1  4267 126 MICROARRAY DATASET OF TRANSIENT AND PERMANENT DNA METHYLATION CHANGES IN HELA CELLS UNDERGOING INORGANIC ARSENIC-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION. THE NOVEL DATASET PRESENTED HERE REPRESENTS THE RESULTS OF THE CHANGING PATTERN OF DNA METHYLATION PROFILES IN HELA CELLS EXPOSED TO CHRONIC LOW DOSE (0.5 MICROM) SODIUM ARSENITE, RESULTING IN EPITHELIAL-TO-MESENCHYMAL TRANSITION, AS WELL AS DNA METHYLATION PATTERNS IN CELLS WHERE INORGANIC ARSENIC HAS BEEN REMOVED. INORGANIC ARSENIC IS A KNOWN CARCINOGEN, THOUGH NOT MUTAGENIC. SEVERAL MECHANISMS HAVE BEEN PROPOSED AS TO HOW INORGANIC ARSENIC DRIVES CARCINOGENESIS SUCH AS REGULATION OF THE CELL?S REDOX POTENTIAL AND/OR EPIGENETICS. IN FACT, THERE ARE GENE SPECIFIC STUDIES AND LIMITED GENOME-WIDE STUDIES THAT HAVE IMPLICATED EPIGENETIC FACTORS SUCH AS DNA METHYLATION IN INORGANIC ARSENIC-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT). HOWEVER, GENOME-WIDE STUDIES ABOUT THE IMPACT OF 1) CHRONIC, LOW-DOSE INORGANIC ARSENIC EXPOSURE ON DNA METHYLATION PATTERNS DURING INORGANIC ARSENIC-INDUCED EPITHELIAL-TO-MESENCHYMAL TRANSITION, AND 2) THE REMOVAL INORGANIC ARSENIC (REVERSAL) ON DNA METHYLATION PATTERNS, IS LACKING. FOR THIS DATASET, TWO REPLICATES WERE PERFORMED WITH EACH OF THE SAMPLES - NON-TREATED, INORGANIC ARSENIC-TREATED, AND REVERSE-TREATED CELLS. WE PROVIDE NORMALIZED AND PROCESSED DATA, AND LOG2 FOLD CHANGE IN DNA METHYLATION. THE RAW MICROARRAY DATA ARE AVAILABLE THROUGH NCBI GEO, ACCESSION NUMBER GSE95232 AND A RELATED RESEARCH PAPER HAS BEEN ACCEPTED FOR PUBLISHED IN TOXICOLOGY AND APPLIED PHARMACOLOGY (ECKSTEIN ET AL., 2017) [1].	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  6562  51 TRANSIENT AND PERMANENT CHANGES IN DNA METHYLATION PATTERNS IN INORGANIC ARSENIC-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION. CHRONIC LOW DOSE INORGANIC ARSENIC EXPOSURE CAUSES CELLS TO TAKE ON AN EPITHELIAL-TO-MESENCHYMAL PHENOTYPE, WHICH IS A CRUCIAL PROCESS IN CARCINOGENESIS. INORGANIC ARSENIC IS NOT A MUTAGEN AND THUS EPIGENETIC ALTERATIONS HAVE BEEN IMPLICATED IN THIS PROCESS. INDEED, DURING THE EPITHELIAL-TO-MESENCHYMAL TRANSITION, MORPHOLOGIC CHANGES TO CELLS CORRELATE WITH CHANGES IN CHROMATIN STRUCTURE AND GENE EXPRESSION, ULTIMATELY DRIVING THIS PROCESS. HOWEVER, STUDIES ON THE EFFECTS OF INORGANIC ARSENIC EXPOSURE/WITHDRAWAL ON THE EPITHELIAL-TO-MESENCHYMAL TRANSITION AND THE IMPACT OF EPIGENETIC ALTERATIONS IN THIS PROCESS ARE LIMITED. IN THIS STUDY WE USED HIGH-RESOLUTION MICROARRAY ANALYSIS TO MEASURE THE CHANGES IN DNA METHYLATION IN CELLS UNDERGOING INORGANIC ARSENIC-INDUCED EPITHELIAL-TO-MESENCHYMAL TRANSITION, AND ON THE REVERSAL OF THIS PROCESS, AFTER REMOVAL OF THE INORGANIC ARSENIC EXPOSURE. WE FOUND THAT CELLS EXPOSED TO CHRONIC, LOW-DOSE INORGANIC ARSENIC EXPOSURE SHOWED 30,530 SITES WERE DIFFERENTIALLY METHYLATED, AND WITH INORGANIC ARSENIC WITHDRAWAL SEVERAL DIFFERENTIAL METHYLATED SITES WERE REVERSED, ALBEIT NOT COMPLETELY. FURTHERMORE, THESE CHANGES IN DNA METHYLATION MAINLY CORRELATED WITH CHANGES IN GENE EXPRESSION AT MOST SITES TESTED BUT NOT AT ALL. THIS STUDY SUGGESTS THAT DNA METHYLATION CHANGES ON GENE EXPRESSION ARE NOT CLEAR-CUT AND PROVIDE A PLATFORM TO BEGIN TO UNCOVER THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION, SPECIFICALLY WITHIN THE CONTEXT OF INORGANIC ARSENIC TREATMENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3  2961  34 GENETIC AND EPIGENETIC MECHANISMS IN METAL CARCINOGENESIS AND COCARCINOGENESIS: NICKEL, ARSENIC, AND CHROMIUM. CHRONIC EXPOSURE TO NICKEL(II), CHROMIUM(VI), OR INORGANIC ARSENIC (IAS) HAS LONG BEEN KNOWN TO INCREASE CANCER INCIDENCE AMONG AFFECTED INDIVIDUALS. