1 5430 110 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 2 2260 36 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 3 4664 34 NEW IMMUNE HORIZONS IN THERAPEUTICS AND DIAGNOSTIC APPROACHES TO PREECLAMPSIA. HYPERTENSIVE DISORDERS OF PREGNANCY (HDP) ARE ONE OF THE COMMONEST MALADIES, AFFECTING 5%-10% OF PREGNANCIES WORLDWIDE. THE AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS (ACOG) IDENTIFIES FOUR CATEGORIES OF HDP, NAMELY GESTATIONAL HYPERTENSION (GH), PREECLAMPSIA (PE), CHRONIC HYPERTENSION (CH), AND CH WITH SUPERIMPOSED PE. PE IS A MULTISYSTEM, HETEROGENEOUS DISORDER THAT ENCOMPASSES 2%-8% OF ALL PREGNANCY-RELATED COMPLICATIONS, CONTRIBUTING TO ABOUT 9% TO 26% OF MATERNAL DEATHS IN LOW-INCOME COUNTRIES AND 16% IN HIGH-INCOME COUNTRIES. THESE TRANSLATE TO 50 000 MATERNAL DEATHS AND OVER 500 000 FETAL DEATHS WORLDWIDE, THEREFORE DEMANDING HIGH PRIORITY IN UNDERSTANDING CLINICAL PRESENTATION, SCREENING, DIAGNOSTIC CRITERIA, AND EFFECTIVE MANAGEMENT. PE IS ACCOMPANIED BY UTEROPLACENTAL INSUFFICIENCY LEADING TO VASCULAR AND METABOLIC CHANGES, VASOCONSTRICTION, AND END-ORGAN ISCHEMIA. PE IS DIAGNOSED AFTER 20 WEEKS OF PREGNANCY IN WOMEN WHO WERE PREVIOUSLY NORMOTENSIVE OR HYPERTENSIVE. BESIDES SHALLOW TROPHOBLAST INVASION AND INADEQUATE REMODELING OF UTERINE ARTERIES, DYSREGULATION OF THE NONIMMUNE SYSTEM HAS BEEN THE FOCAL POINT IN PE. THIS RESULTS FROM ABERRANT IMMUNE SYSTEM ACTIVATION AND IMBALANCED DIFFERENTIATION OF T CELLS. FURTHER, A FAILURE OF TOLERANCE TOWARD THE SEMI-ALLOGENIC FETUS RESULTS DUE TO ALTERED DISTRIBUTION OF TREGS SUCH AS CD4+FOXP3+ OR CD4+CD25+CD127(LOW) FOXP3+ CELLS, THEREBY CREATING A CYTOTOXIC ENVIRONMENT BY SUBOPTIMAL PRODUCTION OF IMMUNOSUPPRESSIVE CYTOKINES LIKE IL-10, IL-4, AND IL-13. ALSO, INTRACELLULAR PRODUCTION OF COMPLEMENT PROTEIN C5A MAY RESULT IN DECREASED FOXP3+ REGULATORY T CELLS. WITH IMMUNE SYSTEM DYSFUNCTION AS A MAJOR DRIVER IN PE PATHOGENESIS, IT IS LOGICAL THAT THERAPEUTIC TARGETING OF COMPONENTS OF THE IMMUNE SYSTEM WITH PHARMACOLOGIC AGENTS LIKE ANTI-INFLAMMATORY AND IMMUNE-MODULATING MOLECULES ARE EITHER BEING USED OR UNDER CLINICAL TRIAL. CHOLESTEROL SYNTHESIS INHIBITORS LIKE PRAVASTATIN MAY IMPROVE PLACENTAL PERFUSION IN PE, WHILE ECULIZUMAB (MONOCLONAL ANTIBODY INHIBITING C5) AND SMALL MOLECULAR INHIBITOR OF C5A, ZILUCOPLAN ARE UNDER INVESTIGATION. MONOCLONAL ANTIBODY AGAINST IL-17(SECUKINUMAB) HAS BEEN PROPOSED TO ALTER THE TH IMBALANCE IN PE. AUTOLOGOUS TREG THERAPY AND IMMUNE CHECKPOINT INHIBITORS LIKE ANTI-CTLA-4 ARE EMERGING AS NEW CANDIDATES IN IMMUNE HORIZONS FOR PE MANAGEMENT IN THE FUTURE. 