1   935 199 CHRONIC LOW-DOSE EXPOSURE TO XENOESTROGEN AMBIENT AIR POLLUTANTS AND BREAST CANCER RISK: XENAIR PROTOCOL FOR A CASE-CONTROL STUDY NESTED WITHIN THE FRENCH E3N COHORT. BACKGROUND: BREAST CANCER IS THE MOST FREQUENT CANCER IN WOMEN IN INDUSTRIALIZED COUNTRIES. LIFESTYLE AND ENVIRONMENTAL FACTORS, PARTICULARLY ENDOCRINE-DISRUPTING POLLUTANTS, HAVE BEEN SUGGESTED TO PLAY A ROLE IN BREAST CANCER RISK. CURRENT EPIDEMIOLOGICAL STUDIES, ALTHOUGH NOT FULLY CONSISTENT, SUGGEST A POSITIVE ASSOCIATION OF BREAST CANCER RISK WITH EXPOSURE TO SEVERAL INTERNATIONAL AGENCY FOR RESEARCH ON CANCER GROUP 1 AIR-POLLUTANT CARCINOGENS, SUCH AS PARTICULATE MATTER, POLYCHLORINATED BIPHENYLS (PCB), DIOXINS, BENZO[A]PYRENE (BAP), AND CADMIUM. HOWEVER, EPIDEMIOLOGICAL STUDIES REMAIN SCARCE AND INCONSISTENT. IT HAS BEEN PROPOSED THAT THE MENOPAUSAL STATUS COULD MODIFY THE RELATIONSHIP BETWEEN POLLUTANTS AND BREAST CANCER AND THAT THE ASSOCIATION VARIES WITH HORMONE RECEPTOR STATUS. OBJECTIVE: THE XENAIR PROJECT WILL INVESTIGATE THE ASSOCIATION OF BREAST CANCER RISK (OVERALL AND BY HORMONE RECEPTOR STATUS) WITH CHRONIC EXPOSURE TO SELECTED AIR POLLUTANTS, INCLUDING PARTICULATE MATTER, NITROGEN DIOXIDE (NO2), OZONE (O3), BAP, DIOXINS, PCB-153, AND CADMIUM. METHODS: OUR RESEARCH IS BASED ON A CASE-CONTROL STUDY NESTED WITHIN THE FRENCH NATIONAL E3N COHORT OF 5222 INVASIVE BREAST CANCER CASES IDENTIFIED DURING FOLLOW-UP FROM 1990 TO 2011, AND 5222 MATCHED CONTROLS. A QUESTIONNAIRE WAS SENT TO ALL PARTICIPANTS TO COLLECT THEIR LIFETIME RESIDENTIAL ADDRESSES AND INFORMATION ON INDOOR POLLUTION. WE WILL ASSESS THESE EXPOSURES USING COMPLEMENTARY MODELS OF LAND-USE REGRESSION, ATMOSPHERIC DISPERSION, AND REGIONAL CHEMISTRY-TRANSPORT (CHIMERE) MODELS, VIA A GEOGRAPHIC INFORMATION SYSTEM. ASSOCIATIONS WITH BREAST CANCER RISK WILL BE MODELED USING CONDITIONAL LOGISTIC REGRESSION MODELS. WE WILL ALSO STUDY THE IMPACT OF EXPOSURE ON DNA METHYLATION AND INTERACTIONS WITH GENETIC POLYMORPHISMS. APPROPRIATE STATISTICAL METHODS, INCLUDING BAYESIAN MODELING, PRINCIPAL COMPONENT ANALYSIS, AND CLUSTER ANALYSIS, WILL BE USED TO ASSESS THE IMPACT OF MULTIPOLLUTANT EXPOSURE. THE FRACTION OF BREAST CANCER CASES ATTRIBUTABLE TO AIR POLLUTION WILL BE ESTIMATED. RESULTS: THE XENAIR PROJECT WILL CONTRIBUTE TO CURRENT KNOWLEDGE ON THE HEALTH EFFECTS OF AIR POLLUTION AND IDENTIFY AND UNDERSTAND ENVIRONMENTAL MODIFIABLE RISK FACTORS RELATED TO BREAST CANCER RISK. CONCLUSIONS: THE RESULTS WILL PROVIDE RELEVANT EVIDENCE TO GOVERNMENTS AND POLICY-MAKERS TO IMPROVE EFFECTIVE PUBLIC HEALTH PREVENTION STRATEGIES ON AIR POLLUTION. THE XENAIR DATASET CAN BE USED IN FUTURE EFFORTS TO STUDY THE EFFECTS OF EXPOSURE TO AIR POLLUTION ASSOCIATED WITH OTHER CHRONIC CONDITIONS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15167.	2020	
                                                                                                                                                                                                                                                                                                                                                                
2  3267  30 HEPATOCELLULAR CARCINOMA AND POSSIBLE CHEMICAL AND BIOLOGICAL CAUSES: A REVIEW. THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) IS A MULTISTEP PROCESS. IN HCC, PROGRESSIVE AND MORPHOLOGICALLY DISTINCT PRENEOPLASTIC LESIONS/ALTERATIONS ASSOCIATED WITH CHRONIC LIVER INJURY, INFLAMMATION, HEPATOCELLULAR DEGENERATION/REGENERATION, NECROSIS, AND SMALL-CELL DYSPLASIA CAN BE OBSERVED. THE INCIDENCE OF HCC EXHIBITS REGIONAL AND ETHNIC DIFFERENCES. SEVERAL CYTOTOXIC AND DNA-DAMAGING CHEMICALS ARE SUGGESTED TO BE THE UNDERLYING CAUSES OF HCC-FOR EXAMPLE, ACRYLAMIDE, PERFLUOROOCTANOIC ACID (PFOA), POLYCHLORINATED BIPHENYLS (PCBS), BENZO(A)PYRENE (BAP), PERFLUORINATED CHEMICALS (PFCS), VINYL CHLORIDE MONOMER (VCM), AND DIETARY CONTAMINANTS (AFLATOXINS, OCHRATOXINS). ALSO SUGGESTED ARE SUBSTANCES OF ABUSE (ALCOHOL) AND BIOLOGICAL AGENTS, SUCH AS HEPATITIS B AND C AND HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1). THESE CAN ACT THROUGH GENETIC AND/OR EPIGENETIC MECHANISMS. THIS REVIEW WILL SHORTLY ADDRESS THE GENETIC AND EPIGENETIC