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  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4  3120  40 GESTATIONAL HYPOXIA AND BLOOD-BRAIN BARRIER PERMEABILITY: EARLY ORIGINS OF CEREBROVASCULAR DYSFUNCTION INDUCED BY EPIGENETIC MECHANISMS. FETAL CHRONIC HYPOXIA LEADS TO INTRAUTERINE GROWTH RESTRICTION (IUGR), WHICH IS LIKELY TO REDUCE OXYGEN DELIVERY TO THE BRAIN AND INDUCE LONG-TERM NEUROLOGICAL IMPAIRMENTS. THESE INDICATE A MODULATORY ROLE FOR OXYGEN IN CEREBROVASCULAR DEVELOPMENT. DURING INTRAUTERINE HYPOXIA, THE FETAL CIRCULATION SUFFERS MARKED ADAPTATIONS IN THE FETAL CARDIAC OUTPUT TO MAINTAIN OXYGEN AND NUTRIENT DELIVERY TO VITAL ORGANS, KNOWN AS THE "BRAIN-SPARING PHENOTYPE." THIS IS A WELL-CHARACTERIZED RESPONSE; HOWEVER, LITTLE IS KNOWN ABOUT THE POSTNATAL COURSE AND OUTCOMES OF THIS FETAL CEREBROVASCULAR ADAPTATION. IN ADDITION, SEVERAL NEURODEVELOPMENTAL DISORDERS HAVE THEIR ORIGINS DURING GESTATION. STILL, FEW STUDIES HAVE FOCUSED ON HOW INTRAUTERINE FETAL HYPOXIA MODULATES THE NORMAL BRAIN DEVELOPMENT OF THE BLOOD-BRAIN BARRIER (BBB) IN THE IUGR NEONATE. THE BBB IS A CELLULAR STRUCTURE FORMED BY THE NEUROVASCULAR UNIT (NVU) AND IS ORGANIZED BY A MONOLAYER OF ENDOTHELIAL AND MURAL CELLS. THE BBB REGULATES THE ENTRY OF PLASMA CELLS AND MOLECULES FROM THE SYSTEMIC CIRCULATION TO THE BRAIN. A HIGHLY SELECTIVE PERMEABILITY SYSTEM ACHIEVES THIS THROUGH INTEGRAL MEMBRANE PROTEINS IN BRAIN ENDOTHELIAL CELLS. BBB BREAKDOWN AND DYSFUNCTION IN CEREBROVASCULAR DISEASES LEAD TO LEAKAGE OF BLOOD COMPONENTS INTO THE BRAIN PARENCHYMA, CONTRIBUTING TO NEUROLOGICAL DEFICITS. THE FETAL BRAIN CIRCULATION IS PARTICULARLY SUSCEPTIBLE IN IUGR AND IS PROPOSED TO BE ONE OF THE MAIN PATHOLOGICAL PROCESSES DERIVING BBB DISRUPTION. IN THE LAST DECADE, SEVERAL EPIGENETIC MECHANISMS ACTIVATED BY IU HYPOXIA HAVE BEEN PROPOSED TO REGULATE THE POSTNATAL BBB PERMEABILITY. HOWEVER, FEW MECHANISTIC STUDIES ABOUT THIS TOPIC ARE AVAILABLE, AND LITTLE EVIDENCE SHOWS CONTROVERSY. THEREFORE, IN THIS MINI-REVIEW, WE ANALYZE THE BBB PERMEABILITY-ASSOCIATED EPIGENETIC MECHANISMS IN THE BRAIN EXPOSED TO CHRONIC INTRAUTERINE HYPOXIA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  1895  32 ENDOTHELIAL DYSFUNCTION IN INDIVIDUALS BORN AFTER FETAL GROWTH RESTRICTION: CARDIOVASCULAR AND RENAL CONSEQUENCES AND PREVENTIVE APPROACHES. INDIVIDUALS BORN AFTER INTRAUTERINE GROWTH RESTRICTION (IUGR) HAVE AN INCREASED RISK OF PERINATAL MORBIDITY/MORTALITY, AND THOSE WHO SURVIVE FACE LONG-TERM CONSEQUENCES SUCH AS CARDIOVASCULAR-RELATED DISEASES, INCLUDING SYSTEMIC