1 4504 112 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2  649  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3 4066  38 MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION AS AN INDICATOR OF OFFSPRING METABOLIC SYNDROME RISK IN LATER LIFE THROUGH EPIGENETIC IMPRINTING: A SYSTEMATIC REVIEW. AIMS: THIS REVIEW EXAMINED WHETHER MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION EFFECTS AN OFFSPRING'S LIKELIHOOD OF DEVELOPING CHRONIC METABOLIC RELATED CONDITIONS DUE TO EPIGENETIC IMPRINTING. METHODS: A LITERATURE SEARCH WAS CONDUCTED IN MULTIPLE SCIENCE DATABASES AND LIMITED TO STUDIES PUBLISHED AFTER 2012, IN ENGLISH LANGUAGE AND PEER REVIEWED. THE DATA FROM SELECTED ARTICLES WERE EXTRACTED AND A QUALITATIVE APPROACH WAS EMPLOYED DUE TO HETEROGENEITY OF RESULTS. RESULTS: NEWBORNS FROM OBESE FATHERS SHOWED ALTERED METHYLATION OVERALL AND SIGNIFICANT HYPOMETHYLATION AT THE INSULIN-LIKE GROWTH FACTOR 2 (IGF2) GENE. HIGH MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) WAS ASSOCIATED WITH ALTERED OFFSPRING DNA METHYLATION LEVELS AND GESTATIONAL DIABETES MELLITUS INDUCED SIGNIFICANTLY INCREASED METHYLATION LEVELS IN OFFSPRING. GESTATIONAL WEIGHT GAIN WAS NOT ASSOCIATED WITH DIFFERENTIALLY METHYLATED CORD BLOOD. BIRTH WEIGHT WAS HIGHER IN OFFSPRING EXPOSED TO FAMINE IN EARLY GESTATION. OFFSPRING BORN POST MATERNAL BARIATRIC SURGERY SHOWED A LOWER PERCENTAGE OF BODY FAT AND IMPROVED FASTING INSULIN LEVELS COMPARED TO SIBLINGS BORN PRE-MATERNAL BARIATRIC SURGERY. CONCLUSIONS: THE AVAILABLE EVIDENCE SUGGESTS THAT POOR MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION CAN INCREASE THE RISK OF METABOLIC SYNDROME IN OFFSPRING, THROUGH EPIGENETIC IMPRINTING. POTENTIAL PARENTS SHOULD BE ADVISED THAT MAINTAINING A HEALTHY DIET AND BMI IS LIKELY TO REDUCE THE RISK OF METABOLIC SYNDROME IN OFFSPRING.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  520  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5 5192  31 PRENATAL ENVIRONMENTAL STRESSORS AND DNA METHYLATION LEVELS IN PLACENTA AND PERIPHERAL TISSUES OF MOTHERS AND NEONATES EVALUATED BY APPLYING ARTIFICIAL NEURAL NETWORKS. EXPOSURE TO ENVIRONMENTAL STRESSORS DURING PREGNANCY PLAYS AN IMPORTANT ROLE IN INFLUENCING SUBSEQUENT SUSCEPTIBILITY TO CERTAIN CHRONIC DISEASES THROUGH THE MODULATION OF EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION. OUR AIM WAS TO EXPLORE THE CONNECTIONS BETWEEN ENVIRONMENTAL EXPOSURES DURING GESTATION WITH DNA METHYLATION OF PLACENTAL CELLS, MATERNAL AND NEONATAL BUCCAL CELLS BY APPLYING ARTIFICIAL NEURAL NETWORKS (ANNS). A TOTAL OF 28 MOTHER-INFANT PAIRS WERE ENROLLED. DATA ON GESTATIONAL EXPOSURE TO ADVERSE ENVIRONMENTAL FACTORS AND ON MOTHER HEALTH STATUS WERE COLLECTED THROUGH THE ADMINISTRATION OF A QUESTIONNAIRE. DNA METHYLATION ANALYSES AT BOTH GENE-SPECIFIC AND GLOBAL LEVEL WERE ANALYZED IN PLACENTAS, MATERNAL AND NEONATAL BUCCAL CELLS. IN THE PLACENTA, THE CONCENTRATIONS OF VARIOUS METALS AND DIOXINS WERE ALSO ANALYZED. ANALYSIS OF ANNS REVEALED THAT SUBOPTIMAL BIRTH WEIGHT IS ASSOCIATED WITH PLACENTAL H19 METHYLATION, MATERNAL STRESS DURING PREGNANCY WITH METHYLATION LEVELS OF NR3C1 AND BDNF IN PLACENTAS AND MOTHER'S BUCCAL DNA, RESPECTIVELY, AND EXPOSURE TO AIR POLLUTANTS WITH MATERNAL MGMT METHYLATION. ASSOCIATIONS WERE ALSO OBSERVED BETWEEN PLACENTAL CONCENTRATIONS OF LEAD, CHROMIUM, CADMIUM AND MERCURY WITH METHYLATION LEVELS OF OXTR IN PLACENTAS, HSD11B2 IN MATERNAL BUCCAL CELLS AND PLACENTAS, MECP2 IN NEONATAL BUCCAL CELLS, AND MTHFR IN MATERNAL BUCCAL CELLS. FURTHERMORE, DIOXIN CONCENTRATIONS WERE ASSOCIATED WITH PLACENTAL RELN, NEONATAL HSD11B2 AND MATERNAL H19 GENE METHYLATION LEVELS. CURRENT RESULTS SUGGEST THAT EXPOSURE OF PREGNANT WOMEN TO ENVIRONMENTAL STRESSORS DURING PREGNANCY COULD INDUCE ABERRANT METHYLATION LEVELS IN GENES LINKED TO SEVERAL PATHWAYS IMPORTANT FOR EMBRYOGENESIS IN BOTH THE PLACENTA, POTENTIALLY AFFECTING FOETAL DEVELOPMENT, AND IN THE PERIPHERAL TISSUES OF MOTHERS AND INFANTS, POTENTIALLY PROVIDING PERIPHERAL BIOMARKERS OF ENVIRONMENTAL