1 4015 162 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  654  54 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3 6280  49 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  652  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  653  29 BISPHENOL A, HYPERTENSION, AND CARDIOVASCULAR DISEASES: EPIDEMIOLOGICAL, LABORATORY, AND CLINICAL TRIAL EVIDENCE. BISPHENOL A (BPA) EXPOSURE HAS BECOME ONE OF THE MOST COMMON ENVIRONMENTAL CHEMICAL EXPOSURES IN HUMANS. THERE IS GROWING EVIDENCE REGARDING AN ASSOCIATION BETWEEN BPA EXPOSURE, HYPERTENSION, AND CARDIOVASCULAR DISEASES (CVD). IF BPA EXPOSURE IS INDEED ASSOCIATED WITH RAISED BLOOD PRESSURE AND CVD, IT WOULD BE A MAJOR PUBLIC HEALTH PROBLEM. THEREFORE, WE REVIEWED THE EPIDEMIOLOGICAL, LABORATORY, AND CLINICAL TRIAL EVIDENCE FOR AN ASSOCIATION BETWEEN BPA EXPOSURE, CVD, AND HYPERTENSION, AND DISCUSSED THE POSSIBLE MECHANISMS IN THIS ARTICLE. CROSS-SECTIONAL STUDIES IN VARIOUS ETHNICITIES SUGGESTED A POSSIBLE ASSOCIATION BETWEEN BPA EXPOSURE AND HYPERTENSION; THIS ASSOCIATION WAS SUPPORTED BY A PANEL STUDY AND A RANDOMIZED CLINICAL TRIAL. DESPITE THE DISCORDANCE AMONG CROSS-SECTIONAL STUDIES ABOUT AN ASSOCIATION BETWEEN BPA EXPOSURE AND CVD, A LONGITUDINAL STUDY SHOWS THAT BPA EXPOSURE IS A RISK FACTOR FOR CVD. THE EFFECTS OF BPA EXPOSURE SUCH AS ENDOCRINAL DISTURBANCE, INDUCTION OF OXIDATIVE STRESS AND INFLAMMATION, EPIGENETIC CHANGE, AND LINKS WITH OTHER CHRONIC DISEASES MAY HIGHLIGHT A POSSIBLE MECHANISM BETWEEN BPA EXPOSURE, CVD, AND HYPERTENSION. TO CLARIFY THE CAUSAL RELATIONSHIP, WELL-DESIGNED STUDIES ARE NEEDED IN THE FUTURE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6  904  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7 1599  37 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES.	2014	
                                                                                                                                                                                                       
8  457  46 APPLYING A MULTISCALE SYSTEMS BIOLOGY APPROACH TO STUDY THE EFFECT OF CHRONIC LOW-DOSE EXPOSURE TO URANIUM IN RAT KIDNEYS. PURPOSE: TO EXAMINE THE EFFECTS OF LOW-DOSE EXPOSURE TO URANIUM WITH A SYSTEMS BIOLOGY APPROACH, A MULTISCALE HIGH-THROUGHPUT MULTI-OMICS ANALYSIS WAS APPLIED WITH A PROTOCOL FOR CHRONIC EXPOSURE TO THE RAT KIDNEY. METHODS: MALE AND FEMALE RATS WERE CONTAMINATED FOR NINE MONTHS THROUGH THEIR DRINKING WATER WITH A NONTOXIC SOLUTION OF URANYL NITRATE. A MULTISCALE APPROACH ENABLED CLINICAL MONITORING ASSOCIATED WITH METABOLOMIC AND TRANSCRIPTOMIC (MRNA AND MICRORNA) ANALYSES. RESULTS: A SEX-INTERACTION EFFECT WAS OBSERVED IN THE KIDNEY, URINE, AND PLASMA METABOLOMES OF CONTAMINATED RATS. MOREOVER, URINE AND KIDNEY METABOLIC PROFILES CORRELATED AND CONFIRMED THAT THE PRIMARY DYSREGULATED METABOLISMS ARE THOSE OF NICOTINATE-NICOTINAMIDE AND OF UNSATURATED FATTY ACID BIOSYNTHESIS. UPSTREAM OF THE