1  2777 139 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  3179  42 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3  3145  35 GLOBAL POPULATION VARIATION IN PLACENTAL SIZE AND STRUCTURE: EVIDENCE FROM CEBU, PHILIPPINES. INTRODUCTION: PLACENTAL MORPHOLOGY INFLUENCES THE INTRAUTERINE ENVIRONMENT AND FETAL GROWTH, WHICH HELP SET LIFE-COURSE HEALTH TRAJECTORIES ACROSS GENERATIONS. LITTLE IS KNOWN ABOUT PLACENTAL CHARACTERISTICS IN POPULATIONS WITH CHRONIC NUTRITIONAL INSUFFICIENCY WHERE BIRTH WEIGHTS TEND TO BE LOWER, AND HOW THESE RELATIONSHIPS BETWEEN BIRTH AND PLACENTAL WEIGHTS VARY ACROSS POPULATIONS. METHODS: WE COLLECTED WEIGHTS AND STEREOLOGICALLY-DETERMINED VILLOUS MASS AND SURFACE AREA OF 21 PLACENTAS FROM OFFSPRING OF WOMEN ENROLLED IN A BIRTH COHORT STUDY IN METROPOLITAN CEBU, PHILIPPINES, A LOW-INCOME POPULATION. WE IDENTIFIED 15 SAMPLES FROM OTHER GLOBAL POPULATIONS RANGING FROM LOW TO HIGH INCOME THAT HAD SIMILAR DATA TO OURS TO ASSESS PATTERNS OF VARIATION BETWEEN BIRTH AND PLACENTAL WEIGHTS AND MICROSCOPIC CHARACTERISTICS. WE RANKED THE POPULATION SAMPLES IN ORDER FOR EACH CHARACTERISTIC. RESULTS: MEAN BIRTH WEIGHT IN CEBU WAS 3162 +/- 80 G (RANKED 9/16) AND PLACENTAL WEIGHT WAS 454 +/- 32 G (RANKED 12/16). BIRTH:PLACENTAL WEIGHT RATIO WAS 7.0 (RANKED 3/16). AVERAGE VILLOUS SURFACE AREA FOR CEBU PLACENTAS WAS 6.5 M(2) (RANKED 9/12); BIRTH WEIGHT:VILLOUS SURFACE AREA WAS 0.048 G/M(2) (RANKED 4/12). DISCUSSION: PLACENTAS FROM CEBU PRODUCED HEAVIER NEONATES PER UNITS OF PLACENTAL WEIGHT AND VILLOUS SURFACE AREA THAN MOST OTHER POPULATIONS, DESPITE LOWER VILLOUS SURFACE AREAS AND LESS COMPLEX SURFACE-TO-VOLUME TOPOGRAPHY. THIS RANGE OF PLACENTAL EFFICIENCY SPURS QUESTIONS ABOUT THE MECHANISMS BY WHICH PLACENTAL MORPHOLOGY OPTIMIZES EFFICIENCY IN DIFFERENT ENVIRONMENTAL CONTEXTS DURING GESTATION. PLACENTAL VARIATION BOTH WITHIN AND ACROSS POPULATIONS IS LIKELY DUE TO MANY INTERSECTING ENVIRONMENTAL, METABOLIC, AND (EPI)GENETIC FACTORS THAT WILL REQUIRE ADDITIONAL RESEARCH TO CLARIFY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4  6018  41 THE ASSOCIATION OF EPIGENETIC AGE ACCELERATION AND MULTIMORBIDITY AT AGE 90 IN THE WOMEN'S HEALTH INITIATIVE. BACKGROUND: EPIGENETIC AGE ACCELERATION (EAA), A MEASURE OF ACCELERATED BIOLOGICAL AGING, HAS BEEN ASSOCIATED WITH INCREASED RISK OF SEVERAL AGE-RELATED CHRONIC CONDITIONS. THIS IS THE FIRST STUDY TO PROSPECTIVELY EXAMINE THE RELATIONSHIP BETWEEN EAA AND BOTH MULTIMORBIDITY COUNT AND A WEIGHTED MULTIMORBIDITY SCORE AMONG LONG-LIVED POSTMENOPAUSAL WOMEN. METHODS: WE INCLUDED 1,951 WOMEN FROM THE WOMEN'S HEALTH INITIATIVE WHO COULD HAVE SURVIVED TO AGE 90. EAA WAS ESTIMATED USING THE HORVATH PAN-TISSUE, HANNUM, PHENOAGE AND GRIMAGE "CLOCKS." TWELVE CHRONIC CONDITIONS WERE INCLUDED IN THE MULTIMORBIDITY COUNT. THE MULTIMORBIDITY SCORE WAS WEIGHTED FOR EACH MORBIDITY'S RELATIONSHIP WITH MORTALITY IN THE STUDY POPULATION. USING MIXED-EFFECTS POISSON AND LINEAR REGRESSION MODELS THAT INCLUDED BASELINE COVARIATES ASSOCIATED WITH BOTH EAA AND MULTIMORBIDITY, WE ESTIMATED RELATIVE RISKS (RRS) AND 95% CONFIDENCE INTERVALS (CIS) FOR THE RELATIONSHIPS BETWEEN EACH EAA MEASURE AT STUDY BASELINE WITH BOTH