1  4691 182 NEWBORNS OF OBESE PARENTS HAVE ALTERED DNA METHYLATION PATTERNS AT IMPRINTED GENES. BACKGROUND: SEVERAL EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED ASSOCIATIONS BETWEEN PERICONCEPTIONAL ENVIRONMENTAL EXPOSURES AND HEALTH STATUS OF THE OFFSPRING IN LATER LIFE. ALTHOUGH THESE ENVIRONMENTALLY RELATED EFFECTS HAVE BEEN ATTRIBUTED TO EPIGENETIC CHANGES, SUCH AS DNA METHYLATION SHIFTS AT IMPRINTED GENES, LITTLE IS KNOWN ABOUT THE POTENTIAL EFFECTS OF MATERNAL AND PATERNAL PRECONCEPTIONAL OVERNUTRITION OR OBESITY. OBJECTIVE: WE EXAMINED PARENTAL PRECONCEPTIONAL OBESITY IN RELATION TO DNA METHYLATION PROFILES AT MULTIPLE HUMAN IMPRINTED GENES IMPORTANT IN NORMAL GROWTH AND DEVELOPMENT, SUCH AS: MATERNALLY EXPRESSED GENE 3 (MEG3), MESODERM-SPECIFIC TRANSCRIPT (MEST), PATERNALLY EXPRESSED GENE 3 (PEG3), PLEIOMORPHIC ADENOMA GENE-LIKE 1 (PLAGL1), EPSILON SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 (SGCE/PEG10) AND NEURONATIN (NNAT). METHODS: WE MEASURED METHYLATION PERCENTAGES AT THE DIFFERENTIALLY METHYLATED REGIONS (DMRS) BY BISULFITE PYROSEQUENCING IN DNA EXTRACTED FROM UMBILICAL CORD BLOOD LEUKOCYTES OF 92 NEWBORNS. PRECONCEPTIONAL OBESITY, DEFINED AS BMI ?30 KG M(-2), WAS ASCERTAINED THROUGH STANDARDIZED QUESTIONNAIRES. RESULTS: AFTER ADJUSTING FOR POTENTIAL CONFOUNDERS AND CLUSTER EFFECTS, PATERNAL OBESITY WAS SIGNIFICANTLY ASSOCIATED WITH LOWER METHYLATION LEVELS AT THE MEST (BETA=-2.57; S.E.=0.95; P=0.008), PEG3 (BETA=-1.71; S.E.=0.61; P=0.005) AND NNAT (BETA=-3.59; S.E.=1.76; P=0.04) DMRS. CHANGES RELATED TO MATERNAL OBESITY DETECTED AT OTHER LOCI WERE AS FOLLOWS: BETA-COEFFICIENT WAS +2.58 (S.E.=1.00; P=0.01) AT THE PLAGL1 DMR AND -3.42 (S.E.=1.69; P=0.04) AT THE MEG3 DMR. CONCLUSION: WE FOUND ALTERED METHYLATION OUTCOMES AT MULTIPLE IMPRINT REGULATORY REGIONS IN CHILDREN BORN TO OBESE PARENTS, COMPARED WITH CHILDREN BORN TO NON-OBESE PARENTS. IN SPITE OF THE SMALL SAMPLE SIZE, OUR DATA SUGGEST A PRECONCEPTIONAL INFLUENCE OF PARENTAL LIFE-STYLE OR OVERNUTRITION ON THE (RE)PROGRAMMING OF IMPRINT MARKS DURING GAMETOGENESIS AND EARLY DEVELOPMENT. MORE SPECIFICALLY, THE SIGNIFICANT AND INDEPENDENT ASSOCIATION BETWEEN PATERNAL OBESITY AND THE OFFSPRING'S METHYLATION STATUS SUGGESTS THE SUSCEPTIBILITY OF THE DEVELOPING SPERM FOR ENVIRONMENTAL INSULTS. THE ACQUIRED IMPRINT INSTABILITY MAY BE CARRIED ONTO THE NEXT GENERATION AND INCREASE THE RISK FOR CHRONIC DISEASES IN ADULTHOOD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2  4010  57 LOW MATERNAL ADHERENCE TO A MEDITERRANEAN DIET IS ASSOCIATED WITH INCREASE IN METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION IN FEMALE INFANTS. DIET IS DICTATED BY THE SURROUNDING ENVIRONMENT, AS FOOD ACCESS AND AVAILABILITY MAY CHANGE DEPENDING ON WHERE ONE LIVES. MATERNAL DIET DURING PREGNANCY IS AN IMPORTANT PART OF THE IN UTERO ENVIRONMENT, AND MAY AFFECT THE EPIGENOME. STUDIES LOOKING AT OVERALL DIET PATTERN IN RELATION TO DNA METHYLATION HAVE BEEN LACKING. THE MEDITERRANEAN DIET IS KNOWN FOR ITS HEALTH BENEFITS, INCLUDING DECREASED INFLAMMATION, WEIGHT LOSS, AND MANAGEMENT OF CHRONIC DISEASES. THIS STUDY ASSESSES THE ASSOCIATION BETWEEN MATERNAL ADHERENCE TO A MEDITERRANEAN DIET PATTERN DURING PREGNANCY AND INFANT DNA METHYLATION AT BIRTH. MEDITERRANEAN DIET ADHERENCE IN EARLY PREGNANCY WAS MEASURED IN 390 WOMEN ENROLLED IN THE NEWBORN EPIGENETIC STUDY, AND DNA METHYLATION WAS ASSESSED IN THEIR INFANTS AT BIRTH. MULTINOMIAL LOGISTIC REGRESSION WAS USED TO ASSESS THE ASSOCIATION BETWEEN ADHERENCE TO A MEDITERRANEAN DIET AND INFANT METHYLATION AT THE MEG3, MEG3-IG, PLEIOMORPHIC ADENOMA GENE-LIKE 1, INSULIN-LIKE GROWTH FACTOR 2 GENE, H19, MESODERM-SPECIFIC TRANSCRIPT, NEURONATIN, PATERNALLY EXPRESSED GENE 3, SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 REGIONS, MEASURED BY PYROSEQUENCING. INFANTS OF MOTHERS WITH A LOW ADHERENCE TO A MEDITERRANEAN DIET HAD A GREATER ODDS OF HYPO-METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION (DMR). SEX-STRATIFIED MODELS SHOWED THAT THIS ASSOCIATION WAS PRESENT IN GIRLS ONLY. THIS STUDY PROVIDES EARLY EVIDENCE ON THE ASSOCIATION BETWEEN OVERALL DIET PATTERN AND METHYLATION AT THE 9 DMRS INCLUDED IN THIS STUDY, AND SUGGESTS THAT MATERNAL DIET CAN HAVE A SEX-SPECIFIC IMPACT ON INFANT DNA METHYLATION AT SPECIFIC IMPRINTED DMRS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3   518  66 ASSOCIATIONS BETWEEN ANTIBIOTIC EXPOSURE DURING