MECHANISMS OF HCC AND FOCUS ON CYTOTOXIC AND DNA-DAMAGING CHEMICALS AND BIOLOGICAL AGENTS, EXPOSURE TO WHICH ARE SUGGESTED TO LEAD TO HCC INITIATION, PROMOTION, AND/OR PROGRESSION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3  5307  46 PROXIMITY UTILIZING BIOTINYLATION OF NUCLEAR PROTEINS IN VIVO. INTRODUCTION: THE HUMAN GENOME CONSISTS OF ROUGHLY 30,000 GENES CODING FOR OVER 500,000 DIFFERENT PROTEINS, OF WHICH MORE THAN 10,000 PROTEINS CAN BE PRODUCED BY THE CELL AT ANY GIVEN TIME (THE CELLULAR "PROTEOME"). IT HAS BEEN ESTIMATED THAT OVER 80% OF PROTEINS DO NOT OPERATE ALONE, BUT IN COMPLEXES. THESE PROTEIN-PROTEIN INTERACTIONS (PPI) ARE REGULATED BY SEVERAL MECHANISMS. FOR EXAMPLE, POST-TRANSLATIONAL MODIFICATIONS (METHYLATION, ACETYLATION, PHOSPHORYLATION, OR UBIQUITINATION) OR METAL-BINDING CAN LEAD TO CONFORMATIONAL CHANGES THAT ALTER THE AFFINITY AND KINETIC PARAMETERS OF THE INTERACTION. MANY PPIS ARE PART OF LARGER CELLULAR NETWORKS OF INTERACTIONS OR INTERACTOMES. INDEED, THESE INTERACTIONS ARE AT THE CORE OF THE ENTIRE INTERACTOMICS SYSTEM OF ANY LIVING CELL, AND SO, ABERRANT PPIS ARE THE BASIS OF MULTIPLE DISEASES, SUCH AS NEURODEGENERATIVE DISEASES AND CANCER. THE OBJECTIVE OF THIS STUDY WAS TO DEVELOP A METHOD OF MONITORING PROTEIN-PROTEIN INTERACTIONS AND PROXIMITY DEPENDENCE IN VIVO. METHODS: THE BIOTIN LIGASE BIRA WAS FUSED TO THE PROTEIN OF INTEREST, AND THE BIOTIN ACCEPTOR PEPTIDE (BAP) WAS FUSED TO AN INTERACTING PARTNER TO MAKE THE DETECTION OF ITS BIOTINYLATION POSSIBLE BY WESTERN BLOT OR MASS SPECTROMETRY. RESULTS: USING SEVERAL EXPERIMENTAL SYSTEMS (BIRA.A + BAP.B), WE SHOWED THAT THE BIOTINYLATION IS INTERACTION/PROXIMITY DEPENDENT. HERE, A AND B ARE THE NEXT NUCLEAR PROTEINS USED IN THE EXPERIMENTS - 3 PARALOGUES OF HETEROCHROMATIN PROTEIN HP1ALPHA (CBX5), HP1BETA (CBX1), HP1GAMMA (CBX3), WILD TYPE AND TRANSCRIPTION MUTANT FACTOR KAP1, TRANSLESION DNA POLYMERASE POLH AND E3, UBIQUITIN LIGASE RAD18, PROLIFERATIVE CELL NUCLEAR ANTIGEN (PCNA), UBIQUITIN UB, SUMO-2/3, DIFFERENT TYPES AND ISOFORMS OF HISTONES H2A, H2AZ, H3.1, H3.3, CENPA, H2A.BBD, AND MACROH2A. THE VARIANT OF THIS APPROACH IS TERMED PUB-NCHIP (PROXIMITY UTILIZING BIOTINYLATION WITH NATIVE CHROMATIN IMMUNO-PRECIPITATION) AND IS DESIGNED TO PURIFY AND STUDY THE PROTEIN COMPOSITION OF CHROMATIN IN PROXIMITY TO THE NUCLEAR PROTEIN OF INTEREST. USING THE RAD18 PROTEIN AS A MODEL, WE DEMONSTRATED THAT THE RAD18-PROXIMAL CHROMATIN IS ENRICHED IN SOME H4 ACETYLATED SPECIES. MOREOVER, THE RAD18-PROXIMAL CHROMATIN CONTAINING A REPLACEMENT HISTONE H2AZ HAS A DIFFERENT PATTERN OF H4 ACETYLATION. CONCLUSION: PROGRESS IN THE LAST DECADE IN CANCER DRUG THERAPY HAS LED US TO THE CONCLUSION THAT THE NUCLEUS OF EUKARYOTIC CELLS IS AN ACTIVE SITE FOR MANY CELLULAR PROCESSES IMPORTANT TO THE DEVELOPMENT OF CANCER. THESE PROCESSES INCLUDE CHANGES IN GENETIC AND EPIGENETIC LANDSCAPE (E. G. METHYLATION OF DNA, MODIFICATION OF HISTONES) AND THE EXPRESSION LEVELS OF TRANSCRIPTION FACTORS, WHICH REGULATES GENE PRODUCTS (E.G. HYPOXIA-INDUCIBLE FACTOR 1ALPHA (HIF-1ALPHA) IN CHRONIC ANEMIA, ETC.) WHERE PROTEIN-PROTEIN INTERACTIONS PLAY IMPORTANT ROLE. UNDERSTANDING THE NATURE OF PROTEIN-PROTEIN INTERACTIONS MAY IMPROVE DESIGN STRATEGIES FOR SMALL-MOLECULE PPI MODULATORS. PPI ASSAY TECHNOLOGIES THAT CLOSELY REFLECT PHYSIOLOGICAL CONDITIONS HOLD THE KEY TO DEVELOPING SPECIFIC ANTI-CANCER DRUGS.	2014	

4   846  45 CHILDHOOD EXPOSURE TO AMBIENT POLYCYCLIC AROMATIC HYDROCARBONS IS LINKED TO EPIGENETIC MODIFICATIONS AND IMPAIRED SYSTEMIC IMMUNITY IN T CELLS. BACKGROUND: EVIDENCE SUGGESTS THAT EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) INCREASES ATOPY; IT IS UNCLEAR HOW PAH EXPOSURE IS LINKED TO INCREASED SEVERITY OF ATOPIC DISEASES. OBJECTIVE: WE HYPOTHESIZED THAT AMBIENT PAH EXPOSURE IS LINKED TO IMPAIRMENT OF IMMUNITY IN ATOPIC CHILDREN (DEFINED AS CHILDREN WITH ASTHMA AND/OR ALLERGIC RHINITIS) FROM FRESNO, CALIFORNIA, AN AREA WITH ELEVATED AMBIENT PAHS. METHODS: WE RECRUITED 256 SUBJECTS FROM FRESNO, CA. AMBIENT PAH CONCENTRATIONS (NG/M(3) ) WERE MEASURED USING A SPATIAL-TEMPORAL REGRESSION MODEL OVER MULTIPLE TIME PERIODS. ASTHMA DIAGNOSIS WAS DETERMINED BY CURRENT NHLBI CRITERIA. PHENOTYPING