EXPOSURE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6 4085  41 MATERNAL OBESITY AND GESTATIONAL DIABETES REPROGRAM THE METHYLOME OF OFFSPRING BEYOND BIRTH BY INDUCING EPIGENETIC SIGNATURES IN METABOLIC AND DEVELOPMENTAL PATHWAYS. BACKGROUND: OBESITY IS A NEGATIVE CHRONIC METABOLIC HEALTH CONDITION THAT REPRESENTS AN ADDITIONAL RISK FOR THE DEVELOPMENT OF MULTIPLE PATHOLOGIES. EPIDEMIOLOGICAL STUDIES HAVE SHOWN HOW MATERNAL OBESITY OR GESTATIONAL DIABETES MELLITUS DURING PREGNANCY CONSTITUTE SERIOUS RISK FACTORS IN RELATION TO THE APPEARANCE OF CARDIOMETABOLIC DISEASES IN THE OFFSPRING. FURTHERMORE, EPIGENETIC REMODELLING MAY HELP EXPLAIN THE MOLECULAR MECHANISMS THAT UNDERLIE THESE EPIDEMIOLOGICAL FINDINGS. THUS, IN THIS STUDY WE EXPLORED THE DNA METHYLATION LANDSCAPE OF CHILDREN BORN TO MOTHERS WITH OBESITY AND GESTATIONAL DIABETES DURING THEIR FIRST YEAR OF LIFE. METHODS: WE USED ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS TO PROFILE MORE THAN 770,000 GENOME-WIDE CPG SITES IN BLOOD SAMPLES FROM A PAEDIATRIC LONGITUDINAL COHORT CONSISTING OF 26 CHILDREN BORN TO MOTHERS WHO SUFFERED FROM OBESITY OR OBESITY WITH GESTATIONAL DIABETES MELLITUS DURING PREGNANCY AND 13 HEALTHY CONTROLS (MEASUREMENTS TAKEN AT 0, 6 AND 12 MONTH; TOTAL N = 90). WE CARRIED OUT CROSS-SECTIONAL AND LONGITUDINAL ANALYSES TO DERIVE DNA METHYLATION ALTERATIONS ASSOCIATED WITH DEVELOPMENTAL AND PATHOLOGY-RELATED EPIGENOMICS. RESULTS: WE IDENTIFIED ABUNDANT DNA METHYLATION CHANGES DURING CHILD DEVELOPMENT FROM BIRTH TO 6 MONTHS AND, TO A LESSER EXTENT, UP TO 12 MONTHS OF AGE. USING CROSS-SECTIONAL ANALYSES, WE DISCOVERED DNA METHYLATION BIOMARKERS MAINTAINED ACROSS THE FIRST YEAR OF LIFE THAT COULD DISCRIMINATE CHILDREN BORN TO MOTHERS WHO SUFFERED FROM OBESITY OR OBESITY WITH GESTATIONAL DIABETES. IMPORTANTLY, ENRICHMENT ANALYSES SUGGESTED THAT THESE ALTERATIONS CONSTITUTE EPIGENETIC SIGNATURES THAT AFFECT GENES AND PATHWAYS INVOLVED IN THE METABOLISM OF FATTY ACIDS, POSTNATAL DEVELOPMENTAL PROCESSES AND MITOCHONDRIAL BIOENERGETICS, SUCH AS CPT1B, SLC38A4, SLC35F3 AND FN3K. FINALLY, WE OBSERVED EVIDENCE OF AN INTERACTION BETWEEN DEVELOPMENTAL DNA METHYLATION CHANGES AND MATERNAL METABOLIC CONDITION ALTERATIONS. CONCLUSIONS: OUR OBSERVATIONS HIGHLIGHT THE FIRST SIX MONTHS OF DEVELOPMENT AS BEING THE MOST CRUCIAL FOR EPIGENETIC REMODELLING. FURTHERMORE, OUR RESULTS SUPPORT THE EXISTENCE OF SYSTEMIC INTRAUTERINE FOETAL PROGRAMMING LINKED TO OBESITY AND GESTATIONAL DIABETES THAT AFFECTS THE CHILDHOOD METHYLOME BEYOND BIRTH, WHICH INVOLVES ALTERATIONS RELATED TO METABOLIC PATHWAYS, AND WHICH MAY INTERACT WITH ORDINARY POSTNATAL DEVELOPMENT PROGRAMMES.	2023	
             
7 5294  29 PROTECTIVE EFFECTS OF MATERNAL METHYL DONOR SUPPLEMENTATION ON ADULT OFFSPRING OF HIGH FAT DIET-FED DAMS. OBESITY HAS BECOME A GLOBAL PUBLIC HEALTH PROBLEM ASSOCIATED WITH METABOLIC DYSFUNCTION AND CHRONIC DISORDERS. IT HAS BEEN SHOWN THAT THE RISK OF OBESITY AND THE DNA METHYLATION PROFILES OF THE OFFSPRING CAN BE AFFECTED BY MATERNAL NUTRITION, SUCH AS HIGH-FAT DIET (HFD) CONSUMPTION. THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER METABOLIC DYSREGULATION AND PHYSIOLOGICAL ABNORMALITIES IN OFFSPRING CAUSED BY MATERNAL HFD CAN BE ALLEVIATED BY THE TREATMENT OF METHYL DONORS DURING PREGNANCY AND LACTATION OF DAMS. FEMALE C57BL/6 MICE WERE ASSIGNED TO SPECIFIC GROUPS AND GIVEN DIFFERENT NUTRIENTS (CONTROL DIET, CONTROL+MET, HFD AND HFD+MET) THROUGHOUT GESTATION AND LACTATION. OFFSPRING OF EACH GROUP WERE WEANED ONTO A CONTROL DIET AT 3 WEEKS OF AGE. PHYSIOLOGICAL (WEIGHT GAIN AND ADIPOSE COMPOSITION) AND METABOLIC (PLASMA BIOCHEMICAL ANALYSES) OUTCOMES WERE ASSESSED IN MALE AND FEMALE ADULT OFFSPRING. EXPRESSION AND DNA METHYLATION PROFILES OF OBESOGENIC-RELATED GENES INCLUDING PPAR GAMMA, FATTY ACID SYNTHASE, LEPTIN AND ADIPONECTIN WERE ALSO DETECTED IN VISCERAL FAT OF OFFSPRING. THE RESULTS SHOWED THAT DIETARY SUPPLEMENTATION WITH METHYL DONORS CAN PREVENT THE ADVERSE EFFECTS OF MATERNAL HFD ON OFFSPRING. CHANGES IN