METABOLIC PATHWAYS, TRANSCRIPTOMIC PROFILES OF THE KIDNEY REVEAL GENE ACTIVITY FOCUSED ON GENE REGULATION MECHANISMS, CELL SIGNALING, CELL STRUCTURE, DEVELOPMENTAL PROCESSES, AND CELL PROLIFERATION. EXAMINATION OF EPIGENETIC POST-TRANSCRIPTIONAL GENE REGULATION PROCESSES SHOWED SIGNIFICANT DYSREGULATION OF 70 MICRO-RNAS. THE MULTI-OMICS APPROACH HIGHLIGHTED THE ACTIVITIES OF THE CELLS' BIOLOGICAL PROCESSES ON MULTIPLE SCALES THROUGH ANALYSIS OF GENE EXPRESSION, CONFIRMED BY CHANGES OBSERVED IN THE METABOLOME. CONCLUSION: OUR RESULTS SHOWED CHANGES IN MULTI-OMIC PROFILES OF RATS EXPOSED TO LOW DOSES OF URANIUM CONTAMINATION, COMPARED WITH CONTROLS. THESE CHANGES INVOLVED GENE EXPRESSION AS WELL AS MODIFICATIONS IN THE TRANSCRIPTOME AND THE METABOLOME. THE METABOLOMIC PROFILE CONFIRMED THAT THE MAIN MOLECULAR TARGETS OF URANIUM IN KIDNEY CELLS ARE THE METABOLISM OF NICOTINATE-NICOTINAMIDE AND THE BIOSYNTHESIS OF UNSATURATED FATTY ACIDS. ADDITIONALLY, GENE EXPRESSION ANALYSIS SHOWED THAT THE METABOLISM OF FATTY ACIDS IS TARGETED BY PROCESSES ASSOCIATED WITH CELL FUNCTION. THESE RESULTS DEMONSTRATE THAT MULTISCALE SYSTEMS BIOLOGY IS USEFUL IN ELUCIDATING THE MOST DISCRIMINATIVE PATHWAYS FROM GENOMIC TO METABOLOMIC LEVELS FOR ASSESSING THE BIOLOGICAL IMPACT OF THIS LOW-LEVEL ENVIRONMENTAL EXPOSURE, I.E. THE EXPOSOME.	2019	
                           
9 2920  47 GENE-SET ANALYSIS IS SEVERELY BIASED WHEN APPLIED TO GENOME-WIDE METHYLATION DATA. MOTIVATION: DNA METHYLATION IS AN EPIGENETIC MARK THAT CAN STABLY REPRESS GENE EXPRESSION. BECAUSE OF ITS BIOLOGICAL AND CLINICAL SIGNIFICANCE, SEVERAL METHODS HAVE BEEN DEVELOPED TO COMPARE GENOME-WIDE PATTERNS OF METHYLATION BETWEEN GROUPS OF SAMPLES. THE APPLICATION OF GENE SET ANALYSIS TO IDENTIFY RELEVANT GROUPS OF GENES THAT ARE ENRICHED FOR DIFFERENTIALLY METHYLATED GENES IS OFTEN A MAJOR COMPONENT OF THE ANALYSIS OF THESE DATA. THIS CAN BE USED, FOR EXAMPLE, TO IDENTIFY PROCESSES OR PATHWAYS THAT ARE PERTURBED IN DISEASE DEVELOPMENT. WE SHOW THAT GENE-SET ANALYSIS, AS IT IS TYPICALLY APPLIED TO GENOME-WIDE METHYLATION ASSAYS, IS SEVERELY BIASED AS A RESULT OF DIFFERENCES IN THE NUMBERS OF CPG SITES ASSOCIATED WITH DIFFERENT CLASSES OF GENES AND GENE PROMOTERS. RESULTS: WE DEMONSTRATE THIS BIAS USING PUBLISHED DATA FROM A STUDY OF DIFFERENTIAL CPG ISLAND METHYLATION IN LUNG CANCER AND A DATASET WE GENERATED TO STUDY METHYLATION CHANGES IN PATIENTS WITH LONG-STANDING ULCERATIVE COLITIS. WE SHOW THAT SEVERAL OF THE GENE SETS THAT SEEM ENRICHED WOULD ALSO BE IDENTIFIED WITH RANDOMIZED DATA. WE SUGGEST TWO EXISTING APPROACHES THAT CAN BE ADAPTED TO CORRECT THE BIAS. ACCOUNTING FOR THE BIAS IN THE LUNG CANCER AND ULCERATIVE COLITIS DATASETS PROVIDES NOVEL BIOLOGICAL INSIGHTS INTO THE ROLE OF METHYLATION IN CANCER DEVELOPMENT AND CHRONIC INFLAMMATION, RESPECTIVELY. OUR RESULTS HAVE SIGNIFICANT IMPLICATIONS FOR MANY PREVIOUS GENOME-WIDE METHYLATION STUDIES THAT HAVE