1 3586 278 IMPACT OF THE POLYCARBONATE STRIPPERS USED IN ASSISTED REPRODUCTION TECHNIQUES ON EMBRYONIC DEVELOPMENT. STUDY QUESTION: DO DAILY MANIPULATIONS OF PREIMPLANTATION EMBRYOS WITH POLYCARBONATE (PC)-MADE BISPHENOL A (BPA)-RELEASING STRIPPERS INFLUENCE EMBRYO DEVELOPMENT? SUMMARY ANSWER: COMPARED TO GLASS STRIPPERS, PC STRIPPERS ENHANCE THE BLASTOCYST DEVELOPMENT RATE BUT THIS DOES NOT SEEM TO BE BPA-RELATED. WHAT IS KNOWN ALREADY: PC STRIPPERS HAVE BEEN SHOWN TO RELEASE TINY AMOUNTS (AROUND 0.5 NG/ML BPA) OF BPA IN ROUTINE HUMAN IVF PROCEDURES. A CHRONIC EXPOSURE TO BPA EITHER IN VIVO OR IN VITRO DURING THE PREIMPLANTATION PERIOD CAN IMPACT POST-IMPLANTATION AND POST-NATAL DEVELOPMENT. BPA CAN ACT RAPIDLY BY BINDING TO MEMBRANE RECEPTORS AND INDUCING RAPID NON-GENOMIC EFFECTS. STUDY DESIGN, SIZE, DURATION: THIS EXPERIMENTAL STUDY USING MOUSE EMBRYOS HAD A BALANCED DESIGN AND BLINDED EVALUATIONS OF THE ENDPOINTS. PARTICIPANTS/MATERIALS, SETTING, METHODS: IN VIVO FERTILIZED ZYGOTES WERE OBTAINED FROM OUTBRED SWISS CD1 MICE CROSSINGS AFTER AN OVARIAN STIMULATION. THE ZYGOTES WERE ALLOCATED TO THREE DAILY HANDLING CONDITIONS (HCS) AND CULTURED UNTIL DAY 4 IN A SINGLE HUMAN COMMERCIAL MEDIUM. EACH DAY, THE EMBRYOS WERE HANDLED FOR 20 S EITHER IN A PC STRIPPER (HC1) OR IN A GLASS STRIPPER (HC2). IN HC3, THE EMBRYOS WERE PRE-EXPOSED TO 0.5 NG/ML BPA BEFORE BEING HANDLED FOR 20 S IN A GLASS STRIPPER. HANDLING OPERATIONS WERE REPEATED ON DAYS 1, 2 AND 3. EMBRYO DEVELOPMENT WAS ASSESSED BLINDLY ON DAY 4. EXPANDED BLASTOCYSTS WERE SELECTED FOR A TRANSCRIPTOMIC ANALYSIS USING AGILENT SUREPRINT G3 MOUSE GE V2 MICROARRAYS AND THE RETROTRANSPOSON LINE1-ORF2 EXPRESSION WAS ANALYSED USING QRT-PCR, AS A PROXY FOR A GLOBAL EVALUATION OF THE EPIGENETIC STATUS. MAIN RESULTS AND THE ROLE OF CHANCE: COMPARED TO THE EMBRYOS MANIPULATED IN HC2 (N = 243), THOSE IN HC1 (N = 228) DEVELOPED SIGNIFICANTLY MORE OFTEN TO THE BLASTOCYST STAGE (55 VS 46%; P < 0.05). IT APPEARS THE EFFECT OF THESE PC STRIPPERS WAS NOT BPA-RELATED BECAUSE EMBRYOS PRE-EXPOSED TO BPA (HC3, N = 230) SHOWED NO DIFFERENCE IN THE BLASTOCYST RATE WHEN COMPARED TO HC2 (43 VS 46%). WHEN ANALYSING SAME-STAGE BLASTOCYSTS, WE NOTICED NO DIFFERENCE IN THE EMBRYO GENE EXPRESSION BETWEEN THE THREE HC GROUPS. LARGE SCALE DATA: HTTPS://WWW.NCBI.NLM.NIH.GOV/GEO/QUERY/ACC.CGI?ACC=GSE148868. LIMITATIONS, REASONS FOR CAUTION: OUR RESULTS USING A MOUSE MODEL DESIGNED TO MIMIC HUMAN CONDITIONS (OUTBRED STRAIN, HUMAN COMMERCIAL IVF DISHES AND A UNIQUE COMMERCIAL HUMAN EMBRYONIC CULTURE MEDIA) ARE REASSURING SINCE NO GENE WAS FOUND TO BE DIFFERENTIALLY EXPRESSED, INCLUDING LINE-1 GENES, AS A PROXY FOR A GLOBAL EVALUATION OF THE EPIGENETIC STATUS. HOWEVER, NO GLOBAL EPIGENETIC ANALYSIS OF THE GENOME HAS BEEN PERFORMED. FURTHERMORE, WE DID NOT EVALUATE POST-IMPLANTATION EVENTS, ALTHOUGH BPA EXPOSURE DURING PERI-CONCEPTION COULD AFFECT FOETO-PLACENTAL AND POST-NATAL DEVELOPMENT. WIDER IMPLICATIONS OF THE FINDINGS: BASED ON THE PRECAUTIONARY PRINCIPLE, SEVERAL EUROPEAN COUNTRIES BANNED THE USE OF BPA IN BABY BOTTLES AND FOOD PACKAGING SEVERAL YEARS BEFORE EUROPEAN AGENCIES TOOK AN OFFICIAL POSITION. THE QUESTION OF APPLYING THIS PRINCIPLE TO PLASTICS IN CLOSED CONTACT WITH HUMAN EMBRYOS IS RAISED. FURTHER STUDIES ARE NEEDED FOR A DECISION TO BE MADE. STUDY FUNDING/COMPETING INTEREST(S): THIS STUDY WAS SUPPORTED BY A GRANT FROM THE AGENCE DE BIOMEDECINE (AOR 2016). THE AUTHORS DECLARE NO COMPETING INTEREST.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2 6084  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3 5093  87 PLACENTAS FROM PREGNANCIES CONCEIVED BY IVF/ICSI HAVE A REDUCED DNA METHYLATION LEVEL AT THE H19 AND MEST DIFFERENTIALLY METHYLATED REGIONS. STUDY QUESTION: DOES IVF/ICSI HAVE AN EFFECT ON THE EPIGENETIC REGULATION OF THE HUMAN PLACENTA? SUMMARY ANSWER: WE FOUND A REDUCED DNA METHYLATION LEVEL AT THE H19 AND MEST DIFFERENTIALLY METHYLATED REGIONS (DMRS), AND AN INCREASED RNA EXPRESSION OF H19 IN PLACENTAS FROM PREGNANCIES CONCEIVED BY IVF/ICSI WHEN COMPARED WITH PLACENTAS FROM SPONTANEOUS CONCEPTION. WHAT IS KNOWN ALREADY: CHANGES IN FETAL ENVIRONMENT ARE ASSOCIATED WITH ADVERSE HEALTH OUTCOMES. THE PLACENTA IS PIVOTAL FOR INTRAUTERINE ENVIRONMENT. ANIMAL STUDIES SHOW THAT EPIGENETIC REGULATION PLAYS AN IMPORTANT ROLE IN THESE ENVIRONMENT-INDUCED PHENOTYPIC EFFECTS. ALSO, THE PREIMPLANTATION EMBRYO ENVIRONMENT AFFECTS BIRTHWEIGHT AS WELL AS THE RISK OF CHRONIC ADULT DISEASES. EPIGENETIC