AND FUNCTIONAL IMMUNE MEASUREMENTS WERE PERFORMED FROM ISOLATED CELLS. FOR EPIGENETIC MEASUREMENTS, DNA WAS ISOLATED AND PYROSEQUENCED. RESULTS: WE SHOW THAT HIGHER AVERAGE PAH EXPOSURE WAS SIGNIFICANTLY ASSOCIATED WITH IMPAIRED TREG FUNCTION AND INCREASED METHYLATION IN THE FORKHEAD BOX PROTEIN 3 (FOXP3) LOCUS (P < 0.05), CONDITIONAL ON ATOPIC STATUS. THESE EPIGENETIC MODIFICATIONS WERE SIGNIFICANTLY LINKED TO DIFFERENTIAL PROTEIN EXPRESSION OF FOXP3 (P < 0.001). METHYLATION WAS ASSOCIATED WITH CELLULAR FUNCTIONAL CHANGES, SPECIFICALLY TREG DYSFUNCTION, AND AN INCREASE IN TOTAL PLASMA IGE LEVELS. PROTEIN EXPRESSION OF IL-10 DECREASED AND IFN-GAMMA INCREASED AS THE EXTENT OF PAH EXPOSURE INCREASED. THE STRENGTH OF THE ASSOCIATIONS GENERALLY INCREASED AS THE TIME WINDOW FOR AVERAGE PAH EXPOSURE INCREASED FROM 24 HR TO 1 YEAR, SUGGESTING MORE OF A CHRONIC RESPONSE. SIGNIFICANT ASSOCIATIONS WITH CHRONIC PAH EXPOSURE AND IMMUNE OUTCOMES WERE ALSO OBSERVED IN SUBJECTS WITH ALLERGIC RHINITIS. CONCLUSIONS AND CLINICAL RELEVANCE: COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT INCREASED AMBIENT PAH EXPOSURE IS ASSOCIATED WITH IMPAIRED SYSTEMIC IMMUNITY AND EPIGENETIC MODIFICATIONS IN A KEY LOCUS INVOLVED IN ATOPY: FOXP3, WITH A HIGHER IMPACT ON ATOPIC CHILDREN. THE RESULTS SUGGEST THAT INCREASED ATOPIC CLINICAL SYMPTOMS IN CHILDREN COULD BE LINKED TO INCREASED PAH EXPOSURE IN AIR POLLUTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  3063  54 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 </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6  5492  21 REVIEW OF ARSENIC TOXICITY, SPECIATION AND POLYADENYLATION OF CANONICAL HISTONES. ARSENIC CONTAMINATION IMPACTS HUNDREDS OF MILLIONS OF PEOPLE IN THE WORLD. ARSENIC IS A WELL-ESTABLISHED HUMAN CARCINOGEN AND HAS BEEN SHOWN TO CAUSE SKIN, LUNG, BLADDER, LIVER, PROSTATE AND KIDNEY CANCERS, IN HUMANS. MECHANISMS THAT UNDERLIE ARSENIC-MEDIATED CARCINOGENESIS, INCLUDING EPIGENETIC ALTERATIONS, REMAIN LARGELY UNKNOWN. HUMAN EXPOSURE TO ARSENIC IS REVIEWED, AND THE MECHANISMS OF ITS ACUTE AND CHRONIC TOXICITY AND MECHANISMS OF ITS CARCINOGENESIS IN HUMANS ARE DISCUSSED. ARSENIC IS ONE OF THE FEW METALS THAT IS METABOLIZED IN VIVO, AND ARSENIC METHYLATION AND HOW THIS RESULTS IN A SHORTER HALF-LIFE IN VIVO ARE DISCUSSED. A REVIEW OF RECENT FINDINGS THAT ARSENIC CAUSES LOSS IN THE CELLULAR LEVELS OF STEM LOOP BINDING PROTEIN (SLBP) RESULTING IN POLYADENYLATION OF CANONICAL HISTONES (H3.1) AS A DEFAULT, INCREASING LEVELS OF H3.1 PROTEIN OUTSIDE OF S-PHASE. MALIGNANT CELL TRANSFORMATION IS INDUCED BY KNOCKDOWN OF SLBP AND BY OVEREXPRESSION OF POLYADENYLATED H3.1. ARSENIC INDUCED POLYADENYLATION OF H3.1 CAUSES ENHANCED LEVELS OF H3.1 PROTEIN DISPLACING H3.3 PROTEIN FROM ITS CELLULAR BINDING SITES, SINCE THE TWO PROTEINS DIFFER BY ONLY 5 AMINO ACIDS. KNOCKDOWN OF H3.3 ALONE CAN INDUCE CARCINOGENESIS, AND THEREFORE DISPLACEMENT OF FUNCTIONAL H3.3 PROTEIN BY INCREASED H3.1 PROTEIN, IS LIKELY A MECHANISM OF ARSENIC CARCINOGENESIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7   502  50 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8  3411  26 HP1GAMMA PREVENTS ACTIVATION OF THE CGAS/STING PATHWAY BY PRESERVING NUCLEAR ENVELOPE AND GENOMIC INTEGRITY IN COLON ADENOCARCINOMA CELLS. CHRONIC INFLAMMATORY PROCESSES IN THE INTESTINE RESULT IN SERIOUS CONDITIONS SUCH AS INFLAMMATORY BOWEL DISEASE (IBD) AND CANCER. AN INCREASED DETECTION OF CYTOPLASMIC DNA SENSORS HAS BEEN REPORTED IN THE IBD COLON MUCOSA, SUGGESTING THEIR CONTRIBUTION IN MUCOSAL INFLAMMATION. YET, THE MECHANISMS ALTERING DNA HOMEOSTASIS AND TRIGGERING THE ACTIVATION OF DNA SENSORS REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE SHOW THAT THE EPIGENETIC REGULATOR HP1GAMMA PLAYS A ROLE IN PRESERVING NUCLEAR ENVELOPE AND GENOMIC INTEGRITY IN ENTEROCYTIC CELLS, THEREBY PROTECTING AGAINST THE PRESENCE OF CYTOPLASMIC DNA. ACCORDINGLY, HP1 LOSS OF FUNCTION LED TO THE INCREASED DETECTION OF CGAS/STING, A CYTOPLASMIC DNA SENSOR THAT TRIGGERS INFLAMMATION. THUS, IN ADDITION TO ITS ROLE AS A TRANSCRIPTIONAL SILENCER, HP1GAMMA MAY ALSO EXERT ANTI-INFLAMMATORY PROPERTIES BY PREVENTING THE ACTIVATION OF THE ENDOGENOUS CYTOPLASMIC DNA RESPONSE IN THE GUT EPITHELIUM.