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND THAT CARCINOGENIC RISKS ASSOCIATED WITH CHROMATE AND IAS EXPOSURES WERE SUBSTANTIALLY HIGHER THAN PREVIOUSLY THOUGHT, WHICH LED TO MAJOR REVISIONS OF THE FEDERAL STANDARDS REGULATING AMBIENT AND DRINKING WATER LEVELS. GENOTOXIC EFFECTS OF CR(VI) AND IAS ARE STRONGLY INFLUENCED BY THEIR INTRACELLULAR METABOLISM, WHICH CREATES SEVERAL REACTIVE INTERMEDIATES AND BYPRODUCTS. TOXIC METALS ARE CAPABLE OF POTENT AND SURPRISINGLY SELECTIVE ACTIVATION OF STRESS-SIGNALING PATHWAYS, WHICH ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF HUMAN CANCERS. DEPENDING ON THE METAL, ASCORBATE (VITAMIN C) HAS BEEN FOUND TO ACT EITHER AS A STRONG ENHANCER OR SUPPRESSOR OF TOXIC RESPONSES IN HUMAN CELLS. IN ADDITION TO GENETIC DAMAGE VIA BOTH OXIDATIVE AND NONOXIDATIVE (DNA ADDUCTS) MECHANISMS, METALS CAN ALSO CAUSE SIGNIFICANT CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS, LEADING TO EPIGENETIC SILENCING OR REACTIVATION OF GENE EXPRESSION. IN VITRO GENOTOXICITY EXPERIMENTS AND RECENT ANIMAL CARCINOGENICITY STUDIES PROVIDED STRONG SUPPORT FOR THE IDEA THAT METALS CAN ACT AS COCARCINOGENS IN COMBINATION WITH NONMETAL CARCINOGENS. COCARCINOGENIC AND COMUTAGENIC EFFECTS OF METALS ARE LIKELY TO STEM FROM THEIR ABILITY TO INTERFERE WITH DNA REPAIR PROCESSES. OVERALL, METAL CARCINOGENESIS APPEARS TO REQUIRE THE FORMATION OF SPECIFIC METAL COMPLEXES, CHROMOSOMAL DAMAGE, AND ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS PROMOTING SURVIVAL AND EXPANSION OF GENETICALLY/EPIGENETICALLY ALTERED CELLS.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4   477  25 ARSENIC PROJECTS IN SE ASIA. EARLY LIFE EXPOSURE TO INORGANIC ARSENIC IS ASSOCIATED WITH A WIDE RANGE OF MALIGNANT AND CHRONIC DISEASE OUTCOMES IN HUMANS. PRENATAL ARSENIC EXPOSURE MAY GIVE RISE TO ADVERSE EFFECTS ON CHILD HEALTH AND DEVELOPMENT AS ARSENIC READILY PASSES THROUGH THE PLACENTA IN HUMAN BEINGS. THE IMPACT OF MATERNAL ARSENIC EXPOSURE ON FETAL GENE EXPRESSION WAS CONDUCTED IN PREGNANT WOMEN LIVING IN SOUTHERN THAILAND. ARSENIC EXPOSED NEWBORNS HAD SIGNIFICANTLY HIGHER LEVELS OF ARSENIC IN CORD BLOOD, AND A SET OF GENES ASSOCIATED WITH NUMEROUS BIOLOGICAL PATHWAYS, INCLUDING CELL SIGNALING, APOPTOSIS, INFLAMMATORY AND STRESS RESPONSE. A SLIGHT INCREASE IN PROMOTER METHYLATION OF P53 IN CORD BLOOD LYMPHOCYTES WHICH CORRELATED WITH ARSENIC ACCUMULATION IN NAILS WAS OBSERVED IN THESE EXPOSED NEWBORNS. A FOLLOW-UP STUDY ON THESE EXPOSED CHILDREN SHOWED A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE, MEASURED AS 8-HYDROXYDEOXYGUANOSINE (8-OHDG) IN SALIVA. IN ADDITION, LEVELS OF URINARY 8-OHDG EXCRETION AND SALIVARY HOGG1 EXPRESSION WERE SIGNIFICANTLY DECREASED IN EXPOSED CHILDREN SUGGESTING A DEFECT IN REPAIR OF 8-OHDG IN ARSENIC-EXPOSED CHILDREN. OUR STUDY INDICATES THAT PRENATAL ARSENIC AND CONTINUED EXPOSURE THROUGH EARLY CHILDHOOD CAN TRIGGER VARIOUS GENETIC AND EPIGENETIC ALTERATIONS THAT MAY LEAD TO DISEASE DEVELOPMENT LATER IN LIFE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5   474  24 ARSENIC BIOTRANSFORMATION AS A CANCER PROMOTING FACTOR BY INDUCING DNA DAMAGE AND DISRUPTION OF REPAIR MECHANISMS. CHRONIC EXPOSURE TO ARSENIC IN DRINKING WATER POSES A MAJOR GLOBAL HEALTH CONCERN. POPULATIONS EXPOSED TO HIGH CONCENTRATIONS OF ARSENIC-CONTAMINATED DRINKING WATER SUFFER SERIOUS HEALTH CONSEQUENCES, INCLUDING ALARMING CANCER INCIDENCE AND DEATH RATES. ARSENIC IS BIOTRANSFORMED THROUGH SEQUENTIAL ADDITION OF METHYL GROUPS, ACQUIRED FROM S-ADENOSYLMETHIONINE (SAM). METABOLISM OF ARSENIC GENERATES A VARIETY OF GENOTOXIC AND CYTOTOXIC SPECIES, DAMAGING DNA DIRECTLY AND INDIRECTLY, THROUGH THE GENERATION OF REACTIVE OXIDATIVE SPECIES AND INDUCTION OF DNA ADDUCTS, STRAND BREAKS AND CROSS LINKS, AND INHIBITION OF THE DNA REPAIR PROCESS ITSELF. SINCE SAM IS THE METHYL GROUP DONOR USED BY DNA METHYLTRANSFERASES TO MAINTAIN NORMAL EPIGENETIC PATTERNS IN ALL HUMAN CELLS, ARSENIC IS ALSO POSTULATED TO AFFECT MAINTENANCE OF NORMAL DNA METHYLATION PATTERNS, CHROMATIN STRUCTURE, AND GENOMIC STABILITY. THE BIOLOGICAL PROCESSES UNDERLYING THE CANCER PROMOTING FACTORS OF ARSENIC METABOLISM, RELATED TO DNA DAMAGE AND REPAIR, WILL BE DISCUSSED HERE.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6   502  35 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	