DRAWN CONCLUSIONS ON THE BASIS OF SUCH STRONGLY BIASED ANALYSIS. CONTACT: CATHAL.SEOIGHE@NUIGALWAY.IE SUPPLEMENTARY INFORMATION: SUPPLEMENTARY DATA ARE AVAILABLE AT BIOINFORMATICS ONLINE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10 3292  44 HIGH FAT DIET AND EXERCISE LEAD TO A DISRUPTED AND PATHOGENIC DNA METHYLOME IN MOUSE LIVER. HIGH-FAT DIET CONSUMPTION AND SEDENTARY LIFESTYLE ELEVATES RISK FOR OBESITY, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CANCER. EXERCISE TRAINING CONVEYS HEALTH BENEFITS IN POPULATIONS WITH OR WITHOUT THESE CHRONIC CONDITIONS. DIET AND EXERCISE REGULATE GENE EXPRESSION BY MEDIATING EPIGENETIC MECHANISMS IN MANY TISSUES; HOWEVER, SUCH EFFECTS ARE POORLY DOCUMENTED IN THE LIVER, A CENTRAL METABOLIC ORGAN. TO DISSECT THE CONSEQUENCES OF DIET AND EXERCISE ON THE LIVER EPIGENOME, WE MEASURED DNA METHYLATION, USING REDUCED REPRESENTATION BISULFITE SEQUENCING, AND TRANSCRIPTION, USING RNA-SEQ, IN MICE MAINTAINED ON A FAST FOOD DIET WITH SEDENTARY LIFESTYLE OR EXERCISE, COMPARED WITH CONTROL DIET WITH AND WITHOUT EXERCISE. OUR ANALYSES REVEAL THAT GENOME-WIDE DIFFERENTIAL DNA METHYLATION AND EXPRESSION OF GENE CLUSTERS ARE INDUCED BY DIET AND/OR EXERCISE. A COMBINATION OF FAST FOOD AND EXERCISE TRIGGERS EXTENSIVE GENE ALTERATIONS, WITH ENRICHMENT OF CARBOHYDRATE/LIPID METABOLIC PATHWAYS AND MUSCLE DEVELOPMENTAL PROCESSES. THROUGH EVALUATION OF PUTATIVE PROTECTIVE EFFECTS OF EXERCISE ON DIET-INDUCED DNA METHYLATION, WE SHOW THAT HYPERMETHYLATION IS EFFECTIVELY PREVENTED, ESPECIALLY AT PROMOTERS AND ENHANCERS, WHEREAS HYPOMETHYLATION IS ONLY PARTIALLY ATTENUATED. WE ASSESSED DIET-INDUCED DNA METHYLATION CHANGES ASSOCIATED WITH LIVER CANCER-RELATED EPIGENETIC MODIFICATIONS AND IDENTIFIED SIGNIFICANT INCREASES AT LIVER-SPECIFIC ENHANCERS IN FAST FOOD GROUPS, SUGGESTING PARTIAL LOSS OF LIVER CELL IDENTITY. HYPERMETHYLATION AT A SUBSET OF GENE PROMOTERS WAS ASSOCIATED WITH INHIBITION OF TISSUE DEVELOPMENT AND PROMOTION OF CARCINOGENIC PROCESSES. OUR STUDY DEMONSTRATES EXTENSIVE REPROGRAMMING OF THE EPIGENOME BY DIET AND EXERCISE, EMPHASIZING THE FUNCTIONAL RELEVANCE OF EPIGENETIC MECHANISMS AS AN INTERFACE BETWEEN LIFESTYLE MODIFICATIONS AND PHENOTYPIC ALTERATIONS.	2017	
                                                                                                                                                                                                                                                                                                                          
