1 4107 158 MECHANISMS AFFECTING NEUROENDOCRINE AND EPIGENETIC REGULATION OF BODY WEIGHT AND ONSET OF PUBERTY: POTENTIAL IMPLICATIONS IN THE CHILD BORN SMALL FOR GESTATIONAL AGE (SGA). SIGNALING PEPTIDES PRODUCED IN PERIPHERAL TISSUES SUCH AS GUT, ADIPOSE TISSUE, AND PANCREAS COMMUNICATE WITH BRAIN CENTERS, SUCH AS HYPOTHALAMUS AND HINDBRAIN TO MANAGE ENERGY HOMEOSTASIS. THESE REGULATORY MECHANISMS OF ENERGY INTAKE AND STORAGE HAVE EVOLVED DURING LONG PERIODS OF HUNGER IN THE EVOLUTION OF MAN TO PROTECT THE SPECIES FROM EXTINCTION. IT IS NOW CLEAR THAT THESE CIRCUITRIES ARE INFLUENCED BY PRENATAL AND POSTNATAL ENVIRONMENTAL FACTORS INCLUDING ENDOCRINE DISRUPTIVE CHEMICALS. HYPOTHALAMIC APPETITE REGULATORY SYSTEMS DEVELOP AND MATURE IN UTERO AND EARLY INFANCY, AND INVOLVE SIGNALING PATHWAYS THAT ARE IMPORTANT ALSO FOR THE REGULATION OF PUBERTY ONSET. RECENT STUDIES IN HUMANS AND ANIMALS HAVE SHOWN THAT METABOLIC PATHWAYS INVOLVED IN REGULATION OF GROWTH, BODY WEIGHT GAIN AND SEXUAL MATURATION ARE LARGELY AFFECTED BY EPIGENETIC PROGRAMMING THAT CAN IMPACT BOTH CURRENT AND FUTURE GENERATIONS. IN PARTICULAR, INTRAUTERINE AND EARLY INFANTILE DEVELOPMENTAL PHASES OF HIGH PLASTICITY ARE SUSCEPTIBLE TO FACTORS THAT AFFECT METABOLIC PROGRAMMING THAT THEREFORE, AFFECT METABOLIC FUNCTION THROUGHOUT LIFE. IN CHILDREN BORN SMALL FOR GESTATIONAL AGE, POOR NUTRITIONAL CONDITIONS DURING GESTATION CAN MODIFY METABOLIC SYSTEMS TO ADAPT TO EXPECTATIONS OF CHRONIC UNDERNUTRITION. THESE CHILDREN ARE POTENTIALLY POORLY EQUIPPED TO COPE WITH ENERGY-DENSE DIETS AND ARE POSSIBLY PROGRAMMED TO STORE AS MUCH ENERGY AS POSSIBLE, LEADING TO LATER OBESITY, METABOLIC SYNDROME, DISTURBED REGULATION OF NORMAL PUBERTY AND EARLY ONSET OF CARDIOVASCULAR DISEASE. MOST CASES OF DISTURBED ENERGY BALANCE ARE LIKELY A RESULT OF A COMBINATION OF GENETICS, EPIGENETICS AND ENVIRONMENT. THIS REVIEW WILL DISCUSS POTENTIAL MECHANISMS LINKING INTRAUTERINE GROWTH RETARDATION WITH CHANGES IN GROWTH, ENERGY HOMEOSTASIS AND SEXUAL MATURATION. 2012 2 4202 33 METABOLIC SYNDROME IN CHILDREN BORN SMALL-FOR-GESTATIONAL AGE. BEING BORN SMALL-FOR-GESTATIONAL AGE AND A RAPID INCREASE IN WEIGHT DURING EARLY CHILDHOOD AND INFANCY HAS BEEN STRONGLY LINKED WITH CHRONIC DISEASES, INCLUDING METABOLIC SYNDROME, WHICH HAS BEEN RELATED TO INTRAUTERINE LIFE ENVIRONMENT AND LINKED TO EPIGENETIC FETAL PROGRAMMING. METABOLIC SYNDROME INCLUDES WAIST CIRCUMFERENCE >/= 90(TH) PERCENTILE FOR AGE, SEX AND RACE, HIGHER LEVELS OF BLOOD PRESSURE, TRIGLYCERIDES AND FASTING GLUCOSE, AND LOW LEVELS OF HDL-CHOLESTEROL. INSULIN RESISTANCE MAY BE PRESENT AS EARLY AS 1 YEAR OF AGE, AND OBESITY AND/OR TYPE 2 DIABETES ARE MORE PREVALENT IN THOSE BORN SGA THAN THOSE BORN AGA. THE PROGRAMMING OF ADAPTIVE RESPONSES IN CHILDREN BORN SGA INCLUDES AN ASSOCIATION WITH INCREASED BLOOD PRESSURE, CHANGES IN ENDOTHELIAL FUNCTION, ARTERIAL PROPERTIES AND CORONARY DISEASE. EARLY INTERVENTIONS SHOULD BE DIRECTED TO APPROPRIATE MATERNAL NUTRITION, BEFORE AND DURING PREGNANCY, PROMOTION OF BREAST FEEDING, AND PREVENTION OF RAPID WEIGHT GAIN DURING INFANCY, AND TO PROMOTE A HEALTHY LIFESTYLE. 2011 3 1152 73 CONSEQUENCES OF EARLY LIFE PROGRAMING BY GENETIC AND ENVIRONMENTAL INFLUENCES: A SYNTHESIS REGARDING PUBERTAL TIMING. SEXUAL MATURATION IS CLOSELY TIED TO GROWTH AND BODY WEIGHT GAIN, SUGGESTING THAT REGULATIVE METABOLIC PATHWAYS ARE SHARED BETWEEN SOMATIC AND PUBERTAL DEVELOPMENT. THE PRE- AND POSTNATAL ENVIRONMENT AFFECTS BOTH GROWTH AND PUBERTAL DEVELOPMENT, INDICATING THAT COMMON PATHWAYS ARE AFFECTED BY THE ENVIRONMENT. INTRAUTERINE AND EARLY INFANTILE DEVELOPMENTAL PHASES ARE CHARACTERIZED BY HIGH PLASTICITY AND THEREBY SUSCEPTIBILITY TO FACTORS THAT AFFECT METABOLIC FUNCTION AS WELL