7   490  31 ASSESSING THE IMPACT OF ARSENIC METABOLISM EFFICIENCY ON DNA METHYLATION USING MENDELIAN RANDOMIZATION. BACKGROUND: ARSENIC EXPOSURE AFFECTS >100 MILLION PEOPLE GLOBALLY AND INCREASES RISK FOR CHRONIC DISEASES. ONE POSSIBLE TOXICITY MECHANISM IS EPIGENETIC MODIFICATION. PREVIOUS EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) HAVE IDENTIFIED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG-SPECIFIC DNA METHYLATION. TO PROVIDE ADDITIONAL EVIDENCE THAT OBSERVED ASSOCIATIONS REPRESENT CAUSAL RELATIONSHIPS, WE EXAMINE THE ASSOCIATION BETWEEN GENETIC DETERMINANTS OF ARSENIC METABOLISM EFFICIENCY (PERCENT DIMETHYLARSINIC ACID, DMA%, IN URINE) AND DNA METHYLATION AMONG INDIVIDUALS FROM THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (N = 379) AND BANGLADESH VITAMIN E AND SELENIUM TRIAL (N = 393). METHODS: WE USED MULTIVARIATE LINEAR MODELS TO ASSESS THE ASSOCIATION OF METHYLATION AT 221 ARSENIC-ASSOCIATED CPGS WITH DMA% AND MEASURES OF GENETICALLY PREDICTED DMA% DERIVED FROM THREE SNPS (RS9527, RS11191527, AND RS61735836). WE ALSO CONDUCTED TWO-SAMPLE MENDELIAN RANDOMIZATION ANALYSES TO ESTIMATE THE ASSOCIATION BETWEEN ARSENIC METABOLISM EFFICIENCY AND CPG METHYLATION. RESULTS: AMONG THE ASSOCIATIONS BETWEEN DMA% AND METHYLATION AT EACH OF 221 CPGS, 64% WERE DIRECTIONALLY CONSISTENT WITH ASSOCIATIONS OBSERVED BETWEEN ARSENIC EXPOSURE AND THE 221 CPGS FROM A PRIOR EWAS. SIMILARLY, AMONG THE ASSOCIATIONS BETWEEN GENETICALLY PREDICTED DMA% AND EACH CPG, 62% WERE DIRECTIONALLY CONSISTENT WITH THE PRIOR EWAS RESULTS. TWO-SAMPLE MENDELIAN RANDOMIZATION ANALYSES PRODUCED SIMILAR CONCLUSIONS. CONCLUSION: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT ARSENIC EXPOSURE EFFECTS DNA METHYLATION AT SPECIFIC CPGS IN WHOLE BLOOD. OUR NOVEL APPROACH FOR ASSESSING THE IMPACT OF ARSENIC EXPOSURE ON DNA METHYLATION REQUIRES LARGER SAMPLES IN ORDER TO DRAW MORE ROBUST CONCLUSIONS FOR SPECIFIC CPG SITES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8  4840  30 ONCOGENOMIC DISRUPTIONS IN ARSENIC-INDUCED CARCINOGENESIS. CHRONIC EXPOSURE TO ARSENIC AFFECTS MORE THAN 200 MILLION PEOPLE WORLDWIDE, AND HAS BEEN ASSOCIATED WITH MANY ADVERSE HEALTH EFFECTS, INCLUDING CANCER IN SEVERAL ORGANS. THERE IS ACCUMULATING EVIDENCE THAT ARSENIC BIOTRANSFORMATION, A STEP IN THE ELIMINATION OF ARSENIC FROM THE HUMAN BODY, CAN INDUCE CHANGES AT A GENETIC AND EPIGENETIC LEVEL, LEADING TO CARCINOGENESIS. AT THE GENETIC LEVEL, ARSENIC INTERFERES WITH KEY CELLULAR PROCESSES SUCH AS DNA DAMAGE-REPAIR AND CHROMOSOMAL STRUCTURE, LEADING TO GENOMIC INSTABILITY. AT THE EPIGENETIC LEVEL, ARSENIC PLACES A HIGH DEMAND ON THE CELLULAR METHYL POOL, LEADING TO GLOBAL HYPOMETHYLATION AND HYPERMETHYLATION OF SPECIFIC GENE PROMOTERS. THESE ARSENIC-ASSOCIATED DNA ALTERATIONS RESULT IN THE DEREGULATION OF BOTH ONCOGENIC AND TUMOUR-SUPPRESSIVE GENES. FURTHERMORE, RECENT REPORTS HAVE IMPLICATED ABERRANT EXPRESSION OF NON-CODING RNAS AND THE CONSEQUENTIAL DISRUPTION OF SIGNALING PATHWAYS IN THE CONTEXT OF ARSENIC-INDUCED CARCINOGENESIS. THIS ARTICLE PROVIDES AN OVERVIEW OF THE ONCOGENOMIC ANOMALIES ASSOCIATED WITH ARSENIC EXPOSURE AND CONVEYS THE IMPORTANCE OF NON-CODING RNAS IN THE ARSENIC-INDUCED CARCINOGENIC PROCESS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9   633  23 BIOLOGICAL EFFECTS AND EPIDEMIOLOGICAL CONSEQUENCES OF ARSENIC EXPOSURE, AND REAGENTS THAT CAN AMELIORATE ARSENIC DAMAGE IN VIVO. THROUGH CONTAMINATED DIET, WATER, AND OTHER FORMS OF ENVIRONMENTAL EXPOSURE, ARSENIC AFFECTS HUMAN HEALTH. THERE ARE MANY U.S. AND WORLDWIDE "HOT SPOTS" WHERE THE ARSENIC LEVEL IN PUBLIC WATER EXCEEDS THE MAXIMUM EXPOSURE LIMIT. THE BIOLOGICAL EFFECTS OF CHRONIC ARSENIC EXPOSURE INCLUDE GENERATION OF REACTIVE OXYGEN SPECIES (ROS), LEADING TO OXIDATIVE STRESS AND DNA DAMAGE, EPIGENETIC DNA MODIFICATION, INDUCTION OF GENOMIC INSTABILITY, AND INFLAMMATION AND IMMUNOMODULATION, ALL OF WHICH CAN INITIATE CARCINOGENESIS. HIGH ARSENIC EXPOSURE IS EPIDEMIOLOGICALLY ASSOCIATED WITH SKIN, LUNG, BLADDER, LIVER, KIDNEY AND PANCREATIC CANCER, AND CARDIOVASCULAR, NEURONAL, AND OTHER