OF 2,878 NON-HISPANIC WHITE WOMEN FROM THE SISTER STUDY (UNITED STATES, 2004-2015) WHO PROVIDED DETAILED QUESTIONNAIRE INFORMATION ON LIFETIME ALCOHOL USE. ROBUST LINEAR REGRESSION MODELING WAS USED TO IDENTIFY SIGNIFICANT ASSOCIATIONS (FALSE DISCOVERY RATE OF Q < 0.05) BETWEEN THE NUMBER OF ALCOHOLIC DRINKS PER WEEK AND DNA METHYLATION AT 5,458 CYTOSINE-PHOSPHATE-GUANINE (CPG) SITES. ASSOCIATIONS WERE REPLICATED (P < 0.05) FOR 677 CPGS IN AN INDEPENDENT SET OF 187 BLOOD DNA SAMPLES FROM THE SISTER STUDY AND FOR 628 CPGS IN AN INDEPENDENT SET OF 171 NORMAL BREAST DNA SAMPLES; 1,207 CPGS WERE REPLICATED IN EITHER BLOOD OR NORMAL BREAST, WITH 98 CPGS REPLICATED IN BOTH TISSUES. INDIVIDUAL GENE EFFECTS WERE NOTABLE FOR PHOSPHOGLYCERATE DEHYDROGENASE (PGHDH), PEPTIDYL-PROLYL CIS-TRANS ISOMERASE (PPIF), SOLUTE CARRIER 15 (SLC15), SOLUTE CARRIER FAMILY 43 MEMBER 1 (SLC43A1), AND SOLUTE CARRIER FAMILY 7 MEMBER 11 (SLC7A11). WE ALSO FOUND THAT HIGH ALCOHOL CONSUMPTION WAS ASSOCIATED WITH SIGNIFICANTLY LOWER GLOBAL METHYLATION AS MEASURED BY THE AVERAGE OF CPGS ON THE ENTIRE ARRAY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8   974  30 CHRONIC OCCUPATIONAL EXPOSURE ENDURED BY TOBACCO FARMERS FROM BRAZIL AND ASSOCIATION WITH DNA DAMAGE. TOBACCO FARMING IS AN IMPORTANT ECONOMIC INCOME IN BRAZIL, ALTHOUGH IT HAS BEEN CHALLENGED AS REGARD THE OCCUPATIONAL EXPOSURE TO BOTH PESTICIDES AND NICOTINE ENDURED BY FARMERS. CHRONIC OCCUPATIONAL EXPOSURE TO COMPLEX MIXTURES CAN LEAD TO HEALTH HAZARDOUS. WE EXAMINED GENOMIC INSTABILITY AND EPIGENETIC CHANGES IN TOBACCO FARMERS OCCUPATIONALLY EXPOSED TO PESTICIDE MIXTURES AND NICOTINE AT TOBACCO FIELDS. DNA DAMAGE WAS ASSESSED BY ALKALINE COMET ASSAY IN BLOOD CELLS. GENOMIC DNA WAS ISOLATED, AND TELOMERE LENGTH WAS MEASURED USING QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY. WE MEASURED 5-METHYL-2'-DEOXYCYTIDINE, A MARKER OF GLOBAL DNA METHYLATION, AND P16 PROMOTER METHYLATION. THE OXIDATIVE PROFILE WAS EVALUATED BY TROLOX EQUIVALENT ANTIOXIDANT CAPACITY AND LIPID PEROXIDATION (THIOBARBITURIC ACID REACTIVE SUBSTANCES) IN SERUM. EXPOSURE PARAMETERS, PLASMA COTININE AND INORGANIC ELEMENT LEVELS, WERE ALSO MEASURED. DNA DAMAGE WAS SIGNIFICANTLY ELEVATED FOR FARMERS IN RELATION TO UNEXPOSED GROUP (P < 0.001; MANN-WHITNEY TEST) AND POSITIVELY ASSOCIATED WITH YEARS OF EXPOSURE. INVERSE RELATIONSHIP BETWEEN DNA DAMAGE AND TOTAL EQUIVALENT ANTIOXIDANT ACTIVITY WAS DEMONSTRATED FOR EXPOSED AND UNEXPOSED GROUPS. EXPOSED GROUP SHOWED SIGNIFICANTLY SHORTER TELOMERES (P < 0.001; UNPAIRED T-TEST) AND DNA HYPOMETHYLATION (P < 0.001; UNPAIRED T-TEST), AS WELL AS P16 HYPERMETHYLATION (P = 0.003; MANN-WHITNEY TEST). LIPID PEROXIDATION WAS INCREASED FOR EXPOSED GROUP IN RELATION TO UNEXPOSED ONE (P = 0.02; MANN-WHITNEY TEST) AND PRESENTED A POSITIVE CORRELATION WITH GLOBAL DNA METHYLATION (P = 0.0264). FARMERS HAVE INCREASED PLASMA COTININE LEVELS (P < 0.001) AND INORGANIC ELEMENTS (PHOSPHORUS, SULPHUR AND CHLORINE) IN RELATION TO UNEXPOSED GROUP. ELEVATED OXIDATIVE STRESS LEVELS DUE TO CHRONIC OCCUPATIONAL PESTICIDE MIXTURES AND NICOTINE EXPOSURE IN TOBACCO FARMERS WERE ASSOCIATED WITH HIGHER DNA DAMAGE, SHORTER TELOMERES AND ALTERED DNA METHYLATION. TELOMERE-ACCELERATED ATTRITION DUE TO EXPOSURE MAY BE POTENTIAL INTERMEDIATE STEP BEFORE A DISEASE STATE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9  3083  31 GENOME-WIDE SCREEN OF DNA METHYLATION CHANGES INDUCED BY LOW DOSE X-RAY RADIATION IN MICE. EPIGENETIC MECHANISMS PLAY A KEY ROLE IN NON-TARGETED EFFECTS OF RADIATION. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE GLOBAL HYPOMETHYLATION AND PROMOTER HYPERMETHYLATION OF PARTICULAR GENES INDUCED BY LOW DOSE RADIATION (LDR). THIRTY MALE BALB/C MICE WERE DIVIDED INTO 3 GROUPS: CONTROL, ACUTELY EXPOSED (0.5 GY X-RAYS), AND CHRONIC EXPOSURE FOR 10 DAYS (0.05GY/DX10D). HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) AND MEDIP-QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) WERE USED TO STUDY METHYLATION PROFILES. DNMT1 AND MBD2 EXPRESSION WAS DETERMINED BY QPCR AND WESTERN BLOT ASSAYS. METHYLATION AND EXPRESSION OF RAD23B AND DDIT3 WERE DETERMINED BY BISULFATE SEQUENCING PRIMERS (BSP) AND QPCR, RESPECTIVELY. THE RESULTS SHOW THAT LDR INDUCED GENOMIC HYPOMETHYLATION IN BLOOD 2 H POSTIRRADITAION, BUT WAS NOT RETAINED AT 1-MONTH. DNMT1 AND MBD2 WERE DOWNREGULATED IN A TISSUE-SPECIFIC MANNER BUT DID NOT PERSIST. SPECIFIC HYPERMETHYLATION WAS OBSERVED FOR 811 REGIONS IN THE GROUP RECEIVING CHRONIC EXPOSURE, WHICH COVERED ALMOST ALL KEY BIOLOGICAL PROCESSES AS INDICATED BY GO AND KEGG PATHWAY ANALYSIS. EIGHT HYPERMETHYLATED GENES (RAD23B, TDG, CCND1, DDIT3, LLGL1, RASL11A, TBX2, SCL6A15) WERE VERIFIED BY MEDIP-QPCR. AMONG THEM, RAD23B AND DDIT3 GENE DISPLAYED TISSUE-SPECIFIC METHYLATION AND DOWNREGULATION, WHICH PERSISTED FOR 1-MONTH POSTIRRADIATION. THUS, LDR INDUCED GLOBAL HYPOMETHYLATION AND TISSUE-SPECIFIC PROMOTER HYPERMETHYLATION OF PARTICULAR GENES. PROMOTER HYPERMETHYLATION, RATHER THAN GLOBAL HYPOMETHYLATION, WAS RELATIVELY STABLE. DYSREGULATION OF METHYLATION MIGHT BE CORRELATED WITH DOWN-REGULATION OF DNMT1 AND MBD2, BUT MUCH BETTER UNDERSTANDING THE MOLECULAR MECHANISMS INVOLVED IN THIS PROCESS WILL REQUIRE FURTHER STUDY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10  4244  29 METHYLATION STATUS OF COX-2 IN BLOOD LEUKOCYTE DNA AND RISK OF GASTRIC CANCER IN A HIGH-RISK CHINESE POPULATION. BACKGROUND: METHYLATION IS A COMMON EPIGENETIC MODIFICATION WHICH MAY PLAY A CRUCIAL ROLE IN CANCER DEVELOPMENT. TO INVESTIGATE THE ASSOCIATION BETWEEN METHYLATION OF COX-2 IN BLOOD LEUKOCYTE DNA AND RISK OF GASTRIC CANCER (GC), A NESTED CASE-CONTROL STUDY WAS CONDUCTED IN LINQU COUNTY, SHANDONG PROVINCE, A HIGH RISK AREA OF GC IN CHINA. METHODS: ASSOCIATION BETWEEN BLOOD LEUKOCYTE DNA METHYLATION OF COX-2 AND RISK OF GC WAS INVESTIGATED IN 133 GCS AND 285 SUPERFICIAL GASTRITIS (SG)/ CHRONIC ATROPHIC GASTRITIS (CAG). THE TEMPORAL TREND OF COX-2 METHYLATION LEVEL DURING GC DEVELOPMENT WAS FURTHER EXPLORED IN 74 PRE-GC AND 95 POST-GC SAMPLES (INCLUDING 31 CASES WITH BOTH PRE- AND POST-GC SAMPLES). IN ADDITION, THE ASSOCIATION OF DNA METHYLATION AND RISK OF PROGRESSION TO GC WAS EVALUATED IN 74 PRE-GC SAMPLES AND THEIR RELEVANT INTESTINAL METAPLASIA (IM)/DYSPLASIA (DYS) CONTROLS. METHYLATION LEVEL WAS DETERMINED BY QUANTITATIVE METHYLATION-SPECIFIC PCR (QMSP). ODDS RATIOS (ORS) AND 95% CONFIDENCE INTERVALS (CIS) WERE CALCULATED BY UNCONDITIONAL LOGISTIC REGRESSION ANALYSIS. RESULTS: THE MEDIANS OF COX-2 METHYLATION LEVELS WERE 2.3% AND 2.2% IN GC CASES AND CONTROLS, RESPECTIVELY. NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN COX-2 METHYLATION AND RISK OF GC (OR, 1.15; 95% CI: 0.70-1.88). HOWEVER, THE TEMPORAL TREND ANALYSIS SHOWED THAT COX-2 METHYLATION LEVELS WERE ELEVATED AT 1-4 YEARS AHEAD OF CLINICAL GC DIAGNOSIS COMPARED WITH THE YEAR OF GC DIAGNOSIS (3.0% VS. 2.2%, P=0.01). FURTHER VALIDATION IN 31 GCS WITH BOTH PRE- AND POST-GC SAMPLES INDICATED THAT COX-2 METHYLATION LEVELS WERE SIGNIFICANTLY DECREASED AT THE YEAR OF GC DIAGNOSIS COMPARED WITH PRE-GC SAMPLES (1.5% VS. 2.5%, P=0.02). NO SIGNIFICANT ASSOCIATION BETWEEN COX-2 METHYLATION AND RISK OF PROGRESSION TO GC WAS FOUND IN SUBJECTS WITH IM (OR, 0.50; 95% CI: 0.18-1.42) OR DYS (OR, 0.70; 95% CI: 0.23-2.18). ADDITIONALLY, WE FOUND THAT ELDER PEOPLE HAD INCREASED RISK OF COX-2 HYPERMETHYLATION (OR, 1.55; 95% CI: 1.02-2.36) AND SUBJECTS WHO EVER INFECTED WITH H. PYLORI HAD DECREASED RISK OF COX-2 HYPERMETHYLATION (OR, 0.54; 95% CI: 0.34-0.88). CONCLUSIONS: COX-2 METHYLATION EXISTS IN BLOOD LEUKOCYTE DNA BUT AT A LOW LEVEL. COX-2 METHYLATION LEVELS IN BLOOD LEUKOCYTE DNA MAY CHANGE DURING GC DEVELOPMENT.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  5191  35 PRENATAL DEXAMETHASONE EXPOSURE PROGRAMS THE DECREASED TESTOSTERONE SYNTHESIS IN OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS. PRENATAL DEXAMETHASONE EXPOSURE (PDE) CAN DECREASE MATERNAL ENDOGENOUS GLUCOCORTICOID LEVEL AND INDUCE TESTICULAR DYSPLASIA IN MALE OFFSPRING RATS. IN THIS STUDY WE INVESTIGATED LOW LEVEL ENDOGENOUS GLUCOCORTICOID-MEDIATED TESTICULAR DYSPLASIA IN PDE OFFSPRING AND ELUCIDATED THE INTRAUTERINE EPIGENETIC PROGRAMMING MECHANISMS. PREGNANT RATS WERE INJECTED WITH DEXAMETHASONE (0.2 MG.KG(-1).D(-1), SC) ON GESTATIONAL DAY (GD) 9-20. THE OFFSPRING RAT BLOOD AND TESTIS WERE COLLECTED AFTER EUTHANASIA ON GD20, POSTNATAL WEEK (PW) 12 OR PW28. WE SHOWED THAT PDE INDUCED ABNORMAL MORPHOLOGY OF TESTIS AND SIGNIFICANTLY DECREASED THE EXPRESSION OF TESTOSTERONE SYNTHESIS-RELATED GENES AS WELL AS TESTOSTERONE PRODUCTION BEFORE AND AFTER BIRTH. MEANWHILE, SERUM CORTICOSTERONE, THE EXPRESSION AND HISTONE 3 LYSINE 14 ACETYLATION (H3K14AC) OF TESTICULAR INSULIN-LIKE GROWTH FACTOR 1 (IGF1) WERE SIGNIFICANTLY DECREASED. AFTER THE PREGNANT RATS WERE SUBJECTED TO CHRONIC STRESS FOR 2 WEEKS (PW10-12), SERUM CORTICOSTERONE LEVEL WAS INCREASED IN THE ADULT PDE OFFSPRING, AND THE ABOVE-MENTIONED OTHER INDICATORS WERE ALSO IMPROVED. CULTURED LEYDIG CELLS (TM3) WERE TREATED WITH CORTICOSTERONE (62.5-500 NM) IN VITRO. WE SHOWED THAT CORTICOSTERONE CONCENTRATION-DEPENDENTLY INHIBITED GLUCOCORTICOID RECEPTOR ALPHA (GRALPHA) AND MIR-124-3P EXPRESSION, INCREASED HISTONE DEACETYLASE 5 (HDAC5) EXPRESSION, AND DECREASED IGF1 H3K14AC LEVEL AND THE EXPRESSION OF IGF1/STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR), SUGGESTING THAT CORTICOSTERONE AT