1  5093 245 PLACENTAS FROM PREGNANCIES CONCEIVED BY IVF/ICSI HAVE A REDUCED DNA METHYLATION LEVEL AT THE H19 AND MEST DIFFERENTIALLY METHYLATED REGIONS. STUDY QUESTION: DOES IVF/ICSI HAVE AN EFFECT ON THE EPIGENETIC REGULATION OF THE HUMAN PLACENTA? SUMMARY ANSWER: WE FOUND A REDUCED DNA METHYLATION LEVEL AT THE H19 AND MEST DIFFERENTIALLY METHYLATED REGIONS (DMRS), AND AN INCREASED RNA EXPRESSION OF H19 IN PLACENTAS FROM PREGNANCIES CONCEIVED BY IVF/ICSI WHEN COMPARED WITH PLACENTAS FROM SPONTANEOUS CONCEPTION. WHAT IS KNOWN ALREADY: CHANGES IN FETAL ENVIRONMENT ARE ASSOCIATED WITH ADVERSE HEALTH OUTCOMES. THE PLACENTA IS PIVOTAL FOR INTRAUTERINE ENVIRONMENT. ANIMAL STUDIES SHOW THAT EPIGENETIC REGULATION PLAYS AN IMPORTANT ROLE IN THESE ENVIRONMENT-INDUCED PHENOTYPIC EFFECTS. ALSO, THE PREIMPLANTATION EMBRYO ENVIRONMENT AFFECTS BIRTHWEIGHT AS WELL AS THE RISK OF CHRONIC ADULT DISEASES. EPIGENETIC PROCESSES ARE SENSITIVE TO THE ENVIRONMENT, ESPECIALLY DURING THE PERIOD AROUND CONCEPTION. STUDY DESIGN AND PARTICIPANTS: PLACENTAL TISSUE WAS COLLECTED FROM 35 SPONTANEOUSLY CONCEIVED PREGNANCIES AND 35 IVF/ICSI (5 IVF, 30 ICSI) DERIVED PREGNANCIES. WE QUANTITATIVELY ANALYSED THE DNA METHYLATION PATTERNS OF A NUMBER OF CONSECUTIVE CPGS IN THE CORE REGIONS OF DMRS AND OTHER REGULATORY REGIONS OF IMPRINTED GENES, SINCE THESE ARE INVOLVED IN PLACENTAL AND FETAL GROWTH AND DEVELOPMENT. METHODS: BY USING PYROSEQUENCING, THE DNA METHYLATION AT SEVEN GERMLINE-DERIVED PRIMARY DMRS WAS ANALYSED QUANTITATIVELY. FIVE OF THESE ARE MATERNALLY METHYLATED (MEST ISOFORM ALPHA AND BETA, PEG3, KCNQ1OT1 AND SNRPN) AND TWO ARE PATERNALLY METHYLATED [H19 DMR AND THE INTERGENIC REGION BETWEEN DLK1 AND MEG3 (IG-DMR)]. THE POST-FERTILIZATION-DERIVED SECONDARY DMRS, IGF2 (DMR0 AND 2) AND IG-DMR (CG7, ALSO CALLED MEG3 DMR), AND THE MEG3 PROMOTER REGION WERE EXAMINED AS WELL. IN CASE OF DIFFERENTIAL METHYLATION BETWEEN THE TWO GROUPS, THE EFFECT ON GENE EXPRESSION WAS ASSESSED BY QUANTITATIVE REAL-TIME PCR. MAIN RESULTS AND THE ROLE OF CHANCE: BOTH THE PROMOTER REGION OF MEST ISOFORM ALPHA AND BETA AND THE 6TH CTCF BINDING SITE WITHIN THE H19 DMR WERE SIGNIFICANTLY HYPOMETHYLATED IN THE IVF/ICSI GROUP. THE PHENOMENON WAS CONSISTENTLY OBSERVED OVER ALL CPG SITES ANALYSED AND NOT RESTRICTED TO SINGLE CPG SITES. THE OTHER PRIMARY AND SECONDARY DMRS WERE NOT AFFECTED. EXPRESSION OF H19 WAS INCREASED IN THE IVF/ICSI GROUP, WHILE THAT OF IGF2 AND MEST REMAINED SIMILAR. LIMITATIONS, REASONS FOR CAUTION: IN THE IVF/ICSI GROUP, MOSTLY ICSI PREGNANCIES WERE INVESTIGATED. THE ICSI TECHNIQUE OR MALE SUBFERTILITY COULD BE A CONFOUNDING FACTOR. THEREFORE, OUR RESULTS ARE LESS GENERALIZABLE TO IVF PREGNANCIES. WIDER IMPLICATIONS OF THE FINDINGS: THE CLINICAL EFFECTS OF THE OBSERVED PLACENTAL HYPOMETHYLATIONS ON THE DEVELOPMENTAL PROGRAMMING OF THE IVF/ICSI PROGENY, IF ANY, ARE AS YET UNKNOWN. WHETHER THE HYPOMETHYLATION IS AN ADAPTATION OF THE PLACENTA TO MAINTAIN FETAL SUPPLY AND AMELIORATE THE EFFECTS OF ENVIRONMENTAL CUES, OR WHETHER IT IS A DEREGULATION LEADING TO DERANGED DEVELOPMENTAL PROGRAMMING WITH OR WITHOUT INCREASED VULNERABILITY FOR DISEASE, CONSISTENT WITH THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS, NEEDS FURTHER INVESTIGATION. STUDY FUNDING/COMPETING INTEREST(S): PARTLY FUNDED BY AN UNRESTRICTED RESEARCH GRANT BY ORGANON BV (NOW MSD BV) WITHOUT ANY ROLE IN STUDY DESIGN, DATA COLLECTION AND ANALYSIS, OR PREPARATION OF THE MANUSCRIPT. NO CONFLICT OF INTERESTS TO DECLARE. TRIAL REGISTRATION NUMBER: DUTCH TRIAL REGISTRY (NTR) NUMBER 1298.	2013	

2  4036  32 MACROPHAGE EPIGENETIC MEMORIES OF EARLY LIFE INJURY DRIVE NEONATAL NOCICEPTIVE PRIMING. THE DEVELOPING PERIPHERAL NERVOUS AND IMMUNE SYSTEMS ARE FUNCTIONALLY DISTINCT FROM ADULTS. THESE SYSTEMS ARE VULNERABLE TO EFFECTS OF EARLY LIFE INJURY WHICH CAN INFLUENCE OUTCOMES RELATED TO NOCICEPTION FOLLOWING SUBSEQUENT INJURY LATER IN LIFE (I.E. "NEONATAL NOCICEPTIVE PRIMING"). THE UNDERPINNINGS OF THIS PHENOMENON ARE LARGELY UNKNOWN, ALTHOUGH MACROPHAGES CAN BE EPIGENETICALLY TRAINED BY INJURY. WE FOUND THAT MACROPHAGES ARE BOTH NECESSARY AND PARTIALLY SUFFICIENT TO DRIVE NEONATAL NOCICEPTIVE PRIMING POSSIBLY DUE TO A LONG-LASTING EPIGENETIC REMODELING OF PERIPHERAL MACROPHAGES. THE P75 NEUROTROPHIC