AS RELATED REPRODUCTIVE FUNCTION THROUGHOUT LIFE. IN CHILDREN BORN SMALL FOR GESTATIONAL AGE, POOR NUTRITIONAL CONDITIONS DURING GESTATION CAN MODIFY METABOLIC SYSTEMS TO ADAPT TO EXPECTATIONS OF CHRONIC UNDERNUTRITION. THESE CHILDREN ARE POTENTIALLY POORLY EQUIPPED TO COPE WITH ENERGY-DENSE DIETS AND ARE POSSIBLY PROGRAMMED TO STORE AS MUCH ENERGY AS POSSIBLE, CAUSING RAPID WEIGHT GAIN WITH THE RISK FOR ADULT DISEASE AND PREMATURE ONSET OF PUBERTY. ENVIRONMENTAL FACTORS CAN CAUSE MODIFICATIONS TO THE GENOME, SO-CALLED EPIGENETIC CHANGES, TO AFFECT GENE EXPRESSION AND SUBSEQUENTLY MODIFY PHENOTYPIC EXPRESSION OF GENOMIC INFORMATION. EPIGENETIC MODIFICATIONS, WHICH OCCUR IN CHILDREN BORN SMALL FOR GESTATIONAL AGE, ARE THOUGHT TO UNDERLIE PART OF THE METABOLIC PROGRAMMING THAT SUBSEQUENTLY EFFECTS BOTH SOMATIC AND PUBERTAL DEVELOPMENT. 2016 4 3578 39 IMPACT OF PARENTAL OVER- AND UNDERWEIGHT ON THE HEALTH OF OFFSPRING. PARENTAL EXCESS WEIGHT AND ESPECIALLY PREGESTATIONAL MATERNAL OBESITY AND EXCESSIVE WEIGHT GAIN DURING PREGNANCY HAVE BEEN RELATED TO AN INCREASED RISK OF METABOLIC (OBESITY, TYPE 2 DIABETES, CARDIOVASCULAR DISEASE, METABOLIC SYNDROME) AND NONMETABOLIC (CANCER, OSTEOPOROSIS, ASTHMA, NEUROLOGIC ALTERATIONS) DISEASES IN THE OFFSPRING, PROBABLY MEDIATED BY EPIGENETIC MECHANISMS OF FETAL PROGRAMMING. MATERNAL UNDERWEIGHT IS LESS COMMON IN DEVELOPED SOCIETIES, BUT THE DISCREPANCY BETWEEN A POOR NUTRITIONAL ENVIRONMENT IN UTERO AND A NORMAL OR EXCESSIVE POSTNATAL FOOD SUPPLY WITH RAPID GROWTH CATCH-UP APPEARS TO BE THE MAIN CANDIDATE MECHANISM OF THE DEVELOPMENT OF CHRONIC DISEASES DURING THE OFFSPRING'S ADULTHOOD. THE ROLE OF THE POSTNATAL ENVIRONMENT IN BOTH SCENARIOS (PARENTAL OVERWEIGHT OR UNDERWEIGHT) ALSO SEEMS TO INFLUENCE THE OFFSPRING'S HEALTH. LIFESTYLE INTERVENTIONS BEFORE AND DURING PREGNANCY IN BOTH PARENTS, BUT ESPECIALLY IN THE MOTHER, AS WELL AS IN CHILDREN AFTER BIRTH, ARE ADVISABLE TO COUNTERACT THE MANY UNDESIRABLE CHRONIC CONDITIONS DESCRIBED. 2019 5 2801 32 FEMALE OBESITY: SHORT- AND LONG-TERM CONSEQUENCES ON THE OFFSPRING. THE WORLDWIDE PREVALENCE OF OBESITY HAS RISEN OVER THE PAST FEW DECADES AND WOMEN ARE CURRENTLY MORE LIKELY THAN EVER TO ENTER PREGNANCY OBESE. PRE-PREGNANCY OBESITY AND EXCESSIVE GESTATIONAL WEIGHT GAIN INCREASE MISCARRIAGE RATES AND OBSTETRIC AND NEONATAL COMPLICATIONS, WHICH RESULT IN A LOWER HEALTHY LIVE BIRTH RATE. IN ADDITION TO ITS NEGATIVE CONSEQUENCES FOR THE MOTHER, OBESITY HAS BEEN SHOWN TO BE AN IMPORTANT RISK FACTOR FOR CHRONIC ILLNESSES, SUCH AS CARDIOVASCULAR DISEASE, METABOLIC SYNDROME AND TYPE 2 DIABETES IN THE ADOLESCENCE AND ADULTHOOD OF THE OFFSPRING. MOREOVER, MATERNAL OBESITY CAUSES PSYCHOLOGICAL PROBLEMS, PHYSICAL DISABILITIES AND HIGHER HEALTHCARE COSTS. FETAL PROGRAMMING OF METABOLIC FUNCTION INDUCED BY OBESITY, THROUGH PHYSIOLOGICAL AND/OR EPIGENETIC MECHANISMS, MAY HAVE AN INTERGENERATIONAL EFFECT AND COULD, THUS, PERPETUATE OBESITY IN THE NEXT GENERATION. IN ORDER TO BREAK THIS VICIOUS CIRCLE AND AVOID SERIOUS SHORT- AND LONG-TERM NEGATIVE OUTCOMES FOR BOTH MOTHERS AND FETUSES, THE PREVENTION AND ADEQUATE MANAGEMENT OF OBESITY AND GESTATIONAL WEIGHT GAIN ARE ESSENTIAL. 