1 1939 151 EPIDEMIOLOGY AND (PATHO)PHYSIOLOGY OF FOLIC ACID SUPPLEMENT USE IN OBESE WOMEN BEFORE AND DURING PREGNANCY. PRECONCEPTION FOLIC ACID SUPPLEMENT USE IS A WELL-KNOWN METHOD OF PRIMARY PREVENTION OF NEURAL TUBE DEFECTS (NTDS). OBESE WOMEN ARE AT A HIGHER RISK FOR HAVING A CHILD WITH A NTD. AS DIFFERENT INTERNATIONAL RECOMMENDATIONS ON FOLIC ACID SUPPLEMENT USE FOR OBESE WOMEN BEFORE AND DURING PREGNANCY EXIST, THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF EPIDEMIOLOGY OF FOLATE DEFICIENCY IN OBESE (PRE)PREGNANT WOMEN, ELABORATES ON POTENTIAL MECHANISMS UNDERLYING FOLATE DEFICIENCY, AND DISCUSSES CONSIDERATIONS FOR THE USAGE OF HIGHER DOSES OF FOLIC ACID SUPPLEMENTS. WOMEN WITH OBESITY MORE OFTEN SUFFER FROM AN ABSOLUTE FOLATE DEFICIENCY, AS THEY ARE LESS COMPLIANT TO PERICONCEPTIONAL FOLIC ACID SUPPLEMENT USE RECOMMENDATIONS. IN ADDITION, THEIR DIETARY FOLATE INTAKE IS LIMITED DUE TO AN UNBALANCED DIET (RELATIVE MALNUTRITION). THE ASSOCIATION OF OBESITY AND NTDS ALSO SEEMS TO BE INDEPENDENT OF FOLATE INTAKE, WITH STUDIES SUGGESTING AN INCREASED NEED OF FOLATE (RELATIVE DEFICIENCY) DUE TO DERANGEMENTS INVOLVED IN OTHER PATHWAYS. THE RELATIVE FOLATE DEFICIENCY, AS A RESULT OF AN INCREASED METABOLIC NEED FOR FOLATE IN OBESE WOMEN, CAN BE DUE TO: (1) LOW-GRADE CHRONIC INFLAMMATION (2) INSULIN RESISTANCE, (3) INOSITOL, AND (4) DYSBIOTIC GUT MICROBIOME, WHICH PLAYS A ROLE IN FOLATE PRODUCTION AND UPTAKE. IN ALL THESE PATHWAYS, THE FOLATE-DEPENDENT ONE-CARBON METABOLISM IS INVOLVED. IN CONCLUSION, SCIENTIFIC EVIDENCE OF THE INVOLVEMENT OF SEVERAL FOLATE-RELATED PATHWAYS IMPLIES TO INCREASE THE RECOMMENDED FOLIC ACID SUPPLEMENTATION IN OBESE WOMEN. HOWEVER, THE PHYSIOLOGICAL UPTAKE OF SYNTHETIC FOLIC ACID IS LIMITED AND SIDE-EFFECTS OF UNMETABOLIZED FOLIC ACID IN MOTHERS AND OFFSPRING, IN PARTICULAR VARIATIONS IN EPIGENETIC (RE)PROGRAMMING WITH LONG-TERM HEALTH EFFECTS, CANNOT BE EXCLUDED. THEREFORE, WE EMPHASIZE ON THE URGENT NEED FOR FURTHER RESEARCH AND PRECONCEPTION PERSONALIZED COUNSELING ON FOLATE STATUS, LIFESTYLE, AND MEDICAL CONDITIONS. 2021 2 6305 48 THE QUESTION IS WHETHER INTAKE OF FOLIC ACID FROM DIET ALONE DURING PREGNANCY IS SUFFICIENT. PREGNANCY AND FOLIC ACID: PREGNANCY IS THE MOST IMPORTANT PERIOD IN LIFE OF EVERY WOMAN, PARTIALLY FOR THE NUMBER OF PHYSIOLOGICAL ADAPTATIONS SHE IS GOING THROUGH, PARTIALLY FOR THE EXPECTANCE OF NEW LIFE. IN ADDITION, PREGNANCY IS THE "CRITICAL WINDOW" FOR DEVELOPMENT LATER IN