MULTIMORBIDITY COUNT AND WEIGHTED MULTIMORBIDITY SCORE AT AGE 90, RESPECTIVELY. RESULTS: FOR EVERY ONE-STANDARD DEVIATION INCREASE IN AGEACCELPHENO, THE RATE OF MULTIMORBIDITY ACCUMULATION INCREASED 6% (RR=1.06; 95% CI=1.01-1.12; P=0.025) AND THE MULTIMORBIDITY SCORE BY 7% (RR=1.07; 95% CI=1.01-1.13; P=0.014) FOR WOMEN WHO SURVIVED TO AGE 90. THE RESULTS FOR A ONE-STANDARD DEVIATION INCREASE IN AGEACCELHORVATH, AGEACCELHANNUM AND AGEACCELGRIM WITH MULTIMORBIDITY ACCUMULATION AND SCORE WERE WEAKER COMPARED TO AGEACCELPHENO, AND THE LATTER TWO DID NOT REACH STATISTICAL SIGNIFICANCE. CONCLUSION: AGEACCELPHENO AND AGEACCELHANNUM MAY PREDICT MULTIMORBIDITY COUNT AND SCORE AT AGE 90 IN OLDER WOMEN AND, THUS, MAY BE USEFUL AS A BIOMARKER PREDICTOR OF MULTIMORBIDITY BURDEN IN THE LAST DECADES OF LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5   521  44 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	
                                                                                                                                                                                                                                                  
6  1955  40 EPIGENETIC AGE ACCELERATION PREDICTS CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY IN A GERMAN CASE COHORT. BACKGROUND: PREVIOUS STUDIES HAVE DEVELOPED MODELS PREDICTING METHYLATION AGE FROM DNA METHYLATION IN BLOOD AND OTHER TISSUES (EPIGENETIC CLOCK) AND SUGGESTED THE DIFFERENCE BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGES AS A MARKER OF HEALTHY AGING. THE GOAL OF THIS STUDY WAS TO CONFIRM AND EXPAND SUCH OBSERVATIONS BY INVESTIGATING WHETHER DIFFERENT CONCEPTS OF THE EPIGENETIC CLOCKS IN A POPULATION-BASED COHORT ARE ASSOCIATED WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. RESULTS: DNA METHYLATION AGE WAS ESTIMATED IN A COHORT OF 1863 OLDER PEOPLE, AND THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE (DELTAAGE) WAS CALCULATED. A CASE-COHORT DESIGN AND WEIGHTED PROPORTIONAL COX HAZARD MODELS WERE USED TO ESTIMATE ASSOCIATIONS OF DELTAAGE WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. HAZARD RATIOS FOR DELTAAGE (PER 5 YEARS) CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HORVATH WERE 1.23 (95 % CI 1.10-1.38) FOR ALL-CAUSE MORTALITY, 1.22 (95 % CI 1.03-1.45) FOR CANCER MORTALITY, AND 1.19 (95 % CI 0.98-1.43) FOR CARDIOVASCULAR MORTALITY AFTER ADJUSTMENT FOR BATCH EFFECTS, AGE, SEX, EDUCATIONAL LEVEL, HISTORY OF CHRONIC DISEASES, HYPERTENSION, SMOKING STATUS, BODY MASS INDEX, AND LEUCOCYTE DISTRIBUTION. ASSOCIATIONS WERE SIMILAR BUT WEAKER FOR DELTAAGE CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HANNUM. CONCLUSIONS: THESE RESULTS SHOW THAT AGE ACCELERATION IN TERMS OF THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE IS AN INDEPENDENT PREDICTOR OF ALL-CAUSE AND CAUSE-SPECIFIC MORTALITY AND MAY BE USEFUL AS A GENERAL MARKER OF HEALTHY AGING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7   518  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8  2406  37 EPIGENETIC RESPONSES TO RHINOVIRUS EXPOSURE IN AIRWAY EPITHELIAL CELLS ARE CORRELATED WITH KEY TRANSCRIPTIONAL PATHWAYS IN CHRONIC RHINOSINUSITIS. BACKGROUND: VIRUSES MAY DRIVE