1  3121 180 GESTATIONAL INTERMITTENT HYPOXIA INDUCES ENDOTHELIAL DYSFUNCTION, REDUCES PERIVASCULAR ADIPONECTIN AND CAUSES EPIGENETIC CHANGES IN ADULT MALE OFFSPRING. KEY POINTS: OBSTRUCTIVE SLEEP APNOEA (OSA) IS CHARACTERIZED BY INTERMITTENT HYPOXIA, WHICH CAUSES OXIDATIVE STRESS AND INFLAMMATION AND INCREASES THE RISK OF CARDIOVASCULAR DISEASE. OSA DURING PREGNANCY CAUSES ADVERSE MATERNAL AND FETAL OUTCOMES. THE EFFECTS OF PRE-EXISTING OSA IN PREGNANT WOMEN ON CARDIOMETABOLIC OUTCOMES IN THE OFFSPRING ARE UNKNOWN. WE EVALUATED BASIC METABOLIC PARAMETERS, AS WELL AS AORTIC VASCULAR AND PERIVASCULAR ADIPOSE TISSUE (PVAT) FUNCTION IN RESPONSE TO ADIPONECTIN, AND EXAMINED DNA METHYLATION OF ADIPONECTIN GENE PROMOTER IN PVAT IN 16-WEEK-OLD ADULT OFFSPRING EXPOSED TO GESTATIONAL INTERMITTENT HYPOXIA (GIH). GIH DECREASED BODY WEIGHTS AT WEEK 1 IN BOTH MALE AND FEMALE OFFSPRING, AND CAUSED SUBSEQUENT INCREASES IN BODY WEIGHT AND FOOD CONSUMPTION IN MALE OFFSPRING ONLY. ADULT FEMALE OFFSPRING HAD NORMAL LEVELS OF LIPIDS, GLUCOSE AND INSULIN, WITH NO ENDOTHELIAL DYSFUNCTION. ADULT MALE OFFSPRING EXHIBITED DYSLIPIDAEMIA, INSULIN RESISTANCE AND HYPERLEPTINAEMIA. DECREASED ENDOTHELIAL-DEPENDENT VASODILATATION, LOSS OF ANTI-CONTRACTILE ACTIVITY OF PVAT AND LOW CIRCULATING PVAT ADIPONECTIN LEVELS, AS WELL AS INCREASED PRO-INFLAMMATORY GENE EXPRESSION AND DNA METHYLATION OF ADIPONECTIN GENE PROMOTER, OCCURRED IN ADULT MALE OFFSPRING. OUR RESULTS SUGGEST THAT MALE OFFSPRING OF WOMEN WITH OSA COULD BE AT RISK OF DEVELOPING CARDIOMETABOLIC DISEASE DURING ADULTHOOD. ABSTRACT: PERTURBATIONS DURING PREGNANCY CAN PROGRAM THE OFFSPRING TO DEVELOP CARDIOMETABOLIC DISEASES LATER IN LIFE. OBSTRUCTIVE SLEEP APNOEA (OSA) IS A CHRONIC CONDITION THAT FREQUENTLY AFFECTS PREGNANCIES AND LEADS TO ADVERSE FETAL OUTCOMES. WE ASSESSED THE OFFSPRING OF FEMALE MICE EXPERIENCING GESTATIONAL INTERMITTENT HYPOXIA (GIH), A HALLMARK OF OSA, FOR CHANGES IN METABOLIC PROFILES, AORTIC NITRIC OXIDE (NO)-DEPENDENT RELAXATIONS, PERIVASCULAR ADIPOSE TISSUE (PVAT) ANTI-CONTRACTILE ACTIVITIES AND THE RESPONSES TO ADIPONECTIN, AND DNA METHYLATION OF THE ADIPONECTIN GENE PROMOTER IN PVAT TISSUE. PREGNANT MOUSE DAMS WERE EXPOSED TO INTERMITTENT HYPOXIC CYCLES ( FIO2 21-12%) FOR 18 DAYS. GIH RESULTED IN LOWER BODY WEIGHTS OF PUPS AT WEEK 1, FOLLOWED BY SIGNIFICANT WEIGHT GAIN BY WEEK 16 OF AGE IN MALE BUT NOT FEMALE OFFSPRING. PLASMA LIPIDS, LEPTIN AND INSULIN RESISTANCE WERE HIGHER IN GIH MALE ADULT OFFSPRING. ENDOTHELIUM-DEPENDENT RELAXATION IN RESPONSE TO ACH AND THE ANTI-CONTRACTILE ACTIVITY OF PVAT IN THE ABDOMINAL AORTA WAS REDUCED IN GIH ADULT MALE OFFSPRING. INCUBATION OF ARTERIES FROM GIH ADULT MALE OFFSPRING WITH ADIPONECTIN RESTORED THE ANTI-CONTRACTILE ACTIVITY OF PVAT. BOTH CIRCULATING AND PVAT TISSUE HOMOGENATE LEVELS OF ADIPONECTIN, AS WELL AS GENE EXPRESSION OF ADIPONECTIN IN PVAT, WERE LOWER IN GIH MALE OFFSPRING, ALONG WITH AN INCREASED GENE EXPRESSION OF INFLAMMATORY CYTOKINES. PYROSEQUENCING OF ADIPONECTIN GENE PROMOTER IN PVAT SHOWED INCREASED DNA METHYLATION IN GIH MALE OFFSPRING. OUR RESULTS INDICATE THAT GIH LEADS TO VASCULAR DISEASE IN ADULT MALE OFFSPRING THROUGH PVAT DYSFUNCTION, WHICH WAS ASSOCIATED WITH LOW ADIPONECTIN LEVELS AND EPIGENETIC MODIFICATIONS ON THE ADIPONECTIN GENE PROMOTER.	2019	

2  4138  41 MECHANISMS OF MICROGLIAL ACTIVATION IN MODELS OF INFLAMMATION AND HYPOXIA: IMPLICATIONS FOR CHRONIC INTERMITTENT HYPOXIA. CHRONIC INTERMITTENT HYPOXIA (CIH) IS A HALLMARK OF SLEEP APNOEA, A CONDITION ASSOCIATED WITH DIVERSE CLINICAL DISORDERS. CIH AND SLEEP APNOEA ARE CHARACTERIZED BY INCREASED REACTIVE OXYGEN SPECIES FORMATION, PERIPHERAL AND CNS INFLAMMATION, NEURONAL DEATH AND NEUROCOGNITIVE DEFICITS. FEW STUDIES HAVE EXAMINED THE ROLE OF MICROGLIA, THE RESIDENT CNS IMMUNE CELLS, IN MODELS OF CIH. THUS, LITTLE IS KNOWN CONCERNING THEIR DIRECT CONTRIBUTIONS TO NEUROPATHOLOGY