PREGNANCY, BIRTH WEIGHT AND ABERRANT METHYLATION AT IMPRINTED GENES AMONG OFFSPRING. OBJECTIVES: LOW BIRTH WEIGHT (LBW) HAS BEEN ASSOCIATED WITH COMMON ADULT-ONSET CHRONIC DISEASES, INCLUDING OBESITY, CARDIOVASCULAR DISEASE, TYPE II DIABETES AND SOME CANCERS. THE ETIOLOGY OF LBW IS MULTI-FACTORIAL. HOWEVER, RECENT EVIDENCE SUGGESTS EXPOSURE TO ANTIBIOTICS MAY ALSO INCREASE THE RISK OF LBW. THE MECHANISMS UNDERLYING THIS ASSOCIATION ARE UNKNOWN, ALTHOUGH EPIGENETIC MECHANISMS ARE HYPOTHESIZED. IN THIS STUDY, WE EVALUATED THE ASSOCIATION BETWEEN MATERNAL ANTIBIOTIC USE AND LBW AND EXAMINED THE POTENTIAL ROLE OF ALTERED DNA METHYLATION THAT CONTROLS GROWTH REGULATORY IMPRINTED GENES IN THESE ASSOCIATIONS. METHODS: BETWEEN 2009-2011, 397 PREGNANT WOMEN WERE ENROLLED AND FOLLOWED UNTIL DELIVERY. PRENATAL ANTIBIOTIC USE WAS ASCERTAINED THROUGH MATERNAL SELF-REPORT. IMPRINTED GENES METHYLATION LEVELS WERE MEASURED AT DIFFERENTIALLY METHYLATED REGIONS (DMRS) USING BISULFITE PYROSEQUENCING. GENERALIZED LINEAR MODELS WERE USED TO EXAMINE ASSOCIATIONS AMONG ANTIBIOTIC USE, BIRTH WEIGHT AND DMR METHYLATION FRACTIONS. RESULTS: AFTER ADJUSTING FOR INFANT GENDER, RACE/ETHNICITY, MATERNAL BODY MASS INDEX, DELIVERY ROUTE, GESTATIONAL WEIGHT GAIN, GESTATIONAL AGE AT DELIVERY, FOLIC ACID INTAKE, PHYSICAL ACTIVITY, MATERNAL SMOKING AND PARITY, ANTIBIOTIC USE DURING PREGNANCY WAS ASSOCIATED WITH 138 G LOWER BIRTH WEIGHT COMPARED WITH NON-ANTIBIOTIC USE (BETA-COEFFICIENT=-132.99, S.E.=50.70, P=0.008). THESE ASSOCIATIONS WERE STRONGEST IN NEWBORNS OF WOMEN WHO REPORTED ANTIBIOTIC USE OTHER THAN PENICILLINS (BETA-COEFFICIENT=-135.57, S.E.=57.38, P=0.02). METHYLATION AT FIVE DMRS, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) AND PEG3 (P=0.08), WAS ASSOCIATED WITH MATERNAL ANTIBIOTIC USE; AMONG THESE, ONLY METHYLATION AT THE PLAGL1 DMR WAS ALSO ASSOCIATED WITH BIRTH WEIGHT. CONCLUSION: WE REPORT AN INVERSE ASSOCIATION BETWEEN IN UTERO EXPOSURE TO ANTIBIOTICS AND LOWER INFANT BIRTH WEIGHT AND PROVIDE THE FIRST EMPIRICAL EVIDENCE SUPPORTING IMPRINTED GENE PLASTICITY IN THESE ASSOCIATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4  1521  60 DNA METHYLATION AT IMPRINT REGULATORY REGIONS IN PRETERM BIRTH AND INFECTION. OBJECTIVE: TO AID IN UNDERSTANDING LONG-TERM HEALTH CONSEQUENCES OF INTRAUTERINE INFECTIONS IN PRETERM BIRTH, WE EVALUATED DNA METHYLATION AT 9 DIFFERENTIALLY METHYLATED REGIONS THAT REGULATE IMPRINTED GENES BY TYPE OF PRETERM BIRTH (SPONTANEOUS PRETERM LABOR, PRETERM PREMATURE RUPTURE OF MEMBRANES, OR MEDICALLY INDICATED [FETAL GROWTH RESTRICTION AND PREECLAMPSIA]) AND INFECTION STATUS (CHORIOAMNIONITIS OR FUNISITIS). STUDY DESIGN: DATA ON TYPE OF PRETERM BIRTH AND INFECTION STATUS WERE ABSTRACTED FROM MEDICAL RECORDS AND STANDARDIZED PATHOLOGY REPORTS IN 73 PRETERM INFANTS ENROLLED IN THE NEWBORN EPIGENETICS STUDY, A PROSPECTIVE COHORT STUDY OF MOTHER-INFANT DYADS IN DURHAM, NC. CORD BLOOD WAS COLLECTED AT BIRTH, AND INFANT DNA METHYLATION LEVELS AT THE H19, IGF2, MEG3, MEST, SGCE/PEG10, PEG3, NNAT, AND PLAGL1 DIFFERENTIALLY METHYLATED REGIONS WERE MEASURED USING BISULFITE PYROSEQUENCING. ONE-WAY ANALYSES OF VARIANCE AND LOGISTIC REGRESSION MODELS WERE USED TO COMPARE DNA METHYLATION LEVELS BY TYPE OF PRETERM BIRTH AND INFECTION STATUS. RESULTS: DNA METHYLATION LEVELS DID NOT DIFFER AT ANY OF THE REGIONS (P > .20) BETWEEN INFANTS BORN VIA SPONTANEOUS PRETERM LABOR (AVERAGE N = 29), PRETERM PREMATURE RUPTURE OF MEMBRANES (AVERAGE N = 17), OR MEDICALLY INDICATED PRETERM BIRTH (AVERAGE N = 40). LEVELS WERE SIGNIFICANTLY INCREASED AT PLAGL1 IN INFANTS WITH CHORIOAMNIONITIS (N = 10, 64.4%) COMPARED WITH INFANTS WITHOUT CHORIOAMNIONITIS (N = 63, 57.9%), P < .01. DNA METHYLATION LEVELS WERE ALSO INCREASED AT PLAGL1 FOR INFANTS WITH FUNISITIS (N = 7, 63.3%) COMPARED WITH INFANTS WITHOUT FUNISITIS (N = 66, 58.3%), P < .05. CONCLUSION: DYSREGULATION OF PLAGL1 HAS BEEN ASSOCIATED WITH ABNORMAL DEVELOPMENT AND CANCER. EARLY-LIFE EXPOSURES, INCLUDING INFECTION/INFLAMMATION, MAY AFFECT EPIGENETIC CHANGES THAT INCREASE SUSCEPTIBILITY TO LATER CHRONIC DISEASE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  2351  69 EPIGENETIC REGULATION OF NEWBORNS' IMPRINTED GENES RELATED TO GESTATIONAL GROWTH: PATTERNING BY PARENTAL RACE/ETHNICITY AND MATERNAL SOCIOECONOMIC STATUS. BACKGROUND: CHILDREN BORN TO PARENTS WITH LOWER INCOME AND EDUCATION ARE AT RISK FOR OBESITY AND LATER-LIFE RISK OF