FACTOR RECEPTOR (NTR) WAS OBSERVED TO BE AN IMPORTANT EFFECTOR IN REGULATING NEONATAL NOCICEPTIVE PRIMING. P75NTR MODULATES THE INFLAMMATORY PROFILE AND RESPONSES OF RODENT AND HUMAN MACROPHAGES. THIS "PAIN MEMORY" WAS ABLE TO BE TRANSFERRED TO A NAIVE HOST TO ALTER SEX-SPECIFIC PAIN-RELATED BEHAVIORS. THIS STUDY REVEALS A NOVEL MECHANISM BY WHICH ACUTE POST-SURGICAL PAIN MAY TRANSITION TO CHRONIC PAIN IN CHILDREN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3  1784  71 EFFECT OF ALCOHOL CONSUMPTION ON CPG METHYLATION IN THE DIFFERENTIALLY METHYLATED REGIONS OF H19 AND IG-DMR IN MALE GAMETES: IMPLICATIONS FOR FETAL ALCOHOL SPECTRUM DISORDERS. BACKGROUND: EXPOSURE TO ALCOHOL IN UTERO IS THE MAIN ATTRIBUTABLE CAUSE OF FETAL ALCOHOL SPECTRUM DISORDERS (FASD) WHICH IN ITS MOST SEVERE FORM IS CHARACTERIZED BY IRREVERSIBLE BEHAVIORAL AND COGNITIVE DISABILITY. PATERNAL PRECONCEPTION DRINKING IS NOT CONSIDERED TO BE A SIGNIFICANT RISK FACTOR, EVEN THOUGH ANIMAL STUDIES HAVE DEMONSTRATED THAT CHRONIC PATERNAL ALCOHOL CONSUMPTION HAS A DETRIMENTAL EFFECT ON THE PHYSICAL AND MENTAL DEVELOPMENT OF OFFSPRING EVEN IN THE ABSENCE OF IN UTERO ALCOHOL EXPOSURE. IT HAS BEEN DOCUMENTED THAT ALCOHOL CAN REDUCE THE LEVELS AND ACTIVITY OF DNA METHYLTRANSFERASES RESULTING IN DNA HYPOMETHYLATION AND THAT REDUCED METHYLTRANSFERASE ACTIVITY CAN CAUSE ACTIVATION OF NORMALLY SILENCED GENES. THE AIM OF THIS STUDY WAS TO ESTABLISH A LINK BETWEEN ALCOHOL USE IN MEN AND HYPOMETHYLATION OF PATERNALLY IMPRINTED LOCI IN SPERM DNA IN GENOMIC REGIONS CRITICAL FOR EMBRYONIC DEVELOPMENT, THUS PROVIDING A MECHANISM FOR PATERNAL EFFECTS IN THE AETIOLOGY OF FASD. METHODS: SPERM DNA FROM MALE VOLUNTEERS WAS BISULFITE TREATED AND THE METHYLATION PATTERNS OF 2 DIFFERENTIALLY METHYLATED REGIONS (DMRS), H19 AND IG-DMR, ANALYZED FOLLOWING SEQUENCING OF INDIVIDUAL CLONES. THE METHYLATION PATTERNS WERE CORRELATED WITH THE ALCOHOL CONSUMPTION LEVELS OF THE VOLUNTEER MALES. RESULTS: THERE WAS A PATTERN OF INCREASED DEMETHYLATION WITH ALCOHOL CONSUMPTION AT THE 2 IMPRINTED LOCI WITH A SIGNIFICANT DIFFERENCE OBSERVED AT THE IG-DMR BETWEEN THE NONDRINKING AND HEAVY ALCOHOL CONSUMING GROUPS. GREATER INTER-INDIVIDUAL VARIATION IN AVERAGE METHYLATION WAS OBSERVED AT THE H19 DMR AND INDIVIDUAL CLONES WERE MORE EXTENSIVELY DEMETHYLATED THAN THOSE OF THE IG-DMR. CPG SITE #4 IN THE IG-DMR WAS PREFERENTIALLY DEMETHYLATED AMONG ALL INDIVIDUALS AND ALONG WITH THE H19 DMR CPG SITE #7 LOCATED WITHIN THE CTCF BINDING SITE 6 SHOWED SIGNIFICANT DEMETHYLATION IN THE ALCOHOL CONSUMING GROUPS COMPARED WITH THE CONTROL GROUP. CONCLUSION: THIS STUDY DEMONSTRATES A CORRELATION BETWEEN CHRONIC ALCOHOL USE AND DEMETHYLATION OF NORMALLY HYPERMETHYLATED IMPRINTED REGIONS IN SPERM DNA. WE HYPOTHESIZE THAT, SHOULD THESE EPIGENETIC CHANGES IN IMPRINTED GENES BE TRANSMITTED THROUGH FERTILIZATION, THEY WOULD ALTER THE CRITICAL GENE EXPRESSION DOSAGES REQUIRED FOR NORMAL PRENATAL DEVELOPMENT RESULTING IN OFFSPRING WITH FEATURES OF FASD.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4  4691  70 NEWBORNS OF OBESE PARENTS HAVE ALTERED DNA METHYLATION PATTERNS AT IMPRINTED GENES. BACKGROUND: SEVERAL EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED ASSOCIATIONS BETWEEN PERICONCEPTIONAL ENVIRONMENTAL EXPOSURES AND HEALTH STATUS OF THE OFFSPRING IN LATER LIFE. ALTHOUGH THESE ENVIRONMENTALLY RELATED EFFECTS HAVE BEEN ATTRIBUTED TO EPIGENETIC CHANGES, SUCH AS DNA METHYLATION SHIFTS AT IMPRINTED GENES, LITTLE IS KNOWN ABOUT THE POTENTIAL EFFECTS OF MATERNAL AND PATERNAL PRECONCEPTIONAL OVERNUTRITION OR OBESITY. OBJECTIVE: WE EXAMINED PARENTAL PRECONCEPTIONAL OBESITY IN RELATION TO DNA METHYLATION PROFILES AT MULTIPLE HUMAN IMPRINTED GENES IMPORTANT IN NORMAL GROWTH AND DEVELOPMENT, SUCH AS: MATERNALLY EXPRESSED GENE 3 (MEG3), MESODERM-SPECIFIC TRANSCRIPT (MEST), PATERNALLY EXPRESSED GENE 3 (PEG3), PLEIOMORPHIC ADENOMA GENE-LIKE 1 (PLAGL1), EPSILON SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 (SGCE/PEG10) AND NEURONATIN (NNAT). METHODS: WE MEASURED METHYLATION PERCENTAGES AT THE DIFFERENTIALLY METHYLATED REGIONS (DMRS) BY BISULFITE PYROSEQUENCING IN DNA EXTRACTED FROM UMBILICAL CORD BLOOD LEUKOCYTES OF 92 NEWBORNS. PRECONCEPTIONAL OBESITY, DEFINED AS BMI ?30 KG M(-2), WAS ASCERTAINED THROUGH STANDARDIZED QUESTIONNAIRES. RESULTS: AFTER ADJUSTING FOR POTENTIAL CONFOUNDERS AND CLUSTER EFFECTS, PATERNAL OBESITY WAS SIGNIFICANTLY ASSOCIATED WITH LOWER METHYLATION LEVELS AT THE MEST (BETA=-2.57; S.E.