1 1825 106 EFFECTS OF HIGH-DOSE BISPHENOL A ON THE MOUSE ORAL MUCOSA: A POSSIBLE LINK WITH ORAL CANCERS. BISPHENOL A (BPA) IS AN ENDOCRINE DISRUPTING CHEMICAL ABLE TO PROMOTE HORMONE-RESPONSIVE TUMORS. THE MAJOR ROUTE OF BPA CONTAMINATION BEING ORAL, THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE BPA EFFECTS ON ORAL CELLS. HERE, WE EVALUATED THE IMPACT OF SUB-CHRONIC IN VIVO EXPOSURE TO BPA AND ITS IN VITRO EFFECTS ON NEOPLASTIC AND NON-NEOPLASTIC ORAL CELLS. WE EVALUATED THE ORAL MUCOSA OF MICE CHRONICALLY EXPOSED TO BPA (200 MG/L). THE RESPONSE OF KERATINOCYTES (NOK-SI) AND HEAD AND NECK (HN) SQUAMOUS CELL CARCINOMA (SCC), HN12 AND HN13 CELL LINES TO BPA WAS EXAMINED. IN VIVO, BPA ACCUMULATED IN ORAL TISSUES AND CAUSED AN INCREASE IN EPITHELIAL PROLIFERATIVE ACTIVITY. BPA DISRUPTED THE FUNCTION OF KERATINOCYTES BY ALTERING PRO-SURVIVAL AND PROLIFERATIVE PATHWAYS AND THE SECRETION OF CYTOKINES AND GROWTH FACTORS. IN TUMOR CELLS, BPA INDUCED PROLIFERATIVE, INVASIVE, PRO-ANGIOGENIC, AND EPIGENETIC PATHS. OUR DATA HIGHLIGHT THE HARMFUL EFFECTS OF BPA ON ORAL MUCOSA AND, TUMORIGENIC AND NON-TUMORIGENIC CELLS. ADDITIONALLY, BPA MAY BE A MODIFIER OF ORAL CANCER CELL BEHAVIOR BY PROMPTING A FUNCTIONAL SHIFT TO A MORE AGGRESSIVE PHENOTYPE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2  898  28 CHRONIC EXPOSURE OF MICE TO BISPHENOL-A ALTERS UTERINE FIBROBLAST GROWTH FACTOR SIGNALING AND LEADS TO ABERRANT EPITHELIAL PROLIFERATION. UTERINE EPITHELIAL PROLIFERATION IS REGULATED IN A PARACRINE MANNER BY A COMPLEX INTERPLAY BETWEEN ESTROGEN (E) AND PROGESTERONE (P) SIGNALING, IN WHICH E STIMULATES PROLIFERATION AND P INHIBITS IT. PERTURBATION OF STEROID HORMONE SIGNALING WITHIN THE UTERINE MILIEU COULD CONTRIBUTE TO THE DEVELOPMENT OF ENDOMETRIAL HYPERPLASIA AND CANCER. IT IS WELL ESTABLISHED THAT BISPHENOL-A (BPA) IS AN ENDOCRINE-DISRUPTING CHEMICAL WITH WEAK ESTROGENIC EFFECTS, ALTHOUGH LITTLE IS KNOWN ABOUT HOW IT AFFECTS STEROID HORMONE SIGNALING IN THE ADULT UTERUS. BECAUSE BPA ACTS AS A WEAK E, WE HYPOTHESIZED THAT CHRONIC EXPOSURE TO BPA WOULD CREATE AN IMBALANCE BETWEEN E AND P SIGNALING AND CAUSE CHANGES IN THE UTERUS, SUCH AS ABERRANT EPITHELIAL PROLIFERATION. INDEED, EXPOSURE TO AN ENVIRONMENTALLY RELEVANT DOSE OF BPA HAD A UTEROTROPHIC AFFECT. BPA-TREATED MICE SHOWED INCREASED PROLIFERATION, NOTABLY IN THE GLANDULAR EPITHELIUM, WHICH ARE SITES OF ORIGIN FOR ENDOMETRIAL HYPERPLASIA AND CANCER. INCREASED PROLIFERATION APPEARED TO BE MEDIATED THROUGH A SIMILAR MECHANISM AS E-INDUCED PROLIFERATION, VIA ACTIVATION OF THE FIBROBLAST GROWTH FACTOR RECEPTOR PATHWAY AND PHOSPHORYLATION OF THE ERK1/2 MITOGEN-ACTIVATED PROTEIN KINASES IN THE EPITHELIUM. INTERESTINGLY, BPA REDUCED EXPRESSION OF HEART AND NEURAL CREST DERIVATIVES EXPRESSED 2 (HAND2), A KNOWN MEDIATOR OF THE ANTIPROLIFERATIVE EFFECTS OF P. BPA ALSO INCREASED METHYLATION OF A CPG ISLAND IN THE HAND2 GENE PROMOTER, SUGGESTING THAT BPA MAY PROMOTE EPITHELIAL PROLIFERATION THROUGH EPIGENETIC SILENCING OF ANTIPROLIFERATIVE FACTORS LIKE HAND2. COLLECTIVELY, THESE FINDINGS ESTABLISH THAT CHRONIC EXPOSURE TO BPA