PROCESSES ARE SENSITIVE TO THE ENVIRONMENT, ESPECIALLY DURING THE PERIOD AROUND CONCEPTION. STUDY DESIGN AND PARTICIPANTS: PLACENTAL TISSUE WAS COLLECTED FROM 35 SPONTANEOUSLY CONCEIVED PREGNANCIES AND 35 IVF/ICSI (5 IVF, 30 ICSI) DERIVED PREGNANCIES. WE QUANTITATIVELY ANALYSED THE DNA METHYLATION PATTERNS OF A NUMBER OF CONSECUTIVE CPGS IN THE CORE REGIONS OF DMRS AND OTHER REGULATORY REGIONS OF IMPRINTED GENES, SINCE THESE ARE INVOLVED IN PLACENTAL AND FETAL GROWTH AND DEVELOPMENT. METHODS: BY USING PYROSEQUENCING, THE DNA METHYLATION AT SEVEN GERMLINE-DERIVED PRIMARY DMRS WAS ANALYSED QUANTITATIVELY. FIVE OF THESE ARE MATERNALLY METHYLATED (MEST ISOFORM ALPHA AND BETA, PEG3, KCNQ1OT1 AND SNRPN) AND TWO ARE PATERNALLY METHYLATED [H19 DMR AND THE INTERGENIC REGION BETWEEN DLK1 AND MEG3 (IG-DMR)]. THE POST-FERTILIZATION-DERIVED SECONDARY DMRS, IGF2 (DMR0 AND 2) AND IG-DMR (CG7, ALSO CALLED MEG3 DMR), AND THE MEG3 PROMOTER REGION WERE EXAMINED AS WELL. IN CASE OF DIFFERENTIAL METHYLATION BETWEEN THE TWO GROUPS, THE EFFECT ON GENE EXPRESSION WAS ASSESSED BY QUANTITATIVE REAL-TIME PCR. MAIN RESULTS AND THE ROLE OF CHANCE: BOTH THE PROMOTER REGION OF MEST ISOFORM ALPHA AND BETA AND THE 6TH CTCF BINDING SITE WITHIN THE H19 DMR WERE SIGNIFICANTLY HYPOMETHYLATED IN THE IVF/ICSI GROUP. THE PHENOMENON WAS CONSISTENTLY OBSERVED OVER ALL CPG SITES ANALYSED AND NOT RESTRICTED TO SINGLE CPG SITES. THE OTHER PRIMARY AND SECONDARY DMRS WERE NOT AFFECTED. EXPRESSION OF H19 WAS INCREASED IN THE IVF/ICSI GROUP, WHILE THAT OF IGF2 AND MEST REMAINED SIMILAR. LIMITATIONS, REASONS FOR CAUTION: IN THE IVF/ICSI GROUP, MOSTLY ICSI PREGNANCIES WERE INVESTIGATED. THE ICSI TECHNIQUE OR MALE SUBFERTILITY COULD BE A CONFOUNDING FACTOR. THEREFORE, OUR RESULTS ARE LESS GENERALIZABLE TO IVF PREGNANCIES. WIDER IMPLICATIONS OF THE FINDINGS: THE CLINICAL EFFECTS OF THE OBSERVED PLACENTAL HYPOMETHYLATIONS ON THE DEVELOPMENTAL PROGRAMMING OF THE IVF/ICSI PROGENY, IF ANY, ARE AS YET UNKNOWN. WHETHER THE HYPOMETHYLATION IS AN ADAPTATION OF THE PLACENTA TO MAINTAIN FETAL SUPPLY AND AMELIORATE THE EFFECTS OF ENVIRONMENTAL CUES, OR WHETHER IT IS A DEREGULATION LEADING TO DERANGED DEVELOPMENTAL PROGRAMMING WITH OR WITHOUT INCREASED VULNERABILITY FOR DISEASE, CONSISTENT WITH THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS, NEEDS FURTHER INVESTIGATION. STUDY FUNDING/COMPETING INTEREST(S): PARTLY FUNDED BY AN UNRESTRICTED RESEARCH GRANT BY ORGANON BV (NOW MSD BV) WITHOUT ANY ROLE IN STUDY DESIGN, DATA COLLECTION AND ANALYSIS, OR PREPARATION OF THE MANUSCRIPT. NO CONFLICT OF INTERESTS TO DECLARE. TRIAL REGISTRATION NUMBER: DUTCH TRIAL REGISTRY (NTR) NUMBER 1298.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4 2632  55 EPIGENOME-WIDE DNA METHYLATION AND PESTICIDE USE IN THE AGRICULTURAL LUNG HEALTH STUDY. BACKGROUND: PESTICIDE EXPOSURE IS ASSOCIATED WITH MANY LONG-TERM HEALTH OUTCOMES; THE POTENTIAL UNDERLYING MECHANISMS ARE NOT WELL ESTABLISHED FOR MOST ASSOCIATIONS. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, MAY CONTRIBUTE. INDIVIDUAL PESTICIDES MAY BE ASSOCIATED WITH SPECIFIC DNA METHYLATION PATTERNS BUT NO EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) HAS EVALUATED METHYLATION IN RELATION TO INDIVIDUAL PESTICIDES. OBJECTIVES: WE CONDUCTED AN EWAS OF DNA METHYLATION IN RELATION TO SEVERAL PESTICIDE ACTIVE INGREDIENTS. METHODS: THE AGRICULTURAL LUNG HEALTH STUDY IS A CASE-CONTROL STUDY OF ASTHMA, NESTED WITHIN THE AGRICULTURAL HEALTH STUDY. WE ANALYZED BLOOD DNA METHYLATION MEASURED USING ILLUMINA'S EPIC ARRAY IN 1,170 MALE FARMERS OF EUROPEAN ANCESTRY. FOR PESTICIDES STILL ON THE MARKET AT BLOOD COLLECTION (2009-2013), WE EVALUATED NINE ACTIVE INGREDIENTS FOR WHICH AT LEAST 30 PARTICIPANTS REPORTED PAST AND CURRENT (WITHIN THE LAST 12 MONTHS) USE, AS WELL AS SEVEN BANNED ORGANOCHLORINES WITH AT LEAST 30 PARTICIPANTS REPORTING PAST USE. WE USED ROBUST LINEAR REGRESSION TO COMPARE METHYLATION AT INDIVIDUAL C-PHOSPHATE-G SITES (CPGS) AMONG USERS OF A SPECIFIC PESTICIDE TO NEVER USERS. RESULTS: USING FAMILY-WISE ERROR RATE (P < 9 X 10-8) OR FALSE-DISCOVERY RATE (FDR < 0.05), WE IDENTIFIED 162 DIFFERENTIALLY METHYLATED CPGS ACROSS 8 OF 9 CURRENTLY MARKETED ACTIVE INGREDIENTS (ACETOCHLOR, ATRAZINE, DICAMBA, GLYPHOSATE, MALATHION, METOLACHLOR, MESOTRIONE, AND PICLORAM) AND ONE BANNED ORGANOCHLORINE (HEPTACHLOR). DIFFERENTIALLY METHYLATED CPGS WERE UNIQUE TO EACH ACTIVE INGREDIENT, AND A DOSE-RESPONSE RELATIONSHIP WITH LIFETIME DAYS OF USE WAS OBSERVED FOR MOST. SIGNIFICANT CPGS WERE ENRICHED FOR TRANSCRIPTION MOTIFS AND 28% OF CPGS WERE ASSOCIATED WITH WHOLE BLOOD CIS-GENE EXPRESSION, SUPPORTING FUNCTIONAL EFFECTS OF FINDINGS. WE CORROBORATED A PREVIOUSLY REPORTED ASSOCIATION BETWEEN DICHLORODIPHENYLTRICHLOROETHANE (BANNED IN THE UNITED STATES IN 1972) AND EPIGENETIC AGE ACCELERATION. DISCUSSION: WE IDENTIFIED DIFFERENTIAL METHYLATION FOR SEVERAL ACTIVE INGREDIENTS IN MALE FARMERS OF EUROPEAN ANCESTRY. THESE MAY SERVE AS BIOMARKERS OF CHRONIC EXPOSURE AND COULD INFORM MECHANISMS OF LONG-TERM HEALTH OUTCOMES FROM PESTICIDE EXPOSURE. HTTPS://DOI.ORG/10.1289/EHP8928.