=0.95; P=0.008), PEG3 (BETA=-1.71; S.E.=0.61; P=0.005) AND NNAT (BETA=-3.59; S.E.=1.76; P=0.04) DMRS. CHANGES RELATED TO MATERNAL OBESITY DETECTED AT OTHER LOCI WERE AS FOLLOWS: BETA-COEFFICIENT WAS +2.58 (S.E.=1.00; P=0.01) AT THE PLAGL1 DMR AND -3.42 (S.E.=1.69; P=0.04) AT THE MEG3 DMR. CONCLUSION: WE FOUND ALTERED METHYLATION OUTCOMES AT MULTIPLE IMPRINT REGULATORY REGIONS IN CHILDREN BORN TO OBESE PARENTS, COMPARED WITH CHILDREN BORN TO NON-OBESE PARENTS. IN SPITE OF THE SMALL SAMPLE SIZE, OUR DATA SUGGEST A PRECONCEPTIONAL INFLUENCE OF PARENTAL LIFE-STYLE OR OVERNUTRITION ON THE (RE)PROGRAMMING OF IMPRINT MARKS DURING GAMETOGENESIS AND EARLY DEVELOPMENT. MORE SPECIFICALLY, THE SIGNIFICANT AND INDEPENDENT ASSOCIATION BETWEEN PATERNAL OBESITY AND THE OFFSPRING'S METHYLATION STATUS SUGGESTS THE SUSCEPTIBILITY OF THE DEVELOPING SPERM FOR ENVIRONMENTAL INSULTS. THE ACQUIRED IMPRINT INSTABILITY MAY BE CARRIED ONTO THE NEXT GENERATION AND INCREASE THE RISK FOR CHRONIC DISEASES IN ADULTHOOD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  1094  46 COHORT PROFILE: THE DUTCH FAMINE BIRTH COHORT (DFBC)- A PROSPECTIVE BIRTH COHORT STUDY IN THE NETHERLANDS. PURPOSE: THE DUTCH FAMINE BIRTH COHORT STUDY WAS SET UP TO INVESTIGATE THE EFFECTS OF ACUTE MATERNAL UNDERNUTRITION OF THE 1944-1945 DUTCH FAMINE DURING THE SPECIFIC STAGES OF GESTATION ON LATER HEALTH, WITH A PARTICULAR FOCUS ON CHRONIC CARDIOVASCULAR AND METABOLIC DISEASES, AGEING AND MENTAL HEALTH. PARTICIPANTS: THE DUTCH FAMINE BIRTH COHORT CONSISTS OF 2414 SINGLETONS BORN ALIVE AND AT TERM IN THE WILHELMINA GASTHUIS IN AMSTERDAM AROUND THE TIME OF THE DUTCH FAMINE (1943-1947) WHOSE BIRTH RECORDS HAVE BEEN KEPT. THE COHORT HAS BEEN TRACED AND STUDIED SINCE 1994, WHEN THE FIRST DATA COLLECTION STARTED. THE COHORT HAS BEEN INTERVIEWED AND PHYSICALLY EXAMINED IN SEVERAL WAVES OF DATA COLLECTION SINCE THAT TIME, ALLOWING REPEATED MEASURES OF A WIDE RANGE OF PHENOTYPIC INFORMATION AS WELL AS THE COLLECTION OF BIOLOGICAL SAMPLES (BLOOD, URINE, BUCCAL SWABS), FUNCTIONAL TESTING (OF HEART, LUNGS, KIDNEY, HPA AXIS) AND IMAGING OF THE BRAIN (MRI) AND VASCULATURE (ULTRASOUND). ADDITIONALLY, GENETIC AND EPIGENETIC INFORMATION WAS COLLECTED. THROUGH LINKAGE WITH REGISTRIES, MORTALITY AND MORBIDITY INFORMATION OF THE ENTIRE COHORT HAS BEEN OBTAINED. FINDINGS TO DATE: PRENATAL FAMINE EXPOSURE HAD LASTING CONSEQUENCES FOR HEALTH IN LATER LIFE. THE EFFECTS OF FAMINE DEPENDED ON ITS TIMING DURING THE GESTATION AND THE ORGANS AND TISSUES DEVELOPING AT THAT TIME, WITH MOST EFFECTS AFTER EXPOSURE TO FAMINE IN EARLY GESTATION. THE EFFECTS OF FAMINE WERE WIDESPREAD AND AFFECTED THE STRUCTURE AND FUNCTION OF MANY ORGANS AND TISSUES, RESULTED IN ALTERED BEHAVIOUR AND INCREASED RISKS OF CHRONIC DEGENERATIVE DISEASES AND INCREASED MORTALITY. THE EFFECTS OF FAMINE WERE INDEPENDENT OF SIZE AT BIRTH, WHICH SUGGESTS THAT PROGRAMMING MAY OCCUR WITHOUT ALTERING SIZE AT BIRTH. FUTURE PLANS: AS THE COHORT AGES, WE WILL BE ASSESSING THE EFFECTS OF PRENATAL UNDERNUTRITION ON (BRAIN) AGEING, COGNITIVE DECLINE AND DEMENTIA, AS WELL AS OVERALL MORBIDITY AND MORTALITY. REGISTRATION: THE DUTCH FAMINE BIRTH COHORT IS NOT LINKED TO A CLINICAL TRIAL.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6  3586  87 IMPACT OF THE POLYCARBONATE STRIPPERS USED IN ASSISTED REPRODUCTION TECHNIQUES ON EMBRYONIC DEVELOPMENT. STUDY QUESTION: DO DAILY MANIPULATIONS OF PREIMPLANTATION EMBRYOS WITH POLYCARBONATE (PC)-MADE BISPHENOL A (BPA)-RELEASING STRIPPERS INFLUENCE EMBRYO DEVELOPMENT? SUMMARY ANSWER: COMPARED TO GLASS STRIPPERS, PC STRIPPERS ENHANCE THE BLASTOCYST DEVELOPMENT RATE BUT THIS DOES NOT SEEM TO BE BPA-RELATED. WHAT IS KNOWN ALREADY: PC STRIPPERS HAVE BEEN SHOWN TO RELEASE TINY AMOUNTS (AROUND 0.5 NG/ML BPA) OF BPA IN ROUTINE HUMAN IVF PROCEDURES. A CHRONIC EXPOSURE TO BPA EITHER IN VIVO OR IN VITRO DURING THE PREIMPLANTATION PERIOD CAN IMPACT POST-IMPLANTATION AND POST-NATAL DEVELOPMENT. BPA CAN ACT RAPIDLY BY BINDING TO MEMBRANE RECEPTORS AND INDUCING RAPID NON-GENOMIC EFFECTS. STUDY DESIGN, SIZE, DURATION: THIS EXPERIMENTAL STUDY USING MOUSE EMBRYOS HAD A BALANCED DESIGN AND BLINDED EVALUATIONS OF THE ENDPOINTS. PARTICIPANTS/MATERIALS, SETTING, METHODS: IN VIVO FERTILIZED ZYGOTES WERE OBTAINED FROM OUTBRED SWISS CD1 MICE CROSSINGS AFTER AN OVARIAN STIMULATION. THE ZYGOTES WERE ALLOCATED TO THREE DAILY HANDLING CONDITIONS (HCS) AND CULTURED UNTIL DAY 4 IN A SINGLE HUMAN COMMERCIAL MEDIUM. EACH DAY, THE EMBRYOS WERE HANDLED FOR 20 S EITHER IN A PC STRIPPER (HC1) OR IN A GLASS STRIPPER (HC2). IN HC3, THE EMBRYOS WERE PRE-EXPOSED TO 0.5 NG/ML BPA BEFORE BEING HANDLED FOR 20 S IN A GLASS STRIPPER. HANDLING OPERATIONS WERE REPEATED ON DAYS 1, 2 AND 3. EMBRYO DEVELOPMENT WAS ASSESSED BLINDLY ON DAY 4. EXPANDED BLASTOCYSTS WERE SELECTED FOR A TRANSCRIPTOMIC ANALYSIS USING AGILENT SUREPRINT G3 MOUSE GE V2 MICROARRAYS AND THE RETROTRANSPOSON LINE1-ORF2 EXPRESSION WAS ANALYSED USING QRT-PCR, AS A PROXY FOR A GLOBAL EVALUATION OF THE EPIGENETIC STATUS. MAIN RESULTS AND THE ROLE OF CHANCE: COMPARED TO THE EMBRYOS MANIPULATED IN HC2 (N = 243), THOSE IN HC1 (N = 228) DEVELOPED SIGNIFICANTLY MORE OFTEN TO THE BLASTOCYST STAGE (55 VS 46%; P < 0.05). IT APPEARS THE EFFECT OF THESE PC STRIPPERS WAS NOT BPA-RELATED BECAUSE EMBRYOS PRE-EXPOSED TO BPA (HC3, N = 230) SHOWED NO DIFFERENCE IN THE BLASTOCYST RATE WHEN COMPARED TO HC2 (43 VS 46%). WHEN ANALYSING SAME-STAGE BLASTOCYSTS, WE NOTICED NO DIFFERENCE IN THE EMBRYO GENE EXPRESSION BETWEEN THE THREE HC GROUPS. LARGE SCALE DATA: HTTPS://WWW.NCBI.NLM.NIH.GOV/GEO/QUERY/ACC.CGI?ACC=GSE148868. LIMITATIONS, REASONS FOR CAUTION: OUR RESULTS USING A MOUSE MODEL DESIGNED TO MIMIC HUMAN CONDITIONS (OUTBRED STRAIN, HUMAN COMMERCIAL IVF DISHES AND A UNIQUE COMMERCIAL HUMAN EMBRYONIC CULTURE MEDIA) ARE REASSURING SINCE NO GENE WAS FOUND TO BE DIFFERENTIALLY EXPRESSED, INCLUDING LINE-1 GENES, AS A PROXY FOR A GLOBAL EVALUATION OF THE EPIGENETIC STATUS. HOWEVER, NO GLOBAL EPIGENETIC ANALYSIS OF THE GENOME HAS BEEN PERFORMED. FURTHERMORE, WE DID NOT EVALUATE POST-IMPLANTATION EVENTS, ALTHOUGH BPA EXPOSURE DURING PERI-CONCEPTION COULD AFFECT FOETO-PLACENTAL AND POST-NATAL DEVELOPMENT. WIDER IMPLICATIONS OF THE FINDINGS: BASED ON THE PRECAUTIONARY PRINCIPLE, SEVERAL EUROPEAN COUNTRIES BANNED THE USE OF BPA IN BABY BOTTLES AND FOOD PACKAGING SEVERAL YEARS BEFORE EUROPEAN AGENCIES TOOK AN OFFICIAL POSITION. THE QUESTION OF APPLYING THIS PRINCIPLE TO PLASTICS IN CLOSED CONTACT WITH HUMAN EMBRYOS IS RAISED. FURTHER STUDIES ARE NEEDED FOR A DECISION TO BE MADE. STUDY FUNDING/COMPETING INTEREST(S): THIS STUDY WAS SUPPORTED BY A GRANT FROM THE AGENCE DE BIOMEDECINE (AOR 2016). THE AUTHORS DECLARE NO COMPETING INTEREST.	2021	
                                                                                        
7  3304  80 HIGH-GLUCOSE CONCENTRATIONS CHANGE DNA METHYLATION LEVELS IN HUMAN IVM OOCYTES. STUDY QUESTION: WHAT ARE THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON DNA METHYLATION OF HUMAN OOCYTES? SUMMARY ANSWER: HIGH-GLUCOSE CONCENTRATIONS ALTERED DNA METHYLATION LEVELS OF PEG3 AND ADIPONECTIN IN HUMAN IN VITRO MATURATION OOCYTES. WHAT IS KNOWN ALREADY: MATERNAL DIABETES HAS A DETRIMENTAL INFLUENCE ON OOCYTE QUALITY INCLUDING EPIGENETIC MODIFICATIONS, AS SHOWN IN NON-HUMAN MAMMALIAN SPECIES. STUDY DESIGN, SIZE, DURATION: IMMATURE METAPHASE I (MI) STAGE OOCYTES OF GOOD QUALITY WERE RETRIEVED FROM PATIENTS WHO HAD NORMAL OVARIAN POTENTIAL AND WHO UNDERWENT ICSI IN THE REPRODUCTIVE MEDICINE CENTER OF PEOPLE'S HOSPITAL OF ZHENGZHOU UNIVERSITY. MI OOCYTES WERE CULTURED IN MEDIUM WITH DIFFERENT GLUCOSE CONCENTRATIONS (CONTROL, 10 MM AND 15 MM) IN VITRO AND 48 H LATER, OOCYTES WITH FIRST POLAR BODY EXTRUSION WERE COLLECTED TO CHECK THE DNA METHYLATION LEVELS. PARTICIPANTS/MATERIALS, SETTING, METHODS: MI OOCYTES UNDERWENT IN VITRO MATURATION (IVM) AT 37 DEGREES C WITH 5% MIXED GAS FOR 48 H. THEN THE MATURE OOCYTES WERE TREATED WITH BISULFITE BUFFER. TARGET SEQUENCES WERE AMPLIFIED USING NESTED OR HALF-NESTED PCR AND THE DNA METHYLATION STATUS WAS TESTED USING COMBINED BISULFITE RESTRICTION ANALYSIS (COBRA) AND BISULFITE SEQUENCING (BS). MAIN RESULTS AND THE ROLE OF CHANCE: HIGH-GLUCOSE CONCENTRATIONS SIGNIFICANTLY DECREASED THE FIRST POLAR BODY EXTRUSION RATE. COMPARED TO CONTROLS, THE DNA