IMPAIRS STEROID HORMONE SIGNALING IN THE MOUSE UTERUS, AND MAY CONTRIBUTE TO THE PATHOGENESIS OF UTERINE HYPERPLASIA AND CANCER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3  652  30 BISPHENOL A AS EPIGENETIC MODULATOR: SETTING THE STAGE FOR CARCINOGENESIS? BACKGROUND: BISPHENOL A (BPA) IS ONE OF THE MOST WIDELY PRODUCED CHEMICALS WORLDWIDE AND IS OFTEN USED IN THE PRODUCTION OF FOOD AND BEVERAGE CONTAINERS. AS A RESULT OF BPA CONTACT WITH FOOD, DRINK AND TOILETRIES, ITS INGESTION AND ABSORPTION BY HUMANS HAS BEEN GROWING. THE INDUSTRIALIZATION AND MODERN LIFESTYLES BROUGHT A CONSTANT EXPOSURE TO SEVERAL HEALTH-DISTURBING COMPOUNDS AND USHERED A NEW ERA OF CHRONIC DISEASES. THE ENDOCRINE DISRUPTOR POTENTIAL OF BPA IS WELL KNOWN, BUT THE RESEARCH AROUND ITS EPIGENOTOXIC EFFECTS RAISED FURTHER CONCERNS WHETHER CHRONIC EXPOSURE TO BPA CAN CONTRIBUTE TO CHRONIC HUMAN ILLNESS, INCLUDING CANCER IN HORMONE-SENSITIVE ORGANS. MATERIALS AND METHODS: FOCUSING ON COMPUTERIZED DATABASES, WE REVIEWED ORIGINAL AND REVIEW ARTICLES WHICH ELUCIDATE AND LINK SOME OF THE INFORMATION ALREADY AVAILABLE ABOUT BPA AND RELATED EPIGENETIC ALTERATIONS. RESULTS: A NUMBER OF STUDIES INDICATE THAT SHORT-TERM ADMINISTRATION OF LOW OR HIGH-DOSES OF BPA MAY BE ASSOCIATED WITH AN INCREASED RISK OF EPIGENETIC MODIFICATIONS, INCREASING THE RISK FOR CARCINOGENESIS. HOWEVER, IT IS CLEAR THAT MORE STUDIES CONSIDERING REAL DAILY EXPOSURES ARE ESSENTIAL TO DEFINE A REAL TOLERABLE DAILY INTAKE AND TO TIGHTEN UP MANUFACTORY REGULATIONS. CONCLUSION: IN THIS REVIEW, WE HIGHLIGHT SOME EVIDENCES SUGGESTING A RELATIONSHIP BETWEEN BPA EXPOSURE, GENOTOXIC ACTIVITY AND EPIGENETIC MODIFICATIONS, WHICH MAY PRIME FOR CARCINOGENESIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4  654  29 BISPHENOL S INDUCED EPIGENETIC AND TRANSCRIPTIONAL CHANGES IN HUMAN BREAST CANCER CELL LINE MCF-7. IN RECENT YEARS, CONCERNS ABOUT USING BISPHENOL A (BPA) IN DAILY CONSUME PRODUCTS AND ITS EFFECTS IN MANY CHRONIC HUMAN DISEASES HAVE PROMPTED THE REMOVAL OF BPA. HOWEVER, THE WIDELY USED BPA ALTERNATIVES, INCLUDING BISPHENOL S (BPS), HAVE A HIGH STRUCTURAL SIMILARITY WITH BPA, SUGGESTING THAT THEY MAY HAVE SIMILAR BIOLOGICAL EFFECTS TOWARDS HUMAN BEINGS. INDEED, BPS WAS ALSO FOUND TO HAVE ENDOCRINE-DISRUPTING EFFECTS. EPIGENETIC MECHANISM WAS REPORTED TO BE INVOLVED IN BPA-INDUCED BIOLOGICAL EFFECTS IN BOTH IN VITRO AND IN VIVO MODELS. HOWEVER, THERE IS NO ASSESSMENT ON WHETHER BPS COULD CAUSE EPIGENETIC CHANGES. IN THIS WORK, WE INVESTIGATED THE POSSIBLE EPIGENETIC EFFECTS OF BPS THAT MIGHT INDUCE IN HUMAN BREAST CANCER CELL LINE MCF-7. WE FOUND THAT BPS COULD CHANGE DNA METHYLATION LEVEL OF TRANSPOSONS. BESIDES, METHYLATION STATUS IN PROMOTER OF BREAST CANCER RELATED GENES CDH1, SFN, TNFRSF10C WERE ALSO CHANGED, WHICH IMPLIED THAT BPS MIGHT PLAY A ROLE IN THE DEVELOPMENT OF BREAST CANCER. GENE EXPRESSION PROFILING SHOWED THAT SOME GENES RELATED TO BREAST CANCER PROGRESSION WERE UPREGULATED, INCLUDING THBS4, PPARGC1A, CREB5, COL5A3. GENE ONTOLOGY (GO) ANALYSIS OF THE DIFFERENTIALLY EXPRESSED GENES REVEALED THE SIGNIFICANTLY CHANGES IN PI3K-AKT SIGNALING PATHWAY AND EXTRACELLULAR MATRIX, WHICH WERE RELATED TO THE PROLIFERATION, MIGRATION AND INVASION OF BREAST CANCER CELLS. THESE RESULTS ILLUSTRATED THAT BPS EXPOSURE MIGHT PLAY ROLES IN THE PROGRESSION OF BREAST CANCER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