THE EXPRESSION AND DNA METHYLATION OF OBESOGENIC-RELATED GENES INDICATED THAT EPIGENETIC REGULATION MAY CONTRIBUTE TO THE EFFECTS OF MATERNAL DIETARY FACTORS ON OFFSPRING OUTCOMES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8 3208  36 HEAD CIRCUMFERENCE AS AN EPIGENETIC RISK FACTOR FOR MATERNAL NUTRITION. NUTRITION INDICATORS FOR MALNUTRITION CAN BE SCREENED BY MANY SIGNS SUCH AS STUNTING, UNDERWEIGHT OR OBESITY, MUSCLE WASTING, AND LOW CALORIC AND NUTRIENTS INTAKE. THOSE DEFICIENCIES ARE ALSO ASSOCIATED WITH LOW SOCIOECONOMIC STATUS. ANTHROPOMETRY CAN ASSESS NUTRITIONAL STATUS BY MATERNAL WEIGHT MEASUREMENTS DURING PREGNANCY. HOWEVER, MOST STUDIES HAVE FOCUSED PRIMARILY ON IDENTIFYING CHANGES IN WEIGHT OR BODY MASS INDEX (BMI), AND THEIR EFFECTS ON NEONATAL MEASURES AT PRESENT TIME. WHEREAS HEAD CIRCUMFERENCE (HC) HAS BEEN ASSOCIATED WITH NUTRITION IN THE PAST. WHEN THE MOTHER WAS EXPOSED TO POOR NUTRITION AND UNFAVORABLE SOCIAL CONDITIONS DURING FETAL LIFE, IT WAS HYPOTHESIZED THAT THE INTERGENERATIONAL CYCLE WAS POTENTIALLY MEDIATED BY EPIGENETIC MECHANISMS. TO INVESTIGATE THIS THEORY, MATERNAL HEAD CIRCUMFERENCE (MHC) WAS ASSOCIATED WITH NEONATAL HEAD CIRCUMFERENCE (NHC) IN PREGNANT WOMEN WITHOUT PREEXISTING CHRONIC CONDITIONS, DIFFERENTIATED BY SOCIODEMOGRAPHIC CHARACTERISTICS. A MULTIPLE LINEAR REGRESSION MODEL SHOWED THAT EACH 1 CM-INCREASE IN MHC CORRELATED WITH A 0.11 CM INCREASE IN NHC (BETA95% CI 0.07 TO 0.15). NOTWITHSTANDING, ASSOCIATIONS BETWEEN MATERNAL AND NEONATAL ANTHROPOMETRICS ACCORDING TO GESTATIONAL AGE AT BIRTH HAVE BEEN EXTENSIVELY EXPLAINED. PATH ANALYSIS SHOWED THE INFLUENCE OF SOCIAL STATUS AND THE LATENT VARIABLE WAS SOCIOECONOMIC STATUS. A MODEL OF MATERNAL HEIGHT AND HEAD CIRCUMFERENCE WAS TESTED WITH EFFECTS ON NEONATAL HC. THE SOCIAL VARIABLE LACKED SIGNIFICANCE TO PREDICT NEONATAL HC IN THE TOTAL SAMPLE (P = 0.212) AND IN THE SOUTH/SOUTHEAST (P = 0.095), IN CONTRAST TO THE NORTHEAST (P = 0.047). THIS STUDY HIGHLIGHTS THE POTENTIAL INTERGENERATIONAL INFLUENCE OF MATERNAL NUTRITION ON HC, SUGGESTING THAT MATERNAL NUTRITION MAY BE MORE RELEVANT IN FAMILIES WITH MAJOR SOCIAL VULNERABILITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 4065  31 MATERNAL AND GESTATIONAL INFLUENCES ON CHILDHOOD BLOOD PRESSURE. EXPOSURES THAT CONTRIBUTE TO A SUB-OPTIMAL INTRAUTERINE ENVIRONMENT CAN HAVE AN EFFECT ON THE DEVELOPING FETUS. IMPAIRED FETAL GROWTH THAT RESULTS IN LOW BIRTH WEIGHT IS AN ESTABLISHED RISK FACTOR FOR CARDIO-METABOLIC DISORDERS LATER IN LIFE. RECENT EPIDEMIOLOGIC AND PROSPECTIVE COHORT STUDIES THAT INCLUDE THE MATERNAL AND GESTATIONAL PERIOD HAVE IDENTIFIED MATERNAL AND GESTATIONAL CONDITIONS THAT CONFER INCREASED RISK FOR SUBSEQUENT CARDIO-METABOLIC DISORDERS IN THE ABSENCE OF LOW BIRTH WEIGHT. MATERNAL PRE-CONCEPTION HEALTH STATUS, INCLUDING CHRONIC OBESITY AND TYPE 2 DIABETES, INCREASE RISK FOR CHILDHOOD OBESITY AND OBESITY-RELATED HIGHER BLOOD PRESSURE (BP) IN CHILD OFFSPRING. MATERNAL GESTATIONAL EXPOSURES, INCLUDING GESTATIONAL DIABETES, GESTATIONAL HYPERTENSION, AND PREECLAMPSIA, ARE ASSOCIATED WITH HIGHER BP IN OFFSPRING. OTHER MATERNAL EXPOSURES SUCH AS CIGARETTE SMOKE AND AIR POLLUTION ALSO INCREASE RISK FOR HIGHER BP IN CHILD OFFSPRING. RECENT, BUT LIMITED, DATA INDICATE THAT ASSISTED REPRODUCTIVE TECHNOLOGIES CAN BE ASSOCIATED WITH HYPERTENSION IN CHILDHOOD, DESPITE OTHERWISE NORMAL GESTATION AND HEALTHY NEWBORN. GESTATIONAL EXPOSURES ASSOCIATED WITH HIGHER BP IN CHILDHOOD CAN BE RELATED TO FAMILIAL LIFESTYLE FACTORS, GENETICS, OR EPIGENETIC MODIFICATION OF FETAL DEOXYRIBONUCLEIC ACID (DNA). THESE FACTORS, OR COMBINATION OF FACTORS, AS WELL AS OTHER ADVERSE INTRAUTERINE CONDITIONS, COULD INDUCE FETAL PROGRAMING LEADING TO HEALTH CONSEQUENCES IN LATER LIFE. CURRENT AND DEVELOPING RESEARCH WILL PROVIDE ADDITIONAL INSIGHTS ON GESTATIONAL EXPOSURES AND FETAL ADJUSTMENTS THAT INCREASE RISK FOR HIGHER BP LEVELS IN CHILDHOOD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10 5090  33 PLACENTAL ADIPONECTIN GENE DNA METHYLATION LEVELS ARE ASSOCIATED