2013 6 4065 41 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 7 4075 30 MATERNAL HIGH-FAT DIET IMPAIRS LEPTIN SIGNALING AND UP-REGULATES TYPE-1 CANNABINOID RECEPTOR WITH SEX-SPECIFIC EPIGENETIC CHANGES IN THE HYPOTHALAMUS OF NEWBORN RATS. MATERNAL NUTRITIONAL IMBALANCES TRIGGER DEVELOPMENTAL ADAPTATIONS INVOLVING EARLY EPIGENETIC MECHANISMS ASSOCIATED WITH ADULT CHRONIC DISEASE. MATERNAL HIGH-FAT (HF) DIET PROMOTES OBESITY AND HYPOTHALAMIC LEPTIN RESISTANCE IN MALE RAT OFFSPRING AT WEANING AND ADULTHOOD. LEPTIN RESISTANCE IS ASSOCIATED WITH OVER ACTIVATION OF THE ENDOCANNABINOID SYSTEM (ECS). THE ECS MAINLY CONSISTS OF ENDOCANNABINOIDS DERIVED FROM N-6 FATTY ACIDS AND CANNABINOID RECEPTORS (CB1 CODED BY CNR1 AND CB2 CODED BY CNR2). THE CB1 ACTIVATION IN HYPOTHALAMUS STIMULATES FEEDING AND APPETITE FOR FAT WHILE CB2 ACTIVATION SEEMS TO PLAY AN IMMUNOMODULATORY ROLE. WE DEMONSTRATED THAT MATERNAL HF DIET INCREASES HYPOTHALAMIC CB1 IN MALE OFFSPRING WHILE INCREASES CB2 IN FEMALE OFFSPRING AT BIRTH, PRIOR TO OBESITY DEVELOPMENT. HOWEVER, THE MOLECULAR MECHANISMS BEHIND THESE CHANGES REMAIN UNEXPLORED. WE HYPOTHESIZED THAT MATERNAL HF DIET WOULD DOWN-REGULATE LEPTIN SIGNALING AND UP-REGULATE CNR1 MRNA LEVELS IN THE HYPOTHALAMUS OF THE OFFSPRING AT BIRTH, ASSOCIATED WITH SEX-SPECIFIC CHANGES IN EPIGENETIC MARKERS AND SEX STEROID SIGNALING. TO TEST OUR HYPOTHESIS, WE USED PROGENITOR FEMALE RATS THAT RECEIVED CONTROL DIET (C, 9% FAT) OR ISOCALORIC HIGH-FAT DIET (HF, 28% FAT) FROM 8 WEEKS BEFORE MATING UNTIL DELIVERY. BLOOD, HYPOTHALAMUS AND CARCASS FROM C AND HF MALE AND FEMALE OFFSPRING WERE COLLECTED FOR BIOCHEMICAL AND MOLECULAR ANALYSES AT BIRTH. MATERNAL HF DIET DOWN-REGULATED THE TRANSCRIPTIONAL FACTOR STAT3 IN THE HYPOTHALAMUS OF MALE AND FEMALE OFFSPRING, BUT INDUCED HYPOLEPTINEMIA ONLY IN MALES AND DECREASED PHOSPHORYLATED STAT3 ONLY IN FEMALE OFFSPRING. BECAUSE LEPTIN ACTS THROUGH STAT3 PATHWAY TO INHIBIT CENTRAL ECS, OUR RESULTS SUGGEST THAT LEPTIN PATHWAY IMPAIRMENT MIGHT CONTRIBUTE TO INCREASED LEVELS OF CRN1 MRNA IN HYPOTHALAMUS OF BOTH SEX OFFSPRING. BESIDES, MATERNAL HF DIET INCREASED THE HISTONE ACETYLATION PERCENTAGE OF CNR1 PROMOTER IN MALE OFFSPRING AND INCREASED THE ANDROGEN RECEPTOR BINDING TO THE CNR1 PROMOTER, WHICH CAN CONTRIBUTE TO HIGHER EXPRESSION OF CNR1 IN NEWBORN HF OFFSPRING. MATERNAL HF DIET INCREASED PLASMA N6 TO N3 FATTY ACID RATIO IN MALE OFFSPRING, WHICH IS AN IMPORTANT RISK FACTOR TO METABOLIC DISEASES AND MIGHT INDICATE AN OVER ACTIVATION OF ENDOCANNABINOID SIGNALING. THUS, ALTHOUGH MATERNAL HF DIET PROGRAMS A SIMILAR PHENOTYPE IN ADULT OFFSPRING OF BOTH SEXES (OBESITY, HYPERPHAGIA AND HIGHER PREFERENCE FOR FAT), HERE WE SHOWED THAT MOLECULAR MECHANISMS INVOLVING LEPTIN SIGNALING, ECS, EPIGENETIC MARKERS AND SEX HORMONE SIGNALING WERE MODIFIED PRIOR TO OBESITY DEVELOPMENT AND CAN DIFFER BETWEEN NEWBORN MALE AND FEMALE OFFSPRING. THESE OBSERVATIONS MAY PROVIDE MOLECULAR INSIGHTS INTO SEX-SPECIFIC TARGETS FOR ANTI-OBESITY THERAPIES. 2019 8 3595 36 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 9 5178 36 PREGNANCY AS A FUNDAMENTAL DETERMINANT OF CHILD HEALTH: A REVIEW. PURPOSE OF REVIEW: MATERNAL CONDITIONS AND EXPOSURES DURING PREGNANCY INCLUDING OVER- AND UNDERNUTRITION ARE ASSOCIATED WITH POOR CHILDBIRTH OUTCOMES, GROWTH, DEVELOPMENT AND CHRONIC CHILDHOOD DISEASES. WE EXAMINED CONTEMPORARY PREGNANCY-RELATED DETERMINANTS OF CHILD HEALTH. RECENT FINDINGS: WHILE MATERNAL UNDERNUTRITION REMAINS A MAJOR CONTRIBUTOR TO LOW BIRTH WEIGHT, MATERNAL OBESITY AFFECTS FOETAL GROWTH, BIRTH WEIGHT, SURVIVAL AND IS ASSOCIATED WITH CHILDHOOD OBESITY, ASTHMA AND AUTISTIC SPECTRUM DISORDERS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC CHANGES, THE PRENATAL MICROBIOME AND MATERNAL IMMUNE ACTIVATION (MIA), A NEUROINFLAMMATORY PROCESS INDUCED BY DIET AND OTHER EXPOSURES CAUSE FOETAL PROGRAMMING RESULTING IN THESE CHRONIC CHILDHOOD DISEASES. MATERNAL DIET IS POTENTIALLY A MODIFIABLE RISK FACTOR FOR CONTROLLING LOW BIRTH WEIGHT, OBESITY AND CHRONIC DISEASE IN CHILDHOOD. FURTHER STUDIES ARE WARRANTED TO REFINE GUIDANCE ON DIETARY RESTRICTION AND PHYSICAL ACTIVITY DURING PREGNANCY AND DETERMINE HOW MIA AND PRENATAL MICROBIOTA CAN BE APPLIED TO CONTROL CHILDHOOD DISEASES ARISING FROM PROGRAMMING. 