HYPERTENSION, ATHEROSCLEROSIS, CORONARY HEART DISEASE AND CHRONIC KIDNEY DISEASE. IN ADDITION TO THE DEMONSTRATED LONG-TERM EFFECTS OF DECREASED NEPHRON ENDOWMENT AND HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, INDIVIDUALS BORN AFTER IUGR ALSO EXHIBIT EARLY ALTERATIONS IN VASCULAR STRUCTURE AND FUNCTION, WHICH HAVE BEEN IDENTIFIED AS KEY FACTORS OF THE DEVELOPMENT OF CARDIOVASCULAR-RELATED DISEASES. THE ENDOTHELIUM PLAYS A MAJOR ROLE IN MAINTAINING VASCULAR FUNCTION AND HOMEOSTASIS. THEREFORE, IT IS NOT SURPRISING THAT IMPAIRED ENDOTHELIAL FUNCTION CAN LEAD TO THE LONG-TERM DEVELOPMENT OF VASCULAR-RELATED DISEASES. ENDOTHELIAL DYSFUNCTION, PARTICULARLY IMPAIRED ENDOTHELIUM-DEPENDENT VASODILATION AND VASCULAR REMODELING, INVOLVES DECREASED NITRIC OXIDE (NO) BIOAVAILABILITY, IMPAIRED ENDOTHELIAL NO SYNTHASE FUNCTIONALITY, INCREASED OXIDATIVE STRESS, ENDOTHELIAL PROGENITOR CELLS DYSFUNCTION AND ACCELERATED VASCULAR SENESCENCE. PREVENTIVE APPROACHES SUCH AS BREASTFEEDING, SUPPLEMENTATION WITH FOLATE, VITAMINS, ANTIOXIDANTS, L-CITRULLINE, L-ARGININE AND TREATMENT WITH NO MODULATORS REPRESENT PROMISING STRATEGIES FOR IMPROVING ENDOTHELIAL FUNCTION, MITIGATING LONG-TERM OUTCOMES AND POSSIBLY PREVENTING IUGR OF VASCULAR ORIGIN. MOREOVER, THE IDENTIFICATION OF EARLY BIOMARKERS OF ENDOTHELIAL DYSFUNCTION, ESPECIALLY EPIGENETIC BIOMARKERS, COULD ALLOW EARLY SCREENING AND FOLLOW-UP OF INDIVIDUALS AT RISK OF DEVELOPING CARDIOVASCULAR AND RENAL DISEASES, THUS CONTRIBUTING TO THE DEVELOPMENT OF PREVENTIVE AND THERAPEUTIC STRATEGIES TO AVERT THE LONG-TERM EFFECTS OF ENDOTHELIAL DYSFUNCTION IN INFANTS BORN AFTER IUGR.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6  5156  31 PRE-BIRTH ORIGINS OF ALLERGY AND ASTHMA. ALLERGY IS A CHRONIC DISEASE THAT CAN DEVELOP AS EARLY AS INFANCY, SUGGESTING THAT EARLY LIFE FACTORS ARE IMPORTANT IN ITS AETIOLOGY. VARIABLE ASSOCIATIONS BETWEEN SIZE AT BIRTH, A CRUDE MARKER OF THE FETAL ENVIRONMENT, AND ALLERGY HAVE BEEN REPORTED IN HUMANS AND REQUIRE COMPREHENSIVE REVIEW. ASSOCIATIONS BETWEEN BIRTH WEIGHT AND ALLERGY ARE HOWEVER CONFOUNDED IN HUMANS, AND WE AND OTHERS HAVE THEREFORE BEGUN EXPLORING THE EFFECTS OF EARLY LIFE EVENTS ON ALLERGY IN EXPERIMENTAL MODELS. IN PARTICULAR, WE ARE USING OVINE MODELS TO INVESTIGATE WHETHER AND HOW A RESTRICTED ENVIRONMENT BEFORE BIRTH PROTECTS AGAINST ALLERGY, WHETHER METHYL DONOR AVAILABILITY CONTRIBUTES TO ALLERGIC PROTECTION IN IUGR, AND WHY MATERNAL ASTHMA DURING PREGNANCY IS ASSOCIATED WITH INCREASED RISKS OF ALLERGIC DISEASE IN CHILDREN. WE FOUND THAT EXPERIMENTAL INTRAUTERINE GROWTH