OR THE CELLULAR MECHANISMS REGULATING THEIR ACTIVITIES DURING OR FOLLOWING PATHOLOGICAL CIH. IN THIS REVIEW, WE IDENTIFY GAPS IN KNOWLEDGE REGARDING CIH-INDUCED MICROGLIAL ACTIVATION, AND PROPOSE MECHANISMS BASED ON DATA FROM RELATED MODELS OF HYPOXIA AND/OR HYPOXIA-REOXYGENATION. CIH MAY DIRECTLY AFFECT MICROGLIA, OR MAY HAVE INDIRECT EFFECTS VIA THE PERIPHERY OR OTHER CNS CELLS. PERIPHERAL INFLAMMATION MAY INDIRECTLY ACTIVATE MICROGLIA VIA ENTRY OF PRO-INFLAMMATORY MOLECULES INTO THE CNS, AND/OR ACTIVATION OF VAGAL AFFERENTS THAT TRIGGER CNS INFLAMMATION. CIH-INDUCED RELEASE OF DAMAGE-ASSOCIATED MOLECULAR PATTERNS FROM INJURED CNS CELLS MAY ALSO ACTIVATE MICROGLIA VIA INTERACTIONS WITH PATTERN RECOGNITION RECEPTORS EXPRESSED ON MICROGLIA. FOR EXAMPLE, TOLL-LIKE RECEPTORS ACTIVATE MITOGEN-ACTIVATED PROTEIN KINASE/TRANSCRIPTION FACTOR PATHWAYS REQUIRED FOR MICROGLIAL INFLAMMATORY GENE EXPRESSION. ALTHOUGH EPIGENETIC EFFECTS FROM CIH HAVE NOT YET BEEN STUDIED IN MICROGLIA, POTENTIAL EPIGENETIC MECHANISMS IN MICROGLIAL REGULATION ARE DISCUSSED, INCLUDING MICRORNAS, HISTONE MODIFICATIONS AND DNA METHYLATION. EPIGENETIC EFFECTS CAN OCCUR DURING CIH, OR LONG AFTER IT HAS ENDED. A BETTER UNDERSTANDING OF CIH EFFECTS ON MICROGLIAL ACTIVITIES MAY BE IMPORTANT TO REVERSE CIH-INDUCED NEUROPATHOLOGY IN PATIENTS WITH SLEEP DISORDERED BREATHING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
3  2359  57 EPIGENETIC REGULATION OF REDOX STATE MEDIATES PERSISTENT CARDIORESPIRATORY ABNORMALITIES AFTER LONG-TERM INTERMITTENT HYPOXIA. KEY POINTS: THE EFFECTS OF SHORT-TERM (ST; 10 DAYS) AND LONG-TERM (LT; 30 DAYS) INTERMITTENT HYPOXIA (IH) ON BLOOD PRESSURE (BP), BREATHING AND CAROTID BODY (CB) CHEMOSENSORY REFLEX WERE EXAMINED IN ADULT RATS. ST- AND LT-IH TREATED RATS EXHIBITED HYPERTENSION, IRREGULAR BREATHING WITH APNOEA AND AUGMENTED THE CB CHEMOSENSORY REFLEX, WITH ALL THESE RESPONSES BECOMING NORMALIZED DURING RECOVERY FROM ST- BUT NOT FROM LT-IH. THE PERSISTENT CARDIORESPIRATORY RESPONSES TO LT-IH WERE ASSOCIATED WITH ELEVATED REACTIVE OXYGEN SPECIES (ROS) LEVELS IN THE CB AND ADRENAL MEDULLA, WHICH WERE A RESULT OF DNA METHYLATION-DEPENDENT SUPPRESSION OF GENES ENCODING ANTI-OXIDANT ENZYMES (AOES). TREATING RATS WITH DECITABINE EITHER DURING LT-IH OR DURING RECOVERY FROM LT-IH PREVENTED DNA METHYLATION OF AOE GENES, NORMALIZED THE EXPRESSION OF AOE GENES AND ROS LEVELS, REVERSED THE HEIGHTENED CB CHEMOSENSORY REFLEX AND HYPERTENSION, AND ALSO STABILIZED BREATHING. ABSTRACT: RODENTS EXPOSED TO CHRONIC INTERMITTENT HYPOXIA (IH), SIMULATING BLOOD O(2) SATURATION PROFILES DURING OBSTRUCTIVE SLEEP APNOEA (OSA), HAVE BEEN SHOWN TO EXHIBIT A HEIGHTENED CAROTID BODY (CB) CHEMOSENSORY REFLEX AND HYPERTENSION. CB CHEMOSENSORY REFLEX ACTIVATION ALSO RESULTS IN UNSTABLE BREATHING WITH APNOEAS. HOWEVER, THE EFFECT OF CHRONIC IH ON BREATHING IS NOT KNOWN. IN THE PRESENT STUDY, WE EXAMINED THE EFFECTS OF CHRONIC IH ON BREATHING ALONG WITH BLOOD PRESSURE (BP) AND ASSESSED WHETHER THE AUTONOMIC RESPONSES ARE NORMALIZED AFTER RECOVERY FROM CHRONIC IH. STUDIES WERE PERFORMED ON ADULT, MALE, SPRAGUE-DAWLEY RATS EXPOSED TO EITHER SHORT-TERM (ST; 10 DAYS) OR LONG-TERM (LT, 30 DAYS) IH. RATS EXPOSED TO EITHER ST- OR LT-IH EXHIBITED HYPERTENSION, IRREGULAR BREATHING WITH APNOEAS, AN AUGMENTED CB CHEMOSENSORY REFLEX AS INDICATED BY ELEVATED CB NEURAL ACTIVITY AND PLASMA CATECHOLAMINE LEVELS, AND ELEVATED REACTIVE OXYGEN SPECIES (ROS) LEVELS IN THE CB AND ADRENAL MEDULLA (AM). ALL THESE EFFECTS WERE NORMALIZED AFTER RECOVERY FROM ST-IH BUT NOT FROM LT-IH. ANALYSIS OF THE MOLECULAR MECHANISMS UNDERLYING THE PERSISTENT EFFECTS OF LT-IH REVEALED INCREASED DNA METHYLATION OF GENES ENCODING ANTI-OXIDANT ENZYMES (AOES). TREATMENT WITH DECITABINE, A DNA METHYLATION INHIBITOR, EITHER DURING LT-IH OR DURING RECOVERY FROM LT-IH, PREVENTED DNA METHYLATION, NORMALIZED THE EXPRESSION OF