11 3738  49 INORGANIC ARSENIC-INDUCED CELLULAR TRANSFORMATION IS COUPLED WITH GENOME WIDE CHANGES IN CHROMATIN STRUCTURE, TRANSCRIPTOME AND SPLICING PATTERNS. BACKGROUND: ARSENIC (AS) EXPOSURE IS A SIGNIFICANT WORLDWIDE ENVIRONMENTAL HEALTH CONCERN. LOW DOSE, CHRONIC ARSENIC EXPOSURE HAS BEEN ASSOCIATED WITH A HIGHER THAN NORMAL RISK OF SKIN, LUNG, AND BLADDER CANCER, AS WELL AS CARDIOVASCULAR DISEASE AND DIABETES. WHILE ARSENIC-INDUCED BIOLOGICAL CHANGES PLAY A ROLE IN DISEASE PATHOLOGY, LITTLE IS KNOWN ABOUT THE DYNAMIC CELLULAR CHANGES RESULTING FROM ARSENIC EXPOSURE AND WITHDRAWAL. RESULTS: IN THESE STUDIES, WE SOUGHT TO UNDERSTAND THE MOLECULAR MECHANISMS BEHIND THE BIOLOGICAL CHANGES INDUCED BY ARSENIC EXPOSURE. A COMPREHENSIVE GLOBAL APPROACH WAS EMPLOYED TO DETERMINE GENOME-WIDE CHANGES TO CHROMATIN STRUCTURE, TRANSCRIPTOME PATTERNS AND SPLICING PATTERNS IN RESPONSE TO CHRONIC LOW DOSE ARSENIC AND ITS SUBSEQUENT WITHDRAWAL. OUR RESULTS SHOW THAT CELLS EXPOSED TO CHRONIC LOW DOSES OF SODIUM ARSENITE HAVE DISTINCT TEMPORAL AND COORDINATED CHROMATIN, GENE EXPRESSION, AND MIRNA CHANGES CONSISTENT WITH DIFFERENTIATION AND ACTIVATION OF MULTIPLE BIOCHEMICAL PATHWAYS. MOST OF THESE TEMPORAL PATTERNS IN GENE EXPRESSION ARE REVERSED WHEN ARSENIC IS WITHDRAWN. HOWEVER, SOME GENE EXPRESSION PATTERNS REMAINED ALTERED, PLAUSIBLY AS A RESULT OF AN ADAPTIVE RESPONSE BY CELLS. ADDITIONALLY, THE CORRELATION OF CHANGES TO GENE EXPRESSION AND CHROMATIN STRUCTURE SOLIDIFY THE ROLE OF CHROMATIN STRUCTURE IN GENE REGULATORY CHANGES DUE TO ARSENITE EXPOSURE. LASTLY, WE SHOW THAT ARSENITE EXPOSURE INFLUENCES GENE REGULATION BOTH AT THE INITIATION OF TRANSCRIPTION AS WELL AS AT THE LEVEL OF SPLICING. CONCLUSIONS: OUR RESULTS SHOW THAT ADAPTATION OF CELLS TO IAS-MEDIATED EMT IS COUPLED TO CHANGES IN CHROMATIN STRUCTURE EFFECTING DIFFERENTIAL TRANSCRIPTIONAL AND SPLICING PATTERNS OF GENES. THESE STUDIES PROVIDE NEW INSIGHTS INTO THE MECHANISM OF IAS-MEDIATED PATHOLOGY, WHICH INCLUDES EPIGENETIC CHROMATIN CHANGES COUPLED WITH CHANGES TO THE TRANSCRIPTOME AND SPLICING PATTERNS OF KEY GENES.	2015	
                                                                                                                                                                                               
12 6790  30 [DNA METHYLATION ANALYSIS IN ENVIRONMENTAL AND OCCUPATIONAL CANCER RESEARCH]. THE PRESENT PAPER REVIEWS RECENT LABORATORY METHODS AND EXPERIMENTAL EVIDENCE CONCERNING EPIGENETIC BIOMARKERS INVOLVED IN CARCINOGENESIS MECHANISMS. WE INTRODUCE DNA METHYLATION AND ITS ROLE IN GENE EXPRESSION CONTROL. DNA METHYLATION ANALYSIS MAY ALLOW TO IDENTIFY EARLY CHANGES LEADING TO CANCER AND OTHER CHRONIC DISEASES. WE DESCRIBE HERE STRATEGIES FOR LABORATORY ANALYSES AND THEIR POSSIBLE APPLICATIONS. WE EXAMINE RESULTS FROM RECENT EXPERIMENTAL STUDIES SUGGESTING THAT THE EFFECTS OF CERTAIN OCCUPATIONAL AGENTS ARE MEDIATED BY ALTERATIONS IN DNA METHYLATION. PLANNING AND CONDUCTING INVESTIGATIONS ON EXPOSED HUMAN SUBJECTS WILL ALLOW TO VERIFY WHETHER DNA METHYLATION CHANGES IDENTIFIED IN ANIMAL AND IN-VITRO STUDIES MAY BE USED AS EARLY-EFFECT AND SUSCEPTIBILITY BIOMARKERS. DNA METHYLATION ANALYSIS HAS THE POTENTIAL FOR FUTURE APPLICATIONS IN RISK ASSESSMENT AND PREVENTION PROGRAMS CONDUCTED ON SUBJECTS EXPOSED TO HUMAN CARCINOGENS.