COMMON CHRONIC DISEASES, AND EPIGENETICS HAS BEEN HYPOTHESISED TO LINK THESE ASSOCIATIONS. HOWEVER, EPIGENETIC TARGETS ARE UNKNOWN. WE FOCUS ON A CLUSTER OF WELL-CHARACTERISED GENOMICALLY IMPRINTED GENES BECAUSE THEIR MONOALLELIC EXPRESSION IS REGULATED BY DNA METHYLATION AT DIFFERENTIALLY METHYLATED REGIONS (DMRS), ARE CRITICAL IN FETAL GROWTH, AND DNA METHYLATION PATTERNS AT BIRTH HAVE BEEN ASSOCIATED WITH INCREASED RISK OF BIRTH WEIGHT EXTREMES AND OVERWEIGHT STATUS OR OBESITY IN EARLY CHILDHOOD. METHODS: WE MEASURED DNA METHYLATION AT DMRS REGULATING GENOMICALLY IMPRINTED DOMAINS (IGF2/H19, DLK1/MEG3, NNAT AND PLAGL1) USING UMBILICAL CORD BLOOD LEUCOCYTES FROM 619 INFANTS RECRUITED IN DURHAM, NORTH CAROLINA IN 2010-2011. WE EXAMINED DIFFERENCES IN DNA METHYLATION LEVELS BY RACE/ETHNICITY OF BOTH PARENTS, AND THE ROLE THAT MATERNAL SOCIOECONOMIC STATUS (SES) MAY PLAY IN THE ASSOCIATION BETWEEN RACE/ETHNIC EPIGENETIC DIFFERENCES. RESULTS: UNADJUSTED RACE/ETHNIC DIFFERENCES ONLY WERE EVIDENT FOR DMRS REGULATING MEG3 AND IGF2; RACE/ETHNIC DIFFERENCES PERSISTED IN IGF2/H19 AND NNAT AFTER ACCOUNTING FOR INCOME AND EDUCATION. CONCLUSIONS: RESULTS SUGGEST THAT PARENTAL FACTORS MAY NOT ONLY INFLUENCE DNA METHYLATION, BUT ALSO DO SO IN WAYS THAT VARY BY DMR. FINDINGS SUPPORT THE HYPOTHESIS THAT EPIGENETICS MAY LINK THE OBSERVED LOWER SES DURING THE PRENATAL PERIOD AND POOR OUTCOMES SUCH AS LOW BIRTH WEIGHT; LOWER BIRTH WEIGHT HAS PREVIOUSLY BEEN ASSOCIATED WITH ADULT-ONSET CHRONIC DISEASES AND CONDITIONS THAT INCLUDE CARDIOVASCULAR DISEASES, DIABETES, OBESITY AND SOME CANCERS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6  4853  77 OPPOSING EPIGENETIC SIGNATURES IN HUMAN SPERM BY INTAKE OF FAST FOOD VERSUS HEALTHY FOOD. ANIMAL EXPERIMENTS HAVE DEMONSTRATED THAT DIETS HIGH IN FATS CREATE A HARMFUL ENVIRONMENT FOR DEVELOPING SPERM CELLS, CONTRIBUTING TO IMPAIRED REPRODUCTIVE HEALTH AND INDUCED RISK FOR CHRONIC DISEASES IN THE NEXT GENERATION. CHANGES AT THE LEVEL OF THE EPIGENOME HAVE BEEN SUGGESTED TO UNDERLIE THESE OBSERVATIONS. HUMAN DATA ARE LIMITED TO VERIFY THIS HYPOTHESIS. WHILE WE EARLIER DEMONSTRATED A LINK BETWEEN MALE OBESITY AND DNA METHYLATION CHANGES AT IMPRINTED GENES IN MATURE SPERM CELLS AND NEWBORNS, IT IS CURRENTLY UNKNOWN IF -OR HOW- A PATERNAL EATING PATTERN (RELATED TO OBESITY) IS RELATED TO INDICES FOR EPIGENETIC INHERITANCE. WE HERE AIM TO EXAMINE A YET UNEXPLORED LINK BETWEEN CONSUMPTION OF HEALTHY (RICH IN VITAMINS AND FIBERS) OR UNHEALTHY ("FAST") FOODS AND METHYLATION AT IMPRINT REGULATORY REGIONS IN DNA OF SPERM. WE OBTAINED SEMEN AND DATA FROM 67 MEN, AS PART OF A NORTH CAROLINA-BASED STUDY: THE INFLUENCE OF THE ENVIRONMENT ON GAMETIC EPIGENETIC REPROGRAMMING (TIEGER) STUDY. DIETARY DATA INCLUDED INTAKE OF FRUITS/NUTS, VEGETABLES/SOUPS, WHOLE GRAIN BREAD, MEAT, SEAFOOD/FISH, AND FATTY OR PROCESSED FOOD ITEMS. MULTIPLE REGRESSION MODELS WERE USED TO EXPLORE THE ASSOCIATION BETWEEN DIETARY HABITS AND CLINICAL SPERM PARAMETERS AS WELL AS DNA METHYLATION LEVELS, QUANTIFIED USING BISULFITE PYROSEQUENCING AT 12 DIFFERENTIALLY METHYLATED REGIONS (DMRS) OF THE FOLLOWING IMPRINTED GENES: GRB10, IGF2, H19, MEG3, NDN, NNAT, PEG1/MEST, PEG3, PLAGL1, SNRPN, AND SGCE/PEG10. AFTER ADJUSTING FOR AGE, OBESITY STATUS AND RECRUITMENT METHOD, WE FOUND THAT TOTAL MOTILE COUNT (TMC) WAS SIGNIFICANTLY HIGHER IF MEN CONSUMED FRUITS/NUTS (BETA=+6.9, SE=1.9, P=0.0005) AND VEGETABLES (BETA=+5.4, SE=1.9, P=0.006), WHEREAS CONSUMPTION OF FRIES WAS ASSOCIATED WITH LOWER TMC (BETA=-20.2, SE=8.7, P=0.024). SEMEN VOLUME WAS ALSO HIGHER IF VEGETABLES OR FRUITS/NUTS WERE FREQUENTLY CONSUMED (BETA=+0.06, SE=0.03, P=0.03). SIMILARLY, OUR SPERM EPIGENETIC ANALYSES SHOWED OPPOSING ASSOCIATIONS FOR HEALTHY VERSUS FAST FOOD ITEMS. FREQUENT CONSUMPTION OF FRIES WAS RELATED TO A HIGHER CHANCE OF SPERM BEING METHYLATED AT THE MEG3-IG CPG4 SITE (OR=1.073, 95%CI: 1.035-1.112), AND HIGH CONSUMPTION OF VEGETABLES WAS ASSOCIATED WITH A LOWER RISK OF DNA METHYLATION AT THE NNAT CPG3 SITE (OR=0.941, 95%CI: 0.914-0.968). THESE RESULTS REMAINED SIGNIFICANT AFTER ADJUSTING FOR MULTIPLE TESTING. WE CONCLUDE THAT DIETARY HABITS ARE LINKED TO SPERM EPIGENETIC OUTCOMES. IF CARRIED INTO THE NEXT GENERATION PATERNAL UNHEALTHY DIETARY PATTERNS MAY RESULT IN ADVERSE METABOLIC CONDITIONS AND INCREASED RISK FOR CHRONIC DISEASES IN OFFSPRING.