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5 1579  48 DNA METHYLATION PROFILE OF LIVER OF MICE CONCEIVED BY IN VITRO FERTILIZATION. OFFSPRING GENERATED BY IN VITRO FERTILIZATION (IVF) ARE BELIEVED TO BE HEALTHY BUT DISPLAY A POSSIBLE PREDISPOSITION TO CHRONIC DISEASES, LIKE HYPERTENSION AND GLUCOSE INTOLERANCE. SINCE EPIGENETIC CHANGES ARE BELIEVED TO UNDERLIE SUCH PHENOTYPE, THIS STUDY AIMED AT DESCRIBING GLOBAL DNA METHYLATION CHANGES IN THE LIVER OF ADULT MICE GENERATED BY NATURAL MATING (FB GROUP) OR BY IVF. EMBRYOS WERE GENERATED BY IVF OR NATURAL MATING. AT 30 WEEKS OF AGE, MICE WERE SACRIFICED. THE LIVER WAS REMOVED, AND GLOBAL DNA METHYLATION WAS ASSESSED USING WHOLE-GENOME BISULFITE SEQUENCING (WGBS). GENOMIC REGIONS FOR ENRICHMENT ANALYSIS TOOL (GREAT) AND G:PROFILERBETA WERE USED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) AND FOR FUNCTIONAL ENRICHMENT ANALYSIS. OVERREPRESENTED GENE ONTOLOGY TERMS WERE SUMMARIZED WITH REVIGO, WHILE CANONICAL PATHWAYS (CPS) WERE IDENTIFIED WITH INGENUITY(R) PATHWAY ANALYSIS. OVERALL, 2692 DMRS (4.91%) WERE DIFFERENT BETWEEN THE GROUPS. THE MAJORITY OF DMRS (84.92%) WERE HYPOMETHYLATED IN THE IVF GROUP. SURPRISINGLY, ONLY 0.16% OF CPG ISLANDS WERE DIFFERENTIALLY METHYLATED AND ONLY A FEW DMRS WERE LOCATED ON KNOWN GENE PROMOTERS (N = 283) OR ENHANCERS (N = 190). NOTABLY, THE LONG-INTERSPERSED ELEMENT (LINE), SHORT-INTERSPERSED ELEMENT (SINE), AND LONG TERMINAL REPEAT (LTR1) TRANSPOSABLE ELEMENTS SHOWED REDUCED METHYLATION (P < 0.05) IN IVF LIVERS. CELLULAR METABOLIC PROCESS, HEPATIC FIBROSIS, AND INSULIN RECEPTOR SIGNALING WERE SOME OF THE PRINCIPAL BIOLOGICAL PROCESSES AND CPS MODIFIED BY IVF. IN SUMMARY, IVF MODIFIES THE DNA METHYLATION SIGNATURE IN THE ADULT LIVER, RESULTING IN HYPOMETHYLATION OF GENES INVOLVED IN METABOLISM AND GENE TRANSCRIPTION REGULATION. THESE FINDINGS MAY SHED LIGHT ON THE MECHANISMS UNDERLYING THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6 3304  87 HIGH-GLUCOSE CONCENTRATIONS CHANGE DNA METHYLATION LEVELS IN HUMAN IVM OOCYTES. STUDY QUESTION: WHAT ARE THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON DNA METHYLATION OF HUMAN OOCYTES? SUMMARY ANSWER: HIGH-GLUCOSE CONCENTRATIONS ALTERED DNA METHYLATION LEVELS OF PEG3 AND ADIPONECTIN IN HUMAN IN VITRO MATURATION OOCYTES. WHAT IS KNOWN ALREADY: MATERNAL DIABETES HAS A DETRIMENTAL INFLUENCE ON OOCYTE QUALITY INCLUDING EPIGENETIC MODIFICATIONS, AS SHOWN IN NON-HUMAN MAMMALIAN SPECIES. STUDY DESIGN, SIZE, DURATION: IMMATURE METAPHASE I (MI) STAGE OOCYTES OF GOOD QUALITY WERE RETRIEVED FROM PATIENTS WHO HAD NORMAL OVARIAN POTENTIAL AND WHO UNDERWENT ICSI IN THE REPRODUCTIVE MEDICINE CENTER OF PEOPLE'S HOSPITAL OF ZHENGZHOU UNIVERSITY. MI OOCYTES WERE CULTURED IN MEDIUM WITH DIFFERENT GLUCOSE CONCENTRATIONS (CONTROL, 10 MM AND 15 MM) IN VITRO AND 48 H LATER, OOCYTES WITH FIRST POLAR BODY EXTRUSION WERE COLLECTED TO CHECK THE DNA METHYLATION LEVELS. PARTICIPANTS/MATERIALS, SETTING, METHODS: MI OOCYTES UNDERWENT IN VITRO MATURATION (IVM) AT 37 DEGREES C WITH 5% MIXED GAS FOR 48 H. THEN THE MATURE OOCYTES WERE TREATED WITH BISULFITE BUFFER. TARGET SEQUENCES WERE AMPLIFIED USING NESTED OR HALF-NESTED PCR AND THE DNA METHYLATION STATUS WAS TESTED USING COMBINED BISULFITE RESTRICTION ANALYSIS (COBRA) AND BISULFITE SEQUENCING (BS). MAIN RESULTS AND THE ROLE OF CHANCE: HIGH-GLUCOSE CONCENTRATIONS SIGNIFICANTLY DECREASED THE FIRST POLAR BODY EXTRUSION RATE. COMPARED TO CONTROLS, THE DNA METHYLATION LEVELS OF PEG3 IN HUMAN IVM OOCYTES WERE SIGNIFICANTLY HIGHER IN 10 MM (P < 0.001) AND 15 MM (P < 0.001) CONCENTRATIONS OF GLUCOSE. BUT THE DNA METHYLATION LEVEL OF H19 WAS NOT AFFECTED BY HIGH-GLUCOSE CONCENTRATIONS IN HUMAN IVM OOCYTES. WE ALSO FOUND THAT THERE WAS A DECREASE IN DNA METHYLATION LEVELS IN THE PROMOTER OF ADIPONECTIN IN HUMAN IVM OOCYTES BETWEEN CONTROLS