DISEASES. THIS REVIEW BRIEFLY SUMMARIZES THE BIOLOGICAL EFFECTS OF ARSENIC EXPOSURE AND EPIDEMIOLOGICAL CANCER STUDIES WORLDWIDE, AND PROVIDES AN OVERVIEW FOR EMERGING RODENT-BASED STUDIES OF REAGENTS THAT CAN AMELIORATE THE EFFECTS OF ARSENIC EXPOSURE IN VIVO. THESE REAGENTS MAY BE TRANSLATED TO HUMAN POPULATIONS FOR DISEASE PREVENTION. WE PROPOSE THE IMPORTANCE OF DEVELOPING A BIOMARKER-BASED PRECISION PREVENTION APPROACH FOR THE HEALTH ISSUES ASSOCIATED WITH ARSENIC EXPOSURE THAT AFFECTS MILLIONS OF PEOPLE WORLDWIDE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10  6553  30 TRANSGENERATIONAL EFFECTS IN DNA METHYLATION, GENOTOXICITY AND REPRODUCTIVE PHENOTYPE BY CHRONIC ARSENIC EXPOSURE. AN EMERGING CONCERN IS THE INFLUENCES OF EARLY LIFE EXPOSURE TO ENVIRONMENTAL TOXICANTS ON OFFSPRING CHARACTERISTICS IN LATER LIFE. SINCE RECENT EVIDENCE SUGGESTS A TRANSGENERATIONAL TRANSFERENCE OF ABERRANT PHENOTYPES FROM EXPOSED-PARENTS TO NON-EXPOSED OFFSPRING RELATED TO ADULT-ONSET DISEASES INCLUDING REPRODUCTIVE PHENOTYPE. THE TRANSGENERATIONAL POTENTIAL OF ARSENIC A WELL KNOW GENOTOXIC AND EPIGENETIC MODIFIER AGENT HAS NOT BEEN ASSESSED IN MAMMALS UNTIL NOW. IN THIS EXPERIMENTAL STUDY, WE EVALUATED THE TRANSGENERATIONAL EFFECTS OF ARSENIC IN A RAT MODEL WITH CHRONIC EXPOSURE TO ARSENIC. RATS CHRONICALLY EXPOSED TO ARSENIC IN DRINKING WATER (1 MG AS(2)O(3)/ML) (F0) WERE MATED TO PRODUCE THE ARSENIC LINEAGE (F1, F2, AND F3). THE ARSENIC TOXIC EFFECTS ON WERE EVALUATED OVER THE FOUR GENERATIONS BY ANALYZING THE DNA METHYLATION PERCENTAGE, GENOTOXICITY IN WBC AND PHYSICAL AND REPRODUCTIVE PARAMETERS, INCLUDING SPERM QUALITY PARAMETERS AND HISTOPATHOLOGICAL EVALUATION OF THE GONADS. CHRONIC EXPOSURE TO ARSENIC CAUSED GENOTOXIC DAMAGE (F0-F3) DIFFERENT METHYLATION PATTERNS, ALTERATIONS IN PHYSICAL AND REPRODUCTIVE PARAMETERS, ABERRANT MORPHOLOGY IN THE OVARIES (F0 AND F1) AND TESTICLES (F1-F3), AND A DECREASE IN THE QUALITY OF SPERM (F0-F3, EXCEPT F2). PARENTAL CHRONIC ARSENIC EXPOSURE CAUSES TRANSGENERATIONAL GENOTOXICITY AND CHANGES IN GLOBAL DNA METHYLATION WHICH MIGHT BE ASSOCIATED WITH REPRODUCTIVE DEFECTS IN RATS. COMBINED WITH RECENT STUDIES REVEAL THAT DISTURBANCES IN THE EARLY LIFE OF AN INDIVIDUAL CAN AFFECT THE HEALTH OF LATER GENERATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11   480  30 ARSENIC-INDUCED CARCINOGENESIS: THE IMPACT OF MIRNA DYSREGULATION. ARSENIC IS A TOXIC METALLOID WIDELY PRESENT IN THE EARTH'S CRUST, AND IS A PROVEN HUMAN CARCINOGEN. CHRONIC ARSENIC EXPOSURE MAINLY THROUGH DRINKING WATER CAUSES SKIN, LUNG, AND URINARY BLADDER CANCERS, AND IS ASSOCIATED WITH LIVER, PROSTATE, AND KIDNEY CANCERS, CARDIOVASCULAR AND NEUROLOGICAL DISORDERS, AND DIABETES. SEVERAL MODES OF ACTION HAVE BEEN SUGGESTED IN ARSENIC CARCINOGENESIS. HOWEVER, THE MOLECULAR ETIOLOGY OF ARSENIC-INDUCED CANCER REMAINS UNCLEAR. RECENT EVIDENCE CLEARLY INDICATES THAT GENE EXPRESSION MODIFICATIONS INDUCED BY ARSENIC MAY INVOLVE EPIGENETIC ALTERATIONS, INCLUDING MIRNA DYSREGULATION. MANY MIRNAS HAVE BEEN IMPLICATED IN DIFFERENT HUMAN CANCERS AS A CONSEQUENCE OF LOSSES AND OR GAINS OF MIRNA FUNCTION THAT CONTRIBUTE TO CANCER DEVELOPMENT. PROGRESS IN IDENTIFYING MIRNA DYSREGULATION INDUCED BY ARSENIC HAS BEEN MADE USING DIFFERENT APPROACHES AND MODELS. THE PRESENT REVIEW DISCUSSES THE RECENT DATA REGARDING DYSREGULATED EXPRESSION OF MIRNA IN ARSENIC-INDUCED MALIGNANT TRANSFORMATION IN VITRO, GAPS IN CURRENT UNDERSTANDING AND DEFICIENCIES IN CURRENT MODELS FOR ARSENIC-INDUCED CARCINOGENESIS, AND FUTURE DIRECTIONS OF RESEARCH THAT WOULD IMPROVE OUR KNOWLEDGE REGARDING THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  1917  40 ENVIRONMENTAL ARSENIC EXPOSURE: FROM GENETIC SUSCEPTIBILITY TO PATHOGENESIS. MORE THAN 200 MILLION PEOPLE IN 70 COUNTRIES ARE EXPOSED TO ARSENIC THROUGH DRINKING WATER. CHRONIC EXPOSURE TO THIS METALLOID HAS BEEN ASSOCIATED WITH THE ONSET OF MANY DISEASES, INCLUDING CANCER. EPIDEMIOLOGICAL EVIDENCE SUPPORTS ITS CARCINOGENIC POTENTIAL, HOWEVER, DETAILED MOLECULAR MECHANISMS