2023 4 218 33 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 5 167 30 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 6 5091 31 PLACENTAL DISEASES ASSOCIATED WITH ASSISTED REPRODUCTIVE TECHNOLOGY. THE PLACENTA DEVELOPS FROM THE OUTER TROPHOBLASTIC LAYER FOLLOWING THE DIFFERENTIATION OF THE FERTILIZED OVUM AND IS THEREFORE MORE SUSCEPTIBLE TO EPIGENETIC REGULATORY CHANGES CAUSED BY ENVIRONMENTAL INTERVENTIONS AND INFLUENCES DURING ASSISTED REPRODUCTIVE TECHNOLOGY. FURTHERMORE, THE PLACENTA REGULATES THE DEVELOPMENT OF THE FETAL HEART, BRAIN, KIDNEYS, BONES, AND OTHER TISSUES AND ORGANS [1]. PLACENTAL DYSPLASIA LEADS TO POOR PERINATAL OUTCOMES AS WELL AS LONG-TERM HEALTH RISKS LATER IN LIFE, INCLUDING NEURODEVELOPMENTAL DISORDERS, TUMORS, AND ADULT METABOLIC SYNDROME [2,3]. IN VIEW OF THE DECISIVE ROLE OF THE PLACENTA DURING INTRAUTERINE FETAL DEVELOPMENT, GRAHAM J. BURTON, AN EXPERT IN PLACENTOLOGY FROM THE UNIVERSITY OF CAMBRIDGE, FORMALLY PROPOSED THE THEORY OF "PLACENTA-DERIVED CHRONIC DISEASES" IN 2018 BASED ON EMBRYONIC-DERIVED DISEASES [4]. IN THIS REVIEW, WE SUMMARIZED THE CHANGES IN PLACENTAL MORPHOLOGY AND STRUCTURE, GROWTH DYNAMICS, IMPRINTED AND NON-IMPRINTED GENES, AND OTHER ASPECTS ATTRIBUTABLE TO ASSISTED REPRODUCTION TECHNOLOGY. OUR REVIEW PROVIDES A THEORETICAL BASIS FOR FURTHER RESEARCH ON PLACENTAL CHANGES CAUSED BY ASSISTED REPRODUCTIVE TECHNOLOGY THAT ARE MOST STRONGLY ASSOCIATED WITH AN INCREASED RISK OF NEONATAL LONG-TERM DISEASES. 2021 7 3452 22 HYPERTENSIVE DISORDERS OF PREGNANCY SHARE COMMON CFDNA METHYLATION PROFILES. HYPERTENSIVE DISORDERS OF PREGNANCY (HDP) CONTRIBUTE SUBSTANTIALLY TO PERINATAL MORBIDITY AND MORTALITY. EPIGENETIC CHANGES POINT TOWARDS CARDIO-METABOLIC DYSREGULATION FOR THESE VASCULAR DISORDERS. IN EARLY PREGNANCY, EPIGENETIC CHANGES USING CELL FREE DNA (CFDNA) ARE LARGELY UNEXPLORED. WE AIMED TO INVESTIGATE THESE IN HDP BETWEEN 11 AND 14 WEEKS OF GESTATION BY ANALYSIS OF CFDNA METHYLATION PROFILES IN PATIENTS WITH HYPERTENSIVE DISORDERS. WE IDENTIFIED PATIENTS WITHOUT CHRONIC HYPERTENSION BUT WITH SUBSEQUENT DEVELOPMENT OF PREECLAMPSIA (PE) (N = 11), WITH CHRONIC HYPERTENSION (HT) BUT WITHOUT PE DEVELOPMENT (N = 14), AND LACKING BOTH PE AND HT (N = 422). WE MATCHED PATIENTS ACCORDING TO PE RISK FACTORS INTO THREE GROUPS (N = 5 EACH GROUP): (1) PE: NO HT BUT PE DEVELOPMENT, (2) HT: CHRONIC HYPERTENSION BUT NO PE AND (3) CONTROL: NO PE OR HT. WE SUCCESSFULLY OPTIMIZED OUR CFDNA ISOLATION PROCESS PRIOR TO WHOLE GENOME BISULFITE SEQUENCING. ANALYSIS OF CFDNA METHYLATION CHANGES INDICATE A COMMON PREDISPOSITION IN PE AND HT GROUPS, CHIEFLY OF MATERNAL ORIGIN. ASSESSMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS AND ANNOTATED GENES POINT TOWARDS A COMMON CARDIOVASCULAR PREDISPOSITION IN PREECLAMPSIA AND HYPERTENSION GROUPS IN THE FIRST TRIMESTER. WE POSTULATE THE PIVOTAL ROLE OF THE MATERNAL CARDIOVASCULAR SYSTEM IN HDP, WHICH IS ALREADY EVIDENT IN THE FIRST TRIMESTER. 2022 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 2511 33 EPIGENETICS AND PREECLAMPSIA: PROGRAMMING OF FUTURE OUTCOMES. PREGNANCY IS KNOWN TO INDUCE RAPID, PROGRESSIVE, AND SUBSTANTIAL CHANGES TO THE CARDIOVASCULAR SYSTEM, ULTIMATELY FACILITATING SUCCESSFUL PREGNANCY OUTCOMES. WOMEN WHO DEVELOP HYPERTENSIVE DISORDERS DURING PREGNANCY ARE CONSIDERED TO HAVE "FAILED" THE CARDIOVASCULAR STRESS TEST OF PREGNANCY AND LIKELY REPRESENT A SUBPOPULATION WITH INADEQUATE