AOE GENES, ROS LEVELS, CB CHEMOSENSORY REFLEX AND BP, AND ALSO STABILIZED BREATHING. THESE RESULTS SUGGEST THAT PERSISTENT CARDIORESPIRATORY ABNORMALITIES CAUSED BY LT-IH ARE MEDIATED BY EPIGENETIC RE-PROGRAMMING OF THE REDOX STATE IN THE CB CHEMOSENSORY REFLEX PATHWAY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4   231  31 ADAPTIVE CARDIORESPIRATORY CHANGES TO CHRONIC CONTINUOUS AND INTERMITTENT HYPOXIA. THIS CHAPTER REVIEWS CARDIORESPIRATORY ADAPTATIONS TO CHRONIC HYPOXIA (CH) EXPERIENCED AT HIGH ALTITUDE AND CARDIORESPIRATORY PATHOLOGIES ELICITED BY CHRONIC INTERMITTENT HYPOXIA (CIH) OCCURRING WITH OBSTRUCTIVE SLEEP APNEA (OSA). SHORT-TERM CH INCREASES BREATHING (VENTILATORY ACCLIMATIZATION TO HYPOXIA) AND BLOOD PRESSURE (BP) THROUGH CAROTID BODY (CB) CHEMO REFLEX. HYPERPLASIA OF GLOMUS CELLS, ALTERATIONS IN ION CHANNELS, AND RECRUITMENT OF ADDITIONAL EXCITATORY MOLECULES ARE IMPLICATED IN THE HEIGHTENED CB CHEMO REFLEX BY CH. TRANSCRIPTIONAL ACTIVATION OF HYPOXIA-INDUCIBLE FACTORS (HIF-1 AND 2) IS A MAJOR MOLECULAR MECHANISM UNDERLYING RESPIRATORY ADAPTATIONS TO SHORT-TERM CH. HIGH-ALTITUDE NATIVES EXPERIENCING LONG-TERM CH EXHIBIT BLUNTED HYPOXIC VENTILATORY RESPONSE (HVR) AND REDUCED BP DUE TO DESENSITIZATION OF CB RESPONSE TO HYPOXIA AND IMPAIRED PROCESSING OF CB SENSORY INFORMATION AT THE CENTRAL NERVOUS SYSTEM. VENTILATORY CHANGES EVOKED BY LONG-TERM CH ARE NOT READILY REVERSED AFTER RETURN TO SEA LEVEL. OSA PATIENTS AND RODENTS SUBJECTED TO CIH EXHIBIT HEIGHTENED CB CHEMO REFLEX, INCREASED HYPOXIC VENTILATORY RESPONSE, AND HYPERTENSION. INCREASED GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IS A MAJOR CELLULAR MECHANISM UNDERLYING CIH-INDUCED ENHANCED CB CHEMO REFLEX AND THE ENSUING CARDIORESPIRATORY PATHOLOGIES. ROS GENERATION BY CIH IS MEDIATED BY NONTRANSCRIPTIONAL, DISRUPTED HIF-1 AND HIF-2-DEPENDENT TRANSCRIPTIONS AS WELL AS EPIGENETIC MECHANISMS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  5128  48 POSTNATAL INTERMITTENT HYPOXIA ENHANCES PHRENIC AND REDUCES VAGAL UPPER AIRWAY MOTOR ACTIVITIES IN RATS BY EPIGENETIC MECHANISMS. NEW FINDINGS: WHAT IS THE CENTRAL QUESTION OF THIS STUDY? WHAT ARE THE ALTERATIONS IN RESPIRATORY MOTOR ACTIVITY THAT MAY UNDERLIE VENTILATORY DYSFUNCTIONS IN JUVENILE AND ADULT ANIMALS EXPOSED TO POSTNATAL CHRONIC INTERMITTENT HYPOXIA? WHAT IS THE MAIN FINDING AND ITS IMPORTANCE? POSTNATAL CHRONIC INTERMITTENT HYPOXIA MODIFIES THE MOTOR ACTIVITY TO PUMPING AND UPPER AIRWAY RESPIRATORY MUSCLES IN RATS, MEDIATED BY EPIGENETIC DNA HYPERMETHYLATION, ENHANCING RESTING PULMONARY VENTILATION AND PREDISPOSING TO COLLAPSE OF THE UPPER AIRWAYS IN JUVENILE AND ADULT LIFE. ABSTRACT: PERIODS OF APNOEA, COMMONLY OBSERVED IN PREMATURES AND NEWBORNS, ARE AN IMPORTANT RISK FACTOR FOR THE DEVELOPMENT OF CARDIORESPIRATORY DISEASES IN ADULTHOOD. IN THE PRESENT STUDY, WE EVALUATED CHANGES IN PULMONARY VENTILATION AND RESPIRATORY MOTOR PATTERN IN JUVENILE AND ADULT RATS EXPOSED TO POSTNATAL CHRONIC INTERMITTENT HYPOXIA (PCIH). NEWBORN MALE HOLTZMAN RATS (P1) WERE SUBMITTED TO PCIH (6% O(2) FOR 30 S, EVERY 9 MIN, 8 H A DAY (09.30-17.30 H)) DURING THEIR FIRST 10 DAYS OF LIFE, WHILE CONTROL ANIMALS WERE MAINTAINED UNDER NORMOXIC CONDITIONS (20.8% O(2) ). THEREAFTER, ANIMALS OF BOTH GROUPS WERE MAINTAINED UNDER NORMOXIA UNTIL THE EXPERIMENTS. UNANAESTHETIZED JUVENILE PCIH RATS (N = 27) EXHIBITED ELEVATED TIDAL VOLUME AND RESPIRATORY IRREGULARITIES (P < 0.05) COMPARED TO CONTROL RATS (N = 7). DECEREBRATE, ARTERIALLY PERFUSED IN SITU PREPARATIONS OF JUVENILE PCIH RATS (N = 11) DISPLAYED AUGMENTED PHRENIC NERVE (PN) BURST AMPLITUDE AND REDUCED CENTRAL VAGUS NERVE ACTIVITY IN COMPARISON TO CONTROLS (N = 10). AT ADULTHOOD, PCIH RATS (N = 5) SHOWED ENHANCED TIDAL VOLUME (P < 0.05) AND INCREASED RESPIRATORY VARIABILITY COMPARED TO THE CONTROL GROUP (N = 5). THE PCIH-INDUCED CHANGES IN VENTILATION AND RESPIRATORY MOTOR OUTPUTS WERE PREVENTED BY TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE (1 MG KG(-1) , I.P.) DURING THE EXPOSURE TO PCIH. OUR DATA DEMONSTRATE THAT PCIH IN RATS IMPACTS, IN A PERSISTENT WAY, CONTROL OF THE RESPIRATORY PATTERN, INCREASING PN ACTIVITY TO THE DIAPHRAGM AND REDUCING THE VAGAL-RELATED ACTIVITY TO LARYNGEAL MUSCLES, WHICH, RESPECTIVELY, MAY CONTRIBUTE TO IMPROVE RESTING PULMONARY VENTILATION AND PREDISPOSE TO COLLAPSE OF THE UPPER AIRWAYS DURING QUIET BREATHING.