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  6089  68 THE EFFECTS OF DEPRESSION AND USE OF ANTIDEPRESSIVE MEDICINES DURING PREGNANCY ON THE METHYLATION STATUS OF THE IGF2 IMPRINTED CONTROL REGIONS IN THE OFFSPRING. IN UTERO EXPOSURES TO ENVIRONMENTAL FACTORS MAY RESULT IN PERSISTENT EPIGENETIC MODIFICATIONS AFFECTING NORMAL DEVELOPMENT AND SUSCEPTIBILITY TO CHRONIC DISEASES IN LATER LIFE. WE EXPLORED THE RELATIONSHIP BETWEEN EXPOSURE OF THE GROWING FETUS TO MATERNAL DEPRESSION OR ANTIDEPRESSANTS AND DNA METHYLATION AT TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) OF THE IMPRINTED INSULIN-LIKE GROWTH FACTOR 2 (IGF2) GENE. ABERRANT DNA METHYLATION AT THE IGF2 AND NEIGHBORING H19 DMRS HAS BEEN ASSOCIATED WITH DEREGULATED IGF2 EXPRESSION, CHILDHOOD CANCERS AND SEVERAL CHRONIC DISEASES DURING ADULTHOOD. OUR STUDY POPULATION IS COMPRISED OF PREGNANT MOTHERS AND THEIR NEWBORNS (N = 436), AS PART OF THE NEWBORN EPIGENETICS STUDY (NEST). A STANDARDIZED QUESTIONNAIRE WAS COMPLETED AND MEDICAL RECORD DATA WERE ABSTRACTED TO ASCERTAIN MATERNAL DEPRESSION AND ANTIDEPRESSIVE DRUG USE. DMR METHYLATION LEVELS IN UMBILICAL CORD BLOOD LEUKOCYTES WERE QUANTIFIED USING PYROSEQUENCING. FROM THE 436 NEWBORNS, LABORATORY DATA WERE OBTAINED FOR 356 INDIVIDUALS AT THE IGF2 DMRS, AND FOR 411 INDIVIDUALS AT THE H19 DMRS; ABOUT HALF OF EACH GROUP WAS AFRICAN AMERICAN OR CAUCASIAN. WHILE OVERALL NO ASSOCIATION BETWEEN DEPRESSION AND METHYLATION PROFILES WAS FOUND, WE OBSERVED A SIGNIFICANT HYPERMETHYLATION OF THE H19 DMRS IN NEWBORNS OF AFRICAN AMERICAN (N = 177) BUT NOT CAUCASIAN (N = 168) MOTHERS WHO REPORTED THE USE OF ANTIDEPRESSIVE DRUGS DURING PREGNANCY (BETA = +6.89, P = 0.01). OF NOTE, OUR DATA REVEAL A RACE-INDEPENDENT ASSOCIATION BETWEEN SMOKING DURING PREGNANCY AND METHYLATION AT THE IGF2 DMR (+3.05%, P = 0.01). IN CONCLUSION, OUR FINDINGS SUGGEST A RACE-DEPENDENT RESPONSE RELATED TO MATERNAL USE OF ANTIDEPRESSANTS AT ONE OF THE IGF2 DMRS IN THE OFFSPRING.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  2903  59 GENDER-SPECIFIC METHYLATION DIFFERENCES IN RELATION TO PRENATAL EXPOSURE TO CIGARETTE SMOKE. EPIGENETIC ALTERATIONS MAY MECHANISTICALLY EXPLAIN THE DEVELOPMENTAL ORIGINS OF ADULT DISEASE, NAMELY THE HYPOTHESIS THAT MANY COMPLEX ADULT CHRONIC DISEASES ORIGINATE AS A RESULT OF CONDITIONS ENCOUNTERED IN UTERO. IF TRUE, EPIGENETICALLY REGULATED IMPRINTED GENES, CRITICAL TO NORMAL GROWTH AND DEVELOPMENT, MAY PARTIALLY MEDIATE THESE OUTCOMES. WE DETERMINED THE INFLUENCE OF IN UTERO EXPOSURE TO CIGARETTE SMOKING ON METHYLATION AT TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) REGULATING INSULIN-LIKE GROWTH FACTOR 2 (IGF2) AND H19, AND HOW THIS MIGHT RELATE TO BIRTH WEIGHT OF INFANTS BORN TO 418 PREGNANT WOMEN. SMOKING STATUS WAS ASCERTAINED THROUGH SELF-REPORT AND MEDICAL RECORDS. BISULFITE PYROSEQUENCING WAS USED TO MEASURE METHYLATION IN UMBILICAL CORD BLOOD DNAS. LEAST SQUARES DNA METHYLATION MEANS AT EACH DMR AND BIRTH WEIGHT WERE COMPARED BETWEEN INFANTS OF SMOKERS AND NON-SMOKERS, USING GENERALIZED LINEAR MODELS. WHILE THERE WERE NO SIGNIFICANT DIFFERENCES AT THE H19 DMR, INFANTS BORN TO SMOKERS HAD HIGHER METHYLATION AT THE IGF2 DMR THAN THOSE BORN TO NEVER SMOKERS OR THOSE WHO QUIT DURING PREGNANCY (49.5%, SD=8.0 VERSUS 46.6%, SD=5.6 AND 45.8%, SD=6.3, RESPECTIVELY; P=0.0002). THE SMOKING-RELATED INCREASE IN METHYLATION WAS MOST PRONOUNCED IN MALE OFFSPRING (P FOR SEX INTERACTION=0.03), FOR WHOM APPROXIMATELY 20% OF SMOKING-RELATED LOW BIRTH WEIGHT WAS MEDIATED BY DNA METHYLATION AT THE IGF2 DMR. OUR FINDINGS SUGGEST THAT IGF2 DMR PLASTICITY IS AN IMPORTANT MECHANISM BY WHICH IN UTERO ADJUSTMENTS TO ENVIRONMENTAL TOXICANTS ARE CONFERRED. LARGER STUDIES TO REPLICATE THESE FINDINGS ARE REQUIRED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9   520  51 ASSOCIATIONS BETWEEN MATERNAL PRENATAL STRESS, METHYLATION CHANGES IN IGF1 AND IGF2, AND BIRTH WEIGHT. MATERNAL STRESS HAS BEEN LINKED TO LOW BIRTH WEIGHT IN NEWBORNS. ONE POTENTIAL PATHWAY INVOLVES EPIGENETIC CHANGES AT CANDIDATE GENES THAT MAY MEDIATE THE EFFECTS OF PRENATAL MATERNAL STRESS ON BIRTH WEIGHT. THIS RELATIONSHIP HAS BEEN DOCUMENTED IN STRESS-RELATED GENES, SUCH AS NR3C1. THERE IS LESS LITERATURE EXPLORING THE EFFECT OF STRESS ON GROWTH-RELATED GENES. IGF1 AND IGF2 HAVE BEEN IMPLICATED IN FETAL GROWTH AND DEVELOPMENT, THOUGH VIA DIFFERENT MECHANISMS AS IGF2 IS UNDER IMPRINTING CONTROL. IN THIS STUDY, WE TESTED FOR ASSOCIATIONS BETWEEN PRENATAL