1 2077 139 EPIGENETIC DISRUPTION OF PLACENTAL GENES BY CHRONIC MATERNAL CAFETERIA DIET IN RATS. MATERNAL DIET HAS IMPACT ON REPRODUCTION, FETAL DEVELOPMENT AND OFFSPRING BEHAVIOR, ALTHOUGH MOLECULAR MECHANISMS REMAINED UNKNOWN. OUR AIMS WERE TO ASSESS (1) THE EFFECTS OF A CAFETERIA (CAF) DIET (WESTERN DIET HABITS) ON FEMALE REPRODUCTIVE PERFORMANCE, FETAL AND PLACENTAL PARAMETERS ON GESTATIONAL DAY 21 AND LITTER SIZE AND PUP WEIGHT AT BIRTH; AND (2) PLACENTAL MESSENGER RNA (MRNA) EXPRESSION AND EPIGENETIC REGULATION OF INSULIN-LIKE GROWTH FACTOR (IGF) AND VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND THEIR RECEPTORS. FEMALE WISTAR RATS WERE FED WITH CONTROL OR CAF DIET FROM WEANING UNTIL PARTURITION. AT WEEK 14 AFTER DIETS STARTED, FEMALES WERE MATED AND HALF OF THE ANIMALS WERE EUTHANIZED ON GESTATIONAL DAY 21 TO EVALUATE REPRODUCTIVE PARAMETERS INCLUDING THE PREGNANCY RATE, NUMBER OF CORPORA LUTEA, IMPLANTATION SITES AND RESORPTION SITES. MOREOVER, FETAL WEIGHT AND LENGTH, PLACENTAL WEIGHT, AND PLACENTAL INDEX WERE RECORDED. PLACENTAS WERE COLLECTED FOR MRNA QUANTIFICATION AND DNA METHYLATION ANALYSIS. THE REMAINING ANIMALS WERE ALLOWED TO GIVE BIRTH AND THE NUMBER AND WEIGHT OF THE PUPS WERE EVALUATED. CAF DIET DID NOT AFFECT REPRODUCTIVE PERFORMANCE OR FETAL WEIGHT AND LENGTH. HOWEVER, CAF-FED ANIMALS SHOWED A DECREASE IN PLACENTAL WEIGHT AND INDEX AND THE PUPS EXHIBITED A LOW BIRTH WEIGHT. ADDITIONALLY, WE FOUND AN UPREGULATION OF IGF2 AND A DOWN REGULATION OF VEGF PLACENTAL MRNA EXPRESSION IN CAF DAMS, ASSOCIATED WITH METHYLATION STATUS CHANGES OF THEIR PROMOTERS. WE CONCLUDE THAT FEMALE CHRONIC CAF DIET CONSUMPTION IMPAIRS FETO-PLACENTAL DEVELOPMENT AND COULD BE EXPLAINED BY AN EPIGENETIC DISRUPTION OF IGF AND VEGF SYSTEMS. 2022 2 1758 29 EARLY ORIGINS OF HEART DISEASE: LOW BIRTH WEIGHT AND THE ROLE OF THE INSULIN-LIKE GROWTH FACTOR SYSTEM IN CARDIAC HYPERTROPHY. EPIDEMIOLOGICAL STUDIES INDICATE THAT POOR GROWTH BEFORE BIRTH IS ASSOCIATED WITH LEFT VENTRICULAR HYPERTROPHY AND AN INCREASED RISK OF DEATH FROM HEART DISEASE LATER IN LIFE. IN FETAL LIFE, THE INSULIN-LIKE GROWTH FACTOR (IGF) SYSTEM HAS BEEN IMPLICATED IN PHYSIOLOGICAL GROWTH OF THE HEART, WHEREAS IN POSTNATAL LIFE IGFS CAN BE INVOLVED IN BOTH PHYSIOLOGICAL AND PATHOLOGICAL CARDIAC HYPERTROPHY. A REDUCTION IN SUBSTRATE SUPPLY IN FETAL LIFE, RESULTING IN CHRONIC HYPOXAEMIA AND INTRAUTERINE GROWTH RESTRICTION, RESULTS IN INCREASED CARDIAC IGF-1R, IGF-2 AND IGF-2R GENE EXPRESSION; AND THERE IS ALSO EVIDENCE FOR A ROLE OF THE IGF-2 RECEPTOR IN THE ENSUING CARDIAC HYPERTROPHY. THE PERSISTENT HIGH LEVEL OF CARDIAC IGF-2R GENE EXPRESSION FROM FETAL TO POSTNATAL LIFE MAY BE DUE TO EPIGENETIC CHANGES IN KEY CARDIAC HYPERTROPHY REGULATORY PATHWAYS. 2012 3 1724 29 DYSREGULATION OF EPIGENETIC RELATED GENES IN DIABETIC TRIGGER FINGER PATIENTS; PRELIMINARY ANALYSIS OF PATIENT-DERIVED SAMPLES. BACKGROUND: TRIGGER FINGER (TF), A PAINFUL CONDITION INVOLVING A FINGER FLEXOR TENDON, IS A COMMON PROBLEM WITH A PREVALENCE OF ~2-3% IN THE GENERAL POPULATION. HOWEVER, THE TF PREVALENCE IS HIGHER AMONG DIABETIC PATIENTS-RANGES FROM 6.7% TO 10%. WE HAVE ANALYZED THE EXPRESSION OF THE EXTRACELLULAR MATRIX, INFLAMMATION, AND EPIGENETIC RELATED GENES IN DIABETIC AND NON-DIABETES TF. WE HYPOTHESIZED THAT DIABETES CONDITION INDUCES ALTER THE EXPRESSION OF EPIGENETIC MODIFICATION GENES IN DIABETIC PATIENTS AND ONE OF THE UNDERLYING DETERMINANTS FOR MORE PREVALENCE OF TF IN DIABETIC PATIENTS. METHOD: TISSUES FROM THE FINGERS OF PATIENTS WITH SYMPTOMATIC TRIGGER FINGERS WERE COLLECTED. WE HAD THREE GROUPS: CARPAL TUNNEL SYNDROME (AS A CONTROL), TRIGGER FINGER, AND DIABETIC TRIGGER FINGER. A QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION WAS PERFORMED. THE GENE EXPRESSION OF EXTRACELLULAR MATRIX (ECM) COMPONENTS [COL-I, COL-II, COL-X, AGGRECAN], DNA METHYLTRANSFERASES ENZYMES (DNMT1, DNMT3), GROWTH FACTORS (TGF-B, IGF), AND HISTONE DEACETYLASE ENZYMES (HDAC1, HDAC2) WERE EVALUATED IN ALL GROUPS. RESULTS: THE MRNA EXPRESSION OF COL-I, COL-II, AGGRECAN WAS SIGNIFICANTLY HIGHER IN THE PULLY A1 OF DIABETIC PATIENTS (P= 0.0164, P=0.0351, P=0.0399, RESPECTIVELY) AS COMPARED TO NON-DIABETIC TF PATIENTS. DIABETES WAS ASSOCIATED WITH A SIGNIFICANT INCREASE IN THE DNMT3 EXPRESSION COMPARED TO NON-DIABETIC TF PATIENTS (P=0.0485). HDAC1 AND HDAC2 GENE EXPRESSION WERE UP-REGULATED IN DIABETIC TF THAN NON-DIABETIC TF. CONCLUSION: THE CHRONIC STATE OF HYPERGLYCEMIA INDUCES EPIGENETIC MODIFICATION OF GENE EXPRESSIONS IN TRIGGER FINGERS. THIS SEEMS TO HAVE A SIGNIFICANT IMPACT ON THE DEVELOPMENT, RECURRENCE, AND PROGRESSION OF TRIGGER FINGER IN DIABETIC PATIENTS. 