IMMUNE MECHANISMS RESPONSIBLE FOR CHRONIC RHINOSINUSITIS WITH NASAL POLYPOSIS (CRSWNP), BUT LITTLE IS KNOWN ABOUT THE UNDERLYING MOLECULAR MECHANISMS. OBJECTIVES: TO IDENTIFY EPIGENETIC AND TRANSCRIPTIONAL RESPONSES TO A COMMON UPPER RESPIRATORY PATHOGEN, RHINOVIRUS (RV), THAT ARE SPECIFIC TO PATIENTS WITH CRSWNP USING A PRIMARY SINONASAL EPITHELIAL CELL CULTURE MODEL. METHODS: AIRWAY EPITHELIAL CELLS WERE COLLECTED AT SURGERY FROM PATIENTS WITH CRSWNP (CASES) AND FROM CONTROLS WITHOUT SINUS DISEASE, CULTURED, AND THEN EXPOSED TO RV OR VEHICLE FOR 48 H. DIFFERENTIAL GENE EXPRESSION AND DNA METHYLATION (DNAM) BETWEEN CASES AND CONTROLS IN RESPONSE TO RV WERE DETERMINED USING LINEAR MIXED MODELS. WEIGHTED GENE CO-EXPRESSION ANALYSIS (WGCNA) WAS USED TO IDENTIFY (A) CO-REGULATED GENE EXPRESSION AND DNAM SIGNATURES, AND (B) GENES, PATHWAYS, AND REGULATORY MECHANISMS SPECIFIC TO CRSWNP. RESULTS: WE IDENTIFIED 5585 DIFFERENTIAL TRANSCRIPTIONAL AND 261 DNAM RESPONSES (FDR <0.10) TO RV BETWEEN CRSWNP CASES AND CONTROLS. THESE DIFFERENTIAL RESPONSES FORMED THREE CO-EXPRESSION/CO-METHYLATION MODULES THAT WERE RELATED TO CRSWNP AND THREE THAT WERE RELATED TO RV (BONFERRONI CORRECTED P < .01). MOST (95%) OF THE DIFFERENTIALLY METHYLATED CPGS (DMCS) WERE IN MODULES RELATED TO CRSWNP, WHEREAS THE DIFFERENTIALLY EXPRESSED GENES (DEGS) WERE MORE EQUALLY DISTRIBUTED BETWEEN THE CRSWNP- AND RV-RELATED MODULES. GENES IN THE CRSWNP-RELATED MODULES WERE ENRICHED IN KNOWN CRS AND/OR VIRAL RESPONSE IMMUNE PATHWAYS. CONCLUSION: RV ACTIVATES SPECIFIC EPIGENETIC PROGRAMS AND CORRELATED TRANSCRIPTIONAL NETWORKS IN THE SINONASAL EPITHELIUM OF INDIVIDUALS WITH CRSWNP. THESE NOVEL OBSERVATIONS SUGGEST EPIGENETIC SIGNATURES SPECIFIC TO PATIENTS WITH CRSWNP MODULATE RESPONSE TO VIRAL PATHOGENS AT THE MUCOSAL ENVIRONMENTAL INTERFACE. DETERMINING HOW VIRAL RESPONSE PATHWAYS ARE INVOLVED IN EPITHELIAL INFLAMMATION IN CRSWNP COULD LEAD TO THERAPEUTIC TARGETS FOR THIS BURDENSOME AIRWAY DISORDER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9   713  39 CADMIUM EXPOSURE AND AGE-ASSOCIATED DNA METHYLATION CHANGES IN NON-SMOKING WOMEN FROM NORTHERN THAILAND. DNA METHYLATION CHANGES WITH AGE, AND MAY SERVE AS A BIOMARKER OF AGING. CADMIUM (CD) MODIFIES CELLULAR PROCESSES THAT PROMOTE AGING AND DISRUPTS METHYLATION GLOBALLY. WHETHER CD MODIFIES AGING PROCESSES BY INFLUENCING ESTABLISHMENT OF AGE-ASSOCIATED METHYLATION MARKS IS CURRENTLY UNKNOWN. IN THIS PILOT STUDY, WE CHARACTERIZED METHYLATION PROFILES IN > 450 000 CPG SITES IN 40 NON-SMOKING WOMEN (AGE 40-80) DIFFERENTIALLY EXPOSED TO ENVIRONMENTAL CD FROM THAILAND. BASED ON SPECIFIC GRAVITY ADJUSTED URINARY CD, WE CLASSIFIED THEM AS HIGH (HE) AND LOW (LE) EXPOSED AND AGE-MATCHED WITHIN 5 YEARS. URINARY CD WAS DEFINED AS BELOW 2 MICROG/L IN THE LE GROUP. WE PREDICTED EPIGENETIC AGE (DNAM-AGE) USING TWO PUBLISHED METHODS BY HORVATH AND HANNUM AND EXAMINED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGIC AGE (DELTAAGE). WE ASSESSED DIFFERENCES BY CD EXPOSURE USING LINEAR MIXED MODELS ADJUSTED FOR ESTIMATED WHITE BLOOD CELL PROPORTIONS, BMI, AND URINARY CREATININE. WE IDENTIFIED 213 AGE-ASSOCIATED CPG SITES IN OUR POPULATION (P < 