LOWER THAN PHYSIOLOGICAL LEVEL (<500 NM) INHIBITED TESTOSTERONE SYNTHESIS BY REDUCING H3K14AC AND THE EXPRESSION LEVEL OF IGF1 THROUGH GRALPHA/MIR-124-3P/HDAC5 PATHWAY. IN CONCLUSION, PDE CAN CAUSE PERSISTENT INHIBITION OF TESTOSTERONE SYNTHESIS BEFORE AND AFTER BIRTH IN THE OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12   525  21 ASSOCIATIONS OF BODY COMPOSITION AND PHYSICAL ACTIVITY LEVEL WITH MULTIPLE MEASURES OF EPIGENETIC AGE ACCELERATION. EPIGENETIC CLOCKS USE DNA METHYLATION TO ESTIMATE BIOLOGICAL AGE. WHETHER BODY COMPOSITION AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH THESE CLOCKS IS NOT WELL UNDERSTOOD. USING BLOOD SAMPLES COLLECTED AT ENROLLMENT (2003-2009) FROM 2,758 WOMEN IN THE US NATIONWIDE SISTER STUDY, WE CALCULATED 6 EPIGENETIC AGE ACCELERATION METRICS USING 4 EPIGENETIC CLOCKS (HANNUM, HORVATH, PHENOAGE, GRIMAGE). RECREATIONAL PHYSICAL ACTIVITY WAS SELF-REPORTED, AND ADIPOSITY MEASURES WERE ASSESSED BY TRAINED MEDICAL EXAMINERS (BODY MASS INDEX (BMI), WAIST-TO-HIP RATIO (WTH), WAIST CIRCUMFERENCE). IN CROSS-SECTIONAL ANALYSES, ALL ADIPOSITY MEASURES WERE ASSOCIATED WITH EPIGENETIC AGE ACCELERATION. THE STRONGEST ASSOCIATION WAS FOR BMI AND PHENOAGE, A MEASURE OF BIOLOGICAL AGE THAT CORRELATES WITH CHRONIC DISEASE (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 3.15 YEARS, 95% CONFIDENCE INTERVAL (CI): 2.41, 3.90; P FOR TREND < 0.001). IN A MUTUAL-ADJUSTMENT MODEL, BOTH WERE ASSOCIATED WITH PHENOAGE AGE ACCELERATION (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 2.69 YEARS, 95% CI: 1.90, 3.48; P FOR TREND < 0.001; QUARTILE 4 VS.1 WTH, BETA = 1.00 YEARS, 95% CI: 0.34, 1.65; P FOR TREND < 0.008). AFTER ADJUSTMENT, PHYSICAL ACTIVITY WAS ASSOCIATED ONLY WITH GRIMAGE (QUARTILE 4 VS. 1, BETA = -0.42 YEARS, 95% CI: -0.70, -0.14; P FOR TREND = 0.001). PHYSICAL ACTIVITY ATTENUATED THE WAIST CIRCUMFERENCE ASSOCIATIONS WITH PHENOAGE AND GRIMAGE. EXCESS ADIPOSITY WAS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION; PHYSICAL ACTIVITY MIGHT ATTENUATE ASSOCIATIONS WITH WAIST CIRCUMFERENCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13  3715  36 INHERITED EFFECTS OF LOW-DOSE EXPOSURE TO METHYLMERCURY IN NEURAL STEM CELLS. METHYLMERCURY (MEHG) IS AN ENVIRONMENTAL CONTAMINANT WITH RECOGNIZED NEUROTOXIC EFFECTS, PARTICULARLY TO THE DEVELOPING NERVOUS SYSTEM. IN THE PRESENT STUDY, WE SHOW THAT NANOMOLAR CONCENTRATIONS OF MEHG CAN INDUCE LONG-LASTING EFFECTS IN NEURAL STEM CELLS (NSCS). WE INVESTIGATED SHORT-TERM DIRECT AND LONG-TERM INHERITED EFFECTS OF EXPOSURE TO MEHG (2.5 OR 5.0 NM) USING PRIMARY CULTURES OF RAT EMBRYONIC CORTICAL NSCS. WE FOUND THAT MEHG HAD NO ADVERSE EFFECT ON CELL VIABILITY BUT REDUCED NSC PROLIFERATION AND ALTERED THE EXPRESSION OF CELL CYCLE REGULATORS (P16 AND P21) AND SENESCENCE-ASSOCIATED MARKERS. IN ADDITION, WE DEMONSTRATED A DECREASE IN GLOBAL DNA METHYLATION IN THE EXPOSED CELLS, INDICATING THAT EPIGENETIC CHANGES MAY BE INVOLVED IN THE MECHANISMS UNDERLYING THE MEHG-INDUCED EFFECTS. THESE CHANGES WERE OBSERVED IN CELLS DIRECTLY EXPOSED TO MEHG (PARENT CELLS) AND IN THEIR DAUGHTER CELLS CULTURED UNDER MEHG-FREE CONDITIONS. IN AGREEMENT