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9   642  49 BIOMARKERS OF PARTICULATE MATTER EXPOSURE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: A SYSTEMATIC REVIEW. BACKGROUND: IN RECENT YEARS, AMBIENT PARTICULATE MATTER (PM) EXPOSURE HAS BEEN STRONGLY LINKED WITH HEALTH EFFECTS. ELEVATED LEVELS OF PM IN POLLUTED AIR HAVE BEEN CORRELATED WITH THE ONSET AND DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS SYSTEMATIC REVIEW WAS CONDUCTED TO EVALUATE BIOMARKERS THAT COULD REFLECT THE EFFECTS OF PM EXPOSURE IN PATIENTS WITH COPD. METHODS: WE PERFORMED A SYSTEMATIC REVIEW OF STUDIES PUBLISHED ON BIOMARKERS ASSOCIATED WITH PM EXPOSURE IN PATIENTS WITH COPD BETWEEN JANUARY 01, 2012 AND JUNE 30, 2022 IN PUBMED/MEDLINE, EMBASE, AND COCHRANE DATABASES. STUDIES THAT INCLUDED DATA ON BIOMARKERS WITH COPD EXPOSED PM WERE ELIGIBLE FOR INCLUSION. BIOMARKERS WERE CLASSIFIED INTO 4 GROUPS ACCORDING TO THEIR MECHANISMS. RESULTS: OF THE 105 STUDIES IDENTIFIED, 22 WERE INCLUDED IN THIS STUDY. NEARLY 50 BIOMARKERS HAVE BEEN PROPOSED IN THE STUDIES INCLUDED IN THIS REVIEW, AND THE MOST STUDIED IN RELATION TO PM ARE SEVERAL INTERLEUKINS. VARIOUS MECHANISMS HAVE BEEN REPORTED BY WHICH PM INDUCES AND AGGRAVATES COPD. SIX STUDIES RELATED TO OXIDATIVE STRESS, ONE RELATED TO DIRECT EFFECT OF INNATE AND ADAPTIVE IMMUNE SYSTEMS, 16 ASSOCIATED WITH GENETIC REGULATION OF INFLAMMATION, AND TWO RELATED TO EPIGENETIC REGULATION OF PHYSIOLOGY AND SUSCEPTIBILITY WERE FOUND. BIOMARKERS RELATED TO THESE MECHANISMS WERE DETECTED IN SERUM, SPUTUM, URINE, EXHALED BREATH CONCENTRATION (EBC), AND SHOWED VARIOUS CORRELATIONS WITH PM IN COPD. CONCLUSIONS: VARIOUS BIOMARKERS HAVE SHOWN POTENTIAL IN PREDICTING THE EXTENT OF PM EXPOSURE IN COPD PATIENTS. FUTURE STUDIES ARE NEEDED TO ESTABLISH RECOMMENDATIONS FOR REGULATION TO REDUCE AIRBORNE PM, WHICH COULD BE USED TO DEVELOP STRATEGIES FOR PREVENTION AND MANAGEMENT OF ENVIRONMENTAL RESPIRATORY DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10   298  52 AIR POLLUTION AND AIRWAY DISEASE. EPIDEMIOLOGICAL AND TOXICOLOGICAL RESEARCH CONTINUES TO SUPPORT A LINK BETWEEN URBAN AIR POLLUTION AND AN INCREASED INCIDENCE AND/OR SEVERITY OF AIRWAY DISEASE. DETRIMENTAL EFFECTS OF OZONE (O(3)), NITROGEN DIOXIDE (NO(2)) AND PARTICULATE MATTER (PM), AS WELL AS TRAFFIC-RELATED POLLUTION AS A WHOLE, ON RESPIRATORY SYMPTOMS AND FUNCTION ARE WELL DOCUMENTED. NOT ONLY DO WE HAVE STRONG EPIDEMIOLOGICAL EVIDENCE OF A RELATIONSHIP BETWEEN AIR POLLUTION AND EXACERBATION OF ASTHMA AND RESPIRATORY MORBIDITY AND MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT RECENT STUDIES, PARTICULARLY IN URBAN AREAS, HAVE SUGGESTED A ROLE FOR POLLUTANTS IN THE DEVELOPMENT OF BOTH ASTHMA AND COPD. SIMILARLY, WHILE PREVALENCE AND SEVERITY OF ATOPIC CONDITIONS APPEAR TO BE MORE COMMON IN URBAN COMPARED WITH RURAL COMMUNITIES, EVIDENCE IS EMERGING THAT TRAFFIC-RELATED POLLUTANTS MAY CONTRIBUTE TO THE DEVELOPMENT OF ALLERGY. FURTHERMORE, NUMEROUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST AN ASSOCIATION BETWEEN EXPOSURE TO NO(2) , O(3) , PM AND COMBUSTION PRODUCTS OF BIOMASS FUELS AND AN INCREASED SUSCEPTIBILITY TO AND MORBIDITY FROM RESPIRATORY INFECTION. GIVEN THE CONSIDERABLE CONTRIBUTION THAT TRAFFIC EMISSIONS MAKE TO URBAN AIR POLLUTION RESEARCHERS HAVE SOUGHT TO CHARACTERIZE THE RELATIVE TOXICITY OF TRAFFIC-RELATED PM POLLUTANTS. RECENT ADVANCES IN MECHANISMS IMPLICATED IN THE ASSOCIATION OF AIR POLLUTANTS AND AIRWAY DISEASE INCLUDE EPIGENETIC ALTERATION OF GENES BY COMBUSTION-RELATED POLLUTANTS AND HOW POLYMORPHISMS IN GENES INVOLVED IN ANTIOXIDANT PATHWAYS AND AIRWAY INFLAMMATION CAN MODIFY RESPONSES TO AIR POLLUTION EXPOSURES. OTHER INTERESTING EPIDEMIOLOGICAL OBSERVATIONS RELATED TO INCREASED HOST SUSCEPTIBILITY INCLUDE A POSSIBLE LINK BETWEEN CHRONIC PM EXPOSURE DURING CHILDHOOD AND VULNERABILITY TO COPD IN ADULTHOOD, AND THAT INFANTS SUBJECTED TO HIGHER PRENATAL LEVELS OF AIR POLLUTION MAY BE AT GREATER RISK OF DEVELOPING RESPIRATORY CONDITIONS. WHILE THE CHARACTERIZATION OF POLLUTANT COMPONENTS AND SOURCES PROMISE TO GUIDE POLLUTION CONTROL STRATEGIES, THE IDENTIFICATION OF SUSCEPTIBLE SUBPOPULATIONS WILL BE NECESSARY IF TARGETED THERAPY/PREVENTION OF POLLUTION-INDUCED RESPIRATORY DISEASES IS TO BE DEVELOPED.