1 6270 182 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	

2 5090  51 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
3  649  49 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4 4085  55 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	
            
5 5192  53 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 5294  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7 1439  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                     
8 2149  38 EPIGENETIC MARKERS TO PREDICT CONVERSION FROM GESTATIONAL DIABETES TO TYPE 2 DIABETES. CONTEXT: LIFESTYLE FACTORS MEDIATE EPIGENETIC CHANGES THAT CAN CAUSE CHRONIC DISEASES. ALTHOUGH ANIMAL AND LABORATORY STUDIES LINK EPIGENETIC CHANGES TO DIABETES, EPIGENETIC INFORMATION IN WOMEN WITH GESTATIONAL DIABETES (GDM) AND TYPE 2 DIABETES IS LACKING. OBJECTIVE: THIS STUDY SOUGHT TO MEASURE EPIGENETIC MARKERS ACROSS PREGNANCY AND EARLY POSTPARTUM AND IDENTIFY MARKERS THAT COULD BE USED AS PREDICTORS FOR CONVERSION FROM GDM TO TYPE 2 DIABETES. DESIGN: GLOBAL HISTONE H3 DIMETHYLATION WAS MEASURED IN WHITE BLOOD CELLS AT THREE TIME POINTS: 30 WK GESTATION, 8-10 WK POSTPARTUM, AND 20 WK POSTPARTUM, FROM FOUR GROUPS OF WOMEN WITH AND WITHOUT DIABETES. SETTING AND PARTICIPANTS: A TOTAL OF 39 PARTICIPANTS (SIX TO NINE IN EACH GROUP) WERE RECRUITED INCLUDING: NONDIABETIC WOMEN; WOMEN WITH GDM WHO DEVELOPED POSTPARTUM TYPE 2 DIABETES; WOMEN WITH GDM WITHOUT POSTPARTUM TYPE 2 DIABETES; AND WOMEN WITH TYPE 2 DIABETES. MAIN OUTCOME MEASURE: PERCENTAGES OF DIMETHYLATION OF H3 HISTONES RELATIVE TO TOTAL H3 HISTONE METHYLATION WERE COMPARED BETWEEN DIABETIC/NONDIABETIC GROUPS USING APPROPRIATE COMPARATIVE STATISTICS. RESULTS: H3K27 DIMETHYLATION WAS 50-60% LOWER AT 8-10 AND 20 WK POSTPARTUM IN WOMEN WITH GDM WHO DEVELOPED TYPE 2 DIABETES, COMPARED WITH NONDIABETIC WOMEN. H3K4 DIMETHYLATION WAS 75% LOWER AT 8-10 WK POSTPARTUM IN WOMEN WITH GDM WHO SUBSEQUENTLY DEVELOPED TYPE 2 DIABETES COMPARED WITH WOMEN WHO HAD GDM WHO DID NOT. CONCLUSIONS: THE PERCENTAGE OF DIMETHYLATION OF HISTONES H3K27 AND H3K4 VARIED WITH DIABETIC STATE AND HAS THE POTENTIAL AS A PREDICTIVE TOOL TO IDENTIFY WOMEN WHO WILL CONVERT FROM GDM TO TYPE 2 DIABETES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  520  43 ASSOCIATIONS BETWEEN MATERNAL PRENATAL STRESS, METHYLATION CHANGES IN IGF1 AND IGF2, AND BIRTH WEIGHT. MATERNAL STRESS HAS BEEN LINKED TO LOW BIRTH WEIGHT IN NEWBORNS. ONE POTENTIAL PATHWAY INVOLVES EPIGENETIC CHANGES AT CANDIDATE GENES THAT MAY MEDIATE THE EFFECTS OF PRENATAL MATERNAL STRESS ON BIRTH WEIGHT. THIS RELATIONSHIP HAS BEEN DOCUMENTED IN STRESS-RELATED GENES, SUCH AS NR3C1. THERE IS LESS LITERATURE EXPLORING THE EFFECT OF STRESS ON GROWTH-RELATED GENES. IGF1 AND IGF2 HAVE BEEN IMPLICATED IN FETAL GROWTH AND DEVELOPMENT, THOUGH VIA DIFFERENT MECHANISMS AS IGF2 IS UNDER IMPRINTING CONTROL. IN THIS STUDY, WE TESTED FOR