STRESS, METHYLATION OF IGF1 AND IGF2, AND BIRTH WEIGHT. A TOTAL OF 24 MOTHER-NEWBORN DYADS IN THE DEMOCRATIC REPUBLIC OF CONGO WERE ENROLLED. ETHNOGRAPHIC INTERVIEWS WERE CONDUCTED WITH MOTHERS AT DELIVERY TO GATHER CULTURALLY RELEVANT WAR-RELATED AND CHRONIC STRESSORS. DNA METHYLATION DATA WERE GENERATED FROM MATERNAL VENOUS, CORD BLOOD AND PLACENTAL TISSUE SAMPLES. MULTIVARIATE REGRESSIONS WERE USED TO TEST FOR ASSOCIATIONS BETWEEN STRESS MEASURES, DNA METHYLATION AND BIRTH WEIGHT IN EACH OF THE THREE TISSUE TYPES. WE FOUND AN ASSOCIATION BETWEEN IGF2 METHYLATION IN MATERNAL BLOOD AND BIRTH WEIGHT. PREVIOUS LITERATURE ON THE RELATIONSHIP BETWEEN IGF2 METHYLATION AND BIRTH WEIGHT HAS FOCUSED ON METHYLATION AT KNOWN DIFFERENTIALLY METHYLATED REGIONS IN CORD BLOOD OR PLACENTAL SAMPLES. OUR FINDINGS INDICATE THERE MAY BE LINKS BETWEEN THE MATERNAL EPIGENOME AND LOW BIRTH WEIGHT THAT RELY ON MECHANISMS OUTSIDE KNOWN IMPRINTING PATHWAYS. IT THUS MAY BE IMPORTANT TO CONSIDER THE EFFECT OF MATERNAL EXPOSURES AND EPIGENETIC PROFILES ON BIRTH WEIGHT EVEN IN THE SETTING OF MATERNALLY IMPRINTED GENES SUCH AS IGF2.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  5093  70 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	

11  4504  35 MOTHER'S PRE-PREGNANCY BMI AND PLACENTAL CANDIDATE MIRNAS: FINDINGS FROM THE ENVIRONAGE BIRTH COHORT. THERE IS INCREASING EVIDENCE THAT THE PREDISPOSITION FOR DEVELOPMENT OF CHRONIC DISEASES ARISES AT THE EARLIEST TIMES OF LIFE. IN THIS CONTEXT, MATERNAL PRE-PREGNANCY WEIGHT MIGHT MODIFY FETAL METABOLISM AND THE CHILD'S PREDISPOSITION TO DEVELOP DISEASE LATER IN LIFE. THE AIM OF THIS STUDY IS TO INVESTIGATE THE ASSOCIATION BETWEEN MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) AND MIRNA ALTERATIONS IN PLACENTAL TISSUE AT BIRTH. IN 211 MOTHER-NEWBORN PAIRS FROM THE ENVIRONAGE BIRTH COHORT, WE ASSESSED PLACENTAL EXPRESSION OF SEVEN MIRNAS IMPORTANT IN CRUCIAL CELLULAR PROCESSES IMPLICATED IN ADIPOGENESIS AND/OR OBESITY. MULTIPLE LINEAR REGRESSION MODELS WERE USED TO ADDRESS THE ASSOCIATIONS BETWEEN PRE-PREGNANCY BMI AND PLACENTAL CANDIDATE MIRNA EXPRESSION. MATERNAL PRE-PREGNANCY BMI AVERAGED (+/-SD) 23.9 (+/-4.1) KG/M(2). IN NEWBORN GIRLS (NOT IN BOYS) PLACENTAL MIR-20A, MIR-34A AND MIR-222 EXPRESSION WAS LOWER WITH HIGHER MATERNAL PRE-PREGNANCY BMI. IN ADDITION, THE ASSOCIATION BETWEEN MATERNAL PRE-PREGNANCY BMI AND PLACENTAL EXPRESSION OF THESE MIRNAS IN GIRLS WAS MODIFIED BY GESTATIONAL WEIGHT GAIN. THE LOWER EXPRESSION OF THESE MIRNAS IN PLACENTA IN ASSOCIATION WITH PRE-PREGNANCY BMI, WAS ONLY EVIDENT IN MOTHERS WITH LOW WEIGHT GAIN (<14 KG). THE PLACENTAL EXPRESSION OF MIR-20A, MIR-34A, MIR-146A, MIR-210 AND MIR-222 MAY PROVIDE A SEX-SPECIFIC BASIS FOR EPIGENETIC EFFECTS OF PRE-PREGNANCY BMI.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  4066  59 MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION AS AN INDICATOR OF OFFSPRING METABOLIC SYNDROME RISK IN LATER LIFE THROUGH EPIGENETIC IMPRINTING: A SYSTEMATIC REVIEW. AIMS: THIS REVIEW EXAMINED WHETHER MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION EFFECTS AN OFFSPRING'S LIKELIHOOD OF DEVELOPING CHRONIC METABOLIC RELATED CONDITIONS DUE TO EPIGENETIC IMPRINTING. METHODS: A LITERATURE SEARCH WAS CONDUCTED IN MULTIPLE SCIENCE DATABASES AND LIMITED TO STUDIES PUBLISHED AFTER 2012, IN ENGLISH LANGUAGE AND PEER REVIEWED. THE DATA FROM SELECTED ARTICLES WERE EXTRACTED AND A QUALITATIVE APPROACH WAS EMPLOYED DUE TO HETEROGENEITY OF RESULTS. RESULTS: NEWBORNS FROM OBESE FATHERS SHOWED ALTERED METHYLATION OVERALL AND SIGNIFICANT HYPOMETHYLATION AT THE INSULIN-LIKE GROWTH FACTOR 2 (IGF2) GENE. HIGH MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) WAS ASSOCIATED WITH ALTERED OFFSPRING DNA METHYLATION LEVELS AND GESTATIONAL DIABETES MELLITUS INDUCED SIGNIFICANTLY INCREASED METHYLATION LEVELS IN OFFSPRING. GESTATIONAL WEIGHT GAIN WAS NOT ASSOCIATED WITH DIFFERENTIALLY METHYLATED CORD BLOOD. BIRTH WEIGHT WAS HIGHER IN OFFSPRING EXPOSED TO FAMINE IN EARLY GESTATION. OFFSPRING BORN POST MATERNAL BARIATRIC SURGERY SHOWED A LOWER PERCENTAGE OF BODY FAT AND IMPROVED FASTING INSULIN LEVELS COMPARED TO SIBLINGS BORN PRE-MATERNAL BARIATRIC SURGERY. CONCLUSIONS: THE AVAILABLE EVIDENCE SUGGESTS THAT POOR MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION CAN INCREASE THE RISK OF METABOLIC SYNDROME IN OFFSPRING, THROUGH EPIGENETIC IMPRINTING. POTENTIAL PARENTS SHOULD BE ADVISED THAT MAINTAINING A HEALTHY DIET AND BMI IS LIKELY TO REDUCE THE RISK OF METABOLIC SYNDROME IN OFFSPRING.