5  651  24 BISPHENOL A AND PHTHALATES MODULATE PERITONEAL MACROPHAGE FUNCTION IN FEMALE MICE INVOLVING SYMD2-H3K36 DIMETHYLATION. AMPLE EVIDENCE SUGGESTS THAT ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO BISPHENOL A (BPA) AND PHTHALATE, TWO CHEMICALS WIDELY USED IN THE PLASTICS INDUSTRY, DISTURBS HOMEOSTASIS OF INNATE IMMUNITY AND CAUSES INFLAMMATORY DISEASES. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS OF THESE TOXICANTS IN THE REGULATION OF MACROPHAGE INFLAMMATORY FUNCTIONS REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE ADDRESSED THE EFFECT OF CHRONIC EXPOSURE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE, EITHER IN VITRO OR IN VIVO, ON THE INFLAMMATORY REPROGRAMING OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT BPA AND PHTHALATES ADVERSELY AFFECTED EXPRESSION LEVELS OF THE PROINFLAMMATORY CYTOKINES AND MEDIATORS IN RESPONSE TO LIPOPOLYSACCHARIDE STIMULATION. EXPOSURE TO THESE TOXICANTS ALSO AFFECTED GENE EXPRESSION OF SCAVENGER RECEPTORS AND PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT THE EPIGENETIC INHIBITORS DIFFERENTIALLY MODULATED TARGET GENE EXPRESSION IN THESE CELLS. FURTHER ANALYSIS REVEALED THAT CERTAIN HISTONE MODIFICATION ENZYMES WERE ABERRANTLY EXPRESSED IN RESPONSE TO BPA OR PHTHALATE EXPOSURE, LEADING TO ALTERATION IN THE LEVELS OF H3K36 ACETYLATION AND DIMETHYLATION, TWO CHROMATIN MODIFICATIONS THAT ARE CRITICAL FOR TRANSCRIPTIONAL EFFICACY AND ACCURACY. OUR RESULTS FURTHER REVEALED THAT SILENCING OF H3K36-SPECIFIC METHYLTRANSFERASE SMYD2 EXPRESSION OR INHIBITION OF SMYD2 ENZYMATIC ACTIVITY ATTENUATED H3K36 DIMETHYLATION AND ENHANCED INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR-ALPHA EXPRESSION BUT DAMPENED THE PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. IN SUMMARY, OUR RESULTS INDICATE THAT PERITONEAL MACROPHAGES ARE VULNERABLE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE. THESE ENVIRONMENTAL TOXICANTS AFFECT PHENOTYPIC PROGRAMMING OF MACROPHAGES VIA EPIGENETIC MECHANISMS INVOLVING SMYD2-MEDIATED H3K36 MODIFICATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6 1655  22 DOSE-DEPENDENCE, SEX- AND TISSUE-SPECIFICITY, AND PERSISTENCE OF RADIATION-INDUCED GENOMIC DNA METHYLATION CHANGES. RADIATION IS A WELL-KNOWN GENOTOXIC AGENT AND HUMAN CARCINOGEN THAT GIVES RISE TO A VARIETY OF LONG-TERM EFFECTS. ITS DETRIMENTAL INFLUENCE ON CELLULAR FUNCTION IS ACTIVELY STUDIED NOWADAYS. ONE OF THE MOST ANALYZED, YET LEAST UNDERSTOOD LONG-TERM EFFECTS OF IONIZING RADIATION IS TRANSGENERATIONAL GENOMIC INSTABILITY. THE INHERITANCE OF GENOMIC INSTABILITY SUGGESTS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS, SUCH AS CHANGES OF THE METHYLATION OF CYTOSINE RESIDUES LOCATED WITHIN CPG DINUCLEOTIDES. IN THE CURRENT STUDY WE EVALUATED THE DOSE-DEPENDENCE OF THE RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION CHANGES. WE ALSO ANALYZED THE EFFECTS OF ACUTE AND CHRONIC HIGH DOSE (5GY) EXPOSURE ON DNA METHYLATION IN LIVER, SPLEEN, AND LUNG TISSUES OF MALE AND FEMALE MICE AND EVALUATED THE POSSIBLE PERSISTENCE OF THE RADIATION-INDUCED DNA METHYLATION CHANGES. HERE WE REPORT THAT RADIATION-INDUCED DNA METHYLATION CHANGES WERE SEX- AND TISSUE-SPECIFIC, DOSE-DEPENDENT, AND PERSISTENT. IN PARALLEL WE HAVE STUDIED THE LEVELS OF DNA DAMAGE IN THE EXPOSED TISSUES. BASED ON THE CORRELATION BETWEEN THE LEVELS OF DNA METHYLATION AND DNA DAMAGE WE PROPOSE THAT RADIATION-INDUCED GLOBAL GENOME DNA HYPOMETHYLATION IS DNA REPAIR-RELATED.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  416  23 ANALYSIS OF THE DYNAMIC ABERRANT LANDSCAPE OF DNA METHYLATION AND GENE EXPRESSION DURING ARSENIC-INDUCED CELL TRANSFORMATION. INORGANIC ARSENIC IS A WELL-KNOWN CARCINOGEN ASSOCIATED WITH SEVERAL TYPES OF CANCER, BUT THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS ARE NOT FULLY UNDERSTOOD. RECENT EVIDENCE POINTS TO EPIGENETIC DYSREGULATION AS AN IMPORTANT MECHANISM IN THIS PROCESS; HOWEVER, THE EFFECTS OF EPIGENETIC ALTERATIONS IN GENE EXPRESSION HAVE NOT BEEN EXPLORED IN DEPTH. USING MICROARRAY DATA AND APPLYING A MULTIVARIATE CLUSTERING ANALYSIS IN A GAUSSIAN MIXTURE MODEL, WE DESCRIBE THE ALTERATIONS IN DNA METHYLATION AROUND THE PROMOTER REGION AND THE IMPACT ON GENE EXPRESSION IN HACAT CELLS DURING THE TRANSFORMATION PROCESS CAUSED BY CHRONIC EXPOSURE TO ARSENIC. USING THIS CLUSTERING APPROACH, THE GENES WERE GROUPED ACCORDING TO THEIR METHYLATION AND EXPRESSION STATUS IN THE EPIGENETIC LANDSCAPE, AND THE CHANGES THAT OCCURRED DURING THE CELLULAR TRANSFORMATION WERE IDENTIFIED ADEQUATELY. THUS, WE PRESENT A VALUABLE METHOD FOR IDENTIFYING EPIGENOMIC DYSREGULATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 2483  22 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  266  30 ADVERSE OUTCOME PATHWAYS FOR IONIZING RADIATION AND BREAST CANCER INVOLVE DIRECT AND INDIRECT DNA DAMAGE, OXIDATIVE STRESS, INFLAMMATION, GENOMIC INSTABILITY, AND INTERACTION WITH HORMONAL REGULATION OF THE BREAST. KNOWLEDGE ABOUT ESTABLISHED BREAST CARCINOGENS CAN SUPPORT IMPROVED AND MODERNIZED TOXICOLOGICAL TESTING METHODS BY IDENTIFYING KEY MECHANISTIC EVENTS. IONIZING RADIATION (IR) INCREASES THE RISK OF BREAST CANCER, ESPECIALLY FOR WOMEN AND FOR EXPOSURE AT YOUNGER AGES, AND EVIDENCE OVERALL SUPPORTS A LINEAR DOSE-RESPONSE RELATIONSHIP. WE USED THE ADVERSE OUTCOME PATHWAY (AOP) FRAMEWORK TO OUTLINE AND EVALUATE THE EVIDENCE LINKING IONIZING RADIATION WITH BREAST CANCER FROM MOLECULAR INITIATING EVENTS TO THE ADVERSE OUTCOME THROUGH INTERMEDIATE KEY EVENTS, CREATING A QUALITATIVE AOP. WE IDENTIFIED KEY EVENTS BASED ON REVIEW ARTICLES, SEARCHED PUBMED FOR RECENT LITERATURE ON KEY EVENTS AND IR, AND IDENTIFIED ADDITIONAL PAPERS USING REFERENCES. WE MANUALLY CURATED PUBLICATIONS AND EVALUATED DATA QUALITY. IONIZING RADIATION DIRECTLY AND INDIRECTLY CAUSES DNA DAMAGE AND INCREASES PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES (RONS). RONS LEAD TO DNA DAMAGE AND