CHILDHOOD, AS A PERIOD OF FOETAL PROGRAMMING DURING WHICH NUTRITION PLAYS ONE OF CRUCIAL ROLES. DESPITE THE GENERAL BELIEF THAT NUTRITION THROUGH PREGNANCY IS ADEQUATE AND CHARACTERIZED BY BETTER NUTRITIONAL HABITS, A NUMBER OF STUDIES DO NOT CORROBORATE THIS BELIEF. ROLE OF FOLIC ACID: AN ADEQUATE FOLATE BLOOD LEVEL IS NECESSARY FOR NORMAL CELL GROWTH, SYNTHESIS OF SEVERAL COMPOUNDS INCLUDING DEOXYRIBONUCLEIC ACID AND RIBONUCLEIC ACID, PROPER BRAIN AND NEUROLOGIC FUNCTIONS; IT IS INCLUDED IN THE REGULATION OF HOMOCYSTEINE LEVEL, AND CLOSELY RELATED TO THE VITAMIN B12 METABOLISM. FOLATE DEFICIENCY IN PREGNANCY IS RELATED TO NEURAL TUBE DEFECTS, OTHER NEUROLOGICAL DISORDERS, PRETERM DELIVERY AND LOW BIRTH WEIGHT. FOOD SOURCES: A CORRELATION BETWEEN FOLATE AND THE PREVENTION OF BROAD SPECTRUM OF CHRONIC DISEASES HAS BEEN CONFIRMED. EMERGING EVIDENCE FROM THE EPIGENETIC STUDIES IS NOW BRINGING EVEN MORE LIGHT ON THE LEVEL OF SIGNIFICANCE OF FOLIC ACID. A WIDE RANGE OF PLANT AND ANIMAL FOODS ARE THE NATURAL SOURCES OF FOLATE; LIVER, YEAST, MUSHROOMS, AND GREEN LEAFY VEGETABLES BEING THE MOST SIGNIFICANT. DIFFERENT WAYS OF FOOD PREPARATION INFLUENCE THE FOLATE STABILITY AND ITS BIOAVAILABILITY VARIES FROM 25 TO 50% FROM FOODS, 85% FROM ENRICHED FOODS OR 100% FROM SUPPLEMENTS. CONCLUSION: A GREAT AMOUNT OF SCIENTIFIC RESULTS HAS LED TO OFFICIAL RECOMMENDATIONS FOR FOLIC ACID SUPPLEMENTATION IN PREGNANT WOMEN AS WELL AS IN A NUMBER OF OBLIGATORY OR VOLUNTARY FORTIFICATION PROGRAMMES IN ORDER TO PREVENT THE FOLATE DEFICIENCY ON THE LEVEL OF DIFFERENT POPULATION GROUPS. NEVERTHELESS, THERE MUST BE A CERTAIN LEVEL OF PRECAUTION FOR ELDERLY BECAUSE FOLATE CAN MASK THE VITAMIN B12 DEFICIENCY WITH POSSIBLE FATAL OUTCOMES. 2014 3 5569 42 ROLE OF MATERNAL VITAMINS IN PROGRAMMING HEALTH AND CHRONIC DISEASE. VITAMIN CONSUMPTION PRIOR TO AND DURING PREGNANCY HAS INCREASED AS A RESULT OF PROACTIVE RECOMMENDATIONS BY HEALTH PROFESSIONALS, WIDE AVAILABILITY OF VITAMIN SUPPLEMENTS, AND LIBERAL FOOD-FORTIFICATION POLICIES. FOLIC ACID, ALONE OR IN COMBINATION WITH OTHER B VITAMINS, IS THE MOST RECOMMENDED VITAMIN CONSUMED DURING PREGNANCY BECAUSE DEFICIENCY OF THIS VITAMIN LEADS TO BIRTH DEFECTS IN THE INFANT. FOLIC ACID AND OTHER B VITAMINS ARE ALSO INTEGRAL COMPONENTS OF BIOCHEMICAL PROCESSES THAT ARE ESSENTIAL TO THE DEVELOPMENT OF REGULATORY SYSTEMS THAT CONTROL THE ABILITY OF THE OFFSPRING TO ADAPT TO THE EXTERNAL ENVIRONMENT. ALTHOUGH FEW HUMAN STUDIES HAVE