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  287  36 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  228  40 ADAPTATION OF THE HUMAN POPULATION TO THE ENVIRONMENT: CURRENT KNOWLEDGE, CLUES FROM CZECH CYTOGENETIC AND "OMICS" BIOMONITORING STUDIES AND POSSIBLE MECHANISMS. THE HUMAN POPULATION IS CONTINUALLY EXPOSED TO NUMEROUS HARMFUL ENVIRONMENTAL STRESSORS, CAUSING NEGATIVE HEALTH EFFECTS AND/OR DEREGULATION OF BIOMARKER LEVELS. HOWEVER, STUDIES REPORTING NO OR EVEN POSITIVE IMPACTS OF SOME STRESSORS ON HUMANS ARE ALSO SOMETIMES PUBLISHED. THE MAIN AIM OF THIS REVIEW IS TO PROVIDE A COMPREHENSIVE OVERVIEW OF THE LAST DECADE OF CZECH BIOMONITORING RESEARCH, CONCERNING THE EFFECT OF VARIOUS LEVELS OF AIR POLLUTION (BENZO[A]PYRENE) AND RADIATION (URANIUM, X-RAY EXAMINATION AND NATURAL RADON BACKGROUND), ON THE DIFFERENTLY EXPOSED POPULATION GROUPS. BECAUSE SOME RESULTS OBTAINED FROM CYTOGENETIC STUDIES WERE OPPOSITE THAN HYPOTHESIZED, WE HAVE SEARCHED FOR A MEANINGFUL INTERPRETATION IN GENOMIC/EPIGENETIC STUDIES. A DETAILED ANALYSIS OF OUR DATA SUPPORTED BY THE STUDIES OF OTHERS AND CURRENT EPIGENETIC KNOWLEDGE, LEADS TO A HYPOTHESIS OF THE VERSATILE MECHANISM OF ADAPTATION TO ENVIRONMENTAL STRESSORS VIA DNA METHYLATION SETTINGS WHICH MAY EVEN ORIGINATE IN PRENATAL DEVELOPMENT, AND HELP TO REDUCE THE RESULTING DNA DAMAGE LEVELS. THIS HYPOTHESIS IS FULLY IN AGREEMENT WITH UNEXPECTED DATA FROM OUR STUDIES (E.G. LOWER LEVELS OF DNA DAMAGE IN SUBJECTS FROM HIGHLY POLLUTED REGIONS THAN IN CONTROLS OR IN SUBJECTS EXPOSED REPEATEDLY TO A POLLUTANT THAN IN THOSE WITHOUT PREVIOUS EXPOSURE), AND IS ALSO SUPPORTED BY DIFFERENCES IN DNA METHYLATION PATTERNS IN GROUPS FROM REGIONS WITH VARIOUS LEVELS OF POLLUTION. IN LIGHT OF THE ADAPTATION HYPOTHESIS, THE FOLLOWING POINTS MAY BE SUGGESTED FOR FUTURE RESEARCH: (I) THE CHRONIC AND ACUTE EXPOSURE OF STUDY SUBJECTS SHOULD BE DISTINGUISHED; (II) THE EXPOSURE HISTORY SHOULD BE MAPPED INCLUDING PLACE OF RESIDENCE DURING THE LIFE AND PRENATAL DEVELOPMENT; (III) CHANGES OF EPIGENETIC MARKERS SHOULD BE MONITORED OVER TIME. IN SUMMARY, INVESTIGATION OF HUMAN ADAPTATION TO THE ENVIRONMENT, ONE OF THE MOST IMPORTANT PROCESSES OF SURVIVAL, IS A NEW CHALLENGE FOR FUTURE RESEARCH IN THE FIELD OF HUMAN BIOMONITORING THAT MAY CHANGE OUR VIEW ON THE RESULTS OF BIOMARKER ANALYSES AND POTENTIAL NEGATIVE HEALTH IMPACTS OF THE ENVIRONMENT.	2017	

15 1583  34 DNA METHYLATION PROFILES OF BLOOD CELLS ARE DISTINCT BETWEEN EARLY-ONSET OBESE AND CONTROL INDIVIDUALS. OBESITY IS A HIGHLY PREVALENT, CHRONIC DISORDER THAT HAS BEEN INCREASING IN INCIDENCE IN YOUNG PATIENTS. BOTH EPIGENETIC AND GENETIC ABERRATIONS MAY PLAY A ROLE IN THE PATHOGENESIS OF OBESITY. THEREFORE, IN-DEPTH EPIGENOMIC AND GENOMIC ANALYSES WILL ADVANCE OUR UNDERSTANDING OF THE DETAILED MOLECULAR MECHANISMS UNDERLYING OBESITY AND AID IN THE SELECTION OF POTENTIAL BIOMARKERS FOR OBESITY IN YOUTH. HERE, WE