EPIGENETIC CHANGES LEADING TO MUTATIONS AND GENOMIC INSTABILITY (GI). PROLIFERATION AMPLIFIES THE EFFECTS OF DNA DAMAGE AND MUTATIONS LEADING TO THE AO OF BREAST CANCER. SEPARATELY, RONS AND DNA DAMAGE ALSO INCREASE INFLAMMATION. INFLAMMATION CONTRIBUTES TO DIRECT AND INDIRECT EFFECTS (EFFECTS IN CELLS NOT DIRECTLY REACHED BY IR) VIA POSITIVE FEEDBACK TO RONS AND DNA DAMAGE, AND SEPARATELY INCREASES PROLIFERATION AND BREAST CANCER THROUGH PRO-CARCINOGENIC EFFECTS ON CELLS AND TISSUE. FOR EXAMPLE, GENE EXPRESSION CHANGES ALTER INFLAMMATORY MEDIATORS, RESULTING IN IMPROVED SURVIVAL AND GROWTH OF CANCER CELLS AND A MORE HOSPITABLE TISSUE ENVIRONMENT. ALL OF THESE EVENTS OVERLAP AT MULTIPLE POINTS WITH EVENTS CHARACTERISTIC OF "BACKGROUND" INDUCTION OF BREAST CARCINOGENESIS, INCLUDING HORMONE-RESPONSIVE PROLIFERATION, OXIDATIVE ACTIVITY, AND DNA DAMAGE. THESE OVERLAPS MAKE THE BREAST PARTICULARLY SUSCEPTIBLE TO IONIZING RADIATION AND REINFORCE THAT THESE BIOLOGICAL ACTIVITIES ARE IMPORTANT CHARACTERISTICS OF CARCINOGENS. AGENTS THAT INCREASE THESE BIOLOGICAL PROCESSES SHOULD BE CONSIDERED POTENTIAL BREAST CARCINOGENS, AND PREDICTIVE METHODS ARE NEEDED TO IDENTIFY CHEMICALS THAT INCREASE THESE PROCESSES. TECHNIQUES ARE AVAILABLE TO MEASURE RONS, DNA DAMAGE AND MUTATION, CELL PROLIFERATION, AND SOME INFLAMMATORY PROTEINS OR PROCESSES. IMPROVED ASSAYS ARE NEEDED TO MEASURE GI AND CHRONIC INFLAMMATION, AS WELL AS THE INTERACTION WITH HORMONALLY DRIVEN DEVELOPMENT AND PROLIFERATION. SEVERAL METHODS MEASURE DIVERSE EPIGENETIC CHANGES, BUT IT IS NOT CLEAR WHICH CHANGES ARE RELEVANT TO BREAST CANCER. IN ADDITION, MOST TOXICOLOGICAL ASSAYS ARE NOT CONDUCTED IN MAMMARY TISSUE, AND SO IT IS A PRIORITY TO EVALUATE IF RESULTS FROM OTHER TISSUES ARE GENERALIZABLE TO BREAST, OR TO CONDUCT ASSAYS IN BREAST TISSUE. DEVELOPING AND APPLYING THESE ASSAYS TO IDENTIFY EXPOSURES OF CONCERN WILL FACILITATE EFFORTS TO REDUCE SUBSEQUENT BREAST CANCER RISK.	2020	

10  904  30 CHRONIC EXPOSURE TO CADMIUM INDUCES DIFFERENTIAL METHYLATION IN MICE SPERMATOZOA. CADMIUM EXPOSURE IS UBIQUITOUS AND HAS BEEN LINKED TO DISEASES INCLUDING CANCERS AND REPRODUCTIVE DEFECTS. SINCE CADMIUM IS NONMUTAGENIC, IT IS THOUGHT TO EXERT ITS GENE DYSREGULATORY EFFECTS THROUGH EPIGENETIC REPROGRAMMING. SEVERAL STUDIES HAVE IMPLICATED GERMLINE EXPOSURE TO CADMIUM IN DEVELOPMENTAL REPROGRAMMING. HOWEVER, MOST OF THESE STUDIES HAVE FOCUSED ON MATERNAL EXPOSURE, WHILE THE IMPACT ON SPERM FERTILITY AND DISEASE SUSCEPTIBILITY HAS RECEIVED LESS ATTENTION. IN THIS STUDY, WE USED REDUCED REPRESENTATION BISULFITE SEQUENCING TO COMPREHENSIVELY INVESTIGATE THE IMPACT OF CHRONIC CADMIUM EXPOSURE ON MOUSE SPERMATOZOA DNA METHYLATION. ADULT MALE C57BL/J6 MICE WERE PROVIDED WATER WITH OR WITHOUT CADMIUM CHLORIDE FOR 9 WEEKS. SPERM, TESTES, LIVER, AND KIDNEY TISSUES WERE COLLECTED AT THE END OF THE TREATMENT PERIOD. CADMIUM EXPOSURE WAS CONFIRMED THROUGH GENE EXPRESSION ANALYSIS OF METALLOTHIONEIN-1 AND 2, 2 WELL-KNOWN CADMIUM-INDUCED GENES. ANALYSIS OF SPERM DNA METHYLATION CHANGES REVEALED 1788 DIFFERENTIALLY METHYLATED SITES PRESENT AT REGULATORY