10(-4)). COUNTERINTUITIVELY, THE MEAN DELTAAGE WAS SMALLER IN HE VS. LE (HANNUM: 3.6 VS. 7.6 YEARS, P = 0.0093; HORVATH: 2.4 VS. 4.5 YEARS, P = 0.1308). THE CD EXPOSED GROUP WAS ASSOCIATED WITH CHANGES IN METHYLATION (P < 0.05) AT 12, 8, AND 20 AGE-ASSOCIATED SITES IDENTIFIED IN OUR POPULATION, HANNUM, AND HORVATH. FROM THE RESULTS OF THIS PILOT STUDY, ELEVATED CD EXPOSURE IS ASSOCIATED WITH METHYLATION CHANGES AT AGE-ASSOCIATED SITES AND SMALLER DIFFERENCES BETWEEN DNAM-AGE AND CHRONOLOGIC AGE, IN CONTRAST TO EXPECTED AGE-ACCELERATING EFFECTS. CD MAY MODIFY EPIGENETIC AGING, AND BIOMARKERS OF AGING WARRANT FURTHER INVESTIGATION WHEN EXAMINING CD AND ITS RELATIONSHIP WITH CHRONIC DISEASE AND MORTALITY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  5395  40 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  3929  35 LIVER EPIGENOME CHANGES IN PATIENTS WITH HEPATOPULMONARY SYNDROME: A PILOT STUDY. THE HEPATOPULMONARY SYNDROME (HPS) IS DEFINED BY THE PRESENCE OF PULMONARY GAS EXCHANGE ABNORMALITIES DUE TO INTRAPULMONARY VASCULAR DILATATIONS IN PATIENTS WITH CHRONIC LIVER DISEASE. CHANGES IN DNA METHYLATION REFLECT THE GENOMIC VARIATION. SINCE LIVER TRANSPLANT (LT) REVERTS HPS WE HYPOTHESIZED THAT IT MAY BE ASSOCIATED WITH SPECIFIC LIVER EPIGENETIC CHANGES. THUS, THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF THE LIVER EPIGENOME IN PATIENTS WITH HPS. WE EXTRACTED DNA FROM PARAFFIN EMBEDDED LIVER TISSUE SAMPLES FROM 10 PATIENTS WITH HPS AND 10 AGE-, SEX- AND MELD (MODEL FOR END-STAGE LIVER DISEASE)-MATCHED CONTROLS. DNA METHYLATION WAS DETERMINED USING THE 850K ARRAY (ILLUMINA). WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS (WGCNA) WAS USED TO IDENTIFY MODULES RELATED TO DEFINING PHYSIOLOGIC CHARACTERISTICS OF HPS. ONLY 12 OUT OF THE 20 LIVER BIOPSIES (7 HPS AND 5 CONTROLS) HAD SUFFICIENT QUALITY TO BE ANALYZED. NONE OF THE 802,688 DNA PROBES ANALYZED IN THE CASE CONTROL COMPARISON ACHIEVED A SIGNIFICANT FALSE DISCOVERY RATE (FDR). WGCNA IDENTIFIED 5 CO-METHYLATED GENE-MODULES ASSOCIATED TO HPS MARKERS, MAINLY RELATED TO NERVOUS AND NEUROENDOCRINE SYSTEM, APOPTOTIC PROCESSES, GUT BACTERIAL TRANSLOCATION, ANGIOGENESIS AND VASCULAR REMODELING ONTOLOGIES. TO CONCLUDE, HPS IS ASSOCIATED WITH NERVOUS/NEUROENDOCRINE SYSTEM AND VASCULAR REMODELING RELATED LIVER EPIGENETIC CHANGES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12  5957  41 TELOMERE LENGTH AND EPIGENETIC AGE ACCELERATION IN ADOLESCENTS WITH ANXIETY DISORDERS. EVIDENCE ON THE RELATIONSHIP BETWEEN GENETICS AND MENTAL HEALTH ARE FLOURISHING. HOWEVER, FEW STUDIES ARE EVALUATING EARLY BIOMARKERS THAT MIGHT LINK GENES, ENVIRONMENT, AND PSYCHOPATHOLOGY. WE AIMED TO STUDY TELOMERE LENGTH (TL) AND EPIGENETIC AGE ACCELERATION (AA) IN A COHORT OF ADOLESCENTS WITH AND WITHOUT ANXIETY DISORDERS (N = 234). WE EVALUATED A REPRESENTATIVE SUBSAMPLE OF PARTICIPANTS AT BASELINE AND AFTER 5 YEARS (N = 76) AND CATEGORIZED THEM ACCORDING TO THEIR ANXIETY DISORDER DIAGNOSIS AT BOTH TIME POINTS: (1) CONTROL GROUP (NO ANXIETY DISORDER, N = 18), (2) VARIABLE GROUP (ANXIETY DISORDER IN ONE EVALUATION, N = 38), AND (3) PERSISTENT GROUP (ANXIETY DISORDER AT BOTH TIME POINTS, N = 20). WE ASSESSED RELATIVE MEAN TL BY