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13   649  55 BIRTHWEIGHT, MATERNAL WEIGHT TRAJECTORIES AND GLOBAL DNA METHYLATION OF LINE-1 REPETITIVE ELEMENTS. LOW BIRTHWEIGHT, PREMATURE BIRTH, INTRAUTERINE GROWTH RETARDATION, AND MATERNAL MALNUTRITION HAVE BEEN RELATED TO AN INCREASED RISK OF CARDIOVASCULAR DISEASE, TYPE 2 DIABETES MELLITUS, OBESITY, AND NEUROPSYCHIATRIC DISORDERS LATER IN LIFE. CONVERSELY, HIGH BIRTHWEIGHT HAS BEEN LINKED TO FUTURE RISK OF CANCER. GLOBAL DNA METHYLATION ESTIMATED BY THE METHYLATION OF REPETITIVE SEQUENCES IN THE GENOME IS AN INDICATOR OF SUSCEPTIBILITY TO CHRONIC DISEASES. WE USED DATA AND BIOSPECIMENS FROM AN EPIGENETIC BIRTH COHORT TO EXPLORE THE ASSOCIATION BETWEEN TRAJECTORIES OF FETAL AND MATERNAL WEIGHT AND LINE-1 METHYLATION IN 319 MOTHER-CHILD DYADS. NEWBORNS WITH LOW OR HIGH BIRTHWEIGHT HAD SIGNIFICANTLY LOWER LINE-1 METHYLATION LEVELS IN THEIR CORD BLOOD COMPARED TO NORMAL WEIGHT INFANTS AFTER ADJUSTING FOR GESTATIONAL AGE, SEX OF THE CHILD, MATERNAL AGE AT DELIVERY, AND MATERNAL SMOKING DURING PREGNANCY (P = 0.007 AND P = 0.036, RESPECTIVELY), BUT THE MAGNITUDE OF THE DIFFERENCE WAS SMALL. INFANTS BORN PREMATURELY ALSO HAD LOWER LINE-1 METHYLATION LEVELS IN CORD BLOOD COMPARED TO TERM INFANTS, AND THIS DIFFERENCE, THOUGH SMALL, WAS STATISTICALLY SIGNIFICANT (P = 0.004). WE DID NOT FIND IMPORTANT ASSOCIATIONS BETWEEN MATERNAL PREPREGNANCY BMI OR GESTATIONAL WEIGHT GAIN AND GLOBAL METHYLATION OF THE CORD BLOOD OR FETAL PLACENTAL TISSUE. IN CONCLUSION, WE FOUND SIGNIFICANT DIFFERENCES IN CORD BLOOD LINE-1 METHYLATION AMONG NEWBORNS WITH LOW AND HIGH BIRTHWEIGHT AS WELL AS AMONG PREMATURELY BORN INFANTS. FUTURE STUDIES MAY ELUCIDATE WHETHER CHROMOSOMAL INSTABILITIES OR OTHER FUNCTIONAL CONSEQUENCES OF THESE CHANGES CONTRIBUTE TO THE INCREASED RISK OF CHRONIC DISEASES AMONG INDIVIDUALS WITH THESE CHARACTERISTICS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14  1956  48 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15   521  51 ASSOCIATIONS BETWEEN MATERNAL PSYCHOSOCIAL STRESS, DNA METHYLATION, AND NEWBORN BIRTH WEIGHT IDENTIFIED BY INVESTIGATING METHYLATION AT INDIVIDUAL, REGIONAL, AND GENOME LEVELS. STRESS IS KNOWN TO AFFECT HEALTH THROUGHOUT LIFE AND INTO FUTURE GENERATIONS, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNKNOWN. WE TESTED THE HYPOTHESIS THAT MATERNAL PSYCHOSOCIAL STRESS INFLUENCES DNA METHYLATION (DNAM), WHICH IN TURN IMPACTS NEWBORN HEALTH OUTCOMES. SPECIFICALLY, WE ANALYZED DNAM AT INDIVIDUAL, REGIONAL, AND GENOME-WIDE LEVELS TO TEST FOR ASSOCIATIONS WITH MATERNAL STRESS AND NEWBORN BIRTH WEIGHT. MATERNAL VENOUS BLOOD AND NEWBORN CORD BLOOD (N = 24 AND 22, RESPECTIVELY) WERE ASSAYED FOR METHYLATION AT APPROXIMATELY 450,000 CPG SITES. METHYLATION WAS ANALYZED BY EXAMINING CPG SITES INDIVIDUALLY IN AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS), AS REGIONAL GROUPS USING VARIABLY METHYLATED REGION (VMR) ANALYSIS IN MATERNAL BLOOD ONLY, AND THROUGH THE EPIGENOME-WIDE MEASURES USING GENOME-WIDE MEAN METHYLATION (GMM), HORVATH'S EPIGENETIC CLOCK, AND MITOTIC AGE. THESE METHYLATION MEASURES WERE TESTED FOR ASSOCIATION WITH THREE MEASURES OF MATERNAL STRESS (MATERNAL WAR TRAUMA, CHRONIC STRESS, AND EXPERIENCE OF SEXUAL VIOLENCE) AND ONE HEALTH OUTCOME (NEWBORN BIRTH WEIGHT). WE OBSERVED THAT MATERNAL EXPERIENCES OF WAR TRAUMA, CHRONIC STRESS, AND SEXUAL ASSAULT WERE EACH ASSOCIATED WITH DECREASED NEWBORN BIRTH WEIGHT (P < 1.95 X 10(-7) IN ALL CASES). TESTING INDIVIDUAL CPG SITES USING EWAS, WE OBSERVED NO ASSOCIATIONS BETWEEN DNAM AND ANY MEASURE OF MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER MATERNAL OR CORD BLOOD, AFTER BONFERRONI MULTIPLE TESTING CORRECTION. HOWEVER, THE TOP-RANKED CPG SITE IN MATERNAL BLOOD THAT ASSOCIATED WITH MATERNAL CHRONIC STRESS AND SEXUAL VIOLENCE BEFORE MULTIPLE TESTING CORRECTION IS LOCATED NEAR THE SPON1 GENE. TESTING AT A REGIONAL LEVEL, WE FOUND INCREASED METHYLATION OF A VMR IN MATERNAL BLOOD NEAR SPON1 THAT WAS ASSOCIATED WITH CHRONIC STRESS AND SEXUAL VIOLENCE AFTER BONFERRONI MULTIPLE TESTING CORRECTION (P = 1.95 X 10(-7) AND 8.3 X 10(-6), RESPECTIVELY). AT THE EPIGENOMIC LEVEL, CORD BLOOD GMM WAS ASSOCIATED WITH SIGNIFICANTLY HIGHER LEVELS OF WAR TRAUMA (P = 0.025) AND WAS SUGGESTIVELY ASSOCIATED WITH SEXUAL VIOLENCE (P = 