1 2727 196 EXPLAINING THE BLACK-WHITE DISPARITY IN PRETERM BIRTH: A CONSENSUS STATEMENT FROM A MULTI-DISCIPLINARY SCIENTIFIC WORK GROUP CONVENED BY THE MARCH OF DIMES. IN 2017-2019, THE MARCH OF DIMES CONVENED A WORKGROUP WITH BIOMEDICAL, CLINICAL, AND EPIDEMIOLOGIC EXPERTISE TO REVIEW KNOWLEDGE OF THE CAUSES OF THE PERSISTENT BLACK-WHITE DISPARITY IN PRETERM BIRTH (PTB). MULTIPLE DATABASES WERE SEARCHED TO IDENTIFY HYPOTHESIZED CAUSES EXAMINED IN PEER-REVIEWED LITERATURE, 33 HYPOTHESIZED CAUSES WERE REVIEWED FOR WHETHER THEY PLAUSIBLY AFFECT PTB AND EITHER OCCUR MORE/LESS FREQUENTLY AND/OR HAVE A LARGER/SMALLER EFFECT SIZE AMONG BLACK WOMEN VS. WHITE WOMEN. WHILE DEFINITIVE PROOF IS LACKING FOR MOST POTENTIAL CAUSES, MOST ARE BIOLOGICALLY PLAUSIBLE. NO SINGLE DOWNSTREAM OR MIDSTREAM FACTOR EXPLAINS THE DISPARITY OR ITS SOCIAL PATTERNING, HOWEVER, MANY LIKELY PLAY LIMITED ROLES, E.G., WHILE GENETIC FACTORS LIKELY CONTRIBUTE TO PTB, THEY EXPLAIN AT MOST A SMALL FRACTION OF THE DISPARITY. RESEARCH LINKS MOST HYPOTHESIZED MIDSTREAM CAUSES, INCLUDING SOCIOECONOMIC FACTORS AND STRESS, WITH THE DISPARITY THROUGH THEIR INFLUENCE ON THE HYPOTHESIZED DOWNSTREAM FACTORS. SOCIOECONOMIC FACTORS ALONE CANNOT EXPLAIN THE DISPARITY'S SOCIAL PATTERNING. CHRONIC STRESS COULD AFFECT PTB THROUGH NEUROENDOCRINE AND IMMUNE MECHANISMS LEADING TO INFLAMMATION AND IMMUNE DYSFUNCTION, STRESS COULD ALTER A WOMAN'S MICROBIOTA, IMMUNE RESPONSE TO INFECTION, CHRONIC DISEASE RISKS, AND BEHAVIORS, AND TRIGGER EPIGENETIC CHANGES INFLUENCING PTB RISK. AS AN UPSTREAM FACTOR, RACISM IN MULTIPLE FORMS HAS REPEATEDLY BEEN LINKED WITH THE PLAUSIBLE MIDSTREAM/DOWNSTREAM FACTORS, INCLUDING SOCIOECONOMIC DISADVANTAGE, STRESS, AND TOXIC EXPOSURES. RACISM IS THE ONLY FACTOR IDENTIFIED THAT DIRECTLY OR INDIRECTLY COULD EXPLAIN THE RACIAL DISPARITIES IN THE PLAUSIBLE MIDSTREAM/DOWNSTREAM CAUSES AND THE OBSERVED SOCIAL PATTERNING. HISTORICAL AND CONTEMPORARY SYSTEMIC RACISM CAN EXPLAIN THE RACIAL DISPARITIES IN SOCIOECONOMIC OPPORTUNITIES THAT DIFFERENTIALLY EXPOSE AFRICAN AMERICANS TO LIFELONG FINANCIAL STRESS AND ASSOCIATED HEALTH-HARMING CONDITIONS. SEGREGATION PLACES BLACK WOMEN IN STRESSFUL SURROUNDINGS AND EXPOSES THEM TO ENVIRONMENTAL HAZARDS. RACE-BASED DISCRIMINATORY TREATMENT IS A PERVASIVE STRESSOR FOR BLACK WOMEN OF ALL SOCIOECONOMIC LEVELS, CONSIDERING BOTH INCIDENTS AND THE CONSTANT VIGILANCE NEEDED TO PREPARE ONESELF FOR POTENTIAL INCIDENTS. RACISM IS A HIGHLY PLAUSIBLE, MAJOR UPSTREAM CONTRIBUTOR TO THE BLACK-WHITE DISPARITY IN PTB THROUGH MULTIPLE PATHWAYS AND BIOLOGICAL MECHANISMS. WHILE MUCH IS UNKNOWN, EXISTING KNOWLEDGE AND CORE VALUES (EQUITY, JUSTICE) SUPPORT ADDRESSING RACISM IN EFFORTS TO ELIMINATE THE RACIAL DISPARITY IN PTB. 2021 2 5215 24 PRETERM BIRTH AND ITS LONG-TERM EFFECTS: METHYLATION TO MECHANISMS. THE EPIGENETIC PATTERNS ESTABLISHED DURING DEVELOPMENT MAY INFLUENCE GENE EXPRESSION OVER A LIFETIME AND INCREASE SUSCEPTIBILITY TO CHRONIC DISEASE. BEING BORN PRETERM (<37 WEEKS OF GESTATION) IS ASSOCIATED WITH INCREASED RISK MORTALITY AND MORBIDITY FROM BIRTH UNTIL ADULTHOOD. THIS BRIEF REVIEW EXPLORES THE POTENTIAL ROLE OF DNA METHYLATION IN PRETERM BIRTH (PTB) AND ITS POSSIBLE LONG-TERM CONSEQUENCES AND PROVIDES AN OVERVIEW OF THE PHYSIOLOGICAL PROCESSES CENTRAL TO PTB AND RECENT DNA METHYLATION STUDIES OF PTB. 2014 3 