AND OOCYTES EXPOSED TO 10 MM GLUCOSE (P = 0.028). LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: IT IS NOT CLEAR WHETHER THE ALTERATIONS ARE BENEFICIAL OR NOT FOR THE EMBRYO DEVELOPMENT AND OFFSPRING HEALTH. THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON THE WHOLE PROCESS OF OOCYTE MATURATION ARE STILL NOT ELUCIDATED. ANOTHER ISSUE IS THAT THE NUMBER OF OOCYTES USED IN THIS STUDY WAS LIMITED. WIDER IMPLICATIONS OF THE FINDINGS: THIS IS THE FIRST TIME THAT THE EFFECTS OF HIGH-GLUCOSE CONCENTRATION ON DNA METHYLATION OF HUMAN OOCYTES HAVE BEEN ELUCIDATED. OUR RESULT INDICATES THAT IN HUMANS, THE HIGH RISK OF CHRONIC DISEASES IN OFFSPRING FROM DIABETIC MOTHERS MAY ORIGINATE FROM ABNORMAL DNA MODIFICATIONS IN OOCYTES. STUDY FUNDING/COMPETING INTEREST(S): THIS WORK WAS SUPPORTED BY THE FUND OF NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA (81401198) AND DOCTOR FOUNDATION OF QINGDAO AGRICULTURAL UNIVERSITY (1116008).THE AUTHORS DECLARE THAT THERE ARE NO POTENTIAL CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  745  97 CANNABIS ALTERS EPIGENETIC INTEGRITY AND ENDOCANNABINOID SIGNALLING IN THE HUMAN FOLLICULAR NICHE. STUDY QUESTION: DO PHYTOCANNABINOIDS (PCS) AFFECT FOLLICULAR ENDOCANNABINOID SIGNALLING AND THE EPIGENOME IN THE SURROUNDING GRANULOSA CELLS (GCS)? SUMMARY ANSWER: EXPOSURE TO PCS INCREASES THE EXPRESSION OF ENDOCANNABINOID RECEPTORS AND REDUCES DNA METHYLATION ENZYME EXPRESSION AND GLOBAL DNA METHYLATION IN NAIVE GCS. WHAT IS KNOWN ALREADY: CANNABIS PLANT DERIVATIVES, KNOWN AS PCS, ARE USED FOR MEDICINAL AND RECREATIONAL PURPOSES. THE MAIN PC, TETRAHYDROCANNABINOL (THC), IS THE THIRD MOST COMMONLY USED SUBSTANCE BY WOMEN OF CHILDBEARING AGE, HENCE KNOWLEDGE OF THE EFFECT IT HAS ON REPRODUCTION IS OF UTMOST IMPORTANCE. THC EXERTS ITS EFFECTS VIA RECEPTORS OF THE ENDOCANNABINOID SYSTEM (ECS) AND CAN INTERFERE WITH FOLLICULOGENESIS, OOCYTE DEVELOPMENT AND OVULATION. ENDOCANNABINOIDS HAVE BEEN MEASURED IN FOLLICULAR FLUID (FF) OBTAINED DURING OOCYTE RETRIEVAL AND ARE IMPLICATED IN CONTROLLING FOLLICULOGENESIS. IT HAS BEEN ESTABLISHED THAT IN THE PLACENTA, PCS DISRUPT ENDOCANNABINOID HOMEOSTASIS VIA IMPAIRMENT OF THE SYNTHETIC AND DEGRADING ENZYMES, LEADING TO A NET INCREASE OF ENDOCANNABINOID LEVELS. FINALLY, PREVIOUS STUDIES HAVE SHOWN THAT THC ALTERS METHYLATION AND HISTONE MODIFICATIONS IN SPERM, BRAIN AND BLOOD CELLS. STUDY DESIGN, SIZE, DURATION: THIS STUDY INCLUDED AN IN VIVO COHORT ASSESSMENT OF CANNABIS EXPOSURE AND ITS EFFECTS ON THE FOLLICLE AND IN VITRO ASSAYS CONDUCTED TO VALIDATE THE IN VIVO FINDINGS AND TO EXPLORE POSSIBLE MECHANISMS OF ACTION. PARTICIPANTS/MATERIALS, SETTING, METHODS: A TOTAL OF 318 FF SAMPLES, FROM 261 PATIENTS UNDERGOING IVF TREATMENT AT A PRIVATE FERTILITY CLINIC WHO CONSENTED FOR BIOBANKING BIOLOGICAL WASTE MATERIAL BETWEEN JANUARY 2018 AND JULY 2019, WERE INCLUDED IN THIS STUDY. CONCENTRATIONS OF PCS AND ENDOCANNABINOIDS WERE ASSESSED IN FF BY LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY (LC-MS/MS). EXPOSURE TO PCS WAS DETERMINED BASED ON THESE MEASURED LEVELS. LEVELS OF BOTH ENDOCANNABINOID RECEPTORS (CB1R, CB2R) AND THE DE NOVO DNA METHYLATING ENZYME, DNMT3B, IN GCS WERE ASSESSED BY FLOW CYTOMETRY BOTH IN VITRO AND IN VIVO AND GLOBAL DNA METHYLATION WAS ASSESSED IN VITRO BY ELISA. IN VIVO EFFECTS WERE ASSESSED BY COMPARING SAMPLES POSITIVE FOR AT LEAST ONE PC, WITH SAMPLES NEGATIVE FOR ALL MEASURED PCS. IN VITRO EFFECTS WERE DETERMINED IN NAIVE GCS, OBTAINED CONCURRENTLY WITH FF SAMPLES THAT HAD TESTED NEGATIVE FOR ALL PCS. THESE GCS WERE TREATED WITH DIFFERENT COMBINATIONS OF THE MAIN THREE PCS. MAIN RESULTS AND THE ROLE OF CHANCE: OVERALL, 17 PATIENTS (6.4%) WERE POSITIVE FOR CANNABIS CONSUMPTION. FURTHERMORE, THE PREVALENCE OF CANNABIS POSITIVITY IN THE FF INCREASED FROM 4% OF THE TESTED SAMPLES THAT WERE COLLECTED PRIOR TO NATIONAL LEGALISATION IN OCTOBER 2018 TO 12% OF THOSE COLLECTED FOLLOWING LEGALISATION. OF NOTE, 59% OF PATIENTS WHO TESTED POSITIVE FOR PCS (10 OF 17) REPORTED PREVIOUS OR ONGOING EXPOSURE TO CANNABIS UPON THEIR INITIAL INTAKE. ENDOCANNABINOID LEVELS WERE NOT AFFECTED BY THE PRESENCE OF PCS. CB2R WAS MORE PREVALENT THAN CB1R IN GCS AND ITS EXPRESSION INCREASED FOLLOWING ACUTE AND CHRONIC IN VITRO EXPOSURE TO PCS. THE EXPRESSION OF DNMT3B AND GLOBAL METHYLATION DECREASED FOLLOWING EXPOSURE, SUGGESTING THAT CANNABIS MAY AFFECT THE EPIGENOME IN THE FOLLICULAR NICHE. THE ACUTE CHANGES WERE SUSTAINED THROUGHOUT CHRONIC TREATMENT. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: OUR STUDY IS LIMITED BY LACK OF DETAILS REGARDING MODE, FREQUENCY AND TIMING OF PC CONSUMPTION. MOREOVER, WE WERE NOT ABLE TO ADEQUATELY ASSESS THE EFFECT OF PCS ON IMMEDIATE OR LONG-TERM CLINICAL OUTCOMES, DUE TO THE SMALL SAMPLE SIZE AND THE LACK OF FOLLOW UP. FUTURE, LARGE-SCALE STUDIES SHOULD FOCUS ON ASSESS THE CLINICAL IMPLICATIONS OF CANNABIS EXPOSURE, VALIDATE OUR FINDINGS, AND DETERMINE TO WHAT EXTENT CANNABIS AFFECTS THE EPIGENOME OVARIAN FOLLICLE AND THE DEVELOPING OOCYTE. WIDER IMPLICATIONS OF THE FINDINGS: TO OUR KNOWLEDGE, THIS IS THE FIRST STUDY MEASURING PCS IN FF BY LC-MS/MS. WE SHOW THAT CONSUMING CANNABIS ALTERS THE ECS IN THE DEVELOPING FOLLICLE, AND DIRECTLY AFFECTS DNMT EXPRESSION AND GLOBAL DNA METHYLATION LEVELS. CANNABIS LEGALISATION AND USE IS INCREASING WORLDWIDE, THEREFORE FURTHER UNDERSTANDING ITS ROLE IN FEMALE FERTILITY AND FOLLICULOGENESIS IS CRITICAL. STUDY FUNDING/COMPETING INTEREST(S): ALL FUNDING WAS PROVIDED BY CREATE FERTILITY CENTRE THROUGH THE REINVESTMENT OF CLINICAL EARNINGS. THE AUTHORS DECLARE NO COMPETING INTERESTS.	2021	

8 3652  53 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9 6547  51 TRANSCRIPTOMICS OF LONG-TERM MEDITATION PRACTICE: EVIDENCE FOR PREVENTION OR REVERSAL OF STRESS EFFECTS HARMFUL TO HEALTH. BACKGROUND AND OBJECTIVES: STRESS CAN OVERLOAD ADAPTIVE MECHANISMS, LEADING TO EPIGENETIC EFFECTS HARMFUL TO HEALTH. RESEARCH ON THE REVERSAL OF THESE EFFECTS IS IN ITS INFANCY. EARLY RESULTS SUGGEST SOME MEDITATION TECHNIQUES HAVE HEALTH BENEFITS THAT GROW WITH REPEATED PRACTICE. THIS STUDY FOCUSED ON POSSIBLE TRANSCRIPTOMIC EFFECTS OF 38 YEARS OF TWICE-DAILY TRANSCENDENTAL MEDITATION((R)) (TM((R))) PRACTICE. MATERIALS AND METHODS: FIRST, USING ILLUMINA((R)) BEADCHIP MICROARRAY TECHNOLOGY, DIFFERENCES IN GLOBAL GENE EXPRESSION IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE SOUGHT BETWEEN HEALTHY PRACTITIONERS AND TIGHTLY MATCHED CONTROLS (N = 12, AGE 65). SECOND, THESE MICROARRAY RESULTS WERE VERIFIED ON A SUBSET OF GENES USING QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) AND WERE VALIDATED USING QPCR IN LARGER TM AND CONTROL GROUPS (N = 45, AGE 63). BIOINFORMATICS INVESTIGATION EMPLOYED INGENUITY((R)) PATHWAY ANALYSIS (IPA((R))), DAVID, GENOMATIX, AND R PACKAGES. RESULTS: THE 200 GENES AND LOCI FOUND TO MEET STRICT CRITERIA FOR DIFFERENTIAL EXPRESSION IN THE MICROARRAY EXPERIMENT SHOWED CONTRASTING PATTERNS OF EXPRESSION THAT DISTINGUISHED THE TWO GROUPS. DIFFERENTIAL EXPRESSION RELATING TO IMMUNE FUNCTION AND ENERGY EFFICIENCY WERE MOST APPARENT. IN THE TM GROUP, RELATIVE TO THE CONTROL, ALL 49 GENES ASSOCIATED WITH INFLAMMATION WERE DOWNREGULATED, WHILE GENES ASSOCIATED WITH ANTIVIRAL AND ANTIBODY COMPONENTS OF THE DEFENSE RESPONSE WERE UPREGULATED. THE LARGEST EXPRESSION DIFFERENCES WERE SHOWN BY SIX GENES RELATED TO ERYTHROCYTE FUNCTION THAT APPEARED TO REFLECT A CONDITION OF LOWER ENERGY EFFICIENCY IN THE CONTROL GROUP. RESULTS SUPPORTING THESE GENE EXPRESSION DIFFERENCES WERE OBTAINED WITH QPCR-MEASURED EXPRESSION BOTH IN THE WELL-MATCHED MICROARRAY GROUPS AND IN THE LARGER, LESS WELL-MATCHED GROUPS. CONCLUSIONS: THESE FINDINGS ARE CONSISTENT WITH PREDICTIONS BASED ON RESULTS FROM EARLIER RANDOMIZED TRIALS OF MEDITATION AND MAY PROVIDE EVIDENCE FOR STRESS-RELATED MOLECULAR MECHANISMS UNDERLYING REDUCTIONS IN ANXIETY, POST-TRAUMATIC STRESS DISORDER (PTSD), CARDIOVASCULAR DISEASE (CVD), AND OTHER CHRONIC DISORDERS AND DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10 1503  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 5722  47 SISTER CHROMATID EXCHANGE AND PROLIFERATIVE RATE INDEX IN THE LONGITUDINAL RISK ASSESSMENT OF OCCUPATIONAL EXPOSURE TO PESTICIDES. AT PRESENT, THERE ARE MORE THAN 1,000 CHEMICALS CLASSIFIED AS PESTICIDES AND MANY REPORTS HAVE SHOWN THAT SOME OF THEM HAVE GENOTOXIC PROPERTIES. IN THE PRESENT LONGITUDINAL STUDY, POSSIBLE GENETIC DAMAGE ON A POPULATION OF WORKERS OCCUPATIONALLY EXPOSED TO A MIXTURE OF PESTICIDES BY USING SISTER CHROMATID EXCHANGE (SCE) ANALYSIS HAS BEEN EVALUATED. AS AN ADDITIONAL CYTOGENETIC PARAMETER, THE PROPORTION OF LYMPHOCYTES THAT UNDERGO ONE, TWO OR THREE CELL DIVISIONS AS WELL AS PROLIFERATIVE RATE INDEX HAVE BEEN DETERMINED. THIS STUDY WAS PERFORMED ON THE EXPOSED GROUP OF WORKERS EMPLOYED IN PESTICIDE PRODUCTION, SIMULTANEOUSLY EXPOSED TO A COMPLEX MIXTURE OF PESTICIDES (ATRAZINE, ALACHLOR, CYANAZINE, 2,4-DICHLOROPHENOXYACETIC