2022 10 1376 46 DEVELOPMENTAL PROGRAMMING OF BODY COMPOSITION: UPDATE ON EVIDENCE AND MECHANISMS. PURPOSE OF REVIEW: A GROWING BODY OF EPIDEMIOLOGICAL AND EXPERIMENTAL DATA INDICATE THAT NUTRITIONAL OR ENVIRONMENTAL STRESSORS DURING EARLY DEVELOPMENT CAN INDUCE LONG-TERM ADAPTATIONS THAT INCREASE RISK OF OBESITY, DIABETES, CARDIOVASCULAR DISEASE, AND OTHER CHRONIC CONDITIONS-A PHENOMENON TERMED "DEVELOPMENTAL PROGRAMMING." A COMMON PHENOTYPE IN HUMANS AND ANIMAL MODELS IS ALTERED BODY COMPOSITION, WITH REDUCED MUSCLE AND BONE MASS, AND INCREASED FAT MASS. IN THIS REVIEW, WE SUMMARIZE THE RECENT LITERATURE LINKING PRENATAL FACTORS TO FUTURE BODY COMPOSITION AND EXPLORE CONTRIBUTING MECHANISMS. RECENT FINDINGS: MANY PRENATAL EXPOSURES, INCLUDING INTRAUTERINE GROWTH RESTRICTION, EXTREMES OF BIRTH WEIGHT, MATERNAL OBESITY, AND MATERNAL DIABETES, ARE ASSOCIATED WITH INCREASED FAT MASS, REDUCED MUSCLE MASS, AND DECREASED BONE DENSITY, WITH EFFECTS REPORTED THROUGHOUT INFANCY AND CHILDHOOD, AND PERSISTING INTO MIDDLE AGE. MECHANISMS AND MEDIATORS INCLUDE MATERNAL DIET, BREASTMILK COMPOSITION, METABOLITES, APPETITE REGULATION, GENETIC AND EPIGENETIC INFLUENCES, STEM CELL COMMITMENT AND FUNCTION, AND MITOCHONDRIAL METABOLISM. DIFFERENCES IN BODY COMPOSITION ARE A COMMON PHENOTYPE FOLLOWING DISRUPTIONS TO THE PRENATAL ENVIRONMENT, AND MAY CONTRIBUTE TO DEVELOPMENTAL PROGRAMMING OF OBESITY AND DIABETES RISK. 2019 11 5190 35 PRENATAL CAUSES OF KIDNEY DISEASE. IT HAS RECENTLY BEEN INCREASINGLY RECOGNISED THAT DISTURBED INTRA-UTERINE DEVELOPMENT MAY IMPACT ON RENAL AND CARDIOVASCULAR RISK IN ADULT LIFE, E.G. ALBUMINURIA AND CHRONIC KIDNEY DISEASE, HYPERTENSION, TYPE 2 DIABETES OR CARDIOVASCULAR EVENTS. ACCORDING TO BARKER'S HYPOTHESIS, WHEN RESOURCES IN UTERO ARE RESTRICTED, THEIR ALLOCATION TO THE DEVELOPMENT OF THE KIDNEY AND PANCREATIC ISLETS IS RESTRICTED TO GUARANTEE APPROPRIATE DEVELOPMENT OF THE BRAIN AND HEART. THE UNDERLYING EPIGENETIC MECHANISMS INVOLVE MODIFICATION OF GENE EXPRESSION BY ALTERED DNA METHYLATION AND HISTONE ACETYLATION AS WELL AS BY ALLOCATION OF STEM CELLS. THE RESULT OF THIS TRADE-OFF BETWEEN THE BRAIN AND KIDNEY DURING ORGANOGENESIS IS A DIMINISHED NUMBER OF NEPHRONS ('NEPHRON UNDERDOSING') WHICH PREDISPOSES TO ALBUMINURIA AND RISK OF CHRONIC KIDNEY DISEASE, AS WELL AS HYPERTENSION. IN PARALLEL, CHANGED APPETITE CENTRES, INSULIN RESISTANCE AND BETA-CELL DEVELOPMENT PREDISPOSE TO OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES AND THE RESULTING RENAL SEQUELAE. NUMEROUS FACTORS MAY TRIGGER INTRA-UTERINE RESTRICTION OF FETAL GROWTH, SUCH AS UTERINE UNDERPERFUSION, MATERNAL MALNUTRITION, HYPERGLYCAEMIA AND HYPERINSULINAEMIA OF THE MOTHER, SMOKING OR MEDICATIONS. 2009 12 6545 36 TRANSCRIPTOMIC AND EPIGENETIC CHANGES IN THE HYPOTHALAMUS ARE INVOLVED IN AN INCREASED SUSCEPTIBILITY TO A HIGH-FAT-SUCROSE DIET IN PRENATALLY STRESSED FEMALE RATS. DISTURBANCES IN THE PRENATAL PERIOD ARE LINKED TO METABOLIC DISORDERS IN ADULTHOOD, IMPLYING THE HYPOTHALAMIC SYSTEMS OF APPETITE AND ENERGY BALANCE REGULATION. IN ORDER TO ANALYZE THE CENTRAL EFFECTS OF A HIGH-FAT-SUCROSE (HFS) DIET IN PRENATALLY STRESSED (PNS) FEMALE ADULT RATS, WISTAR DAMS WERE EXPOSED TO CHRONIC-MILD-STRESS DURING THE THIRD WEEK OF GESTATION AND WERE THEN COMPARED WITH UNSTRESSED CONTROLS. ADULT FEMALE OFFSPRING WERE FED A CHOW OR HFS DIET FOR 10 WEEKS. CHANGES IN BODY WEIGHT, ADIPOSITY AS WELL AS EXPRESSION AND METHYLATION LEVELS OF SELECTED HYPOTHALAMIC GENES WERE ANALYZED. PNS INDUCED LOWER BIRTHWEIGHT AND BODY LENGTH WITH NO CHANGES IN BODY FAT MASS. AFTER THE HFS DIET, THE EXPECTED OVERWEIGHT MODEL WAS OBSERVED ACCOMPANIED BY HIGHER ADIPOSITY AND INSULIN RESISTANCE, WHICH WAS WORSENED BY PNS. THE STRESS MODEL INDUCED