2020 4 4983 43 PATHOPHYSIOLOGY, CELLULAR AND MOLECULAR MECHANISMS OF FOETAL GROWTH RETARDATION. IN MAMMALS, SIZE AT BIRTH IS THE OUTCOME OF LENGTH OF GESTATION AND RATE OF FOETAL GROWTH. IN THE ABSENCE OF PREMATURE DELIVERY, FOETAL SIZE WITHIN SPECIES IS DETERMINED PRINCIPALLY BY FOETAL GROWTH RATE WHICH IS DEPENDENT ON BOTH GENETIC AND EPIGENETIC FACTORS. FAILURE OF EITHER OF THESE MECHANISMS LEADS TO FOETAL GROWTH RETARDATION. IN MAMMALS, INCLUDING HUMAN INFANTS, FOETAL GROWTH RETARDATION CAN OCCUR NATURALLY OR PATHOLOGICALLY. ONE MAJOR CAUSE FOR NATURAL FOETAL GROWTH RETARDATION OR RUNTING IS THE INCREASE IN LITTER SIZE. IN MANY CASES, HOWEVER, THE CAUSE OF RUNTING IS UNKNOWN. PARENTAL GENOTYPE OR ANTIGENIC DIFFERENCES BETWEEN THE MOTHER AND THE DEVELOPING CONCEPTUS MAY BE POTENTIAL CAUSES. PATHOLOGICAL FOETAL GROWTH RETARDATION OR INTRAUTERINE GROWTH RETARDATION (IUGR) IS DUE TO GENETIC CAUSES (CHROMOSOMAL ABNORMALITIES OR INHERITED SYNDROMES) OR EPIGENETIC CAUSES (INTRAUTERINE INFECTIONS, TOXINS AND CHEMICALS, MATERNAL DISEASES OF PREGNANCY AFFECTING THE PLACENTA). THE UNDERLYING PATHOPHYSIOLOGICAL PROCESSES THAT OCCUR AT THE CELLULAR AND MOLECULAR LEVEL IN IUGR ARE STILL UNKNOWN. REDUCTION IN THE SUPPLY OF SUBSTRATES THAT ARE NECESSARY FOR NORMAL CELLULAR FUNCTION, AND ALTERATION IN MEDIATOR MOLECULES THAT REGULATE CELLULAR GROWTH AND DIFFERENTIATION, ARE IMPORTANT MECHANISMS. A DECREASE IN GROWTH PROMOTING FACTORS OR AN INCREASE IN GROWTH INHIBITORY FACTORS MAY LEAD TO GROWTH FAILURE. GROWTH FACTORS AND THEIR RECEPTORS ARE EXPRESSED IN THE DEVELOPING EMBRYO (AS EARLY AS THE 1-2-CELL STAGE), PLACENTA AND MATERNAL UTERINE TISSUES, SUGGESTING THAT THESE MOLECULES MAY PLAY A ROLE IN REGULATING NORMAL GROWTH AND DIFFERENTIATION OF THE CONCEPTUS AS WELL AS MATERNAL REPRODUCTIVE TISSUES. THE LOCAL EXPRESSION WITHIN DEVELOPING TISSUES INDICATES THAT THESE FACTORS ACT IN EITHER AUTOCRINE OR PARACRINE MECHANISM. RECENT STUDIES USING GENE TARGETING TO KNOCK OUT ONE ALLELE OF INSULIN-LIKE GROWTH FACTOR II (IGF II) GENE IN MICE WHICH RESULTED IN GROWTH RETARDED PUPS AT BIRTH, STRONGLY SUPPORT THE IMPORTANCE OF LOCAL IGF II IN REGULATING TISSUE GROWTH. FOETAL GROWTH RETARDATION HAS ALSO BEEN INDUCED EXPERIMENTALLY IN SEVERAL SPECIES USING ONE OF THE FOLLOWING METHODS: (I) MATERNAL UNDERNUTRITION, (II) CHRONIC HYPOXIA, (III) PROLONGED REDUCTION IN UTERINE BLOOD FLOW, (IV) REDUCTION IN PLACENTAL SIZE, AND (V) ENDOCRINE ALTERATIONS. THESE MODELS PROVIDE USEFUL INFORMATION ON THE PHYSIOLOGICAL MECHANISMS UNDERLYING A SPECIFIC TYPE OF GROWTH RETARDATION. THESE IN-VIVO MODELS AND IN-VIVO TISSUE CULTURE MODELS CAN NOW BE ANALYSED BY BIOCHEMICAL AND MOLECULAR BIOLOGICAL TECHNIQUES TO UNRAVEL THE BASIC MECHANISMS THAT UNDERLIE FOETAL GROWTH RETARDATION. 1993 5 3695 21 INFLAMMATORY DISEASES AND GROWTH: EFFECTS ON THE GH-IGF AXIS AND ON GROWTH PLATE. THIS REVIEW BRIEFLY DESCRIBES THE MOST COMMON CHRONIC INFLAMMATORY DISEASES IN CHILDHOOD, SUCH AS CYSTIC FIBROSIS (CF), INFLAMMATORY BOWEL DISEASES (IBDS), JUVENILE IDIOPATHIC ARTHRITIS (JIA), AND INTRAUTERINE GROWTH RESTRICTION (IUGR) THAT CAN BE CONSIDERED, AS SUCH, FOR THE CHANGES REPORTED IN THE PLACENTA AND CORD BLOOD OF THESE SUBJECTS. CHANGES IN GROWTH HORMONE (GH) SECRETION, GH RESISTANCE, AND CHANGES IN THE INSULIN-LIKE GROWTH FACTOR (IGF) SYSTEM ARE DESCRIBED MAINLY IN RELATIONSHIP WITH THE INCREASE IN NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND PRO-INFLAMMATORY CYTOKINES. CHANGES IN THE GROWTH PLATE ARE ALSO REPORTED AS WELL AS A POTENTIAL ROLE FOR MICRORNAS (MIRNAS) AND THUS EPIGENETIC CHANGES IN CHRONIC INFLAMMATION. MANY MECHANISMS LEADING TO GROWTH FAILURE ARE CURRENTLY KNOWN; HOWEVER, IT IS CLEAR THAT FURTHER RESEARCH IN THE FIELD IS STILL WARRANTED. 