1595 44 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 4 418 43 ANCESTRAL EXPOSURE TO STRESS EPIGENETICALLY PROGRAMS PRETERM BIRTH RISK AND ADVERSE MATERNAL AND NEWBORN OUTCOMES. BACKGROUND: CHRONIC STRESS IS CONSIDERED TO BE ONE OF MANY CAUSES OF HUMAN PRETERM BIRTH (PTB), BUT NO DIRECT EVIDENCE HAS YET BEEN PROVIDED. HERE WE SHOW IN RATS THAT STRESS ACROSS GENERATIONS HAS DOWNSTREAM EFFECTS ON ENDOCRINE, METABOLIC AND BEHAVIOURAL MANIFESTATIONS OF PTB POSSIBLY VIA MICRORNA (MIRNA) REGULATION. METHODS: PREGNANT DAMS OF THE PARENTAL GENERATION WERE EXPOSED TO STRESS FROM GESTATIONAL DAYS 12 TO 18. THEIR PREGNANT DAUGHTERS (F1) AND GRAND-DAUGHTERS (F2) EITHER WERE STRESSED OR REMAINED AS NON-STRESSED CONTROLS. GESTATIONAL LENGTH, MATERNAL GESTATIONAL WEIGHT GAIN, BLOOD GLUCOSE AND PLASMA CORTICOSTERONE LEVELS, LITTER SIZE AND OFFSPRING WEIGHT GAIN FROM POSTNATAL DAYS 1 TO 30 WERE RECORDED IN EACH GENERATION, INCLUDING F3. MATERNAL BEHAVIOURS WERE ANALYSED FOR THE FIRST HOUR AFTER COMPLETED PARTURITION, AND OFFSPRING SENSORIMOTOR DEVELOPMENT WAS RECORDED ON POSTNATAL DAY (P) 7. F0 THROUGH F2 MATERNAL BRAIN FRONTAL CORTEX, UTERUS AND PLACENTA MIRNA AND GENE EXPRESSION PATTERNS WERE USED TO IDENTIFY STRESS-INDUCED EPIGENETIC REGULATORY PATHWAYS OF MATERNAL BEHAVIOUR AND PREGNANCY MAINTENANCE. RESULTS: PROGRESSIVELY UP TO THE F2 GENERATION, STRESS GRADUALLY REDUCED GESTATIONAL LENGTH, MATERNAL WEIGHT GAIN AND BEHAVIOURAL ACTIVITY, AND INCREASED BLOOD GLUCOSE LEVELS. REDUCED OFFSPRING GROWTH AND DELAYED BEHAVIOURAL DEVELOPMENT IN THE STRESS COHORT WAS RECOGNIZABLE AS EARLY AS P7, WITH THE GREATEST EFFECT IN THE F3 OFFSPRING OF TRANSGENERATIONALLY STRESSED MOTHERS. FURTHERMORE, STRESS ALTERED MIRNA EXPRESSION PATTERNS IN THE BRAIN AND UTERUS OF F2 MOTHERS, INCLUDING THE MIR-200 FAMILY, WHICH REGULATES PATHWAYS RELATED TO BRAIN PLASTICITY AND PARTURITION, RESPECTIVELY. MAIN MIR-200 FAMILY TARGET GENES IN THE UTERUS, STAT5B, ZEB1 AND ZEB2, WERE DOWNREGULATED BY MULTIGENERATIONAL STRESS IN THE F1 GENERATION. ZEB2 WAS ALSO REDUCED IN THE STRESSED F2 GENERATION, SUGGESTING A CAUSAL MECHANISM FOR DISTURBED PREGNANCY MAINTENANCE. ADDITIONALLY, STRESS INCREASED PLACENTAL MIR-181A, A MARKER OF HUMAN PTB. CONCLUSIONS: THE FINDINGS INDICATE THAT A FAMILY HISTORY OF STRESS MAY PROGRAM CENTRAL AND PERIPHERAL PATHWAYS REGULATING GESTATIONAL LENGTH AND MATERNAL AND NEWBORN HEALTH OUTCOMES IN THE MATERNAL LINEAGE. THIS NEW PARADIGM MAY MODEL THE ORIGIN OF MANY HUMAN PTB CAUSES. 2014 5 2605 32 EPIGENETICS-A POTENTIAL MEDIATOR BETWEEN AIR POLLUTION AND PRETERM BIRTH. PRETERM BIRTH IS A MAJOR CAUSE OF INFANT MORBIDITY AND MORTALITY AND A POTENTIAL RISK FACTOR FOR ADULT CHRONIC DISEASE. WITH OVER 15 MILLION INFANTS BORN PRETERM WORLDWIDE EACH YEAR, PRETERM BIRTH POSES A GLOBAL HEALTH CONCERN. THERE IS A POSSIBLE ASSOCIATION BETWEEN AIR POLLUTION AND PRETERM BIRTH, THOUGH STUDIES HAVE BEEN INCONSISTENT, LIKELY DUE TO VARIATION IN STUDY DESIGN. HOW AIR POLLUTION INDUCES HEALTH EFFECTS IS UNCERTAIN; HOWEVER, STUDIES HAVE REPEATEDLY DEMONSTRATED THE EFFECTS OF AIR POLLUTION ON EPIGENETIC MODIFICATIONS. MORE RECENT EVIDENCE SUGGESTS THAT EPIGENETICS MAY, IN TURN, BE LINKED TO PRETERM BIRTH. DISCOVERY OF ENVIRONMENTALLY MODIFIABLE EPIGENETIC PROCESSES CONNECTED TO PRETERM BIRTH MAY HELP TO IDENTIFY WOMEN AT RISK OF PRETERM BIRTH, AND ULTIMATELY LEAD TO DEVELOPMENT OF NEW PRETERM BIRTH PREVENTION MEASURES. 