HIGHER ENERGY INTAKE IN ADULTHOOD. HYPOTHALAMIC GENE EXPRESSION ANALYSIS REVEALED THAT THE HFS DIET DECREASED SLC6A3 (DOPAMINE ACTIVE TRANSPORTER), NPY (NEUROPEPTIDE Y) AND IR (INSULIN RECEPTOR) AND INCREASED POMC (PRO-OPIOMELANOCORTIN). HYPOTHALAMIC DNA METHYLATION LEVELS IN THE PROMOTER REGION OF SLC6A3 REVEALED THAT SLC6A3 WAS HYPERMETHYLATED BY THE HFS DIET IN CPG SITE -53 BP TO THE TRANSCRIPTION START SITE. HFS DIET ALSO HYPERMETHYLATED CPG SITE -167 BP OF THE POMC PROMOTER ONLY IN NONSTRESSED ANIMALS. NO CORRELATIONS WERE FOUND BETWEEN GENE EXPRESSION AND DNA METHYLATION LEVELS. THESE RESULTS IMPLY THAT EARLY-LIFE STRESS IN FEMALES INCREASED PREDISPOSITION TO DIET-INDUCED OBESITY IN ADULTHOOD. 2012 13 4886 36 OVERWEIGHT AND OBESITY BEFORE, DURING AND AFTER PREGNANCY: PART 1: PATHOPHYSIOLOGY, MOLECULAR BIOLOGY AND EPIGENETIC CONSEQUENCES. OVERWEIGHT AND OBESITY BEFORE CONCEPTION AS WELL AS EXCESSIVE WEIGHT GAIN DURING PREGNANCY ARE ASSOCIATED WITH ENDOCRINOLOGICAL CHANGES OF MOTHER AND FETUS. INSULIN RESISTANCE PHYSIOLOGICALLY INCREASES DURING PREGNANCY, ADDITIONAL OBESITY FURTHER INCREASES INSULIN RESISTANCE. IN COMBINATION WITH REDUCED INSULIN SECRETION THIS LEADS TO GESTATIONAL DIABETES WHICH MAY DEVELOP INTO TYPE-2-DIABETES. THE ADIPOSE TISSUE PRODUCES TNF-ALPHA, INTERLEUKINS AND LEPTIN AND UPREGULATES THESE ADIPOKINES. INSULIN RESISTANCE AND OBESITY INDUCE INFLAMMATORY PROCESSES AND VASCULAR DYSFUNCTION, WHICH EXPLAINS THE INCREASED RATE OF PREGNANCY-RELATED HYPERTENSION AND PRE-ECLAMPSIA IN OBESE PREGNANT WOMEN. BETWEEN 14 AND 28 GESTATIONAL WEEKS, THE FETAL ADIPOSE TISSUE IS GENERATED AND THE NUMBER OF FAT LOBULES IS DETERMINED. THEREAFTER, AN INCREASE IN ADIPOSE TISSUE IS ARRANGED BY AN ENLARGEMENT OF THE LOBULES (HYPERTROPHY), OR EVEN AN INCREASE IN THE NUMBER OF FAT CELLS (HYPERPLASIA). HUMAN AND ANIMAL STUDIES HAVE SHOWN THAT MATERNAL OBESITY "PROGRAMMES" THE OFFSPRING FOR FURTHER OBESITY AND CHRONIC DISEASE. PREGNANT WOMEN, MIDWIVES, PHYSICIANS AND HEALTH CARE POLITICIANS SHOULD BE BETTER INFORMED ABOUT PREVENTION, PATHOPHYSIOLOGICAL MECHANISMS, AND THE BURDEN FOR SOCIETY CAUSED BY OBESITY BEFORE, DURING AND AFTER PREGNANCY. 2014 14 6873 42 [PREVENTION OF OBESITY FROM PERINATAL STAGE]. OBESITY IS ONE OF THE MAJOR HEALTH PROBLEMS AND A DETERMINING FACTOR IN THE PREVALENCE OF DISEASES SUCH AS METABOLIC SYNDROME, ASTHMA, SLEEP APNEA, INFERTILITY AND VARIOUS TYPES OF CANCER. ITS ORIGIN IS MULTIFACTORIAL, INVOLVING GENETIC, SOCIOECONOMIC AND ENVIRONMENTAL FACTORS. THESE LAST ONES CONTRIBUTE MOSTLY TO EXPLAIN THE CURRENT EPIDEMIC GROWTH OF THIS DISEASE. THE SEDENTARY LIFESTYLE, INADEQUATE DIET, LACK OF SLEEP, ALTERATIONS IN INTESTINAL MICROBIOTA AND STRESS ARE FACTORS RELATED TO ITS DEVELOPMENT. SINCE BARKER PRESENTED HIS HYPOTHESIS ABOUT THE "FETAL ORIGIN OF ADULT DISEASES", THERE ARE INCREASING NUMBER OF STUDIES THAT SHOW THE INFLUENCE OF AN INADEQUATE NUTRITIONAL STATUS AND MATERNAL WEIGHT IN THE DEVELOPMENT OF CHRONIC DISEASES, AS OBESITY IN OFFSPRING. THE NUTRITIONAL DEFICIENCIES OF THE PREGNANT MOTHER CAUSE EPIGENETIC MODIFICATIONS AND ABNORMAL PROGRAMMING OF THE DEVELOPMENT OFORGANS AND DEVICES, ADAPTING THE FETUS TO THIS SITUATION OF DEFICIENCY AND BEING ABLE TO ADAPT TO AN OBESOGENIC ENVIRONMENT AFTER BIRTH, INCREASING ITS PROPENSITY TO OBESITY. ALSO, POOR MATERNAL NUTRITIONAL STATUS IS RELATED TO INTRAUTERINE GROWTH RETARDATION AND LOW BIRTH WEIGHT INFANTS, WITH A HIGHER RISK OF CHILDHOOD AND ADULT CENTRAL OBESITY. CURRENTLY, DEFICIENT INTAKE OF MICRONUTRIENTS AND OVERWEIGHT OR MATERNAL OBESITY TEND TO OVERLAP, AND THIS COMBINATION MAY EXACERBATE THE INCREASE IN OBESITY IN THE OFFSPRING. IT IS IMPORTANT TO IDENTIFY PREGNANT MOTHERS AT RISK OF SUFFERING NUTRITIONAL ALTERATIONS AND ESTABLISH THEIR IMPROVEMENT AS A PRIMARY PREVENTION STRATEGY FOR OVERWEIGHT AND OBESITY. 