1 5658 117 SEX-DIMORPHIC PATHWAYS IN THE ASSOCIATIONS BETWEEN MATERNAL TRAIT ANXIETY, INFANT BDNF METHYLATION, AND NEGATIVE EMOTIONALITY. MATERNAL ANTENATAL ANXIETY IS AN EMERGING RISK FACTOR FOR CHILD EMOTIONAL DEVELOPMENT. BOTH SEX AND EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, MAY CONTRIBUTE TO THE EMBEDDING OF MATERNAL DISTRESS INTO EMOTIONAL OUTCOMES. HERE, WE INVESTIGATED SEX-DEPENDENT PATTERNS IN THE ASSOCIATION BETWEEN ANTENATAL MATERNAL TRAIT ANXIETY, METHYLATION OF THE BRAIN-DERIVED NEUROTROPHIC FACTOR GENE (BDNF DNAM), AND INFANT NEGATIVE EMOTIONALITY (NE). MOTHER-INFANT DYADS (N = 276) WERE RECRUITED AT DELIVERY. MATERNAL TRAIT ANXIETY, AS A MARKER OF ANTENATAL CHRONIC STRESS EXPOSURE, WAS ASSESSED SOON AFTER DELIVERY USING THE STAIT-TRAIT ANXIETY INVENTORY (STAI-Y). INFANTS' BDNF DNAM AT BIRTH WAS ASSESSED IN 11 CPG SITES IN BUCCAL CELLS WHEREAS INFANTS' NE WAS ASSESSED AT 3 (N = 225) AND 6 MONTHS (N = 189) USING THE INFANT BEHAVIOR QUESTIONNAIRE-REVISED (IBQ-R). HIERARCHICAL LINEAR ANALYSES SHOWED THAT HIGHER MATERNAL ANTENATAL ANXIETY WAS ASSOCIATED WITH GREATER 6-MONTH-OLDS' NE. FURTHERMORE, MATERNAL ANTENATAL ANXIETY PREDICTED GREATER INFANTS' BDNF DNAM IN FIVE CPG SITES IN MALES BUT NOT IN FEMALES. HIGHER METHYLATION AT THESE SITES WAS ASSOCIATED WITH GREATER 3-TO-6-MONTH NE INCREASE, INDEPENDENTLY OF INFANTS' SEX. MATERNAL ANTENATAL ANXIETY EMERGED AS A RISK FACTOR FOR INFANT'S NE. BDNF DNAM MIGHT MEDIATE THIS EFFECT IN MALES. THESE RESULTS MAY INFORM THE DEVELOPMENT OF STRATEGIES TO PROMOTE MOTHERS AND INFANTS' EMOTIONAL WELL-BEING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2 6315  42 THE RELATIONSHIP OF MATERNAL AND CHILD METHYLATION OF THE GLUCOCORTICOID RECEPTOR NR3C1 DURING EARLY CHILDHOOD AND SUBSEQUENT CHILD PSYCHOPATHOLOGY AT SCHOOL-AGE IN THE CONTEXT OF MATERNAL INTERPERSONAL VIOLENCE-RELATED POST-TRAUMATIC STRESS DISORDER. INTRODUCTION: INTERPERSONAL VIOLENT (IPV) EXPERIENCES WHEN THEY BEGIN IN CHILDHOOD AND CONTINUE IN VARIOUS FORMS DURING ADULTHOOD OFTEN LEAD TO CHRONIC POST-TRAUMATIC STRESS DISORDER (PTSD) THAT IS ASSOCIATED IN MULTIPLE STUDIES WITH HYPOCORTISOLISM AND LOWER PERCENTAGE OF METHYLATION OF THE PROMOTER REGION OF THE GENE CODING FOR THE GLUCOCORTICOID RECEPTOR (NR3C1). THIS PROSPECTIVE, LONGITUDINAL STUDY EXAMINED THE RELATIONSHIP OF NR3C1 METHYLATION AMONG MOTHERS WITH IPV-RELATED PTSD AND THEIR TODDLERS AND THEN LOOKED AT THE RELATIONSHIP OF MATERNAL NR3C1 METHYLATION AND CHILD PSYCHOPATHOLOGY AT SCHOOL AGE. METHODS: FORTY-EIGHT MOTHERS WERE EVALUATED FOR LIFE-EVENTS HISTORY AND POST-TRAUMATIC STRESS DISORDER VIA STRUCTURED CLINICAL INTERVIEW WHEN THEIR CHILDREN WERE AGES 12-42 MONTHS (MEAN AGE 26.7 MONTHS, SD 8.8). THEIR CHILDREN'S PSYCHOPATHOLOGY IN TERMS OF INTERNALIZING SYMPTOMS AND EXTERNALIZING BEHAVIORS WAS EVALUATED USING THE CHILD BEHAVIOR CHECKLIST AT AGES 5-9 YEARS (MEAN AGE 7 YEARS, SD 1.1). PERCENTAGE OF METHYLATION FOR THE NR3C1 GENE PROMOTER REGION WAS ASSESSED FROM DNA EXTRACTED FROM MATERNAL AND CHILD SALIVA USING BISULFITE PYROSEQUENCING. DATA ANALYSIS INVOLVED PARAMETRIC AND NON-PARAMETRIC CORRELATIONS AND MULTIPLE LINEAR AND LOGISTIC REGRESSION MODELING. RESULTS: LOGISTIC REGRESSION MODELS USING CHILD NR3C1 METHYLATION AS THE DEPENDENT VARIABLE AND MATERNAL NR3C1 METHYLATION AND PTSD GROUP STATUS AS PREDICTORS, AS WELL AS THE