1 3378 132 HIV INDUCED NITRIC OXIDE AND LIPID PEROXIDATION, INFLUENCES NEONATAL BIRTHWEIGHT IN A SOUTH AFRICAN POPULATION. HIV HAS BEEN IMPLICATED IN ADVERSE BIRTH OUTCOMES, DUE TO INCREASED OXIDATIVE STRESS AND INFLAMMATION. IN ADDITION, HIV HAS BEEN REPORTED TO INCREASE NITRIC OXIDE LEVELS. THEREFORE THE COMBINED EXPOSURES TO HIV AND TRAFFIC-RELATED AIR POLLUTION, WITHIN SOUTH DURBAN, SOUTH AFRICA (SA), MAY LEAD TO ADVERSE BIRTH OUTCOMES. HOWEVER, THE EXACT MECHANISM IS STILL UNKNOWN; THIS STUDY AIMED TO IDENTIFY A POTENTIAL MECHANISM. FIRST, THE INFLUENCE OF HIV ON OXIDATIVE AND NITROSATIVE STRESS MARKERS IN PREGNANT WOMEN WAS ASSESSED. SECONDLY, THE EFFECT OF THESE STRESS MAKERS AND EXPOSURE TO OXIDES OF NITROGEN (NOX) ON NEONATAL BIRTHWEIGHT (BW) WAS EVALUATED. FINALLY, THE EFFECT HIV AND TRAFFIC-RELATED POLLUTION EXPOSURE HAS ON THE OXIDATIVE AND ENDOPLASMIC PROFILE AND EPIGENETIC REGULATION OF NRF2-KEAP1 PATHWAY BY MIR-144 AND MIR-28 IN PREGNANT WOMEN WAS DETERMINED. WOMEN, IN THEIR THIRD TRIMESTER WITH SINGLETON PREGNANCIES, WHO WERE HIV+ AND HIV-, WERE RECRUITED FROM DURBAN, SA. BIOMARKER LEVELS OF SERUM NITRITES/NITRATES (NO) AND MALONDIALDEHYDE (MDA) WERE ANALYSED AND MRNA EXPRESSION LEVELS OF OXIDATIVE AND ENDOPLASMIC STRESS RESPONSE GENES WERE ASSESSED. LAND REGRESSION MODELLING WAS PERFORMED TO DETERMINE NOX EXPOSURE LEVELS. HIV EXPOSURE DURING PREGNANCY WAS ASSOCIATED WITH INCREASED NO LEVELS. NO WAS SHOWN TO REDUCE NEONATAL BW. NO AND MDA WAS FOUND TO RECIPROCALLY INCREASE EACH OTHER, WITH HIV DIFFERENTIALLY INFLUENCING MDA'S EFFECT ON BW. HIV DOWN-REGULATED MIR-144 WHICH WAS NEGATIVELY ASSOCIATED WITH NRF2, SUGGESTING A POTENTIAL MECHANISM FOR HIV ASSOCIATED CHRONIC OXIDATIVE STRESS. THIS STUDY PROPOSES THAT NO PLAYS A KEY ROLE IN NEONATAL BW REDUCTION IN RESPONSE TO HIV AND TRAFFIC-RELATED AIR POLLUTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 5189  25 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3 6084  42 THE EFFECT OF TRAINING ABOUT ENVIRONMENTAL TOXICANT BISPHENOL-A EXPOSURE IN PREGNANCY ON MATERNAL URINE BISPHENOL-A LEVEL. PURPOSE: BISPHENOL A (BPA) IS AN ENVIRONMENTAL TOXIN, CLEARLY CAPABLE OF INITIATING EPIGENETIC MODIFICATIONS, LEADING TO THE DEVELOPMENT OF NUMEROUS HUMAN ILLNESSES SUCH AS METABOLIC, REPRODUCTIVE, AND BEHAVIOURAL ABNORMALITIES. IT ALSO CAUSES OXIDATIVE STRESS, WHICH HAS BEEN SHOWN TO BE ALLEVIATED BY SELENIUM SUPPLEMENTATION. THE PURPOSE OF THIS STUDY WAS TO DETERMINE THE EFFECT OF TRAINING OF BPA EXPOSURE DURING PREGNANCY ON URINE BPA LEVELS. METHODS: THIS RESEARCH ENROLLED 30 PREGNANT WOMEN WHO WERE IN THEIR FIRST TRIMESTER AND WERE FREE OF CHRONIC ILLNESS. WOMEN WERE ASKED QUESTIONS ON THEIR SOCIODEMOGRAPHIC FEATURES, ANTHROPOMETRIC MEASURES, OBSTETRIC CHARACTERISTICS, BPA AWARENESS LEVEL, BPA EXPOSURE AND THE HEALTH PRACTICES IN PREGNANCY SCALE AS A PRE-TEST AND POST-TEST. THE INITIAL URINE SAMPLES WERE TAKEN FROM WOMEN IN THEIR FIRST TRIMESTER AND STORED IN BPA-FREE BAGS. THEN, TRAINING WAS DELIVERED TO ENCOURAGE BPA EXPOSURE REDUCTION AND MATERNAL HEALTH AWARENESS. FIRST-TRIMESTER FACE-TO-FACE INSTRUCTION AND BROCHURE DISTRIBUTION WERE FOLLOWED BY REFRESHER, REMINDER, AND FOLLOW-UP TRAININGS DURING THE SECOND AND THIRD TRIMESTERS. URINE SAMPLES FROM WOMEN IN THEIR SECOND AND THIRD TRIMESTERS WERE OBTAINED AGAIN. THE LEVELS OF BPA IN URINE WERE MEASURED USING THE LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY ON 90 SAMPLES. EACH PERSON'S URINE CONCENTRATION DIFFERS, THUS THE CREATININE LEVEL IN ALL SAMPLES WAS ALSO CALCULATED AND