CARDIOVASCULAR ACCOMMODATION. PREECLAMPSIA IS A SERIOUS COMPLICATION WITH A MYRIAD OF MANIFESTATIONS IN BOTH MOTHER AND OFFSPRING. THIS PREGNANCY SYNDROME IS A POLYGENIC DISEASE AND HAS NOW BEEN LINKED TO A GREATER INCIDENCE OF CARDIOVASCULAR DISEASE. MOREOVER, OFFSPRINGS BORN TO PREECLAMPTIC MOTHERS EXHIBIT AN ELEVATED RISK OF CARDIOVASCULAR DISEASE, STROKE, AND MENTAL DISORDERS DURING ADULTHOOD. THIS SUGGESTS THAT PREECLAMPSIA NOT ONLY EXPOSES THE MOTHER AND THE FETUS TO COMPLICATIONS DURING PREGNANCY BUT ALSO PROGRAMS CHRONIC DISEASES DURING ADULTHOOD IN THE OFFSPRING. THE ETIOLOGY OF PREECLAMPSIA REMAINS UNKNOWN, WITH VARIOUS THEORIES BEING SUGGESTED TO EXPLAIN ITS ORIGIN. IT IS PRIMARILY THOUGHT TO BE ASSOCIATED WITH POOR PLACENTATION AND ENTAILS EXCESSIVE MATERNAL INFLAMMATION AND ENDOTHELIAL DYSFUNCTION. IT IS WELL ESTABLISHED NOW THAT THE MATERNAL IMMUNE SYSTEM AND THE PLACENTA ARE INVOLVED IN A HIGHLY CHOREOGRAPHED CROSS TALK THAT UNDERLIES ADEQUATE SPIRAL ARTERY REMODELING REQUIRED FOR UTEROPLACENTAL PERFUSION AND FREE FLOW OF NUTRIENTS TO THE FETUS. ALTHOUGH IT IS NOT CLEAR WHETHER IMMUNOLOGICAL ALTERATIONS OCCUR EARLY DURING PREGNANCY, STUDIES HAVE PROPOSED THAT DYSREGULATED SYSTEMIC AND PLACENTAL IMMUNITY CONTRIBUTE TO IMPAIRED ANGIOGENESIS AND THE ONSET OF PREECLAMPSIA. RECENTLY EMERGED STRONG EVIDENCE SUGGESTS A POTENTIAL LINK AMONG EPIGENETICS, MICRORNAS (MIRNAS), AND PREGNANCY COMPLICATIONS. THIS CHAPTER WILL FOCUS ON IMPORTANT ASPECTS OF EPIGENETICS, IMMUNOLOGICAL ASPECTS, AND CARDIOVASCULAR AND VASCULAR REMODELING OF PREECLAMPSIA. 2018 10 4504 29 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 11 2077 28 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 12 3975 39 LONG-TERM CONSEQUENCES OF PLACENTAL VASCULAR PATHOLOGY ON THE MATERNAL AND OFFSPRING CARDIOVASCULAR SYSTEMS. OVER THE LAST THIRTY YEARS, EVIDENCE HAS BEEN ACCUMULATING THAT HYPERTENSIVE DISORDERS OF PREGNANCY (HDP) AND, SPECIFICALLY, PREECLAMPSIA (PE) PRODUCE NOT ONLY LONG-TERM EFFECTS ON THE PREGNANT WOMAN, BUT HAVE ALSO LASTING CONSEQUENCES FOR THE FETUS. AT THE CORE OF THESE CONSEQUENCES IS THE PHENOMENON KNOWN AS DEFECTIVE DEEP PLACENTATION, BEING PRESENT IN VIRTUALLY EVERY MAJOR OBSTETRICAL SYNDROME. THE PROFOUND PLACENTAL VASCULAR LESIONS CHARACTERISTIC OF THIS PATHOLOGY CAN INDUCE LONG-TERM ADVERSE CONSEQUENCES FOR THE PREGNANT WOMAN'S ENTIRE ARTERIAL SYSTEM. IN ADDITION, PLACENTAL GROWTH RESTRICTION AND FUNCTION CAN, IN TURN, CAUSE A DECREASED BLOOD SUPPLY TO THE FETUS, WITH LONG-LASTING EFFECTS. WOMEN WITH A HISTORY OF HDP HAVE AN INCREASED RISK OF CARDIOVASCULAR DISEASES (CVD) COMPARED WITH WOMEN WITH NORMAL PREGNANCIES. SPECIFICALLY, THESE SUBJECTS ARE AT A FUTURE HIGHER RISK OF: HYPERTENSION; CORONARY ARTERY DISEASE; HEART FAILURE; PERIPHERAL VASCULAR DISEASE; CEREBROVASCULAR ACCIDENTS (STROKE); CVD-RELATED MORTALITY. VASCULAR PATHOLOGY IN PREGNANCY AND CVD MAY SHARE A COMMON ETIOLOGY AND MAY HAVE COMMON RISK FACTORS, WHICH ARE UNMASKED BY THE "STRESS" OF PREGNANCY. IT IS ALSO