METHYLATION LEVELS OF PEG3 IN HUMAN IVM OOCYTES WERE SIGNIFICANTLY HIGHER IN 10 MM (P < 0.001) AND 15 MM (P < 0.001) CONCENTRATIONS OF GLUCOSE. BUT THE DNA METHYLATION LEVEL OF H19 WAS NOT AFFECTED BY HIGH-GLUCOSE CONCENTRATIONS IN HUMAN IVM OOCYTES. WE ALSO FOUND THAT THERE WAS A DECREASE IN DNA METHYLATION LEVELS IN THE PROMOTER OF ADIPONECTIN IN HUMAN IVM OOCYTES BETWEEN CONTROLS AND OOCYTES EXPOSED TO 10 MM GLUCOSE (P = 0.028). LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: IT IS NOT CLEAR WHETHER THE ALTERATIONS ARE BENEFICIAL OR NOT FOR THE EMBRYO DEVELOPMENT AND OFFSPRING HEALTH. THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON THE WHOLE PROCESS OF OOCYTE MATURATION ARE STILL NOT ELUCIDATED. ANOTHER ISSUE IS THAT THE NUMBER OF OOCYTES USED IN THIS STUDY WAS LIMITED. WIDER IMPLICATIONS OF THE FINDINGS: THIS IS THE FIRST TIME THAT THE EFFECTS OF HIGH-GLUCOSE CONCENTRATION ON DNA METHYLATION OF HUMAN OOCYTES HAVE BEEN ELUCIDATED. OUR RESULT INDICATES THAT IN HUMANS, THE HIGH RISK OF CHRONIC DISEASES IN OFFSPRING FROM DIABETIC MOTHERS MAY ORIGINATE FROM ABNORMAL DNA MODIFICATIONS IN OOCYTES. STUDY FUNDING/COMPETING INTEREST(S): THIS WORK WAS SUPPORTED BY THE FUND OF NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA (81401198) AND DOCTOR FOUNDATION OF QINGDAO AGRICULTURAL UNIVERSITY (1116008).THE AUTHORS DECLARE THAT THERE ARE NO POTENTIAL CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8   520  52 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9  3429  44 HUNGRY IN THE WOMB: WHAT ARE THE CONSEQUENCES? LESSONS FROM THE DUTCH FAMINE. AN INCREASING BODY OF EVIDENCE SUGGESTS THAT POOR NUTRITION AT THE VERY BEGINNING OF LIFE - EVEN BEFORE BIRTH - LEADS TO LARGE AND LONG TERM NEGATIVE CONSEQUENCES FOR BOTH MENTAL AND PHYSICAL HEALTH. THIS PAPER REVIEWS THE EVIDENCE FROM STUDIES ON THE DUTCH FAMINE, WHICH INVESTIGATED THE EFFECTS OF PRENATAL UNDERNUTRITION ON LATER HEALTH. THE EFFECTS OF FAMINE APPEARED TO DEPEND ON ITS TIMING DURING GESTATION, AND THE ORGANS AND TISSUES UNDERGOING CRITICAL PERIODS OF DEVELOPMENT AT THAT TIME. EARLY GESTATION APPEARED TO BE THE MOST VULNERABLE PERIOD. PEOPLE WHO WERE CONCEIVED DURING THE FAMINE WERE AT INCREASED RISK OF SCHIZOPHRENIA AND DEPRESSION, THEY HAD A MORE ATHEROGENIC PLASMA LIPID PROFILE, WERE MORE RESPONSIVE TO STRESS AND HAD A DOUBLED RATE OF CORONARY HEART DISEASE. ALSO, THEY PERFORMED WORSE ON COGNITIVE TASKS WHICH MAY BE A SIGN OF ACCELERATED AGEING. PEOPLE EXPOSED DURING ANY PERIOD OF GESTATION HAD MORE TYPE 2 DIABETES. FUTURE INVESTIGATION WILL EXPAND ON THE FINDING THAT THE EFFECTS OF PRENATAL FAMINE EXPOSURE MAY REACH DOWN ACROSS GENERATIONS, POSSIBLY THROUGH EPIGENETIC MECHANISMS. RECENT EVIDENCE SUGGESTS THAT SIMILAR EFFECTS OF PRENATAL UNDERNUTRITION ARE FOUND IN AFRICA, WHERE MANY ARE UNDERNOURISHED. HUNGER IS A MAJOR PROBLEM WORLDWIDE WITH ONE IN SEVEN INHABITANTS OF THIS PLANET SUFFERING FROM LACK OF FOOD. ADEQUATELY FEEDING WOMEN BEFORE AND DURING PREGNANCY MAY BE A PROMISING STRATEGY IN PREVENTING CHRONIC DISEASES WORLDWIDE.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
10   518  54 ASSOCIATIONS BETWEEN ANTIBIOTIC EXPOSURE DURING PREGNANCY, BIRTH WEIGHT AND ABERRANT METHYLATION AT IMPRINTED GENES AMONG OFFSPRING. OBJECTIVES: LOW BIRTH WEIGHT (LBW) HAS BEEN ASSOCIATED WITH COMMON ADULT-ONSET CHRONIC DISEASES, INCLUDING OBESITY, CARDIOVASCULAR DISEASE, TYPE II DIABETES AND SOME CANCERS. THE ETIOLOGY OF LBW IS MULTI-FACTORIAL. HOWEVER, RECENT EVIDENCE SUGGESTS EXPOSURE TO ANTIBIOTICS MAY ALSO INCREASE THE RISK OF LBW. THE MECHANISMS UNDERLYING THIS ASSOCIATION ARE UNKNOWN, ALTHOUGH EPIGENETIC MECHANISMS ARE HYPOTHESIZED. IN THIS STUDY, WE EVALUATED THE ASSOCIATION BETWEEN MATERNAL ANTIBIOTIC USE AND LBW AND EXAMINED THE POTENTIAL ROLE OF ALTERED DNA METHYLATION THAT CONTROLS GROWTH REGULATORY IMPRINTED GENES IN THESE ASSOCIATIONS. METHODS: BETWEEN 2009-2011, 397 PREGNANT WOMEN WERE ENROLLED AND FOLLOWED UNTIL DELIVERY. PRENATAL ANTIBIOTIC USE WAS ASCERTAINED THROUGH MATERNAL SELF-REPORT. IMPRINTED GENES METHYLATION LEVELS WERE MEASURED AT DIFFERENTIALLY METHYLATED REGIONS (DMRS) USING BISULFITE PYROSEQUENCING. GENERALIZED LINEAR MODELS WERE USED TO EXAMINE ASSOCIATIONS AMONG ANTIBIOTIC USE, BIRTH WEIGHT AND DMR METHYLATION FRACTIONS. RESULTS: AFTER ADJUSTING FOR INFANT GENDER, RACE/ETHNICITY, MATERNAL BODY MASS INDEX, DELIVERY ROUTE, GESTATIONAL WEIGHT GAIN, GESTATIONAL AGE AT DELIVERY, FOLIC ACID INTAKE, PHYSICAL ACTIVITY, MATERNAL SMOKING AND PARITY, ANTIBIOTIC USE DURING PREGNANCY WAS ASSOCIATED WITH 138 G LOWER BIRTH WEIGHT COMPARED WITH NON-ANTIBIOTIC USE (BETA-COEFFICIENT=-132.99, S.E.