RESTRICTION (IUGR) IN SHEEP REDUCED CUTANEOUS RESPONSES TO ANTIGENS IN PROGENY, DESPITE NORMAL OR ELEVATED IGE RESPONSES. FURTHERMORE, MATERNAL METHYL DONOR SUPPLEMENTATION IN LATE PREGNANCY PARTIALLY REVERSED EFFECTS OF EXPERIMENTAL IUGR, CONSISTENT WITH THE PROPOSAL THAT EPIGENETIC PATHWAYS UNDERLIE SOME BUT NOT ALL EFFECTS OF IUGR ON ALLERGIC SUSCEPTIBILITY. OVINE EXPERIMENTAL ALLERGIC ASTHMA WITH EXACERBATIONS REDUCES RELATIVE FETAL SIZE IN LATE GESTATION, WITH SOME CHANGES IN IMMUNE POPULATIONS IN FETAL THYMUS SUGGESTIVE OF INCREASED ACTIVATION. MATERNAL ALLERGIC ASTHMA IN MICE ALSO PREDISPOSES PROGENY TO ALLERGY DEVELOPMENT. IN CONCLUSION, THESE FINDINGS IN EXPERIMENTAL MODELS PROVIDE DIRECT EVIDENCE THAT A PERTURBED ENVIRONMENT BEFORE BIRTH ALTERS IMMUNE SYSTEM DEVELOPMENT AND POSTNATAL FUNCTION, AND PROVIDE OPPORTUNITIES TO INVESTIGATE UNDERLYING MECHANISMS AND DEVELOP AND EVALUATE INTERVENTIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7  4214  33 METHIONINE METABOLISM IN YUCATAN MINIATURE SWINE. METHIONINE IS AN ESSENTIAL AMINO ACID WHICH WHEN NOT INCORPORATED INTO PROTEIN, CAN BE CONVERTED TO S-ADENOSYLMETHIONINE, THE UNIVERSAL METHYL DONOR IN OVER 200 TRANSMETHYLATION REACTIONS, WHICH INCLUDE CREATINE AND PHOSPHATIDYLCHOLINE (PC) SYNTHESIS, AS WELL AS DEOXYRIBONUCLEIC ACID (DNA) METHYLATION. FOLLOWING TRANSMETHYLATION, HOMOCYSTEINE IS FORMED, WHICH CAN BE CONVERTED TO CYSTEINE VIA TRANSSULFURATION OR REMETHYLATED TO METHIONINE BY RECEIVING A METHYL GROUP FROM FOLATE OR BETAINE. CHANGES TO METHYL GROUP AVAILABILITY IN UTERO CAN LEAD TO PERMANENT CHANGES IN EPIGENETIC PATTERNS OF DNA METHYLATION, WHICH HAS BEEN IMPLICATED IN "FETAL PROGRAMMING", A PHENOMENON ASSOCIATED WITH POOR NUTRITION DURING FETAL DEVELOPMENT THAT RESULTS IN LOW BIRTH WEIGHT AND DISEASE IN LATER LIFE. IT HAS BEEN SHOWN THAT PROGRAMMING CAN ALSO OCCUR IN THE NEONATE. OUR GLOBAL OBJECTIVE WAS TO UNDERSTAND HOW THE VARIABILITY OF NUTRIENTS INVOLVED IN METHIONINE METABOLISM CAN AFFECT METHIONINE AND METHYL GROUP AVAILABILITY. WE HYPOTHESIZE THAT NUTRIENTS THAT CONVERGE ON METHIONINE METABOLISM CAN AFFECT METHIONINE AVAILABILITY FOR ITS VARIOUS FUNCTIONS. IN THIS THESIS, WE USED INTRAUTERINE GROWTH RESTRICTED (IUGR) PIGLETS TO INVESTIGATE WHETHER A GLOBAL NUTRITIONAL INSULT IN UTERO CAN LEAD TO A PERTURBED METHIONINE METABOLISM. OUR RESULTS DEMONSTRATE THAT IUGR PIGLETS HAVE A LOWER CAPACITY TO DISPOSE OF HOMOCYSTEINE VIA BOTH TRANSSULFURATION AND REMETHYLATION PATHWAYS, AS WELL AS A LOWER INCORPORATION OF METHYL GROUPS INTO PC. THE SECOND OBJECTIVE OF THIS THESIS WAS