PERFORMED MICROARRAY-BASED DNA METHYLATION AND GENE EXPRESSION PROFILING OF PERIPHERAL WHITE BLOOD CELLS OBTAINED FROM SIX YOUNG, OBESE INDIVIDUALS AND SIX HEALTHY CONTROLS. WE OBSERVED THAT THE HIERARCHICAL CLUSTERING OF DNA METHYLATION, BUT NOT GENE EXPRESSION, CLEARLY SEGREGATES THE OBESE INDIVIDUALS FROM THE CONTROLS, SUGGESTING THAT THE METABOLIC DISTURBANCE THAT OCCURS AS A RESULT OF OBESITY AT A YOUNG AGE MAY AFFECT THE DNA METHYLATION OF PERIPHERAL BLOOD CELLS WITHOUT ACCOMPANYING TRANSCRIPTIONAL CHANGES. TO EXAMINE THE GENOME-WIDE DIFFERENCES IN THE DNA METHYLATION PROFILES OF YOUNG OBESE AND CONTROL INDIVIDUALS, WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES AND INVESTIGATED THEIR GENOMIC AND EPIGENOMIC CONTEXTS. THE ABERRANT DNA METHYLATION PATTERNS IN OBESE INDIVIDUALS CAN BE SUMMARIZED AS RELATIVE GAINS AND LOSSES OF DNA METHYLATION IN GENE PROMOTERS AND GENE BODIES, RESPECTIVELY. WE ALSO OBSERVED THAT THE CPG ISLANDS OF OBESE INDIVIDUALS ARE MORE SUSCEPTIBLE TO DNA METHYLATION COMPARED TO CONTROLS. OUR PILOT STUDY SUGGESTS THAT THE GENOME-WIDE ABERRANT DNA METHYLATION PATTERNS OF OBESE INDIVIDUALS MAY ADVANCE NOT ONLY OUR UNDERSTANDING OF THE EPIGENOMIC PATHOGENESIS BUT ALSO EARLY SCREENING OF OBESITY IN YOUTH.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16 2075  41 EPIGENETIC DIFFERENCES IN INFLAMMATION GENES OF MONOZYGOTIC TWINS ARE RELATED TO PARENT-CHILD EMOTIONAL AVAILABILITY AND HEALTH. THE INFLAMMATORY RESPONSE IS AN IMMUNE DEFENSE ENGAGED IMMEDIATELY AFTER INJURY OR INFECTION. CHRONIC INFLAMMATION CAN BE DELETERIOUS FOR VARIOUS HEALTH OUTCOMES AND IS CHARACTERIZED BY HIGH LEVELS OF PRO-INFLAMMATORY MARKERS SUCH AS C-REACTIVE PROTEIN (CRP), INTERLEUKIN 6 (IL-6), AND TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA). A LARGE BODY OF RESEARCH DEMONSTRATES THESE INFLAMMATORY MARKERS ARE RESPONSIVE TO STRESS AND QUALITY OF SOCIAL RELATIONSHIPS THROUGHOUT THE LIFESPAN. FOR EXAMPLE, THE QUALITY OF THE EARLY PARENTAL BOND PREDICTS VARIOUS HEALTH OUTCOMES AND MAY BE DRIVEN BY CHANGES IN IMMUNE FUNCTION. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, MAY BE ONE MECHANISM BY WHICH EARLY SOCIAL EXPERIENCES SHAPE IMMUNE FUNCTIONING. THE PRESENT STUDY USED A MONOZYGOTIC TWIN DIFFERENCE DESIGN TO ASSESS IF MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR AND 2.5 YEARS PREDICTED IMMUNE GENE METHYLATION AT 8 YEARS OF AGE. FURTHER, WE ASSESSED IF INFLAMMATION GENE METHYLATION WAS RELATED TO GENERAL HEALTH PROBLEMS (E.G. INFECTIONS, ALLERGIES, ETC.). WE FOUND THAT MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR, BUT NOT 2.5 YEARS, WAS RELATED TO METHYLATION OF VARIOUS IMMUNE GENES IN MONOZYGOTIC TWINS. FURTHERMORE, TWIN PAIRS DISCORDANT IN HEALTH PROBLEMS HAVE MORE DIFFERENCE IN IMMUNE GENE METHYLATION COMPARED TO TWIN PAIRS CONCORDANT FOR HEALTH PROBLEMS, SUGGESTING THAT METHYLATION OF IMMUNE GENES MAY HAVE FUNCTIONAL CONSEQUENCES FOR GENERAL HEALTH. THESE RESULTS SUGGEST THAT THE EMOTIONAL COMPONENT OF ATTACHMENT QUALITY DURING INFANCY CONTRIBUTES TO IMMUNE EPIGENETIC PROFILES IN CHILDHOOD, WHICH MAY INFLUENCE GENERAL HEALTH.