WITH MOTHERS' BLOOD GLUCOSE CONCENTRATION. GROWING EVIDENCE SUGGESTS THAT EPIGENETIC PROFILE CHANGES OCCURRING DURING FETAL DEVELOPMENT IN RESPONSE TO IN UTERO ENVIRONMENT VARIATIONS COULD BE ONE OF THE MECHANISMS INVOLVED IN THE EARLY DETERMINANTS OF ADULT CHRONIC DISEASES. IN THIS STUDY, WE TESTED WHETHER MATERNAL GLYCEMIC STATUS IS ASSOCIATED WITH THE ADIPONECTIN GENE (ADIPOQ) DNA METHYLATION PROFILE IN PLACENTA TISSUE, IN MATERNAL CIRCULATING BLOOD CELLS, AND IN CORD BLOOD CELLS. WE FOUND THAT LOWER DNA METHYLATION LEVELS IN THE PROMOTER OF ADIPOQ ON THE FETAL SIDE OF THE PLACENTA WERE CORRELATED WITH HIGHER MATERNAL GLUCOSE LEVELS DURING THE SECOND TRIMESTER OF PREGNANCY (2-H GLUCOSE AFTER THE ORAL GLUCOSE TOLERANCE TEST; R(S) </= -0.21, P < 0.05). LOWER DNA METHYLATION LEVELS ON THE MATERNAL SIDE OF THE PLACENTA WERE ASSOCIATED WITH HIGHER INSULIN RESISTANCE INDEX (HOMEOSTASIS MODEL ASSESSMENT OF INSULIN RESISTANCE) DURING THE SECOND AND THIRD TRIMESTERS OF PREGNANCY (R(S) </= -0.27, P < 0.05). FINALLY, LOWER DNA METHYLATION LEVELS WERE ASSOCIATED WITH HIGHER MATERNAL CIRCULATING ADIPONECTIN LEVELS THROUGHOUT PREGNANCY (R(S) </= -0.26, P < 0.05). IN CONCLUSION, THE ADIPOQ DNA METHYLATION PROFILE WAS ASSOCIATED WITH MATERNAL GLUCOSE STATUS AND WITH MATERNAL CIRCULATING ADIPONECTIN CONCENTRATION. BECAUSE ADIPONECTIN IS SUSPECTED TO HAVE INSULIN-SENSITIZING PROPRIETIES, THESE EPIGENETIC ADAPTATIONS HAVE THE POTENTIAL TO INDUCE SUSTAINED GLUCOSE METABOLISM CHANGES IN THE MOTHER AND OFFSPRING LATER IN LIFE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11 4010  38 LOW MATERNAL ADHERENCE TO A MEDITERRANEAN DIET IS ASSOCIATED WITH INCREASE IN METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION IN FEMALE INFANTS. DIET IS DICTATED BY THE SURROUNDING ENVIRONMENT, AS FOOD ACCESS AND AVAILABILITY MAY CHANGE DEPENDING ON WHERE ONE LIVES. MATERNAL DIET DURING PREGNANCY IS AN IMPORTANT PART OF THE IN UTERO ENVIRONMENT, AND MAY AFFECT THE EPIGENOME. STUDIES LOOKING AT OVERALL DIET PATTERN IN RELATION TO DNA METHYLATION HAVE BEEN LACKING. THE MEDITERRANEAN DIET IS KNOWN FOR ITS HEALTH BENEFITS, INCLUDING DECREASED INFLAMMATION, WEIGHT LOSS, AND MANAGEMENT OF CHRONIC DISEASES. THIS STUDY ASSESSES THE ASSOCIATION BETWEEN MATERNAL ADHERENCE TO A MEDITERRANEAN DIET PATTERN DURING PREGNANCY AND INFANT DNA METHYLATION AT BIRTH. MEDITERRANEAN DIET ADHERENCE IN EARLY PREGNANCY WAS MEASURED IN 390 WOMEN ENROLLED IN THE NEWBORN EPIGENETIC STUDY, AND DNA METHYLATION WAS ASSESSED IN THEIR INFANTS AT BIRTH. MULTINOMIAL LOGISTIC REGRESSION WAS USED TO ASSESS THE ASSOCIATION BETWEEN ADHERENCE TO A MEDITERRANEAN DIET AND INFANT METHYLATION AT THE MEG3, MEG3-IG, PLEIOMORPHIC ADENOMA GENE-LIKE 1, INSULIN-LIKE GROWTH FACTOR 2 GENE, H19, MESODERM-SPECIFIC TRANSCRIPT, NEURONATIN, PATERNALLY EXPRESSED GENE 3, SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 REGIONS, MEASURED BY PYROSEQUENCING. INFANTS OF MOTHERS WITH A LOW ADHERENCE TO A MEDITERRANEAN DIET HAD A GREATER ODDS OF HYPO-METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION (DMR). SEX-STRATIFIED MODELS SHOWED THAT THIS ASSOCIATION WAS PRESENT IN GIRLS ONLY. THIS STUDY PROVIDES EARLY EVIDENCE ON THE ASSOCIATION BETWEEN OVERALL DIET PATTERN AND METHYLATION AT THE 9 DMRS INCLUDED IN THIS STUDY, AND SUGGESTS THAT MATERNAL DIET CAN HAVE A SEX-SPECIFIC IMPACT ON INFANT DNA METHYLATION AT SPECIFIC IMPRINTED DMRS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12 1439  31 DIFFERENTIAL PLACENTAL CPG METHYLATION IS ASSOCIATED WITH CHRONIC LUNG DISEASE OF PREMATURITY. BACKGROUND: CHRONIC LUNG DISEASE (CLD) IS THE MOST COMMON PULMONARY MORBIDITY IN EXTREMELY PRETERM INFANTS. IT IS UNCLEAR TO WHAT EXTENT PRENATAL EXPOSURES INFLUENCE THE RISK OF CLD. EPIGENETIC VARIATION IN PLACENTA DNA METHYLATION MAY BE ASSOCIATED WITH DIFFERENTIAL RISK OF CLD, AND THESE ASSOCIATIONS MAY BE DEPENDENT UPON SEX. METHODS: DATA WERE OBTAINED FROM A MULTI-CENTER COHORT OF INFANTS BORN EXTREMELY PRETERM (<28 WEEKS' GESTATION) AND AN EPIGENOME-WIDE APPROACH WAS USED