2017 6 5430 28 REGULATORS INVOLVED IN TROPHOBLAST SYNCYTIALIZATION IN THE PLACENTA OF INTRAUTERINE GROWTH RESTRICTION. PLACENTAL DYSFUNCTION REFERS TO THE INSUFFICIENCY OF PLACENTAL PERFUSION AND CHRONIC HYPOXIA DURING EARLY PREGNANCY, WHICH IMPAIRS PLACENTAL FUNCTION AND CAUSES INADEQUATE SUPPLY OF OXYGEN AND NUTRIENTS TO THE FETUS, AFFECTING FETAL DEVELOPMENT AND HEALTH. FETAL INTRAUTERINE GROWTH RESTRICTION, ONE OF THE MOST COMMON OUTCOMES OF PREGNANCY-INDUCED HYPERTENSIONS, CAN BE CAUSED BY PLACENTAL DYSFUNCTION, RESULTING FROM DEFICIENT TROPHOBLAST SYNCYTIALIZATION, INADEQUATE TROPHOBLAST INVASION AND IMPAIRED VASCULAR REMODELING. DURING PLACENTAL DEVELOPMENT, CYTOTROPHOBLASTS FUSE TO FORM A MULTINUCLEATED SYNCYTIA BARRIER, WHICH SUPPLIES OXYGEN AND NUTRIENTS TO MEET THE METABOLIC DEMANDS FOR FETAL GROWTH. A REDUCTION IN THE CELL FUSION INDEX AND THE NUMBER OF NUCLEI IN THE SYNCYTIOTROPHOBLAST ARE FOUND IN THE PLACENTAS OF PREGNANCIES COMPLICATED BY IUGR, SUGGESTING THAT THE OCCURRENCE OF IUGR MAY BE RELATED TO INADEQUATE TROPHOBLAST SYNCYTIALIZATION. DURING THE MULTIPLE PROCESSES OF TROPHOBLASTS SYNCYTIALIZATION, SPECIFIC PROTEINS AND SEVERAL SIGNALING PATHWAYS ARE INVOLVED IN COORDINATING THESE EVENTS AND REGULATING PLACENTAL FUNCTION. IN ADDITION, EPIGENETIC MODIFICATIONS, CELL METABOLISM, SENESCENCE, AND AUTOPHAGY ARE ALSO INVOLVED. STUDY FINDINGS HAVE INDICATED SEVERAL ABNORMALLY EXPRESSED SYNCYTIALIZATION-RELATED PROTEINS AND SIGNALING PATHWAYS IN THE PLACENTAS OF PREGNANCIES COMPLICATED BY IUGR, SUGGESTING THAT THESE ELEMENTS MAY PLAY A CRUCIAL ROLE IN THE OCCURRENCE OF IUGR. IN THIS REVIEW, WE DISCUSS THE REGULATORS OF TROPHOBLAST SYNCYTIALIZATION AND THEIR ABNORMAL EXPRESSION IN THE PLACENTAS OF PREGNANCIES COMPLICATED BY IUGR. 2023 7 3813 35 INTRAUTERINE GROWTH RESTRICTION INHIBITS EXPRESSION OF EUKARYOTIC ELONGATION FACTOR 2 KINASE, A REGULATOR OF PROTEIN TRANSLATION. NUTRIENT DEPRIVATION SUPPRESSES PROTEIN SYNTHESIS BY BLOCKING PEPTIDE ELONGATION. TRANSCRIPTIONAL UPREGULATION AND ACTIVATION OF EUKARYOTIC ELONGATION FACTOR 2 KINASE (EEF2K) BLOCKS PEPTIDE ELONGATION BY PHOSPHORYLATING EUKARYOTIC ELONGATION FACTOR 2. PREVIOUS STUDIES EXAMINING PLACENTAS FROM INTRAUTERINE GROWTH RESTRICTED (IUGR) NEWBORN INFANTS SHOW DECREASED EEF2K EXPRESSION AND ACTIVITY DESPITE CHRONIC NUTRIENT DEPRIVATION. HOWEVER, THE EFFECT OF IUGR ON HEPATIC EEF2K EXPRESSION IN THE FETUS IS UNKNOWN. WE, THEREFORE, EXAMINED THE TRANSCRIPTIONAL REGULATION OF HEPATIC EEF2K GENE EXPRESSION IN A SPRAGUE-DAWLEY RAT MODEL OF IUGR. WE FOUND DECREASED HEPATIC EEF2K MRNA AND PROTEIN LEVELS IN IUGR OFFSPRING AT BIRTH COMPARED WITH CONTROL, CONSISTENT WITH PREVIOUS PLACENTAL OBSERVATIONS. FURTHERMORE, THE CPG ISLAND WITHIN THE EEF2K PROMOTER DEMONSTRATED INCREASED METHYLATION AT A CRITICAL USF 1/2 TRANSCRIPTION FACTOR BINDING SITE. IN VITRO METHYLATION OF THIS BINDING SITE CAUSED NEAR COMPLETE LOSS OF EEF2K PROMOTER ACTIVITY, DESIGNATING THIS PROMOTER AS METHYLATION SENSITIVE. THE EEF2K PROMOTOR IN IUGR OFFSPRING ALSO LOST THE PROTECTIVE HISTONE COVALENT MODIFICATIONS ASSOCIATED WITH UNMETHYLATED CGIS. IN ADDITION, THE +1 NUCLEOSOME WAS DISPLACED 3' AND RNA POLYMERASE LOADING WAS REDUCED AT THE IUGR EEF2K PROMOTER. OUR FINDINGS PROVIDE EVIDENCE TO EXPLAIN WHY IUGR-INDUCED CHRONIC NUTRIENT DEPRIVATION DOES NOT RESULT IN THE UPREGULATION OF EEF2K GENE TRANSCRIPTION. 2016 8 4360 34 MIR-6769B-5P TARGETS CCND-1 TO REGULATE PROLIFERATION IN CADMIUM-TREATED PLACENTAL TROPHOBLASTS: ASSOCIATION WITH THE IMPAIRMENT OF FETAL GROWTH. ENVIRONMENTAL CADMIUM (CD) IS POSITIVELY ASSOCIATED WITH PLACENTAL IMPAIRMENT AND FETAL GROWTH RETARDATION. NEVERTHELESS, ITS POTENTIAL MECHANISMS REMAIN UNCLEAR. MICRORNAS (MIRNAS) ARE KNOWN TO INFLUENCE PLACENTAL DEVELOPMENT AND FETAL GROWTH. THIS WORK WAS AIMED TO DETERMINE WHICH MIRNAS ARE INVOLVED IN CD-IMPAIRED PLACENTAL AND FETAL DEVELOPMENT BASED ON THE MRNA AND MIRNA EXPRESSION PROFILES ANALYSIS. AS A RESULT, GESTATIONAL CD EXPOSURE DECEASED FETAL AND PLACENTAL WEIGHT, AND REDUCED THE PROTEIN LEVEL OF PCNA IN HUMAN AND MOUSE PLACENTAE. FURTHERMORE, THE RESULTS OF MRNA MICROARRAY SHOWED THAT CD-DOWNREGULATED MRNAS WERE PREDICTIVELY