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11   865  33 CHRONIC ACRYLAMIDE EXPOSURE IN MALE MICE RESULTS IN ELEVATED DNA DAMAGE IN THE GERMLINE AND HERITABLE INDUCTION OF CYP2E1 IN THE TESTES. ACUTE ACRYLAMIDE EXPOSURE IN MALE RODENTS RESULTS IN REDUCED REPRODUCTIVE PERFORMANCE AND DOMINANT LETHALITY. HOWEVER, THE REPRODUCTIVE EFFECTS OF LOW DOSE CHRONIC EXPOSURE, WHICH BETTER REFLECTS THE NATURE OF HUMAN EXPOSURE, REMAIN FAR LESS CERTAIN. HUMAN DIETARY CONSUMPTION OF ACRYLAMIDE HAS BEEN ESTIMATED AT AN AVERAGE OF 1-4 MICROG/KG BW/DAY. IN ORDER TO SIMULATE THIS EXPOSURE, MALE MICE WERE PROVIDED WITH ACRYLAMIDE (1 MICROG/ML) VIA THEIR DRINKING WATER CONTINUOUSLY FOR SIX MONTHS, WHICH WAS EQUIVALENT TO A HUMAN DOSE OF 10.5 MICROG/ KG BW/DAY. THIS EXPOSURE REGIME INCREASED DNA DAMAGE IN THE SPERMATOZOA, WITHOUT AFFECTING A CONCOMITANT REDUCTION IN OVERALL FERTILITY. THE OFFSPRING OF ACRYLAMIDE TREATED MICE DID NOT HAVE AN INCREASED INCIDENCE OF SKIN PAPILLOMA FORMATION FOLLOWING THE TWO-STAGE TUMOR INDUCTION PROTOCOL. HOWEVER, THE MALE OFFSPRING OF ACRYLAMIDE TREATED FATHERS HAD SIGNIFICANTLY INCREASED LEVELS OF DNA DAMAGE IN THEIR SPERMATOZOA, DESPITE HAVING HAD NO DIRECT TOXICANT EXPOSURE. IT WAS ALSO FOUND THAT THE F0, AND MOST CRUCIALLY, F1 MICE HAD INCREASED LEVELS OF CYP2E1 PROTEIN IN THEIR GERM CELLS. THIS IS SIGNIFICANT AS CYP2E1 IS THE SOLE ENZYME RESPONSIBLE FOR CONVERSION OF ACRYLAMIDE TO ITS HARMFUL METABOLITE GLYCIDAMIDE. THIS ALTERED EXPRESSION MAY BE DUE TO EPIGENETIC ALTERATIONS. ADDITIONALLY, THE F0 AND F1 MICE HAD INCREASED OXIDATIVE ADDUCTS IN THE DNA OF THEIR GERM CELLS, WHICH WAS HYPOTHESIZED TO ARISE AS A BYPRODUCT OF INCREASED CYP2E1 ACTIVITY. THEREFORE, CHRONIC PATERNAL ACRYLAMIDE EXPOSURE IN MICE HAS CONSEQUENCES FOR THEIR OFFSPRING, AND RAISES CONCERNS FOR THE EFFECTS OF ACRYLAMIDE EXPOSURE IN THE HUMAN POPULATION AND THE ACCUMULATED EFFECTS WITH MULTIPLE GENERATIONS OF EXPOSURE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12  5010  40 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID.	1994	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  5760  40 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  5960  33 TELOMERE LENGTH IN HEPATOCELLULAR CARCINOMA AND PAIRED ADJACENT NON-TUMOR TISSUES BY QUANTITATIVE PCR. TELOMERE SHORTENING LIMITS THE PROLIFERATIVE CAPACITY OF HUMAN CELLS, RESTRAINS THE REGENERATIVE CAPACITY OF ORGAN SYSTEMS DURING CHRONIC DISEASES AND AGING AND ALSO INDUCES CHROMOSOMAL INSTABILITY AS WELL AS INITIATION OF CANCER. PREVIOUS STUDIES DEMONSTRATED THAT TELOMERES ARE OFTEN SIGNIFICANTLY SHORTER IN TUMOR TISSUE, INCLUDING HEPATOCELLULAR CARCINOMA (HCC), COMPARED TO THE SURROUNDING TISSUE, BUT TELOMERE LENGTH IN HCC TISSUES WAS NOT CORRELATED WITH SEVERAL CLINICAL PARAMETERS, SUCH AS AGE, SEX, HBV OR HCV INFECTIONS AND TUMOR SIZE. IN THE PRESENT STUDY, THE TELOMERE LENGTH RATIO OF 36 PAIRED HCC, AND THEIR ADJACENT NON-TUMOR TISSUES WAS MEASURED BY QUANTITATIVE PCR (Q-PCR). THE MEAN TELOMERE LENGTHS (SD) FOR HCC AND ADJACENT NON-TUMOR TISSUES WERE 0.26 (0.10) AND 0.47 (0.20) RESPECTIVELY (T = 6.22, P < 0.0001). THERE WAS A LARGE DIFFERENCE IN THE DISTRIBUTION OF SUBJECTS BASED ON TELOMERE LENGTH IN TUMOR AND ADJACENT NON-TUMOR TISSUES. THE NUMBER OF TUMORS WITH TELOMERE LENGTH SHORTER THAN 0.50 WAS MUCH HIGHER THAN THAT OF ADJACENT NON-TUMOR TISSUES; MORE THAN 90% OF THE TISSUES WITH TELOMERE LENGTH > OR = 0.50 WERE ADJACENT NON-TUMOR TISSUES. THE CORRELATIONS BETWEEN TELOMERE LENGTH AND AFLATOXIN B1- AND POLYCYCLIC AROMATIC HYDROCARBON-DNA ADDUCTS LEVEL, P53 MUTATIONS AND P16 HYPERMETHYLATION STATUS WERE ALSO TESTED, BUT NO SIGNIFICANT ASSOCIATIONS WERE FOUND. THE RELATIONSHIP BETWEEN TELOMERE LENGTH SHORTENING, CHEMICAL CARCINOGEN EXPOSURE, AND GENETIC AND EPIGENETIC CHANGES IN HEPATOCARCINOGENESIS NEEDS FURTHER INVESTIGATION.