REAL-TIME QUANTITATIVE PCR AND DNA METHYLATION BY INFINIUM HUMANMETHYLATION450 BEADCHIP. WE CALCULATED AA USING THE HORVATH AGE ESTIMATION ALGORITHM AND ANALYZED DIFFERENCES AMONG GROUPS USING GENERALIZED LINEAR MIXED MODELS. THE PERSISTENT GROUP OF ANXIETY DISORDER DID NOT CHANGE TL OVER TIME (P = 0.495). THE VARIABLE GROUP HAD HIGHER BASELINE TL (P = 0.003) BUT NO ACCELERATED TL EROSION IN COMPARISON TO THE NON-ANXIETY CONTROL GROUP (P = 0.053). FURTHERMORE, THERE WERE NO DIFFERENCES IN AA AMONG GROUPS OVER TIME. OUR FINDINGS SUGGEST THAT ADOLESCENTS WITH CHRONIC ANXIETY DID NOT CHANGE TELOMERE LENGTH OVER TIME, WHICH COULD BE RELATED TO A DELAY IN NEURONAL DEVELOPMENT IN THIS PERIOD OF LIFE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13  2734  44 EXPLORING THE RELATIONSHIP BETWEEN DNA METHYLATION AGE MEASURES AND PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN WITH EARLY-STAGE BREAST CANCER. PURPOSE: THE EPIGENETIC CLOCK HAS BEEN ACKNOWLEDGED AS AN INDICATOR FOR MOLECULAR AGING, BUT FEW STUDIES HAVE EXAMINED POSSIBLE ASSOCIATIONS OF DNA METHYLATION (DNAM) AGE OR AGE ACCELERATION (AA) WITH SYMPTOM BURDEN IN INDIVIDUALS WHO ARE TREATED FOR CANCER. THIS STUDY EXPLORED THE ASSOCIATION OF DNAM AGE OR AA WITH PSYCHONEUROLOGICAL (PN) SYMPTOMS, INCLUDING COGNITIVE IMPAIRMENT, FATIGUE, SLEEP DISTURBANCES, PAIN, AND DEPRESSIVE SYMPTOMS, IN BREAST CANCER SURVIVORS OVER A 2-YEAR PERIOD. METHODS: WE MEASURED PN SYMPTOMS USING RELIABLE INSTRUMENTS AND DNAM LEVELS BY INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 72). DNAM AGE WAS CALCULATED BY THE HORVATH, GRIM, AND HANNUM-BASED INTRINSIC AND EXTRINSIC AGE ESTIMATIONS. AA WAS DEFINED BY THE RESIDUAL REGRESSING ESTIMATED EPIGENETIC AGE ON CHRONOLOGICAL AGE. MIXED REGRESSION MODELS WERE FITTED FOR AA AND CHANGES IN AA TO STUDY THE ASSOCIATION OVER TIME. SEPARATE LINEAR REGRESSION MODELS AND A MIXED-EFFECTS MODEL WERE FITTED FOR AA AT EACH TIME POINT. RESULTS: HORVATH-AA, GRIM-AA, AND EXTRINSIC EPIGENETIC AA WERE SIGNIFICANTLY CHANGED OVER TIME, WHILE INTRINSIC EPIGENETIC AA DID NOT EXHIBIT ANY TEMPORAL CHANGES. INCREASED AA WAS ASSOCIATED WITH GREATER ANXIETY AND FATIGUE, AS WELL AS WORSE COGNITIVE MEMORY, ADJUSTING FOR RACE, BMI, INCOME, CHEMOTHERAPY, RADIATION THERAPY, AND CHRONOLOGICAL AGE. INCREASED DNAM AGE WAS ASSOCIATED WITH GREATER ANXIETY OVER 2 YEARS. CONCLUSION: OUR FINDINGS SUGGEST DNAM AGE AND AA MAY BE ASSOCIATED WITH PN SYMPTOMS OVER THE COURSE OF CANCER TREATMENT AND SURVIVORSHIP. SOME PN SYMPTOMS MAY BE AMENABLE TO PREVENTIVE INTERVENTIONS TARGETED TO EPIGENETIC CLOCKS THAT INFLUENCE AGING-ASSOCIATED PROCESSES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14   520  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15  3785  27 INTERGENERATIONAL EFFECTS OF PRE-PREGNANCY CHRONIC LIPOPOLYSACCHARIDE FROM PORPHYROMONAS GINGIVALIS ON THE LEARNING, MEMORY AND SEIZURE SUSCEPTIBILITY OF OFFSPRING. OBJECTIVE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EFFECTS OF PRE-PREGNANCY CHRONIC EXPOSURE TO PORPHYROMONAS GINGIVALIS LPS (PG LPS) ON THE LEARNING, MEMORY, AND SEIZURE SUSCEPTIBILITY OF THE OFFSPRING. DESIGN: TO ACHIEVE PERIODONTITIS, PG LPS (5 MUG/KG) WAS INJECTED INTO THE GINGIVAL