CORRELATED WITH SEVERAL BIOLOGICAL PROCESSES, INCLUDING CELL PROLIFERATION, DIFFERENTIATION AND MOTILITY. IN ADDITION, THE RESULTS OF MIRNA MICROARRAY AND QPCR ASSAY DEMONSTRATED THAT CD SIGNIFICANTLY INCREASED THE LEVEL OF MIR-6769B-5P, MIR-146B-5P AND MIR-452-5P. INTEGRATED ANALYSIS OF CD-UPREGULATED MIRNAS PREDICTED TARGET GENES AND CD-DOWNREGULATED MRNAS FOUND THAT OVERLAPPING MRNAS, SUCH AS CCND1, CDK13, RINT1 AND CDC26 WERE ALSO SIGNIFICANTLY ASSOCIATED WITH CELL PROLIFERATION. FURTHER EXPERIMENTS SHOWED THAT MIR-6769B-5P INHIBITOR, BUT NOT MIR-146B-5P AND MIR-452-5P, MARKEDLY REVERSED CD-DOWNREGULATED THE EXPRESSION OF PROLIFERATION-RELATED MRNAS, AND THEREBY RESTORED CD-DECREASED THE PROTEINS LEVEL OF CCND1 AND PCNA IN HUMAN PLACENTAL TROPHOBLASTS. DUAL LUCIFERASE REPORTER ASSAY FURTHER REVEALED THAT MIR-6769B-5P DIRECTLY TARGETS CCND1. FINALLY, THE CASE-CONTROL STUDY DEMONSTRATED THAT INCREASED MIR-6769B-5P LEVEL AND IMPAIRED CELL PROLIFERATION WERE OBSERVED IN SMALL-FOR-GESTATIONAL-AGE HUMAN PLACENTAE. IN CONCLUSION, MIR-6769B-5P TARGETS CCND-1 TO REGULATE PROLIFERATION IN CD-TREATED PLACENTAL TROPHOBLASTS, WHICH IS ASSOCIATED WITH THE IMPAIRMENT OF FETAL GROWTH. OUR FINDINGS IMPLY THAT PLACENTAL MIR-6769B-5P MAY BE USED AS AN EPIGENETIC MARKER FOR ENVIRONMENTAL POLLUTANTS-CAUSED FETAL GROWTH RESTRICTION AND ITS LATE-ONSET CHRONIC DISEASES. 2021 9 2260 37 EPIGENETIC PROCESSES DURING PREECLAMPSIA AND EFFECTS ON FETAL DEVELOPMENT AND CHRONIC HEALTH. PREECLAMPSIA (PE), THE LEADING CAUSE OF MATERNAL AND FETAL MORBIDITY AND MORTALITY, IS ASSOCIATED WITH POOR FETAL GROWTH, INTRAUTERINE GROWTH RESTRICTION (IUGR) AND LOW BIRTH WEIGHT (LBW). OFFSPRING OF WOMEN WHO HAD PE ARE AT INCREASED RISK FOR CARDIOVASCULAR (CV) DISEASE LATER IN LIFE. HOWEVER, THE EXACT ETIOLOGY OF PE IS UNKNOWN. MOREOVER, THERE ARE NO EFFECTIVE INTERVENTIONS TO TREAT PE OR ALLEVIATE IUGR AND THE DEVELOPMENTAL ORIGINS OF CHRONIC DISEASE IN THE OFFSPRING. THE PLACENTA IS CRITICAL TO FETAL GROWTH AND DEVELOPMENT. EPIGENETIC REGULATORY PROCESSES SUCH AS HISTONE MODIFICATIONS, MICRORNAS AND DNA METHYLATION PLAY AN IMPORTANT ROLE IN PLACENTAL DEVELOPMENT INCLUDING CONTRIBUTIONS TO THE REGULATION OF TROPHOBLAST INVASION AND REMODELING OF THE SPIRAL ARTERIES. EPIGENETIC PROCESSES THAT LEAD TO CHANGES IN PLACENTAL GENE EXPRESSION IN PE MEDIATE DOWNSTREAM EFFECTS THAT CONTRIBUTE TO THE DEVELOPMENT OF PLACENTA DYSFUNCTION, A CRITICAL MEDIATOR IN THE ONSET OF PE, IMPAIRED FETAL GROWTH AND IUGR. THEREFORE, THIS REVIEW WILL FOCUS ON EPIGENETIC PROCESSES THAT CONTRIBUTE TO THE PATHOGENESIS OF PE AND IUGR. UNDERSTANDING THE EPIGENETIC MECHANISMS THAT CONTRIBUTE TO NORMAL PLACENTAL DEVELOPMENT AND THE INITIATING EVENTS IN PE MAY LEAD TO NOVEL THERAPEUTIC TARGETS IN PE THAT IMPROVE FETAL GROWTH AND MITIGATE INCREASED CV RISK IN THE OFFSPRING. 2021 10 4089 42 MATERNAL OBESITY PROGRAMS SENESCENCE SIGNALING AND GLUCOSE METABOLISM IN OSTEO-PROGENITORS FROM RAT AND HUMAN. NUTRITIONAL STATUS DURING INTRAUTERINE AND EARLY POSTNATAL LIFE IMPACTS THE RISK OF CHRONIC DISEASES, PRESUMABLY VIA EPIGENETIC MECHANISMS. HOWEVER, EVIDENCE ON THE IMPACT OF GESTATIONAL EVENTS ON REGULATION OF EMBRYONIC BONE CELL FATE IS SPARSE. WE INVESTIGATED THE EFFECTS OF MATERNAL OBESITY ON FETAL OSTEOBLAST DEVELOPMENT IN BOTH RODENTS AND HUMANS. FEMALE RATS WERE FED CONTROL OR AN OBESOGENIC HIGH-FAT DIET (HFD) FOR 12 WEEKS AND MATED WITH MALE RATS FED CONTROL DIETS, AND RESPECTIVE MATERNAL DIETS WERE CONTINUED DURING PREGNANCY. EMBRYONIC RAT OSTEOGENIC CALVARIAL CELLS (EOCCS) WERE TAKEN FROM GESTATIONAL DAY 18.5 FETUSES FROM CONTROL AND HFD DAMS. EOCCS FROM HFD OBESE DAMS SHOWED INCREASES IN P53/P21-MEDIATED CELL SENESCENCE SIGNALING BUT DECREASED GLUCOSE METABOLISM. DECREASED AEROBIC GLYCOLYSIS IN HFD-EOCCS WAS ASSOCIATED WITH DECREASED OSTEOBLASTIC CELL DIFFERENTIATION AND PROLIFERATION. UMBILICAL CORD HUMAN MESENCHYMAL STEM CELLS (MSCS) FROM 24 PREGNANT WOMEN (12 OBESE AND 12 LEAN) ALONG WITH PLACENTAS WERE COLLECTED UPON DELIVERY. THE UMBILICAL CORD MSCS OF OBESE MOTHERS DISPLAYED LESS POTENTIAL TOWARD OSTEOBLASTOGENESIS AND MORE TOWARDS ADIPOGENESIS. HUMAN MSCS AND PLACENTA FROM OBESE MOTHERS ALSO EXHIBITED INCREASED CELL SENESCENCE SIGNALING, WHEREAS MSCS SHOWED DECREASED GLUCOSE METABOLISM AND INSULIN RESISTANCE. FINALLY, WE SHOWED THAT OVEREXPRESSION OF P53 LINKED INCREASED CELL SENESCENCE SIGNALING AND DECREASED GLUCOSE METABOLISM IN FETAL OSTEO-PROGENITORS FROM OBESE RATS AND HUMANS. THESE FINDINGS SUGGEST PROGRAMMING OF FETAL PREOSTEOBLASTIC CELL SENESCENCE SIGNALING AND GLUCOSE METABOLISM BY MATERNAL OBESITY. 