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  2940  43 GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL AND SENSITIVE COPD-DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5). EVEN THOUGH CLINICAL, EPIDEMIOLOGICAL AND TOXICOLOGICAL STUDIES HAVE PROGRESSIVELY PROVIDED A BETTER KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS, FURTHER IN VITRO STUDIES ON RELEVANT CELL SYSTEMS ARE STILL NEEDED. HENCE, AIMING OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS, PRIMARY HUMAN BRONCHIAL EPITHELIAL CELLS DERIVED FROM NORMAL SUBJECTS (NHBE) OR SENSITIVE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED PATIENTS (DHBE) WERE DIFFERENTIATED AT THE AIR-LIQUID INTERFACE. THEREAFTER, THEY WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) TO STUDY THE OCCURRENCE OF SOME RELEVANT GENETIC AND/OR EPIGENETIC ENDPOINTS. CONCENTRATION-, EXPOSURE- AND SEASON-DEPENDENT INCREASES OF OH-B[A]P METABOLITES IN NHBE, AND TO A LESSER EXTENT, COPD-DHBE CELLS WERE REPORTED; HOWEVER, THERE WERE MORE TETRA-OH-B[A]P AND 8-OHDG DNA ADDUCTS IN COPD-DHBE CELLS. NO INCREASE IN PRIMARY DNA STRAND BREAK NOR CHROMOSOMAL ABERRATION WAS OBSERVED IN REPEATEDLY EXPOSED CELLS. TELOMERE LENGTH AND TELOMERASE ACTIVITY WERE MODIFIED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN NHBE AND PARTICULARLY COPD-DHBE CELLS. THERE WERE A GLOBAL DNA HYPOMETHYLATION, A P16 GENE PROMOTER HYPERMETHYLATION, AND A DECREASING DNA METHYLTRANSFERASE ACTIVITY IN NHBE AND NOTABLY COPD-DHBE CELLS REPEATEDLY EXPOSED. CHANGES IN SITE-SPECIFIC METHYLATION, ACETYLATION, AND PHOSPHORYLATION OF HISTONE H3 (I.E., H3K4ME3, H3K9AC, H3K27AC, AND H3S10PH) AND RELATED ENZYME ACTIVITIES OCCURRED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN ALL THE REPEATEDLY EXPOSED CELLS. COLLECTIVELY, THESE RESULTS HIGHLIGHTED THE KEY ROLE PLAYED BY GENETIC AND EVEN EPIGENETIC EVENTS IN NHBE AND PARTICULARLY SENSITIVE COPD-DHBE CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) AND THEIR DIFFERENT RESPONSIVENESS. WHILE THESE SPECIFIC EPIGENETIC CHANGES HAVE BEEN ALREADY DESCRIBED IN COPD AND EVEN LUNG CANCER PHENOTYPES, OUR FINDINGS SUPPORTED THAT, TOGETHER WITH GENETIC EVENTS, THESE EPIGENETIC EVENTS COULD DRAMATICALLY CONTRIBUTE TO THE SHIFT FROM HEALTHY TO DISEASED PHENOTYPES FOLLOWING REPEATED EXPOSURE TO RELATIVELY LOW DOSES OF AIR POLLUTION-DERIVED PM(2.5).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16  6492  46 TRAFFIC-RELATED AIR POLLUTION AND GROUND-LEVEL OZONE ASSOCIATED GLOBAL DNA HYPOMETHYLATION AND BULKY DNA ADDUCT FORMATION. STUDIES HAVE INDICATED THAT AIR POLLUTION, INCLUDING SURFACE-LEVEL OZONE (O(3)), CAN SIGNIFICANTLY INFLUENCE THE RISK OF CHRONIC DISEASES. TO BETTER UNDERSTAND THE CARCINOGENIC MECHANISMS OF AIR POLLUTANTS AND IDENTIFY PREDICTIVE DISEASE BIOMARKERS, WE EXAMINED THE ASSOCIATION BETWEEN TRAFFIC-RELATED POLLUTANTS WITH DNA METHYLATION ALTERATIONS AND BULKY DNA ADDUCTS, TWO BIOMARKERS OF CARCINOGEN EXPOSURE AND CANCER RISK, IN THE PERIPHERAL BLOOD OF 140 VOLUNTEERS-95 TRAFFIC POLICE OFFICERS, AND 45 UNEXPOSED SUBJECTS. THE DNA METHYLATION AND ADDUCT MEASUREMENTS WERE PERFORMED BY BISULFITE-PCR AND PYROSEQUENCING AND (32)P-POSTLABELING ASSAY. AIRBORNE LEVELS OF BENZO(A)PYRENE [B(A)P], CARBON MONOXIDE, AND TROPOSPHERIC O(3) WERE DETERMINED BY PERSONAL EXPOSURE BIOMONITORING OR BY FIXED MONITORING STATIONS. OVERALL, AIR POLLUTION EXPOSURE WAS ASSOCIATED WITH A SIGNIFICANT REDUCTION (1.41 UNITS) IN GLOBAL DNA METHYLATION (95% C.I. -2.65-0.04, P = 0.026). THE DECREMENT IN ALU REPETITIVE ELEMENTS WAS GREATEST IN THE POLICEMEN WORKING DOWNTOWN (95% C.I. -3.23--0.49, P = 0.008). THE DNA ADDUCTS WERE FOUND TO BE SIGNIFICANTLY INCREASED (0.45 UNITS) IN THE MUNICIPAL OFFICERS WITH RESPECT TO UNEXPOSED SUBJECTS (95% C.I. 0.02-0.88, P = 0.039), MAINLY IN THOSE WHO WERE CONTROLLING TRAFFIC IN DOWNTOWN AREAS (95% C.I. 0.39-1.29, P < 0.001). REGRESSION MODELS INDICATED AN INCREMENT OF ALU METHYLATION AT HIGHER B(A)P CONCENTRATIONS (95% C.I. 0.03-0.60, P = 0.032). MOREOVER, STATISTICAL MODELS SHOWED A DECREMENT IN ALU METHYLATION AND AN INCREMENT OF DNA DAMAGE ONLY ABOVE THE CUT-OFF VALUE OF 30 MICROG/M(3) O(3). A SIGNIFICANT INCREMENT OF 0.73 UNITS OF IL-6 GENE METHYLATION WAS ALSO FOUND IN SMOKERS WITH RESPECT TO NON-SMOKERS. OUR RESULTS HIGHLIGHTED THE ROLE OF AIR POLLUTION ON EPIGENETIC ALTERATIONS AND GENOTOXIC EFFECTS, ESPECIALLY ABOVE THE TARGET VALUE OF 30 MICROG/M(3) SURFACE-LEVEL O(3), SUPPORTING THE NECESSITY FOR DEVELOPING PUBLIC HEALTH STRATEGIES AIMED TO REDUCE TRAFFIC-RELATED AIR