REGIONS IN SPERM OF MICE EXPOSED TO CADMIUM COMPARED WITH VEHICLE (CONTROL) MICE. FURTHERMORE, MOST OF THESE DIFFERENTIAL METHYLATION CHANGES POSITIVELY CORRELATED WITH CHANGES IN GENE EXPRESSION AT BOTH THE TRANSCRIPTION INITIATION STAGE AS WELL AS THE SPLICING LEVELS. INTERESTINGLY, THE GENES TARGETED BY CADMIUM EXPOSURE ARE INVOLVED IN SEVERAL CRITICAL DEVELOPMENTAL PROCESSES. OUR RESULTS PRESENT A COMPREHENSIVE ANALYSIS OF THE SPERM METHYLOME IN RESPONSE TO CHRONIC CADMIUM EXPOSURE. THESE DATA, THEREFORE, HIGHLIGHT A FOUNDATIONAL FRAMEWORK TO STUDY GENE EXPRESSION PATTERNS THAT MAY AFFECT FERTILITY IN THE EXPOSED INDIVIDUAL AS WELL AS THEIR OFFSPRING, THROUGH PATERNAL INHERITANCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  818  20 CHARACTERISTICS OF THE SPECTRUM OF PROLIFERATIVE LESIONS OBSERVED IN THE KIDNEY AND URINARY BLADDER OF FISCHER 344 RATS AND B6C3F1 MICE. MANY RODENT RENAL AND BLADDER CARCINOGENS RELY UPON EPIGENETIC MECHANISMS OF CARCINOGENESIS; SUCH MECHANISMS ARE LIKELY TO INFLUENCE THE SPECTRUM OF URINARY TRACT TUMORS OBSERVED IN CONTROL AND TREATED ANIMALS. THIS IS REFLECTED IN SEVERAL FEATURES OF CHEMICALLY INDUCED RODENT URINARY TRACT NEOPLASMS, INCLUDING A LOW OVERALL TUMOR INCIDENCE, AN INCREASED PREVALENCE OF URINARY TRACT TUMORS IN RATS COMPARED TO MICE AND MALES COMPARED TO FEMALES, THE TENDENCY FOR EPITHELIAL TUMORS TO PREDOMINATE OVER NONEPITHELIAL TYPES, AND DEMONSTRATED LINKS TO CHRONIC PROGRESSIVE NEPHROPATHY AND UROLITHIASIS. SUCH TENDENCIES ARE ALSO CHARACTERISTIC OF SPONTANEOUS URINARY TRACT TUMORS IN RODENTS. DATA TO SUPPORT THESE OBSERVATIONS CAN BE DERIVED FROM LARGE HISTORICAL DATABASES SUCH AS THE TOXICOLOGY DATA MANAGEMENT SYSTEM, MAINTAINED BY NATIONAL TOXICOLOGY PROGRAM.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12 5894  23 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13 5292  24 PROSTATIC INFLAMMATION ENHANCES BASAL-TO-LUMINAL DIFFERENTIATION AND ACCELERATES INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN. CHRONIC INFLAMMATION HAS BEEN SHOWN TO PROMOTE THE INITIATION AND PROGRESSION OF DIVERSE MALIGNANCIES BY INDUCING GENETIC AND EPIGENETIC ALTERATIONS. IN THIS STUDY, WE INVESTIGATE AN ALTERNATIVE MECHANISM THROUGH WHICH INFLAMMATION PROMOTES THE INITIATION OF PROSTATE CANCER. ADULT MURINE PROSTATE EPITHELIA ARE COMPOSED PREDOMINANTLY OF BASAL AND LUMINAL CELLS. PREVIOUS STUDIES REVEALED THAT THE TWO LINEAGES ARE LARGELY SELF-SUSTAINED WHEN RESIDING IN THEIR NATIVE MICROENVIRONMENT. TO INTERROGATE WHETHER TISSUE INFLAMMATION ALTERS THE DIFFERENTIATION PROGRAM OF BASAL CELLS, WE CONDUCTED LINEAGE TRACING OF BASAL CELLS USING A K14-CREER;MTMG MODEL IN CONCERT WITH A MURINE MODEL OF PROSTATITIS INDUCED BY INFECTION FROM THE UROPATHOGENIC BACTERIA CP9. WE SHOW THAT ACUTE PROSTATITIS CAUSES TISSUE DAMAGE AND CREATES A TISSUE MICROENVIRONMENT THAT INDUCES THE DIFFERENTIATION OF BASAL CELLS INTO LUMINAL CELLS, AN ALTERATION THAT RARELY OCCURS UNDER NORMAL PHYSIOLOGICAL CONDITIONS. PREVIOUSLY WE SHOWED THAT A MOUSE MODEL WITH PROSTATE BASAL CELL-SPECIFIC DELETION OF PHOSPHATASE AND TENSIN HOMOLOG (K14-CREER;PTEN(FL/FL)) DEVELOPS PROSTATE CANCER WITH A LONG LATENCY, BECAUSE DISEASE INITIATION IN THIS MODEL REQUIRES AND IS LIMITED BY THE DIFFERENTIATION OF TRANSFORMATION-RESISTANT BASAL CELLS INTO TRANSFORMATION-COMPETENT LUMINAL CELLS. HERE, WE SHOW THAT CP9-INDUCED PROSTATITIS SIGNIFICANTLY ACCELERATES THE INITIATION OF PROSTATIC INTRAEPITHELIAL NEOPLASIA IN THIS MODEL. OUR RESULTS DEMONSTRATE THAT INFLAMMATION RESULTS IN A TISSUE MICROENVIRONMENT THAT ALTERS THE NORMAL PROSTATE EPITHELIAL CELL DIFFERENTIATION PROGRAM AND THAT THROUGH THIS CELLULAR PROCESS INFLAMMATION ACCELERATES THE INITIATION OF PROSTATE CANCER WITH A BASAL CELL ORIGIN.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14 6280  24 THE PLASTICIZER BISPHENOL A PERTURBS THE HEPATIC EPIGENOME: A SYSTEMS LEVEL ANALYSIS OF THE MIRNOME. UBIQUITOUS EXPOSURE TO BISPHENOL A (BPA), AN ENDOCRINE DISRUPTOR (ED), HAS RAISED CONCERNS FOR BOTH HUMAN AND ECOSYSTEM HEALTH. EPIGENETIC FACTORS, INCLUDING MICRORNAS (MIRNAS), ARE KEY REGULATORS OF GENE EXPRESSION DURING CANCER. THE EFFECT OF BPA EXPOSURE ON THE ZEBRAFISH EPIGENOME REMAINS POORLY CHARACTERIZED. ZEBRAFISH REPRESENTS AN EXCELLENT MODEL TO STUDY CANCER AS THE ORGANISM DEVELOPS A DISEASE THAT RESEMBLES HUMAN CANCER. USING ZEBRAFISH AS A SYSTEMS TOXICOLOGY MODEL, WE HYPOTHESIZED THAT CHRONIC BPA-EXPOSURE IMPACTS THE MIRNOME IN ADULT ZEBRAFISH AND ESTABLISHES AN EPIGENOME MORE SUSCEPTIBLE TO CANCER DEVELOPMENT. AFTER A 3 WEEK EXPOSURE TO 100 NM BPA, RNA FROM THE LIVER WAS EXTRACTED TO PERFORM HIGH THROUGHPUT MRNA AND MIRNA SEQUENCING. DIFFERENTIAL EXPRESSION (DE) ANALYSES COMPARING BPA-EXPOSED TO CONTROL SPECIMENS WERE PERFORMED USING ESTABLISHED BIOINFORMATICS PIPELINES. IN THE BPA-EXPOSED LIVER, 6188 MRNAS AND 15 MIRNAS WERE DIFFERENTLY EXPRESSED (Q </= 0.1). BY ANALYZING HUMAN ORTHOLOGS OF THE DE ZEBRAFISH GENES, SIGNATURES ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD), OXIDATIVE PHOSPHORYLATION, MITOCHONDRIAL DYSFUNCTION AND CELL CYCLE WERE UNCOVERED. CHRONIC EXPOSURE TO BPA HAS A SIGNIFICANT IMPACT ON THE LIVER MIRNOME AND TRANSCRIPTOME IN ADULT ZEBRAFISH WITH THE POTENTIAL TO CAUSE ADVERSE HEALTH OUTCOMES INCLUDING CANCER.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15 6564  26 TRANSIENT EXPOSURE TO ELEVATED GLUCOSE LEVELS CAUSES PERSISTENT CHANGES IN DERMAL MICROVASCULAR ENDOTHELIAL CELL RESPONSES TO INJURY. BACKGROUND: THE PURPOSE OF THIS STUDY WAS TO DETERMINE WHETHER ELEVATED GLUCOSE CAN INDUCE A DERMAL MICROVASCULAR ENDOTHELIAL CELL METABOLIC MEMORY, THUS AFFECTING ANGIOGENESIS IN THE REPAIR PROCESS OF MAMMALIAN CUTANEOUS WOUND. WE HYPOTHESIZED THAT TRANSIENT ELEVATED GLUCOSE LEVELS CAUSE SUSTAINED ALTERATION OF ENDOTHELIAL CELL RESPONSES TO INJURY AND PERSISTENT EPIGENETIC CHANGES IN GENE EXPRESSION. METHODS: HUMAN DERMAL MICROVASCULAR ENDOTHELIAL CELLS WERE EXPOSED TO EXPERIMENTAL CONDITIONS WITH OR WITHOUT 30 MM D-GLUCOSE. THE CONTROL GROUP WAS MAINTAINED AT 5 MM D-GLUCOSE; WHILE IN THE TRANSIENT GLUCOSE GROUP, AFTER BEING EXPOSED TO 30 MM D-GLUCOSE FOR TWO DAYS, THEN BEING PUT UNDER THE CONTROL CONDITIONS DURING THE