INTERACTION INDICATED THAT ALL THREE OF THESE SIGNIFICANTLY PREDICTED CHILD NR3C1 METHYLATION. THESE FINDINGS REMAINED SIGNIFICANT WHEN CONTROLLING FOR CHILD AGE, SEX AND MATERNAL CHILD ABUSE HISTORY. OVERALL, MATERNAL NR3C1 METHYLATION WHEN CHILDREN WERE TODDLERS WAS NEGATIVELY AND SIGNIFICANTLY ASSOCIATED WITH CHILD EXTERNALIZING BEHAVIOR SEVERITY AT SCHOOL AGE. DISCUSSION: WE FOUND THAT CORRELATIONS BETWEEN MOTHERS AND THEIR CHILDREN OF NR3C1 METHYLATION LEVELS OVERALL AND AT ALL INDIVIDUAL CPG SITES OF INTEREST WERE SIGNIFICANT ONLY IN THE IPV-PTSD GROUP. THE LATTER FINDINGS SUPPORT THAT NR3C1 METHYLATION IN MOTHERS POSITIVELY AND STATISTICALLY SIGNIFICANTLY CORRELATES WITH NR3C1 METHYLATION IN THEIR CHILDREN ONLY IN PRESENCE OF IPV-PTSD IN THE MOTHERS. THIS MATERNAL EPIGENETIC SIGNATURE WITH RESPECT TO THIS GLUCOCORTICOID RECEPTOR IS SIGNIFICANTLY ASSOCIATED WITH CHILD BEHAVIOR THAT MAY WELL POSE A RISK FOR INTERGENERATIONAL TRANSMISSION OF VIOLENCE AND RELATED PSYCHOPATHOLOGY.	2022	

3 5192  38 PRENATAL ENVIRONMENTAL STRESSORS AND DNA METHYLATION LEVELS IN PLACENTA AND PERIPHERAL TISSUES OF MOTHERS AND NEONATES EVALUATED BY APPLYING ARTIFICIAL NEURAL NETWORKS. EXPOSURE TO ENVIRONMENTAL STRESSORS DURING PREGNANCY PLAYS AN IMPORTANT ROLE IN INFLUENCING SUBSEQUENT SUSCEPTIBILITY TO CERTAIN CHRONIC DISEASES THROUGH THE MODULATION OF EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION. OUR AIM WAS TO EXPLORE THE CONNECTIONS BETWEEN ENVIRONMENTAL EXPOSURES DURING GESTATION WITH DNA METHYLATION OF PLACENTAL CELLS, MATERNAL AND NEONATAL BUCCAL CELLS BY APPLYING ARTIFICIAL NEURAL NETWORKS (ANNS). A TOTAL OF 28 MOTHER-INFANT PAIRS WERE ENROLLED. DATA ON GESTATIONAL EXPOSURE TO ADVERSE ENVIRONMENTAL FACTORS AND ON MOTHER HEALTH STATUS WERE COLLECTED THROUGH THE ADMINISTRATION OF A QUESTIONNAIRE. DNA METHYLATION ANALYSES AT BOTH GENE-SPECIFIC AND GLOBAL LEVEL WERE ANALYZED IN PLACENTAS, MATERNAL AND NEONATAL BUCCAL CELLS. IN THE PLACENTA, THE CONCENTRATIONS OF VARIOUS METALS AND DIOXINS WERE ALSO ANALYZED. ANALYSIS OF ANNS REVEALED THAT SUBOPTIMAL BIRTH WEIGHT IS ASSOCIATED WITH PLACENTAL H19 METHYLATION, MATERNAL STRESS DURING PREGNANCY WITH METHYLATION LEVELS OF NR3C1 AND BDNF IN PLACENTAS AND MOTHER'S BUCCAL DNA, RESPECTIVELY, AND EXPOSURE TO AIR POLLUTANTS WITH MATERNAL MGMT METHYLATION. ASSOCIATIONS WERE ALSO OBSERVED BETWEEN PLACENTAL CONCENTRATIONS OF LEAD, CHROMIUM, CADMIUM AND MERCURY WITH METHYLATION LEVELS OF OXTR IN PLACENTAS, HSD11B2 IN MATERNAL BUCCAL CELLS AND PLACENTAS, MECP2 IN NEONATAL BUCCAL CELLS, AND MTHFR IN MATERNAL BUCCAL CELLS. FURTHERMORE, DIOXIN CONCENTRATIONS WERE ASSOCIATED WITH PLACENTAL RELN, NEONATAL HSD11B2 AND MATERNAL H19 GENE METHYLATION LEVELS. CURRENT RESULTS SUGGEST THAT EXPOSURE OF PREGNANT WOMEN TO ENVIRONMENTAL STRESSORS DURING PREGNANCY COULD INDUCE ABERRANT METHYLATION LEVELS IN GENES LINKED TO SEVERAL PATHWAYS IMPORTANT FOR EMBRYOGENESIS IN BOTH THE PLACENTA, POTENTIALLY AFFECTING FOETAL DEVELOPMENT, AND IN THE PERIPHERAL TISSUES OF MOTHERS AND INFANTS, POTENTIALLY PROVIDING PERIPHERAL BIOMARKERS OF ENVIRONMENTAL EXPOSURE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  668  36 BNDF METHYLATION IN MOTHERS AND NEWBORNS IS ASSOCIATED WITH MATERNAL EXPOSURE TO WAR TRAUMA. BACKGROUND: THE BDNF GENE CODES FOR BRAIN-DERIVED NEUROTROPHIC FACTOR, A GROWTH FACTOR INVOLVED IN NEURAL