2017 15 2806 43 FETAL PROGRAMMING AND THE RISK OF NONCOMMUNICABLE DISEASE. THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) HYPOTHESIS PROPOSES THAT ENVIRONMENTAL CONDITIONS DURING FETAL AND EARLY POST-NATAL DEVELOPMENT INFLUENCE LIFELONG HEALTH AND CAPACITY THROUGH PERMANENT EFFECTS ON GROWTH, STRUCTURE AND METABOLISM. THIS HAS BEEN CALLED 'PROGRAMMING'. THE HYPOTHESIS IS SUPPORTED BY EPIDEMIOLOGICAL EVIDENCE IN HUMANS LINKING NEWBORN SIZE, AND INFANT GROWTH AND NUTRITION, TO ADULT HEALTH OUTCOMES, AND BY EXPERIMENTS IN ANIMALS SHOWING THAT MATERNAL UNDER- AND OVER-NUTRITION AND OTHER INTERVENTIONS (E.G., GLUCOCORTICOID EXPOSURE) DURING PREGNANCY LEAD TO ABNORMAL METABOLISM AND BODY COMPOSITION IN THE ADULT OFFSPRING. EARLY LIFE PROGRAMMING IS NOW THOUGHT TO BE IMPORTANT IN THE ETIOLOGY OF OBESITY, TYPE 2 DIABETES, AND CARDIOVASCULAR DISEASE, OPENING UP THE POSSIBILITY THAT THESE COMMON DISEASES COULD BE PREVENTED BY ACHIEVING OPTIMAL FETAL AND INFANT DEVELOPMENT. THIS IS LIKELY TO HAVE ADDITIONAL BENEFITS FOR INFANT SURVIVAL AND HUMAN CAPITAL (E.G., IMPROVED COGNITIVE PERFORMANCE AND PHYSICAL WORK CAPACITY). FETAL NUTRITION IS INFLUENCED BY THE MOTHER'S DIET AND BODY SIZE AND COMPOSITION, BUT HARD EVIDENCE THAT THE NUTRITION OF THE HUMAN MOTHER PROGRAMMES CHRONIC DISEASE RISK IN HER OFFSPRING IS CURRENTLY LIMITED. RECENT FINDINGS FROM FOLLOW-UP OF CHILDREN BORN AFTER RANDOMISED NUTRITIONAL INTERVENTIONS IN PREGNANCY ARE MIXED, BUT SHOW SOME EVIDENCE OF BENEFICIAL EFFECTS ON VASCULAR FUNCTION, LIPID CONCENTRATIONS, GLUCOSE TOLERANCE AND INSULIN RESISTANCE. WORK IN EXPERIMENTAL ANIMALS SUGGESTS THAT EPIGENETIC PHENOMENA, WHEREBY GENE EXPRESSION IS MODIFIED BY DNA METHYLATION, AND WHICH ARE SENSITIVE TO THE NUTRITIONAL ENVIRONMENT IN EARLY LIFE, MAY BE ONE MECHANISM UNDERLYING PROGRAMMING. 2013 16 4066 36 MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION AS AN INDICATOR OF OFFSPRING METABOLIC SYNDROME RISK IN LATER LIFE THROUGH EPIGENETIC IMPRINTING: A SYSTEMATIC REVIEW. AIMS: THIS REVIEW EXAMINED WHETHER MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION EFFECTS AN OFFSPRING'S LIKELIHOOD OF DEVELOPING CHRONIC METABOLIC RELATED CONDITIONS DUE TO EPIGENETIC IMPRINTING. METHODS: A LITERATURE SEARCH WAS CONDUCTED IN MULTIPLE SCIENCE DATABASES AND LIMITED TO STUDIES PUBLISHED AFTER 2012, IN ENGLISH LANGUAGE AND PEER REVIEWED. THE DATA FROM SELECTED ARTICLES WERE EXTRACTED AND A QUALITATIVE APPROACH WAS EMPLOYED DUE TO HETEROGENEITY OF RESULTS. RESULTS: NEWBORNS FROM OBESE FATHERS SHOWED ALTERED METHYLATION OVERALL AND SIGNIFICANT HYPOMETHYLATION AT THE INSULIN-LIKE GROWTH FACTOR 2 (IGF2) GENE. HIGH MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) WAS ASSOCIATED WITH ALTERED OFFSPRING DNA METHYLATION LEVELS AND GESTATIONAL DIABETES MELLITUS INDUCED SIGNIFICANTLY INCREASED METHYLATION LEVELS IN OFFSPRING. GESTATIONAL WEIGHT GAIN WAS NOT ASSOCIATED WITH DIFFERENTIALLY METHYLATED CORD BLOOD. BIRTH WEIGHT WAS HIGHER IN OFFSPRING EXPOSED TO FAMINE IN EARLY GESTATION. OFFSPRING BORN POST MATERNAL BARIATRIC SURGERY SHOWED A LOWER PERCENTAGE OF BODY FAT AND IMPROVED FASTING INSULIN LEVELS COMPARED TO SIBLINGS BORN PRE-MATERNAL BARIATRIC SURGERY. CONCLUSIONS: THE AVAILABLE EVIDENCE SUGGESTS THAT POOR MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION CAN INCREASE THE RISK OF METABOLIC SYNDROME IN OFFSPRING, THROUGH EPIGENETIC IMPRINTING. POTENTIAL PARENTS SHOULD BE ADVISED THAT MAINTAINING A HEALTHY DIET AND BMI IS LIKELY TO REDUCE THE RISK OF METABOLIC SYNDROME IN OFFSPRING. 