2016 6 5169 54 PRECONCEPTIONAL STRESS AND RACIAL DISPARITIES IN PRETERM BIRTH: AN OVERVIEW. OBJECTIVE: WE REVIEWED THE EVIDENCE FOR THREE THEORIES OF HOW PRECONCEPTIONAL PSYCHOSOCIAL STRESS COULD ACT AS A CONTRIBUTING DETERMINANT OF EXCESS PRETERM BIRTH RISK AMONG AFRICAN AMERICAN WOMEN: EARLY LIFE DEVELOPMENTAL PLASTICITY AND EPIGENETIC PROGRAMMING OF ADULT NEUROENDOCRINE SYSTEMS; BLUNTING, WEATHERING, OR DYSFUNCTION OF NEUROENDOCRINE AND IMMUNE FUNCTION IN RESPONSE TO CHRONIC STRESS ACTIVATION THROUGH THE LIFE COURSE; INDIVIDUALS' ADOPTION OF RISKY BEHAVIORS SUCH AS SMOKING AS A RESPONSE TO STRESSFUL STIMULI. METHODS: BASIC SCIENCE, CLINICAL, AND EPIDEMIOLOGIC STUDIES INDEXED IN MEDLINE AND WEB OF SCIENCE DATABASES ON PRECONCEPTIONAL PSYCHOSOCIAL STRESS, PRETERM BIRTH AND RACE WERE REVIEWED. RESULTS: MIXED EVIDENCE LEANS TOWARDS MODEST ASSOCIATIONS BETWEEN PRECONCEPTIONAL CHRONIC STRESS AND PRETERM BIRTH (FOR EXAMPLE COMMON ODDS RATIOS OF 1.2-1.4), PARTICULARLY IN AFRICAN AMERICAN WOMEN, BUT IT IS UNCLEAR WHETHER THIS ASSOCIATION IS CAUSAL OR EXPLAINS A SUBSTANTIAL PORTION OF THE BLACK-WHITE RACIAL DISPARITY IN PRETERM BIRTH. THE STRESS-PRETERM BIRTH ASSOCIATION MAY BE MEDIATED BY HYPOTHALAMIC-PITUITARY-ADRENAL AXIS DYSFUNCTION AND SUSCEPTIBILITY TO BACTERIAL VAGINOSIS, ALTHOUGH THESE MECHANISMS ARE INCOMPLETELY UNDERSTOOD. EVIDENCE FOR THE ROLE OF EPIGENETIC OR EARLY LIFE PROGRAMMING AS A DETERMINANT OF RACIAL DISPARITIES IN PRETERM BIRTH RISK IS MORE CIRCUMSTANTIAL. CONCLUSIONS: PRECONCEPTIONAL STRESS, DIRECTLY OR IN INTERACTION WITH HOST GENETIC SUSCEPTIBILITY OR INFECTION, REMAINS AN IMPORTANT HYPOTHESIZED RISK FACTOR FOR UNDERSTANDING AND REDUCING RACIAL DISPARITIES IN PRETERM BIRTH. FUTURE STUDIES THAT INTEGRATE ADEQUATELY SIZED EPIDEMIOLOGIC SAMPLES WITH MEASURES OF STRESS, INFECTION, AND GENE EXPRESSION, WILL ADVANCE OUR KNOWLEDGE AND ALLOW DEVELOPMENT OF TARGETED INTERVENTIONS. 2011 7 1521 30 DNA METHYLATION AT IMPRINT REGULATORY REGIONS IN PRETERM BIRTH AND INFECTION. OBJECTIVE: TO AID IN UNDERSTANDING LONG-TERM HEALTH CONSEQUENCES OF INTRAUTERINE INFECTIONS IN PRETERM BIRTH, WE EVALUATED DNA METHYLATION AT 9 DIFFERENTIALLY METHYLATED REGIONS THAT REGULATE IMPRINTED GENES BY TYPE OF PRETERM BIRTH (SPONTANEOUS PRETERM LABOR, PRETERM PREMATURE RUPTURE OF MEMBRANES, OR MEDICALLY INDICATED [FETAL GROWTH RESTRICTION AND PREECLAMPSIA]) AND INFECTION STATUS (CHORIOAMNIONITIS OR FUNISITIS). STUDY DESIGN: DATA ON TYPE OF PRETERM BIRTH AND INFECTION STATUS WERE ABSTRACTED FROM MEDICAL RECORDS AND STANDARDIZED PATHOLOGY REPORTS IN 73 PRETERM INFANTS ENROLLED IN THE NEWBORN EPIGENETICS STUDY, A PROSPECTIVE COHORT STUDY OF MOTHER-INFANT DYADS IN DURHAM, NC. CORD BLOOD WAS COLLECTED AT BIRTH, AND INFANT DNA METHYLATION LEVELS AT THE H19, IGF2, MEG3, MEST, SGCE/PEG10, PEG3, NNAT, AND PLAGL1 DIFFERENTIALLY METHYLATED REGIONS WERE MEASURED USING BISULFITE PYROSEQUENCING. ONE-WAY ANALYSES OF VARIANCE AND LOGISTIC REGRESSION MODELS WERE USED TO COMPARE DNA METHYLATION LEVELS BY TYPE OF PRETERM BIRTH AND INFECTION STATUS. RESULTS: DNA METHYLATION LEVELS DID NOT DIFFER AT ANY OF THE REGIONS (P > .20) BETWEEN INFANTS BORN VIA SPONTANEOUS PRETERM LABOR (AVERAGE N = 29), PRETERM PREMATURE RUPTURE OF MEMBRANES (AVERAGE N = 17), OR MEDICALLY INDICATED