TO DETERMINE WHETHER VARIATION IN METHIONINE SUPPLY AND DEMAND CAN AFFECT METHIONINE AVAILABILITY. WE DEMONSTRATED THAT STIMULATING EITHER ACUTE OR CHRONIC CREATINE SYNTHESIS LEADS TO LOWER METHYL INCORPORATION INTO PROTEIN AND PC IN PIGS. FURTHERMORE, WHEN METHIONINE IS LIMITING, SUPPLEMENTATION WITH EITHER FOLATE OR BETAINE LEADS TO HIGHER METHIONINE AVAILABILITY FOR PROTEIN SYNTHESIS. FINALLY, BECAUSE CREATINE IS INCREASINGLY BEING UTILIZED AS AN ERGOGENIC AND NEUROPROTECTIVE SUPPLEMENT, WE WANTED TO DETERMINE WHETHER PROVISION OF THE CREATINE PRECURSOR, GUANIDINOACETATE (GAA), COULD EFFECTIVELY INCREASE TISSUE CREATINE STORES. WE SHOWED THAT 2.5 WEEKS OF SUPPLEMENTATION WITH GAA IS MORE EFFECTIVE THAN CREATINE AT INCREASING HEPATIC AND MUSCLE CREATINE STORES. THE RESULTS OF THIS THESIS DEMONSTRATE THAT THE PRESENCE OF IUGR, AN INCREASED DEMAND FOR CREATINE SYNTHESIS, OR THE SUPPLEMENTATION WITH REMETHYLATION NUTRIENTS CAN EACH AFFECT METHIONINE AVAILABILITY; ALL ARE IMPORTANT WHEN CONSIDERING NEONATAL NUTRIENT REQUIREMENTS. FURTHERMORE, ALTHOUGH GAA IS EFFECTIVE AT INCREASING LEVELS OF TISSUE CREATINE, HIGHER GAA METHYLATION CAN LIMIT METHIONINE AVAILABILITY FOR GROWTH AND SYNTHESIS OF PC.	2016	

8  4983  44 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	
                                                           
9  3595  28 IMPLICATIONS OF MATERNAL CONDITIONS AND PREGNANCY COURSE ON OFFSPRING'S MEDICAL PROBLEMS IN ADULT LIFE. IN THE LAST DECADE, NUMEROUS EPIDEMIOLOGICAL, CLINICAL AND EXPERIMENTAL DATA SHOW THAT PERICONCEPTIONAL, PERINATAL AND POSTNATAL ENVIRONMENT DETERMINES THE OFFSPRING'S RISK FOR LATER-LIFE CHRONIC DISEASE. FOR THIS PHENOMENON, THE TERM "FETAL" OR "PERINATAL PROGRAMMING" IS USED. IN EXPOSED OFFSPRING ALREADY IN CHILDHOOD AND EARLY ADULTHOOD, METABOLIC AND CARDIOVASCULAR CHANGES CAN BE OBSERVED, LEADING TO OBESITY, DIABETES AND HYPERTENSION. NOWADAYS, THE MODE OF CONCEPTION (E.G., IN VITRO FERTILIZATION), MATERNAL METABOLIC CONDITIONS (E.G., UNDERNUTRITION, OVERNUTRITION, DIABETES) AND COMPLICATIONS DURING PREGNANCY (E.G., PREECLAMPSIA, INTRAUTERINE GROWTH RESTRICTION) ARE SUSPECTED TO BE NEGATIVE PREDICTORS FOR OFFSPRING'S LONG-TERM HEALTH. MECHANISMS RESPONSIBLE FOR THESE EFFECTS STILL REMAIN MAINLY UNCLEAR, BUT INCLUDE EPIGENETIC, TRANSCRIPTIONAL, ENDOPLASMIC RETICULUM STRESS, AND REACTIVE OXYGEN SPECIES. THIS REVIEW PRESENTS A PIECE OF THE PUZZLE WITH REGARDS TO PERICONCEPTIONAL AND EARLY PERINATAL CONDITIONS DETERMINING LATER-LIFE RISK FOR CHRONIC ADULT DISEASE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  