0.053). THE OTHER TWO EPIGENOME-WIDE MEASURES WERE NOT ASSOCIATED WITH MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER TISSUE TYPE. DESPITE OUR SMALL SAMPLE SIZE, WE IDENTIFIED ASSOCIATIONS EVEN AFTER CONSERVATIVE MULTIPLE TESTING CORRECTION. SPECIFICALLY, WE FOUND ASSOCIATIONS BETWEEN DNAM AND THE THREE MEASURES OF MATERNAL STRESS ACROSS BOTH TISSUES; SPECIFICALLY, A VMR IN MATERNAL BLOOD AND GMM IN CORD BLOOD WERE BOTH ASSOCIATED WITH DIFFERENT MEASURES OF MATERNAL STRESS. THE ASSOCIATION OF CORD BLOOD GMM, BUT NOT MATERNAL BLOOD GMM, WITH MATERNAL STRESS MAY SUGGEST DIFFERENT RESPONSES TO STRESS IN MOTHER AND NEWBORN. IT IS NOTEWORTHY THAT WE FOUND ASSOCIATIONS ONLY WHEN CPG SITES WERE ANALYZED IN AGGREGATE, EITHER AS VMRS OR AS A BROAD SUMMARY MEASURE OF GMM.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16  6491  51 TRAFFIC-DERIVED PARTICULATE MATTER EXPOSURE AND HISTONE H3 MODIFICATION: A REPEATED MEASURES STUDY. BACKGROUND: AIRBORNE PARTICULATE MATTER (PM) MAY INDUCE EPIGENETIC CHANGES THAT POTENTIALLY LEAD TO CHRONIC DISEASES. HISTONE MODIFICATIONS REGULATE GENE EXPRESSION BY INFLUENCING CHROMATIN STRUCTURE THAT CAN CHANGE GENE EXPRESSION STATUS. WE EVALUATED WHETHER TRAFFIC-DERIVED PM EXPOSURE IS ASSOCIATED WITH FOUR TYPES OF ENVIRONMENTALLY INDUCIBLE GLOBAL HISTONE H3 MODIFICATIONS. METHODS: THE BEIJING TRUCK DRIVER AIR POLLUTION STUDY INCLUDED 60 TRUCK DRIVERS AND 60 OFFICE WORKERS EXAMINED TWICE, 1-2 WEEKS APART, FOR AMBIENT PM(10) (BOTH DAY-OF AND 14-DAY AVERAGE EXPOSURES), PERSONAL PM(2.5), BLACK CARBON (BC), AND ELEMENTAL COMPONENTS (POTASSIUM, SULFUR, IRON, SILICON, ALUMINUM, ZINC, CALCIUM, AND TITANIUM). FOR BOTH PM(10) MEASURES, WE OBTAINED HOURLY AMBIENT PM(10) DATA FOR THE STUDY PERIOD FROM THE BEIJING MUNICIPAL ENVIRONMENTAL BUREAU'S 27 REPRESENTATIVELY DISTRIBUTED MONITORING STATIONS. WE THEN CALCULATED A 24H AVERAGE FOR EACH EXAMINATION DAY AND A MOVING AVERAGE OF AMBIENT PM(10) MEASURED IN THE 14 DAYS PRIOR TO EACH EXAMINATION. EXAMINATIONS MEASURED GLOBAL LEVELS OF H3 LYSINE 9 ACETYLATION (H3K9AC), H3 LYSINE 9 TRI-METHYLATION (H3K9ME3), H3 LYSINE 27 TRI-METHYLATION (H3K27ME3), AND H3 LYSINE 36 TRI-METHYLATION (H3K36ME3) IN BLOOD LEUKOCYTES COLLECTED AFTER WORK. WE USED ADJUSTED LINEAR MIXED-EFFECT MODELS TO EXAMINE PERCENT CHANGES IN HISTONE MODIFICATIONS PER EACH MUG/M(3) INCREASE IN PM EXPOSURE. RESULTS: IN ALL PARTICIPANTS EACH MUG/M(3) INCREASE IN 14-DAY AVERAGE AMBIENT PM(10) EXPOSURE WAS ASSOCIATED WITH LOWER H3K27ME3 (BETA=-1.1%, 95% CI: -1.6, -0.6) AND H3K36ME3 LEVELS (BETA=-0.8%, 95% CI: -1.4, -0.1). OCCUPATION-STRATIFIED ANALYSES SHOWED ASSOCIATIONS BETWEEN BC AND BOTH H3K9AC AND H3K36ME3 THAT WERE STRONGER IN OFFICE WORKERS (BETA=4.6%, 95% CI: 0.9, 8.4; AND BETA=4.1%, 95% CI: 1.3; 7.0 RESPECTIVELY) THAN IN TRUCK DRIVERS (BETA=0.1%, 95% CI: -1.3, 1.5; AND BETA=0.9%, 95% CI: -0.9, 2.7, RESPECTIVELY; BOTH P(INTERACTION) <0.05). SEX-STRATIFIED ANALYSES SHOWED ASSOCIATIONS BETWEEN EXAMINATION-DAY PM(10) AND H3K9AC, AND BETWEEN BC AND H3K9ME3, WERE STRONGER IN WOMEN (BETA=10.7%, 95% CI: 5.4, 16.2; AND BETA=7.5%, 95% CI: 1.2, 14.2, RESPECTIVELY) THAN IN MEN (BETA=1.4%, 95% CI: -0.9, 3.7; AND BETA=0.9%, 95% CI: -0.9, 2.7, RESPECTIVELY; BOTH P(INTERACTION) <0.05). WE OBSERVED NO ASSOCIATIONS BETWEEN PERSONAL PM(2.5) OR ELEMENTAL COMPONENTS AND HISTONE MODIFICATIONS. CONCLUSIONS: OUR RESULTS SUGGEST A POSSIBLE ROLE OF GLOBAL HISTONE H3 MODIFICATIONS IN EFFECTS OF TRAFFIC-DERIVED PM EXPOSURES, PARTICULARLY BC EXPOSURE. FUTURE STUDIES SHOULD ASSESS THE ROLES OF THESE MODIFICATIONS IN HUMAN DISEASES AND AS POTENTIAL MEDIATORS OF AIR POLLUTION-INDUCED DISEASE, IN PARTICULAR BC EXPOSURE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17   899  43 CHRONIC EXPOSURE TO A LOW CONCENTRATION OF BISPHENOL A DURING FOLLICLE CULTURE AFFECTS THE EPIGENETIC STATUS OF GERMINAL VESICLES AND METAPHASE II OOCYTES. OBJECTIVE: TO DETERMINE WHETHER EXPOSURE TO LOW CONCENTRATIONS OF THE ENDOCRINE DISRUPTING CHEMICAL BISPHENOL A (BPA) DURING FOLLICLE CULTURE AND OOCYTE GROWTH ALTERS THE METHYLATION STATUS OF DIFFERENTIALLY METHYLATED REGIONS (DMRS) OF IMPRINTED GENES AND HISTONE POSTTRANSLATIONAL MODIFICATION PATTERNS IN MAMMALIAN OOCYTES. DESIGN: COMPARATIVE AND CONTROL STUDY. SETTING: EXPERIMENTAL LABORATORY. ANIMAL(S): C57/BL6JXCBA/CA MICE. INTERVENTION(S): EXPOSURE OF OOCYTES TO 3 NM OR 300 NM BPA DURING FOLLICLE CULTURE FROM PREANTRAL TO ANTRAL