PRETERM BIRTH (AVERAGE N = 40). LEVELS WERE SIGNIFICANTLY INCREASED AT PLAGL1 IN INFANTS WITH CHORIOAMNIONITIS (N = 10, 64.4%) COMPARED WITH INFANTS WITHOUT CHORIOAMNIONITIS (N = 63, 57.9%), P < .01. DNA METHYLATION LEVELS WERE ALSO INCREASED AT PLAGL1 FOR INFANTS WITH FUNISITIS (N = 7, 63.3%) COMPARED WITH INFANTS WITHOUT FUNISITIS (N = 66, 58.3%), P < .05. CONCLUSION: DYSREGULATION OF PLAGL1 HAS BEEN ASSOCIATED WITH ABNORMAL DEVELOPMENT AND CANCER. EARLY-LIFE EXPOSURES, INCLUDING INFECTION/INFLAMMATION, MAY AFFECT EPIGENETIC CHANGES THAT INCREASE SUSCEPTIBILITY TO LATER CHRONIC DISEASE. 2013 8 6625 50 UNDERSTANDING RACIAL DISPARITIES OF PRETERM BIRTH THROUGH THE PLACENTA. THE RACIAL DISPARITY ASSOCIATED WITH PRETERM BIRTH IS A PUBLIC HEALTH CONCERN IN THE UNITED STATES. THE PLACENTA IS THE PRINCIPAL METABOLIC, RESPIRATORY, AND ENDOCRINE ORGAN OF THE FETUS AND A KEY ROUTE BY WHICH ENVIRONMENTAL EXPOSURES ARE TRANSMITTED FROM MOTHER TO OFFSPRING. AVAILABLE AT EVERY DELIVERY, IT MAY SERVE AS A MARKER OF DIFFERENCES IN PRENATAL EXPOSURES THAT MANIFEST DIFFERENTLY BY RACE. RECENTLY, WE DESCRIBED DIFFERENCES IN PLACENTAL PATHOLOGY BETWEEN AFRICAN-AMERICAN AND WHITE PRETERM BIRTHS: THE PREVALENCE OF CHRONIC INFLAMMATION WAS HIGHER AMONG AFRICAN-AMERICAN WOMEN'S PLACENTAS COMPARED WITH THOSE OF WHITE WOMEN. SIMILARLY, RACIAL DIFFERENCES HAVE BEEN SHOWN IN PLACENTAL MALPERFUSION AND PLACENTAL WEIGHT. SOCIAL DETERMINANTS SUCH AS POVERTY AND STRESS FROM DISCRIMINATION HAVE BEEN IMPLICATED IN RACIAL DISPARITIES IN PRETERM BIRTH. TO DATE, HOWEVER, THE UNDERLYING BIOLOGICAL MECHANISMS, WHETHER THROUGH INFLAMMATORY, OXIDATIVE STRESS, OR OTHER PATHWAYS INVOLVING EPIGENETIC PROGRAMMING, REMAIN LARGELY UNKNOWN. THE PLACENTA, COMPLEMENTED BY MATERNAL AND UMBILICAL CORD BLOOD BIOMARKERS, MAY PROVIDE IMPORTANT INFORMATION ON THE PERINATAL ENVIRONMENT THAT EXPLAINS THE ORIGINS OF RACIAL DISPARITIES IN PRETERM BIRTH RATES AND SUBSEQUENT HEALTH OUTCOMES. THIS ARTICLE REVIEWS EXISTING LITERATURE AND CURRENT RESEARCH GAPS. OPPORTUNITIES ARE DISCUSSED FOR FUTURE PLACENTAL RESEARCH THAT MAY REVEAL NOVEL MECHANISMS LEADING TO THE DEVELOPMENT OF NEW APPROACHES IN THE PREVENTION AND MANAGEMENT OF PRETERM BIRTH AND ITS OUTCOMES. 2021 9 5658 29 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 10 4916 23 PAIN-RELATED INCREASE IN SEROTONIN TRANSPORTER GENE METHYLATION ASSOCIATES WITH EMOTIONAL REGULATION IN 4.5-YEAR-OLD PRETERM-BORN CHILDREN. AIM: THE MAIN GOAL OF THIS STUDY WAS TO ASSESS THE ASSOCIATION BETWEEN PAIN-RELATED INCREASE IN SEROTONIN TRANSPORTER GENE (SLC6A4) METHYLATION AND EMOTIONAL DYSREGULATION IN 4.5-YEAR-OLD PRETERM CHILDREN COMPARED WITH FULL-TERM MATCHED COUNTERPARTS. METHODS: PRETERM (N = 29) AND FULL-TERM (N = 26) CHILDREN RECRUITED FROM TWO ITALIAN HOSPITALS WERE FOLLOWED-UP FROM OCTOBER 2011 TO DECEMBER 2017. SLC6A4 METHYLATION WAS ASSESSED FROM CORD BLOOD AT BIRTH FROM BOTH GROUPS AND PERIPHERAL BLOOD AT DISCHARGE FOR PRETERM ONES. AT 4.5 YEARS, EMOTIONAL REGULATION (IE, ANGER, FEAR AND SADNESS) WAS ASSESSED THROUGH AN OBSERVATIONAL STANDARDISED PROCEDURE. RESULTS: PRETERM CHILDREN (18 FEMALES; MEAN AGE = 4.5, RANGE = 4.3-4.8) SHOWED GREATER ANGER DISPLAY COMPARED WITH FULL-TERM CONTROLS (14 FEMALES; MEAN AGE = 4.5, RANGE = 4.4-4.9) IN RESPONSE TO EMOTIONAL STRESS. CONTROLLING FOR ADVERSE LIFE EVENTS OCCURRENCE FROM DISCHARGE TO 4.5 YEARS AND SLC6A4 METHYLATION AT BIRTH, CPG-SPECIFIC SLC6A4 METHYLATION IN THE NEONATAL PERIOD WAS PREDICTIVE OF GREATER ANGER DISPLAY IN PRETERM CHILDREN BUT NOT IN FULL-TERM ONES. CONCLUSION: THESE FINDINGS CONTRIBUTE TO HIGHLIGHT HOW EPIGENETIC REGULATION OF SEROTONIN TRANSPORTER GENE IN RESPONSE TO NICU PAIN EXPOSURE CONTRIBUTES TO LONG-LASTING PROGRAMMING OF ANGER REGULATION IN PRETERM CHILDREN. 