4083  26 MATERNAL NUTRITION AND FETAL DEVELOPMENT. NUTRITION IS THE MAJOR INTRAUTERINE ENVIRONMENTAL FACTOR THAT ALTERS EXPRESSION OF THE FETAL GENOME AND MAY HAVE LIFELONG CONSEQUENCES. THIS PHENOMENON, TERMED "FETAL PROGRAMMING," HAS LED TO THE RECENT THEORY OF "FETAL ORIGINS OF ADULT DISEASE." NAMELY, ALTERATIONS IN FETAL NUTRITION AND ENDOCRINE STATUS MAY RESULT IN DEVELOPMENTAL ADAPTATIONS THAT PERMANENTLY CHANGE THE STRUCTURE, PHYSIOLOGY, AND METABOLISM OF THE OFFSPRING, THEREBY PREDISPOSING INDIVIDUALS TO METABOLIC, ENDOCRINE, AND CARDIOVASCULAR DISEASES IN ADULT LIFE. ANIMAL STUDIES SHOW THAT BOTH MATERNAL UNDERNUTRITION AND OVERNUTRITION REDUCE PLACENTAL-FETAL BLOOD FLOWS AND STUNT FETAL GROWTH. IMPAIRED PLACENTAL SYNTHESES OF NITRIC OXIDE (A MAJOR VASODILATOR AND ANGIOGENESIS FACTOR) AND POLYAMINES (KEY REGULATORS OF DNA AND PROTEIN SYNTHESIS) MAY PROVIDE A UNIFIED EXPLANATION FOR INTRAUTERINE GROWTH RETARDATION IN RESPONSE TO THE 2 EXTREMES OF NUTRITIONAL PROBLEMS WITH THE SAME PREGNANCY OUTCOME. THERE IS GROWING EVIDENCE THAT MATERNAL NUTRITIONAL STATUS CAN ALTER THE EPIGENETIC STATE (STABLE ALTERATIONS OF GENE EXPRESSION THROUGH DNA METHYLATION AND HISTONE MODIFICATIONS) OF THE FETAL GENOME. THIS MAY PROVIDE A MOLECULAR MECHANISM FOR THE IMPACT OF MATERNAL NUTRITION ON BOTH FETAL PROGRAMMING AND GENOMIC IMPRINTING. PROMOTING OPTIMAL NUTRITION WILL NOT ONLY ENSURE OPTIMAL FETAL DEVELOPMENT, BUT WILL ALSO REDUCE THE RISK OF CHRONIC DISEASES IN ADULTS.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  4084  29 MATERNAL NUTRITION DURING PREGNANCY AND HEALTH OF THE OFFSPRING. THE ABILITY OF MOTHER TO PROVIDE NUTRIENTS AND OXYGEN FOR HER BABY IS A CRITICAL FACTOR FOR FETAL HEALTH AND ITS SURVIVAL. FAILURE IN SUPPLYING THE ADEQUATE AMOUNT OF NUTRIENTS TO MEET FETAL DEMAND CAN LEAD TO FETAL MALNUTRITION. THE FETUS RESPONDS AND ADAPTS TO UNDERNUTRITION BUT BY DOING SO IT PERMANENTLY ALTERS THE STRUCTURE AND FUNCTION OF THE BODY. MATERNAL OVERNUTRITION ALSO HAS LONG-LASTING AND DETRIMENTAL EFFECTS ON THE HEALTH OF THE OFFSPRING. THERE IS GROWING EVIDENCE THAT MATERNAL NUTRITION CAN INDUCE EPIGENETIC MODIFICATIONS OF THE FETAL GENOME. ONLY RELATIVELY RECENTLY HAS EVIDENCE FROM EPIDEMIOLOGICAL AND ANIMAL STUDIES EMERGED SUGGESTING THAT FETAL RESPONSES TO THE INTRAUTERINE ENVIRONMENT MAY UNDERLIE THE PREVALENCE OF MANY CHRONIC DISEASES OF ADULTHOOD INCLUDING TYPE 2 (NON-INSULIN-DEPENDENT) DIABETES. IT IS NOW OF CRUCIAL IMPORTANCE TO GAIN THE UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THE RELATIONSHIP BETWEEN FETAL ALTERATIONS TO THE INTRA-UTERINE ENVIRONMENT AND THEIR LONG-TERM EFFECTS ON THE HEALTH OF AN INDIVIDUAL.