DEVELOPMENT, CELL DIFFERENTIATION, AND SYNAPTIC PLASTICITY. PRESENT IN BOTH THE BRAIN AND PERIPHERY, BDNF PLAYS CRITICAL ROLES THROUGHOUT THE BODY AND IS ESSENTIAL FOR PLACENTAL AND FETAL DEVELOPMENT. RODENT STUDIES SHOW THAT EARLY LIFE STRESS, INCLUDING PRENATAL STRESS, BROADLY ALTERS BDNF METHYLATION, WITH PRESUMED CHANGES IN GENE EXPRESSION. NO STUDIES HAVE ASSESSED PRENATAL EXPOSURE TO MATERNAL TRAUMATIC STRESS AND BDNF METHYLATION IN HUMANS. THIS STUDY EXAMINED ASSOCIATIONS OF PRENATAL EXPOSURE TO MATERNAL STRESS AND BDNF METHYLATION AT CPG SITES ACROSS THE BDNF GENE. RESULTS: AMONG 24 MOTHERS AND NEWBORNS IN THE EASTERN DEMOCRATIC REPUBLIC OF CONGO, A REGION WITH EXTREME CONFLICT AND VIOLENCE TO WOMEN, MATERNAL EXPERIENCES OF WAR TRAUMA AND CHRONIC STRESS WERE ASSOCIATED WITH BDNF METHYLATION IN UMBILICAL CORD BLOOD, PLACENTAL TISSUE, AND MATERNAL VENOUS BLOOD. ASSOCIATIONS OF MATERNAL STRESS AND BDNF METHYLATION SHOWED HIGH TISSUE SPECIFICITY. THE MAJORITY OF SIGNIFICANT ASSOCIATIONS WERE OBSERVED IN PUTATIVE TRANSCRIPTION FACTOR BINDING REGIONS. CONCLUSIONS: THIS IS THE FIRST STUDY IN HUMANS TO EXAMINE BDNF METHYLATION IN RELATION TO PRENATAL EXPOSURE TO MATERNAL STRESS IN THREE TISSUES SIMULTANEOUSLY AND THE FIRST IN ANY MAMMALIAN SPECIES TO REPORT ASSOCIATIONS OF PRENATAL STRESS AND BDNF METHYLATION IN PLACENTAL TISSUE. THE FINDINGS ADD TO THE GROWING BODY OF EVIDENCE HIGHLIGHTING THE IMPORTANCE OF CONSIDERING EPIGENETIC EFFECTS WHEN EXAMINING THE IMPACTS OF TRAUMA AND STRESS, NOT ONLY FOR ADULTS BUT ALSO FOR OFFSPRING EXPOSED VIA EFFECTS TRANSMITTED BEFORE BIRTH.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  575  42 BDNF METHYLATION AND MATERNAL BRAIN ACTIVITY IN A VIOLENCE-RELATED SAMPLE. IT IS KNOWN THAT INCREASED CIRCULATING GLUCOCORTICOIDS IN THE WAKE OF EXCESSIVE, CHRONIC, REPETITIVE STRESS INCREASES ANXIETY AND IMPAIRS BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) SIGNALING. RECENT STUDIES OF BDNF GENE METHYLATION IN RELATION TO MATERNAL CARE HAVE LINKED HIGH BDNF METHYLATION LEVELS IN THE BLOOD OF ADULTS TO LOWER QUALITY OF RECEIVED MATERNAL CARE MEASURED VIA SELF-REPORT. YET THE SPECIFIC MECHANISMS BY WHICH THESE PHENOMENA OCCUR REMAIN TO BE ESTABLISHED. THE PRESENT STUDY EXAMINES THE LINK BETWEEN METHYLATION OF THE BDNF GENE PROMOTER REGION AND PATTERNS OF NEURAL ACTIVITY THAT ARE ASSOCIATED WITH MATERNAL RESPONSE TO STRESSFUL VERSUS NON-STRESSFUL CHILD STIMULI WITHIN A SAMPLE THAT INCLUDES MOTHERS WITH INTERPERSONAL VIOLENCE-RELATED PTSD (IPV-PTSD). 46 MOTHERS UNDERWENT FMRI. THE CONTRAST OF NEURAL ACTIVITY WHEN WATCHING CHILDREN-INCLUDING THEIR OWN-WAS THEN CORRELATED TO BDNF METHYLATION. CONSISTENT WITH THE EXISTING LITERATURE, THE PRESENT STUDY FOUND THAT MATERNAL BDNF METHYLATION WAS ASSOCIATED WITH HIGHER LEVELS OF MATERNAL ANXIETY AND GREATER CHILDHOOD EXPOSURE TO DOMESTIC VIOLENCE. FMRI RESULTS SHOWED A POSITIVE CORRELATION OF BDNF METHYLATION WITH MATERNAL BRAIN ACTIVITY IN THE ANTERIOR CINGULATE (ACC), AND VENTROMEDIAL PREFRONTAL CORTEX (VMPFC), REGIONS GENERALLY CREDITED WITH A REGULATORY FUNCTION TOWARD BRAIN AREAS THAT ARE GENERATING EMOTIONS. FURTHERMORE WE FOUND A NEGATIVE CORRELATION OF BDNF METHYLATION WITH THE ACTIVITY OF THE RIGHT HIPPOCAMPUS. SINCE OUR STIMULI FOCUS ON STRESSFUL PARENTING CONDITIONS, THESE DATA SUGGEST THAT THE CORRELATION BETWEEN VMPFC/ACC