POSSIBLE THAT THE FUTURE OCCURRENCE OF A CVD MAY BE THE CONSEQUENCE OF ENDOTHELIAL DYSFUNCTION GENERATED BY PREGNANCY-INDUCED HYPERTENSION THAT PERSISTS AFTER DELIVERY. ALTHOUGH BIOCHEMICAL AND BIOPHYSICAL MARKERS OF PE ABOUND, INFORMATION ON MARKERS FOR A COMPARATIVE EVALUATION IN THE VARIOUS GROUPS IS STILL LACKING. LONG-TERM CONSEQUENCES FOR THE FETUS ARE AN INTEGRAL PART OF THE THEORY OF A FETAL ORIGIN OF A NUMBER OF ADULT DISEASES, KNOWN AS THE BARKER HYPOTHESIS. INDEED, INTRAUTERINE MALNUTRITION AND FETAL GROWTH RESTRICTION REPRESENT SIGNIFICANT RISK FACTORS FOR THE DEVELOPMENT OF CHRONIC HYPERTENSION, DIABETES, STROKE AND DEATH FROM CORONARY ARTERY DISEASE IN ADULTS. OTHER FACTORS WILL ALSO INFLUENCE THE DEVELOPMENT LATER IN LIFE OF HYPERTENSION, CORONARY AND MYOCARDIAL DISEASE; THEY INCLUDE PARENTAL GENETIC DISPOSITION, EPIGENETIC MODIFICATIONS, ENDOTHELIAL DYSFUNCTION, CONCURRENT INTRAUTERINE EXPOSURES, AND THE LIFESTYLE OF THE AFFECTED INDIVIDUAL. 2021 13 3145 27 GLOBAL POPULATION VARIATION IN PLACENTAL SIZE AND STRUCTURE: EVIDENCE FROM CEBU, PHILIPPINES. INTRODUCTION: PLACENTAL MORPHOLOGY INFLUENCES THE INTRAUTERINE ENVIRONMENT AND FETAL GROWTH, WHICH HELP SET LIFE-COURSE HEALTH TRAJECTORIES ACROSS GENERATIONS. LITTLE IS KNOWN ABOUT PLACENTAL CHARACTERISTICS IN POPULATIONS WITH CHRONIC NUTRITIONAL INSUFFICIENCY WHERE BIRTH WEIGHTS TEND TO BE LOWER, AND HOW THESE RELATIONSHIPS BETWEEN BIRTH AND PLACENTAL WEIGHTS VARY ACROSS POPULATIONS. METHODS: WE COLLECTED WEIGHTS AND STEREOLOGICALLY-DETERMINED VILLOUS MASS AND SURFACE AREA OF 21 PLACENTAS FROM OFFSPRING OF WOMEN ENROLLED IN A BIRTH COHORT STUDY IN METROPOLITAN CEBU, PHILIPPINES, A LOW-INCOME POPULATION. WE IDENTIFIED 15 SAMPLES FROM OTHER GLOBAL POPULATIONS RANGING FROM LOW TO HIGH INCOME THAT HAD SIMILAR DATA TO OURS TO ASSESS PATTERNS OF VARIATION BETWEEN BIRTH AND PLACENTAL WEIGHTS AND MICROSCOPIC CHARACTERISTICS. WE RANKED THE POPULATION SAMPLES IN ORDER FOR EACH CHARACTERISTIC. RESULTS: MEAN BIRTH WEIGHT IN CEBU WAS 3162 +/- 80 G (RANKED 9/16) AND PLACENTAL WEIGHT WAS 454 +/- 32 G (RANKED 12/16). BIRTH:PLACENTAL WEIGHT RATIO WAS 7.0 (RANKED 3/16). AVERAGE VILLOUS SURFACE AREA FOR CEBU PLACENTAS WAS 6.5 M(2) (RANKED 9/12); BIRTH WEIGHT:VILLOUS SURFACE AREA WAS 0.048 G/M(2) (RANKED 4/12). DISCUSSION: PLACENTAS FROM CEBU PRODUCED HEAVIER NEONATES PER UNITS OF PLACENTAL WEIGHT AND VILLOUS SURFACE AREA THAN MOST OTHER POPULATIONS, DESPITE LOWER VILLOUS SURFACE AREAS AND LESS COMPLEX SURFACE-TO-VOLUME TOPOGRAPHY. THIS RANGE OF PLACENTAL EFFICIENCY SPURS QUESTIONS ABOUT THE MECHANISMS BY WHICH PLACENTAL MORPHOLOGY OPTIMIZES EFFICIENCY IN DIFFERENT ENVIRONMENTAL CONTEXTS DURING GESTATION. PLACENTAL VARIATION BOTH WITHIN AND ACROSS POPULATIONS IS LIKELY DUE TO MANY INTERSECTING ENVIRONMENTAL, METABOLIC, AND (EPI)GENETIC FACTORS THAT WILL REQUIRE ADDITIONAL RESEARCH TO CLARIFY. 