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  5197  29 PRENATAL GLUCOCORTICOIDS EXPOSURE AND FETAL ADRENAL DEVELOPMENTAL PROGRAMMING. CLINICALLY, WE APPLY SYNTHETIC GLUCOCORTICOIDS TO TREAT FETAL AND MATERNAL DISEASES, SUCH AS PREMATURE LABOR AND AUTOIMMUNE DISEASES. ALTHOUGH ITS CLINICAL EFFICACY IS POSITIVE, THE FETUS WILL BE EXPOSED TO EXOGENOUS SYNTHETIC GLUCOCORTICOIDS. PRENATAL ADVERSE ENVIRONMENTS (SUCH AS XENOBIOTICS EXPOSURE, MALNUTRITION, INFECTION, HYPOXIA AND STRESS) CAN CAUSE FETUSES OVEREXPOSURE TO EXCESSIVE ENDOGENOUS MATERNAL GLUCOCORTICOIDS. THE LEVEL OF GLUCOCORTICOIDS IS THE KEY TO FETAL TISSUE MATURATION AND POSTNATAL FATE. A LARGE NUMBER OF STUDIES HAVE FOUND THAT PRENATAL GLUCOCORTICOIDS EXPOSURE CAN LEAD TO FETAL ADRENAL DYSPLASIA AND DYSFUNCTION, CONTINUING AFTER BIRTH AND EVEN INTO ADULTHOOD. AS THE CORE ORGAN OF FETAL-ORIGINATED ADULT DISEASES, FETAL ADRENAL DYSPLASIA IS CLOSELY RELATED TO THE SUSCEPTIBILITY AND OCCURRENCE OF MULTIPLE CHRONIC DISEASES, AND THERE ARE ALSO OBVIOUS GENDER DIFFERENCES. HOWEVER, ITS INTRAUTERINE PROGRAMMING MECHANISMS HAVE NOT BEEN FULLY ELUCIDATED. THIS REVIEW SUMMARIZES RECENT ADVANCES IN PRENATAL GLUCOCORTICOIDS EXPOSURE AND FETAL ADRENAL DEVELOPMENTAL PROGRAMMING ALTERATIONS, WHICH IS OF GREAT SIGNIFICANCE FOR EXPLAINING ADRENAL DEVELOPMENTAL TOXICITY AND THE INTRAUTERINE ORIGIN OF FETAL-ORIGINATED ADULT DISEASES.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13  5693  27 SILENCING OF MATERNAL HEPATIC GLUCOCORTICOID RECEPTOR IS ESSENTIAL FOR NORMAL FETAL DEVELOPMENT IN MICE. EXCESSIVE OR CHRONIC STRESS CAN LEAD TO A VARIETY OF DISEASES DUE TO ABERRANT ACTIVATION OF THE GLUCOCORTICOID RECEPTOR (GR), A LIGAND ACTIVATED TRANSCRIPTION FACTOR. PREGNANCY REPRESENTS A PARTICULAR WINDOW OF SENSITIVITY IN WHICH EXCESSIVE STRESS CAN HAVE ADVERSE OUTCOMES, PARTICULARLY ON THE DEVELOPING FETUS. HERE WE SHOW MATERNAL HEPATIC STRESS HORMONE RESPONSIVENESS IS DIMINISHED VIA EPIGENETIC SILENCING OF THE GLUCOCORTICOID RECEPTOR DURING PREGNANCY. PROVOCATIVELY, REINSTALLATION OF GR TO HEPATOCYTES DURING PREGNANCY BY ADENO-ASSOCIATED VIRAL TRANSDUCTION DYSREGULATES GENES INVOLVED IN PROLIFERATION, RESULTING IN IMPAIRED PREGNANCY-INDUCED HEPATOMEGALY. DISRUPTION OF THE MATERNAL HEPATIC ADAPTATION TO PREGNANCY RESULTS IN IN UTERO GROWTH RESTRICTION (IUGR). THESE DATA DEMONSTRATE PREGNANCY ANTAGONIZES THE LIVER-SPECIFIC EFFECTS OF STRESS HORMONE SIGNALING IN THE MATERNAL COMPARTMENT TO ULTIMATELY SUPPORT THE HEALTHY DEVELOPMENT