ACID, AND MALATHION). THE BLOOD SAMPLES OF THE EXPOSED SUBJECTS WERE COLLECTED IN THREE DIFFERENT PERIODS: BEFORE THE BEGINNING OF THE NEW PESTICIDE PRODUCTION PERIOD, AFTER 8 MONTHS OF EVERYDAY WORK IN THE PESTICIDE PRODUCTION, AND 8 MONTHS AFTER THE REMOVAL OF SUBJECTS OUT OF THE PRODUCTION. IN ALL THREE SAMPLINGS, THE MEAN VALUE OF SCE AND NUMBER OF CELLS WITH HIGH SISTER CHROMATID EXCHANGE FREQUENCY (HFC) IN THE EXPOSED GROUP WAS SIGNIFICANTLY HIGHER IN THE COMPARISON WITH THE CONTROL GROUP. THERE WERE NO DIFFERENCES IN THE PROLIFERATIVE RATE INDEX (PRI) BETWEEN THE CONTROL AND EXPOSED GROUP, REGARDLESS OF THE SAMPLING PERIOD. IN BOTH GROUPS EXAMINED, THE MAJORITY OF LYMPHOCYTES WERE FOUND IN THE SECOND CELL DIVISION, FOLLOWING CULTIVATION. THESE RESULTS SUGGEST THAT THE INCREASE IN THE NUMBER OF SCE FOUND IN THE EXPOSED SUBJECTS IS NOT THE RESULT OF EITHER CYTOTOXIC OR EPIGENETIC ACTION OF PESTICIDE MIXTURE, BUT CHRONIC OCCUPATIONAL EXPOSURE TO MIXTURE OF PESTICIDES.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12 1537  36 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13 3991  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14 1573  41 DNA METHYLATION PATTERNS IN NEWBORNS EXPOSED TO TOBACCO IN UTERO. BACKGROUND: MATERNAL SMOKING DURING PREGNANCY IS A MAJOR RISK FACTOR FOR ADVERSE HEALTH OUTCOMES. THE MAIN OBJECTIVE OF THE STUDY WAS TO ASSESS THE IMPACT OF IN UTERO TOBACCO EXPOSURE ON DNA METHYLATION IN CHILDREN BORN AT TERM WITH APPROPRIATE WEIGHT AT BIRTH. METHODS: TWENTY MOTHER-NEWBORN DYADS, AFTER UNCOMPLICATED PREGNANCIES, IN THE ABSENCE OF PERINATAL ILLNESS WERE INCLUDED. ALL MOTHERS WERE HEALTHY WITH NO CARDIOVASCULAR RISK FACTORS, EXCEPT FOR THE ASSOCIATED RISKS AMONG THOSE MOTHERS WHO SMOKED. UMBILICAL CORD BLOOD AND MATERNAL PERIPHERAL VENOUS BLOOD WERE COLLECTED AND AN EPIGENOME-WIDE ASSOCIATION STUDY WAS PERFORMED USING A 450 K EPIGENOME-WIDE SCAN (ILLUMINA INFINIUM HUMANMETHYLATION 450BEADCHIP) WITH ADJUSTMENT TO NORMALIZE THE DNA METHYLATION FOR DATA CELL VARIABILITY IN WHOLE BLOOD. RESULTS: THE MATERNAL PLASMATIC COTININE LEVELS RANGED FROM 10.70-115.40 NG/ML IN THE EXPOSED GROUP TO 0-0.59 NG/ML IN THE NON-EXPOSED GROUP. AFTER ADJUSTING FOR MULTIPLE COMPARISONS IN 427102 PROBES, STATISTICALLY SIGNIFICANT DIFFERENCES FOR 31 CPG SITES, ASSOCIATED TO 25 GENES WERE OBSERVED. THERE WAS A GREATER THAN EXPECTED PROPORTION OF STATISTICALLY-SIGNIFICANT LOCI LOCATED IN CPG ISLANDS (FISHER'S EXACT TEST, P = 0.029) AND OF THOSE CPG ISLANDS, 90.3% EXHIBIT HIGHER METHYLATION LEVELS IN THE EXPOSED GROUP. THE MOST STRIKING AND SIGNIFICANT CPG SITE, CG05727225, IS LOCATED IN THE CHROMOSOME 11P15.4, WITHIN THE ADRENOMEDULLIN GENE. CONCLUSIONS: IN UTERO TOBACCO EXPOSURE, EVEN IN THE ABSENCE OF FETAL GROWTH RESTRICTION, MAY ALTER THE EPIGENOME, CONTRIBUTING TO GLOBAL DNA HYPOMETHYLATION. THEREFORE, DNA STATUS CAN BE USED AS A BIOMARKER OF PRENATAL INSULTS. CONSIDERING THE POSSIBILITY TO REVERSE EPIGENETIC MODIFICATIONS, A WINDOW OF OPPORTUNITY EXISTS TO CHANGE THE PROGRAMMED CHRONIC DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15 1450  43 DISAGREEMENT BETWEEN TWO COMMON BIOMARKERS OF GLOBAL DNA METHYLATION. BACKGROUND: THE QUANTIFICATION OF GLOBAL DNA METHYLATION HAS BEEN ESTABLISHED IN EPIGENETIC SCREENING. AS MORE PRACTICABLE ALTERNATIVES TO THE HPLC-BASED GOLD STANDARD, THE METHYLATION ANALYSIS OF CPG ISLANDS IN REPEATABLE ELEMENTS (LINE-1) AND THE LUMINOMETRIC METHYLATION ASSAY (LUMA) OF OVERALL 5-METHYLCYTOSINE CONTENT IN "CCGG" RECOGNITION SITES ARE MOST WIDELY USED. BOTH METHODS ARE APPLIED AS VIRTUALLY EQUIVALENT, DESPITE THE HINTS THAT THEIR RESULTS ONLY PARTLY AGREE. THIS TRIGGERED THE PRESENT AGREEMENT ASSESSMENTS. RESULTS: THREE DIFFERENT HUMAN CELL TYPES (CULTURED MCF7 AND SHSY5Y CELL LINES TREATED WITH DIFFERENT CHEMICAL MODULATORS OF DNA METHYLATION AND WHOLE BLOOD DRAWN FROM PAIN PATIENTS AND HEALTHY VOLUNTEERS) WERE SUBMITTED TO THE GLOBAL DNA METHYLATION ASSAYS EMPLOYING LINE-1 OR LUMA-BASED PYROSEQUENCING MEASUREMENTS. THE AGREEMENT BETWEEN THE TWO BIOASSAYS WAS ASSESSED USING GENERALLY ACCEPTED APPROACHES TO THE STATISTICS FOR LABORATORY METHOD COMPARISON STUDIES. ALTHOUGH GLOBAL DNA METHYLATION LEVELS MEASURED BY THE TWO METHODS CORRELATED, FIVE DIFFERENT LINES OF STATISTICAL EVIDENCE CONSISTENTLY REJECTED THE ASSUMPTION OF COMPLETE AGREEMENT. SPECIFICALLY, A BIAS WAS OBSERVED BETWEEN THE TWO METHODS. IN ADDITION, BOTH THE MAGNITUDE AND DIRECTION OF BIAS WERE