OF FIVE FEMALE RATS EVERY 48 H FOR THREE WEEKS. FIVE CONTROL FEMALE RATS RECEIVED SALINE (0.9 %) AND FIVE FEMALE WERE KEPT INTACT. THE CONCENTRATIONS OF TNF-ALPHA AND IL-6 WERE MEASURED IN THE BLOOD SAMPLES. ONE WEEK AFTER THE FINAL INJECTION, FEMALES WERE MATED WITH INTACT MALES. FOLLOWING BIRTH AND WEANING, TWO MALE AND TWO FEMALE OFFSPRING WERE RANDOMLY SELECTED FROM EACH MOTHER, AND NEW GROUPS OF MALE AND FEMALE OFFSPRING WERE DEFINED FOR BEHAVIORAL ASSESSMENTS. MORRIS WATER MAZE WAS USED TO EVALUATE SPATIAL MEMORY, SHUTTLE BOX WAS USED TO INVESTIGATE AVOIDANCE MEMORY AND A PENTYLENETETRAZOLE-INDUCED SEIZURE WAS USED TO EVALUATE SEIZURE SUSCEPTIBILITY IN THE OFFSPRING. RESULTS: SPATIAL LEARNING AND AVOIDANCE MEMORY SIGNIFICANTLY DECREASED IN BOTH MALE AND FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE RATS, COMPARED TO THE CONTROL OFFSPRING. LATENCY TO REACH SEIZURE STAGES 1 AND 2 SIGNIFICANTLY INCREASED IN THE MALE OFFSPRING, BUT NOT THE FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE, COMPARED TO THE CONTROL OFFSPRING. HOWEVER, NO SIGNIFICANT DIFFERENCE WAS FOUND IN LATENCY TO REACH STAGES 3-5. CONCLUSION: PRE-PREGNANCY EXPOSURE TO PG LPS COULD AFFECT SOME BEHAVIORAL FUNCTIONS IN BOTH MALE AND FEMALE OFFSPRING INTERGENERATIONALLY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16   173  35 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17   649  43 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18  3557  28 IMPACT OF BMI AND WAIST CIRCUMFERENCE ON EPIGENOME-WIDE DNA METHYLATION AND IDENTIFICATION OF EPIGENETIC BIOMARKERS IN BLOOD: AN EWAS IN MULTI-ETHNIC ASIAN INDIVIDUALS. BACKGROUND: THE PREVALENCE OF OBESITY AND ITS RELATED CHRONIC DISEASES HAVE BEEN INCREASING ESPECIALLY IN ASIAN COUNTRIES. OBESITY-RELATED GENETIC VARIANTS HAVE BEEN IDENTIFIED, BUT THESE EXPLAIN LITTLE OF THE VARIATION IN BMI. RECENT STUDIES REPORTED ASSOCIATIONS BETWEEN DNA METHYLATION AND OBESITY, MOSTLY IN NON-ASIAN POPULATIONS. METHODS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ON GENERAL ADIPOSITY (BODY MASS INDEX, BMI) AND ABDOMINAL ADIPOSITY (WAIST CIRCUMFERENCE, WC) IN 409 MULTI-ETHNIC ASIAN INDIVIDUALS AND REPLICATED BMI AND WAIST-ASSOCIATED DNA METHYLATION CPGS IDENTIFIED IN OTHER POPULATIONS. THE CROSS-LAGGED PANEL MODEL AND MENDELIAN RANDOMIZATION WERE USED TO ASSESS THE TEMPORAL RELATIONSHIP BETWEEN METHYLATION AND BMI. THE TEMPORAL RELATIONSHIP BETWEEN THE IDENTIFIED CPGS AND INFLAMMATION AND METABOLIC MARKERS WAS ALSO EXAMINED. RESULTS: EWAS IDENTIFIED 116 DNA METHYLATION CPGS INDEPENDENTLY ASSOCIATED WITH BMI AND EIGHT INDEPENDENTLY ASSOCIATED WITH WC AT FALSE DISCOVERY RATE P(FDR) < 0.05 IN 409 ASIAN SAMPLES. WE REPLICATED 110 BMI-ASSOCIATED CPGS PREVIOUSLY REPORTED IN EUROPEANS AND IDENTIFIED SIX NOVEL BMI-ASSOCIATED CPGS AND TWO NOVEL WC-ASSOCIATED CPGS. WE OBSERVED HIGH CONSISTENCY IN ASSOCIATION DIRECTION OF EFFECT COMPARED TO STUDIES IN OTHER POPULATIONS. CAUSAL RELATIONSHIP ANALYSES INDICATED THAT BMI WAS MORE LIKELY TO BE THE CAUSE OF DNA METHYLATION ALTERATION, RATHER THAN THE CONSEQUENCE. THE CAUSAL ANALYSES USING BMI-ASSOCIATED METHYLATION RISK SCORE ALSO SUGGESTED THAT HIGHER LEVELS OF THE INFLAMMATION MARKER IL-6 WERE LIKELY THE CONSEQUENCE OF METHYLATION CHANGE. CONCLUSION: OUR STUDY PROVIDES EVIDENCE OF AN ASSOCIATION BETWEEN OBESITY AND DNA METHYLATION IN MULTI-ETHNIC ASIANS AND SUGGESTS THAT OBESITY CAN DRIVE METHYLATION CHANGE. THE RESULTS ALSO SUGGESTED POSSIBLE CAUSAL INFLUENCE THAT OBESITY-RELATED METHYLATION CHANGES MIGHT HAVE ON INFLAMMATION AND LIPOPROTEIN LEVELS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