2016 11 5191 39 PRENATAL DEXAMETHASONE EXPOSURE PROGRAMS THE DECREASED TESTOSTERONE SYNTHESIS IN OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS. PRENATAL DEXAMETHASONE EXPOSURE (PDE) CAN DECREASE MATERNAL ENDOGENOUS GLUCOCORTICOID LEVEL AND INDUCE TESTICULAR DYSPLASIA IN MALE OFFSPRING RATS. IN THIS STUDY WE INVESTIGATED LOW LEVEL ENDOGENOUS GLUCOCORTICOID-MEDIATED TESTICULAR DYSPLASIA IN PDE OFFSPRING AND ELUCIDATED THE INTRAUTERINE EPIGENETIC PROGRAMMING MECHANISMS. PREGNANT RATS WERE INJECTED WITH DEXAMETHASONE (0.2 MG.KG(-1).D(-1), SC) ON GESTATIONAL DAY (GD) 9-20. THE OFFSPRING RAT BLOOD AND TESTIS WERE COLLECTED AFTER EUTHANASIA ON GD20, POSTNATAL WEEK (PW) 12 OR PW28. WE SHOWED THAT PDE INDUCED ABNORMAL MORPHOLOGY OF TESTIS AND SIGNIFICANTLY DECREASED THE EXPRESSION OF TESTOSTERONE SYNTHESIS-RELATED GENES AS WELL AS TESTOSTERONE PRODUCTION BEFORE AND AFTER BIRTH. MEANWHILE, SERUM CORTICOSTERONE, THE EXPRESSION AND HISTONE 3 LYSINE 14 ACETYLATION (H3K14AC) OF TESTICULAR INSULIN-LIKE GROWTH FACTOR 1 (IGF1) WERE SIGNIFICANTLY DECREASED. AFTER THE PREGNANT RATS WERE SUBJECTED TO CHRONIC STRESS FOR 2 WEEKS (PW10-12), SERUM CORTICOSTERONE LEVEL WAS INCREASED IN THE ADULT PDE OFFSPRING, AND THE ABOVE-MENTIONED OTHER INDICATORS WERE ALSO IMPROVED. CULTURED LEYDIG CELLS (TM3) WERE TREATED WITH CORTICOSTERONE (62.5-500 NM) IN VITRO. WE SHOWED THAT CORTICOSTERONE CONCENTRATION-DEPENDENTLY INHIBITED GLUCOCORTICOID RECEPTOR ALPHA (GRALPHA) AND MIR-124-3P EXPRESSION, INCREASED HISTONE DEACETYLASE 5 (HDAC5) EXPRESSION, AND DECREASED IGF1 H3K14AC LEVEL AND THE EXPRESSION OF IGF1/STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR), SUGGESTING THAT CORTICOSTERONE AT LOWER THAN PHYSIOLOGICAL LEVEL (<500 NM) INHIBITED TESTOSTERONE SYNTHESIS BY REDUCING H3K14AC AND THE EXPRESSION LEVEL OF IGF1 THROUGH GRALPHA/MIR-124-3P/HDAC5 PATHWAY. IN CONCLUSION, PDE CAN CAUSE PERSISTENT INHIBITION OF TESTOSTERONE SYNTHESIS BEFORE AND AFTER BIRTH IN THE OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS. 2022 12 2173 32 EPIGENETIC MECHANISMS INVOLVED IN INTRAUTERINE GROWTH RESTRICTION AND ABERRANT KIDNEY DEVELOPMENT AND FUNCTION. INTRAUTERINE GROWTH RESTRICTION (IUGR) DUE TO UTEROPLACENTAL INSUFFICIENCY RESULTS IN A PLACENTA THAT IS UNABLE TO PROVIDE ADEQUATE NUTRIENTS AND OXYGEN TO THE FETUS. THESE GROWTH-RESTRICTED BABIES HAVE AN INCREASED RISK OF HYPERTENSION AND CHRONIC KIDNEY DISEASE LATER IN LIFE. IN RATS, BOTH MALE AND FEMALE GROWTH-RESTRICTED OFFSPRING HAVE NEPHRON DEFICITS BUT ONLY MALES DEVELOP KIDNEY DYSFUNCTION AND HIGH BLOOD PRESSURE. IN ADDITION, THERE IS TRANSGENERATIONAL TRANSMISSION OF NEPHRON DEFICITS AND HYPERTENSION RISK. THEREFORE, EPIGENETIC MECHANISMS MAY EXPLAIN THE SEX-SPECIFIC PROGRAMMING AND MULTIGENERATIONAL TRANSMISSION OF IUGR-RELATED PHENOTYPES. EXPRESSION OF DNA METHYLTRANSFERASES (DNMT1AND DNMT3A) AND IMPRINTED GENES (PEG3, SNRPN, KCNQ1, AND CDKN1C) WERE INVESTIGATED IN KIDNEY TISSUES OF SHAM AND IUGR RATS IN F1 (EMBRYONIC DAY 20 (E20) AND POSTNATAL DAY 1 (PN1)) AND F2 (6 AND 12 MONTHS OF AGE, PATERNAL AND MATERNAL LINES) GENERATIONS (N = 6-13/GROUP). IN COMPARISON TO SHAM OFFSPRING, F1 IUGR RATS HAD A 19% DECREASE IN DNMT3A EXPRESSION AT E20 (P < 0.05), WITH DECREASED CDKN1C (19%, P < 0.05) AND INCREASED KCNQ1 (1.6-FOLD, P < 0.01) AT PN1. THERE WAS A SEX-SPECIFIC DIFFERENCE IN CDKN1C AND SNRPN EXPRESSION AT E20, WITH 29% AND 34% HIGHER EXPRESSION IN IUGR MALES COMPARED TO FEMALES, RESPECTIVELY (P < 0.05). PEG3 SEX-SPECIFIC EXPRESSION WAS LOST IN THE F2 IUGR OFFSPRING, ONLY IN THE MATERNAL LINE. THESE FINDINGS SUGGEST THAT EPIGENETIC MECHANISMS MAY BE ALTERED IN RENAL EMBRYONIC AND/OR FETAL DEVELOPMENT IN GROWTH-RESTRICTED OFFSPRING, WHICH COULD ALTER KIDNEY FUNCTION, PREDISPOSING THESE OFFSPRING TO KIDNEY DISEASE LATER IN