2020 11 2419 43 EPIGENETIC SIGNATURE OF CHRONIC MATERNAL STRESS LOAD DURING PREGNANCY MIGHT BE A POTENTIAL BIOMARKER FOR SPONTANEOUS PRETERM BIRTH. PRETERM BIRTH IS THE LEADING CAUSE OF MORTALITY IN NEWBORN INFANTS AND CAN LEAD TO SIGNIFICANT NEONATAL MORBIDITIES. SPONTANEOUS PRETERM BIRTH ACCOUNTS FOR AT LEAST 50.0% OF ALL PRETERM BIRTHS. WE ARGUE THAT CHRONIC MATERNAL STRESS LOAD, WHICH IS AN IMPORTANT RISK FACTOR FOR SPONTANEOUS PRETERM BIRTH, COULD BE REPRESENTED BY EPIGENETIC SIGNATURE OF SEVERAL SPECIFIC GENETIC LOCI IN THE MOTHER'S BLOOD. A LITERATURE SEARCH WAS DONE IN PUBMED WITH THE FOLLOWING KEYWORDS: "DNA METHYLATION," "EPIGENETICS," "MATERNAL STRESS" AND "PRETERM BIRTH" FROM YEAR 2000 TO 2017. WE SUGGEST THAT THESE GENETIC LOCI MIGHT BE RELATED TO VULNERABILITY AND HYPERSENSIBILITY OF STRESS RESPONSE DURING PREGNANCY IN WOMEN WITH PRETERM BIRTHS. THE MOTHER'S EPI-GENETIC STRESS BIOPROFILE WAS SUPPOSED TO BE A RESULT OF CHRONIC MATERNAL STRESS LOAD SINCE HER BIRTH. THIS EPIGENETIC BIOPROFILE MIGHT ALSO BE A POTENTIAL BIOMARKER FOR SPONTANEOUS PRETERM BIRTH. DNA METHYLATION CHANGES ARE TISSUE-SPECIFIC AND HUMAN STRESS RESPONSE MANIFESTS MOSTLY THROUGH THE CENTRAL NERVOUS SYSTEM (CNS). NEVERTHELESS, WE FOUND EVIDENCE THAT METHYLATION CHANGES OF DNA ISOLATED FROM BLOOD LEUCOCYTES MIGHT BE A RELIABLE MEASURE OF STRESS-RELATED EPIGENETIC CHANGES THAT OCCUR IN THE CNS. EVALUATING BIOLOGICAL MECHANISMS THROUGH THE DEVELOPMENT OF SIMPLE ASSAYS BASED ON EPIGENETIC CHANGES TO MEASURE CHRONIC STRESS LOADS IN EXPECTANT MOTHERS CAN LEAD TO OUR ABILITY TO PREPARE MORE EFFECTIVE MEASURES FOR THE PREVENTION OF PRETERM BIRTHS, AS WELL AS LEADING TO MORE EFFECTIVE TREATMENT STRATEGIES FOR BOTH EXPECTANT MOTHERS AND THEIR NEWBORNS. 2018 12 518 35 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 13 4504 23 MOTHER'S PRE-PREGNANCY BMI AND PLACENTAL CANDIDATE MIRNAS: FINDINGS FROM THE ENVIRONAGE BIRTH COHORT. THERE IS INCREASING EVIDENCE THAT THE PREDISPOSITION FOR DEVELOPMENT OF CHRONIC DISEASES ARISES AT THE EARLIEST TIMES OF LIFE. IN THIS CONTEXT, MATERNAL PRE-PREGNANCY WEIGHT MIGHT MODIFY FETAL METABOLISM AND THE CHILD'S PREDISPOSITION TO DEVELOP DISEASE LATER IN LIFE. THE AIM OF THIS STUDY IS TO INVESTIGATE THE ASSOCIATION BETWEEN MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) AND MIRNA ALTERATIONS IN PLACENTAL TISSUE AT BIRTH. IN 211 MOTHER-NEWBORN PAIRS FROM THE ENVIRONAGE BIRTH COHORT, WE ASSESSED PLACENTAL EXPRESSION OF SEVEN MIRNAS IMPORTANT IN CRUCIAL CELLULAR PROCESSES IMPLICATED IN ADIPOGENESIS AND/OR OBESITY. MULTIPLE LINEAR REGRESSION MODELS WERE USED TO ADDRESS THE ASSOCIATIONS BETWEEN PRE-PREGNANCY BMI AND PLACENTAL CANDIDATE MIRNA EXPRESSION. MATERNAL PRE-PREGNANCY BMI AVERAGED (+/-SD) 23.9 (+/-4.1) KG/M(2). IN NEWBORN GIRLS (NOT IN BOYS) PLACENTAL MIR-20A, MIR-34A AND MIR-222 EXPRESSION WAS LOWER WITH HIGHER MATERNAL PRE-PREGNANCY BMI. IN ADDITION, THE ASSOCIATION