ACTIVITY AND BDNF METHYLATION MAY BE LINKED TO MOTHERS WHO ARE AT A DISADVANTAGE WITH RESPECT TO EMOTION REGULATION WHEN FACING STRESSFUL PARENTING SITUATIONS. OVERALL, THIS STUDY PROVIDES EVIDENCE THAT EPIGENETIC SIGNATURES OF STRESS-RELATED GENES CAN BE LINKED TO FUNCTIONAL BRAIN REGIONS REGULATING PARENTING STRESS, THUS ADVANCING OUR UNDERSTANDING OF MOTHERS AT RISK FOR STRESS-RELATED PSYCHOPATHOLOGY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  577  38 BDNF PROMOTER METHYLATION AND GENETIC VARIATION IN LATE-LIFE DEPRESSION. THE REGULATION OF THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS IMPORTANT FOR DEPRESSION PATHOPHYSIOLOGY AND EPIGENETIC REGULATION OF THE BDNF GENE MAY BE INVOLVED. THIS STUDY INVESTIGATED WHETHER BDNF METHYLATION IS A MARKER OF DEPRESSION. ONE THOUSAND AND TWENTY-FOUR PARTICIPANTS WERE RECRUITED AS PART OF A LONGITUDINAL STUDY OF PSYCHIATRIC DISORDERS IN GENERAL POPULATION ELDERLY (AGE ? 65). CLINICAL LEVELS OF DEPRESSION WERE ASSESSED USING THE MINI INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW FOR THE DIAGNOSIS OF MAJOR DEPRESSIVE DISORDER ACCORDING TO THE DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDER IV CRITERIA, AND THE CENTRE FOR EPIDEMIOLOGIC STUDIES DEPRESSION SCALE (CES-D) FOR ASSESSMENT OF MODERATE TO SEVERE DEPRESSIVE SYMPTOMS. BUCCAL DNA METHYLATION AT THE TWO MOST WIDELY STUDIED BDNF PROMOTERS, I AND IV, WAS INVESTIGATED USING THE SEQUENOM MASSARRAY PLATFORM THAT ALLOWS HIGH-THROUGHPUT INVESTIGATION OF METHYLATION AT INDIVIDUAL CPG SITES WITHIN DEFINED GENOMIC REGIONS. IN MULTIVARIATE LINEAR REGRESSION ANALYSES ADJUSTED FOR A RANGE OF PARTICIPANT CHARACTERISTICS INCLUDING ANTIDEPRESSANT USE, DEPRESSION AT BASELINE, AS WELL AS CHRONIC LATE-LIFE DEPRESSION OVER THE 12-YEAR FOLLOW-UP, WERE ASSOCIATED WITH OVERALL HIGHER BDNF METHYLATION LEVELS, WITH TWO SITES SHOWING SIGNIFICANT ASSOCIATIONS (PROMOTER I, DELTA MEAN = 0.4%, P = 0.0002; PROMOTER IV, DELTA MEAN = 5.4%, P = 0.021). THREE SINGLE-NUCLEOTIDE POLYMORPHISMS (RS6265, RS7103411 AND RS908867) WERE ALSO FOUND TO MODIFY THE ASSOCIATION BETWEEN DEPRESSION AND PROMOTER I METHYLATION. AS ONE OF THE LARGEST EPIGENETIC STUDIES OF DEPRESSION, AND THE FIRST INVESTIGATING BDNF METHYLATION IN BUCCAL TISSUE, OUR FINDINGS HIGHLIGHT THE POTENTIAL FOR BUCCAL BDNF METHYLATION TO BE A BIOMARKER OF DEPRESSION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  649  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8 1573  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9 3462  30 HYPOTHALAMIC NR3C1 DNA METHYLATION IN RATS EXPOSED TO PRENATAL STRESS. BACKGROUND: HUMAN AND ANIMAL STUDIES HAVE INDICATED THAT MATERNAL PRENATAL STRESS (PS) HAS MOLECULAR AND BEHAVIORAL EFFECTS DURING PREGNANCY AND EARLY LIFE. THE PRESENT STUDY AIMED TO EVALUATE THE EPIGENETIC CHANGES OF THE NR3C1 GENE INVOLVED IN THE HPA AXIS IN THE HYPOTHALAMIC TISSUES OF RATS EXPOSED TO PS INDUCED BY CHRONIC UNPREDICTABLE MILD STRESS (CUMS). BEHAVIORAL AND MOLECULAR EFFECTS OF THESE CHANGES ON THE NEXT GENERATION WERE ALSO ASSESSED. METHODS AND RESULTS: CUMS PROTOCOL WAS USED TO GENERATE STRESS IN PREGNANT WISTAR RATS. TO DETERMINE THE EFFECTS OF STRESS ON ANHEDONIA AND MOVEMENT, SUCROSE PREFERENCE TEST, FORCED SWIMMING TEST, AND OPEN FIELD TEST WERE PERFORMED. FOLLOWING THESE BEHAVIORAL EXPERIMENTS, BISULFITE SEQUENCING PCR FOR DNA