INVESTIGATED THE LASTING EFFECTS OF HIGH VITAMIN INTAKES DURING PREGNANCY, ANIMAL MODELS HAVE SHOWN THAT EXCESS VITAMIN SUPPLEMENTATION DURING GESTATION IS ASSOCIATED WITH NEGATIVE METABOLIC EFFECTS IN BOTH THE MOTHERS AND THEIR OFFSPRING. THIS RESEARCH FROM ANIMAL MODELS, COMBINED WITH THE RECOGNITION THAT EPIGENETIC REGULATION OF GENE EXPRESSION IS PLASTIC, PROVIDES EVIDENCE FOR FURTHER EXAMINATION OF THESE RELATIONSHIPS IN THE LATER LIFE OF PREGNANT WOMEN AND THEIR CHILDREN. 2016 4 48 32 A CRUCIAL ROLE FOR MATERNAL DIETARY METHYL DONOR INTAKE IN EPIGENETIC PROGRAMMING AND FETAL GROWTH OUTCOMES. THE FETAL ORIGINS OF HEALTH AND DISEASE FRAMEWORK HAS IDENTIFIED EXTREMES IN FETAL GROWTH AND BIRTH WEIGHT AS FACTORS ASSOCIATED WITH THE LIFELONG GENERATION OF CHRONIC DISEASES SUCH AS OBESITY, DIABETES, CARDIOVASCULAR DISEASE, AND HYPERTENSION. MATERNAL NUTRITION PLAYS A CRITICAL ROLE IN FETAL AND PLACENTAL DEVELOPMENT, IN PART BY PROVIDING THE METHYL GROUPS REQUIRED TO ESTABLISH THE FETUS'S GENOME STRUCTURE AND FUNCTION, NOTABLY THROUGH DNA METHYLATION. THE GOAL OF THIS NARRATIVE REVIEW IS TO DESCRIBE THE ROLE OF MATERNAL DIETARY METHYL DONOR (METHIONINE, FOLATE, AND CHOLINE) AND COFACTOR (ZINC AND VITAMINS B2, B6, AND B12) INTAKE IN ONE-CARBON METABOLISM AND DNA METHYLATION IN THE FETUS AND PLACENTA, AS WELL AS THEIR IMPACTS ON FETAL GROWTH AND LIFELONG HEALTH OUTCOMES, WITH SPECIFIC EXAMPLES IN ANIMALS AND HUMANS. BASED ON THE AVAILABLE EVIDENCE, IT IS CONCLUDED THAT INTAKE OF DIFFERENT AMOUNTS OF DIETARY METHYL DONORS AND COFACTORS DURING PREGNANCY MAY ALTER FETAL GROWTH AND DEVELOPMENT, THUS ESTABLISHING A MAJOR LINK BETWEEN EARLY ENVIRONMENTAL EXPOSURE AND DISEASE DEVELOPMENT IN THE OFFSPRING LATER IN LIFE. 2018 5 6724 41 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 6 5089 40 PLACENTAL ADAPTATIONS TO MICRONUTRIENT DYSREGULATION IN THE PROGRAMMING OF CHRONIC DISEASE. POOR NUTRITION DURING PREGNANCY IS KNOWN TO IMPAIR FOETAL DEVELOPMENT AND INCREASE THE RISK OF CHRONIC DISEASE IN OFFSPRING. BOTH MACRONUTRIENTS AND MICRONUTRIENTS ARE REQUIRED FOR A HEALTHY PREGNANCY ALTHOUGH SIGNIFICANTLY LESS IS UNDERSTOOD ABOUT THE ROLE OF MICRONUTRIENTS IN THE PROGRAMMING OF CHRONIC DISEASE. THIS IS DESPITE THE FACT THAT MODERN CALORIE RICH DIETS ARE OFTEN ALSO DEFICIENT IN KEY MICRONUTRIENTS. THE IMPORTANCE OF MICRONUTRIENTS IN GESTATIONAL DISORDERS IS CLEARLY UNDERSTOOD BUT HOW THEY IMPACT LONG TERM DISEASE IN HUMANS REQUIRES FURTHER INVESTIGATION. IN