BETWEEN MATERNAL PRE-PREGNANCY BMI AND PLACENTAL EXPRESSION OF THESE MIRNAS IN GIRLS WAS MODIFIED BY GESTATIONAL WEIGHT GAIN. THE LOWER EXPRESSION OF THESE MIRNAS IN PLACENTA IN ASSOCIATION WITH PRE-PREGNANCY BMI, WAS ONLY EVIDENT IN MOTHERS WITH LOW WEIGHT GAIN (<14 KG). THE PLACENTAL EXPRESSION OF MIR-20A, MIR-34A, MIR-146A, MIR-210 AND MIR-222 MAY PROVIDE A SEX-SPECIFIC BASIS FOR EPIGENETIC EFFECTS OF PRE-PREGNANCY BMI. 2017 14 4090 31 MATERNAL PRE-PREGNANCY BMI, OFFSPRING EPIGENOME-WIDE DNA METHYLATION, AND CHILDHOOD OBESITY: FINDINGS FROM THE BOSTON BIRTH COHORT. BACKGROUND: MATERNAL PRE-PREGNANCY OBESITY IS AN ESTABLISHED RISK FACTOR FOR CHILDHOOD OBESITY. INVESTIGATING EPIGENETIC ALTERATIONS INDUCED BY MATERNAL OBESITY DURING FETAL DEVELOPMENT COULD GAIN MECHANISTIC INSIGHT INTO THE DEVELOPMENTAL ORIGINS OF CHILDHOOD OBESITY. WHILE OBESITY DISPROPORTIONATELY AFFECTS UNDERREPRESENTED RACIAL AND ETHNIC MOTHERS AND CHILDREN IN THE USA, FEW STUDIES INVESTIGATED THE ROLE OF PRENATAL EPIGENETIC PROGRAMMING IN INTERGENERATIONAL OBESITY OF THESE HIGH-RISK POPULATIONS. METHODS: THIS STUDY INCLUDED 903 MOTHER-CHILD PAIRS FROM THE BOSTON BIRTH COHORT, A PREDOMINANTLY URBAN, LOW-INCOME MINORITY BIRTH COHORT. MOTHER-INFANT DYADS WERE ENROLLED AT BIRTH AND THE CHILDREN WERE FOLLOWED PROSPECTIVELY TO AGE 18 YEARS. INFINIUM METHYLATION EPIC BEADCHIP WAS USED TO MEASURE EPIGENOME-WIDE METHYLATION LEVEL OF CORD BLOOD. WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY OF MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) AND CORD BLOOD DNA METHYLATION (DNAM). TO QUANTIFY THE DEGREE TO WHICH CORD BLOOD DNAM MEDIATES THE MATERNAL BMI-CHILDHOOD OBESITY, WE FURTHER INVESTIGATED WHETHER MATERNAL BMI-ASSOCIATED DNAM SITES IMPACT BIRTHWEIGHT OR CHILDHOOD OVERWEIGHT OR OBESITY (OWO) FROM AGE 1 TO AGE 18 AND PERFORMED CORRESPONDING MEDIATION ANALYSES. RESULTS: THE STUDY SAMPLE CONTAINED 52.8% MATERNAL PRE-PREGNANCY OWO AND 63.2% OFFSPRING OWO AT AGE 1-18 YEARS. MATERNAL BMI WAS ASSOCIATED WITH CORD BLOOD DNAM AT 8 CPG SITES (GENOME-WIDE FALSE DISCOVERY RATE [FDR] < 0.05). AFTER ACCOUNTING FOR THE POSSIBLE INTERPLAY OF MATERNAL BMI AND SMOKING, 481 CPG SITES WERE DISCOVERED FOR ASSOCIATION WITH MATERNAL BMI. AMONG THEM 123 CPGS WERE ASSOCIATED WITH CHILDHOOD OWO, RANGING FROM 42% DECREASE TO 87% INCREASE IN OWO RISK FOR EACH SD INCREASE IN DNAM. A TOTAL OF 14 IDENTIFIED CPG SITES SHOWED A SIGNIFICANT MEDIATION EFFECT ON THE MATERNAL BMI-CHILD OWO ASSOCIATION (FDR < 0.05), WITH MEDIATING PROPORTION RANGING FROM 3.99% TO 25.21%. SEVERAL OF THESE 14 CPGS WERE MAPPED TO GENES IN ASSOCIATION WITH ENERGY BALANCE AND METABOLISM (AKAP7) AND ADULTHOOD METABOLIC SYNDROME (CAMK2B). CONCLUSIONS: THIS PROSPECTIVE BIRTH COHORT STUDY IN A HIGH-RISK YET UNDERSTUDIED US POPULATION FOUND THAT MATERNAL PRE-PREGNANCY OWO SIGNIFICANTLY ALTERED DNAM IN NEWBORN CORD BLOOD AND PROVIDED SUGGESTIVE EVIDENCE OF EPIGENETIC INVOLVEMENT IN THE INTERGENERATIONAL RISK OF OBESITY. 