METHYLATION LEVELS OF THE NR3C1 GENE, RT-QPCR FOR MRNA LEVELS, AND WESTERN BLOT TECHNIQUES FOR PROTEIN ANALYSIS WERE USED IN THE HYPOTHALAMIC TISSUE OF SACRIFICED RATS. DEPRESSION-LIKE BEHAVIORS WERE EVIDENT IN THE BEHAVIORAL TESTS OF STRESS-EXPOSED MOTHERS AND PUPS. IN PS-EXPOSED PUPS, HYPOTHALAMIC NR3C1 PROMOTER METHYLATION WAS HIGHER, AND NR3C1 MRNA LEVELS AND NR3C1 PROTEIN LEVELS WERE LOWER COMPARED WITH CONTROLS, REGARDLESS OF SEX. CONCLUSION: OUR RESULTS CONFIRM THE RELATIONSHIP BETWEEN PS AND EPIGENETIC CHANGES OF HPA AXIS-RELATED GENES AND SHOW THAT NR3C1 GENE METHYLATION STATUS IN PUPS IS SENSITIVE TO PS DURING PREGNANCY. ENVIRONMENTAL MATERNAL STRESS MAY HAVE TRANSGENERATIONAL EFFECTS THAT ARE POTENTIALLY ASSOCIATED WITH ADVERSE OUTCOMES IN THE PUPS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10 1537  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11 4612  31 NEONATAL PAIN AND COMT VAL158MET GENOTYPE IN RELATION TO SEROTONIN TRANSPORTER (SLC6A4) PROMOTER METHYLATION IN VERY PRETERM CHILDREN AT SCHOOL AGE. CHILDREN BORN VERY PRETERM ARE EXPOSED TO REPEATED NEONATAL PROCEDURES THAT INDUCE PAIN AND STRESS DURING HOSPITALIZATION IN THE NEONATAL INTENSIVE CARE UNIT (NICU). THE COMT VAL158MET GENOTYPE IS INVOLVED WITH PAIN SENSITIVITY, AND EARLY LIFE STRESS IS IMPLICATED IN ALTERED EXPRESSION OF METHYLATION OF THE SEROTONIN TRANSPORTER. WE EXAMINED: (1) WHETHER METHYLATION OF THE SEROTONIN TRANSPORTER GENE (SLC6A4) PROMOTER DIFFERS BETWEEN VERY PRETERM CHILDREN AND FULL-TERM CONTROLS AT SCHOOL AGE, (2) RELATIONSHIPS WITH CHILD BEHAVIOR PROBLEMS, AND (3) WHETHER THE EXTENT OF NEONATAL PAIN EXPOSURE INTERACTS WITH THE COMT VAL158MET GENOTYPE TO PREDICT SLC6A4 METHYLATION AT 7 YEARS IN THE VERY PRETERM CHILDREN. WE EXAMINED THE ASSOCIATIONS BETWEEN THE COMT GENOTYPES, NEONATAL PAIN EXPOSURE (ADJUSTED FOR NEONATAL CLINICAL CONFOUNDERS), SLC6A4 METHYLATION AND BEHAVIOR PROBLEMS. VERY PRETERM CHILDREN HAD SIGNIFICANTLY HIGHER METHYLATION AT 7/10 CPG SITES IN THE SLC6A4 PROMOTER COMPARED TO FULL-TERM CONTROLS AT 7 YEARS. NEONATAL PAIN (ADJUSTED FOR CLINICAL CONFOUNDERS) WAS SIGNIFICANTLY ASSOCIATED WITH TOTAL CHILD BEHAVIOR PROBLEMS ON THE CHILD BEHAVIOR CHECKLIST (CBCL) QUESTIONNAIRE (ADJUSTED FOR CONCURRENT STRESSORS AND 5HTTLPR GENOTYPE) (P = 0.035). CBCL TOTAL PROBLEMS WAS SIGNIFICANTLY ASSOCIATED WITH GREATER SLC6A4 METHYLATION IN VERY PRETERM CHILDREN (P = 0.01). NEONATAL PAIN (ADJUSTED FOR CLINICAL CONFOUNDERS) AND COMT MET/MET GENOTYPE WERE ASSOCIATED WITH SLC6A4 PROMOTER METHYLATION IN VERY PRETERM CHILDREN AT 7 YEARS (P = 0.001). THESE FINDINGS PROVIDE EVIDENCE THAT BOTH GENETIC PREDISPOSITION AND EARLY ENVIRONMENT NEED TO BE CONSIDERED IN UNDERSTANDING SUSCEPTIBILITY FOR DEVELOPING BEHAVIORAL PROBLEMS IN THIS VULNERABLE POPULATION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12 3914  41 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13 1418  34 DIFFERENCES IN DNA METHYLATION REPROGRAMMING UNDERLIE THE SEXUAL DIMORPHISM OF BEHAVIORAL DISORDER CAUSED BY PRENATAL STRESS IN RATS. PRENATAL STRESS (PS) CAN LEAD TO NEUROENDOCRINE AND EMOTIONAL DISORDERS LATER IN ADOLESCENCE. SEXUAL DIMORPHISM IN THESE NEURODEVELOPMENTAL OUTCOMES HAVE BEEN OBSERVED; HOWEVER, THE UNDERLYING MECHANISMS ARE NOT FULLY UNDERSTOOD. TO ADDRESS THIS ISSUE, WE INVESTIGATED WHETHER THERE ARE SEX DIFFERENCES IN