=50.70, P=0.008). THESE ASSOCIATIONS WERE STRONGEST IN NEWBORNS OF WOMEN WHO REPORTED ANTIBIOTIC USE OTHER THAN PENICILLINS (BETA-COEFFICIENT=-135.57, S.E.=57.38, P=0.02). METHYLATION AT FIVE DMRS, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) AND PEG3 (P=0.08), WAS ASSOCIATED WITH MATERNAL ANTIBIOTIC USE; AMONG THESE, ONLY METHYLATION AT THE PLAGL1 DMR WAS ALSO ASSOCIATED WITH BIRTH WEIGHT. CONCLUSION: WE REPORT AN INVERSE ASSOCIATION BETWEEN IN UTERO EXPOSURE TO ANTIBIOTICS AND LOWER INFANT BIRTH WEIGHT AND PROVIDE THE FIRST EMPIRICAL EVIDENCE SUPPORTING IMPRINTED GENE PLASTICITY IN THESE ASSOCIATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  5200  45 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  4010  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13  2903  61 GENDER-SPECIFIC METHYLATION DIFFERENCES IN RELATION TO PRENATAL EXPOSURE TO CIGARETTE SMOKE. EPIGENETIC ALTERATIONS MAY MECHANISTICALLY EXPLAIN THE DEVELOPMENTAL ORIGINS OF ADULT DISEASE, NAMELY THE HYPOTHESIS THAT MANY COMPLEX ADULT CHRONIC DISEASES ORIGINATE AS A RESULT OF CONDITIONS ENCOUNTERED IN UTERO. IF TRUE, EPIGENETICALLY REGULATED IMPRINTED GENES, CRITICAL TO NORMAL GROWTH AND DEVELOPMENT, MAY PARTIALLY MEDIATE THESE OUTCOMES. WE DETERMINED THE INFLUENCE OF IN UTERO EXPOSURE TO CIGARETTE SMOKING ON METHYLATION AT TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) REGULATING INSULIN-LIKE GROWTH FACTOR 2 (IGF2) AND H19, AND HOW THIS MIGHT RELATE TO BIRTH WEIGHT OF INFANTS BORN TO 418 PREGNANT WOMEN. SMOKING STATUS WAS ASCERTAINED THROUGH SELF-REPORT AND MEDICAL RECORDS. BISULFITE PYROSEQUENCING WAS USED TO MEASURE METHYLATION IN UMBILICAL CORD BLOOD DNAS. LEAST SQUARES DNA METHYLATION MEANS AT EACH DMR AND BIRTH WEIGHT WERE COMPARED BETWEEN INFANTS OF SMOKERS AND NON-SMOKERS, USING GENERALIZED LINEAR MODELS. WHILE THERE WERE NO SIGNIFICANT DIFFERENCES AT THE H19 DMR, INFANTS BORN TO SMOKERS HAD HIGHER METHYLATION AT THE IGF2 DMR THAN THOSE BORN TO NEVER SMOKERS OR THOSE WHO QUIT DURING PREGNANCY (49.5%, SD=8.0 VERSUS 46.6%, SD=5.6 AND 45.8%, SD=6.3, RESPECTIVELY; P=0.0002). THE SMOKING-RELATED INCREASE IN METHYLATION WAS MOST PRONOUNCED IN MALE OFFSPRING (P FOR SEX INTERACTION=0.03), FOR WHOM APPROXIMATELY 20% OF SMOKING-RELATED LOW BIRTH WEIGHT WAS MEDIATED BY DNA METHYLATION AT THE IGF2 DMR. OUR FINDINGS SUGGEST THAT IGF2 DMR PLASTICITY IS AN IMPORTANT MECHANISM BY WHICH IN UTERO ADJUSTMENTS TO ENVIRONMENTAL TOXICANTS ARE CONFERRED. LARGER STUDIES TO REPLICATE THESE FINDINGS ARE REQUIRED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  4612  41 NEONATAL PAIN AND COMT VAL158MET GENOTYPE IN RELATION TO SEROTONIN TRANSPORTER (SLC6A4) PROMOTER METHYLATION IN VERY PRETERM CHILDREN AT SCHOOL AGE. CHILDREN BORN VERY PRETERM ARE EXPOSED TO REPEATED NEONATAL PROCEDURES THAT INDUCE PAIN AND STRESS DURING HOSPITALIZATION IN THE NEONATAL INTENSIVE CARE UNIT (NICU). THE COMT VAL158MET GENOTYPE IS INVOLVED WITH PAIN SENSITIVITY, AND EARLY LIFE STRESS IS IMPLICATED IN ALTERED EXPRESSION OF METHYLATION OF THE SEROTONIN TRANSPORTER. WE EXAMINED: (1) WHETHER METHYLATION OF THE SEROTONIN TRANSPORTER GENE (SLC6A4) PROMOTER DIFFERS BETWEEN VERY PRETERM CHILDREN AND FULL-TERM CONTROLS AT SCHOOL AGE, (2) RELATIONSHIPS WITH CHILD BEHAVIOR PROBLEMS, AND (3) WHETHER THE EXTENT OF NEONATAL PAIN EXPOSURE INTERACTS WITH THE COMT VAL158MET GENOTYPE TO PREDICT SLC6A4 METHYLATION AT 7 YEARS IN THE VERY PRETERM CHILDREN. WE EXAMINED THE ASSOCIATIONS BETWEEN THE COMT GENOTYPES, NEONATAL PAIN EXPOSURE (ADJUSTED FOR NEONATAL CLINICAL CONFOUNDERS), SLC6A4 METHYLATION AND BEHAVIOR PROBLEMS. VERY PRETERM CHILDREN HAD SIGNIFICANTLY HIGHER METHYLATION AT 7/10 CPG SITES IN THE SLC6A4 PROMOTER COMPARED TO FULL-TERM CONTROLS AT 7 YEARS. NEONATAL PAIN (ADJUSTED FOR CLINICAL CONFOUNDERS) WAS SIGNIFICANTLY ASSOCIATED WITH TOTAL CHILD BEHAVIOR PROBLEMS ON THE CHILD BEHAVIOR CHECKLIST (CBCL) QUESTIONNAIRE (ADJUSTED FOR CONCURRENT STRESSORS AND 5HTTLPR GENOTYPE) (P = 0.035). CBCL TOTAL PROBLEMS WAS SIGNIFICANTLY ASSOCIATED WITH GREATER SLC6A4 METHYLATION IN VERY PRETERM CHILDREN (P = 0.01). NEONATAL PAIN (ADJUSTED FOR CLINICAL CONFOUNDERS) AND COMT MET/MET GENOTYPE WERE ASSOCIATED WITH SLC6A4 PROMOTER METHYLATION IN VERY PRETERM CHILDREN AT 7 YEARS (P = 0.001). THESE FINDINGS PROVIDE EVIDENCE THAT BOTH GENETIC PREDISPOSITION AND EARLY ENVIRONMENT NEED TO BE CONSIDERED IN UNDERSTANDING SUSCEPTIBILITY FOR DEVELOPING BEHAVIORAL PROBLEMS IN THIS VULNERABLE POPULATION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  6089  57 THE EFFECTS OF DEPRESSION AND USE OF ANTIDEPRESSIVE MEDICINES DURING PREGNANCY ON THE METHYLATION STATUS OF THE IGF2 IMPRINTED CONTROL REGIONS IN THE OFFSPRING. IN UTERO EXPOSURES TO ENVIRONMENTAL FACTORS MAY RESULT IN PERSISTENT EPIGENETIC MODIFICATIONS AFFECTING NORMAL DEVELOPMENT AND SUSCEPTIBILITY TO CHRONIC DISEASES IN LATER LIFE. WE EXPLORED THE RELATIONSHIP BETWEEN EXPOSURE OF THE GROWING FETUS TO MATERNAL DEPRESSION OR ANTIDEPRESSANTS AND DNA METHYLATION AT TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) OF THE IMPRINTED INSULIN-LIKE GROWTH FACTOR 2 (IGF2) GENE. ABERRANT DNA METHYLATION AT THE IGF2 AND NEIGHBORING H19 DMRS HAS BEEN ASSOCIATED WITH DEREGULATED IGF2 EXPRESSION, CHILDHOOD CANCERS AND SEVERAL CHRONIC DISEASES DURING ADULTHOOD. OUR STUDY POPULATION IS COMPRISED OF PREGNANT MOTHERS AND THEIR NEWBORNS (N = 436), AS PART OF THE NEWBORN EPIGENETICS STUDY (NEST). A STANDARDIZED QUESTIONNAIRE WAS COMPLETED AND MEDICAL RECORD DATA WERE ABSTRACTED TO ASCERTAIN MATERNAL DEPRESSION AND ANTIDEPRESSIVE DRUG USE. DMR METHYLATION LEVELS IN UMBILICAL CORD BLOOD LEUKOCYTES WERE QUANTIFIED USING PYROSEQUENCING. FROM THE 436 NEWBORNS, LABORATORY DATA WERE OBTAINED FOR 356 INDIVIDUALS AT THE IGF2 DMRS, AND FOR 411 INDIVIDUALS AT THE H19 DMRS; ABOUT HALF OF EACH GROUP WAS AFRICAN AMERICAN OR CAUCASIAN. WHILE OVERALL NO ASSOCIATION BETWEEN DEPRESSION AND METHYLATION PROFILES WAS FOUND, WE OBSERVED A SIGNIFICANT HYPERMETHYLATION OF THE H19 DMRS IN NEWBORNS OF AFRICAN AMERICAN (N = 177) BUT NOT CAUCASIAN (N = 168) MOTHERS WHO REPORTED THE USE OF ANTIDEPRESSIVE DRUGS DURING PREGNANCY (BETA = +6.89, P = 0.01). OF NOTE, OUR DATA REVEAL A RACE-INDEPENDENT ASSOCIATION BETWEEN SMOKING DURING PREGNANCY AND METHYLATION AT THE IGF2 DMR (+3.05%, P = 0.01). IN CONCLUSION, OUR FINDINGS SUGGEST A RACE-DEPENDENT RESPONSE RELATED TO MATERNAL USE OF ANTIDEPRESSANTS AT ONE OF THE IGF2 DMRS IN THE OFFSPRING.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  4066  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17  6559  36 TRANSGENERATIONAL INFLUENCE OF PARENTAL MORPHINE EXPOSURE ON PAIN PERCEPTION, ANXIETY-LIKE BEHAVIOR AND PASSIVE AVOIDANCE MEMORY AMONG MALE AND FEMALE OFFSPRING OF WISTAR RATS. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN THE FORMATION AND MAINTENANCE OF MEMORY WITHIN THE BRAIN. MOREOVER, THE EFFECT OF PARENTAL DRUG-EXPOSURE BEFORE GESTATION ON BEHAVIORAL STATE OF OFFSPRING HAS BEEN LITTLE STUDIED. THE MAIN OBJECTIVE OF THE CURRENT STUDY IS TO EVALUATE THE EFFECT OF PARENTAL MORPHINE EXPOSURE ON AVOIDANCE MEMORY, MORPHINE PREFERENCE AND ANXIETY-LIKE BEHAVIOR OF OFFSPRING. THE TOTAL OF 32 MALES AND 32 FEMALES WERE USED FOR MATING. THE ANIMALS WERE TREATED WITH MORPHINE. THE OFFSPRING ACCORDING TO THEIR PARENTAL MORPHINE TREATMENT WAS DIVIDED INTO FOUR GROUPS (N=16) INCLUDING PATERNALLY TREATED, MATERNALLY TREATED, BOTH OF PARENTS TREATED AND NAIVE ANIMALS. THE PAIN PERCEPTION, ANXIETY-LIKE BEHAVIOR, AND AVOIDANCE MEMORY WERE EVALUATED IN THE OFFSPRING. IN THE CURRENT STUDY, THE TOTAL OF 256 OFFSPRING WAS USED FOR THE EXPERIMENTS (4 TASKS X 4 GROUPS OF OFFSPRING X 8 FEMALE OFFSPRING X 8 MALE OFFSPRING). THE FINDING REVEALED THAT THE AVOIDANCE MEMORY AND VISCERAL PAIN WERE REDUCED SIGNIFICANTLY IN MALE AND FEMALE OFFSPRING WITH AT LEAST ONE MORPHINE-TREATED PARENT. MOREOVER, ANXIETY-LIKE BEHAVIOR WAS REDUCED SIGNIFICANTLY IN THE MALE OFFSPRING WITH AT LEAST ONE MORPHINE-TREATED PARENT. WHILE ANXIETY-LIKE BEHAVIOR WAS INCREASED SIGNIFICANTLY IN FEMALE OFFSPRING THAT WERE TREATED BY MORPHINE EITHER MATERNALLY OR BOTH OF PARENTS. THE DATA REVEALED THAT THE ENDOGENOUS OPIOID SYSTEM MAY