ASSOCIATIONS BETWEEN PRENATAL STRESS, METHYLATION OF IGF1 AND IGF2, AND BIRTH WEIGHT. A TOTAL OF 24 MOTHER-NEWBORN DYADS IN THE DEMOCRATIC REPUBLIC OF CONGO WERE ENROLLED. ETHNOGRAPHIC INTERVIEWS WERE CONDUCTED WITH MOTHERS AT DELIVERY TO GATHER CULTURALLY RELEVANT WAR-RELATED AND CHRONIC STRESSORS. DNA METHYLATION DATA WERE GENERATED FROM MATERNAL VENOUS, CORD BLOOD AND PLACENTAL TISSUE SAMPLES. MULTIVARIATE REGRESSIONS WERE USED TO TEST FOR ASSOCIATIONS BETWEEN STRESS MEASURES, DNA METHYLATION AND BIRTH WEIGHT IN EACH OF THE THREE TISSUE TYPES. WE FOUND AN ASSOCIATION BETWEEN IGF2 METHYLATION IN MATERNAL BLOOD AND BIRTH WEIGHT. PREVIOUS LITERATURE ON THE RELATIONSHIP BETWEEN IGF2 METHYLATION AND BIRTH WEIGHT HAS FOCUSED ON METHYLATION AT KNOWN DIFFERENTIALLY METHYLATED REGIONS IN CORD BLOOD OR PLACENTAL SAMPLES. OUR FINDINGS INDICATE THERE MAY BE LINKS BETWEEN THE MATERNAL EPIGENOME AND LOW BIRTH WEIGHT THAT RELY ON MECHANISMS OUTSIDE KNOWN IMPRINTING PATHWAYS. IT THUS MAY BE IMPORTANT TO CONSIDER THE EFFECT OF MATERNAL EXPOSURES AND EPIGENETIC PROFILES ON BIRTH WEIGHT EVEN IN THE SETTING OF MATERNALLY IMPRINTED GENES SUCH AS IGF2.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10 1503  43 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11 4066  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12 3117  60 GESTATIONAL DIABETES MELLITUS EPIGENETICALLY AFFECTS GENES PREDOMINANTLY INVOLVED IN METABOLIC DISEASES. OFFSPRING EXPOSED TO GESTATIONAL DIABETES MELLITUS (GDM) HAVE AN INCREASED RISK FOR CHRONIC DISEASES, AND ONE PROMISING MECHANISM FOR FETAL METABOLIC PROGRAMMING IS EPIGENETICS. THEREFORE, WE POSTULATED THAT GDM EXPOSURE IMPACTS THE OFFSPRING'S METHYLOME AND USED AN EPIGENOMIC APPROACH TO EXPLORE THIS HYPOTHESIS. PLACENTA AND CORD BLOOD SAMPLES WERE OBTAINED FROM 44 NEWBORNS, INCLUDING 30 EXPOSED TO GDM. WOMEN WERE RECRUITED AT FIRST TRIMESTER OF PREGNANCY AND FOLLOWED UNTIL DELIVERY. GDM WAS ASSESSED AFTER A 75-G ORAL GLUCOSE TOLERANCE TEST AT 24-28 WEEKS OF PREGNANCY. DNA METHYLATION WAS MEASURED AT>485,000 CPG SITES (INFINIUM HUMANMETHYLATION450 BEADCHIPS). INGENUITY PATHWAY ANALYSIS WAS CONDUCTED TO IDENTIFY METABOLIC PATHWAYS EPIGENETICALLY AFFECTED BY GDM. OUR RESULTS SHOWED THAT 3,271 AND 3,758 GENES IN PLACENTA AND CORD BLOOD, RESPECTIVELY, WERE POTENTIALLY DIFFERENTIALLY METHYLATED BETWEEN SAMPLES EXPOSED OR NOT TO GDM (P-VALUES DOWN TO 1 X 10(-06); NONE REACHED THE GENOME-WIDE SIGNIFICANCE LEVELS), WITH MORE THAN 25% (N = 1,029) BEING COMMON TO BOTH TISSUES. MEAN DNA METHYLATION DIFFERENCES BETWEEN GROUPS WERE 5.7 +/- 3.2% AND 3.4 +/- 1.9% FOR PLACENTA AND CORD BLOOD, RESPECTIVELY. THESE GENES WERE LIKELY INVOLVED IN THE METABOLIC DISEASES PATHWAY (UP TO 115 GENES (11%), P-VALUES FOR PATHWAYS = 1.9 X 10(-13)<P<4.0 X 10(-03); INCLUDING DIABETES MELLITUS P = 4.3 X 10(-11)). AMONG THE DIFFERENTIALLY METHYLATED GENES, 326 IN PLACENTA AND 117 IN CORD BLOOD WERE ALSO ASSOCIATED WITH NEWBORN WEIGHT. OUR RESULTS THEREFORE SUGGEST THAT GDM HAS EPIGENETIC EFFECTS ON GENES PREFERENTIALLY INVOLVED IN THE METABOLIC DISEASES PATHWAY, WITH CONSEQUENCES ON FETAL GROWTH AND DEVELOPMENT, AND PROVIDE SUPPORTIVE EVIDENCE THAT DNA METHYLATION IS INVOLVED IN FETAL METABOLIC PROGRAMMING.