COMPARED TO THE BPA CONTENT, AND THE RESULTS WERE EVALUATED. RESULTS: OUR STUDY SHOWN THAT BPA EXPOSURE MAY BE LOWERED BY TRAINING. IT HAS BEEN DEMONSTRATED THAT REDUCING BPA EXPOSURE AND INCREASING KNOWLEDGE CAN RESULT IN AN IMPROVEMENT IN HEALTH STATUS. ADDITIONALLY, IT HAS BEEN DEMONSTRATED THAT TRAININGS GREATLY MINIMIZE EXPOSURE-CAUSING BEHAVIOURS. CONCLUSION: IT WAS DISCOVERED THAT WHILE THE DURATION OF A SINGLE TRAINING DOES NOT MAKE A MEANINGFUL EFFECT, THE CONTINUING OF REMINDER TRAININGS DID MAKE A SUBSTANTIAL DIFFERENCE IN THE URINE BPA LEVEL.	2022	
                                                                                                                                                                                                                                                              
4 6794  34 [EFFECT OF BENZO(A)PYRENE ON THE EXPRESSION OF AHR-REGULATED MICRORNA IN FEMALE AND MALE RAT LUNGS]. SMOKING IS THE MAIN RISK FACTOR FOR LUNG CANCER, MAINLY DUE TO PRESENCE OF NITROSAMINES AND POLYCYCLIC AROMATIC HYDROCARBONS, INCLUDING BENZO[A]PYRENE (BP) IN TOBACCO SMOKE COMPOSITION. THE GENOTOXIC EFFECT OF BP IS BASED ON THE HIGH DNA-BINDING ABILITY OF ITS METABOLITES, WHILE THE EPIGENETIC EFFECTS ARE MEDIATED BY A CHANGE IN THE EXPRESSION OF CANCER RELATED GENES OR REGULATORY RNAS. IT HAS BEEN SHOWN THAT WOMEN HAVE A HIGHER RISK TO DEVELOP LUNG CANCER UPON SMOKING RATHER THAN MEN. WE HYPOTHESIZED THAT CROSSTALK BETWEEN SIGNALING PATHWAYS ACTIVATED BY BP AND ESTROGENS COULD UNDERLIE THE SEX-DEPENDENT DIFFERENCES IN MIRNAS EXPRESSION. TO TEST THIS HYPOTHESIS, MALE AND FEMALE RATS WERE SUBJECTED TO SHORT-TERM OR LONG-TERM BP EXPOSURE. USING IN SILICO ANALYSIS, MIRNAS CONTAINING THE ER- AND AHR-BINDING SITES IN THE PROMOTERS OF THE GENES (OR HOST GENES) WERE SELECTED. DURING CHRONIC EXPOSURE OF BP THE EXPRESSION OF MIR-22-3P, -29A-3P, -126A-3P, -193B-5P IN THE LUNGS OF MALE RATS WERE SIGNIFICANTLY INCREASED, WHILE THE LEVEL OF MIRNA-483-3P WERE DECREASED. EXPRESSION OF MIRNA-483-3P WAS UP-REGULATED DURING CHRONIC BP EXPOSURE IN THE LUNGS OF FEMALE RATS AND THE LEVELS OF OTHER STUDIED MIRNAS WERE UNCHANGED. IN TURN, CHANGES IN THE EXPRESSION OF MIRNAS WERE FOLLOWED BY CHANGES IN THE EXPRESSION OF THEIR TARGET GENES, INCLUDING PTEN, EMP2, IGF1, ITGA6, SLC34A2, AND THE OBSERVED CHANGES IN FEMALE AND MALE RAT LUNGS WERE VARIED. THUS, OUR RESULTS SUGGEST THAT SEX-DEPENDENT EPIGENETIC EFFECTS OF BP MAY BE BASED ON DIFFERENT EXPRESSION OF AHR- AND ER- REGULATED MIRNAS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5 4528  27 MULTIGENERATIONAL EFFECTS OF CADMIUM ON THE LIFESPAN AND FERTILITY OF DROSOPHILA MELANOGASTER. ALTHOUGH THE DAMAGE AND TOLERANCE MECHANISMS OF CD STRESS ARE KNOWN, THE DATA ON GENETIC RISK ARE LIMITED. THE AIM OF THIS STUDY WAS TO ASSESS THE CHRONIC TOXICITY OF CD, GENETIC RESPONSES, AND MULTIGENERATIONAL EFFECTS IN FIVE GENERATIONS OF DROSOPHILA MELANOGASTER. FOR EACH GENERATION, LIFESPAN AND FERTILITY WERE STATISTICALLY ANALYSED AND THE EXPRESSION OF APOPTOSIS- (P53 AND CASPASE-3) AND EPIGENESIS-RELATED (DDNMT2 AND DMBD2/3) GENES WAS EXAMINED. LIFESPAN AND FERTILITY SIGNIFICANTLY DECLINED UNDER CD STRESS AND THESE EFFECTS WERE MAINTAINED FOR TWO GENERATIONS AND ONE GENERATION, RESPECTIVELY, WHEN CD STRESS WAS REMOVED. THE EXPRESSION OF P53 AND CASPASE-3 WAS SIGNIFICANTLY UP-REGULATED AFTER EXPOSURE, SUGGESTING THAT APOPTOSIS CONTRIBUTES TO THE RESISTANCE MECHANISM. THEIR ALTERED EXPRESSION WAS RETAINED FOR TWO GENERATIONS. FURTHERMORE, HIGH EXPRESSION OF DDNMT2 AND DMBD2/3 