BE ALTERED IN THE OFFSPRING OF MORPHINE-TREATED PARENT(S), AND EPIGENETIC ROLE COULD BE IMPORTANT. HOWEVER, ANALYSIS OF VARIANCE SIGNIFIED THE IMPORTANT ROLE OF MATERNAL INHERITANCE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  4939  49 PATERNAL NICOTINE EXPOSURE IN RATS PRODUCES LONG-LASTING NEUROBEHAVIORAL EFFECTS IN THE OFFSPRING. STUDIES OF INTERGENERATIONAL EFFECTS OF PARENTAL CHEMICAL EXPOSURE HAVE PRINCIPALLY FOCUSED ON MATERNAL EXPOSURE, PARTICULARLY FOR STUDIES OF ADVERSE NEUROBEHAVIORAL CONSEQUENCES ON THE OFFSPRING. MATERNAL NICOTINE EXPOSURE HAS LONG BEEN KNOWN TO CAUSE ADVERSE NEUROBEHAVIORAL EFFECTS ON THE OFFSPRING. HOWEVER, PATERNAL TOXICANT EXPOSURE HAS ALSO BEEN FOUND TO CAUSE NEUROBEHAVIORAL TOXICITY IN THEIR OFFSPRING. RECENT WORK SUGGESTS THAT PATERNAL NICOTINE EXPOSURE CAN HAVE EPIGENETIC EFFECTS, ALTHOUGH IT REMAINS UNCLEAR WHETHER SUCH CHANGES LEAD TO NEUROBEHAVIORAL EFFECTS. IN THE CURRENT STUDY, WE INVESTIGATED THE EFFECTS OF PATERNAL NICOTINE EXPOSURE ON NEUROBEHAVIORAL DEVELOPMENT OF THEIR OFFSPRING. MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO 0 OR 2 MG/KG/DAY NICOTINE (SC) FOR 56 CONSECUTIVE DAYS WITH TWO CONSECUTIVE 2ML4 OSMOTIC MINIPUMPS. FOLLOWING TREATMENT, THESE MALES WERE MATED WITH DRUG-NAIVE FEMALE RATS. OFFSPRING OF BOTH SEXES WERE TESTED IN A BEHAVIORAL BATTERY TO ASSESS LOCOMOTION, EMOTIONAL FUNCTION AND COGNITION. PATERNAL NICOTINE EXPOSURE DID NOT IMPACT OFFSPRING VIABILITY, HEALTH OR GROWTH. HOWEVER, BEHAVIORAL FUNCTION OF THE OFFSPRING WAS SIGNIFICANTLY ALTERED BY PATERNAL NICOTINE EXPOSURE. MALE OFFSPRING WITH PATERNAL NICOTINE EXPOSURE EXHIBITED LOCOMOTOR HYPERACTIVITY IN THE FIGURE-8 APPARATUS WHEN TESTED DURING ADOLESCENCE. WHEN RETESTED IN ADULTHOOD AND REGARDLESS OF SEX, OFFSPRING OF THE NICOTINE EXPOSED FATHER SHOWED SIGNIFICANTLY REDUCED HABITUATION OF LOCOMOTOR ACTIVITY OVER THE COURSE OF THE SESSION. COMPARED TO CONTROLS, FEMALE OFFSPRING OF NICOTINE-EXPOSED FATHERS SHOWED SIGNIFICANTLY REDUCED RESPONSE LATENCY IN THE RADIAL ARM MAZE TEST. IN ADDITION TO LOCOMOTOR HYPERACTIVITY, THE OFFSPRING OF NICOTINE-EXPOSED FATHERS ALSO SHOWED SIGNIFICANTLY DIMINISHED HABITUATION IN THE NOVEL OBJECT RECOGNITION TEST. THESE RESULTS INDICATE THAT CHRONIC PATERNAL NICOTINE EXPOSURE CAN IMPACT THE BEHAVIOR OF OFFSPRING, PRODUCING LOCOMOTOR HYPERACTIVITY AND IMPAIRED HABITUATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19  3785  33 INTERGENERATIONAL EFFECTS OF PRE-PREGNANCY CHRONIC LIPOPOLYSACCHARIDE FROM PORPHYROMONAS GINGIVALIS ON THE LEARNING, MEMORY AND SEIZURE SUSCEPTIBILITY OF OFFSPRING. OBJECTIVE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EFFECTS OF PRE-PREGNANCY CHRONIC EXPOSURE TO PORPHYROMONAS GINGIVALIS LPS (PG LPS) ON THE LEARNING, MEMORY, AND SEIZURE SUSCEPTIBILITY OF THE OFFSPRING. DESIGN: TO ACHIEVE PERIODONTITIS, PG LPS (5 MUG/KG) WAS INJECTED INTO THE GINGIVAL OF FIVE FEMALE RATS EVERY 48 H FOR THREE WEEKS. FIVE CONTROL FEMALE RATS RECEIVED SALINE (0.9 %) AND FIVE FEMALE WERE KEPT INTACT. THE CONCENTRATIONS OF TNF-ALPHA AND IL-6 WERE MEASURED IN THE BLOOD SAMPLES. ONE WEEK AFTER THE FINAL INJECTION, FEMALES WERE MATED WITH INTACT MALES. FOLLOWING BIRTH AND WEANING, TWO MALE AND TWO FEMALE OFFSPRING WERE RANDOMLY SELECTED FROM EACH MOTHER, AND NEW GROUPS OF MALE AND FEMALE OFFSPRING WERE DEFINED FOR BEHAVIORAL ASSESSMENTS. MORRIS WATER MAZE WAS USED TO EVALUATE SPATIAL MEMORY, SHUTTLE BOX WAS USED TO INVESTIGATE AVOIDANCE MEMORY AND A PENTYLENETETRAZOLE-INDUCED SEIZURE WAS USED TO EVALUATE SEIZURE SUSCEPTIBILITY IN THE OFFSPRING. RESULTS: SPATIAL LEARNING AND AVOIDANCE MEMORY SIGNIFICANTLY DECREASED IN BOTH MALE AND FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE RATS, COMPARED TO THE CONTROL OFFSPRING. LATENCY TO REACH SEIZURE STAGES 1 AND 2 SIGNIFICANTLY INCREASED IN THE MALE OFFSPRING, BUT NOT THE FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE, COMPARED TO THE CONTROL OFFSPRING. HOWEVER, NO SIGNIFICANT DIFFERENCE WAS FOUND IN LATENCY TO REACH STAGES 3-5. CONCLUSION: PRE-PREGNANCY EXPOSURE TO PG LPS COULD AFFECT SOME BEHAVIORAL FUNCTIONS IN BOTH MALE AND FEMALE OFFSPRING INTERGENERATIONALLY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20  3179  53 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED.	2016