EPIGENETIC REPROGRAMMING IN RATS EXPOSED TO PS. PREGNANT FEMALE RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS FROM GESTATIONAL DAY (G)12 TO G18. FROM POSTNATAL DAY (P)38 TO P45, SUBGROUPS OF OFFSPRING INCLUDING BOTH MALES AND FEMALES WERE SUBJECTED TO BEHAVIORAL TESTING AND BRAIN TISSUE SPECIMENS WERE ANALYZED BY DNA PYROSEQUENCING, WESTERN BLOTTING, AND GOLGI STAINING TO ASSESS CHANGES IN METHYLATION PATTERN OF GLUCOCORTICOID RECEPTOR (GR) GENE, EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) AND DNA DEMETHYLASE, AND DENDRITE MORPHOLOGY, RESPECTIVELY. THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE WAS ADMINISTERED TO RATS PRIOR TO PS TO FURTHER EVALUATE THE ROLE OF METHYLATION IN THE SEXUALLY DIMORPHIC EFFECTS OF PS. THE RESULTS SHOWED THAT PS INCREASED ANXIETY-LIKE BEHAVIOR IN OFFSPRING, ESPECIALLY IN FEMALES, WHILE DEPRESSION-LIKE BEHAVIOR WAS INCREASED IN MALE OFFSPRING COMPARED TO CONTROL LITTERMATES. THE METHYLATION PATTERN IN THE PROMOTER REGION OF THE GR GENE DIFFERED BETWEEN MALES AND FEMALES. SEX-SPECIFIC CHANGES IN THE EXPRESSION OF DNMTS (DNMT1 AND DNMT3A) AND DNA DEMETHYLASE (TET METHYLCYTOSINE DIOXYGENASE 2) WERE ALSO OBSERVED. INTERESTINGLY, DECITABINE ALLEVIATED THE BEHAVIORAL DISORDER CAUSED BY PS AND RESTORED DENDRITE DENSITY AND MORPHOLOGY IN FEMALE BUT NOT MALE RATS. THESE FINDINGS SUGGEST THAT DIFFERENT CHANGE PATTERNS OF DNMT AND DEMETHYLASE IN THE TWO SEXES AFTER PS ARE RESPONSIBLE FOR THE SEXUALLY DIMORPHISM, WHICH COULD HAVE IMPLICATIONS FOR THE CLINICAL MANAGEMENT OF STRESS-RELATED DISORDERS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14  524  32 ASSOCIATIONS OF BDNF GENOTYPE AND PROMOTER METHYLATION WITH ACUTE AND LONG-TERM STROKE OUTCOMES IN AN EAST ASIAN COHORT. BACKGROUND: BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN POSTSTROKE RECOVERY. BDNF SECRETION IS INFLUENCED BY GENETIC AND EPIGENETIC PROFILES. THIS STUDY AIMED TO INVESTIGATE WHETHER BDNF VAL66MET POLYMORPHISM AND PROMOTER METHYLATION STATUS WERE ASSOCIATED WITH OUTCOMES AT TWO WEEKS AND ONE YEAR AFTER STROKE. METHODS AND FINDINGS: A TOTAL OF 286 PATIENTS WERE EVALUATED AT THE TIME OF ADMISSION AND TWO WEEKS AFTER STROKE, AND 222 (78%) WERE FOLLOWED ONE YEAR LATER IN ORDER TO EVALUATE CONSEQUENCES OF STROKE AT BOTH ACUTE AND CHRONIC STAGES. STROKE OUTCOMES WERE DICHOTOMISED INTO GOOD AND POOR BY THE MODIFIED RANKIN SCALE. STROKE SEVERITY (NATIONAL INSTITUTES OF HEALTH STROKE SCALE), PHYSICAL DISABILITY (BARTHEL INDEX), AND COGNITIVE FUNCTION (MINI-MENTAL STATE EXAMINATION) WERE MEASURED. ASSOCIATIONS OF BDNF GENOTYPE AND METHYLATION STATUS ON STROKE OUTCOMES AND ASSESSMENT SCALE SCORES WERE INVESTIGATED USING LOGISTIC REGRESSION, REPEATED MEASURES ANOVA AND PARTIAL CORRELATION TESTS. BDNF VAL66MET POLYMORPHISM WAS INDEPENDENTLY ASSOCIATED WITH POOR OUTCOME AT 2 WEEKS AND AT 1 YEAR, AND WITH WORSENING PHYSICAL DISABILITY AND COGNITIVE FUNCTION OVER THAT PERIOD. HIGHER BDNF PROMOTER METHYLATION STATUS WAS INDEPENDENTLY ASSOCIATED WITH WORSE OUTCOMES AT 1 YEAR, AND WITH THE WORSENING OF PHYSICAL DISABILITY AND COGNITIVE FUNCTION. NO SIGNIFICANT GENOTYPE-METHYLATION INTERACTIONS WERE FOUND. CONCLUSIONS: A ROLE FOR BDNF IN POSTSTROKE RECOVERY WAS SUPPORTED, AND CLINICAL UTILITY OF BDNF GENETIC AND EPIGENETIC PROFILE AS PROGNOSTIC BIOMARKERS AND A TARGET FOR DRUG DEVELOPMENT WAS