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6   443  42 AORTA MACROPHAGE INFLAMMATORY AND EPIGENETIC CHANGES IN A MURINE MODEL OF OBSTRUCTIVE SLEEP APNEA: POTENTIAL ROLE OF CD36. OBSTRUCTIVE SLEEP APNEA (OSA) AFFECTS 8-10% OF THE POPULATION, IS CHARACTERIZED BY CHRONIC INTERMITTENT HYPOXIA (CIH), AND CAUSALLY ASSOCIATES WITH CARDIOVASCULAR MORBIDITIES. IN CIH-EXPOSED MICE, CLOSELY MIMICKING THE CHRONICITY OF HUMAN OSA, INCREASED ACCUMULATION AND PROLIFERATION OF PRO-INFLAMMATORY METABOLIC M1-LIKE MACROPHAGES HIGHLY EXPRESSING CD36, EMERGED IN AORTA. TRANSCRIPTOMIC AND MEDIP-SEQ APPROACHES IDENTIFIED ACTIVATION OF PRO-ATHEROGENIC PATHWAYS INVOLVING A COMPLEX INTERPLAY OF HISTONE MODIFICATIONS IN FUNCTIONALLY-RELEVANT BIOLOGICAL PATHWAYS, SUCH AS INFLAMMATION AND OXIDATIVE STRESS IN AORTA MACROPHAGES. DISCONTINUATION OF CIH DID NOT ELICIT SIGNIFICANT IMPROVEMENTS IN AORTA WALL MACROPHAGE PHENOTYPE. HOWEVER, CIH-INDUCED AORTA CHANGES WERE ABSENT IN CD36 KNOCKOUT MICE, OUR RESULTS PROVIDE MECHANISTIC INSIGHTS SHOWING THAT CIH EXPOSURES DURING SLEEP IN ABSENCE OF CONCURRENT PRO-ATHEROGENIC SETTINGS (I.E., GENETIC PROPENSITY OR DIETARY MANIPULATION) LEAD TO THE RECRUITMENT OF CD36(+)(HIGH) MACROPHAGES TO THE AORTIC WALL AND TRIGGER ATHEROGENESIS. FURTHERMORE, LONG-TERM CIH-INDUCED CHANGES MAY NOT BE REVERSIBLE WITH USUAL OSA TREATMENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7   518  49 ASSOCIATIONS BETWEEN ANTIBIOTIC EXPOSURE DURING PREGNANCY, BIRTH WEIGHT AND ABERRANT METHYLATION AT IMPRINTED GENES AMONG OFFSPRING. OBJECTIVES: LOW BIRTH WEIGHT (LBW) HAS BEEN ASSOCIATED WITH COMMON ADULT-ONSET CHRONIC DISEASES, INCLUDING OBESITY, CARDIOVASCULAR DISEASE, TYPE II DIABETES AND SOME CANCERS. THE ETIOLOGY OF LBW IS MULTI-FACTORIAL. HOWEVER, RECENT EVIDENCE SUGGESTS EXPOSURE TO ANTIBIOTICS MAY ALSO INCREASE THE RISK OF LBW. THE MECHANISMS UNDERLYING THIS ASSOCIATION ARE UNKNOWN, ALTHOUGH EPIGENETIC MECHANISMS ARE HYPOTHESIZED. IN THIS STUDY, WE EVALUATED THE ASSOCIATION BETWEEN MATERNAL ANTIBIOTIC USE AND LBW AND EXAMINED THE POTENTIAL ROLE OF ALTERED DNA METHYLATION THAT CONTROLS GROWTH REGULATORY IMPRINTED GENES IN THESE ASSOCIATIONS. METHODS: BETWEEN 2009-2011, 397 PREGNANT WOMEN WERE ENROLLED AND FOLLOWED UNTIL DELIVERY. PRENATAL ANTIBIOTIC USE WAS ASCERTAINED THROUGH MATERNAL SELF-REPORT. IMPRINTED GENES METHYLATION LEVELS WERE MEASURED AT DIFFERENTIALLY METHYLATED REGIONS (DMRS) USING BISULFITE PYROSEQUENCING. GENERALIZED LINEAR MODELS WERE USED TO EXAMINE ASSOCIATIONS AMONG ANTIBIOTIC USE, BIRTH WEIGHT AND DMR METHYLATION FRACTIONS. RESULTS: AFTER ADJUSTING FOR INFANT GENDER, RACE/ETHNICITY, MATERNAL BODY MASS INDEX, DELIVERY ROUTE, GESTATIONAL WEIGHT GAIN, GESTATIONAL AGE AT DELIVERY, FOLIC ACID INTAKE, PHYSICAL ACTIVITY, MATERNAL SMOKING AND PARITY, ANTIBIOTIC USE DURING PREGNANCY WAS ASSOCIATED WITH 138 G LOWER BIRTH WEIGHT COMPARED WITH NON-ANTIBIOTIC USE (BETA-COEFFICIENT=-132.99, S.E.=50.70, P=0.008). THESE ASSOCIATIONS WERE STRONGEST IN NEWBORNS OF WOMEN WHO REPORTED ANTIBIOTIC USE OTHER THAN PENICILLINS (BETA-COEFFICIENT=-135.57, S.E.