WITH OUR IN VITRO DATA, A TREND WAS FOUND FOR DECREASED CELL PROLIFERATION IN THE SUBGRANULAR ZONE IN THE HIPPOCAMPI OF ADULT MICE EXPOSED TO LOW DOSES OF MEHG DURING THE PERINATAL PERIOD. INTERESTINGLY, THIS IMPAIRED PROLIFERATION HAD A MEASURABLE IMPACT ON THE TOTAL NUMBER OF NEURONS IN THE HIPPOCAMPAL DENTATE GYRUS. IMPORTANTLY, THIS EFFECT COULD BE REVERSED BY CHRONIC ANTIDEPRESSANT TREATMENT. OUR STUDY PROVIDES NOVEL EVIDENCE FOR PROGRAMMING EFFECTS INDUCED BY MEHG IN NSCS AND SUPPORTS THE IDEA THAT DEVELOPMENTAL EXPOSURE TO LOW LEVELS OF MEHG MAY RESULT IN LONG-TERM CONSEQUENCES PREDISPOSING TO NEURODEVELOPMENTAL DISORDERS AND/OR NEURODEGENERATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  1588  29 DNA METHYLATION PROFILING IMPLICATES EXPOSURE TO PCBS IN THE PATHOGENESIS OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA. OBJECTIVES: TO CHARACTERIZE THE IMPACT OF PCB EXPOSURE ON DNA METHYLATION IN PERIPHERAL BLOOD LEUCOCYTES AND TO EVALUATE THE CORRESPONDING CHANGES IN RELATION TO POSSIBLE HEALTH EFFECTS, WITH A FOCUS ON B-CELL LYMPHOMA. METHODS: WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY ON 611 ADULTS FREE OF DIAGNOSED DISEASE, LIVING IN ITALY AND SWEDEN, IN WHOM WE ALSO MEASURED PLASMA CONCENTRATIONS OF 6 PCB CONGENERS, DDE AND HEXACHLOROBENZENE. RESULTS: WE IDENTIFIED 650 CPG SITES WHOSE METHYLATION CORRELATES STRONGLY (FDR < 0.01) WITH PLASMA CONCENTRATIONS OF AT LEAST ONE PCB CONGENER. STRONGER EFFECTS WERE OBSERVED IN MALES AND IN SWEDEN. THIS EPIGENETIC EXPOSURE PROFILE SHOWS EXTENSIVE AND HIGHLY STATISTICALLY SIGNIFICANT OVERLAPS WITH PUBLISHED PROFILES ASSOCIATED WITH THE RISK OF FUTURE B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS WELL AS WITH CLINICAL CLL (38 AND 28 CPG SITES, RESPECTIVELY). FOR ALL THESE SITES, THE METHYLATION CHANGES WERE IN THE SAME DIRECTION FOR INCREASING EXPOSURE AND FOR HIGHER DISEASE RISK OR CLINICAL DISEASE STATUS, SUGGESTING AN ETIOLOGICAL LINK BETWEEN EXPOSURE AND CLL. MEDIATION ANALYSIS REINFORCED THE SUGGESTION OF A CAUSAL LINK BETWEEN EXPOSURE, CHANGES IN DNA METHYLATION AND DISEASE. DISEASE CONNECTIVITY ANALYSIS IDENTIFIED MULTIPLE ADDITIONAL DISEASES ASSOCIATED WITH DIFFERENTIALLY METHYLATED GENES, INCLUDING MELANOMA FOR WHICH AN ETIOLOGICAL LINK WITH PCB EXPOSURE IS ESTABLISHED, AS WELL AS DEVELOPMENTAL AND NEUROLOGICAL DISEASES FOR WHICH THERE IS CORRESPONDING EPIDEMIOLOGICAL EVIDENCE. DIFFERENTIALLY METHYLATED GENES INCLUDE MANY HOMEOBOX GENES, SUGGESTING THAT PCBS TARGET STEM CELLS. FURTHERMORE, NUMEROUS POLYCOMB PROTEIN TARGET GENES WERE HYPERMETHYLATED WITH INCREASING EXPOSURE, AN EFFECT KNOWN TO CONSTITUTE AN EARLY MARKER OF CARCINOGENESIS. CONCLUSIONS: THIS STUDY PROVIDES MECHANISTIC EVIDENCE IN SUPPORT OF A LINK BETWEEN EXPOSURE TO PCBS AND THE ETIOLOGY OF CLL AND UNDERLINES THE UTILITY OF OMIC PROFILING IN THE EVALUATION OF THE POTENTIAL TOXICITY OF ENVIRONMENTAL CHEMICALS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  5445  39 REPEATED VAPOR ETHANOL EXPOSURE INDUCES TRANSIENT HISTONE MODIFICATIONS IN THE BRAIN THAT ARE MODIFIED BY GENOTYPE AND BRAIN REGION. BACKGROUND: EMERGING RESEARCH IMPLICATES ETHANOL (ETOH)-INDUCED EPIGENETIC MODIFICATIONS IN REGULATING GENE EXPRESSION AND ETOH CONSUMPTION. HOWEVER, CONSENSUS ON SPECIFIC EPIGENETIC MODIFICATIONS INDUCED BY ETOH HAS NOT YET EMERGED, MAKING IT CHALLENGING TO IDENTIFY MECHANISMS AND DEVELOP TARGETED TREATMENTS. WE HYPOTHESIZED THAT CHRONIC INTERMITTENT ETOH (CIE) INDUCES PERSISTENT CHANGES IN HISTONE MODIFICATIONS ACROSS THE CEREBRAL CORTEX (CCX), NUCLEUS ACCUMBENS (NAC), AND PREFRONTAL CORTEX (PFC), AND THAT THESE HISTONE MODIFICATIONS ARE ALTERED IN A KNOCK-IN MOUSE STRAIN WITH ALTERED SENSITIVITY TO ETOH. METHODS: C57BL/6J (B6) MICE AND ALPHA1SHLA KNOCKIN MICE ON A B6 BACKGROUND WERE EXPOSED TO 16 H OF VAPOR ETOH OR ROOM AIR FOLLOWED BY 8 H OF ROOM AIR FOR 4 CONSECUTIVE DAYS AND SACRIFICED AT MULTIPLE TIME POINTS UP TO 72 H FOLLOWING EXPOSURE. HISTONE MODIFICATIONS WERE ASSESSED USING WESTERN BLOT AND DOT BLOT. RT-QPCR WAS USED TO STUDY EXPRESSION OF CHROMATIN MODIFYING ENZYMES IN NAC AND PFC. RESULTS: IN NAC, CIE SIGNIFICANTLY INCREASED ACETYLATION OF HISTONE SUBUNIT H3 AT LYSINE 9 (H3K9AC) BUT NOT LYSINE 14 (H3K14AC) OR LYSINE 27 (H3K27AC). IN PFC, CIE SIGNIFICANTLY INCREASED H3K9AC BUT NOT H3K14 OR H3K27AC. THERE WERE NO SIGNIFICANT CHANGES AT 8 OR 72 H AFTER ETOH EXPOSURE IN EITHER NAC OR PFC. CIE WAS ALSO ASSOCIATED WITH INCREASED EXPRESSION OF KAT2B, KAT5, AND TET1 IN NAC BUT NOT PFC. IN CCX, CIE HAD A SIGNIFICANT EFFECT ON LEVELS OF H3K18AC; THERE WAS ALSO A SIGNIFICANT EFFECT OF THE ALPHA1SHLA MUTATION ON LEVELS OF H3K27ME3, H3K14AC, AND H3K18AC AS WELL AS A TREND FOR H3S10PK14AC. CONCLUSIONS: THE ETOH-INDUCED HISTONE MODIFICATIONS OBSERVED WERE TRANSIENT AND VARIED SIGNIFICANTLY BETWEEN BRAIN REGIONS. A GENETIC MUTATION THAT ALTERED SENSITIVITY TO ETOH WAS ASSOCIATED WITH ALTERED INDUCTION OF HISTONE MODIFICATIONS DURING CIE. THESE RESULTS HAVE IMPLICATIONS FOR STUDYING ETOH-INDUCED HISTONE MODIFICATIONS AND ETOH SENSITIVITY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16  3558  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  2698  26 EXAMINING MULTI- AND TRANSGENERATIONAL BEHAVIORAL AND MOLECULAR ALTERATIONS RESULTING FROM PARENTAL EXPOSURE TO AN ENVIRONMENTAL PCB AND PBDE MIXTURE. POLYCHLORINATED BIPHENYLS (PCBS) AND POLYBROMINATED DIPHENYL ETHERS (PBDES) ARE PERSISTENT ORGANIC POLLUTANTS EXTENSIVELY USED DURING THE 20(TH) CENTURY AND STILL PRESENT IN AQUATIC ENVIRONMENTS DESPITE THEIR BAN. EFFECTS OF EXPOSURE TO THESE COMPOUNDS OVER GENERATIONS ARE POORLY DOCUMENTED. THEREFORE, OUR AIMS WERE TO CHARACTERIZE BEHAVIORAL RESPONSES AND UNDERLYING MOLECULAR MECHANISMS IN ZEBRAFISH EXPOSED TO AN ENVIRONMENTALLY RELEVANT MIXTURE OF PCBS AND PBDES AS WELL AS IN FOUR UNEXPOSED OFFSPRING GENERATIONS. ZEBRAFISH (F0) WERE CHRONICALLY EXPOSED FROM THE FIRST MEAL ONWARD TO A DIET SPIKED WITH A MIXTURE CONTAINING 22 PCB AND 7 PBDE CONGENERS IN PROPORTIONS AND CONCENTRATIONS REFLECTING ENVIRONMENTAL SITUATIONS (SIGMAPCBS = 1991 AND SIGMAPBDES = 411 NG/G). FOUR OFFSPRING GENERATIONS (F1 TO F4) WERE OBTAINED FROM THIS F0 AND WERE NOT FURTHER EXPOSED. BEHAVIOR WAS ASSESSED AT BOTH LARVAL AND ADULT STAGES. MECHANISMS RELATED TO BEHAVIORAL DEFECTS (HABENULA