ACCOMPANIED CD EXPOSURE, WHICH WAS PASSED ON TO THREE GENERATIONS, SUGGESTING THAT GENETIC MODIFICATIONS IN APOPTOSIS-RELATED GENES ARE CARRIED TO THE OFFSPRING THROUGH EPIGENETIC REGULATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6 3914  32 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  477  35 ARSENIC PROJECTS IN SE ASIA. EARLY LIFE EXPOSURE TO INORGANIC ARSENIC IS ASSOCIATED WITH A WIDE RANGE OF MALIGNANT AND CHRONIC DISEASE OUTCOMES IN HUMANS. PRENATAL ARSENIC EXPOSURE MAY GIVE RISE TO ADVERSE EFFECTS ON CHILD HEALTH AND DEVELOPMENT AS ARSENIC READILY PASSES THROUGH THE PLACENTA IN HUMAN BEINGS. THE IMPACT OF MATERNAL ARSENIC EXPOSURE ON FETAL GENE EXPRESSION WAS CONDUCTED IN PREGNANT WOMEN LIVING IN SOUTHERN THAILAND. ARSENIC EXPOSED NEWBORNS HAD SIGNIFICANTLY HIGHER LEVELS OF ARSENIC IN CORD BLOOD, AND A SET OF GENES ASSOCIATED WITH NUMEROUS BIOLOGICAL PATHWAYS, INCLUDING CELL SIGNALING, APOPTOSIS, INFLAMMATORY AND STRESS RESPONSE. A SLIGHT INCREASE IN PROMOTER METHYLATION OF P53 IN CORD BLOOD LYMPHOCYTES WHICH CORRELATED WITH ARSENIC ACCUMULATION IN NAILS WAS OBSERVED IN THESE EXPOSED NEWBORNS. A FOLLOW-UP STUDY ON THESE EXPOSED CHILDREN SHOWED A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE, MEASURED AS 8-HYDROXYDEOXYGUANOSINE (8-OHDG) IN SALIVA. IN ADDITION, LEVELS OF URINARY 8-OHDG EXCRETION AND SALIVARY HOGG1 EXPRESSION WERE SIGNIFICANTLY DECREASED IN EXPOSED CHILDREN SUGGESTING A DEFECT IN REPAIR OF 8-OHDG IN ARSENIC-EXPOSED CHILDREN. OUR STUDY INDICATES THAT PRENATAL ARSENIC AND CONTINUED EXPOSURE THROUGH EARLY CHILDHOOD CAN TRIGGER VARIOUS GENETIC AND EPIGENETIC ALTERATIONS THAT MAY LEAD TO DISEASE DEVELOPMENT LATER IN LIFE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8 1503  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9  887  26 CHRONIC CORTISOL EXPOSURE IN EARLY DEVELOPMENT LEADS TO NEUROENDOCRINE DYSREGULATION IN ADULTHOOD. OBJECTIVE: CHRONIC EARLY LIFE STRESS CAN AFFECT DEVELOPMENT OF THE NEUROENDOCRINE STRESS SYSTEM, LEADING TO ITS PERSISTENT DYSREGULATION AND CONSEQUENTLY INCREASED DISEASE RISK IN ADULTHOOD. ONE CONTRIBUTING FACTOR IS THOUGHT TO BE EPIGENETIC PROGRAMMING IN RESPONSE TO CHRONIC CORTISOL EXPOSURE DURING EARLY DEVELOPMENT. WE HAVE PREVIOUSLY SHOWN THAT ZEBRAFISH EMBRYOS TREATED CHRONICALLY WITH CORTISOL DEVELOP INTO ADULTS WITH CONSTITUTIVELY ELEVATED WHOLE-BODY CORTISOL AND ABERRANT IMMUNE GENE EXPRESSION. HERE WE FURTHER CHARACTERIZE THAT PHENOTYPE BY ASSESSING PERSISTENT EFFECTS OF THE TREATMENT ON CORTISOL TISSUE DISTRIBUTION AND DYNAMICS, CHROMATIN ACCESSIBILITY, AND ACTIVITIES OF GLUCOCORTICOID-RESPONSIVE REGULATORY GENES KLF9 AND FKBP5. TO THAT END CORTISOL LEVELS IN DIFFERENT TISSUES OF FED AND FASTED ADULTS WERE MEASURED USING ELISA, OPEN CHROMATIN IN ADULT BLOOD CELLS WAS MAPPED USING ATAC-SEQ, AND GENE ACTIVITY IN ADULT BLOOD AND BRAIN CELLS WAS MEASURED USING QRT-PCR. RESULTS: ADULTS DERIVED FROM CORTISOL-TREATED EMBRYOS HAVE ELEVATED WHOLE-BODY CORTISOL WITH ABERRANTLY REGULATED TISSUE DISTRIBUTION AND DYNAMICS THAT CORRELATE WITH DIFFERENTIAL ACTIVITY OF KLF9 AND FKBP5 IN BLOOD AND BRAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10 5385  31 REDOX BALANCE SIGNALLING IN OCCUPATIONAL STRESS: MODIFICATION BY NUTRACEUTICAL INTERVENTION. THERE IS INCREASING EVIDENCE THAT PSYCHOSOCIAL STRESS CAN BE VIEWED AS A SYSTEM-WIDE DERANGEMENT OF CELLULAR HOMEOSTASIS, WITH HEIGHTENED OXIDATIVE STRESS AND TRIGGERED PROINFLAMMATORY MECHANISMS. THE AIM OF THIS STUDY IS TWOFOLD: A) TO REPLICATE FINDINGS THAT PSYCHOLOGICAL STRESS