REMAIN TO BE ELUCIDATED. DESPITE THE GLOBAL MAGNITUDE OF THIS PROBLEM, NOT ALL INDIVIDUALS FACE THE SAME RISK. SUSCEPTIBILITY TO THE TOXIC EFFECTS OF ARSENIC IS INFLUENCED BY ALTERATIONS IN GENES INVOLVED IN ARSENIC METABOLISM, AS WELL AS BIOLOGICAL FACTORS, SUCH AS AGE, GENDER AND NUTRITION. MOREOVER, CHRONIC ARSENIC EXPOSURE RESULTS IN SEVERAL GENOTOXIC AND EPIGENETIC ALTERATIONS TIGHTLY ASSOCIATED WITH THE ARSENIC BIOTRANSFORMATION PROCESS, RESULTING IN AN INCREASED CANCER RISK. IN THIS REVIEW, WE: 1) REVIEW THE ROLES OF INTER-INDIVIDUAL DNA-LEVEL VARIATIONS INFLUENCING THE SUSCEPTIBILITY TO ARSENIC-INDUCED CARCINOGENESIS; 2) DISCUSS THE CONTRIBUTION OF ARSENIC BIOTRANSFORMATION TO CANCER INITIATION; 3) PROVIDE INSIGHTS INTO EMERGING RESEARCH AREAS AND THE CHALLENGES IN THE FIELD; AND 4) COMPILE A RESOURCE OF PUBLICLY AVAILABLE ARSENIC-RELATED DNA-LEVEL VARIATIONS, TRANSCRIPTOME AND METHYLATION DATA. UNDERSTANDING THE MOLECULAR MECHANISMS OF ARSENIC EXPOSURE AND ITS SUBSEQUENT HEALTH EFFECTS WILL SUPPORT EFFORTS TO REDUCE THE WORLDWIDE HEALTH BURDEN AND ENCOURAGE THE DEVELOPMENT OF STRATEGIES FOR MANAGING ARSENIC-RELATED DISEASES IN THE ERA OF PERSONALIZED MEDICINE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13  6078  29 THE EFFECT OF CHRONIC ARSENIC EXPOSURE IN ZEBRAFISH. ARSENIC IS A PREVALENT ENVIRONMENTAL TOXIN AND A GROUP ONE HUMAN CARCINOGENIC AGENT. CHRONIC ARSENIC EXPOSURE HAS BEEN ASSOCIATED WITH MANY HUMAN DISEASES. THE AIM OF THIS STUDY IS TO EVALUATE ZEBRAFISH AS AN ANIMAL MODEL TO ASSESS ARSENIC TOXICITY IN ELEVATED LONG-TERM ARSENIC EXPOSURE. WITH PROLONGED EXPOSURE (6 MONTHS) TO VARIOUS CONCENTRATIONS OF ARSENIC FROM 50 PPB TO 300 PPB, EFFECTS OF ARSENIC ACCUMULATION IN ZEBRAFISH TISSUES, AND PHENOTYPES WERE INVESTIGATED. RESULTS SHOWED THAT THERE ARE NO SIGNIFICANT CHANGES OF ARSENIC RETENTION IN ZEBRAFISH TISSUES, AND ZEBRAFISH DID NOT EXHIBIT ANY VISIBLE TUMOR FORMATION UNDER ARSENIC EXPOSURE CONDITIONS. HOWEVER, THE ZEBRAFISH DEMONSTRATE A DYSFUNCTION IN THEIR NEUROLOGICAL SYSTEM, WHICH IS REFLECTED BY A REDUCTION OF LOCOMOTIVE ACTIVITY. MOREOVER, ELEVATED LEVELS OF THE SUPEROXIDE DISMUTASE (SOD2) PROTEIN WERE DETECTED IN THE EYE AND LIVER, SUGGESTING INCREASED OXIDATIVE STRESS. IN ADDITION, THE PROGENIES OF ARSENIC-TREATED PARENTS DISPLAYED A SMALLER BIOMASS (FOUR-FOLD REDUCTION IN BODY WEIGHT) COMPARED WITH THOSE FROM THEIR PARENTAL CONTROLS. THIS RESULT INDICATES THAT ARSENIC MAY INDUCE GENETIC OR EPIGENETIC CHANGES THAT ARE THEN PASSED ON TO THE NEXT GENERATION. OVERALL, THIS STUDY DEMONSTRATES THAT ZEBRAFISH IS A CONVENIENT VERTEBRATE MODEL WITH ADVANTAGES IN THE EVALUATION OF ARSENIC-ASSOCIATED NEUROLOGICAL DISORDERS AS WELL AS ITS INFLUENCES ON THE OFFSPRING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14   759  30 CASE REPORT OF CUTANEOUS SQUAMOUS CELL CARCINOMA AT THE WRIST JOINT AND THE PUBLIC HEALTH CRISIS OF ARSENICOSIS. CONTEXT: ARSENICOSIS IS CAUSED BY LONG TERM (6 MONTHS PLUS) INGESTION OF ARSENIC ABOVE A SAFE DOSE, CHARACTERIZED BY SKIN LESIONS AND POSSIBLE INVOLVEMENT OF INTERNAL ORGANS. ARSENICOSIS IS COMMON IN INDIA AND BANGLADESH WHERE NATURALLY OCCURRING HIGH CONCENTRATIONS OF ARSENIC IN THE EARTH'S CRUST CONTAMINATE GROUND WATER, CAUSING ADVERSE HEALTH EFFECTS. CASE PRESENTATION: WE REPORT A CASE OF A 55-YEAR-OLD INDIAN MALE, RESIDENT OF A KNOWN ARSENIC ENDEMIC REGION OF UTTAR PRADESH WHO SUFFERED FROM CHARACTERISTIC PULMONARY AND CUTANEOUS FEATURES OF CHRONIC ARSENIC TOXICITY WHICH INCLUDED RADIOLOGICAL FINDINGS OF INTERSTITIAL LUNG DISEASE, HYPERKERATOTIC LESIONS OVER THE PALMS AND SOLES, RAIN DROP LIKE PIGMENTATION OVER THE TRUNK, AND CARCINOMATOUS CHANGES AT THE WRIST JOINT. THE PATIENT WAS STARTED ON CHELATING AGENTS (D-PENICILLAMINE) AND ORAL RETINOIDS (ISOTRETINOIN) FOLLOWED BY THE SURGICAL EXCISION OF THE CARCINOMA. DISCUSSION: ENVIRONMENTAL CONTAMINATION WITH ARSENIC IS A WELL-KNOWN HEALTH HAZARD IN SOUTH ASIAN COUNTRIES. THE MAIN SOURCE IS CONSUMPTION OF CONTAMINATED GROUND WATER FOR DOMESTIC PURPOSES. CUTANEOUS LESIONS, INTERNAL