LIFE. 2021 13 630 15 BIOLOGICAL AND MECHANICAL FACTORS AND EPIGENETIC REGULATION INVOLVED IN TENDON HEALING. TENDONS ARE AN IMPORTANT PART OF THE MUSCULOSKELETAL SYSTEM. CONNECTING MUSCLES TO BONES, TENDONS CONVERT FORCE INTO MOVEMENT. TENDON INJURY CAN BE ACUTE OR CHRONIC. NOTICEABLY, TENDON HEALING REQUIRES A LONG TIME SPAN AND INCLUDES INFLAMMATION, PROLIFERATION, AND REMODELING PROCESSES. THE MISMATCH BETWEEN ENDOGENOUS AND EXOGENOUS HEALING MAY LEAD TO ADHESION CAUSING FURTHER NEGATIVE EFFECTS. MANAGEMENT OF TENDON INJURIES AND COMPLICATIONS SUCH AS SUBSEQUENT ADHESION FORMATION ARE STILL CHALLENGES FOR CLINICIANS. DUE TO NUMEROUS FACTORS, TENDON HEALING IS A COMPLEX PROCESS. THIS REVIEW INTRODUCES THE ROLE OF VARIOUS BIOLOGICAL AND MECHANICAL FACTORS AND EPIGENETIC REGULATION PROCESSES INVOLVED IN TENDON HEALING. 2023 14 167 26 ABNORMAL PLACENTATION ASSOCIATED WITH INFERTILITY AS A MARKER OF OVERALL HEALTH. INFERTILITY AND THE FERTILITY TREATMENTS UTILIZED ARE ASSOCIATED WITH ABNORMAL PLACENTATION LEADING TO ADVERSE PREGNANCY OUTCOMES RELATED TO PLACENTATION, INCLUDING PRETERM BIRTH, LOW BIRTH WEIGHT, PLACENTA ACCRETE AND PLACENTA PREVIA. THIS MAY BE DUE TO THE UNDERLYING GENETICS PREDISPOSING TO INFERTILITY OR THE EPIGENETIC CHANGES ASSOCIATED WITH THE FERTILITY TREATMENTS UTILIZED, AS SPECIFIC DISEASE STATES LEADING TO INFERTILITY ARE AT INCREASED RISK OF ADVERSE OUTCOMES, INCLUDING PLACENTAL ABRUPTION, FETAL LOSS, GDM, AND OUTCOMES RELATED TO PLACENTATION, AS WELL AS THE TREATMENTS UTILIZED INCLUDING IN VITRO FERTILIZATION (IVF) AND NIFT (NON-IVF FERTILITY TREATMENT). PLACENTATION DEFECTS, LEADING TO ADVERSE MATERNAL AND FETAL OUTCOMES, WHICH ARE MORE PRONOUNCED IN THE INFERTILE POPULATION, OCCUR DUE TO CHANGES IN TROPHOBLAST INVASION, VASCULAR DEFECTS, CHANGES IN THE ENVIRONMENTAL MILIEU, CHRONIC INFLAMMATION AND OXIDATIVE STRESS. THESE SIMILAR PROCESSES ARE RECOGNIZED AS MAJOR CONTRIBUTORS TO LIFELONG RISK OF CARDIOVASCULAR AND METABOLIC DISEASE FOR BOTH THE MOTHER AND HER OFFSPRING. THUS, ABNORMAL PLACENTATION, FOUND TO BE MORE PREVALENT IN THE INFERTILE POPULATION, MAY BE THE KEY TO BETTER UNDERSTAND HOW INFERTILITY AFFECTS OVERALL AND LONG TERM HEALTH. 2017 15 4300 29 MICRORNA-19A CONTRIBUTES TO THE EPIGENETIC REGULATION OF TISSUE FACTOR IN DIABETES. BACKGROUND: DIABETES MELLITUS IS CHARACTERIZED BY CHRONIC VASCULAR DISORDER AND PRESENTS A MAIN RISK FACTOR FOR CARDIOVASCULAR MORTALITY. IN PARTICULAR, HYPERGLYCAEMIA AND INFLAMMATORY CYTOKINES INDUCE VASCULAR CIRCULATING TISSUE FACTOR (TF) THAT PROMOTES PRO-THROMBOTIC CONDITIONS IN DIABETES. IT HAS RECENTLY BECOME EVIDENT THAT ALTERATIONS OF THE POST-TRANSCRIPTIONAL REGULATION OF TF VIA SPECIFIC MICRORNA(MIR)S, SUCH AS MIR-126, CONTRIBUTE TO THE PATHOGENESIS OF DIABETES AND ITS COMPLICATIONS. THE ENDOTHELIAL MIR-19A IS INVOLVED IN VASCULAR HOMEOSTASIS AND ATHEROPROTECTION. HOWEVER, ITS ROLE IN DIABETES-RELATED THROMBOGENICITY IS UNKNOWN. UNDERSTANDING MIR-NETWORKS REGULATING PROCOAGULABILITY IN DIABETES MAY HELP TO DEVELOP NEW TREATMENT OPTIONS PREVENTING VASCULAR COMPLICATIONS. METHODS AND RESULTS: PLASMA OF 44 PATIENTS WITH KNOWN DIABETES WAS ASSESSED FOR THE EXPRESSION OF MIR-19A, TF PROTEIN, TF ACTIVITY, AND MARKERS FOR VASCULAR INFLAMMATION. HIGH MIR-19A EXPRESSION WAS ASSOCIATED WITH REDUCED TF PROTEIN, TF-MEDIATED PROCOAGULABILITY, AND VASCULAR INFLAMMATION BASED ON EXPRESSION OF VASCULAR ADHESION MOLECULE-1 AND LEUKOCYTE COUNT. WE FOUND PLASMA EXPRESSION OF MIR-19A TO STRONGLY CORRELATE WITH MIR-126. MIR-19A REDUCED THE TF EXPRESSION ON MRNA AND PROTEIN LEVEL IN HUMAN MICROVASCULAR ENDOTHELIAL CELLS (HMEC) AS WELL AS TF ACTIVITY IN HUMAN MONOCYTES (THP-1), WHILE ANTI-MIR-19A INCREASED THE TF EXPRESSION. INTERESTINGLY, MIR-19A INDUCED VCAM EXPRESSION IN HMEC. HOWEVER, MIR-19A AND MIR-126 CO-TRANSFECTION REDUCED TOTAL ENDOTHELIAL VCAM EXPRESSION AND EXHIBITED ADDITIVE INHIBITION OF A LUCIFERASE REPORTER CONSTRUCT CONTAINING THE F3 3'UTR. CONCLUSIONS: WHILE BOTH MIRS HAVE DIFFERENTIAL FUNCTIONS ON ENDOTHELIAL VCAM EXPRESSION, MIR-19A AND MIR-126 COOPERATE TO EXHIBIT ANTI-THROMBOTIC PROPERTIES VIA REGULATING VASCULAR TF EXPRESSION. MODULATING THE POST-TRANSCRIPTIONAL CONTROL OF TF IN DIABETES MAY PROVIDE A FUTURE ANTI-THROMBOTIC AND ANTI-INFLAMMATORY THERAPY. 