INCREASES OXIDATIVE DAMAGE AND B) TO DETERMINE WHETHER A FERMENTED PAPAYA PREPARATION KNOWN TO EXERT SIGNIFICANT PROTECTIVE ANTIOXIDANT PROPERTIES COULD BUFFER SUCH INCREASES IN NUCLEAR DNA DAMAGE WHILE ALSO INDUCING EPIGENETIC PROTECTIVE MECHANISMS. TWENTY-EIGHT SEDENTARY MEN AND WOMEN (AGE RANGE: 28-52), WHO REPORTED LIVING A STRESSFUL LIFESTYLE BUT WITH AN OVERALL POSITIVE ATTITUDE, WERE RECRUITED FOR THIS STUDY. CHRONIC DISEASES AS WELL AS SEVERE BURNOUT AND USE OF DRUGS FOR ANXIETY CONSTITUTED EXCLUSION CRITERIA. SUBJECTS WERE SUPPLEMENTED FOR 1 MONTH WITH 9 G/DAY (4.5 G TWICE A DAY) OF A CERTIFIED FERMENTED PAPAYA PREPARATION. ALL SUBJECTS WERE GIVEN A STRESS AND SLEEP QUALITY QUESTIONNAIRE TOGETHER WITH A DIET AND LIFE STYLE ASSESSMENT. BLOOD WAS COLLECTED AT 2 AND 4 WEEK, ERYTHROCYTE AND LEUKOCYTE WERE SEPARATED TO ASSESS REDOX BALANCE AND HEME OXYGENASE-1 (HO-1) GENE EXPRESSION WHILE BILIRUBIN OXIDIZED METABOLITES (BOMS) WERE TESTED IN THE URINE. STRESSED INDIVIDUALS SHOWED A SIGNIFICANT ABNORMALITY OF REDOX STATUS WITH INCREASED MDA OF ERYTHROCYTE AND INCREASED LEVEL OF 8-0HDG IN LEUKOCYTE AND BOMS EXCRETION (P<0.05). NUTRACEUTICAL SUPPLEMENTATION BROUGHT ABOUT A NORMALIZATION OF SUCH VALUES ALREADY AT THE 2 WEEK OBSERVATION (P<0.05) TOGETHER WITH A SIGNIFICANT UPREGULATION OF HO-1 (P<0.01). TAKEN TOGETHER, THE RESULTS OF THIS STUDY CONFIRM THAT STRESSFUL OCCUPATIONAL LIFE PER SE, WITHOUT ANY OVERT PSYCHIATRIC ILLNESS, MAY BE ASSOCIATED TO INCREASED OXIDATIVE STRESS. SUPPLEMENTATION WITH FUNCTIONAL FOOD AFFECTING REDOX REGULATION MAY BE PART OF THE THERAPEUTIC ARMAMENTARIUM TO BE CONSIDERED IN THIS CLINICAL SETTING.	2011	
                                                                                                                                                                                                                                                                                                                                                                         
11 1408  40 DIETARY INTAKE IS ASSOCIATED WITH RESPIRATORY HEALTH OUTCOMES AND DNA METHYLATION IN CHILDREN WITH ASTHMA. BACKGROUND: ASTHMA IS AN INCREASINGLY COMMON CHRONIC DISEASE AMONG CHILDREN, AND DATA POINT TOWARD A COMPLEX MECHANISM INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. EPIGENETIC MODIFICATIONS SUCH AS DNA HYPO- OR HYPER-METHYLATION HAVE BEEN SHOWN TO OCCUR IN RESPONSE TO ENVIRONMENTAL EXPOSURES INCLUDING DIETARY NUTRIENTS. METHODS: WITHIN THE CONTEXT OF THE ASTHMA RANDOMIZED TRIAL OF INDOOR WOOD SMOKE (ARTIS) STUDY, WE INVESTIGATED RELATIONSHIPS BETWEEN DIET, ASTHMA HEALTH MEASURES, AND DNA METHYLATION. ASTHMA HEALTH MEASURES INCLUDED A QUALITY OF LIFE INSTRUMENT, DIURNAL PEAK FLOW VARIABILITY (DPFV) AND FORCED EXPIRATORY VOLUME IN THE FIRST SECOND (FEV(1)). DIETARY INTAKE WAS ASSESSED WITH A FOOD FREQUENCY QUESTIONNAIRE. METHYLATION LEVELS OF LINE-1 REPETITIVE ELEMENT AND TWO PROMOTER CPG SITES FOR INTERFERON GAMMA (IFNGAMMA, -186 AND -54) FROM BUCCAL CELL DNA WERE MEASURED USING PYROSEQUENCING ASSAYS. RESULTS: DATA WERE COLLECTED ON 32 CHILDREN WITH ASTHMA LIVING IN WESTERN MONTANA WHO WERE RECRUITED TO THE ARTIS STUDY. SELENIUM AND SEVERAL METHYL DONOR DIETARY NUTRIENTS WERE POSITIVELY ASSOCIATED WITH THE ASTHMA QUALITY OF LIFE MEASURE. INTAKE OF METHYL DONATING NUTRIENTS INCLUDING FOLATE WAS POSITIVELY ASSOCIATED LINE-1 METHYLATION AND NEGATIVELY ASSOCIATED WITH IFNGAMMA CPG-186. HIGHER LEVELS OF LINE-1 METHYLATION WERE ASSOCIATED WITH GREATER DPFV. CONCLUSION: WE IDENTIFIED SEVERAL NUTRIENTS THAT