MATURATION AND C-FOS TRANSCRIPTION) AND METHYLATION (DNMTS TRANSCRIPTION) WERE MONITORED IN LARVAE. EXPOSED ADULT F0 AS WELL AS F1 AND F3 ADULTS DISPLAYED NO BEHAVIORAL CHANGE WHILE F2 EXPRESSED ANXIETY-LIKE BEHAVIOR. LARVAL BEHAVIOR WAS ALSO DISRUPTED, I.E. HYPERACTIVE AFTER LIGHT TO DARK TRANSITION IN F1 OR HYPOACTIVE IN F2, F3 AND F4. BEHAVIORAL DISRUPTIONS MAY BE RELATED TO DEFECT IN HABENULA MATURATION (OBSERVED IN F1) AND CHANGE IN C-FOS TRANSCRIPTION (OBSERVED IN F1 AND F2). TRANSCRIPTION OF THE GENE ENCODING DNA METHYLTRANSFERASE (DNMT3BA) WAS ALSO MODIFIED IN ALL GENERATIONS. OUR RESULTS LEAD US TO HYPOTHESIZE THAT CHRONIC DIETARY EXPOSURE TO AN ENVIRONMENTALLY RELEVANT MIXTURE OF PCB AND PBDE TRIGGERS MULTIGENERATIONAL AND TRANSGENERATIONAL MOLECULAR AND BEHAVIORAL DISRUPTIONS IN A VERTEBRATE MODEL.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18  5100  23 POLYCHLORINATED BIPHENYLS (PCBS) ALTER DNA METHYLATION AND GENOMIC INTEGRITY OF SHEEP FETAL CELLS IN A SIMPLIFIED IN VITRO MODEL OF PREGNANCY EXPOSURE. POLYCHLORINATED BIPHENYLS (PCBS) ARE PERSISTENT ORGANIC POLLUTANTS UBIQUITOUSLY DETECTABLE IN THE ENVIRONMENT AND IN THE FOOD CHAIN. PRENATAL EXPOSURE TO PCBS NEGATIVELY AFFECTS FETAL DEVELOPMENT AND PRODUCES LONG-TERM DETRIMENTAL EFFECTS ON CHILD HEALTH. THE PRESENT STUDY SOUGHT TO EVALUATE THE CYTOTOXIC AND GENOTOXIC EFFECTS OF CHRONIC PCB EXPOSURE ON FETAL CELLS DURING PREGNANCY. TO THIS AIM, SHEEP EMBRYONIC FIBROBLASTS (SEF) AND AMNIOCYTES (SA) WERE CULTURED IN VITRO IN THE PRESENCE OF LOW DOSES OF PCBS FOR A PERIOD OF 120DAYS, COMPARABLE TO THE FULL TERM OF OVINE PREGNANCY. CELLULAR PROLIFERATION RATES, GLOBAL DNA METHYLATION, CHROMOSOME INTEGRITY, AND MARKERS OF DNA DAMAGE WERE EVALUATED AT DIFFERENT TIME POINTS. MOREOVER, SEF TREATED WITH PCBS FOR 60DAYS WERE LEFT UNTREATED FOR ONE FURTHER MONTH AND THEN EXAMINED IN ORDER TO EVALUATE THE REVERSIBILITY OF PCB-INDUCED EPIGENETIC DEFECTS. PCB-TREATED SEF WERE MORE SENSITIVE THAN SA TREATED WITH PCBS, IN TERMS OF LOW CELL PROLIFERATION, AND INCREASED DNA DAMAGE AND GLOBAL DNA METHYLATION, WHICH WERE STILL DETECTABLE AFTER INTERRUPTION OF PCB TREATMENT. THESE DATA INDICATE THAT CHRONIC EXPOSURE OF FETAL CELLS TO PCBS CAUSES PERMANENT GENOMIC AND EPIGENETIC INSTABILITY, WHICH MAY INFLUENCE BOTH PRENATAL AND POST-NATAL GROWTH UP TO ADULTHOOD. OUR IN VITRO MODEL OFFER A SIMPLE AND CONTROLLED MEANS OF STUDYING THE EFFECTS OF DIFFERENT CONTAMINANTS ON FETAL CELLS - ONE THAT COULD SET THE STAGE FOR TARGETED IN VIVO STUDIES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  1788  26 EFFECT OF CHRONIC ETHANOL CONSUMPTION IN RHESUS MACAQUES ON THE NUCLEUS ACCUMBENS CORE TRANSCRIPTOME. THE NUCLEUS ACCUMBENS CORE (NACC) HAS BEEN REPEATEDLY DEMONSTRATED TO BE A KEY COMPONENT OF THE CIRCUITRY ASSOCIATED WITH EXCESSIVE ETHANOL CONSUMPTION. PREVIOUS STUDIES HAVE ILLUSTRATED THAT IN A NONHUMAN PRIMATE (NHP) MODEL OF CHRONIC ETHANOL CONSUMPTION, THERE IS SIGNIFICANT EPIGENETIC REMODELING OF THE NACC. IN THE CURRENT STUDY, RNA-SEQ WAS USED TO EXAMINE GENOME-WIDE GENE EXPRESSION IN EIGHT EACH OF CONTROL, LOW/BINGE (LD*), AND HIGH/VERY HIGH (HD*) RHESUS MACAQUE