19   561  35 BARIATRIC SURGERY-INDUCED WEIGHT LOSS AND ASSOCIATED GENOME-WIDE DNA-METHYLATION ALTERATIONS IN OBESE INDIVIDUALS. BACKGROUND: OBESITY IS A MULTIFACTORIAL AND CHRONIC CONDITION OF GROWING UNIVERSAL CONCERN. IT HAS RECENTLY BEEN REPORTED THAT BARIATRIC SURGERY IS A MORE SUCCESSFUL TREATMENT FOR SEVERE OBESITY THAN OTHER NONINVASIVE INTERVENTIONS, RESULTING IN RAPID SIGNIFICANT WEIGHT LOSS AND ASSOCIATED CHRONIC DISEASE REMISSION. THE IDENTIFICATION OF DISTINCT EPIGENETIC PATTERNS IN PATIENTS WHO ARE OBESE OR HAVE METABOLIC IMBALANCES HAS SUGGESTED A POTENTIAL ROLE FOR EPIGENETIC ALTERATIONS IN CAUSAL OR MEDIATING PATHWAYS IN THE DEVELOPMENT OF OBESITY-RELATED PATHOLOGIES. SPECIFIC CHANGES IN THE EPIGENOME (DNA METHYLOME), ASSOCIATED WITH METABOLIC DISORDERS, CAN BE DETECTED IN THE BLOOD. WE INVESTIGATED WHETHER SUCH EPIGENETIC CHANGES ARE REVERSIBLE AFTER WEIGHT LOSS USING GENOME-WIDE DNA METHYLOME ANALYSIS OF BLOOD SAMPLES FROM INDIVIDUALS WITH SEVERE OBESITY (MEAN BMI ~ 45) UNDERGOING BARIATRIC SURGERY. RESULTS: OUR ANALYSIS REVEALED 41 SIGNIFICANT (BONFERRONI P < 0.05) AND 1169 (FALSE DISCOVERY RATE P < 0.05) SUGGESTIVE DIFFERENTIALLY METHYLATED POSITIONS (DMPS) ASSOCIATED WITH WEIGHT LOSS DUE TO BARIATRIC SURGERY. AMONG THE 41 SIGNIFICANT DMPS, 5 CPGS WERE REPLICATED IN AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS (THE HEAVIER TWIN UNDERWENT DIET-INDUCED WEIGHT LOSS). THE EFFECT SIZES OF THESE 5 CPGS WERE CONSISTENT ACROSS DISCOVERY AND REPLICATION SETS (P < 0.05). WE ALSO IDENTIFIED 192 DIFFERENTIALLY METHYLATED REGIONS (DMRS) AMONG WHICH SMAD6 AND PFKFB3 GENES WERE THE TOP HYPERMETHYLATED AND HYPOMETHYLATED REGIONS, RESPECTIVELY. PATHWAY ENRICHMENT ANALYSIS OF THE DMR-ASSOCIATED GENES SHOWED THAT FUNCTIONAL PATHWAYS RELATED TO IMMUNE FUNCTION AND TYPE 1 DIABETES WERE SIGNIFICANT. WEIGHT LOSS DUE TO BARIATRIC SURGERY ALSO SIGNIFICANTLY DECELERATED EPIGENETIC AGE 12 MONTHS AFTER THE INTERVENTION (MEAN = - 4.29; P = 0.02). CONCLUSIONS: WE IDENTIFIED WEIGHT LOSS-ASSOCIATED DNA-METHYLATION ALTERATIONS TARGETING IMMUNE AND INFLAMMATORY GENE PATHWAYS IN BLOOD SAMPLES FROM BARIATRIC-SURGERY PATIENTS. THE TOP HITS WERE REPLICATED IN SAMPLES FROM AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS FOLLOWING A HYPOCALORIC DIET. ENERGY RESTRICTION AND BARIATRIC SURGERY THUS SHARE CPGS THAT MAY REPRESENT EARLY INDICATORS OF RESPONSE TO THE METABOLIC EFFECTS OF WEIGHT LOSS. THE ANALYSIS OF BARIATRIC SURGERY-ASSOCIATED DMRS SUGGESTS THAT EPIGENETIC REGULATION OF GENES INVOLVED IN ENDOTHELIAL AND ADIPOSE TISSUE FUNCTION IS KEY IN THE PATHOPHYSIOLOGY OF OBESITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20   403  53 ANALYSIS OF EPIGENETIC AGE ACCELERATION AND HEALTHY LONGEVITY AMONG OLDER US WOMEN. IMPORTANCE: ACCELERATED BIOLOGICAL