WERE ASSOCIATED WITH IMPROVED QUALITY OF LIFE MEASURES AMONG CHILDREN WITH ASTHMA. THE IFNGAMMA PROMOTER CPG SITE -186 BUT NOT -54 WAS ASSOCIATED WITH THE INTAKE OF SELECTED DIETARY NUTRIENTS. HOWEVER, IN THIS SMALL POPULATION OF CHILDREN WITH ASTHMA, THE IFNGAMMA PROMOTER CPG SITES WERE NOT ASSOCIATED WITH RESPIRATORY HEALTH MEASURES SO IT REMAINS UNCLEAR THROUGH WHICH EPIGENETIC MECHANISM THESE NUTRIENTS ARE IMPACTING THE QUALITY OF LIFE MEASURE. THESE FINDINGS ADD TO THE EVIDENCE THAT DIETARY NUTRIENTS, PARTICULARLY FOODS CONTAINING METHYL DONORS, MAY BE IMPORTANT FOR EPIGENETIC REGULATION AS IT PERTAINS TO THE CONTROL OF ASTHMA. TRIAL REGISTRATION CLINCIALTRIALS.GOV NCT00807183. REGISTERED 10 DECEMBER 2008.	2017	
                                                                                                                                 
12 6720  31 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  496  37 ASSESSMENT OF THE IMPACT OF HIV INFECTION AND ANTI-RETROVIRAL TREATMENT ON THE CARDIOMETABOLIC HEALTH OF PREGNANT MOTHERS AND THEIR OFFSPRING (ARTMOMSBABES). BACKGROUND: THE RISK OF CARDIOVASCULAR DISEASES (CVDS) IS BECOMING MORE PREVALENT IN PREGNANT WOMEN THOUGH NOT MUCH DATA IS AVAILABLE FOR PREGNANT WOMEN WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV). FOETOPLACENTAL VASCULAR ENDOTHELIAL DYSFUNCTION IS THOUGHT TO BE AT THE ORIGIN OF CHRONIC DISEASES SUCH AS DIABETES AND OBESITY LATER ON IN LIFE. BECAUSE HIV AND ANTI-RETROVIRAL TREATMENT (ARTS) ARE ASSOCIATED WITH ENDOTHELIAL DYSFUNCTION, CHILDREN EXPOSED IN UTERO TO THESE CONDITIONS MAY BE AT GREATER RISK OF DEVELOPING CVDS. DESPITE THE HIGH PREVALENCE OF HIV IN PREGNANT SOUTH AFRICAN WOMEN, LITTLE IS KNOWN ABOUT THE EFFECTS OF ART ON THE CARDIOVASCULAR HEALTH OF THE MOTHER AND OFFSPRING. HENCE, THE PROPOSED STUDY INTENDS TO INVESTIGATE HOW HIV/ARTS MAY AFFECT THE CARDIOVASCULAR HEALTH OF THE MOTHER AND OFFSPRING AT DIFFERENT TIME POINTS DURING THE PREGNANCY AND UP TO 2 YEARS AFTER BIRTH. METHODS: A LONGITUDINAL CASE-CONTROL STUDY IN HIV POSITIVE PREGNANT WOMEN ON ART AND HIV NEGATIVE PREGNANT WOMEN WILL BE CONDUCTED. ALL PREGNANT WOMEN WILL BE ASSESSED FOR CARDIO-METABOLIC RISK FACTORS AND MARKERS (LIPIDS, ANTHROPOMETRIC AND GLYCAEMIC INDIES, OXIDATIVE STRESS), HEMODYNAMIC STATUS (BLOOD PRESSURE PARAMETERS) AND VASCULAR FUNCTION (ARTERIAL COMPLIANCE, RETINAL MICROVASCULATURE, UTERINE ARTERY MEAN PULSATILITY INDEX). CHILD HEALTH WILL BE MONITORED IN UTERO AND POSTNATALLY VIA ROUTINE FOETAL HEALTH SCREENING, PLACENTAL INTEGRITY, ANTHROPOMETRY, BLOOD PRESSURE PARAMETERS, MARKERS OF OXIDATIVE STRESS AND ENDOTHELIAL FUNCTION IN CORD BLOOD AND CARDIOVASCULAR EPIGENETIC MARKERS IN URINE. DISCUSSION: THERE IS A PAUCITY OF STUDIES IN SOUTH AFRICA AND SUB-SAHARA AFRICA AS A WHOLE THAT UTILISED A LONGITUDINAL STUDY MODEL TO ASSESS THE EFFECTS OF ARTS ON VASCULAR ENDOTHELIAL CHANGES IN PREGNANT WOMEN LIVING WITH HIV AND THE CARDIOMETABOLIC HEALTH OF THEIR OFFSPRING. THIS STUDY WILL THEREFORE HELP TO MONITOR CHANGES IN CARDIOMETABOLIC RISK DURING PREGNANCY AND IN CHILDREN EXPOSED IN UTERO TO HIV-INFECTION AND ART USE. FINDINGS FROM THIS STUDY WILL PROVIDE USEFUL INFORMATION FOR DEVELOPING GUIDELINES ON THE USE OF ARTS IN PREGNANCY AND MANAGEMENT OF CARDIOMETABOLIC HEALTH OF THE OFFSPRING OF HIV POSITIVE MOTHERS.	2021	