ORGAN INVOLVEMENT INCLUDING INTERSTITIAL LUNG DISEASE AND CARCINOMAS AS OBSERVED IN OUR PATIENT HAVE BEEN REPORTED IN THE LITERATURE. VARIOUS MECHANISMS LIKE EPIGENETIC CHANGES AND ARSENIC-INDUCED IMMUNE SUPPRESSION HAVE BEEN PROPOSED FOR THE DEVELOPMENT OF CUTANEOUS CARCINOMAS WITH PROLONGED EXPOSURE TO ARSENIC. RELEVANCE TO CLINICAL PRACTICE: AMONG THE VARIOUS CAUSES OF PALMO-PLANTAR HYPERKERATOSIS, ARSENICOSIS SHOULD BE KEPT IN MIND WHEN PRESENTING IN COMBINATION WITH PIGMENTARY CHANGES AND CARCINOMATOUS GROWTH FROM AN ARSENIC-ENDEMIC REGION. CONCLUSIONS: PEOPLE RESIDING IN ARSENIC-ENDEMIC REGIONS SHOULD BE MADE AWARE OF ARSENIC-RELATED HEALTH HAZARDS. RAINWATER HARVESTING AND GOOD NUTRITION ARE THE SIMPLEST MEASURES WHICH COULD BE ADOPTED BY THE EXPOSED POPULATION IN AFFECTED AREAS. SEVERAL METHODS HAVE ALSO BEEN EMPLOYED BY GOVERNMENTAL AND NON-GOVERNMENT ORGANIZATIONS TO SEPARATE ARSENIC FROM CONTAMINATED WATER TO COMBAT ARSENIC-RELATED DISEASES AND CARCINOMAS. COMPETING INTERESTS: THE AUTHORS DECLARE NO COMPETING FINANCIAL INTERESTS.	2021	
                                                                                                                                                                                                                                                                                          
15  2947  40 GENETIC AND EPIGENETIC CHANGES INDUCED BY CHRONIC LOW DOSE EXPOSURE TO ARSENIC OF MOUSE TESTICULAR LEYDIG CELLS. ARSENIC IS AN IMPORTANT ENVIRONMENTAL CARCINOGEN THAT AFFECTS MILLIONS OF PEOPLE WORLDWIDE THROUGH CONTAMINATED WATER SUPPLIES. GENOTOXICITY OF ARSENIC HAS BEEN A TOPIC OF CONTROVERSY. BOTH GENETIC ALTERATIONS (MUTATIONS) AND EPIGENETIC CHANGES (METHYLATION) HAVE BEEN SHOWN TO PLAY A CRUCIAL ROLE IN ENVIRONMENTAL CARCINOGENESIS. CHRONIC EXPOSURE TO ARSENIC HAS BEEN SHOWN TO INDUCE MALIGNANT TRANSFORMATION OF MAMMALIAN CELLS. HOWEVER, THE GENETIC ABERRATIONS INDUCED BY ARSENIC IN THIS PROCESS ARE UNCLEAR. THE PURPOSE OF THIS STUDY WAS TO DETERMINE IF BOTH LOWER (1 PG/ML) AND HIGHER CONCENTRATIONS (100 NG/ML) OF ARSENIC INDUCES EITHER MUTATIONS OR METHYLATION CHANGES THAT COULD LEAD TO THE DEVELOPMENT OF GENOMIC INSTABILITY IN TM3 CELLS, IMMORTALIZED LEYDIG CELLS DERIVED FROM NORMAL MOUSE TESTIS. TWO INDEPENDENT EXPOSURE TIMES WERE USED IN THIS STUDY WHICH RESULTED IN CELLS OF 33 AND 100 GENERATIONS IN AGE. ARSENIC-INDUCED GENETIC AND EPIGENETIC CHANGES WERE SCREENED AT A GENOME-WIDE LEVEL BY RANDOM AMPLIFIED POLYMORPHIC DNA (RAPD), ALSO KNOWN AS AP-PCR METHOD WITH UNDIGESTED DNA AS WELL AS DNA DIGESTED BY THE METHYLATION SENSITIVE ISOSIZOMERIC RESTRICTION ENZYMES MSPI AND HPAII AND UNTREATED CONTROLS. CHANGES IN THE DNA FINGERPRINT OF BOTH, THE RESTRICTION ENZYME DIGESTED DNA (INDICATING METHYLATION CHANGES) AS WELL AS UNDIGESTED DNA (INDICATING MUTATIONS) FROM ARSENIC-TREATED (LOW AS WELL AS HIGH DOSE) SAMPLES WERE OBSERVED AS COMPARED TO THEIR CONTROLS. THUS, THIS STUDY PROVIDES THE FIRST EVIDENCE AT DNA SEQUENCE LEVEL FOR MUTAGENIC POTENTIAL OF ARSENIC. FURTHER CHARACTERIZATION OF THESE ALTERED GENOMIC REGIONS IS UNDERWAY. THE UNDERSTANDING OF THESE GENETIC AND EPIGENETIC CHANGES IN ARSENIC-INDUCED CARCINOGENESIS WILL PROVIDE A BASIS FOR BETTER INTERVENTIONAL APPROACHES IN BOTH THE TREATMENT AND PREVENTION OF ARSENIC-INDUCED CANCER.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16   876  25 CHRONIC ARSENIC INTOXICATION DIAGNOSTIC SCORE (CASIDS). ARSENIC AND ITS COMPOUNDS ARE WELL-ESTABLISHED, POTENT, ENVIRONMENTALLY WIDESPREAD AND PERSISTENT TOXICANTS WITH METABOLIC, GENOTOXIC, MUTAGENIC, TERATOGENIC, EPIGENETIC AND CARCINOGENIC EFFECTS. ARSENIC OCCURS NATURALLY IN THE EARTH'S CRUST, BUT ANTHROPOGENIC ARSENIC EMISSIONS HAVE SURMOUNTED THE EMISSIONS FROM IMPORTANT NATURAL SOURCES SUCH AS VOLCANISM. INORGANIC ARSENICALS EXHIBIT ACUTE AND CHRONIC TOXICITIES IN VIRTUALLY ALL CELL TYPES AND TISSUES, AND HENCE ARSENIC INTOXICATION AFFECTS MULTIPLE SYSTEMS. WHEREAS ACUTE ARSENIC INTOXICATION IS RARE AND RELATIVELY EASY TO DIAGNOSE, CHRONIC