STAGE. MAIN OUTCOME MEASURE(S): METHYLATION STATUS OF DMRS OF MATERNALLY IMPRINTED (SNRPN, IGF2R, AND MEST) AND PATERNALLY IMPRINTED GENE(S) (H19) IN MOUSE GERMINAL VESICLE OOCYTES; TRIMETHYLATION OF HISTONE H3K9, ACETYLATION OF HISTONE H4K12, AND DISTANCE BETWEEN CENTROMERES OF SISTER CHROMATIDS IN METAPHASE II OOCYTES. RESULT(S): EXPOSURE TO 3 NM BPA WAS ASSOCIATED WITH SLIGHTLY ACCELERATED FOLLICLE DEVELOPMENT, STATISTICALLY SIGNIFICANT INCREASES IN ALLELE METHYLATION ERRORS IN DMRS OF MATERNALLY IMPRINTED GENES, AND STATISTICALLY SIGNIFICANT DECREASES IN HISTONE H3K9 TRIMETHYLATION AND INTERKINETOCHORE DISTANCE. CONCLUSION(S): THE DISTURBANCES IN OOCYTE GENOMIC IMPRINTING AND MODIFICATION OF POSTTRANSLATIONAL HISTONE AND CENTROMERE ARCHITECTURE PROVIDE THE FIRST LINK BETWEEN LOW BPA EXPOSURES AND INDUCTION OF EPIGENETIC CHANGES THAT MAY CONTRIBUTE TO CHROMOSOME CONGRESSION FAILURES AND MEIOTIC ERRORS, AND TO ALTERED GENE EXPRESSION THAT MIGHT AFFECT HEALTH OF THE OFFSPRING.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18  6231  34 THE LONG NONCODING RNA MEG3 AND ITS TARGET MIR-147 REGULATE JAK/STAT PATHWAY IN ADVANCED CHRONIC MYELOID LEUKEMIA. BACKGROUND: LONG NON-CODING (LNC) RNAS PLAYS AN IMPORTANT ROLE IN CHRONIC MYELOID LEUKEMIA (CML). IN THIS STUDY, WE AIMED TO UNCOVER THE MECHANISM OF THE LNCRNA MATERNALLY EXPRESSED 3 (MEG3) AND ITS TARGET MICRORNA-147 (MIR-147) IN CML. METHODS: SIXTY CML PATIENTS AND 10 HEALTHY DONORS WERE INCLUDED IN THE STUDY. THE METHYLATION OF MEG3 AND MIR-147 PROMOTER WAS DETERMINED BY METHYLATION-SPECIFIC PCR. THE RELATIONSHIP OF MEG3 AND MIR-147 WAS EXPLORED BY LUCIFERASE ASSAY. THE INTERACTIONS OF PROTEINS WERE STUDIED BY RNA PULL-DOWN ASSAY, RNA IMMUNOPRECIPITATION AND CO-IMMUNOPRECIPITATION. FINDINGS: PATIENTS IN ACCELERATED PHASE CML (CML-AP) AND BLAST PHASE CML (CML-BP) SHOWED LOWER EXPRESSIONS OF MEG3 AND MIR-147 AND HIGHER EXPRESSIONS OF DNMT1, DNMT3B, MBD2, MECP2 AND HDAC1 COMPARED TO THE CONTROLS. THESE PATIENTS ALSO SHOWED A HIGHER DEGREE OF METHYLATION OF MEG3 AND MIR-147 WHILE THERE WAS A REDUCTION AFTER CHIDAMIDE TREATMENT. FURTHERMORE, THE OVEREXPRESSION OF MEG3 AND MIR-147 INHIBITED CELL PROLIFERATION BOTH IN VIVO AND IN VITRO, PROMOTED APOPTOSIS AND DECREASED THE EXPRESSIONS OF DNMT1, DNMT3A, DNMT3B, MBD2, HDAC1 AND MECP2. WE ALSO FOUND MEG3 INTERACTED WITH DNMT1, JAK2, STAT3, HDAC1, AND TYK2, AND JAK2 WAS BOUND TO STAT3, STAT5 AND MYC. MORE INTERESTINGLY, JAK2 WAS BOUND TO TYK2 BY THE BRIDGE OF MEG3. INTERPRETATION: LNCRNA MEG3 AND ITS TARGET MIR-147 MAY SERVE AS A NOVEL THERAPEUTIC TARGET FOR CML BLAST CRISIS, AND CHIDAMIDE MIGHT HAVE A POTENTIAL CLINICAL APPLICATION IN TREATING CML BLAST CRISIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19  2777  45 EXTREMELY LOW BIRTH WEIGHT AND ACCELERATED BIOLOGICAL AGING. BACKGROUND AND OBJECTIVES: EXTREMELY LOW BIRTH WEIGHT (ELBW) (<1000 G) SURVIVORS ARE EXPOSED TO ELEVATED LEVELS OF PHYSIOLOGIC STRESS DURING THEIR LIVES AND MAY BE SUSCEPTIBLE TO ACCELERATED AGING. USING THE OLDEST KNOWN LONGITUDINALLY FOLLOWED COHORT OF ELBW SURVIVORS, WE COMPARED BIOLOGICAL AGING IN THIS GROUP USING AN EPIGENETIC CLOCK TO A SAMPLE OF MATCHED NORMAL BIRTH WEIGHT (NBW) (>2500 G) CONTROL PARTICIPANTS. METHODS: BUCCAL CELLS WERE COLLECTED FROM 45 ELBW SURVIVORS AND 49 NBW CONTROL PARTICIPANTS AT 30 TO 35 YEARS OF AGE. EPIGENETIC AGE WAS CALCULATED FROM THE WEIGHTED AVERAGE OF DNA METHYLATION AT 353 CYTOSINE-PHOSPHATE-GUANINE SEQUENCE WITHIN DNA SITES, BY USING THE ILLUMINA INFINIUM HUMAN METHYLATION EPIC 850K BEADCHIP ARRAY. RESULTS: BEFORE AND AFTER STATISTICALLY ADJUSTING FOR NEUROSENSORY IMPAIRMENT AND THE PRESENCE OF CHRONIC HEALTH CONDITIONS, A SIGNIFICANT SEX BY BIRTH WEIGHT GROUP INTERACTION WAS OBSERVED IN THE 353-SITE EPIGENETIC-CLOCK ASSAY (P = .03), WHEREBY ELBW MEN HAD A SIGNIFICANTLY OLDER EPIGENETIC AGE THAN NBW MEN (4.6 YEARS; P = .01). WOMEN BORN AT ELBW WERE NOT FOUND TO BE EPIGENETICALLY OLDER THAN THEIR NBW PEERS. CONCLUSIONS: THE RESULTS OF THIS STUDY SUGGEST THAT PRENATAL EXPOSURES MAY PLAY AN IMPORTANT ROLE IN AGING, AND THAT MEN BORN PRETERM MAY EXPERIENCE ACCELERATED AGING RELATIVE TO THEIR PEERS. WE FURTHER HIGHLIGHT THE NEED TO MONITOR AND PROMOTE THE HEALTH OF PRETERM SURVIVORS, WITH A PARTICULAR FOCUS ON HEALTHY AGING ACROSS THE LIFE SPAN.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  5200  41 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES.	2016