SUGGESTED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15 6089  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16 2472  29 EPIGENETIC TRANSMISSION OF THE IMPACT OF EARLY STRESS ACROSS GENERATIONS. BACKGROUND: TRAUMATIC EXPERIENCES IN EARLY LIFE ARE RISK FACTORS FOR THE DEVELOPMENT OF BEHAVIORAL AND EMOTIONAL DISORDERS. SUCH DISORDERS CAN PERSIST THROUGH ADULTHOOD AND HAVE OFTEN BEEN REPORTED TO BE TRANSMITTED ACROSS GENERATIONS. METHODS: TO INVESTIGATE THE TRANSGENERATIONAL EFFECT OF EARLY STRESS, MICE WERE EXPOSED TO CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION FROM POSTNATAL DAY 1 TO 14. RESULTS: WE SHOW THAT CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION INDUCES DEPRESSIVE-LIKE BEHAVIORS AND ALTERS THE BEHAVIORAL RESPONSE TO AVERSIVE ENVIRONMENTS IN THE SEPARATED ANIMALS WHEN ADULT. MOST OF THE BEHAVIORAL ALTERATIONS ARE FURTHER EXPRESSED BY THE OFFSPRING OF MALES SUBJECTED TO MATERNAL SEPARATION, DESPITE THE FACT THAT THESE MALES ARE REARED NORMALLY. CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION ALSO ALTERS THE PROFILE OF DNA METHYLATION IN THE PROMOTER OF SEVERAL CANDIDATE GENES IN THE GERMLINE OF THE SEPARATED MALES. COMPARABLE CHANGES IN DNA METHYLATION ARE ALSO PRESENT IN THE BRAIN OF THE OFFSPRING AND ARE ASSOCIATED WITH ALTERED GENE EXPRESSION. CONCLUSIONS: THESE FINDINGS HIGHLIGHT THE NEGATIVE IMPACT OF EARLY STRESS ON BEHAVIORAL RESPONSES ACROSS GENERATIONS AND ON THE REGULATION OF DNA METHYLATION IN THE GERMLINE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17 4072  32 MATERNAL DNA METHYLATION SIGNATURES OF ARSENIC EXPOSURE IS ASSOCIATED WITH ADULT OFFSPRING INSULIN RESISTANCE IN THE STRONG HEART STUDY. EXPOSURE TO LOW TO MODERATE ARSENIC (AS) LEVELS HAS BEEN ASSOCIATED WITH TYPE 2 DIABETES (T2D) AND OTHER CHRONIC DISEASES IN AMERICAN INDIAN COMMUNITIES. PRENATAL EXPOSURE TO AS MAY ALSO INCREASE THE RISK FOR T2D IN ADULTHOOD, AND MATERNAL AS HAS BEEN ASSOCIATED WITH ADULT OFFSPRING METABOLIC HEALTH MEASUREMENTS. WE HYPOTHESIZED THAT T2D-RELATED OUTCOMES IN ADULT OFFSPRING BORN TO WOMEN EXPOSED TO LOW TO MODERATE AS CAN BE EVALUATED UTILIZING A MATERNALLY-DERIVED MOLECULAR BIOSIGNATURE OF AS EXPOSURE. HEREIN, WE EVALUATED THE ASSOCIATION OF MATERNAL DNA METHYLATION WITH INCIDENT T2D AND INSULIN RESISTANCE (HOMEOSTATIC MODEL ASSESSMENT OF INSULIN RESISTANCE [HOMA2-IR]) IN ADULT OFFSPRING. FOR DNA METHYLATION, WE USED 20 DIFFERENTIALLY METHYLATED CYTOSINE-GUANINE DINUCLEOTIDES (CPG) PREVIOUSLY ASSOCIATED WITH THE SUM OF INORGANIC AND METHYLATED AS SPECIES (SIGMAAS) IN URINE IN THE STRONG HEART STUDY (SHS). OF THESE 20 CPGS, WE FOUND SIX CPGS NOMINALLY ASSOCIATED (P < 0.05) WITH HOMA2-IR IN A FULLY ADJUSTED MODEL THAT INCLUDED CLINICALLY RELEVANT COVARIATES AND OFFSPRING ADIPOSITY MEASUREMENTS; A SIMILAR MODEL THAT ADJUSTED INSTEAD FOR MATERNAL ADIPOSITY MEASUREMENTS FOUND THREE CPGS NOMINALLY ASSOCIATED WITH HOMA2-IR, TWO OF WHICH OVERLAPPED THE OFFSPRING ADIPOSITY MODEL. AFTER ADJUSTING FOR MULTIPLE COMPARISONS, CG03036214 REMAINED ASSOCIATED WITH HOMA2-IR (Q < 0.10) IN THE OFFSPRING ADIPOSITY MODEL. THE ODDS RATIO OF INCIDENT T2D INCREASED WITH AN INCREASE IN MATERNAL DNA METHYLATION AT ONE HOMA2-IR ASSOCIATED CPG IN THE MODEL ADJUSTING FOR OFFSPRING ADIPOSITY, CG12116137, WHEREAS ADJUSTING FOR MATERNAL ADIPOSITY HAD A MINIMAL EFFECT ON THE ASSOCIATION. OUR DATA SUGGESTS OFFSPRING ADIPOSITY, RATHER THAN MATERNAL ADIPOSITY, POTENTIALLY INFLUENCES THE EFFECTS OF MATERNAL DNAM SIGNATURES ON OFFSPRING METABOLIC HEALTH PARAMETERS. HERE, WE HAVE PRESENTED EVIDENCE SUPPORTING A ROLE FOR EPIGENETIC BIOSIGNATURES OF MATERNAL AS EXPOSURE AS A POTENTIAL BIOMARKER FOR EVALUATING RISK OF T2D-RELATED OUTCOMES IN OFFSPRING LATER IN LIFE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  520  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