TO IDENTIFY ASSOCIATIONS BETWEEN PLACENTAL DNA METHYLATION AND CLD (N = 423). ASSOCIATIONS WERE EVALUATED USING ROBUST LINEAR REGRESSION ADJUSTING FOR COVARIATES, WITH A FALSE DISCOVERY RATE OF 0.05. ANALYSES STRATIFIED BY SEX WERE USED TO ASSESS DIFFERENCES IN METHYLATION-CLD ASSOCIATIONS. RESULTS: CLD WAS ASSOCIATED WITH DIFFERENTIAL METHYLATION AT 49 CPG SITES REPRESENTING 46 GENES IN THE PLACENTA. CLD WAS ASSOCIATED WITH DIFFERENTIAL METHYLATION OF PROBES WITHIN GENES RELATED TO PATHWAYS INVOLVED IN FETAL LUNG DEVELOPMENT, SUCH AS P53 SIGNALING AND MYO-INOSITOL BIOSYNTHESIS. ASSOCIATIONS BETWEEN CPG METHYLATION AND CLD DIFFERED BY SEX. CONCLUSIONS: DIFFERENTIAL PLACENTAL METHYLATION WITHIN GENES WITH KEY ROLES IN FETAL LUNG DEVELOPMENT MAY REFLECT COMPLEX CELL SIGNALING BETWEEN THE PLACENTA AND FETUS WHICH MEDIATE CLD RISK. THESE PATHWAYS APPEAR TO BE DISTINCT BASED ON FETAL SEX. IMPACT: IN EXTREMELY PRETERM INFANTS, DIFFERENTIAL METHYLATION OF CPG SITES WITHIN PLACENTAL GENES INVOLVED IN PATHWAYS RELATED TO CELL SIGNALING, OXIDATIVE STRESS, AND TROPHOBLAST INVASION IS ASSOCIATED WITH CHRONIC LUNG DISEASE OF PREMATURITY. DNA METHYLATION PATTERNS ASSOCIATED WITH CHRONIC LUNG DISEASE WERE DISTINCTLY BASED ON FETAL SEX, SUGGESTING A POTENTIAL MECHANISM UNDERLYING DIMORPHIC PHENOTYPES. MECHANISMS RELATED TO FETAL HYPOXIA AND PLACENTAL MYO-INOSITOL SIGNALING MAY PLAY A ROLE IN FETAL LUNG PROGRAMMING AND THE DEVELOPMENTAL ORIGINS OF CHRONIC LUNG DISEASE. CONTINUED RESEARCH OF THE RELATIONSHIP BETWEEN THE PLACENTAL EPIGENOME AND CHRONIC LUNG DISEASE COULD INFORM EFFORTS TO AMELIORATE OR PREVENT THIS CONDITION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                     
13 5875  27 SYMPTOMS OF ALLERGIC RHINITIS IN WOMEN DURING EARLY PREGNANCY ARE ASSOCIATED WITH HIGHER PREVALENCE OF ALLERGIC RHINITIS IN THEIR OFFSPRING. BACKGROUND: EPIGENETIC CONTROL OF GENE EXPRESSION PROFILES IS A UBIQUITOUS MECHANISM DURING CELL DIFFERENTIATION, ORGANOGENESIS AND CHRONIC INFLAMMATORY REACTIONS. RECENT STUDIES HAVE SHOWN THAT ALLERGEN EXPOSURE DURING VERY EARLY PREGNANCY INCREASES BRONCHIAL HYPERSENSITIVITY IN OFFSPRING IN A MURINE MODEL OF BRONCHIAL ASTHMA. HOWEVER, NO SUCH PHENOMENA WERE REPORTED IN HUMANS. IN THE PRESENT STUDY, THE ROLE OF EPIGENETIC CONTROL IN THE ONSET OF ALLERGIC DISEASES WAS INVESTIGATED. METHODS: A TOTAL OF 400 PAIRS OF MOTHERS WITH PHYSICIAN-DIAGNOSED ALLERGIC RHINITIS (AR) AND THEIR OFFSPRING (AGE 7-18 MONTHS) WHO PARTICIPATED IN A LARGE-SCALE MEDICAL CHECK-UP WERE ENROLLED IN THIS RETROSPECTIVE COHORT STUDY. FAMILY HISTORY OF ALLERGIC DISEASES AND THE PRESENCE OR ABSENCE OF AR SYMPTOMS DURING PREGNANCY WERE INQUIRED ABOUT USING A SELF-ANSWERED QUESTIONNAIRE. A LOGISTIC REGRESSION MODEL ADJUSTED FOR AGE, GENDER, BIRTH MONTH AND FATHER'S HISTORY OF ALLERGIC DISEASES WAS STATISTICALLY ANALYZED. RESULTS: OFFSPRING WHOSE MOTHERS HAD ANY AR SYMPTOMS DURING EARLY PREGNANCY SHOWED A SIGNIFICANTLY HIGHER ADJUSTED ODDS RATIO FOR THE ONSET OF AR IN OFFSPRING THAN THOSE WHOSE MOTHERS HAD NO SYMPTOMS DURING PREGNANCY (ADJUSTED ODDS RATIO: 6.26, P = 0.036). HOWEVER, THE SYMPTOMS OF AR DURING LATE PREGNANCY SHOWED NO EFFECTS ON THE ODDS RATIO. IN CONTRAST, THE PRESENCE OR ABSENCE OF AR SYMPTOMS DURING EARLY OR LATE PREGNANCY SHOWED NO ASSOCIATION WITH THE PREVALENCE OF FOOD ALLERGY, ATOPIC DERMATITIS OR ASTHMA IN OFFSPRING. CONCLUSIONS: OUR RESULTS SUGGEST THE PRESENCE OF POSSIBLE EPIGENETIC MECHANISMS REGULATING THE ONSET OF AR IN HUMANS PRESUMABLY THROUGH INCREASED ORGAN-SPECIFIC HYPERSENSITIVITY.