14 1567  32 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  422  33 ANNEXIN-A1 DEFICIENCY ATTENUATES STRESS-INDUCED TUMOR GROWTH VIA FATTY ACID METABOLISM IN MICE: AN INTEGRATED MULTIPLE OMICS ANALYSIS ON THE STRESS- MICROBIOME-METABOLITE-EPIGENETIC-ONCOLOGY (SMMEO) AXIS. BACKGROUND: HIGH EMOTIONAL OR PSYCHOPHYSICAL STRESS LEVELS HAVE BEEN CORRELATED WITH AN INCREASED RISK AND PROGRESSION OF VARIOUS DISEASES. HOW STRESS IMPACTS THE GUT MICROBIOTA TO INFLUENCE METABOLISM AND SUBSEQUENT CANCER PROGRESSION IS UNCLEAR. METHODS: FECES AND SERUM SAMPLES FROM BALB/C ANXA1(+/+) AND ANXA1(-/-) MICE WITH OR WITHOUT CHRONIC RESTRAINT STRESS WERE USED FOR 16S RRNA GENE SEQUENCING AND GC-MS METABOLOMICS ANALYSIS TO INVESTIGATE THE EFFECT OF STRESS ON MICROBIOME AND METABOLOMICS DURING STRESS AND BREAST TUMORIGENESIS. BREAST TUMORS SAMPLES FROM STRESSED AND NON-STRESSED MICE WERE USED TO PERFORM WHOLE-GENOME BISULFITE SEQUENCING (WGBS) AND RNASEQ ANALYSIS TO CONSTRUCT THE POTENTIAL NETWORK FROM CANDIDATE HUB GENES. FINALLY, MACHINE LEARNING AND INTEGRATED ANALYSIS WERE USED TO MAP THE AXIS FROM CHRONIC RESTRAINT STRESS TO BREAST CANCER DEVELOPMENT. RESULTS: WE REPORT THAT CHRONIC STRESS PROMOTES BREAST TUMOR GROWTH VIA A STRESS-MICROBIOME-METABOLITE-EPIGENETIC-ONCOLOGY (SMMEO) AXIS. CHRONIC RESTRAINT STRESS IN MICE ALTERS THE MICROBIOME COMPOSITION AND FATTY ACIDS METABOLISM AND INDUCES AN EPIGENETIC SIGNATURE IN TUMORS XENOGRAFTED AFTER STRESS. SUBSEQUENT MACHINE LEARNING AND SYSTEMIC MODELING ANALYSES IDENTIFIED A SIGNIFICANT CORRELATION AMONG MICROBIOME COMPOSITION, METABOLITES, AND DIFFERENTIALLY METHYLATED REGIONS IN STRESSED TUMORS. MOREOVER, SILENCING ANNEXIN-A1 INHIBITS THE CHANGES IN THE GUT MICROBIOME AND FATTY ACID METABOLISM AFTER STRESS AS WELL AS BASAL AND STRESS-INDUCED TUMOR GROWTH. CONCLUSIONS: THESE DATA SUPPORT A PHYSIOLOGICAL AXIS LINKING THE MICROBIOME AND METABOLITES TO CANCER EPIGENETICS AND INFLAMMATION. THE IDENTIFICATION OF THIS AXIS COULD PROPEL THE NEXT PHASE OF EXPERIMENTAL DISCOVERY IN FURTHER UNDERSTANDING THE UNDERLYING MOLECULAR MECHANISM OF TUMORIGENESIS CAUSED BY PHYSIOLOGICAL STRESS.	2022	
                                                                                                                                                                                                                                                                                                                           
16 3356  37 HISTONE H3 LYSINE 27 ACETYLATION PROFILE UNDERGOES TWO GLOBAL SHIFTS IN UNDERNOURISHED CHILDREN AND SUGGESTS ALTERED ONE-CARBON METABOLISM. BACKGROUND: STUNTING IS A CONDITION IN WHICH A CHILD DOES NOT REACH THEIR FULL GROWTH POTENTIAL DUE TO CHRONIC UNDERNUTRITION. IT ARISES DURING THE FIRST 2 YEARS OF A CHILD'S LIFE AND IS ASSOCIATED WITH DEVELOPMENTAL DEFICIENCIES AND LIFE-LONG HEALTH PROBLEMS. CURRENT INTERVENTIONS PROVIDE SOME BENEFIT, BUT NEW APPROACHES TO PREVENTION AND TREATMENT GROUNDED IN A MOLECULAR UNDERSTANDING OF STUNTING ARE NEEDED. EPIGENETIC ANALYSES ARE CRITICAL AS THEY CAN PROVIDE INSIGHT INTO HOW SIGNALS FROM A POOR ENVIRONMENT LEAD TO CHANGES IN CELL FUNCTION. RESULTS: HERE WE PROFILED HISTONE H3 ACETYLATION ON LYSINE 27 (H3K27AC) IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF 18-WEEK-OLD (N = 14) AND 1-YEAR-OLD CHILDREN (N = 22) LIVING IN AN URBAN SLUM IN DHAKA, BANGLADESH. WE SHOW THAT 18-WEEK-OLD CHILDREN DESTINED TO BECOME STUNTED HAVE ELEVATED LEVELS OF H3K27AC OVERALL, FUNCTIONAL ANALYSIS OF WHICH INDICATES ACTIVATION OF THE IMMUNE SYSTEM AND STRESS RESPONSE PATHWAYS AS A PRIMARY RESPONSE TO A POOR ENVIRONMENT WITH HIGH PATHOGEN LOAD. CONVERSELY, OVERT STUNTING AT 1-YEAR-OF AGE IS ASSOCIATED WITH GLOBALLY REDUCED H3K27AC THAT IS INDICATIVE OF METABOLIC