ARSENIC INTOXICATION (CASI) IS COMMON BUT GOES OFTEN MISDIAGNOSED. BASED ON A REVIEW OF THE LITERATURE AS WELL AS OUR OWN CLINICAL EXPERIENCE, WE PROPOSE A CHRONIC ARSENIC INTOXICATION DIAGNOSTIC SCORE (CASIDS). A DISTINCTIVE FEATURE OF CASIDS IS THE USE OF BONE ARSENIC LOAD AS AN ESSENTIAL CRITERION FOR THE INDIVIDUAL RISK ASSESSMENT OF CHRONIC ARSENIC INTOXICATION, COMBINED WITH A SYSTEMIC CLINICAL ASSESSMENT. WE PRESENT CLINICAL EXAMPLES WHERE CASIDS IS APPLIED FOR THE DIAGNOSIS OF CASI, REVIEW THE MAIN TOPICS OF THE TOXICITY OF ARSENIC IN DIFFERENT CELL AND ORGAN SYSTEMS AND DISCUSS THE THERAPY AND PREVENTION OF DISEASE CAUSED OR AGGRAVATED BY CHRONIC ARSENIC INTOXICATION. CASIDS CAN HELP PHYSICIANS ESTABLISH THE DIAGNOSIS OF CASI AND ASSOCIATED CONDITIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  3042  40 GENOME-WIDE ALTERATION OF HISTONE METHYLATION PROFILES ASSOCIATED WITH COGNITIVE CHANGES IN RESPONSE TO DEVELOPMENTAL ARSENIC EXPOSURE IN MICE. INORGANIC ARSENIC IS A XENOBIOTIC ENTERING THE BODY PRIMARILY THROUGH CONTAMINATED DRINKING WATER AND FOOD. THERE ARE DEFINED MECHANISMS THAT DESCRIBE ARSENIC'S ASSOCIATION WITH INCREASED CANCER INCIDENCE, HOWEVER MECHANISMS EXPLAINING ARSENIC EXPOSURE AND NEURODEVELOPMENTAL OR AGING DISORDERS ARE POORLY DEFINED. IN RECENT YEARS, ARSENIC EFFECTS ON EPIGENOME HAVE BECOME A PARTICULAR FOCUS. WE HYPOTHESIZE THAT HUMAN RELEVANT ARSENIC EXPOSURE DURING PARTICULAR DEVELOPMENTAL WINDOWS, OR LONG-TERM EXPOSURE LATER IN LIFE INDUCE PATHOPHYSIOLOGICAL NEURAL CHANGES THROUGH EPIGENOMIC ALTERATIONS, IN PARTICULAR HISTONE METHYLATION PROFILE, MANIFESTING AS COGNITIVE DECLINE. C57BL/6 WILD-TYPE MICE WERE CONTINUALLY EXPOSED TO SODIUM ARSENITE (100 MICROG/L) IN DRINKING WATER PRIOR TO MATING THROUGH WEANING OF THE EXPERIMENTAL PROGENY. A SECOND COHORT OF AGED APP/PS MICE WERE CHRONICALLY EXPOSED TO THE SAME LEVEL OF ARSENIC. COGNITIVE TESTING, HISTOLOGICAL EXAMINATION OF BRAINS AND GENOME-WIDE METHYLATION LEVELS OF H3K4ME3 AND H3K27ME3 EXAMINED AFTER CHIP-SEQ WERE USED TO DETERMINE THE EFFECTS OF ARSENIC EXPOSURE. DEVELOPMENTAL ARSENIC EXPOSURE CAUSED SIGNIFICANTLY DIMINISHED COGNITION IN WILD-TYPE MICE. THE ANALYSIS OF CHIP-SEQ DATA AND EXPERIMENTS WITH MOUSE EMBRYONIC STEM CELLS DEMONSTRATED THAT EPIGENETIC CHANGES INDUCED BY ARSENIC EXPOSURE TRANSLATED INTO GENE EXPRESSION ALTERATIONS ASSOCIATED WITH NEURONAL DEVELOPMENT AND NEUROLOGICAL DISEASE. INCREASED HIPPOCAMPAL AMYLOID PLAQUES LEVELS OF APP/PS MICE AND COGNITIVE DECLINE PROVIDED EVIDENCE THAT ARSENIC EXPOSURE AGGRAVATED AN EXISTING ALZHEIMER'S DISEASE-LIKE PHENOTYPE. WE SHOW DEVELOPMENTAL ARSENIC EXPOSURE SIGNIFICANTLY IMPACTS HISTONE MODIFICATIONS IN BRAIN WHICH REMAIN PRESENT INTO ADULTHOOD AND PROVIDE A POTENTIAL MECHANISM BY WHICH DEVELOPMENTAL ARSENIC EXPOSURE INFLUENCES COGNITIVE FUNCTIONS. WE ALSO SHOW THAT HUMAN RELEVANT, CHRONIC ARSENIC EXPOSURE HAS DELETERIOUS EFFECTS ON ADULT APP/PS MICE AND EXACERBATES EXISTING ALZHEIMER'S DISEASE-LIKE SYMPTOMS. THE RESULTS DEMONSTRATE HOW DEVELOPMENTAL ARSENIC EXPOSURE IMPACTS THE BRAIN EPIGENOME, LEADING TO ALTERED GENE EXPRESSION LATER IN LIFE.	2022	
                                                                                                                                                                                                                                                                                           
18  2921  32 GENE-SPECIFIC DIFFERENTIAL DNA METHYLATION AND CHRONIC ARSENIC EXPOSURE IN AN EPIGENOME-WIDE ASSOCIATION STUDY OF ADULTS IN BANGLADESH. BACKGROUND: INORGANIC ARSENIC IS ONE OF THE MOST COMMON NATURALLY OCCURRING CONTAMINANTS FOUND IN THE ENVIRONMENT. ARSENIC IS ASSOCIATED WITH A NUMBER OF HEALTH OUTCOMES, WITH EPIGENETIC MODIFICATION SUGGESTED AS A POTENTIAL MECHANISM OF TOXICITY. OBJECTIVE: AMONG A SAMPLE OF 400 ADULT PARTICIPANTS, WE EVALUATED THE ASSOCIATION BETWEEN ARSENIC EXPOSURE, AS MEASURED BY BLOOD AND URINARY TOTAL ARSENIC CONCENTRATIONS, AND EPIGENOME-WIDE WHITE BLOOD CELL DNA METHYLATION. METHODS: WE USED LINEAR REGRESSION MODELS TO EXAMINE THE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND METHYLATION AT EACH CPG SITE, ADJUSTED FOR SEX, AGE, AND BATCH. DIFFERENTIALLY METHYLATED LOCI WERE SUBSEQUENTLY EXAMINED IN RELATION TO CORRESPONDING GENE EXPRESSION FOR FUNCTIONAL EVIDENCE OF GENE REGULATION. RESULTS: IN ADJUSTED ANALYSES, WE OBSERVED FOUR DIFFERENTIALLY METHYLATED CPG SITES WITH URINARY TOTAL ARSENIC CONCENTRATION AND THREE DIFFERENTIALLY METHYLATED CPG SITES WITH BLOOD ARSENIC CONCENTRATION, BASED ON THE BONFERRONI-CORRECTED SIGNIFICANCE THRESHOLD OF P < 1 X 10(-7). METHYLATION OF PLA2G2C (PROBE CG04605617) WAS THE MOST SIGNIFICANTLY ASSOCIATED LOCUS IN RELATION TO BOTH URINARY (P = 3.40 X 10(-11)) AND BLOOD ARSENIC CONCENTRATIONS (P = 1.48 X 10(-11)). THREE ADDITIONAL NOVEL METHYLATION LOCI-SQSTM1 (CG01225779), SLC4A4 (CG06121226), AND IGH (CG13651690)--WERE ALSO SIGNIFICANTLY ASSOCIATED WITH ARSENIC EXPOSURE. FURTHER, THERE WAS EVIDENCE OF METHYLATION-RELATED GENE REGULATION BASED ON GENE EXPRESSION FOR A SUBSET OF DIFFERENTIALLY METHYLATED LOCI. CONCLUSIONS: WE OBSERVED SIGNIFICANT ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENE-SPECIFIC DIFFERENTIAL WHITE BLOOD CELL DNA METHYLATION, SUGGESTING THAT EPIGENETIC MODIFICATIONS MAY BE AN IMPORTANT PATHWAY UNDERLYING ARSENIC TOXICITY. THE SPECIFIC DIFFERENTIALLY METHYLATED LOCI IDENTIFIED MAY INFORM POTENTIAL PATHWAYS FOR FUTURE INTERVENTIONS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  6387  26 THE ROLE OF REACTIVE OXYGEN SPECIES IN ARSENIC TOXICITY. ARSENIC POISONING IS A GLOBAL HEALTH PROBLEM. CHRONIC EXPOSURE TO ARSENIC HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF A WIDE RANGE OF DISEASES AND HEALTH PROBLEMS IN HUMANS. ARSENIC EXPOSURE INDUCES THE GENERATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS), WHICH MEDIATE MULTIPLE CHANGES TO CELL BEHAVIOR BY ALTERING SIGNALING PATHWAYS AND EPIGENETIC MODIFICATIONS, OR CAUSE DIRECT OXIDATIVE DAMAGE TO MOLECULES. ANTIOXIDANTS WITH THE POTENTIAL TO REDUCE ROS LEVELS HAVE BEEN SHOWN TO AMELIORATE ARSENIC-INDUCED LESIONS. HOWEVER, EMERGING EVIDENCE SUGGESTS THAT CONSTRUCTIVE ACTIVATION OF ANTIOXIDATIVE PATHWAYS AND DECREASED ROS LEVELS CONTRIBUTE TO CHRONIC ARSENIC TOXICITY IN SOME CASES. THIS REVIEW DETAILS THE PATHWAYS INVOLVED IN ARSENIC-INDUCED REDOX IMBALANCE, AS WELL AS CURRENT STUDIES ON PROPHYLAXIS AND TREATMENT STRATEGIES USING ANTIOXIDANTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20  1811  39 EFFECTS OF ARSENIC TOXICITY BEYOND EPIGENETIC MODIFICATIONS. WORLDWIDE CHRONIC ARSENIC (AS) POISONING BY ARSENIC-CONTAMINATED GROUNDWATER IS ONE OF THE MOST THREATENING PUBLIC HEALTH PROBLEMS. CHRONIC INORGANIC AS (INAS) EXPOSURE HAS BEEN ASSOCIATED WITH VARIOUS FORMS OF CANCERS AND NUMEROUS OTHER PATHOLOGICAL EFFECTS IN HUMANS, COLLECTIVELY KNOWN AS ARSENICOSIS. OVER THE PAST DECADE, EVIDENCE INDICATED THAT AS-INDUCED EPIGENETIC MODIFICATIONS HAVE A ROLE IN THE ADVERSE EFFECTS ON HUMAN HEALTH. THE MAIN OBJECTIVE OF THIS ARTICLE IS TO REVIEW THE EVIDENCE ON EPIGENETIC MODIFICATIONS INDUCED BY ARSENICALS. THE EPIGENETIC COMPONENTS PLAY A CRUCIAL ROLE IN THE REGULATION OF GENE EXPRESSION, AT BOTH TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL LEVELS. WE SYNTHESIZED THE LARGE BODY OF EXISTING RESEARCH ON ARSENIC EXPOSURE AND EPIGENETIC MECHANISMS OF HEALTH OUTCOMES WITH AN EMPHASIS ON RECENT PUBLICATIONS. CHANGES IN PATTERNS OF DNA METHYLATION, HISTONE POSTTRANSLATIONAL MODIFICATIONS, AND MICRORNAS HAVE BEEN REPEATEDLY OBSERVED AFTER INAS EXPOSURE IN LABORATORY STUDIES AND IN STUDIES OF HUMAN POPULATIONS. SUCH ALTERATIONS HAVE THE POTENTIAL TO DISTURB CELLULAR HOMEOSTASIS, RESULTING IN THE MODULATION OF KEY PATHWAYS IN THE AS-INDUCED CARCINOGENESIS. THE PRESENT ARTICLE REVIEWS RECENT DATA ON AS-INDUCED EPIGENETIC EFFECTS AND CONCLUDES THAT IT IS TIME FOR HEIGHTENED AWARENESS OF PATHOGENIC ARSENIC EXPOSURE, PARTICULARLY FOR PREGNANT WOMEN AND CHILDREN, GIVEN THE POTENTIAL FOR A LONG-LASTING DISTURBED CELLULAR HOMEOSTASIS.	2018