19 1595  37 DNA METHYLATION PROVIDES INSIGHT INTO INTERGENERATIONAL RISK FOR PRETERM BIRTH IN AFRICAN AMERICANS. AFRICAN AMERICANS ARE AT INCREASED RISK FOR SPONTANEOUS PRETERM BIRTH (PTB). THOUGH PTB IS HERITABLE, GENETIC STUDIES HAVE NOT IDENTIFIED VARIANTS THAT ACCOUNT FOR ITS INTERGENERATIONAL RISK, PROMPTING THE HYPOTHESIS THAT EPIGENETIC FACTORS MAY ALSO CONTRIBUTE. THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE DNA METHYLATION FROM MATERNAL LEUKOCYTES TO IDENTIFY PATTERNS SPECIFIC TO PTB AND ITS INTERGENERATIONAL RISK. DNA FROM PERIPHERAL LEUKOCYTES FROM AFRICAN AMERICAN WOMEN THAT DELIVERED PRETERM (24-34 WEEKS; N = 16) OR AT TERM (39-41 WEEKS; N = 24) WAS ASSESSED FOR DNA METHYLATION USING THE HUMANMETHYLATION450 BEADCHIP. IN MATERNAL SAMPLES, 17,829 CPG SITES ASSOCIATED WITH PTB, BUT NO CPG SITE REMAINED ASSOCIATED AFTER CORRECTION FOR MULTIPLE COMPARISONS. EXAMINATION OF PAIRED MATERNAL-FETAL SAMPLES IDENTIFIED 5,171 CPG SITES IN WHICH METHYLATION OF MATERNAL SAMPLES CORRELATED WITH METHYLATION OF HER RESPECTIVE FETUS (FDR < 0.05). THESE CORRELATED SITES WERE ENRICHED FOR ASSOCIATION WITH PTB IN MATERNAL LEUKOCYTES. THE MAJORITY OF CORRELATED CPG SITES COULD BE ATTRIBUTED TO ONE OR MORE GENETIC VARIANTS. THEY WERE ALSO SIGNIFICANTLY MORE LIKELY TO BE IN GENES INVOLVED IN METABOLIC, CARDIOVASCULAR, AND IMMUNE PATHWAYS, SUGGESTING A ROLE FOR GENETIC AND ENVIRONMENTAL CONTRIBUTIONS TO PTB RISK AND CHRONIC DISEASE. THE RESULTS OF THIS STUDY MAY PROVIDE INSIGHT INTO THE FACTORS UNDERLYING INTERGENERATIONAL RISK FOR PTB AND ITS CONSEQUENCES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20 2725  32 EXPERIENCES OF TRAUMA AND DNA METHYLATION PROFILES AMONG AFRICAN AMERICAN MOTHERS AND CHILDREN. POTENTIALLY TRAUMATIC EXPERIENCES HAVE BEEN ASSOCIATED WITH CHRONIC DISEASES. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION (DNAM), HAVE BEEN PROPOSED AS AN EXPLANATION FOR THIS ASSOCIATION. WE EXAMINED THE ASSOCIATION OF EXPERIENCES OF TRAUMA WITH EPIGENOME-WIDE DNAM AMONG AFRICAN AMERICAN MOTHERS (N = 236) AND THEIR CHILDREN AGED 3-5 YEARS (N = 232; N = 500), USING THE LIFE EVENTS CHECKLIST-5 (LEC) AND TRAUMATIC EVENTS SCREENING INVENTORY-PARENT REPORT REVISED (TESI-PRR). WE IDENTIFIED NO DNAM SITES SIGNIFICANTLY ASSOCIATED WITH POTENTIALLY TRAUMATIC EXPERIENCE SCORES IN MOTHERS. ONE CPG SITE ON THE ENOX1 GENE WAS METHYLOME-WIDE-SIGNIFICANT IN CHILDREN (FDR-CORRECTED Q-VALUE = 0.05) FROM THE TESI-PRR. THIS PROTEIN-CODING GENE IS ASSOCIATED WITH MENTAL ILLNESS, INCLUDING UNIPOLAR DEPRESSION, BIPOLAR, AND SCHIZOPHRENIA. FUTURE RESEARCH SHOULD FURTHER EXAMINE THE ASSOCIATIONS BETWEEN CHILDHOOD TRAUMA, DNAM, AND HEALTH OUTCOMES AMONG THIS UNDERSTUDIED AND HIGH-RISK GROUP. FINDINGS FROM SUCH LONGITUDINAL RESEARCH MAY INFORM CLINICAL AND TRANSLATIONAL APPROACHES TO PREVENT ADVERSE HEALTH OUTCOMES ASSOCIATED WITH EPIGENETIC CHANGES.	2022