OF EMBRYOS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  5075  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  1365  32 DEVELOPMENTAL ORIGIN OF CHRONIC DISEASES: TOXICOLOGICAL IMPLICATION. HUMAN EPIDEMIOLOGICAL AND EXPERIMENTAL ANIMAL STUDIES SHOW THAT SUBOPTIMAL ENVIRONMENTS IN FETAL AND NEONATAL LIFE EXERTS A PROFOUND INFLUENCE ON PHYSIOLOGICAL FUNCTION AND RISK OF DISEASE IN ADULT LIFE. THE MOLECULAR, CELLULAR, METABOLIC, ENDOCRINE AND PHYSIOLOGICAL ADAPTATIONS TO INTRAUTERINE NUTRITIONAL CONDITIONS RESULT IN PERMANENT ALTERATIONS OF CELLULAR PROLIFERATION AND DIFFERENTIATION OF TISSUES AND ORGAN SYSTEMS, WHICH IN TURN CAN MANIFEST BY PATHOLOGICAL CONSEQUENCES OR INCREASED VULNERABILITY TO CHRONIC DISEASES IN ADULTHOOD. INTRAUTERINE GROWTH RESTRICTION (IUGR) DUE TO INTRAUTERINE DEVELOPMENT DERANGEMENTS IS CONSIDERED THE IMPORTANT FACTOR IN DEVELOPMENT OF SUCH DISEASES AS ESSENTIAL HYPERTENSION, DIABETES MELLITUS, ISCHEMIC DISEASES OF THE HEART, OSTEOPOROSIS, RESPIRATORY, NEUROPSYCHIATRIC AND IMMUNE SYSTEM DISEASES.AN EARLY LIFE EXPOSURES TO DIETARY AND ENVIRONMENTAL EXPOSURES CAN HAVE A IMPORTANT EFFECT ON EPIGENETIC CODE, RESULTING IN DISEASES DEVELOPED LATER IN LIFE. THE CONCEPT OF THE "DEVELOPMENTAL PROGRAMMING" AND DEVELOPMENTAL ORIGINS OF ADULT DISEASES (DOHAD) HAS BECOME WELL ACCEPTED BECAUSE OF THE COMPELLING ANIMAL STUDIES THAT HAVE PRECISELY DEFINED THE OUTCOMES OF SPECIFIC EXPOSURES.THE ENVIRONMENTAL POLLULLUTANTS AND OTHER CHEMICAL TOXICANTS MAY INFLUENCE CRUCIAL CELLULAR FUNCTIONS DURING CRITICAL PERIODS OF FETAL DEVELOPMENT AND PERMANENTLY ALTER THE STRUCTURE OR FUNCTION OF SPECIFIC ORGAN SYSTEMS. DEVELOPMENTAL EPIGENETICS IS BELIEVED TO ESTABLISH "ADAPTIVE" PHENOTYPES TO MEET THE DEMANDS OF THE LATER-LIFE ENVIRONMENT. RESULTING PHENOTYPES THAT MATCH PREDICTED LATER-LIFE DEMANDS WILL PROMOTE HEALTH, WHILE A HIGH DEGREE OF MISMATCH WILL IMPEDE ADAPTABILITY TO LATER-LIFE CHALLENGES AND ELEVATE DISEASE RISK. THE RAPID INTRODUCTION OF SYNTHETIC CHEMICALS, ENVIRONMENTAL POLLUTANTS AND MEDICAL INTERVENTIONS, MAY RESULT IN CONFLICT WITH THE PROGRAMMED ADAPTIVE CHANGES MADE DURING EARLY DEVELOPMENT, AND EXPLAIN THE ALARMING INCREASES IN SOME DISEASES.