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17 3836  33 IONIZING RADIATION POTENTIATES HIGH-FAT DIET-INDUCED INSULIN RESISTANCE AND REPROGRAMS SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS. EXPOSURE TO IONIZING RADIATION INCREASES THE RISK OF CHRONIC METABOLIC DISORDERS SUCH AS INSULIN RESISTANCE AND TYPE 2 DIABETES LATER IN LIFE. WE HYPOTHESIZED THAT IRRADIATION REPROGRAMS THE EPIGENOME OF METABOLIC PROGENITOR CELLS, WHICH COULD ACCOUNT FOR IMPAIRED METABOLISM AFTER CANCER TREATMENT. C57BL/6 MICE WERE TREATED WITH A SINGLE DOSE OF IRRADIATION AND SUBJECTED TO HIGH-FAT DIET (HFD). RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING WERE USED TO CREATE TRANSCRIPTOMIC AND EPIGENOMIC PROFILES OF PREADIPOCYTES AND SKELETAL MUSCLE SATELLITE CELLS COLLECTED FROM IRRADIATED MICE. MICE SUBJECTED TO TOTAL BODY IRRADIATION SHOWED ALTERATIONS IN GLUCOSE METABOLISM AND, WHEN CHALLENGED WITH HFD, MARKED HYPERINSULINEMIA. INSULIN SIGNALING WAS CHRONICALLY DISRUPTED IN SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS COLLECTED FROM IRRADIATED MICE AND DIFFERENTIATED IN CULTURE. EPIGENOMIC PROFILING OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS FROM IRRADIATED ANIMALS REVEALED SUBSTANTIAL DNA METHYLATION CHANGES, NOTABLY FOR GENES REGULATING THE CELL CYCLE, GLUCOSE/LIPID METABOLISM, AND EXPRESSION OF EPIGENETIC MODIFIERS. OUR RESULTS SHOW THAT TOTAL BODY IRRADIATION ALTERS INTRACELLULAR SIGNALING AND EPIGENETIC PATHWAYS REGULATING CELL PROLIFERATION AND DIFFERENTIATION OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS AND PROVIDE A POSSIBLE MECHANISM BY WHICH IRRADIATION USED IN CANCER TREATMENT INCREASES THE RISK FOR METABOLIC DISEASE LATER IN LIFE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18 1269  34 CYTOSINE METHYLATION CHANGES IN ENHANCER REGIONS OF CORE PRO-FIBROTIC GENES CHARACTERIZE KIDNEY FIBROSIS DEVELOPMENT. BACKGROUND: ONE IN ELEVEN PEOPLE IS AFFECTED BY CHRONIC KIDNEY DISEASE, A CONDITION CHARACTERIZED BY KIDNEY FIBROSIS AND PROGRESSIVE LOSS OF KIDNEY FUNCTION. EPIDEMIOLOGICAL STUDIES INDICATE THAT ADVERSE INTRAUTERINE AND POSTNATAL ENVIRONMENTS HAVE A LONG-LASTING ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT. EPIGENETIC INFORMATION REPRESENTS A PLAUSIBLE CARRIER FOR MEDIATING THIS PROGRAMMING EFFECT. HERE WE DEMONSTRATE THAT GENOME-WIDE CYTOSINE METHYLATION PATTERNS OF HEALTHY AND CHRONIC KIDNEY DISEASE TUBULE SAMPLES OBTAINED FROM PATIENTS SHOW SIGNIFICANT DIFFERENCES. RESULTS: WE IDENTIFY DIFFERENTIALLY METHYLATED REGIONS AND VALIDATE THESE IN A LARGE REPLICATION DATASET. THE DIFFERENTIALLY METHYLATED REGIONS ARE RARELY OBSERVED ON PROMOTERS, BUT MOSTLY OVERLAP WITH PUTATIVE ENHANCER REGIONS, AND THEY ARE ENRICHED IN CONSENSUS BINDING SEQUENCES FOR IMPORTANT