2023 15 4691 37 NEWBORNS OF OBESE PARENTS HAVE ALTERED DNA METHYLATION PATTERNS AT IMPRINTED GENES. BACKGROUND: SEVERAL EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED ASSOCIATIONS BETWEEN PERICONCEPTIONAL ENVIRONMENTAL EXPOSURES AND HEALTH STATUS OF THE OFFSPRING IN LATER LIFE. ALTHOUGH THESE ENVIRONMENTALLY RELATED EFFECTS HAVE BEEN ATTRIBUTED TO EPIGENETIC CHANGES, SUCH AS DNA METHYLATION SHIFTS AT IMPRINTED GENES, LITTLE IS KNOWN ABOUT THE POTENTIAL EFFECTS OF MATERNAL AND PATERNAL PRECONCEPTIONAL OVERNUTRITION OR OBESITY. OBJECTIVE: WE EXAMINED PARENTAL PRECONCEPTIONAL OBESITY IN RELATION TO DNA METHYLATION PROFILES AT MULTIPLE HUMAN IMPRINTED GENES IMPORTANT IN NORMAL GROWTH AND DEVELOPMENT, SUCH AS: MATERNALLY EXPRESSED GENE 3 (MEG3), MESODERM-SPECIFIC TRANSCRIPT (MEST), PATERNALLY EXPRESSED GENE 3 (PEG3), PLEIOMORPHIC ADENOMA GENE-LIKE 1 (PLAGL1), EPSILON SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 (SGCE/PEG10) AND NEURONATIN (NNAT). METHODS: WE MEASURED METHYLATION PERCENTAGES AT THE DIFFERENTIALLY METHYLATED REGIONS (DMRS) BY BISULFITE PYROSEQUENCING IN DNA EXTRACTED FROM UMBILICAL CORD BLOOD LEUKOCYTES OF 92 NEWBORNS. PRECONCEPTIONAL OBESITY, DEFINED AS BMI ?30 KG M(-2), WAS ASCERTAINED THROUGH STANDARDIZED QUESTIONNAIRES. RESULTS: AFTER ADJUSTING FOR POTENTIAL CONFOUNDERS AND CLUSTER EFFECTS, PATERNAL OBESITY WAS SIGNIFICANTLY ASSOCIATED WITH LOWER METHYLATION LEVELS AT THE MEST (BETA=-2.57; S.E.=0.95; P=0.008), PEG3 (BETA=-1.71; S.E.=0.61; P=0.005) AND NNAT (BETA=-3.59; S.E.=1.76; P=0.04) DMRS. CHANGES RELATED TO MATERNAL OBESITY DETECTED AT OTHER LOCI WERE AS FOLLOWS: BETA-COEFFICIENT WAS +2.58 (S.E.=1.00; P=0.01) AT THE PLAGL1 DMR AND -3.42 (S.E.=1.69; P=0.04) AT THE MEG3 DMR. CONCLUSION: WE FOUND ALTERED METHYLATION OUTCOMES AT MULTIPLE IMPRINT REGULATORY REGIONS IN CHILDREN BORN TO OBESE PARENTS, COMPARED WITH CHILDREN BORN TO NON-OBESE PARENTS. IN SPITE OF THE SMALL SAMPLE SIZE, OUR DATA SUGGEST A PRECONCEPTIONAL INFLUENCE OF PARENTAL LIFE-STYLE OR OVERNUTRITION ON THE (RE)PROGRAMMING OF IMPRINT MARKS DURING GAMETOGENESIS AND EARLY DEVELOPMENT. MORE SPECIFICALLY, THE SIGNIFICANT AND INDEPENDENT ASSOCIATION BETWEEN PATERNAL OBESITY AND THE OFFSPRING'S METHYLATION STATUS SUGGESTS THE SUSCEPTIBILITY OF THE DEVELOPING SPERM FOR ENVIRONMENTAL INSULTS. THE ACQUIRED IMPRINT INSTABILITY MAY BE CARRIED ONTO THE NEXT GENERATION AND INCREASE THE RISK FOR CHRONIC DISEASES IN ADULTHOOD. 2015 16 646 30 BIRTH MODE AND INFECTIOUS MORBIDITY RISKS IN QOM CHILDREN OF ARGENTINA. OBJECTIVES: CESAREAN DELIVERY MAY INCREASE CHILDHOOD INFECTIOUS MORBIDITY RISKS VIA ALTERED BIRTH EXPOSURES AND SUBSEQUENT IMMUNE, MICROBIAL, AND EPIGENETIC DEVELOPMENT. MANY LATIN AMERICAN INDIGENOUS POPULATIONS EXPERIENCE DUAL BURDENS OF INFECTIOUS AND CHRONIC DISEASES, AND ARE PARTICULARLY VULNERABLE TO RISING RATES OF CESAREAN DELIVERY AND ASSOCIATED ADVERSE OUTCOMES. THE QOM/TOBA ARE AN INDIGENOUS POPULATION IN ARGENTINA EXPERIENCING RAPID LIFESTYLE TRANSITIONS. WE HYPOTHESIZED THAT CESAREAN DELIVERY WOULD BE ASSOCIATED WITH INCREASED RISK OF INFECTIOUS SYMPTOMS IN QOM CHILDREN AFTER ADJUSTING FOR GESTATIONAL AND NUTRITIONAL FACTORS. METHODS: WE CONDUCTED A SECONDARY ANALYSIS OF BIRTH RECORDS AND MONTHLY ANTHROPOMETRIC AND ILLNESS DATA COLLECTED PREVIOUSLY FROM 90 QOM CHILDREN (AGED 1-55 MONTHS). WE TESTED FOR ADDITIVE EFFECTS OF BIRTH MODE ON RISK OF GASTROINTESTINAL (GI) AND RESPIRATORY ILLNESS (RI) IN MIXED-EFFECTS LOGISTIC REGRESSION MODELS ADJUSTING FOR CHILD WEIGHT-FOR-AGE (WAZ), WEANING, AND GESTATIONAL AND MATERNAL AGE. RESULTS: CESAREAN DELIVERIES ACCOUNTED FOR 46% OF BIRTHS AND WERE ASSOCIATED WITH MATERNAL AGE < 20 AND >/= 30 YEARS, GESTATIONAL AGE < 39 WEEKS, AND