DRINKERS. USING AN FDR < 0.05, ZERO GENES WERE SIGNIFICANTLY DIFFERENTIALLY EXPRESSED (DE) BETWEEN LD* AND CONTROLS, SIX GENES BETWEEN HD* AND LD*, AND 734 GENES BETWEEN HD* AND CONTROLS. FOCUSING ON HD* VERSUS CONTROL DE GENES, THE UPREGULATED GENES (N = 366) WERE ENRICHED IN GENES WITH ANNOTATIONS ASSOCIATED WITH SIGNAL RECOGNITION PARTICLE (SRP)-DEPENDENT CO-TRANSLATIONAL PROTEIN TARGETING TO MEMBRANE (FDR < 3 X 10(-59) ), STRUCTURAL CONSTITUENT OF RIBOSOME (FDR < 3 X 10(-47) ), AND RIBOSOMAL SUBUNIT (FDR < 5 X 10(-48) ). DOWNREGULATED GENES (N = 363) WERE ENRICHED IN ANNOTATIONS ASSOCIATED WITH BEHAVIOR (FDR < 2 X 10(-4) ), MEMBRANE ORGANIZATION (FDR < 1 X 10(-4) ), INORGANIC CATION TRANSMEMBRANE TRANSPORTER ACTIVITY (FDR < 2 X 10(-3) ), SYNAPSE PART (FDR < 4 X 10(-10) ), GLUTAMATERGIC SYNAPSE (FDR < 1 X 10(-6) ), AND GABAERGIC SYNAPSE (FDR < 6 X 10(-4) ). INGENUITY PATHWAY ANALYSIS (IPA) REVEALED THAT EIF2 SIGNALING AND MTOR PATHWAYS WERE SIGNIFICANTLY UPREGULATED IN HD* ANIMALS (FDR < 3 X 10(-33) AND <2 X 10(-16) , RESPECTIVELY). OVERALL, THE DATA SUPPORTED OUR WORKING HYPOTHESIS; EXCESSIVE CONSUMPTION WOULD BE ASSOCIATED WITH TRANSCRIPTIONAL DIFFERENCES IN GABA/GLUTAMATE-RELATED GENES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  3609  28 IN UTERO ARSENIC EXPOSURE AND EPIGENOME-WIDE ASSOCIATIONS IN PLACENTA, UMBILICAL ARTERY, AND HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS. EXPOSURE TO ARSENIC EARLY IN LIFE HAS BEEN ASSOCIATED WITH INCREASED RISK OF SEVERAL CHRONIC DISEASES AND IS BELIEVED TO ALTER EPIGENETIC PROGRAMMING IN UTERO. IN THE PRESENT STUDY, WE EVALUATE THE EPIGENOME-WIDE ASSOCIATION OF ARSENIC EXPOSURE IN UTERO AND DNA METHYLATION IN PLACENTA (N = 37), UMBILICAL ARTERY (N = 45) AND HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS (HUVEC) (N = 52) IN A BIRTH COHORT USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP ARRAY. UNADJUSTED AND CELL MIXTURE ADJUSTED ASSOCIATIONS FOR EACH TISSUE WERE EXAMINED ALONG WITH ENRICHMENT ANALYSES RELATIVE TO CPG ISLAND LOCATION AND OMNIBUS PERMUTATION TESTS OF ASSOCIATION AMONG BIOLOGICAL PATHWAYS. ONE CPG IN ARTERY (CG26587014) AND 4 CPGS IN PLACENTA (CG12825509; CG20554753; CG23439277; CG21055948) REACHED A BONFERRONI ADJUSTED LEVEL OF SIGNIFICANCE. SEVERAL CPGS WERE DIFFERENTIALLY METHYLATED IN ARTERY AND PLACENTA WHEN CONTROLLING THE FALSE DISCOVERY RATE (Q-VALUE<0.05), BUT NONE IN HUVEC. ENRICHMENT OF HYPOMETHYLATED CPG ISLANDS WAS OBSERVED FOR ARTERY WHILE HYPERMETHYLATION OF OPEN SEA REGIONS WERE PRESENT IN PLACENTA RELATIVE TO PRENATAL ARSENIC EXPOSURE. THE MELANOGENESIS PATHWAY WAS DIFFERENTIALLY METHYLATED IN ARTERY (MAX F P < 0.001), PLACENTA (MAX F P < 0.001), AND HUVEC (MAX F P = 0.02). SIMILARLY, THE INSULIN-SIGNALING PATHWAY WAS DIFFERENTIALLY METHYLATED IN ARTERY (MAX F P = 0.02), PLACENTA (MAX F P = 0.02), AND HUVEC (MAX F P = 0.02). OUR RESULTS SHOW THAT PRENATAL ARSENIC EXPOSURE CAN ALTER DNA METHYLATION IN ARTERY AND PLACENTA BUT NOT IN HUVEC. FURTHER STUDIES ARE NEEDED TO DETERMINE IF THESE ALTERATIONS IN DNA METHYLATION MEDIATE THE EFFECT OF PRENATAL ARSENIC EXPOSURE AND HEALTH OUTCOMES LATER IN LIFE.	2015