RENAL TRANSCRIPTION FACTORS. THIS INDICATES THEIR IMPORTANCE IN GENE EXPRESSION REGULATION. A CORE SET OF GENES THAT ARE KNOWN TO BE RELATED TO KIDNEY FIBROSIS, INCLUDING GENES ENCODING COLLAGENS, SHOW CYTOSINE METHYLATION CHANGES CORRELATING WITH DOWNSTREAM TRANSCRIPT LEVELS. CONCLUSIONS: OUR REPORT RAISES THE POSSIBILITY THAT EPIGENETIC DYSREGULATION PLAYS A ROLE IN CHRONIC KIDNEY DISEASE DEVELOPMENT VIA INFLUENCING CORE PRO-FIBROTIC PATHWAYS AND CAN AID THE DEVELOPMENT OF NOVEL BIOMARKERS AND FUTURE THERAPEUTICS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19 5097  39 PLASTICS DERIVED ENDOCRINE-DISRUPTING COMPOUNDS AND THEIR EFFECTS ON EARLY DEVELOPMENT. DESPITE THE FACT THAT THE ESTROGENIC EFFECTS OF BISPHENOLS WERE FIRST DESCRIBED 80 YEARS AGO, RECENT DATA ABOUT ITS POTENTIAL NEGATIVE IMPACT ON BIRTH OUTCOME PARAMETERS RAISES A STRONG RATIONALE TO INVESTIGATE FURTHER. THE ADVERSE HEALTH EFFECTS OF PLASTICS RECOMMEND TO MEASURE THE IMPACTS OF ENDOCRINE-DISRUPTING COMPOUNDS (EDCS) SUCH AS BISPHENOLS (BPA, BPS, BPF), BIS(2-ETHYLHEXYL) PHTHALATE, AND DIBUTYL PHTHALATE (DBP) IN HUMAN HEALTH. EXPOSURE TO THESE COMPOUNDS IN UTERO MAY PROGRAM THE DISEASES OF THE TESTIS, PROSTATE, KIDNEY AND ABNORMALITIES IN THE IMMUNE SYSTEM, AND CAUSE TUMORS, UTERINE HEMORRHAGE DURING PREGNANCY AND POLYCYSTIC OVARY. THESE COMPOUNDS ALSO CONTROL THE PROCESSES OF EPIGENETIC TRANSGENERATIONAL INHERITANCE OF ADULT-ONSET DISEASES BY MODULATING DNA METHYLATION AND EPIMUTATIONS IN REPRODUCTIVE CELLS. THE EARLY DEVELOPMENTAL STAGE IS THE MOST SUSCEPTIBLE WINDOW FOR DEVELOPMENTAL AND GENOMIC PROGRAMMING. THE CRITICAL STAGES OF THE EVENTS FOR A NORMAL HUMAN BIRTH LIE BETWEEN THE MANY TRANSITIONS OCCURRING BETWEEN SPERMATOGENESIS, EGG FERTILIZATION AND THE FULLY FORMED FETUS. AS THE CELLS BEGIN TO GROW AND DIFFERENTIATE, THERE ARE CRITICAL BALANCES OF HORMONES, AND PROTEIN SYNTHESIS. DATA ARE EMERGING ON HOW THESE PLASTIC-DERIVED COMPOUNDS AFFECT EMBRYOGENESIS, PLACENTATION AND FETO-PLACENTAL DEVELOPMENT SINCE PREGNANT WOMEN AND UNBORN FETUSES ARE OFTEN EXPOSED TO THESE FACTORS DURING PRECONCEPTION AND THROUGHOUT GESTATION. IMPAIRED EARLY DEVELOPMENT THAT ULTIMATELY INFLUENCES FETAL OUTCOMES IS AT THE CENTER OF MANY DEVELOPMENTAL DISORDERS AND CONTRIBUTES AN INDEPENDENT RISK FACTOR FOR ADULT CHRONIC DISEASES. THIS REVIEW WILL SUMMARIZE THE CURRENT STATUS ON THE IMPACT OF EXPOSURE TO PLASTIC DERIVED EDCS ON THE GROWTH, GENE EXPRESSION, EPIGENETIC AND ANGIOGENIC ACTIVITIES OF THE EARLY FETAL DEVELOPMENT PROCESS AND THEIR POSSIBLE EFFECTS ON BIRTH OUTCOMES.	2020	
                                                                                                                                                                                                                                                                                                     
20 1503  40 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION.	2009