POLLUTION MOLECULAR ALTERATIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17  1787  32 EFFECT OF CHRONIC ALCOHOL EXPOSURE ON GUT VITAMIN B7 UPTAKE: INVOLVEMENT OF EPIGENETIC MECHANISMS AND EFFECT OF ALCOHOL METABOLITES. VITAMIN B7 (BIOTIN) IS ESSENTIAL FOR NORMAL HEALTH AND ITS DEFICIENCY/SUBOPTIMAL LEVELS OCCUR IN A VARIETY OF CONDITIONS INCLUDING CHRONIC ALCOHOLISM. MAMMALS, INCLUDING HUMANS, OBTAIN BIOTIN FROM DIET AND GUT-MICROBIOTA VIA ABSORPTION ALONG THE INTESTINAL TRACT. THE ABSORPTION PROCESS IS CARRIER MEDIATED AND INVOLVES THE SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER (SMVT; SLC5A6). WE HAVE PREVIOUSLY SHOWN THAT CHRONIC ALCOHOL EXPOSURE SIGNIFICANTLY INHIBITS INTESTINAL/COLONIC BIOTIN UPTAKE VIA SUPPRESSION OF SLC5A6 TRANSCRIPTION IN ANIMAL AND CELL LINE MODELS. HOWEVER, LITTLE IS KNOWN ABOUT THE TRANSCRIPTIONAL/EPIGENETIC FACTORS THAT MEDIATE THIS SUPPRESSION. IN ADDITION, THE EFFECT OF ALCOHOL METABOLITES (GENERATED VIA ALCOHOL METABOLISM BY GUT MICROBIOTA AND HOST TISSUES) ON BIOTIN UPTAKE IS STILL UNKNOWN. TO ADDRESS THESE QUESTIONS, WE FIRST DEMONSTRATED THAT CHRONIC ALCOHOL EXPOSURE INHIBITS SMALL INTESTINAL AND COLONIC BIOTIN UPTAKE AND SMVT EXPRESSION IN HUMAN DIFFERENTIATED ENTEROID AND COLONOID MONOLAYERS. WE THEN SHOWED THAT CHRONIC ALCOHOL EXPOSURES OF BOTH, CACO-2 CELLS AND MICE, ARE ASSOCIATED WITH A SIGNIFICANT SUPPRESSION IN EXPRESSION OF THE NUCLEAR FACTOR KLF-4 (NEEDED FOR SLC5A6 PROMOTER ACTIVITY), AS WELL AS WITH EPIGENETIC ALTERATIONS (HISTONE MODIFICATIONS). WE ALSO FOUND THAT CHRONIC EXPOSURE OF NCM460 HUMAN COLONIC EPITHELIAL CELLS AS WELL AS HUMAN DIFFERENTIATED COLONOID MONOLAYERS, TO ALCOHOL METABOLITES (ACETALDEHYDE, ETHYL PALMITATE, ETHYL OLEATE) SIGNIFICANTLY INHIBITED BIOTIN UPTAKE AND SMVT EXPRESSION. THESE FINDINGS SHED LIGHT ONTO THE MOLECULAR/EPIGENETIC MECHANISMS THAT MEDIATE THE INHIBITORY EFFECT OF CHRONIC ALCOHOL EXPOSURE ON INTESTINAL BIOTIN UPTAKE. THEY FURTHER SHOW THAT ALCOHOL METABOLITES ARE ALSO CAPABLE OF INHIBITING BIOTIN UPTAKE IN THE GUT.NEW & NOTEWORTHY USING COMPLEMENTARY MODELS, INCLUDING HUMAN DIFFERENTIATED ENTEROID AND COLONOID MONOLAYERS, THIS STUDY SHOWS THE INVOLVEMENT OF MOLECULAR AND EPIGENETIC MECHANISMS IN MEDIATING THE INHIBITORY EFFECT OF CHRONIC ALCOHOL EXPOSURE ON BIOTIN UPTAKE ALONG THE INTESTINAL TRACT. THE STUDY ALSO SHOWS THAT ALCOHOL METABOLITES (GENERATED BY GUT MICROBIOTA AND HOST TISSUES) CAUSE INHIBITION IN GUT BIOTIN UPTAKE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18  1189  45 CORRELATION BETWEEN GLOBAL METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES AND SERUM C REACTIVE PROTEIN LEVEL MODIFIED BY MTHFR POLYMORPHISM: A CROSS-SECTIONAL STUDY. BACKGROUND: CHRONIC INFLAMMATORY CONDITIONS ARE ASSOCIATED WITH HIGHER TUMOR INCIDENCE THROUGH EPIGENETIC AND GENETIC ALTERATIONS. HERE, WE FOCUSED ON AN ASSOCIATION BETWEEN AN INFLAMMATION MARKER, C-REACTIVE-PROTEIN (CRP), AND GLOBAL DNA METHYLATION LEVELS OF PERIPHERAL BLOOD LEUKOCYTES. METHODS: THE SUBJECTS WERE 384 HEALTHY JAPANESE WOMEN ENROLLED AS THE CONTROL GROUP OF A CASE-CONTROL STUDY FOR BREAST CANCER CONDUCTED FROM 2001 TO 2005. GLOBAL DNA METHYLATION WAS QUANTIFIED BY LUMINOMETRIC METHYLATION ASSAY (LUMA). RESULTS: WITH ADJUSTMENT FOR LIFESTYLE-RELATED FACTORS, INCLUDING FOLATE INTAKE, THE GLOBAL DNA METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES WAS SIGNIFICANTLY BUT WEAKLY INCREASED BY 0.43% PER QUARTILE CATEGORY FOR CRP (P FOR TREND = 0.010). ESTIMATED METHYLATION LEVELS STRATIFIED BY CRP QUARTILE WERE 70.0%, 70.8%, 71.4%, AND 71.3%, RESPECTIVELY. IN ADDITION, INTERACTION BETWEEN POLYMORPHISM OF MTHFR (RS1801133, KNOWN AS C677T) AND CRP WAS SIGNIFICANT (P FOR INTERACTION = 0.046); THE GLOBAL METHYLATION LEVEL WAS SIGNIFICANTLY INCREASED BY 0.61% PER QUARTILE CATEGORY FOR CRP IN THE CT/TT GROUP (THOSE WITH THE MINOR ALLELE T, P FOR TREND = 0.001), WHEREAS NO ASSOCIATION WAS OBSERVED IN THE CC GROUP (WILD TYPE). CONCLUSIONS: OUR STUDY SUGGESTS THAT CRP CONCENTRATION IS WEAKLY ASSOCIATED WITH GLOBAL DNA METHYLATION LEVEL. HOWEVER, THIS ASSOCIATION WAS OBSERVED MORE CLEARLY IN INDIVIDUALS WITH THE MINOR ALLELE OF THE MTHFR MISSENSE SNP RS1801133. BY ELUCIDATING THE COMPLEX MECHANISM