2019 14 5680 26 SHORT- AND LONG-TERM OUTCOMES OF PREECLAMPSIA IN OFFSPRING: REVIEW OF THE LITERATURE. PREECLAMPSIA IS A MULTISYSTEMIC CLINICAL SYNDROME CHARACTERIZED BY THE APPEARANCE OF NEW-ONSET HYPERTENSION AND PROTEINURIA OR HYPERTENSION AND END ORGAN DYSFUNCTION EVEN WITHOUT PROTEINURIA AFTER 20 WEEKS OF PREGNANCY OR POSTPARTUM. RESIDING AT THE SEVERE END OF THE SPECTRUM OF THE HYPERTENSIVE DISORDERS OF PREGNANCY, PREECLAMPSIA OCCURS IN 3 TO 8% OF PREGNANCIES WORLDWIDE AND IS A MAJOR CAUSE OF MATERNAL AND PERINATAL MORBIDITY AND MORTALITY, ACCOUNTING FOR 8-10% OF ALL PRETERM BIRTHS. THE MECHANISM WHEREBY PREECLAMPSIA INCREASES THE RISK OF THE NEURODEVELOPMENTAL, CARDIOVASCULAR, AND METABOLIC MORBIDITY OF THE MOTHER'S OFFSPRING IS NOT WELL KNOWN, BUT IT IS POSSIBLE THAT THE PREECLAMPTIC ENVIRONMENT INDUCES EPIGENETIC CHANGES THAT ADVERSELY AFFECT DEVELOPMENTAL PLASTICITY. THESE DEVELOPMENTAL CHANGES ARE CRUCIAL FOR OPTIMAL FETAL GROWTH AND SURVIVAL BUT MAY LEAD TO AN INCREASED RISK OF CHRONIC MORBIDITY IN CHILDHOOD AND EVEN LATER IN LIFE. THE AIM OF THIS REVIEW IS TO SUMMARIZE BOTH THE SHORT- AND LONG-TERM EFFECTS OF PREECLAMPSIA ON OFFSPRING BASED ON THE CURRENT LITERATURE. 2023 15 4086 27 MATERNAL OBESITY DISRUPTS THE METHIONINE CYCLE IN BABOON PREGNANCY. MATERNAL INTAKE OF DIETARY METHYL-MICRONUTRIENTS (E.G. FOLATE, CHOLINE, BETAINE AND VITAMIN B-12) DURING PREGNANCY IS ESSENTIAL FOR NORMAL MATERNAL AND FETAL METHIONINE METABOLISM, AND IS CRITICAL FOR IMPORTANT METABOLIC PROCESSES INCLUDING THOSE INVOLVED IN DEVELOPMENTAL PROGRAMMING. MATERNAL OBESITY AND NUTRIENT EXCESS DURING PREGNANCY INFLUENCE DEVELOPMENTAL PROGRAMMING POTENTIALLY PREDISPOSING ADULT OFFSPRING TO A VARIETY OF CHRONIC HEALTH PROBLEMS. IN THE PRESENT STUDY, WE HYPOTHESIZED THAT MATERNAL OBESITY WOULD DYSREGULATE THE MATERNAL AND FETAL METHIONINE CYCLE. TO TEST THIS HYPOTHESIS, WE DEVELOPED A NULLIPAROUS BABOON OBESITY MODEL FED A HIGH FAT, HIGH ENERGY DIET (HF-HED) PRIOR TO AND DURING GESTATION, AND EXAMINED METHIONINE CYCLE BIOMARKERS (E.G., CIRCULATING CONCENTRATIONS OF HOMOCYSTEINE, METHIONINE, CHOLINE, BETAINE, KEY AMINO ACIDS, FOLATE, AND VITAMIN B-12). ANIMALS WERE GROUP HOUSED ALLOWING FULL PHYSICAL ACTIVITY AND SOCIAL INTERACTION. MATERNAL PREPREGNANCY PERCENT BODY FAT WAS 5% IN CONTROLS AND 19% IN HF-HED MOTHERS, WHILE FETAL WEIGHT WAS 16% LOWER IN OFFSPRING OF HF-HED MOTHERS AT TERM. MATERNAL AND FETAL HOMOCYSTEINE WERE HIGHER, WHILE MATERNAL AND FETAL VITAMIN B-12 AND BETAINE WERE LOWER IN THE HF-HED GROUP. ELEVATIONS IN CIRCULATING MATERNAL FOLATE WERE EVIDENT IN THE HF-HED GROUP INDICATING IMPAIRED FOLATE METABOLISM (METHYL-TRAP) AS A CONSEQUENCE OF MATERNAL VITAMIN B-12 DEPLETION. FINALLY, FETAL METHIONINE, GLYCINE, SERINE, AND TAURINE WERE LOWER IN THE HF-HED FETUSES. THESE DATA SHOW THAT MATERNAL OBESITY DISTURBS THE METHIONINE CYCLE IN PRIMATE PREGNANCY, PROVIDING A MECHANISM FOR THE EPIGENETIC CHANGES OBSERVED AMONG OBESE PREGNANT WOMEN AND SUGGESTING DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES IN HUMAN PREGNANCIES COMPLICATED BY OBESITY. 