=57.38, P=0.02). METHYLATION AT FIVE DMRS, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) AND PEG3 (P=0.08), WAS ASSOCIATED WITH MATERNAL ANTIBIOTIC USE; AMONG THESE, ONLY METHYLATION AT THE PLAGL1 DMR WAS ALSO ASSOCIATED WITH BIRTH WEIGHT. CONCLUSION: WE REPORT AN INVERSE ASSOCIATION BETWEEN IN UTERO EXPOSURE TO ANTIBIOTICS AND LOWER INFANT BIRTH WEIGHT AND PROVIDE THE FIRST EMPIRICAL EVIDENCE SUPPORTING IMPRINTED GENE PLASTICITY IN THESE ASSOCIATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8  4069  39 MATERNAL CHRONIC FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET THROUGH METHYLATION ALTERATION OF BDNF AND GRIN2B IN OFFSPRING HIPPOCAMPUS. SCOPE: MATERNAL CONSUMPTION OF A HIGH-FAT DIET (HFD) DURING PREGNANCY INCREASES THE RISK OF BEHAVIORAL PROBLEMS. FOLATE PLAYS AN IMPORTANT ROLE IN NEUROPLASTICITY AND THE PRESERVATION OF NEURONAL INTEGRITY. THIS STUDY AIMS AT DETERMINING THE INFLUENCE OF DIETS SUPPLEMENTED WITH FOLATE ON OFFSPRING BEHAVIOR, AND THE MECHANISMS INVOLVED. METHODS AND RESULTS: FEMALE MICE WERE FED A CONTROL DIET, AN HFD, CONTROL DIET SUPPLEMENTED WITH FOLATE, OR AN HFD SUPPLEMENTED WITH FOLATE FOR 5 WEEKS BEFORE MATING. OPEN FIELD TASK AND ELEVATED PLUS MAZE ARE USED TO EVALUATE THE OFFSPRING BEHAVIORS. RESULTS SHOWED THAT OFFSPRING COGNITIVE PERFORMANCE AND ANXIETY-RELATED BEHAVIORS, INCLUDING THOSE RELATED TO OPEN FIELD EXPLORATION AND ELEVATED PLUS MAZE, WERE SIGNIFICANTLY IMPROVED WHEN DAMS WERE TREATED WITH FOLATE IN PREGNANCY. MOREOVER, THE MATERNAL FOLATE SUPPLEMENT DECREASED BDNF AND GRIN2B METHYLATION AND UPREGULATED THEIR EXPRESSIONS IN THE BRAIN OF OFFSPRING, WHICH WERE ASSOCIATED WITH DECREASING THE EXPRESSION OF DNA METHYLTRANSFERASES COMPARED WITH THOSE DAMS WERE TREATED ONLY HFD IN PREGNANCY. CONCLUSION: MATERNAL FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET. THE BENEFICIAL EFFECTS WERE ASSOCIATED WITH METHYLATION AND EXPRESSION ALTERATION OF BDNF AND GRIN2B GENES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  4813  29 OBSTRUCTIVE SLEEP APNEA AND HALLMARKS OF AGING. OBSTRUCTIVE SLEEP APNEA (OSA) IS ONE OF THE MOST COMMON SLEEP DISORDERS. SINCE AGING IS A RISK FACTOR FOR OSA DEVELOPMENT, IT IS EXPECTED THAT ITS PREVALENCE WILL INCREASE WITH THE CURRENT INCREASE IN LIFE SPAN. IN RECENT YEARS, SEVERAL STUDIES HAVE SHOWN THAT OSA POTENTIALLY CONTRIBUTES TO FUNCTIONAL DECLINE, MAINLY PROMPTED BY CHRONIC INTERMITTENT HYPOXIA AND SLEEP FRAGMENTATION. HERE, WE PROPOSE THAT OSA MIGHT ANTICIPATE/AGGRAVATE AGING BY INDUCING CELLULAR AND MOLECULAR IMPAIRMENTS THAT CHARACTERIZE THE AGING PROCESS, SUCH AS STEM CELL EXHAUSTION, TELOMERE ATTRITION AND EPIGENETIC CHANGES. WE SUGGEST THAT FURTHER KNOWLEDGE ON THE IMPACT OF OSA ON AGING MECHANISMS MIGHT CONTRIBUTE TO A BETTER UNDERSTANDING OF HOW OSA MIGHT PUTATIVELY ACCELERATE AGING AND AGING-RELATED DISEASES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10  6545  49 TRANSCRIPTOMIC AND EPIGENETIC CHANGES IN THE HYPOTHALAMUS ARE INVOLVED IN AN INCREASED SUSCEPTIBILITY TO A HIGH-FAT-SUCROSE DIET IN PRENATALLY STRESSED FEMALE RATS. DISTURBANCES IN THE PRENATAL PERIOD ARE LINKED TO METABOLIC DISORDERS IN ADULTHOOD, IMPLYING THE HYPOTHALAMIC SYSTEMS OF APPETITE AND ENERGY BALANCE REGULATION. IN ORDER TO ANALYZE THE CENTRAL EFFECTS OF A HIGH-FAT-SUCROSE (HFS) DIET IN PRENATALLY STRESSED (PNS) FEMALE ADULT RATS, WISTAR DAMS WERE EXPOSED TO CHRONIC-MILD-STRESS DURING THE THIRD WEEK OF GESTATION AND WERE THEN COMPARED WITH UNSTRESSED CONTROLS. ADULT FEMALE OFFSPRING WERE FED A CHOW OR HFS DIET FOR 10 WEEKS. CHANGES IN BODY WEIGHT, ADIPOSITY AS WELL AS EXPRESSION AND METHYLATION LEVELS OF SELECTED HYPOTHALAMIC GENES WERE ANALYZED. PNS INDUCED LOWER BIRTHWEIGHT AND BODY LENGTH WITH NO CHANGES IN BODY FAT MASS. AFTER THE HFS DIET, THE EXPECTED OVERWEIGHT MODEL WAS OBSERVED ACCOMPANIED BY HIGHER ADIPOSITY AND INSULIN RESISTANCE, WHICH WAS WORSENED BY PNS. THE STRESS MODEL INDUCED HIGHER ENERGY INTAKE IN ADULTHOOD. HYPOTHALAMIC GENE EXPRESSION ANALYSIS REVEALED THAT THE HFS DIET DECREASED SLC6A3 (DOPAMINE ACTIVE TRANSPORTER), NPY (NEUROPEPTIDE Y) AND IR (INSULIN RECEPTOR) AND INCREASED POMC (PRO-OPIOMELANOCORTIN). HYPOTHALAMIC DNA METHYLATION LEVELS IN THE PROMOTER REGION OF SLC6A3 REVEALED THAT SLC6A3 WAS HYPERMETHYLATED BY THE HFS DIET IN CPG SITE -53 BP TO THE TRANSCRIPTION START SITE. HFS DIET ALSO HYPERMETHYLATED CPG SITE -167 BP OF THE POMC PROMOTER ONLY IN NONSTRESSED ANIMALS. NO CORRELATIONS WERE FOUND BETWEEN GENE EXPRESSION AND DNA METHYLATION LEVELS. THESE RESULTS IMPLY THAT EARLY-LIFE STRESS IN FEMALES INCREASED PREDISPOSITION TO DIET-INDUCED OBESITY IN ADULTHOOD.