REWIRING AND DOWNREGULATION OF THE IMMUNE SYSTEM AND DNA REPAIR PATHWAYS THAT ARE LIKELY SECONDARY RESPONSES TO CHRONIC EXPOSURE TO A POOR ENVIRONMENT WITH LIMITED NUTRIENTS. AMONG PROCESSES ALTERED IN 1-YEAR-OLD CHILDREN, WE IDENTIFIED ONE-CARBON METABOLISM, THE SIGNIFICANCE OF WHICH IS SUPPORTED BY INTEGRATIVE ANALYSIS WITH RESULTS FROM HISTONE H3 TRIMETHYLATION ON LYSINE 4 (H3K4ME3). TOGETHER, THESE RESULTS SUGGEST ALTERED ONE-CARBON METABOLISM IN THIS POPULATION OF STUNTED CHILDREN. CONCLUSIONS: THE EPIGENOMES OF STUNTED CHILDREN UNDERGO TWO GLOBAL CHANGES IN H3K27AC WITHIN THEIR FIRST YEAR OF LIFE, WHICH ARE ASSOCIATED WITH PROBABLE INITIAL HYPERACTIVE IMMUNE RESPONSES FOLLOWED BY REDUCED METABOLIC CAPACITY. LIMITATION OF ONE-CARBON METABOLITES MAY PLAY A KEY ROLE IN THE DEVELOPMENT OF STUNTING. TRIAL REGISTRATION CLINICALTRIALS.GOV NCT01375647. REGISTERED 17 JUNE 2011, RETROSPECTIVELY REGISTERED, HTTPS://CLINICALTRIALS.GOV/CT2/SHOW/NCT01375647 .	2021	
                                                                                                                          
17 3991  25 LONGITUDINAL EFFECTS OF DEVELOPMENTAL BISPHENOL A, VARIABLE DIET, AND PHYSICAL ACTIVITY ON AGE-RELATED METHYLATION IN BLOOD. RESEARCH INDICATES THAT ENVIRONMENTAL FACTORS CAN ALTER DNA METHYLATION, BUT THE SPECIFIC EFFECTS OF ENVIRONMENTAL EXPOSURES ON EPIGENETIC AGING REMAIN UNCLEAR. HERE, USING A MOUSE MODEL OF HUMAN-RELEVANT EXPOSURES, WE TESTED THE HYPOTHESIS THAT EARLY-LIFE EXPOSURE TO BISPHENOL A (BPA), VARIABLE DIET, AND/OR CHANGES IN PHYSICAL ACTIVITY WOULD MODIFY RATES OF AGE-RELATED METHYLATION AT SEVERAL TARGET REGIONS, AS MEASURED FROM LONGITUDINAL BLOOD SAMPLES (2, 4, AND 10 MONTHS OLD). DNA METHYLATION WAS QUANTIFIED AT TWO REPETITIVE ELEMENTS (LINE-1, IAP), TWO IMPRINTED GENES (IGF2, H19), AND ONE NON-IMPRINTED GENE (ESR1) IN ISOGENIC MICE DEVELOPMENTALLY EXPOSED TO CONTROL, CONTROL + BPA (50 MICROG/KG DIET), WESTERN HIGH-FAT DIET (WHFD), OR WESTERN + BPA DIETS. IN BLOOD SAMPLES, ESR1 DNA METHYLATION INCREASED SIGNIFICANTLY WITH AGE, BUT NO OTHER INVESTIGATED LOCI SHOWED SIGNIFICANT AGE-RELATED METHYLATION. LINE-1 AND IAP BOTH SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE (P < 0.05). ESR1ALSO SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE IN FEMALE MICE (P = 0.02), BUT NOT MALE MICE. PHYSICAL ACTIVITY HAD A NON-SIGNIFICANT POSITIVE EFFECT ON AGE-RELATED ESR1 METHYLATION IN FEMALE BLOOD, SUGGESTING THAT IT MAY PARTIALLY ABROGATE THE EFFECTS OF WHFD ON THE AGING EPIGENOME. THESE RESULTS SUGGEST THAT DEVELOPMENTAL NUTRITIONAL EXPOSURES CAN MODIFY AGE-RELATED DNA METHYLATION PATTERNS AT A GENE RELATED TO GROWTH AND DEVELOPMENT. AS SUCH, ENVIRONMENTAL DEFLECTION OF THE AGING EPIGENOME MAY HELP TO EXPLAIN THE GROWING PREVALENCE OF CHRONIC DISEASES IN HUMAN POPULATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 3652  24 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19 1820  31 EFFECTS OF CHRONIC RESTRAINT STRESS ON THE GLOBAL DNA METHYLATION PROFILE OF RAT LUNG CELLS: MODULATION BY PHYSICAL EXERCISE. THE POTENTIAL OF BEHAVIORAL STRESS TO AFFECT EPIGENETIC MECHANISMS OF NON-ENCEPHALIC TISSUES IS STILL UNDERESTIMATED. IN THE PRESENT STUDY WE EVALUATED THE EFFECTS OF CHRONIC BEHAVIORAL STRESS ON THE DNA METHYLATION PROFILE OF RAT LUNG CELLS. FURTHERMORE, WE EVALUATED THE POTENTIAL OF PHYSICAL EXERCISE TO MODULATE THE CHANGES EVOKED BY BEHAVIORAL STRESS IN LUNG CELLS. MALE WISTAR RATS WERE DIVIDED INTO FOUR EXPERIMENTAL GROUPS: (1) ANIMALS SUBMITTED TO CHRONIC RESTRAINT STRESS (CRS) (ST