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  6818  30 [FETAL PROGRAMMING AS A CAUSE OF CHRONIC DISEASES IN ADULT LIFE]. LONG-TERM ADAPTIVE CHANGES OCCURRING IN A DEVELOPING FETUS IN RESPONSE TO UNSTABLE IN UTERO ENVIRONMENTAL CONDITIONS, WHICH APPEAR AT A PARTICULAR TIME (CRITICAL WINDOW), ARE CALLED INTRAUTERINE OR FETAL PROGRAMMING. THESE ADAPTIVE CHANGES ARE BENEFICIAL DURING THE INTRAUTERINE PERIOD BECAUSE THEY ADAPT THE FETUS TO CURRENT NEEDS, BUT MAY TURN OUT TO BE HARMFUL IN THE END AND LEAD TO DEVELOPMENT OF CHRONIC DISEASES IN ADULT LIFE. FETAL PROGRAMMING MEANS THE STRUCTURAL AND FUNCTIONAL CHANGING OF AN ORGANISM, METABOLISM AND FUNCTION OF SOME CELLS, TISSUES AND SYSTEMS, THAT OCCUR EVEN DESPITE INTRAUTERINE LIMITATIONS. EVENTS OF FETAL LIFE INFLUENCE THE DETERMINATION OF PHYSIOLOGICAL PATTERNS WHICH MAY MANIFEST AS DISEASE PROCESSES IN THE ADULTHOOD (BARKER'S HYPOTHESIS). GENETIC AND ENVIRONMENTAL FACTORS (POOR DIET IN PREGNANCY CHRONIC INTRAUTERINE FETAL HYPOXIA, THE EFFECTS OF XENOBIOTICS AND DRUGS, AS WELL AS HORMONAL DISORDERS) INFLUENCE THE PHENOTYPE OF A NEWBORN AND ARE INVOLVED IN THE INTRAUTERINE PROGRAMMING PROCESS. THE EFFECTS OF FETAL PROGRAMMING MAY BE PASSED ALONG TO THE NEXT GENERATIONS VIA NOT FULLY UNDERSTOOD PATHWAYS, WHICH PROBABLY INCLUDE EPIGENETIC MECHANISMS. MOST OF THE MECHANISMS UNDERLYING THIS PROCESS REMAIN UNCLEAR AND NEED TO BE ELUCIDATED.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  4078  28 MATERNAL INFLAMMATION, GROWTH RETARDATION, AND PRETERM BIRTH: INSIGHTS INTO ADULT CARDIOVASCULAR DISEASE. THE "FETAL ORIGIN OF ADULT DISEASE HYPOTHESIS" ORIGINALLY DESCRIBED BY BARKER ET AL. IDENTIFIED THE RELATIONSHIP BETWEEN IMPAIRED IN UTERO GROWTH AND ADULT CARDIOVASCULAR DISEASE RISK AND DEATH. SINCE THEN, NUMEROUS CLINICAL AND EXPERIMENTAL STUDIES HAVE CONFIRMED THAT EARLY DEVELOPMENTAL INFLUENCES CAN LEAD TO CARDIOVASCULAR, PULMONARY, METABOLIC, AND PSYCHOLOGICAL DISEASES DURING ADULTHOOD WITH AND WITHOUT ALTERATIONS IN BIRTH WEIGHT. THIS SO CALLED "FETAL PROGRAMMING" INCLUDES DEVELOPMENTAL DISRUPTION, IMMEDIATE ADAPTATION, OR PREDICTIVE ADAPTATION AND CAN LEAD TO EPIGENETIC CHANGES AFFECTING A SPECIFIC ORGAN OR OVERALL HEALTH. THE INTRAUTERINE ENVIRONMENT IS DRAMATICALLY IMPACTED BY THE OVERALL MATERNAL HEALTH. BOTH PREMATURE BIRTH OR LOW BIRTH WEIGHT CAN RESULT FROM A VARIETY OF MATERNAL CONDITIONS INCLUDING UNDERNUTRITION OR DYSNUTRITION, METABOLIC DISEASES, CHRONIC MATERNAL STRESSES INDUCED BY INFECTIONS AND INFLAMMATION, AS WELL AS HYPERCHOLESTEROLEMIA AND SMOKING. NUMEROUS ANIMAL STUDIES HAVE SUPPORTED THE IMPORTANCE OF BOTH MATERNAL HEALTH AND MATERNAL ENVIRONMENT ON THE LONG TERM OUTCOMES OF THE OFFSPRING. WITH INCREASING RATES OF OBESITY AND DIABETES AND SURVIVAL OF PRETERM INFANTS BORN AT EARLY GESTATIONAL AGES, THE NEED TO ELUCIDATE MECHANISMS RESPONSIBLE FOR PROGRAMMING OF ADULT CARDIOVASCULAR DISEASE IS ESSENTIAL FOR THE TREATMENT OF UPCOMING GENERATIONS.	2011