2017 17 1373 37 DEVELOPMENTAL ORIGINS OF NONALCOHOLIC FATTY LIVER DISEASE. OBESE PREGNANT WOMEN MAY TRANSMIT THEIR METABOLIC PHENOTYPE TO OFFSPRING, LEADING TO A CYCLE OF OBESITY AND DIABETES OVER GENERATIONS. EARLY CHILDHOOD OBESITY PREDICTS NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), THE MOST COMMON CHRONIC HUMAN LIVER DISEASE. THE FETUS MAY BE VULNERABLE TO STEATOSIS BECAUSE IMMATURE FETAL ADIPOSE DEPOTS ARE NOT AVAILABLE TO BUFFER THE EXCESS TRANSPLACENTAL LIPID DELIVERY IN MATERNAL OBESITY. IN ANIMAL MODELS, IN UTERO HIGH-FAT DIET EXPOSURE RESULTS IN AN INCREASE IN THE ACCUMULATION OF LIVER TRIGLYCERIDES IN OFFSPRING AND INCREASED HEPATIC OXIDATIVE STRESS AND APOPTOSIS, PERHAPS PRIMING THE LIVER FOR LATER DEVELOPMENT OF NAFLD. INNATE IMMUNE DYSFUNCTION AND NECROINFLAMMATORY CHANGES HAVE BEEN OBSERVED IN POSTNATAL OFFSPRING LIVER OF ANIMALS BORN TO HIGH-FAT-FED DAMS. POSTWEANING, LIVERS OF OFFSPRING EXPOSED TO MATERNAL HIGH-FAT FEEDING IN UTERO SHARE PATHOPHYSIOLOGIC FEATURES WITH HUMAN NAFLD, INCLUDING INCREASED DE NOVO LIPOGENESIS AND DECREASED FREE FATTY ACID OXIDATION. HUMAN STUDIES USING MAGNETIC RESONANCE IMAGING HAVE SHOWN THAT MATERNAL BMI PREDICTS INFANT INTRAHEPATOCELLULAR LIPID STORAGE, AS SEEN IN ANIMAL MODELS. THE GENERATIONAL TRANSFER OF NAFLD MAY OCCUR VIA EPIGENETIC CHANGES IN OFFSPRING LIVER. TRANSMISSION OF MICROBIOTA FROM MOTHER TO INFANT MAY IMPACT ENERGY RETENTION AND IMMUNE FUNCTION THAT CONTRIBUTE TO A PREDISPOSITION TO NAFLD. 2014 18 5179 45 PREGNANCY: AN UNDERUTILIZED WINDOW OF OPPORTUNITY TO IMPROVE LONG-TERM MATERNAL AND INFANT HEALTH-AN APPEAL FOR CONTINUOUS FAMILY CARE AND INTERDISCIPLINARY COMMUNICATION. PHYSIOLOGIC ADAPTATIONS DURING PREGNANCY UNMASK A WOMAN'S PREDISPOSITION TO DISEASES. COMPLICATIONS ARE INCREASINGLY PREDICTED BY FIRST-TRIMESTER ALGORITHMS, AMPLIFY A PRE-EXISTING MATERNAL PHENOTYPE AND ACCELERATE RISKS FOR CHRONIC DISEASES IN THE OFFSPRING UP TO ADULTHOOD (BARKER HYPOTHESIS). RECENT EVIDENCE SUGGESTS THAT VICE VERSA, PREGNANCY DISEASES ALSO INDICATE MATERNAL AND EVEN GRANDPARENT'S RISKS FOR CHRONIC DISEASES (REVERSE BARKER HYPOTHESIS). PUB-MED AND EMBASE WERE REVIEWED FOR MESH TERMS "FETAL PROGRAMMING" AND "PREGNANCY COMPLICATIONS COMBINED WITH MATERNAL DISEASE" UNTIL JANUARY 2017. STUDIES LINKING PREGNANCY COMPLICATIONS TO FUTURE CARDIOVASCULAR, METABOLIC, AND THROMBOTIC RISKS FOR MOTHER AND OFFSPRING WERE REVIEWED. WOMEN WITH A HISTORY OF MISCARRIAGE, FETAL GROWTH RESTRICTION, PREECLAMPSIA, PRETERM DELIVERY, OBESITY, EXCESSIVE GESTATIONAL WEIGHT GAIN, GESTATIONAL DIABETES, SUBFERTILITY, AND THROMBOPHILIA MORE FREQUENTLY DEMONSTRATE WITH ECHOCARDIOGRAPHIC ABNORMALITIES, HIGHER FASTING INSULIN, DEVIATING LIPIDS OR CLOTTING FACTORS AND SHOW DEFECTIVE ENDOTHELIAL FUNCTION. THROMBOPHILIA HINTS TO THROMBOTIC RISKS IN LATER LIFE. PREGNANCY ABNORMALITIES CORRELATE WITH FUTURE CARDIOVASCULAR AND METABOLIC COMPLICATIONS AND EARLIER MORTALITY. CONVERSELY, WOMEN WITH A NORMAL PREGNANCY HAVE LOWER RATES OF SUBSEQUENT DISEASES THAN THE GENERAL FEMALE POPULATION CREATING THE TERM: "PREGNANCY AS A WINDOW FOR FUTURE HEALTH." ALTHOUGH THE PLACENTA WORKS AS A GATEKEEPER, MANY PREGNANCY COMPLICATIONS MAY LEAD TO SICKNESS AND EARLIER DEATH IN LATER LIFE WHEN THE CHILD BECOMES AN ADULT. THE EPIGENETIC MECHANISMS AND THE MISMATCH BETWEEN PRE- AND POSTNATAL LIFE HAVE CREATED THE TERM "FETAL ORIGIN OF ADULT DISEASE." UP TO NOW, THE IMPACT OF CARDIOVASCULAR, METABOLIC, OR THROMBOTIC RISK PROFILES HAS BEEN INVESTIGATED SEPARATELY FOR MOTHER AND CHILD. IN THIS MANUSCRIPT, WE STRIVE TO ILLUSTRATE THE CONSEQUENCES FOR BOTH, FETUS AND MOTHER WITHIN A COHESIVE PERSPECTIVE AND THUS TRY TO DEMONSTRATE THE COMPLEX INTERRELATIONSHIP OF GENETICS AND EPIGENETICS FOR LONG-TERM HEALTH OF SOCIETIES AND FUTURE GENERATIONS. MATERNAL-FETAL MEDICINE SPECIALISTS SHOULD HAVE A KEY ROLE IN THE PREVENTION OF NON-COMMUNICABLE DISEASES BY IMPLEMENTING A FRAMEWORK FOR PATIENT CONSULTATION AND INTERDISCIPLINARY NETWORKS. HEALTH-CARE PROVIDERS AND POLICY MAKERS SHOULD INCREASINGLY INVEST IN A STRATIFIED PRIMARY PREVENTION AND FOLLOW-UP TO REDUCE THE INCREASING NUMBER OF MANIFEST CARDIOVASCULAR AND METABOLIC DISEASES AND TO PREVENT WASTE OF HEALTH-CARE RESOURCES. 