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13 6279  45 THE PLACENTA AS A TARGET OF EPIGENETIC ALTERATIONS IN WOMEN WITH GESTATIONAL DIABETES MELLITUS AND POTENTIAL IMPLICATIONS FOR THE OFFSPRING. GESTATIONAL DIABETES MELLITUS (GDM) IS A PREGNANCY COMPLICATION FIRST DETECTED IN THE SECOND OR THIRD TRIMESTER IN WOMEN THAT DID NOT SHOW EVIDENT GLUCOSE INTOLERANCE OR DIABETES BEFORE GESTATION. IN 2019, THE INTERNATIONAL DIABETES FEDERATION REPORTED THAT 15.8% OF LIVE BIRTHS WERE AFFECTED BY HYPERGLYCEMIA DURING PREGNANCY, OF WHICH 83.6% WERE DUE TO GESTATIONAL DIABETES MELLITUS, 8.5% WERE DUE TO DIABETES FIRST DETECTED IN PREGNANCY, AND 7.9% WERE DUE TO DIABETES DETECTED BEFORE PREGNANCY. GDM INCREASES THE SUSCEPTIBILITY TO DEVELOPING CHRONIC DISEASES FOR BOTH THE MOTHER AND THE BABY LATER IN LIFE. UNDER GDM CONDITIONS, THE INTRAUTERINE ENVIRONMENT BECOMES HYPERGLYCEMIC, WHILE ALSO SHOWING HIGH CONCENTRATIONS OF FATTY ACIDS AND PROINFLAMMATORY CYTOKINES, PRODUCING MORPHOLOGICAL, STRUCTURAL, AND MOLECULAR MODIFICATIONS IN THE PLACENTA, AFFECTING ITS FUNCTION; THESE ALTERATIONS MAY PREDISPOSE THE BABY TO DISEASE IN ADULT LIFE. MOLECULAR ALTERATIONS INCLUDE EPIGENETIC MECHANISMS SUCH AS DNA AND RNA METHYLATION, CHROMATIN REMODELING, HISTONE MODIFICATIONS, AND EXPRESSION OF NONCODING RNAS (NCRNAS). THE PLACENTA IS A UNIQUE ORGAN THAT ORIGINATES ONLY IN PREGNANCY, AND ITS MAIN FUNCTION IS COMMUNICATION BETWEEN THE MOTHER AND THE FETUS, ENSURING HEALTHY DEVELOPMENT. THUS, THIS REVIEW PROVIDES UP-TO-DATE INFORMATION REGARDING TWO OF THE BEST-DOCUMENTED (EPIGENETIC) MECHANISMS (DNA METHYLATION AND MIRNA EXPRESSION) ALTERED IN THE HUMAN PLACENTA UNDER GDM CONDITIONS, AS WELL AS POTENTIAL IMPLICATIONS FOR THE OFFSPRING.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14 5166  51 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	
                                                                                                                                                           
15 2757  48 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	
                                                                                        