CONTRAST, ANIMAL STUDIES HAVE DEMONSTRATED HOW DIETS HIGH OR LOW IN SPECIFIC MICRONUTRIENTS INFLUENCE OFFSPRING PHYSIOLOGY. MANY OF THESE STUDIES HIGHLIGHT THE IMPORTANCE OF THE PLACENTA IN DETERMINING DISEASE RISK. THIS REVIEW WILL EXPLORE THE EFFECTS OF INDIVIDUAL VITAMINS, MINERALS AND TRACE ELEMENTS ON OFFSPRING DISEASE OUTCOMES AND DISCUSS SEVERAL KEY PLACENTAL ADAPTATIONS THAT ARE AFFECTED BY MULTIPLE MICRONUTRIENTS. THESE PLACENTAL ADAPTATIONS INCLUDE MICRONUTRIENT INDUCED DYSREGULATION OF OXIDATIVE STRESS, ALTERED METHYL DONOR AVAILABILITY AND ITS IMPACT ON EPIGENETIC MECHANISMS AS WELL AS ENDOCRINE DYSFUNCTION. CRITICAL GAPS IN OUR CURRENT KNOWLEDGE AND THE RELATIVE IMPORTANCE OF DIFFERENT MICRONUTRIENTS AT DIFFERENT GESTATIONAL AGES WILL ALSO BE HIGHLIGHTED. FINALLY, THIS REVIEW WILL DISCUSS THE NEED FOR FURTHER STUDIES TO CHARACTERISE THE MICRONUTRIENT STATUS OF AUSTRALIAN WOMEN OF REPRODUCTIVE AGE AND CORRELATE MICRONUTRIENT STATUS TO PLACENTAL ADAPTATIONS, PREGNANCY COMPLICATIONS AND OFFSPRING DISEASE. 2018 7 1098 36 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 8 6873 38 [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 9 6234 33 THE LONG-TERM EFFECTS OF PRENATAL DEVELOPMENT ON GROWTH AND METABOLISM. PEOPLE WHO WERE SMALL AT BIRTH AND HAD POOR INFANT GROWTH HAVE AN INCREASED RISK OF ADULT CARDIOVASCULAR DISEASE, OSTEOPOROSIS, AND TYPE 2 DIABETES, PARTICULARLY IF THEIR RESTRICTED EARLY GROWTH WAS FOLLOWED BY INCREASED CHILDHOOD WEIGHT GAIN. THESE RELATIONS EXTEND ACROSS THE NORMAL RANGE OF BIRTH SIZE IN A GRADED MANNER, SO REDUCED SIZE IS NOT A PREREQUISITE. IN ADDITION, LARGER BIRTH SIZE IS ASSOCIATED WITH RISKS OF OBESITY AND TYPE 2 DIABETES. THE ASSOCIATIONS APPEAR TO REFLECT DEVELOPMENTAL PLASTIC RESPONSES MADE BY THE FETUS AND INFANT BASED ON CUES ABOUT THE ENVIRONMENT, INFLUENCED BY MATERNAL CHARACTERISTICS INCLUDING DIET, BODY COMPOSITION, STRESS, AND EXERCISE LEVELS. THESE RESPONSES INVOLVE EPIGENETIC PROCESSES THAT MODIFY THE OFFSPRING'S PHENOTYPE. VULNERABILITY TO ILL HEALTH RESULTS IF THE ENVIRONMENT IN INFANCY, CHILDHOOD, AND LATER LIFE IS MISMATCHED TO THE PHENOTYPE INDUCED IN DEVELOPMENT, INFORMED BY THE DEVELOPMENTAL CUES. THIS MISMATCH MAY ARISE THROUGH UNBALANCED DIET OR BODY COMPOSITION OF THE MOTHER OR A CHANGE IN LIFESTYLE FACTORS BETWEEN GENERATIONS. THESE INSIGHTS OFFER NEW POSSIBILITIES FOR THE EARLY DIAGNOSIS AND PREVENTION OF CHRONIC DISEASE. 