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14 6270  38 THE OBESOGENIC ENVIRONMENT: EPIGENETIC MODIFICATIONS IN PLACENTAL MELANOCORTIN 4 RECEPTOR GENE CONNECTED TO GESTATIONAL DIABETES AND SMOKING. BACKGROUND: MATERNAL METABOLIC INSULTS AS WELL AS GESTATIONAL DIABETES MELLITUS (GDM) INFLUENCE THE FETAL HEALTH AND MAY AFFECT 'OFFSPRING'S SUSCEPTIBILITY TO CHRONIC DISEASES VIA EPIGENETIC MODIFICATIONS. GDM, THE MOST COMMON METABOLIC DISORDER IN PREGNANCY, CAN BE CONSIDERED THE RESULT OF COMPLEX INTERACTIONS BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. A CRITICAL POINT IN THIS VIEW IS THE IDENTIFICATION OF GENES WHICH ARE EPIGENETICALLY MODIFIED UNDER THE INFLUENCE OF GDM. THE MELANOCORTIN 4 RECEPTOR (MC4R) GENE PLAYS A CRUCIAL ROLE IN NUTRITIONAL HEALTH BY SUPPRESSING APPETITE AND PARTICIPATING IN ENERGY CONTROL REGULATION. THE CORRELATIONS BETWEEN PREGNANT 'WOMEN'S METABOLIC PROFILES AND PLACENTAL EPIGENETIC MODIFICATIONS OF THIS GENE HAVE BEEN POORLY INVESTIGATED. OBJECTIVE: THE AIM OF THIS STUDY WAS TO EVALUATE THE EFFECT OF GDM AND MATERNAL CLINICAL PARAMETERS AT THE THIRD TRIMESTER OF PREGNANCY TO DNA METHYLATION LEVELS IN THE PLACENTA AT CPG SITES OF MC4R GENE. DESIGN AND METHODS: SOCIO-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS, MEDITERRANEAN DIET ADHERENCE, SMOKING HABITS, AND PHYSICAL ACTIVITY WERE ASSESSED AT THE THIRD TRIMESTER OF PREGNANCY OF 60 CAUCASIAN PREGNANT WOMEN, OF WHICH 33 WITH GDM. CLINICAL PARAMETERS OF THE NEWBORNS WERE RECORDED AT BIRTH. MC4R DNA METHYLATION ON MATERNAL AND FETAL SIDES OF THE PLACENTA WAS ANALYZED USING BISULFITE PYROSEQUENCING. RESULTS: MC4R DNA METHYLATION LEVELS AT CPG1 AND CPG2 WERE LOWER ON THE FETAL SIDE OF THE PLACENTA IN GDM-AFFECTED WOMEN THAN IN NON-GDM-AFFECTED RECRUITS (P = 0.033). MOREOVER, DNA METHYLATION LEVELS ON THE MATERNAL SIDE AT CPG1 WERE POSITIVELY RELATED TO GLUCOSE CONCENTRATION AT 2-H ORAL GLUCOSE TOLERANCE TEST (OGTT). ON THE OTHER HAND, CPG2 DNA METHYLATION WAS POSITIVELY RELATED TO BOTH 1-H AND 2-H DURING OGTT. MATERNAL DNA METHYLATION LEVEL AT CPG2 WAS ALSO ASSOCIATED WITH LOW DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C) AT THE THIRD TRIMESTER OF PREGNANCY (RHO = 0.340, P < 0.05), WHILE CPG1 METHYLATION WAS NEGATIVELY RELATED TO MATERNAL WEIGHT VARIATIONS AT DELIVERY (RHO = -0.316, P < 0.05). SIGNIFICANT ASSOCIATIONS BETWEEN MC4R DNA METHYLATION ON THE MATERNAL SIDE AND LIPID PROFILE AT THIRD TRIMESTER OF PREGNANCY IN WOMEN SMOKERS WERE FOUND. CONCLUSION: OUR RESULTS SUGGEST THAT MC4R METHYLATION PROFILE IN THE PLACENTA IS RELATED TO MATERNAL METABOLIC AND NUTRITIONAL CONDITIONS, POTENTIALLY AFFECTING FETAL PROGRAMMING AND THE FUTURE METABOLIC HEALTH OF THE NEWBORN.	2022	

15 2077  32 EPIGENETIC DISRUPTION OF PLACENTAL GENES BY CHRONIC MATERNAL CAFETERIA DIET IN RATS. MATERNAL DIET HAS IMPACT ON REPRODUCTION, FETAL DEVELOPMENT AND OFFSPRING BEHAVIOR, ALTHOUGH MOLECULAR MECHANISMS REMAINED UNKNOWN. OUR AIMS WERE TO ASSESS (1) THE EFFECTS OF A CAFETERIA (CAF) DIET (WESTERN DIET HABITS) ON FEMALE REPRODUCTIVE PERFORMANCE, FETAL AND PLACENTAL PARAMETERS ON GESTATIONAL DAY 21 AND LITTER SIZE AND PUP WEIGHT AT BIRTH; AND (2) PLACENTAL MESSENGER RNA (MRNA) EXPRESSION AND EPIGENETIC REGULATION OF INSULIN-LIKE GROWTH FACTOR (IGF) AND VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND THEIR RECEPTORS. FEMALE WISTAR RATS WERE FED WITH CONTROL OR CAF DIET FROM WEANING UNTIL PARTURITION. AT WEEK 14 AFTER DIETS STARTED, FEMALES WERE MATED AND HALF OF THE ANIMALS WERE EUTHANIZED ON GESTATIONAL DAY 21 TO EVALUATE REPRODUCTIVE PARAMETERS INCLUDING THE PREGNANCY RATE, NUMBER OF CORPORA LUTEA, IMPLANTATION SITES AND RESORPTION SITES. MOREOVER, FETAL WEIGHT AND LENGTH, PLACENTAL WEIGHT, AND PLACENTAL INDEX WERE RECORDED. PLACENTAS WERE COLLECTED FOR MRNA QUANTIFICATION AND DNA METHYLATION ANALYSIS. THE REMAINING ANIMALS WERE ALLOWED TO GIVE BIRTH AND THE NUMBER AND WEIGHT OF THE PUPS WERE EVALUATED. CAF DIET DID NOT AFFECT REPRODUCTIVE PERFORMANCE OR FETAL WEIGHT AND LENGTH. HOWEVER, CAF-FED ANIMALS SHOWED A DECREASE IN PLACENTAL WEIGHT AND INDEX AND THE PUPS EXHIBITED A LOW BIRTH WEIGHT. ADDITIONALLY, WE FOUND AN UPREGULATION OF IGF2 AND A DOWN REGULATION OF VEGF PLACENTAL MRNA EXPRESSION IN CAF DAMS, ASSOCIATED WITH METHYLATION STATUS CHANGES OF THEIR PROMOTERS. WE CONCLUDE THAT FEMALE CHRONIC CAF DIET CONSUMPTION IMPAIRS FETO-PLACENTAL DEVELOPMENT AND COULD BE EXPLAINED BY AN EPIGENETIC DISRUPTION OF IGF AND VEGF SYSTEMS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  418  40 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	
                                                                                                                                                                                      