TISSUE-DEPENDENT. INTERASSAY DIFFERENCES COULD BE GROUPED BASED ON BAYESIAN STATISTICS, AND THESE GROUPS ALLOWED IN TURN TO RE-IDENTIFY THE ORIGINATING TISSUE. CONCLUSIONS: ALTHOUGH PROVIDING PARTLY CORRELATED MEASUREMENTS OF DNA METHYLATION, INTERCHANGEABILITY OF THE QUANTITATIVE RESULTS OBTAINED WITH LINE-1 AND LUMA WAS JEOPARDIZED BY A CONSISTENT BIAS BETWEEN THE RESULTS. MOREOVER, THE PRESENT ANALYSES STRONGLY INDICATE A TISSUE SPECIFICITY OF THE DIFFERENCES BETWEEN THE TWO METHODS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16 6384  46 THE ROLE OF POLYCARBONATE MONOMER BISPHENOL-A IN INSULIN RESISTANCE. BISPHENOL A (BPA) IS A SYNTHETIC UNIT OF POLYCARBONATE POLYMERS AND EPOXY RESINS, THE TYPES OF PLASTICS THAT COULD BE FOUND IN ESSENTIALLY EVERY HUMAN POPULATION AND INCORPORATED INTO ALMOST EVERY ASPECT OF THE MODERN HUMAN SOCIETY. BPA POLYMERS APPEAR IN A WIDE RANGE OF PRODUCTS, FROM LIQUID STORAGES (PLASTIC BOTTLES, CAN AND GLASS LININGS, WATER PIPES AND TANKS) AND FOOD STORAGES (PLASTICS WRAPS AND CONTAINERS), TO MEDICAL AND DENTAL DEVICES. BPA POLYMERS COULD BE HYDROLYZED SPONTANEOUSLY OR IN A PHOTO- OR TEMPERATURE-CATALYZED PROCESS, PROVIDING WIDESPREAD ENVIRONMENTAL DISTRIBUTION AND CHRONIC EXPOSURE TO THE BPA MONOMER IN CONTEMPORARY HUMAN POPULATIONS. BISPHENOL A IS ALSO A XENOESTROGEN, AN ENDOCRINE-DISRUPTING CHEMICAL (EDC) THAT INTERFERES WITH THE ENDOCRINE SYSTEM MIMICKING THE EFFECTS OF AN ESTROGEN AND COULD POTENTIALLY KEEP OUR ENDOCRINE SYSTEM IN A CONSTANT PERTURBATION THAT PARALLELS ENDOCRINE DISRUPTION ARISING DURING PREGNANCY, SUCH AS INSULIN RESISTANCE (IR). GESTATIONAL INSULIN RESISTANCE REPRESENTS A NATURAL BIOLOGICAL PHENOMENON OF HIGHER INSULIN RESISTANCE IN PERIPHERAL TISSUES OF THE PREGNANT FEMALES, WHEN NUTRIENTS ARE INCREASINGLY BEING DIRECTED TO THE EMBRYO INSTEAD OF BEING STORED IN PERIPHERAL TISSUES. GESTATIONAL DIABETES MELLITUS MAY APPEAR IN HEALTHY NON-DIABETIC FEMALES, DUE TO GESTATIONAL INSULIN RESISTANCE THAT LEADS TO INCREASED BLOOD SUGAR LEVELS AND HYPERINSULINEMIA (INCREASED INSULIN PRODUCTION FROM THE PANCREATIC BETA CELLS). THE HYPOTHESIS STATES THAT UNNOTICED AND CONSTANT EXPOSURE TO THIS ENVIRONMENTAL CHEMICAL MIGHT POTENTIALLY LEAD TO THE FORMATION OF CHRONIC LOW-LEVEL ENDOCRINE DISRUPTIVE STATE THAT RESEMBLES GESTATIONAL INSULIN RESISTANCE, WHICH MIGHT CONTRIBUTE TO THE DEVELOPMENT OF DIABETES. THE INCREASING BODY OF EVIDENCE SUPPORTS THE MAJOR PREMISES OF THIS HYPOTHESIS, AS EXEMPLIFIED BY THE NUMEROUS PUBLICATIONS EXAMINING THE ASSOCIATION OF BPA AND INSULIN RESISTANCE, BOTH EPIDEMIOLOGICAL AND MECHANISTIC. HOWEVER, TO WHAT EXTENT BPA MIGHT CONTRIBUTE TO THE DEVELOPMENT OF DIABETES IN THE MODERN SOCIETIES STILL REMAINS UNKNOWN. IN THIS REVIEW, I DISCUSS THE CHEMICAL PROPERTIES OF BPA AND THE SOURCES OF BPA CONTAMINATION FOUND IN THE ENVIRONMENT AND IN HUMAN TISSUES. I PROVIDE AN OVERVIEW OF MECHANISMS FOR THE PROPOSED ROLE OF BISPHENOL A IN INSULIN RESISTANCE AND DIABETES, AS WELL AS OTHER RELATED DISEASES, SUCH AS CARDIOVASCULAR DISEASES. I DESCRIBE THE TRANSMISSION OF BPA EFFECTS TO THE OFFSPRING AND POSTULATE THAT GENDER RELATED DIFFERENCES MIGHT ORIGINATE FROM DIFFERENCES IN LIVER ENZYME LEVELS, SUCH AS UDP-GLUCURONOSYLTRANSFERASE, WHICH IS INVOLVED IN BPA PROCESSING AND ITS ELIMINATION FROM THE ORGANISM. I DISCUSS THE MOLECULAR MECHANISMS OF BPA ACTION THROUGH NUCLEAR AND MEMBRANE-BOUND ER RECEPTORS, NON-MONOTONIC DOSE RESPONSE, EPIGENETIC MODIFICATIONS OF THE DNA AND PROPOSE THAT CHRONIC EXPOSURE TO WEAK BINDERS, SUCH AS BPA, MAY MIMIC THE EFFECTS OF STRONG BINDERS, SUCH AS ESTROGENS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  667  47 BLOOD-BASED EPIGENOME-WIDE ANALYSES OF 19 COMMON DISEASE STATES: A LONGITUDINAL, POPULATION-BASED LINKED COHORT STUDY OF 18,413 SCOTTISH INDIVIDUALS. BACKGROUND: DNA METHYLATION IS A DYNAMIC EPIGENETIC MECHANISM THAT OCCURS AT CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDE (CPG) SITES. EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) INVESTIGATE THE STRENGTH OF ASSOCIATION BETWEEN METHYLATION AT INDIVIDUAL CPG SITES AND HEALTH OUTCOMES. ALTHOUGH BLOOD METHYLATION MAY ACT AS A PERIPHERAL MARKER OF COMMON DISEASE STATES, PREVIOUS EWAS HAVE TYPICALLY FOCUSED ONLY ON INDIVIDUAL CONDITIONS AND HAVE HAD LIMITED POWER TO DISCOVER DISEASE-ASSOCIATED LOCI. THIS STUDY EXAMINED THE ASSOCIATION OF BLOOD DNA METHYLATION WITH THE PREVALENCE OF 14 DISEASE STATES AND THE INCIDENCE OF 19 DISEASE STATES IN A SINGLE POPULATION OF OVER 