2018 16 218 35 ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL TOTAL CHANGES IN PLACENTAL EPIGENETIC MODIFICATIONS. PREECLAMPSIA IS A COMMON OBSTETRICAL COMPLICATION, HALLMARKED BY NEW-ONSET HYPERTENSION. BELIEVED TO RESULT FROM PLACENTAL INSUFFICIENCY AND CHRONIC PLACENTAL ISCHEMIA, THE SYMPTOMS OF PREECLAMPSIA ARE CAUSED BY RELEASE OF PATHOGENIC FACTORS FROM THE PLACENTA ITSELF, ALTHOUGH THE MECHANISMS OF THEIR REGULATION ARE IN MANY CASES UNKNOWN. ONE POTENTIAL MECHANISM IS THROUGH CHANGES IN PLACENTAL EPIGENETIC CHROMATIN MODIFICATIONS, PARTICULARLY HISTONE ACETYLATION AND DNA METHYLATION. HERE, WE DETERMINED THE EFFECTS OF CHRONIC ISCHEMIA ON GLOBAL EPIGENETIC MODIFICATIONS IN THE RODENT PLACENTA IN VIVO AND ACUTE HYPOXIA IN BEWO PLACENTAL TROPHOBLAST CELLS IN VITRO. PLACENTAL INSUFFICIENCY VIA UTERINE ARTERY RESTRICTION INCREASED MATERNAL BLOOD PRESSURE AND FETAL DEMISE WHILE DECREASING PLACENTAL AND FETAL MASS. GLOBAL PLACENTAL HISTONE H3 ACETYLATION LEVELS WERE SIGNIFICANTLY DECREASED AT H3 K9, K14, K18, K27, AND K56. INTERESTINGLY, WHEN BEWO-IMMORTALIZED PLACENTAL TROPHOBLAST CELLS WERE CULTURED IN OXYGEN CONCENTRATIONS MIMICKING HEALTHY AND ISCHEMIC PLACENTAS, THERE WAS A SIGNIFICANT INCREASE IN ACETYLATED AT K9, K18, K27, AND K56. THIS WAS ASSOCIATED WITH A SMALL BUT SIGNIFICANT DECREASE IN PLACENTAL ACETYL-COA, SUGGESTING DEPLETION IN THE SOURCE OF ACETYL GROUP DONORS. FINALLY, WHILE GLOBAL METHYLATION OF CYTOSINE FROM PLACENTAL DNA WAS LOW IN BOTH GROUPS OF ANIMALS (<1%), THERE WAS APPROXIMATELY 50% INCREASE IN 5-MC IN RESPONSE TO CHRONIC ISCHEMIA. THIS SUGGESTS ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL GLOBAL CHANGES IN HISTONE ACETYLATION IN THE PLACENTA AND THAT CHRONICALLY ALTERED METABOLIC PROFILES COULD AFFECT HISTONE ACETYLATION IN THE PLACENTA, THEREBY REGULATING PRODUCTION OF PATHOGENIC FACTORS FROM THE PLACENTA DURING PREECLAMPSIA. 2019 17 4504 32 MOTHER'S PRE-PREGNANCY BMI AND PLACENTAL CANDIDATE MIRNAS: FINDINGS FROM THE ENVIRONAGE BIRTH COHORT. THERE IS INCREASING EVIDENCE THAT THE PREDISPOSITION FOR DEVELOPMENT OF CHRONIC DISEASES ARISES AT THE EARLIEST TIMES OF LIFE. IN THIS CONTEXT, MATERNAL PRE-PREGNANCY WEIGHT MIGHT MODIFY FETAL METABOLISM AND THE CHILD'S PREDISPOSITION TO DEVELOP DISEASE LATER IN LIFE. THE AIM OF THIS STUDY IS TO INVESTIGATE THE ASSOCIATION BETWEEN MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) AND MIRNA ALTERATIONS IN PLACENTAL TISSUE AT BIRTH. IN 211 MOTHER-NEWBORN PAIRS FROM THE ENVIRONAGE BIRTH COHORT, WE ASSESSED PLACENTAL EXPRESSION OF SEVEN MIRNAS IMPORTANT IN CRUCIAL CELLULAR PROCESSES IMPLICATED IN ADIPOGENESIS AND/OR OBESITY. MULTIPLE LINEAR REGRESSION MODELS WERE USED TO ADDRESS THE ASSOCIATIONS BETWEEN PRE-PREGNANCY BMI AND PLACENTAL CANDIDATE MIRNA EXPRESSION. MATERNAL PRE-PREGNANCY BMI AVERAGED (+/-SD) 23.9 (+/-4.1) KG/M(2). IN NEWBORN GIRLS (NOT IN BOYS) PLACENTAL MIR-20A, MIR-34A AND MIR-222 EXPRESSION WAS LOWER WITH HIGHER MATERNAL PRE-PREGNANCY BMI. IN ADDITION, THE ASSOCIATION BETWEEN MATERNAL PRE-PREGNANCY BMI AND PLACENTAL EXPRESSION OF THESE MIRNAS IN GIRLS WAS MODIFIED BY GESTATIONAL WEIGHT GAIN. THE LOWER EXPRESSION OF THESE MIRNAS IN PLACENTA IN ASSOCIATION WITH PRE-PREGNANCY BMI, WAS ONLY EVIDENT IN MOTHERS WITH LOW WEIGHT GAIN (<14 KG). THE PLACENTAL EXPRESSION OF MIR-20A, MIR-34A, MIR-146A, MIR-210 AND MIR-222 MAY PROVIDE A SEX-SPECIFIC BASIS FOR EPIGENETIC EFFECTS OF PRE-PREGNANCY BMI. 2017 18 6601 32 TWO INTRAUTERINE PROGRAMMING MECHANISMS OF ADULT HYPERCHOLESTEROLEMIA INDUCED BY PRENATAL NICOTINE EXPOSURE IN MALE OFFSPRING RATS. EPIDEMIOLOGIC STUDIES SHOWED THAT LOW BIRTH WEIGHT IS ASSOCIATED WITH HIGH CHOLESTEROL AND AN INCREASED RISK OF CARDIOVASCULAR DISEASES IN ADULTHOOD. THIS STUDY AIMED TO ELUCIDATE THE INTRAUTERINE PROGRAMMING MECHANISMS OF ADULT HYPERCHOLESTEROLEMIA. THE RESULTS SHOWED THAT PRENATAL NICOTINE EXPOSURE (PNE) CAUSED INTRAUTERINE GROWTH RETARDATION AND HYPERCHOLESTEROLEMIA IN MALE ADULT OFFSPRING RATS. HEPATIC CHOLESTEROL SYNTHESIS AND OUTPUT WERE DECEASED IN UTERO BUT INCREASED IN ADULTS; HEPATIC REVERSE CHOLESTEROL TRANSPORT (RCT) PERSISTENTLY