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  1140  37 CONCENTRATION OF FOLIC ACID (FA) IN SERUM OF JAPANESE PREGNANT WOMEN. OBJECTIVES EXPOSURE TO INORGANIC ARSENIC (IAS) IS A WORLD-WIDE HEALTH CONCERN. WE REPORTED THAT JAPANESE CHILDREN AND PREGNANT WOMEN ARE EXPOSED TO MODERATE LEVELS OF IAS THROUGH FOOD. REDUCING IAS CONTAMINATION FROM FOODS OF HIGH IAS IS AN IMPORTANT ISSUE UNIQUE IN JAPAN. INTEGRATED IAS IS METHYLATED TO LESS TOXIC ORGANIC FORMS, AND S-ADENOSYL-L-METHYONINE (SAM), A COMMON METHYL-DONOR OF DNA AND HISTONES, IS UTILIZED IN THIS PROCESS. CHRONIC CONSUMPTION OF SAM BY IAS METABOLISM DUE TO EXPOSURE TO IAS MIGHT ALTER THE EPIGENETIC MODIFICATION OF GENOME. THE SAM BIOSYNTHESIS PATHWAY IS DEPENDENT ON FOLATE CYCLE, AND IT IS POSSIBLE THAT INGESTION OF SUFFICIENT FOLIC ACID (FA) IS PROTECTIVE TO IAS INDUCED TOXICITY. METHODS IN THE COURSE OF OUR CROSS-SECTIONAL BODY BURDEN ANALYSES OF PB AND IAS IN JAPANESE CHILDREN AND PREGNANT WOMEN, TERMED "PBAS STUDY", FA CONCENTRATION IN SERUM OF 104 PREGNANT WOMEN WAS MEASURED. RESULTS MEAN (+/-SEM) OF SERUM FA CONCENTRATION WAS 15.8 +/- 1.3 (NG/ML). THERE ARE SIGNIFICANT NUMBER OF PEOPLE SHOWING VERY HIGH FA (>30 NG/ ML), AND LARGE FRACTION OF THEM WERE TAKING SUPPLEMENTS DAILY. CONCLUSIONS THESE RESULTS SUGGESTED THAT LEVEL OF FA INGESTION OF JAPANESE PREGNANT WOMEN IS HIGH FOR SUPPORTING NORMAL FETAL DEVELOPMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12   520  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  3179  43 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14  4197  46 METABOLIC PROFILES IN OVINE CAROTID ARTERIES WITH DEVELOPMENTAL MATURATION AND LONG-TERM HYPOXIA. BACKGROUND: LONG-TERM HYPOXIA (LTH) IS AN IMPORTANT STRESSOR RELATED TO HEALTH AND DISEASE DURING DEVELOPMENT. AT DIFFERENT TIME POINTS FROM FETUS TO ADULT, WE ARE EXPOSED TO HYPOXIC STRESS BECAUSE OF PLACENTAL INSUFFICIENCY, HIGH-ALTITUDE RESIDENCE, SMOKING, CHRONIC ANEMIA, PULMONARY, AND HEART DISORDERS, AS WELL AS CANCERS. INTRAUTERINE HYPOXIA CAN LEAD TO FETAL GROWTH RESTRICTION AND LONG-TERM SEQUELAE SUCH AS COGNITIVE IMPAIRMENTS, HYPERTENSION, CARDIOVASCULAR DISORDERS, DIABETES, AND SCHIZOPHRENIA. SIMILARLY, PROLONGED HYPOXIC EXPOSURE DURING ADULT LIFE CAN LEAD TO ACUTE MOUNTAIN SICKNESS, CHRONIC FATIGUE, CHRONIC HEADACHE, COGNITIVE IMPAIRMENT, ACUTE CEREBRAL AND/OR PULMONARY EDEMA, AND DEATH. AIM: LTH ALSO CAN LEAD TO ALTERATION IN METABOLITES SUCH AS FUMARATE, 2-OXOGLUTARATE, MALATE, AND LACTATE, WHICH ARE LINKED TO EPIGENETIC REGULATION OF GENE EXPRESSION. IMPORTANTLY, DURING THE INTRAUTERINE LIFE, A FETUS IS UNDER A RELATIVE HYPOXIC ENVIRONMENT, AS COMPARED TO NEWBORN OR ADULT. THUS, THE CHANGES IN GENE EXPRESSION WITH DEVELOPMENT FROM FETUS TO NEWBORN TO ADULT MAY BE AS A CONSEQUENCE OF UNDERLYING CHANGES IN THE METABOLIC PROFILE BECAUSE OF THE HYPOXIC ENVIRONMENT ALONG WITH DEVELOPMENTAL MATURATION. TO EXAMINE THIS POSSIBILITY, WE EXAMINED THE METABOLIC PROFILE IN CAROTID ARTERIES FROM NEAR-TERM FETUS, NEWBORN, AND ADULT SHEEP IN BOTH NORMOXIC AND LONG-TERM HYPOXIC ACCLIMATIZED GROUPS. RESULTS: OUR RESULTS DEMONSTRATE THAT LTH DIFFERENTIALLY REGULATED GLUCOSE METABOLISM, MITOCHONDRIAL METABOLISM, NICOTINAMIDE COFACTOR METABOLISM, OXIDATIVE STRESS AND ANTIOXIDANTS, MEMBRANE LIPID HYDROLYSIS, AND FREE FATTY ACID METABOLISM, EACH OF WHICH MAY PLAY A ROLE IN GENETIC-EPIGENETIC REGULATION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  4944  36 