17  496  35 ASSESSMENT OF THE IMPACT OF HIV INFECTION AND ANTI-RETROVIRAL TREATMENT ON THE CARDIOMETABOLIC HEALTH OF PREGNANT MOTHERS AND THEIR OFFSPRING (ARTMOMSBABES). BACKGROUND: THE RISK OF CARDIOVASCULAR DISEASES (CVDS) IS BECOMING MORE PREVALENT IN PREGNANT WOMEN THOUGH NOT MUCH DATA IS AVAILABLE FOR PREGNANT WOMEN WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV). FOETOPLACENTAL VASCULAR ENDOTHELIAL DYSFUNCTION IS THOUGHT TO BE AT THE ORIGIN OF CHRONIC DISEASES SUCH AS DIABETES AND OBESITY LATER ON IN LIFE. BECAUSE HIV AND ANTI-RETROVIRAL TREATMENT (ARTS) ARE ASSOCIATED WITH ENDOTHELIAL DYSFUNCTION, CHILDREN EXPOSED IN UTERO TO THESE CONDITIONS MAY BE AT GREATER RISK OF DEVELOPING CVDS. DESPITE THE HIGH PREVALENCE OF HIV IN PREGNANT SOUTH AFRICAN WOMEN, LITTLE IS KNOWN ABOUT THE EFFECTS OF ART ON THE CARDIOVASCULAR HEALTH OF THE MOTHER AND OFFSPRING. HENCE, THE PROPOSED STUDY INTENDS TO INVESTIGATE HOW HIV/ARTS MAY AFFECT THE CARDIOVASCULAR HEALTH OF THE MOTHER AND OFFSPRING AT DIFFERENT TIME POINTS DURING THE PREGNANCY AND UP TO 2 YEARS AFTER BIRTH. METHODS: A LONGITUDINAL CASE-CONTROL STUDY IN HIV POSITIVE PREGNANT WOMEN ON ART AND HIV NEGATIVE PREGNANT WOMEN WILL BE CONDUCTED. ALL PREGNANT WOMEN WILL BE ASSESSED FOR CARDIO-METABOLIC RISK FACTORS AND MARKERS (LIPIDS, ANTHROPOMETRIC AND GLYCAEMIC INDIES, OXIDATIVE STRESS), HEMODYNAMIC STATUS (BLOOD PRESSURE PARAMETERS) AND VASCULAR FUNCTION (ARTERIAL COMPLIANCE, RETINAL MICROVASCULATURE, UTERINE ARTERY MEAN PULSATILITY INDEX). CHILD HEALTH WILL BE MONITORED IN UTERO AND POSTNATALLY VIA ROUTINE FOETAL HEALTH SCREENING, PLACENTAL INTEGRITY, ANTHROPOMETRY, BLOOD PRESSURE PARAMETERS, MARKERS OF OXIDATIVE STRESS AND ENDOTHELIAL FUNCTION IN CORD BLOOD AND CARDIOVASCULAR EPIGENETIC MARKERS IN URINE. DISCUSSION: THERE IS A PAUCITY OF STUDIES IN SOUTH AFRICA AND SUB-SAHARA AFRICA AS A WHOLE THAT UTILISED A LONGITUDINAL STUDY MODEL TO ASSESS THE EFFECTS OF ARTS ON VASCULAR ENDOTHELIAL CHANGES IN PREGNANT WOMEN LIVING WITH HIV AND THE CARDIOMETABOLIC HEALTH OF THEIR OFFSPRING. THIS STUDY WILL THEREFORE HELP TO MONITOR CHANGES IN CARDIOMETABOLIC RISK DURING PREGNANCY AND IN CHILDREN EXPOSED IN UTERO TO HIV-INFECTION AND ART USE. FINDINGS FROM THIS STUDY WILL PROVIDE USEFUL INFORMATION FOR DEVELOPING GUIDELINES ON THE USE OF ARTS IN PREGNANCY AND MANAGEMENT OF CARDIOMETABOLIC HEALTH OF THE OFFSPRING OF HIV POSITIVE MOTHERS.	2021	
                                                                                                                                                                                                                                    
18 2419  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19 5166  38 PRECONCEPTION PATERNAL ALCOHOL EXPOSURE EXERTS SEX-SPECIFIC EFFECTS ON OFFSPRING GROWTH AND LONG-TERM METABOLIC PROGRAMMING. BACKGROUND: ALTHOUGH CLINICAL DATA SUPPORT AN ASSOCIATION BETWEEN PATERNAL ALCOHOL USE AND DEFICITS IN CHILD NEUROCOGNITIVE DEVELOPMENT, THE RELATIONSHIP BETWEEN PATERNAL DRINKING AND ALCOHOL-INDUCED GROWTH PHENOTYPES REMAINS CHALLENGING TO DEFINE. USING AN ESTABLISHED MOUSE MODEL OF CHRONIC EXPOSURE, PREVIOUS WORK BY OUR GROUP HAS LINKED PRECONCEPTION PATERNAL ALCOHOL USE TO SEX-SPECIFIC PATTERNS OF FETAL GROWTH RESTRICTION AND PLACENTAL DYSFUNCTION. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE THE LONG-TERM IMPACT OF CHRONIC PRECONCEPTION PATERNAL ALCOHOL USE ON OFFSPRING GROWTH AND METABOLIC PROGRAMMING. RESULTS: PRECONCEPTION PATERNAL ALCOHOL EXPOSURE INDUCED A PROLONGED PERIOD OF FETAL GESTATION AND AN INCREASED INCIDENCE OF INTRAUTERINE GROWTH RESTRICTION, WHICH AFFECTED THE MALE OFFSPRING TO A GREATER EXTENT THAN THE FEMALES. WHILE THE FEMALE OFFSPRING OF ETHANOL-EXPOSED MALES WERE ABLE TO MATCH THE BODY WEIGHTS OF THE CONTROLS WITHIN THE FIRST 2 WEEKS OF POSTNATAL LIFE, MALE OFFSPRING CONTINUED TO DISPLAY AN 11% REDUCTION IN WEIGHT AT 5 WEEKS OF AGE AND A 6% REDUCTION AT 8 WEEKS OF AGE. THE OBSERVED GROWTH DEFICITS ASSOCIATED WITH INSULIN HYPERSENSITIVITY IN THE MALE OFFSPRING, WHILE IN CONTRAST, FEMALES DISPLAYED A MODEST LAG IN THEIR GLUCOSE TOLERANCE TEST. THESE METABOLIC DEFECTS WERE ASSOCIATED WITH AN UP-REGULATION OF GENES WITHIN THE PRO-FIBROTIC TGF-BETA SIGNALING PATHWAY AND INCREASED LEVELS OF CELLULAR HYDROXYPROLINE WITHIN THE LIVERS OF THE MALE OFFSPRING. WE OBSERVED SUPPRESSED CYTOKINE PROFILES WITHIN THE LIVER AND PANCREAS OF BOTH THE MALE AND FEMALE OFFSPRING, WHICH CORRELATED WITH THE UP-REGULATION OF GENES IN THE LIVERX/RETINOIDX/FARNESOIDX RECEPTOR PATHWAYS. HOWEVER, PATTERNS OF GENE EXPRESSION WERE HIGHLY VARIABLE BETWEEN THE OFFSPRING OF ALCOHOL-EXPOSED SIRES. IN THE ADULT OFFSPRING OF ALCOHOL-EXPOSED MALES, WE DID NOT OBSERVE ANY DIFFERENCES IN THE ALLELIC EXPRESSION OF IGF2 OR ANY OTHER IMPRINTED GENES. CONCLUSIONS: THE IMPACT OF PATERNAL ALCOHOL USE ON CHILD DEVELOPMENT IS POORLY EXPLORED AND REPRESENTS A SIGNIFICANT GAP IN OUR UNDERSTANDING OF THE TERATOGENIC EFFECTS OF ETHANOL. OUR STUDIES IMPLICATE PATERNAL EXPOSURE HISTORY AS AN ADDITIONAL AND IMPORTANT MODIFIER OF ALCOHOL-INDUCED GROWTH PHENOTYPES AND CHALLENGE THE CURRENT MATERNAL-CENTRIC EXPOSURE PARADIGM.	2019	
                                                                                                                                                            
20 2757  35 EXPRESSION OF EPIGENETIC MACHINERY GENES IS SENSITIVE TO MATERNAL OBESITY AND WEIGHT LOSS IN RELATION TO FETAL GROWTH IN MICE. BACKGROUND: MATERNAL OBESITY IMPACTS FETAL GROWTH AND PREGNANCY OUTCOMES. TO COUNTERACT THE DELETERIOUS EFFECTS OF OBESITY ON FERTILITY AND PREGNANCY ISSUE, PRECONCEPTIONAL WEIGHT LOSS IS RECOMMENDED TO OBESE WOMEN. WHETHER THIS WEIGHT LOSS IS BENEFICIAL/DETRIMENTAL FOR OFFSPRING REMAINS POORLY EXPLORED. EPIGENETIC MECHANISMS COULD BE AFFECTED BY MATERNAL WEIGHT CHANGES, PERTURBING EXPRESSION OF KEY DEVELOPMENTAL GENES IN THE PLACENTA OR FETUS. OUR AIM WAS TO INVESTIGATE THE EFFECTS OF CHRONIC MATERNAL OBESITY ON FETO-PLACENTAL GROWTH ALONG WITH THE UNDERLYING EPIGENETIC MECHANISMS. WE ALSO TESTED WHETHER PRECONCEPTIONAL WEIGHT LOSS COULD ALLEVIATE THESE EFFECTS. RESULTS: FEMALE MICE WERE FED EITHER A CONTROL DIET (CTRL GROUP), A HIGH-FAT DIET (OBESE (OB) GROUP), OR A HIGH-FAT DIET SWITCHED TO A CONTROL DIET 2 MONTHS BEFORE CONCEPTION (WEIGHT LOSS (WL) GROUP). AT MATING, OB FEMALES PRESENTED AN OBESE PHENOTYPE WHILE WL FEMALES NORMALIZED METABOLIC PARAMETERS. AT EMBRYONIC DAY 18.5 (E18.5), FETUSES FROM OB FEMALES PRESENTED FETAL GROWTH RESTRICTION (FGR; -13 %) AND 28 % OF THE FETUSES WERE SMALL FOR GESTATIONAL AGE (SGA). FETUSES FROM WL FEMALES NORMALIZED THIS PHENOTYPE. THE EXPRESSION OF 60 EPIGENETIC MACHINERY GENES AND 32 METABOLIC GENES WAS MEASURED IN THE FETAL LIVER, PLACENTAL LABYRINTH, AND JUNCTIONAL ZONE. WE REVEALED 23 GENES ALTERED BY MATERNAL WEIGHT TRAJECTORIES IN AT LEAST ONE OF THREE TISSUES. THE FETAL LIVER AND PLACENTAL LABYRINTH WERE MORE RESPONSIVE TO MATERNAL OBESITY THAN JUNCTIONAL ZONE. ONE THIRD (18/60) OF THE EPIGENETIC MACHINERY GENES WERE DIFFERENTIALLY EXPRESSED BETWEEN AT LEAST TWO MATERNAL GROUPS. INTERESTINGLY, GENES INVOLVED IN THE HISTONE ACETYLATION PATHWAY WERE PARTICULARLY ALTERED (13/18). IN OB GROUP, LYSINE ACETYLTRANSFERASES AND BROMODOMAIN-CONTAINING PROTEIN 2 WERE UPREGULATED, WHILE MOST HISTONE DEACETYLASES WERE DOWNREGULATED. IN WL GROUP, THE EXPRESSION OF ONLY A SUBSET OF THESE GENES WAS NORMALIZED. CONCLUSIONS: THIS STUDY HIGHLIGHTS THE HIGH SENSITIVITY OF THE EPIGENETIC MACHINERY GENE EXPRESSION, AND PARTICULARLY THE HISTONE ACETYLATION PATHWAY, TO MATERNAL OBESITY. THESE OBESITY-INDUCED TRANSCRIPTIONAL CHANGES COULD ALTER THE PLACENTAL AND THE HEPATIC EPIGENOME, LEADING TO FGR. PRECONCEPTIONAL WEIGHT LOSS APPEARS BENEFICIAL TO FETAL GROWTH, BUT SOME EFFECTS OF PREVIOUS OBESITY WERE RETAINED IN OFFSPRING PHENOTYPE.	2016