DECEASED BEFORE AND AFTER BIRTH. MEANWHILE, PNE ELEVATED SERUM CORTICOSTERONE LEVEL AND DECREASED HEPATIC IGF1 PATHWAY ACTIVITY IN MALE FETUSES, WHEREAS CONVERSE CHANGES WERE OBSERVED IN MALE ADULTS. THE CHRONIC STRESS MODEL AND CORTISOL-TREATED HEPG2 CELLS VERIFIED THAT EXCESSIVE GLUCOCORTICOID (GC)-INDUCED GC-IGF1 AXIS PROGRAMMING ENHANCED HEPATIC CHOLESTEROL SYNTHESIS AND OUTPUT. IN ADDITION, PNE DECREASED THE EXPRESSION OF SPECIFIC PROTEIN 1 AND P300 ENRICHMENT AND H3K27 ACETYLATION AT THE PROMOTER REGION OF GENES RESPONSIBLE FOR RCT BOTH IN FETAL AND ADULT, MALE LIVERS AND REDUCED EXPRESSION OF THOSE GENES, SIMILAR ALTERATIONS WERE ALSO CONFIRMED IN CORTISOL-TREATED HEPG2 CELLS, SUGGESTING THAT EXCESSIVE GC-RELATED PROGRAMMING INDUCED CONTINUOUS RCT REDUCTION BY EPIGENETIC MODIFICATION. TAKEN TOGETHER, THE "2-PROGRAMMING" APPROACH DISCUSSED ABOVE MAY ULTIMATELY CONTRIBUTE TO THE DEVELOPMENT OF HYPERCHOLESTEROLEMIA IN MALE ADULT OFFSPRING.-ZHOU, J., ZHU, C., LUO, H., SHEN, L., GONG, J., WU, Y., MAGDALOU, J., CHEN, L., GUO, Y., WANG, H. TWO INTRAUTERINE PROGRAMMING MECHANISMS OF ADULT HYPERCHOLESTEROLEMIA INDUCED BY PRENATAL NICOTINE EXPOSURE IN MALE OFFSPRING RATS. 2019 19 5321 33 PULMONARY ARTERY SMOOTH MUSCLE CELL PROLIFERATION AND MIGRATION IN FETAL LAMBS ACCLIMATIZED TO HIGH-ALTITUDE LONG-TERM HYPOXIA: ROLE OF HISTONE ACETYLATION. HIGH-ALTITUDE LONG-TERM HYPOXIA (LTH) IS KNOWN TO INDUCE PULMONARY ARTERIAL SMOOTH MUSCLE CELL (PASMC) PROLIFERATION IN THE FETUS, LEADING TO PULMONARY ARTERIAL REMODELING AND PULMONARY HYPERTENSION OF THE NEWBORN. THE MECHANISMS UNDERLYING THESE CONDITIONS REMAIN ENIGMATIC HOWEVER. WE HYPOTHESIZED THAT EPIGENETIC ALTERATIONS IN FETAL PASMC INDUCED BY HIGH-ALTITUDE LTH MAY PLAY AN IMPORTANT ROLE IN MODULATING THEIR PROLIFERATION DURING PULMONARY ARTERIAL REMODELING. TO TEST THIS HYPOTHESIS, WE HAVE ANALYZED EPIGENETIC ALTERATIONS IN THE PULMONARY VASCULATURE OF FETAL LAMBS EXPOSED TO HIGH-ALTITUDE LTH [PREGNANT EWES WERE KEPT AT 3,801 M ALTITUDE FROM ~40 TO 145 DAYS GESTATION] OR TO SEA LEVEL ATMOSPHERE. INTRAPULMONARY ARTERIES WERE ISOLATED, AND FETAL PASMC WERE CULTURED FROM BOTH CONTROL AND LTH FETUSES. COMPARED WITH CONTROLS, IN LTH FETUS PULMONARY ARTERIES MEASUREMENTS OF HISTONE ACETYLATION AND GLOBAL DNA METHYLATION DEMONSTRATED REDUCED LEVELS OF GLOBAL HISTONE 4 ACETYLATION AND DNA METHYLATION, ACCOMPANIED BY THE LOSS OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P21. TREATMENT OF LTH FETAL PASMCS WITH HISTONE DEACETYLASE (HDAC) INHIBITOR TRICHOSTATIN A DECREASED THEIR PROLIFERATION RATE, IN PART BECAUSE OF ALTERED EXPRESSION OF P21 AT BOTH RNA AND PROTEIN LEVEL. IN PASMC OF LTH FETUSES, HDAC INHIBITION ALSO DECREASED PDGF-INDUCED CELL MIGRATION AND ERK1/2 ACTIVATION AND MODULATED GLOBAL DNA METHYLATION. ON THE BASIS OF THESE OBSERVATIONS, WE PROPOSE THAT EPIGENETIC ALTERATIONS (REDUCED HISTONE ACETYLATION AND DNA METHYLATION) CAUSED BY CHRONIC HYPOXIA LEADS TO FETAL PASMC PROLIFERATION AND VESSEL REMODELING ASSOCIATED WITH VASCULAR PROLIFERATIVE DISEASE AND THAT THIS PROCESS IS REGULATED BY P21. 2012 20 5075 21 PHYSIOLOGICAL ADAPTATION OF THE GROWTH-RESTRICTED FETUS. THE GROWTH-RESTRICTED FETUS IN UTERO IS EXPOSED TO A HOSTILE ENVIRONMENT AND SUFFERS UNDERNUTRITION AND HYPOXIA. TO COPE WITH THE STRESS, THE FETUS CHANGES ITS PHYSIOLOGICAL FUNCTIONS. THESE ADAPTIVE CHANGES AID INTRAUTERINE SURVIVAL; HOWEVER, THEY CAN LEAD TO PERMANENT FUNCTIONAL AND STRUCTURAL CHANGES THAT CAN CONTRIBUTE TO THE DEVELOPMENT OF SERIOUS CHRONIC DISEASES LATER IN LIFE. EPIGENETIC MECHANISMS ARE AN IMPORTANT PART OF THE PATHOPHYSIOLOGICAL PROCESSES BEHIND THIS "DEVELOPMENTAL ORIGIN OF ADULT DISEASES." THE DOMINANT CARDIOVASCULAR ADAPTIVE CHANGE IS THE REDISTRIBUTION OF BLOOD FLOW IN HYPOXIC FETUSES, WITH PREFERENTIAL SUPPLY OF BLOOD TO THE FETAL BRAIN, MYOCARDIUM, AND ADRENAL GLANDS. THE PROPORTION OF BLOOD FROM THE UMBILICAL VEIN TO THE DUCTUS VENOSUS AND FORAMEN OVALE INCREASES, WHICH INCREASES THE CARDIAC OUTPUT OF THE LEFT HEART VENTRICLE. THE INCREASED PERFUSION OF FETAL BRAIN CAN BE FOLLOWED WITH DOPPLER ULTRASOUND AS INCREASED DIASTOLIC VELOCITIES AND DECREASED PULSATILITY INDEX IN THE MIDDLE CEREBRAL ARTERY. 2018