EXPERIMENT. BESIDES, IN THE WHOLE PROCESS OF THE EXPERIMENT, THE CHRONIC GLUCOSE GROUP WAS KEPT IN THE CONDITION WITH 30 MM D-GLUCOSE. PROLIFERATION, MIGRATION, TUBE FORMATION, GENE EXPRESSION AND HISTONE METHYLATION WERE ASSESSED FOR INDIVIDUAL CONDITIONS. RESULTS: TRANSIENT ELEVATED GLUCOSE CAUSED SUSTAINED EFFECTS ON ENDOTHELIAL CELL MIGRATION, TUBE FORMATION AND TIMP3 GENE EXPRESSION. THE EFFECTS ON TIMP3 EXPRESSION WERE ASSOCIATED WITH PERSISTENT CHANGES IN HISTONE MODIFICATION AT THE 5' END OF THE TIMP3 GENE, SUGGESTING AN EPIGENETIC EFFECT. CONCLUSIONS: HYPERGLYCEMIA INDUCED METABOLIC MEMORY COULD PROMOTE THE REGULATION OF TIMP3, AND IT CAN BE USED AS A POSSIBLE INNOVATIVE MOLECULAR TARGET FOR THERAPEUTIC INTERVENTION IN THE TREATMENT OF CHRONIC NON-HEALING DIABETIC WOUNDS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16 2926  23 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17 3659  27 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18 2033  22 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19 3693  29 INFLAMMATORY CELLS CAN ALTER THE LEVELS OF H3K9AC AND GAMMAH2AX IN DYSPLASTIC CELLS AND FAVOR TUMOR PHENOTYPE. ORAL POTENTIALLY MALIGNANT DISORDERS (OPMD) ARE CLINICAL PRESENTATIONS THAT CARRY AN INCREASED RISK OF CANCER DEVELOPMENT. CURRENTLY, EPITHELIAL DYSPLASIA GRADE IS BASED ON ARCHITECTURAL AND CYTOLOGICAL EPITHELIAL CHANGES AND IS USED TO PREDICT THE MALIGNANT TRANSFORMATION OF THESE LESIONS. HOWEVER, PREDICTING WHICH OPMD WILL PROGRESS TO A MALIGNANT TUMOR IS VERY CHALLENGING. INFLAMMATORY INFILTRATES CAN FAVOR CANCER DEVELOPMENT, AND RECENT STUDIES SUGGEST THAT THIS ASSOCIATION WITH OPMD LESIONS MAY BE RELATED TO THE ETIOLOGY AND/OR AGGRESSIVE CLINICAL BEHAVIOR OF THESE LESIONS. EPIGENETIC CHANGES SUCH AS HISTONE MODIFICATIONS MAY MEDIATE CHRONIC INFLAMMATION AND ALSO FAVOR TUMOR CELLS IN IMMUNE RESISTANCE AND EVASION. THIS STUDY AIMED TO EVALUATE THE RELATIONSHIP BETWEEN HISTONE ACETYLATION (H3K9AC) AND DNA DAMAGE IN THE CONTEXT OF DYSPLASTIC LESIONS WITH PROMINENT CHRONIC INFLAMMATION. IMMUNOFLUORESCENCE OF "LOW-RISK" AND "HIGH-RISK" OPMD LESIONS (N = 24) AND INFLAMMATORY FIBROUS HYPERPLASIA (N = 10) AS THE CONTROL GROUP WAS PERFORMED TO ASSESS HISTONE ACETYLATION LEVELS AND DNA DAMAGE THROUGH THE PHOSPHORYLATION OF H2AX (GAMMAH2AX). CELL CO-CULTURE ASSAYS WITH PBMCS AND ORAL KERATINOCYTE CELL LINES (NOK-SI, DOK, AND SCC-25) WERE PERFORMED TO ASSESS PROLIFERATION, ADHESION, MIGRATION, AND EPITHELIAL-MESENCHYMAL TRANSITION (EMT). ORAL DYSPLASTIC LESIONS SHOWED A HYPOACETYLATION OF H3K9 AND LOW LEVELS OF GAMMAH2AX COMPARED TO CONTROL. THE CONTACT OF DYSPLASTIC ORAL KERATINOCYTES WITH PBMCS FAVORED EMT AND THE LOSS OF CELL-CELL ADHESION. ON THE OTHER HAND, P27 LEVELS INCREASED AND CYCLIN E DECREASED IN DOK, INDICATING CELL CYCLE ARREST. WE CONCLUDE THAT THE PRESENCE OF CHRONIC INFLAMMATION ASSOCIATED TO DYSPLASTIC LESIONS IS CAPABLE OF PROMOTING EPIGENETIC ALTERATIONS, WHICH IN TURN CAN FAVOR THE PROCESS OF MALIGNANT TRANSFORMATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20 6562  22 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