2015 16 6279 29 THE PLACENTA AS A TARGET OF EPIGENETIC ALTERATIONS IN WOMEN WITH GESTATIONAL DIABETES MELLITUS AND POTENTIAL IMPLICATIONS FOR THE OFFSPRING. GESTATIONAL DIABETES MELLITUS (GDM) IS A PREGNANCY COMPLICATION FIRST DETECTED IN THE SECOND OR THIRD TRIMESTER IN WOMEN THAT DID NOT SHOW EVIDENT GLUCOSE INTOLERANCE OR DIABETES BEFORE GESTATION. IN 2019, THE INTERNATIONAL DIABETES FEDERATION REPORTED THAT 15.8% OF LIVE BIRTHS WERE AFFECTED BY HYPERGLYCEMIA DURING PREGNANCY, OF WHICH 83.6% WERE DUE TO GESTATIONAL DIABETES MELLITUS, 8.5% WERE DUE TO DIABETES FIRST DETECTED IN PREGNANCY, AND 7.9% WERE DUE TO DIABETES DETECTED BEFORE PREGNANCY. GDM INCREASES THE SUSCEPTIBILITY TO DEVELOPING CHRONIC DISEASES FOR BOTH THE MOTHER AND THE BABY LATER IN LIFE. UNDER GDM CONDITIONS, THE INTRAUTERINE ENVIRONMENT BECOMES HYPERGLYCEMIC, WHILE ALSO SHOWING HIGH CONCENTRATIONS OF FATTY ACIDS AND PROINFLAMMATORY CYTOKINES, PRODUCING MORPHOLOGICAL, STRUCTURAL, AND MOLECULAR MODIFICATIONS IN THE PLACENTA, AFFECTING ITS FUNCTION; THESE ALTERATIONS MAY PREDISPOSE THE BABY TO DISEASE IN ADULT LIFE. MOLECULAR ALTERATIONS INCLUDE EPIGENETIC MECHANISMS SUCH AS DNA AND RNA METHYLATION, CHROMATIN REMODELING, HISTONE MODIFICATIONS, AND EXPRESSION OF NONCODING RNAS (NCRNAS). THE PLACENTA IS A UNIQUE ORGAN THAT ORIGINATES ONLY IN PREGNANCY, AND ITS MAIN FUNCTION IS COMMUNICATION BETWEEN THE MOTHER AND THE FETUS, ENSURING HEALTHY DEVELOPMENT. THUS, THIS REVIEW PROVIDES UP-TO-DATE INFORMATION REGARDING TWO OF THE BEST-DOCUMENTED (EPIGENETIC) MECHANISMS (DNA METHYLATION AND MIRNA EXPRESSION) ALTERED IN THE HUMAN PLACENTA UNDER GDM CONDITIONS, AS WELL AS POTENTIAL IMPLICATIONS FOR THE OFFSPRING. 2021 17 6724 28 VITAMIN D: EFFECTS ON PREGNANCY, MATERNAL, FETAL AND POSTNATAL OUTCOMES. A HIGH PREVALENCE OF VITAMIN D DEFICIENCY AND ITS NEGATIVE CONSEQUENCES FOR HEALTH IS IDENTIFIED AS AREA OF PRIMARY CONCERN FOR SCIENTISTS AND CLINICIANS WORLDWIDE. VITAMIN D DEFICIENCY AFFECTS NOT ONLY BONE HEALTH BUT MANY SOCIALLY SIGNIFICANT ACUTE AND CHRONIC DISEASES. OBSERVATIONAL STUDIES SUPPORT THAT PREGNANT AND LACTATING WOMEN, CHILDREN AND TEENAGERS REPRESENT THE HIGH RISK GROUPS FOR DEVELOPING VITAMIN D DEFICIENCY. CURRENT EVIDENCE HIGHLIGHTS A CRUCIAL ROLE OF VITAMIN D IN PROVIDING THE FETAL LIFE-SUPPORT SYSTEM AND FETUS DEVELOPMENT, INCLUDING IMPLANTATION, PLACENTAL FORMATION, INTRA- AND POSTPARTUM PERIODS. HYPOVITAMINOSIS D DURING PREGNANCY IS ASSOCIATED WITH A HIGHER INCIDENCE OF PLACENTAL INSUFFICIENCY, SPONTANEOUS ABORTIONS AND PRETERM BIRTH, PREECLAMPSIA, GESTATIONAL DIABETES, IMPAIRED FETAL AND CHILDHOOD GROWTH, INCREASED RISK OF AUTOIMMUNE DISEASES FOR OFFSPRINGS. POTENTIAL MECHANISMS FOR THE OBSERVED ASSOCIATIONS CONTAIN METABOLIC, IMMUNOMODULATORY AND ANTIINFLAMMATORY EFFECTS OF VITAMIN D. EPIGENETIC MODIFICATIONS IN VITAMIN D-ASSOCIATED GENES AND FETAL PROGRAMMING ARE OF PARTICULAR INTEREST. THE CONCEPT OF PREVENTING VITAMIN D DEFICIENCY IS ACTIVELY DISCUSSED, INCLUDING SUPPLEMENTATION IN DIFFERENT ETHNIC GROUPS, REQUIRED DOSES, TIME OF INITIATION AND THERAPY DURATION, INFLUENCE ON GESTATION AND CHILDBIRTH. AN ADEQUATE SUPPLY OF VITAMIN D DURING PREGNANCY IMPROVES THE MATERNAL AND FETAL OUTCOMES, SHORT AND LONG TERM HEALTH OF THE OFFSPRING. STILL CURRENT DATA ON RELATIONSHIP BETWEEN MATERNAL VITAMIN D STATUS AND PREGNANCY OUTCOMES REMAINS CONTROVERSIAL. THE LARGE OBSERVATIONAL AND INTERVENTIONAL RANDOMIZED CONTROL TRIALS ARE REQUIRED TO CREATE EVIDENCE-BASED GUIDELINES FOR THE SUPPLEMENTATION OF VITAMIN D IN PREGNANT AND LACTATING WOMEN. 