PRENATAL COMPLICATIONS. GI AND RI RISKS WERE REDUCED IN ASSOCIATION WITH CESAREAN DELIVERY, GREATER WAZ, WEANING, MATERNAL AGE >/= 30 YEARS, AND GESTATIONAL AGE < 39 WEEKS. CONCLUSIONS: THE RELATIONSHIP BETWEEN CESAREAN DELIVERY AND REDUCED INFECTIOUS RISKS MAY REFLECT STATISTICAL CONFOUNDING WITH RELATIVELY RAPID POSTNATAL GROWTH AND GREATER ADIPOSITY. POSTNATAL GROWTH TRAJECTORIES MAY BE IMPORTANT MEDIATORS OF LONG-TERM MORBIDITY RISKS ASSOCIATED WITH CESAREAN DELIVERY. THE FREQUENCY OF CESAREAN DELIVERIES AMONG THE QOM REMAINS CONCERNING GIVEN TRADITIONALLY HIGH RATES OF FERTILITY AND ADOLESCENT PREGNANCY. 2019 17 5962 57 TELOMERES, OXIDATIVE STRESS, AND TIMING FOR SPONTANEOUS TERM AND PRETERM LABOR. TELOMERES ARE NUCLEOPROTEIN COMPLEXES LOCATED AT THE DISTAL ENDS OF CHROMOSOMES. IN ADULTS, PROGRESSIVE TELOMERE SHORTENING OCCURS THROUGHOUT THE LIFETIME AND IS THOUGHT TO CONTRIBUTE TO PROGRESSIVE AGING, PHYSIOLOGICAL SENESCENCE, MULTIORGAN DYSFUNCTION, AND ULTIMATELY, DEATH. AS DISCUSSED IN THIS REVIEW, MULTIPLE LINES OF EVIDENCE PROVIDE SUPPORT FOR THE BIOLOGICAL PLAUSIBILITY THAT A TELOMERE-BASED CLOCK MECHANISM ALSO DETERMINES THE LENGTH OF GESTATION, LEADING TO THE ONSET OF LABOR (PARTURITION). AFTER TELOMERE EXPANSION AT THE BEGINNING OF PREGNANCY, THE TELOMERE LENGTHS IN THE GESTATIONAL TISSUES (IE, THE PLACENTA AND FETAL MEMBRANES) PROGRESSIVELY SHORTEN THROUGHOUT THE REMAINDER OF PREGNANCY. THE RATE OF TELOMERE SHORTENING CAN BE ACCELERATED BY CONDITIONS THAT AFFECT THE MOTHER AND RESULT IN OXIDATIVE STRESS. PRETERM BIRTHS IN THE UNITED STATES ARE ASSOCIATED WITH MULTIPLE RISK FACTORS THAT ARE LINKED WITH INCREASED OXIDATIVE STRESS. ANTIOXIDANT VITAMINS (IE, VITAMINS E AND C) MITIGATE THE EFFECTS OF OXIDATIVE STRESS AND DELAY OR PREVENT TELOMERE SHORTENING. CLINICAL TRIALS WITH VITAMINS E AND C AND WITH MULTIVITAMINS STARTED DURING THE PERICONCEPTION PERIOD HAVE BEEN ASSOCIATED WITH REDUCED RATES OF PRETERM BIRTHS. IN THE UNITED STATES, AFRICAN-AMERICAN WOMEN HAVE A 2-3-FOLD HIGHER RATE OF PRETERM BIRTH. AFRICAN-AMERICAN WOMEN HAVE MULTIPLE RISK FACTORS FOR PREMATURE BIRTH, ALL OF WHICH ARE DISTINCT AND POTENTIALLY ADDITIVE WITH REGARD TO EPIGENETIC TELOMERE SHORTENING. THE "WEATHERING EFFECT" IS THE HYPOTHESIS TO EXPLAIN THE INCREASED RATES OF CHRONIC ILLNESS, DISABILITIES, AND EARLY DEATH OBSERVED IN AFRICAN-AMERICANS. WITH REGARD TO PREGNANCY, ACCELERATED WEATHERING WITH THE ASSOCIATED TELOMERE SHORTENING IN THE GESTATIONAL TISSUES WOULD NOT ONLY EXPLAIN THE PRETERM BIRTH DISPARITY BUT COULD ALSO EXPLAIN WHY HIGHLY EDUCATED, AFFLUENT AFRICAN-AMERICAN WOMEN CONTINUE TO HAVE AN INCREASED RATE OF PRETERM BIRTH. THESE STUDIES SUGGEST THAT THE RACIAL DISPARITIES IN PRETERM BIRTH ARE POTENTIALLY MEDIATED BY TELOMERE SHORTENING PRODUCED BY LIFETIME OR EVEN GENERATIONAL EXPOSURE TO THE EFFECTS OF SYSTEMIC RACISM AND SOCIOECONOMIC MARGINALIZATION. IN CONCLUSION, THIS REVIEW PRESENTS MULTIPLE LINES OF EVIDENCE SUPPORTING A NOVEL HYPOTHESIS REGARDING THE BIOLOGICAL CLOCK MECHANISM THAT DETERMINES THE LENGTH OF PREGNANCY, AND IT OPENS THE POSSIBILITY OF NEW APPROACHES TO PREVENT OR REDUCE THE RATE OF SPONTANEOUS PRETERM BIRTH. 2022 18 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 19 6315 33 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 20 520 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