16 4072  47 MATERNAL DNA METHYLATION SIGNATURES OF ARSENIC EXPOSURE IS ASSOCIATED WITH ADULT OFFSPRING INSULIN RESISTANCE IN THE STRONG HEART STUDY. EXPOSURE TO LOW TO MODERATE ARSENIC (AS) LEVELS HAS BEEN ASSOCIATED WITH TYPE 2 DIABETES (T2D) AND OTHER CHRONIC DISEASES IN AMERICAN INDIAN COMMUNITIES. PRENATAL EXPOSURE TO AS MAY ALSO INCREASE THE RISK FOR T2D IN ADULTHOOD, AND MATERNAL AS HAS BEEN ASSOCIATED WITH ADULT OFFSPRING METABOLIC HEALTH MEASUREMENTS. WE HYPOTHESIZED THAT T2D-RELATED OUTCOMES IN ADULT OFFSPRING BORN TO WOMEN EXPOSED TO LOW TO MODERATE AS CAN BE EVALUATED UTILIZING A MATERNALLY-DERIVED MOLECULAR BIOSIGNATURE OF AS EXPOSURE. HEREIN, WE EVALUATED THE ASSOCIATION OF MATERNAL DNA METHYLATION WITH INCIDENT T2D AND INSULIN RESISTANCE (HOMEOSTATIC MODEL ASSESSMENT OF INSULIN RESISTANCE [HOMA2-IR]) IN ADULT OFFSPRING. FOR DNA METHYLATION, WE USED 20 DIFFERENTIALLY METHYLATED CYTOSINE-GUANINE DINUCLEOTIDES (CPG) PREVIOUSLY ASSOCIATED WITH THE SUM OF INORGANIC AND METHYLATED AS SPECIES (SIGMAAS) IN URINE IN THE STRONG HEART STUDY (SHS). OF THESE 20 CPGS, WE FOUND SIX CPGS NOMINALLY ASSOCIATED (P < 0.05) WITH HOMA2-IR IN A FULLY ADJUSTED MODEL THAT INCLUDED CLINICALLY RELEVANT COVARIATES AND OFFSPRING ADIPOSITY MEASUREMENTS; A SIMILAR MODEL THAT ADJUSTED INSTEAD FOR MATERNAL ADIPOSITY MEASUREMENTS FOUND THREE CPGS NOMINALLY ASSOCIATED WITH HOMA2-IR, TWO OF WHICH OVERLAPPED THE OFFSPRING ADIPOSITY MODEL. AFTER ADJUSTING FOR MULTIPLE COMPARISONS, CG03036214 REMAINED ASSOCIATED WITH HOMA2-IR (Q < 0.10) IN THE OFFSPRING ADIPOSITY MODEL. THE ODDS RATIO OF INCIDENT T2D INCREASED WITH AN INCREASE IN MATERNAL DNA METHYLATION AT ONE HOMA2-IR ASSOCIATED CPG IN THE MODEL ADJUSTING FOR OFFSPRING ADIPOSITY, CG12116137, WHEREAS ADJUSTING FOR MATERNAL ADIPOSITY HAD A MINIMAL EFFECT ON THE ASSOCIATION. OUR DATA SUGGESTS OFFSPRING ADIPOSITY, RATHER THAN MATERNAL ADIPOSITY, POTENTIALLY INFLUENCES THE EFFECTS OF MATERNAL DNAM SIGNATURES ON OFFSPRING METABOLIC HEALTH PARAMETERS. HERE, WE HAVE PRESENTED EVIDENCE SUPPORTING A ROLE FOR EPIGENETIC BIOSIGNATURES OF MATERNAL AS EXPOSURE AS A POTENTIAL BIOMARKER FOR EVALUATING RISK OF T2D-RELATED OUTCOMES IN OFFSPRING LATER IN LIFE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                     
17 5875  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18 1795  37 EFFECT OF DIFFERENT COMBINATION OF MATERNAL AND POSTNATAL DIET ON ADIPOSE TISSUE MORPHOLOGY IN MALE RAT OFFSPRING. PURPOSE: ADIPOSE TISSUE EXPANSION CAN OCCUR THROUGH SEVERAL DIFFERENT WAYS AND, UNDER CERTAIN CONDITIONS, CAN BE CONNECTED WITH CHRONIC INFLAMMATION. TNF-ALPHA IS ONE OF THE IMPORTANT CYTOKINES INVOLVED IN THIS PROCESS. PROLONGED INFLAMMATION IN OBESITY CAN LEAD TO OBESITY-RELATED INSULIN RESISTANCE AND TISSUE DYSFUNCTION. THE AIM OF OUR STUDY WAS TO INVESTIGATE HOW DIFFERENT COMBINATION OF MATERNAL AND POSTNATAL DIET AFFECTS OFFSPRING ADIPOSE TISSUE MORPHOLOGY AND ADIPOSE TISSUE TNF-ALPHA EXPRESSION. METHODS: TEN FEMALE SPRAGUE DAWLEY RATS, 9 WEEKS OLD, WERE RANDOMLY DIVIDED INTO TWO GROUPS AND FED EITHER STANDARD LABORATORY CHOW OR FOOD RICH IN SATURATED FATTY ACIDS DURING 6 WEEKS AND THEN MATED WITH THE SAME MALE RAT. AFTER BIRTH AND LACTATION MALE RAT OFFSPRING FROM BOTH GROUPS WERE DIVIDED INTO FOUR SUBGROUPS DEPENDING ON THE DIET THEY WERE FED UNTIL 22 WEEKS