2018 18 6625 26 UNDERSTANDING RACIAL DISPARITIES OF PRETERM BIRTH THROUGH THE PLACENTA. THE RACIAL DISPARITY ASSOCIATED WITH PRETERM BIRTH IS A PUBLIC HEALTH CONCERN IN THE UNITED STATES. THE PLACENTA IS THE PRINCIPAL METABOLIC, RESPIRATORY, AND ENDOCRINE ORGAN OF THE FETUS AND A KEY ROUTE BY WHICH ENVIRONMENTAL EXPOSURES ARE TRANSMITTED FROM MOTHER TO OFFSPRING. AVAILABLE AT EVERY DELIVERY, IT MAY SERVE AS A MARKER OF DIFFERENCES IN PRENATAL EXPOSURES THAT MANIFEST DIFFERENTLY BY RACE. RECENTLY, WE DESCRIBED DIFFERENCES IN PLACENTAL PATHOLOGY BETWEEN AFRICAN-AMERICAN AND WHITE PRETERM BIRTHS: THE PREVALENCE OF CHRONIC INFLAMMATION WAS HIGHER AMONG AFRICAN-AMERICAN WOMEN'S PLACENTAS COMPARED WITH THOSE OF WHITE WOMEN. SIMILARLY, RACIAL DIFFERENCES HAVE BEEN SHOWN IN PLACENTAL MALPERFUSION AND PLACENTAL WEIGHT. SOCIAL DETERMINANTS SUCH AS POVERTY AND STRESS FROM DISCRIMINATION HAVE BEEN IMPLICATED IN RACIAL DISPARITIES IN PRETERM BIRTH. TO DATE, HOWEVER, THE UNDERLYING BIOLOGICAL MECHANISMS, WHETHER THROUGH INFLAMMATORY, OXIDATIVE STRESS, OR OTHER PATHWAYS INVOLVING EPIGENETIC PROGRAMMING, REMAIN LARGELY UNKNOWN. THE PLACENTA, COMPLEMENTED BY MATERNAL AND UMBILICAL CORD BLOOD BIOMARKERS, MAY PROVIDE IMPORTANT INFORMATION ON THE PERINATAL ENVIRONMENT THAT EXPLAINS THE ORIGINS OF RACIAL DISPARITIES IN PRETERM BIRTH RATES AND SUBSEQUENT HEALTH OUTCOMES. THIS ARTICLE REVIEWS EXISTING LITERATURE AND CURRENT RESEARCH GAPS. OPPORTUNITIES ARE DISCUSSED FOR FUTURE PLACENTAL RESEARCH THAT MAY REVEAL NOVEL MECHANISMS LEADING TO THE DEVELOPMENT OF NEW APPROACHES IN THE PREVENTION AND MANAGEMENT OF PRETERM BIRTH AND ITS OUTCOMES. 2021 19 4065 27 MATERNAL AND GESTATIONAL INFLUENCES ON CHILDHOOD BLOOD PRESSURE. EXPOSURES THAT CONTRIBUTE TO A SUB-OPTIMAL INTRAUTERINE ENVIRONMENT CAN HAVE AN EFFECT ON THE DEVELOPING FETUS. IMPAIRED FETAL GROWTH THAT RESULTS IN LOW BIRTH WEIGHT IS AN ESTABLISHED RISK FACTOR FOR CARDIO-METABOLIC DISORDERS LATER IN LIFE. RECENT EPIDEMIOLOGIC AND PROSPECTIVE COHORT STUDIES THAT INCLUDE THE MATERNAL AND GESTATIONAL PERIOD HAVE IDENTIFIED MATERNAL AND GESTATIONAL CONDITIONS THAT CONFER INCREASED RISK FOR SUBSEQUENT CARDIO-METABOLIC DISORDERS IN THE ABSENCE OF LOW BIRTH WEIGHT. MATERNAL PRE-CONCEPTION HEALTH STATUS, INCLUDING CHRONIC OBESITY AND TYPE 2 DIABETES, INCREASE RISK FOR CHILDHOOD OBESITY AND OBESITY-RELATED HIGHER BLOOD PRESSURE (BP) IN CHILD OFFSPRING. MATERNAL GESTATIONAL EXPOSURES, INCLUDING GESTATIONAL DIABETES, GESTATIONAL HYPERTENSION, AND PREECLAMPSIA, ARE ASSOCIATED WITH HIGHER BP IN OFFSPRING. OTHER MATERNAL