GROUP) DURING THE PERIOD OF THE 67TH-80TH POSTNATAL DAY (PND); (2) ANIMALS SUBMITTED TO PHYSICAL EXERCISE (EX GROUP) DURING THE 53RD-79TH PND; (3) ANIMALS SUBMITTED TO SWIMMING DURING THE 53RD-79TH PND AND TO CRS DURING THE 67TH-80TH PND (EX-ST GROUP); AND (4) ANIMALS NOT SUBMITTED TO STRESS OR SWIMMING PROTOCOLS (CTL). GLOBAL DNA METHYLATION WAS QUANTIFIED USING AN ELISA-BASED APPROACH AND GENE EXPRESSION WAS EVALUATED BY REAL TIME PCR. A DECREASED GLOBAL DNA METHYLATION PROFILE WAS OBSERVED IN THE ST GROUP, HOWEVER PHYSICAL EXERCISE DEMONSTRATED PROTECTION OF LUNG CELLS FROM THIS STRESS-RELATED HYPOMETHYLATION. INCREASED EXPRESSION OF THE DNMT1 GENE WAS EVIDENCED IN THE ST GROUP, WHEREAS PHYSICAL EXERCISE WAS SHOWN TO PROTECT LUNG CELLS FROM THIS STRESS-RELATED EFFECT IN THE EX-ST GROUP. COMPARATIVE ANALYSIS OF THE ST AND EX GROUPS REVEALED OPPOSITE EFFECTS ON THE EXPRESSION OF DNMT3A AND DNMT3B; HOWEVER, A STRESS-RELATED INCREASE IN EXPRESSION OF DNMT3A AND DNMT3B WAS NOT SEEN IN THE EX-ST GROUP. OUR DATA SHOWED THAT BEHAVIORAL STRESS INDUCED SIGNIFICANT CHANGES IN THE DNA METHYLATION PROFILE OF RAT LUNG CELLS AND THAT THIS COULD BE MODULATED BY PHYSICAL EXERCISE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20 3042  30 GENOME-WIDE ALTERATION OF HISTONE METHYLATION PROFILES ASSOCIATED WITH COGNITIVE CHANGES IN RESPONSE TO DEVELOPMENTAL ARSENIC EXPOSURE IN MICE. INORGANIC ARSENIC IS A XENOBIOTIC ENTERING THE BODY PRIMARILY THROUGH CONTAMINATED DRINKING WATER AND FOOD. THERE ARE DEFINED MECHANISMS THAT DESCRIBE ARSENIC'S ASSOCIATION WITH INCREASED CANCER INCIDENCE, HOWEVER MECHANISMS EXPLAINING ARSENIC EXPOSURE AND NEURODEVELOPMENTAL OR AGING DISORDERS ARE POORLY DEFINED. IN RECENT YEARS, ARSENIC EFFECTS ON EPIGENOME HAVE BECOME A PARTICULAR FOCUS. WE HYPOTHESIZE THAT HUMAN RELEVANT ARSENIC EXPOSURE DURING PARTICULAR DEVELOPMENTAL WINDOWS, OR LONG-TERM EXPOSURE LATER IN LIFE INDUCE PATHOPHYSIOLOGICAL NEURAL CHANGES THROUGH EPIGENOMIC ALTERATIONS, IN PARTICULAR HISTONE METHYLATION PROFILE, MANIFESTING AS COGNITIVE DECLINE. C57BL/6 WILD-TYPE MICE WERE CONTINUALLY EXPOSED TO SODIUM ARSENITE (100 MICROG/L) IN DRINKING WATER PRIOR TO MATING THROUGH WEANING OF THE EXPERIMENTAL PROGENY. A SECOND COHORT OF AGED APP/PS MICE WERE CHRONICALLY EXPOSED TO THE SAME LEVEL OF ARSENIC. COGNITIVE TESTING, HISTOLOGICAL EXAMINATION OF BRAINS AND GENOME-WIDE METHYLATION LEVELS OF H3K4ME3 AND H3K27ME3 EXAMINED AFTER CHIP-SEQ WERE USED TO DETERMINE THE EFFECTS OF ARSENIC EXPOSURE. DEVELOPMENTAL ARSENIC EXPOSURE CAUSED SIGNIFICANTLY DIMINISHED COGNITION IN WILD-TYPE MICE. THE ANALYSIS OF CHIP-SEQ DATA AND EXPERIMENTS WITH MOUSE EMBRYONIC STEM CELLS DEMONSTRATED THAT EPIGENETIC CHANGES INDUCED BY ARSENIC EXPOSURE TRANSLATED INTO GENE EXPRESSION ALTERATIONS ASSOCIATED WITH NEURONAL DEVELOPMENT AND NEUROLOGICAL DISEASE. INCREASED HIPPOCAMPAL AMYLOID PLAQUES LEVELS OF APP/PS MICE AND COGNITIVE DECLINE PROVIDED EVIDENCE THAT ARSENIC EXPOSURE AGGRAVATED AN EXISTING ALZHEIMER'S DISEASE-LIKE PHENOTYPE. WE SHOW DEVELOPMENTAL ARSENIC EXPOSURE SIGNIFICANTLY IMPACTS HISTONE MODIFICATIONS IN BRAIN WHICH REMAIN PRESENT INTO ADULTHOOD AND PROVIDE A POTENTIAL MECHANISM BY WHICH DEVELOPMENTAL ARSENIC EXPOSURE INFLUENCES COGNITIVE FUNCTIONS. WE ALSO SHOW THAT HUMAN RELEVANT, CHRONIC ARSENIC EXPOSURE HAS DELETERIOUS EFFECTS ON ADULT APP/PS MICE AND EXACERBATES EXISTING ALZHEIMER'S DISEASE-LIKE SYMPTOMS. THE RESULTS DEMONSTRATE HOW DEVELOPMENTAL ARSENIC EXPOSURE IMPACTS THE BRAIN EPIGENOME, LEADING TO ALTERED GENE EXPRESSION LATER IN LIFE.	2022