18,000 SCOTTISH INDIVIDUALS. METHODS AND FINDINGS: DNA METHYLATION WAS ASSAYED AT 752,722 CPG SITES IN WHOLE-BLOOD SAMPLES FROM 18,413 VOLUNTEERS IN THE FAMILY-STRUCTURED, POPULATION-BASED COHORT STUDY GENERATION SCOTLAND (AGE RANGE 18 TO 99 YEARS). EWAS TESTED FOR CROSS-SECTIONAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 14 PREVALENT DISEASE STATES, AND FOR LONGITUDINAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 19 INCIDENT DISEASE STATES. PREVALENT CASES WERE SELF-REPORTED ON HEALTH QUESTIONNAIRES AT THE BASELINE. INCIDENT CASES WERE IDENTIFIED USING LINKAGE TO SCOTTISH PRIMARY (READ 2) AND SECONDARY (ICD-10) CARE RECORDS, AND THE CENSORING DATE WAS SET TO OCTOBER 2020. THE MEAN TIME-TO-DIAGNOSIS RANGED FROM 5.0 YEARS (FOR CHRONIC PAIN) TO 11.7 YEARS (FOR CORONAVIRUS DISEASE 2019 (COVID-19) HOSPITALISATION). THE 19 DISEASE STATES CONSIDERED IN THIS STUDY WERE SELECTED IF THEY WERE PRESENT ON THE WORLD HEALTH ORGANISATION'S 10 LEADING CAUSES OF DEATH AND DISEASE BURDEN OR INCLUDED IN BASELINE SELF-REPORT QUESTIONNAIRES. EWAS MODELS WERE ADJUSTED FOR AGE AT METHYLATION TYPING, SEX, ESTIMATED WHITE BLOOD CELL COMPOSITION, POPULATION STRUCTURE, AND 5 COMMON LIFESTYLE RISK FACTORS. A STRUCTURED LITERATURE REVIEW WAS ALSO CONDUCTED TO IDENTIFY EXISTING EWAS FOR ALL 19 DISEASE STATES TESTED. THE MEDLINE, EMBASE, WEB OF SCIENCE, AND PREPRINT SERVERS WERE SEARCHED TO RETRIEVE RELEVANT ARTICLES INDEXED AS OF MARCH 27, 2023. FIFTY-FOUR OF APPROXIMATELY 2,000 INDEXED ARTICLES MET OUR INCLUSION CRITERIA: ASSAYED BLOOD-BASED DNA METHYLATION, HAD >20 INDIVIDUALS IN EACH COMPARISON GROUP, AND EXAMINED ONE OF THE 19 CONDITIONS CONSIDERED. FIRST, WE ASSESSED WHETHER THE ASSOCIATIONS IDENTIFIED IN OUR STUDY WERE REPORTED IN PREVIOUS STUDIES. WE IDENTIFIED 69 ASSOCIATIONS BETWEEN CPGS AND THE PREVALENCE OF 4 CONDITIONS, OF WHICH 58 WERE NEWLY DESCRIBED. THE CONDITIONS WERE BREAST CANCER, CHRONIC KIDNEY DISEASE, ISCHEMIC HEART DISEASE, AND TYPE 2 DIABETES MELLITUS. WE ALSO UNCOVERED 64 CPGS THAT ASSOCIATED WITH THE INCIDENCE OF 2 DISEASE STATES (COPD AND TYPE 2 DIABETES), OF WHICH 56 WERE NOT REPORTED IN THE SURVEYED LITERATURE. SECOND, WE ASSESSED REPLICATION ACROSS EXISTING STUDIES, WHICH WAS DEFINED AS THE REPORTING OF AT LEAST 1 COMMON SITE IN >2 STUDIES THAT EXAMINED THE SAME CONDITION. ONLY 6/19 DISEASE STATES HAD EVIDENCE OF SUCH REPLICATION. THE LIMITATIONS OF THIS STUDY INCLUDE THE NONCONSIDERATION OF MEDICATION DATA AND A POTENTIAL LACK OF GENERALIZABILITY TO INDIVIDUALS THAT ARE NOT OF SCOTTISH AND EUROPEAN ANCESTRY. CONCLUSIONS: WE DISCOVERED OVER 100 ASSOCIATIONS BETWEEN BLOOD METHYLATION SITES AND COMMON DISEASE STATES, INDEPENDENTLY OF MAJOR CONFOUNDING RISK FACTORS, AND A NEED FOR GREATER STANDARDISATION AMONG EWAS ON HUMAN DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18 6311  37 THE RELATION BETWEEN DNA METHYLATION PATTERNS AND SERUM CYTOKINE LEVELS IN COMMUNITY-DWELLING ADULTS: A PRELIMINARY STUDY. BACKGROUND: THE LEVELS OF CIRCULATING CYTOKINES FLUCTUATE WITH AGE, ACUTE ILLNESS, AND CHRONIC DISEASE, AND ARE PREDICTIVE OF MORTALITY; THIS IS ALSO TRUE FOR PATTERNS OF DNA (CPG) METHYLATION. GIVEN THAT IMMUNE CELLS ARE PARTICULARLY SENSITIVE TO CHANGES IN THE CONCENTRATION OF CYTOKINES IN THEIR MICROENVIRONMENT, WE HYPOTHESIZED THAT SERUM LEVELS OF TNF, IL-6, IL-8 AND IL-10 WOULD CORRELATE WITH GENOME-WIDE ALTERATIONS IN THE DNA METHYLATION LEVELS OF BLOOD LEUKOCYTES. TO TEST THIS, WE EVALUATED COMMUNITY-DWELLING ADULTS (N = 14; 48-78 YEARS OLD) RECRUITED TO A PILOT STUDY FOR THE CANADIAN LONGITUDINAL STUDY ON AGING (CLSA), EXAMINING DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS USING THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP. RESULTS: WE SHOW THAT, APART FROM AGE, SERUM IL-10 LEVELS EXHIBITED THE MOST SUBSTANTIAL ASSOCIATION TO DNA METHYLATION PATTERNS, FOLLOWED BY TNF, IL-6 AND IL-8. FURTHERMORE, WHILE THE LEVELS OF THESE CYTOKINES WERE HIGHER IN ELDERLY ADULTS, NO ASSOCIATIONS WITH EPIGENETIC ACCELERATED AGING, DERIVED USING THE EPIGENETIC CLOCK, WERE OBSERVED. CONCLUSIONS: AS A PRELIMINARY STUDY WITH A SMALL SAMPLE SIZE, THE CONCLUSIONS DRAWN FROM THIS WORK MUST BE VIEWED WITH CAUTION; HOWEVER, OUR OBSERVATIONS ARE ENCOURAGING AND CERTAINLY WARRANT MORE SUITABLY POWERED STUDIES OF THIS RELATIONSHIP.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19 1345  48 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20  652  50 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