OLD. SAMPLES OF WHITE ADIPOSE TISSUE WERE TAKEN FROM THE SUBCUTANEOUS, EPIDIDYMAL, AND PERIRENAL FAT PAD. ON TISSUE SECTIONS, HISTOMORPHOMETRIC ANALYSIS WAS CONDUCTED USING CELLPROFILER PROGRAM V 2.1.1, AND IMMUNOHISTOCHEMICAL STAINING FOR TNF-ALPHA WAS PERFORMED. RESULTS: GREATER MEAN SURFACE AREA OF SUBCUTANEOUS AND EPIDIDYMAL ADIPOCYTES WAS FOUND IN GROUPS OF MALE RAT OFFSPRING WITH ALTERED DIET. IN PERIRENAL ADIPOSE TISSUE, THE HIGHEST NUMBER OF ADIPOCYTES WAS MEASURED IN THE GROUP WHERE BOTH MOTHER AND OFFSPRING WERE FED A HIGH-FAT DIET. ADIPOCYTE STAINING INTENSITY FOR TNF-ALPHA DID NOT DIFFER SIGNIFICANTLY BETWEEN THE GROUPS. CONCLUSIONS: TOGETHER WITH OUR PREVIOUSLY PUBLISHED DATA, OUR RESULTS LEAD TO THE CONCLUSION THAT ALTERATION OF POSTNATAL DIET CAN LEAD TO TNF-ALPHA AND ADIPOCYTE MORPHOLOGY CHANGES.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19 3118  51 GESTATIONAL DIABETES MELLITUS: GENETIC FACTORS, EPIGENETIC ALTERATIONS, AND MICROBIAL COMPOSITION. GESTATIONAL DIABETES MELLITUS (GDM) IS A COMMON METABOLIC DISORDER, USUALLY DIAGNOSED DURING THE THIRD TRIMESTER OF PREGNANCY THAT USUALLY DISAPPEARS AFTER DELIVERY. IN GDM, THE EXCESS OF GLUCOSE, FATTY ACIDS, AND AMINO ACIDS RESULTS IN FOETUSES LARGE FOR GESTATIONAL AGE. HYPERGLYCAEMIA AND INSULIN RESISTANCE ACCELERATE THE METABOLISM, RAISING THE OXYGEN DEMAND, AND CREATING CHRONIC HYPOXIA AND INFLAMMATION. WOMEN WHO EXPERIENCED GDM AND THEIR OFFSPRING ARE AT RISK OF DEVELOPING TYPE-2 DIABETES, OBESITY, AND OTHER METABOLIC OR CARDIOVASCULAR CONDITIONS LATER IN LIFE. GENETIC FACTORS MAY PREDISPOSE THE DEVELOPMENT OF GDM; HOWEVER, THEY DO NOT ACCOUNT FOR ALL GDM CASES; LIFESTYLE AND DIET ALSO PLAY IMPORTANT ROLES IN GDM DEVELOPMENT BY MODULATING EPIGENETIC SIGNATURES AND THE BODY'S MICROBIAL COMPOSITION; THEREFORE, THIS IS A CONDITION WITH A COMPLEX, MULTIFACTORIAL AETIOLOGY. IN THIS CONTEXT, WE REVISED PUBLISHED REPORTS DESCRIBING GDM-ASSOCIATED SINGLE-NUCLEOTIDE POLYMORPHISMS (SNPS), DNA METHYLATION AND MICRORNA EXPRESSION IN DIFFERENT TISSUES (SUCH AS PLACENTA, UMBILICAL CORD, ADIPOSE TISSUE, AND PERIPHERAL BLOOD), AND MICROBIAL COMPOSITION IN THE GUT, ORAL CAVITY, AND VAGINA FROM PREGNANT WOMEN WITH GDM, AS WELL AS THE BACTERIAL COMPOSITION OF THE OFFSPRING. ALTOGETHER, THESE REPORTS INDICATE THAT A NUMBER OF SNPS ARE ASSOCIATED TO GDM PHENOTYPES AND MAY PREDISPOSE THE DEVELOPMENT OF THE DISEASE. HOWEVER, EXTRINSIC FACTORS (LIFESTYLE, NUTRITION) MODULATE, THROUGH EPIGENETIC MECHANISMS, THE RISK OF DEVELOPING THE DISEASE, AND SOME ASSOCIATION EXISTS BETWEEN THE MICROBIAL COMPOSITION WITH GDM IN AN ORGAN-SPECIFIC MANNER. GENES, EPIGENETIC SIGNATURES, AND MICROBIOTA COULD BE TRANSFERRED TO THE OFFSPRING, INCREASING THE POSSIBILITY OF DEVELOPING CHRONIC DEGENERATIVE CONDITIONS THROUGH POSTNATAL LIFE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20 4010  44 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