OF THE REGULATION OF DNA METHYLATION BY BOTH ACQUIRED AND GENETIC FACTORS, OUR RESULTS MAY BE IMPORTANT FOR CANCER PREVENTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19  3939  22 LNC-IL7R ALLEVIATES PM(2.5)-MEDIATED CELLULAR SENESCENCE AND APOPTOSIS THROUGH EZH2 RECRUITMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: LONG-TERM EXPOSURE TO PM(2.5) (PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER OF </= 2.5 MUM) IS ASSOCIATED WITH PULMONARY INJURY AND EMPHYSEMA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE INVESTIGATED MECHANISMS THROUGH WHICH THE LONG NONCODING RNA LNC-IL7R CONTRIBUTES TO CELLULAR DAMAGE BY INDUCING OXIDATIVE STRESS IN COPD PATIENTS EXPOSED TO PM(2.5). METHODS: ASSOCIATIONS OF SERUM LNC-IL7R LEVELS WITH LUNG FUNCTION, EMPHYSEMA, AND PREVIOUS PM(2.5) EXPOSURE IN COPD PATIENTS WERE ANALYZED. REACTIVE OXYGEN SPECIES AND LNC-IL7R LEVELS WERE MEASURED IN PM(2.5)-TREATED CELLS. THE LEVELS OF LNC-IL7R AND CELLULAR SENESCENCE-ASSOCIATED GENES, NAMELY P16(INK4A) AND P21(CIP1/WAF1), WERE DETERMINED THROUGH LUNG TISSUE SECTION STAINING. THE EFFECTS OF P16(INK4A) OR P21(CIP1/WAF1) REGULATION WERE EXAMINED BY PERFORMING LNC-IL7R OVEREXPRESSION AND KNOCKDOWN ASSAYS. THE FUNCTIONS OF LNC-IL7R-MEDIATED CELL PROLIFERATION, CELL CYCLE, SENESCENCE, COLONY FORMATION, AND APOPTOSIS WERE EXAMINED IN CELLS TREATED WITH PM(2.5). CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE CONDUCTED TO INVESTIGATE THE EPIGENETIC REGULATION OF P21(CIP1/WAF1). RESULTS: LNC-IL7R LEVELS DECREASED IN COPD PATIENTS AND WERE NEGATIVELY CORRELATED WITH EMPHYSEMA OR PM(2.5) EXPOSURE. LNC-IL7R LEVELS WERE UPREGULATED IN NORMAL LUNG EPITHELIAL CELLS BUT NOT IN COPD CELLS EXPOSED TO PM(2.5). LOWER LNC-IL7R EXPRESSION IN PM(2.5)-TREATED CELLS INDUCED P16(INK4A) AND P21(CIP1/WAF1) EXPRESSION BY INCREASING OXIDATIVE STRESS. HIGHER LNC-IL7R EXPRESSION PROTECTED AGAINST CELLULAR SENESCENCE AND APOPTOSIS, WHEREAS LOWER LNC-IL7R EXPRESSION AUGMENTED INJURY IN PM(2.5)-TREATED CELLS. LNC-IL7R AND THE ENHANCER OF ZESTE HOMOLOG 2 (EZH2) SYNERGISTICALLY SUPPRESSED P21(CIP1/WAF1) EXPRESSION THROUGH EPIGENETIC MODULATION. CONCLUSION: LNC-IL7R ATTENUATES PM(2.5)-MEDIATED P21(CIP1/WAF1) EXPRESSION THROUGH EZH2 RECRUITMENT, AND ITS DYSFUNCTION MAY AUGMENT CELLULAR INJURY IN COPD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  2734  40 EXPLORING THE RELATIONSHIP BETWEEN DNA METHYLATION AGE MEASURES AND PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN WITH EARLY-STAGE BREAST CANCER. PURPOSE: THE EPIGENETIC CLOCK HAS BEEN ACKNOWLEDGED AS AN INDICATOR FOR MOLECULAR AGING, BUT FEW STUDIES HAVE EXAMINED POSSIBLE ASSOCIATIONS OF DNA METHYLATION (DNAM) AGE OR AGE ACCELERATION (AA) WITH SYMPTOM BURDEN IN INDIVIDUALS WHO ARE TREATED FOR CANCER. THIS STUDY EXPLORED THE ASSOCIATION OF DNAM AGE OR AA WITH PSYCHONEUROLOGICAL (PN) SYMPTOMS, INCLUDING COGNITIVE IMPAIRMENT, FATIGUE, SLEEP DISTURBANCES, PAIN, AND DEPRESSIVE SYMPTOMS, IN BREAST CANCER SURVIVORS OVER A 2-YEAR PERIOD. METHODS: WE MEASURED PN SYMPTOMS USING RELIABLE INSTRUMENTS AND DNAM LEVELS BY INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 72). DNAM AGE WAS CALCULATED BY THE HORVATH, GRIM, AND HANNUM-BASED INTRINSIC AND EXTRINSIC AGE ESTIMATIONS. AA WAS DEFINED BY THE RESIDUAL REGRESSING ESTIMATED EPIGENETIC AGE ON CHRONOLOGICAL AGE. MIXED REGRESSION MODELS WERE FITTED FOR AA AND CHANGES IN AA TO STUDY THE ASSOCIATION OVER TIME. SEPARATE LINEAR REGRESSION MODELS AND A MIXED-EFFECTS MODEL WERE FITTED FOR AA AT EACH TIME POINT. RESULTS: HORVATH-AA, GRIM-AA, AND EXTRINSIC EPIGENETIC AA WERE SIGNIFICANTLY CHANGED OVER TIME, WHILE INTRINSIC EPIGENETIC AA DID NOT EXHIBIT ANY TEMPORAL CHANGES. INCREASED AA WAS ASSOCIATED WITH GREATER ANXIETY AND FATIGUE, AS WELL AS WORSE COGNITIVE MEMORY, ADJUSTING FOR RACE, BMI, INCOME, CHEMOTHERAPY, RADIATION THERAPY, AND CHRONOLOGICAL AGE. INCREASED DNAM AGE WAS ASSOCIATED WITH GREATER ANXIETY OVER 2 YEARS. CONCLUSION: OUR FINDINGS SUGGEST DNAM AGE AND AA MAY BE ASSOCIATED WITH PN SYMPTOMS OVER THE COURSE OF CANCER TREATMENT AND SURVIVORSHIP. SOME PN SYMPTOMS MAY BE AMENABLE TO PREVENTIVE INTERVENTIONS TARGETED TO EPIGENETIC CLOCKS THAT INFLUENCE AGING-ASSOCIATED PROCESSES.	2022