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  1833  40 EFFECTS OF METHYL DONOR DIETS ON INCISIONAL PAIN IN MICE. BACKGROUND: DIETARY SUPPLEMENTATION WITH METHYL DONORS CAN INFLUENCE THE PROGRAMMING OF EPIGENETIC PATTERNS RESULTING IN PERSISTENT ALTERATIONS IN DISEASE SUSCEPTIBILITY AND BEHAVIOR. HOWEVER, THE DIETARY EFFECTS OF METHYL DONORS ON PAIN HAVE NOT BEEN EXPLORED. IN THIS STUDY, WE EVALUATED THE EFFECTS OF DIETARY METHYL DONOR CONTENT ON PAIN RESPONSES IN MICE. METHODS: MALE AND FEMALE C57BL/6J MICE WERE TREATED WITH HIGH OR LOW METHYL DONOR DIETS EITHER IN THE PERINATAL PERIOD OR AFTER WEANING. MECHANICAL AND THERMAL NOCICEPTIVE SENSITIVITY WERE MEASURED BEFORE AND AFTER INCISION. RESULTS: MICE FED HIGH OR LOW METHYL DONOR DIETS DISPLAYED EQUAL WEIGHT GAIN OVER THE COURSE OF THE EXPERIMENTS. WHEN EXPOSED TO THESE DIETARY MANIPULATIONS IN THE PERINATAL PERIOD, ONLY MALE OFFSPRING OF DAMS FED A HIGH METHYL DONOR DIET DISPLAYED INCREASED MECHANICAL ALLODYNIA. HINDPAW INCISION IN THESE ANIMALS CAUSED ENHANCED NOCICEPTIVE SENSITIZATION, BUT DIETARY HISTORY DID NOT AFFECT THE DURATION OF SENSITIZATION. FOR MICE EXPOSED TO HIGH OR LOW METHYL DONOR DIETS AFTER WEANING, NO SIGNIFICANT DIFFERENCES WERE OBSERVED IN MECHANICAL OR THERMAL NOCICEPTIVE SENSITIVITY EITHER AT BASELINE OR IN RESPONSE TO HINDPAW INCISION. CONCLUSIONS: PERINATAL DIETARY FACTORS SUCH AS METHYL DONOR CONTENT MAY IMPACT PAIN EXPERIENCES IN LATER LIFE. THESE EFFECTS, HOWEVER, MAY BE SPECIFIC TO SEX AND PAIN MODALITY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  1661  41 DOWN-REGULATION OF REDUCED FOLATE CARRIER GENE (RFC1) EXPRESSION AFTER EXPOSURE TO METHOTREXATE IN ZR-75-1 BREAST CANCER CELLS. METHOTREXATE (MTX) IS ADMINISTERED IN INTERVALS OF ONE WEEK OR LONGER IN THE TREATMENT OF CANCER AND AUTOIMMUNE DISEASE. EARLY STUDIES SUGGESTED THAT DAILY MTX ADMINISTRATION WAS ASSOCIATED WITH DECREASED EFFECTIVENESS AND INCREASED TOXICITY, LEADING TO SCHEDULES OF ADMINISTRATION THAT INCLUDE PERIODIC INTERVALS OF REST DURING CHRONIC MTX THERAPY. WE HYPOTHESIZED THAT THESE OBSERVATIONS MAY BE THE RESULT OF THE DOWN-REGULATION OF THE REDUCED FOLATE CARRIER, THE MAJOR ROUTE OF CELLULAR UPTAKE OF BOTH MTX AND THE ENDOGENOUS FOLATES, AFTER MTX EXPOSURE. WE EXPOSED FOLATE-DEPLETED ZR-75-1 BREAST CANCER CELLS TO LOW-DOSE MTX IN THE PRESENCE OF HYPOXANTHINE, ADENOSINE AND THYMIDINE. AFTER 72 H, THE INITIAL RATE OF MTX UPTAKE HAD DECREASED TO 22% OF THE DAY 0 VALUE. WESTERN BLOT ANALYSIS SHOWED DOWN-REGULATION OF RFC1 PROTEIN EXPRESSION, AND NORTHERN BLOT ANALYSIS SHOWED A CORRESPONDING DECREASE IN RFC1 RNA LEVELS. USING AN RT-PCR ASSAY, WE FOUND THAT LEVELS OF RNA TRANSCRIPTS CONTAINING EACH OF THE THREE RFC1 5' NONCODING EXONS WERE DECREASED AFTER EXPOSURE TO MTX, SUGGESTING THAT MTX EXPOSURE CAUSES TRANSCRIPTIONAL DOWN-REGULATION OF RFC1. PROMOTER-REPORTER CONSTRUCT ASSAYS DEMONSTRATED DECREASED ACTIVITY OF RFC1 PROMOTER ELEMENTS UPSTREAM OF THESE EXONS AFTER MTX EXPOSURE. PREEXPOSURE OF THE ZR-75-1 CELLS TO 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, FURTHER DECREASED MTX UPTAKE RATHER THAN REVERSE THE INHIBITION OF RFC1 ACTIVITY, INDICATING THAT RFC1 DOWN-REGULATION AFTER MTX EXPOSURE IS NOT THE RESULT OF METHYLATION OF THE RFC1 PROMOTER. IN SUMMARY, THESE STUDIES DEMONSTRATE THAT MTX EXPOSURE CAN DOWN-REGULATE RFC1 EXPRESSION AND ACTIVITY. THESE ACUTE, INDUCIBLE, EPIGENETIC CHANGES IN RFC1 EXPRESSION MAY ULTIMATELY BE MOLDED INTO THE MORE PERMANENT GENETIC CHANGES THAT RESULT IN THE TRANSPORT-MEDIATED MTX RESISTANCE THAT HAVE BEEN OBSERVED IN MTX-RESISTANT CELL LINES.	2000	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18   765  33 CC-486 MAINTENANCE AFTER STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROMES. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE AFTER ALLOGENEIC STEM CELL TRANSPLANT (ALLOSCT) IN ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROMES (MDS). INJECTABLE AZACITIDINE CAN IMPROVE POST-TRANSPLANT OUTCOMES BUT PRESENTS CHALLENGES WITH EXPOSURE AND COMPLIANCE. ORAL CC-486 ALLOWS EXTENDED DOSING TO PROLONG AZACITIDINE ACTIVITY. WE INVESTIGATED USE OF CC-486 MAINTENANCE THERAPY AFTER ALLOSCT. ADULTS WITH MDS OR AML IN MORPHOLOGIC COMPLETE REMISSION AT CC-486 INITIATION (42 TO 84 DAYS AFTER ALLOSCT) WERE INCLUDED. PATIENTS RECEIVED 1 OF 4 CC-486 DOSING SCHEDULES PER 28-DAY CYCLE FOR UP TO 12 CYCLES. ENDPOINTS INCLUDED SAFETY, PHARMACOKINETICS, GRAFT-VERSUS-HOST DISEASE (GVHD) INCIDENCE, RELAPSE/PROGRESSION RATE, AND SURVIVAL. OF 30 PATIENTS, 7 RECEIVED CC-486 ONCE DAILY FOR 7 DAYS PER CYCLE (200 MG, N = 3; 300 MG, N = 4) AND 23 FOR 14 DAYS PER CYCLE (150 MG, N = 4; 200 MG, N = 19 [EXPANSION COHORT]). GRADES 3 TO 4 ADVERSE EVENTS WERE INFREQUENT AND OCCURRED WITH SIMILAR FREQUENCY ACROSS REGIMENS. STANDARD CONCOMITANT MEDICATIONS DID NOT ALTER CC-486 PHARMACOKINETIC PARAMETERS. THREE PATIENTS (10%) EXPERIENCED GRADE III ACUTE GVHD AND 9 EXPERIENCED CHRONIC GVHD. OF 28 EVALUABLE PATIENTS, 6 (21%) RELAPSED OR HAD PROGRESSIVE DISEASE: 3 OF 7 PATIENTS (43%) WHO HAD RECEIVED 7-DAY DOSING AND 3 OF 23 (13%) WHO HAD RECEIVED 14-DAY DOSING. TRANSPLANT-RELATED MORTALITY WAS 3%. AT 19 MONTHS OF FOLLOW-UP, MEDIAN OVERALL SURVIVAL WAS NOT REACHED. ESTIMATED 1-YEAR SURVIVAL RATES WERE 86% AND 81% IN THE 7-DAY AND 14-DAY DOSING COHORTS, RESPECTIVELY. CC-486 MAINTENANCE WAS GENERALLY WELL TOLERATED, WITH LOW RATES OF RELAPSE, DISEASE PROGRESSION, AND GVHD. CC-486 MAINTENANCE MAY PERMIT EPIGENETIC MANIPULATION OF THE ALLOREACTIVE RESPONSE POSTALLOGRAFT. FINDINGS REQUIRE CONFIRMATION IN RANDOMIZED TRIALS. (CLINICALTRIALS.GOV NCT01835587.).	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19  6089  47 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20  2101  50 EPIGENETIC EFFECTS OF PRENATAL STRESS ON 11BETA-HYDROXYSTEROID DEHYDROGENASE-2 IN THE PLACENTA AND FETAL BRAIN. MATERNAL EXPOSURE TO STRESS DURING PREGNANCY IS ASSOCIATED WITH SIGNIFICANT ALTERATIONS IN OFFSPRING NEURODEVELOPMENT AND ELEVATED MATERNAL GLUCOCORTICOIDS LIKELY PLAY A CENTRAL ROLE IN MEDIATING THESE EFFECTS. PLACENTAL 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 2 (HSD11B2) BUFFERS THE IMPACT OF MATERNAL GLUCOCORTICOID EXPOSURE BY CONVERTING CORTISOL/CORTICOSTERONE INTO INACTIVE METABOLITES. HOWEVER, PREVIOUS STUDIES INDICATE THAT MATERNAL ADVERSITY DURING THE PRENATAL PERIOD CAN LEAD TO A DOWN-REGULATION OF THIS ENZYME. IN THE CURRENT STUDY, WE EXAMINED THE IMPACT OF PRENATAL STRESS (CHRONIC RESTRAINT STRESS DURING GESTATIONAL DAYS 14-20) IN LONG EVANS RATS ON HSD11B2 MRNA IN THE PLACENTA AND FETAL BRAIN (E20) AND ASSESSED THE ROLE OF EPIGENETIC MECHANISMS IN THESE STRESS-INDUCED EFFECTS. IN THE PLACENTA, PRENATAL STRESS WAS ASSOCIATED WITH A SIGNIFICANT DECREASE IN HSD11B2 MRNA, INCREASED MRNA LEVELS OF THE DNA METHYLTRANSFERASE DNMT3A, AND INCREASED DNA METHYLATION AT SPECIFIC CPG SITES WITHIN THE HSD11B2 GENE PROMOTER. WITHIN THE FETAL HYPOTHALAMUS, THOUGH WE FIND NO STRESS-INDUCED EFFECTS ON HSD11B2 MRNA LEVELS, PRENATAL STRESS INDUCED DECREASED CPG METHYLATION WITHIN THE HSD11B2 PROMOTER AND INCREASED METHYLATION AT SITES WITHIN EXON 1. WITHIN THE FETAL CORTEX, HSD11B2 MRNA AND DNA METHYLATION LEVELS WERE NOT ALTERED BY PRENATAL STRESS, THOUGH WE DID FIND STRESS-INDUCED ELEVATIONS IN DNMT1 MRNA IN THIS BRAIN REGION. WITHIN INDIVIDUALS, WE IDENTIFIED CPG SITES WITHIN THE HSD11B2 GENE PROMOTER AND EXON 1 AT WHICH DNA METHYLATION LEVELS WERE HIGHLY CORRELATED BETWEEN THE PLACENTA AND FETAL CORTEX. OVERALL, OUR FINDINGS IMPLICATE DNA METHYLATION AS A MECHANISM BY WHICH PRENATAL STRESS ALTERS HSD11B2 GENE EXPRESSION. THESE FINDINGS HIGHLIGHT THE TISSUE SPECIFICITY OF EPIGENETIC EFFECTS, BUT ALSO RAISE THE INTRIGUING POSSIBILITY OF USING THE EPIGENETIC STATUS OF PLACENTA TO PREDICT CORRESPONDING CHANGES IN THE BRAIN.	2012