AGING IS ASSOCIATED WITH DECREASED PHYSICAL CAPABILITY AND COGNITIVE FUNCTIONING, WHICH ARE ASSOCIATED WITH INCREASED RISK OF MORBIDITY AND MORTALITY. OBJECTIVE: WE INVESTIGATED ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION (EAA), A BIOMARKER ASSOCIATED WITH AGING, AND HEALTHY LONGEVITY AMONG OLDER WOMEN. DESIGN, SETTING, AND PARTICIPANTS: THIS COHORT STUDY WAS A SECONDARY ANALYSIS OF PARTICIPANTS IN THE WOMEN'S HEALTH INITIATIVE (WHI) WHO WERE ELIGIBLE TO SURVIVE TO AGE 90 YEARS BY SEPTEMBER 30, 2020. PARTICIPANTS WERE LOCATED IN MULTIPLE CENTERS. THIS STUDY WAS RESTRICTED TO WOMEN WITH GENOME-WIDE DNA METHYLATION DATA, GENERATED FROM BASELINE BLOOD SAMPLES WITHIN 3 WHI ANCILLARY STUDIES. MEDIAN (IQR) FOLLOW-UP TIMES FROM BASELINE WERE 21.6 (19.6-22.9) YEARS AND 21.4 (19.8-22.7) YEARS FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH AND WITHOUT INTACT MOBILITY, RESPECTIVELY, AND 13.2 (8.8-16.7) FOR WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. DATA WERE ANALYZED FROM DECEMBER 2020 TO JULY 2021. EXPOSURES: EAA WAS ESTIMATED USING 4 ESTABLISHED "CLOCKS": HORVATH PANTISSUE, HANNUM, PHENO, AND GRIM. MAIN OUTCOMES AND MEASURES: USING MULTINOMIAL LOGISTIC REGRESSION, ODDS RATIOS (ORS) AND 95% CIS WERE ESTIMATED FOR 3 HEALTHY LONGEVITY OUTCOMES FOR EACH CLOCK: SURVIVAL TO AGE 90 YEARS WITH INTACT MOBILITY, SURVIVAL TO AGE 90 YEARS WITHOUT INTACT MOBILITY, AND NO SURVIVAL TO AGE 90 YEARS. RESULTS: AMONG 1813 WOMEN, THERE WERE 464 WOMEN (MEAN [SD] AGE AT BASELINE, 71.6 [3.5] YEARS) WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTIONING, 420 WOMEN (MEAN [SD] AGE AT BASELINE, 71.3 [3.2] YEARS) WHO SURVIVED TO AGE 90 YEARS WITHOUT INTACT MOBILITY AND COGNITIVE FUNCTIONING, AND 929 WOMEN (MEAN [SD] AGE AT BASELINE, 70.2 [3.4] YEARS) WHO DID NOT SURVIVE TO AGE 90 YEARS. WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION WERE HEALTHIER AT BASELINE COMPARED WITH WOMEN WHO SURVIVED WITHOUT THOSE OUTCOMES OR WHO DID NOT SURVIVE TO AGE 90 YEARS (EG, 143 WOMEN [30.8%] VS 101 WOMEN [24.0%] AND 202 WOMEN [21.7%] WITH 0 CHRONIC CONDITIONS). THE ODDS OF SURVIVING TO AGE 90 YEARS WITH INTACT MOBILITY WERE LOWER FOR EVERY 1 SD INCREASE IN EAA COMPARED WITH THOSE WHO DID NOT SURVIVE TO AGE 90 YEARS AS MEASURED BY AGEACCELHORVATH (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AGEACCELHANNUM (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AGEACCELPHENO (OR, 0.60; 95% CI, 0.51-0.72; P < .001), AND AGEACCELGRIM (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORS WERE SIMILAR FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION (EG, AGEACCELHORVATH: OR PER 1 SD INCREASE IN EAA, 0.83; 95% CI, 0.71-0.98; P = .03) COMPARED WITH WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. CONCLUSIONS AND RELEVANCE: THESE FINDINGS SUGGEST THAT EAA MAY BE A VALID BIOMARKER ASSOCIATED WITH HEALTHY LONGEVITY AMONG OLDER WOMEN AND MAY BE USED FOR RISK STRATIFICATION AND RISK ESTIMATION OF FUTURE FUNCTIONAL AND COGNITIVE AGING. OUTCOMES SUGGEST THAT FUTURE STUDIES MAY FOCUS ON THE POTENTIAL FOR PUBLIC HEALTH INTERVENTIONS TO COUNTERACT EAA AND ITS ASSOCIATION WITH POOR HEALTH OUTCOMES TO LOWER DISEASE BURDEN WHILE INCREASING LONGEVITY.	2022