2017 19 1098 25 COLLATERAL DAMAGE: MATERNAL OBESITY DURING PREGNANCY CONTINUES TO RISE. IMPORTANCE: THE PANDEMIC OF OBESITY DURING PREGNANCY NOW AFFLICTS 1 OUT OF EVERY 2 PREGNANT WOMEN IN THE UNITED STATES. EVEN THOUGH UNINTENDED PREGNANCY HAS DECREASED TO 45% OF ALL PREGNANCIES, 50% OF THOSE UNINTENDED PREGNANCIES OCCUR IN OBESE WOMEN. OBJECTIVE: THIS STUDY AIMS TO IDENTIFY WHY CURRENT LIFESTYLE INTERVENTIONS FOR OBESE PREGNANCY ARE NOT EFFECTIVE AND WHAT THE NEWER COMPLICATIONS ARE FOR OBESITY DURING PREGNANCY. EVIDENCE ACQUISITION: AVAILABLE LITERATURES ON CURRENT TREATMENTS FOR MATERNAL OBESITY WERE REVIEWED FOR EFFECTIVENESS. EMERGING MATERNAL AND INFANT COMPLICATIONS FROM OBESITY DURING PREGNANCY WERE EXAMINED FOR SIGNIFICANCE. RESULTS: LIMITATIONS IN SUCCESSFUL INTERVENTIONS FELL INTO 3 BASIC CATEGORIES TO INCLUDE THE FOLLOWING: (1) PRECONCEPTION WEIGHT LOSS; (2) BARIATRIC SURGERY BEFORE PREGNANCY; AND (3) PREVENTION OF EXCESSIVE GESTATIONAL WEIGHT GAIN DURING PREGNANCY. EMERGING SIGNIFICANT PHYSIOLOGICAL CHANGES FROM MATERNAL OBESITY IS COMPOSED OF INFLAMMATION (PLACENTA AND HUMAN MILK), METABOLISM (HORMONES, MICROBIOME, FATTY ACIDS), AND OFFSPRING OUTCOMES (BODY COMPOSITION, CONGENITAL MALFORMATIONS, CHRONIC KIDNEY DISEASE, ASTHMA, NEURODEVELOPMENT, AND BEHAVIOR). CONCLUSIONS AND RELEVANCE: ARE CURRENT PREPREGNANCY LIFESTYLE AND BEHAVIORAL INTERVENTIONS FEASIBLE TO PREVENT MATERNAL OBESITY COMPLICATIONS? EPIGENETIC AND METABOLOMIC RESEARCH WILL BE CRITICAL TO DETERMINE WHAT IS NEEDED TO BLUNT THE EFFECTS OF MATERNAL OBESITY AND TO DISCOVER SUCCESSFUL TREATMENT. 2020 20 5209 35 PRENATAL XENOBIOTIC EXPOSURE AND INTRAUTERINE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS PROGRAMMING ALTERATION. THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IS ONE OF THE MOST IMPORTANT NEUROENDOCRINE AXES AND PLAYS AN IMPORTANT ROLE IN STRESS DEFENSE RESPONSES BEFORE AND AFTER BIRTH. PRENATAL EXPOSURE TO XENOBIOTICS, INCLUDING ENVIRONMENTAL TOXINS (SUCH AS SMOKE, SULFUR DIOXIDE AND CARBON MONOXIDE), DRUGS (SUCH AS SYNTHETIC GLUCOCORTICOIDS), AND FOODS AND BEVERAGE CATEGORIES (SUCH AS ETHANOL AND CAFFEINE), AFFECTS FETAL DEVELOPMENT INDIRECTLY BY CHANGING THE MATERNAL STATUS OR DAMAGING THE PLACENTA. CERTAIN XENOBIOTICS (SUCH AS CAFFEINE, ETHANOL AND DEXAMETHASONE) MAY ALSO AFFECT THE FETUS DIRECTLY BY CROSSING THE PLACENTA INTO THE FETUS DUE TO THEIR LIPOPHILIC PROPERTIES AND LOWER MOLECULAR WEIGHTS. ALL OF THESE FACTORS PROBABLY RESULT IN INTRAUTERINE PROGRAMMING ALTERATION OF THE HPA AXIS, WHICH SHOWED A LOW BASAL ACTIVITY BUT HYPERSENSITIVITY TO CHRONIC STRESS. THESE ALTERATIONS WILL, THEREFORE, INCREASE THE SUSCEPTIBILITY TO ADULT NEUROPSYCHIATRIC (SUCH AS DEPRESSION AND SCHIZOPHRENIA) AND METABOLIC DISEASES (SUCH AS HYPERTENSION, DIABETES AND NON-ALCOHOLIC FATTY LIVER DISEASE). THE "OVER-EXPOSURE OF FETUSES TO MATERNAL GLUCOCORTICOIDS" MAY BE THE MAIN INITIATION FACTOR BY WHICH THE FETAL HPA AXIS PROGRAMMING IS ALTERED. MEANTIME, XENOBIOTICS CAN DIRECTLY INDUCE ABNORMAL EPIGENETIC MODIFICATIONS AND EXPRESSION ON THE IMPORTANT FETAL GENES (SUCH AS HIPPOCAMPAL GLUCOCORTICOID RECEPTOR, ADRENAL STEROIDOGENIC ACUTE REGULATORY PROTEIN, ET AL) OR DAMAGE BY IN SITU OXIDATIVE METABOLISM OF FETAL ADRENALS, WHICH MAY ALSO BE CONTRIBUTED TO THE PROGRAMMING ALTERATION OF FETAL HPA AXIS. 2014