EXPOSURES SUCH AS CIGARETTE SMOKE AND AIR POLLUTION ALSO INCREASE RISK FOR HIGHER BP IN CHILD OFFSPRING. RECENT, BUT LIMITED, DATA INDICATE THAT ASSISTED REPRODUCTIVE TECHNOLOGIES CAN BE ASSOCIATED WITH HYPERTENSION IN CHILDHOOD, DESPITE OTHERWISE NORMAL GESTATION AND HEALTHY NEWBORN. GESTATIONAL EXPOSURES ASSOCIATED WITH HIGHER BP IN CHILDHOOD CAN BE RELATED TO FAMILIAL LIFESTYLE FACTORS, GENETICS, OR EPIGENETIC MODIFICATION OF FETAL DEOXYRIBONUCLEIC ACID (DNA). THESE FACTORS, OR COMBINATION OF FACTORS, AS WELL AS OTHER ADVERSE INTRAUTERINE CONDITIONS, COULD INDUCE FETAL PROGRAMING LEADING TO HEALTH CONSEQUENCES IN LATER LIFE. CURRENT AND DEVELOPING RESEARCH WILL PROVIDE ADDITIONAL INSIGHTS ON GESTATIONAL EXPOSURES AND FETAL ADJUSTMENTS THAT INCREASE RISK FOR HIGHER BP LEVELS IN CHILDHOOD. 2020 20 1439 34 DIFFERENTIAL PLACENTAL CPG METHYLATION IS ASSOCIATED WITH CHRONIC LUNG DISEASE OF PREMATURITY. BACKGROUND: CHRONIC LUNG DISEASE (CLD) IS THE MOST COMMON PULMONARY MORBIDITY IN EXTREMELY PRETERM INFANTS. IT IS UNCLEAR TO WHAT EXTENT PRENATAL EXPOSURES INFLUENCE THE RISK OF CLD. EPIGENETIC VARIATION IN PLACENTA DNA METHYLATION MAY BE ASSOCIATED WITH DIFFERENTIAL RISK OF CLD, AND THESE ASSOCIATIONS MAY BE DEPENDENT UPON SEX. METHODS: DATA WERE OBTAINED FROM A MULTI-CENTER COHORT OF INFANTS BORN EXTREMELY PRETERM (<28 WEEKS' GESTATION) AND AN EPIGENOME-WIDE APPROACH WAS USED TO IDENTIFY ASSOCIATIONS BETWEEN PLACENTAL DNA METHYLATION AND CLD (N = 423). ASSOCIATIONS WERE EVALUATED USING ROBUST LINEAR REGRESSION ADJUSTING FOR COVARIATES, WITH A FALSE DISCOVERY RATE OF 0.05. ANALYSES STRATIFIED BY SEX WERE USED TO ASSESS DIFFERENCES IN METHYLATION-CLD ASSOCIATIONS. RESULTS: CLD WAS ASSOCIATED WITH DIFFERENTIAL METHYLATION AT 49 CPG SITES REPRESENTING 46 GENES IN THE PLACENTA. CLD WAS ASSOCIATED WITH DIFFERENTIAL METHYLATION OF PROBES WITHIN GENES RELATED TO PATHWAYS INVOLVED IN FETAL LUNG DEVELOPMENT, SUCH AS P53 SIGNALING AND MYO-INOSITOL BIOSYNTHESIS. ASSOCIATIONS BETWEEN CPG METHYLATION AND CLD DIFFERED BY SEX. CONCLUSIONS: DIFFERENTIAL PLACENTAL METHYLATION WITHIN GENES WITH KEY ROLES IN FETAL LUNG DEVELOPMENT MAY REFLECT COMPLEX CELL SIGNALING BETWEEN THE PLACENTA AND FETUS WHICH MEDIATE CLD RISK. THESE PATHWAYS APPEAR TO BE DISTINCT BASED ON FETAL SEX. IMPACT: IN EXTREMELY PRETERM INFANTS, DIFFERENTIAL METHYLATION OF CPG SITES WITHIN PLACENTAL GENES INVOLVED IN PATHWAYS RELATED TO CELL SIGNALING, OXIDATIVE STRESS, AND TROPHOBLAST INVASION IS ASSOCIATED WITH CHRONIC LUNG DISEASE OF PREMATURITY. DNA METHYLATION PATTERNS ASSOCIATED WITH CHRONIC LUNG DISEASE WERE DISTINCTLY BASED ON FETAL SEX, SUGGESTING A POTENTIAL MECHANISM UNDERLYING DIMORPHIC PHENOTYPES. MECHANISMS RELATED TO FETAL HYPOXIA AND PLACENTAL MYO-INOSITOL SIGNALING MAY PLAY A ROLE IN FETAL LUNG PROGRAMMING AND THE DEVELOPMENTAL ORIGINS OF CHRONIC LUNG DISEASE. CONTINUED RESEARCH OF THE RELATIONSHIP BETWEEN THE PLACENTAL EPIGENOME AND CHRONIC LUNG DISEASE COULD INFORM EFFORTS TO AMELIORATE OR PREVENT THIS CONDITION. 2022