2011 10 2805 42 FETAL MALNUTRITION AND LONG-TERM OUTCOMES. EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT LOWER BIRTHWEIGHT IS ASSOCIATED WITH A WIDE RANGE OF ADVERSE OUTCOMES IN LATER LIFE, INCLUDING POORER 'HUMAN CAPITAL' (SHORTER STATURE, LOWER COGNITIVE PERFORMANCE), INCREASED RISK FACTORS FOR LATER DISEASE (HIGHER BLOOD PRESSURE AND REDUCED GLUCOSE TOLERANCE, AND LUNG, KIDNEY AND IMMUNE FUNCTION), CLINICAL DISEASE (DIABETES, CORONARY HEART DISEASE, CHRONIC LUNG AND KIDNEY DISEASE), AND INCREASED ALL-CAUSE AND CARDIOVASCULAR MORTALITY. HIGHER BIRTHWEIGHT IS ASSOCIATED WITH AN INCREASED RISK OF CANCER AND (IF CAUSED BY GESTATIONAL DIABETES) OBESITY AND DIABETES. THE 'DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE' HYPOTHESIS PROPOSES THAT FETAL NUTRITION HAS PERMANENT EFFECTS ON GROWTH, STRUCTURE AND METABOLISM ('PROGRAMMING'). THIS IS SUPPORTED BY STUDIES IN ANIMALS SHOWING THAT MATERNAL UNDER- AND OVERNUTRITION DURING PREGNANCY CAN PRODUCE SIMILAR ABNORMALITIES IN THE ADULT OFFSPRING. COMMON CHRONIC DISEASES COULD POTENTIALLY BE PREVENTED BY ACHIEVING OPTIMAL FETAL NUTRITION, AND THIS COULD HAVE ADDITIONAL BENEFITS FOR SURVIVAL AND HUMAN CAPITAL. RECENT FOLLOW-UP OF CHILDREN BORN AFTER RANDOMIZED NUTRITIONAL INTERVENTIONS IN PREGNANCY PROVIDES WEAK EVIDENCE OF BENEFICIAL EFFECTS ON GROWTH, VASCULAR FUNCTION, LIPID CONCENTRATIONS, GLUCOSE TOLERANCE AND INSULIN RESISTANCE. ANIMAL STUDIES INDICATE THAT EPIGENETIC PHENOMENA MAY BE AN IMPORTANT MECHANISM UNDERLYING PROGRAMMING, AND THAT NUTRITIONAL INTERVENTIONS MAY NEED TO START PRECONCEPTIONALLY. 2013 11 6088 43 THE EFFECTS OF ASSISTED REPRODUCTION TECHNOLOGIES ON METABOLIC HEALTH AND DISEASEDAGGER. THE INCREASING PREVALENCE OF METABOLIC DISEASES PLACES A SUBSTANTIAL BURDEN ON HUMAN HEALTH THROUGHOUT THE WORLD. IT IS BELIEVED THAT PREDISPOSITION TO METABOLIC DISEASE STARTS EARLY IN LIFE, A PERIOD OF GREAT SUSCEPTIBILITY TO EPIGENETIC REPROGRAMMING DUE TO ENVIRONMENTAL INSULTS. ASSISTED REPRODUCTIVE TECHNOLOGIES (ART), I.E., TREATMENTS FOR INFERTILITY, MAY AFFECT EMBRYO DEVELOPMENT, RESULTING IN MULTIPLE ADVERSE HEALTH OUTCOMES IN POSTNATAL LIFE. THE MOST FREQUENTLY OBSERVED ALTERATION IN ART PREGNANCIES IS IMPAIRED PLACENTAL NUTRIENT TRANSFER. MOREOVER, CONSEQUENT INTRAUTERINE GROWTH RESTRICTION AND LOW BIRTH WEIGHT FOLLOWED BY CATCH-UP GROWTH CAN ALL PREDICT FUTURE OBESITY, INSULIN RESISTANCE, AND CHRONIC METABOLIC DISEASES. IN THIS REVIEW, WE HAVE FOCUSED ON EVIDENCE OF ADVERSE METABOLIC ALTERATIONS ASSOCIATED WITH ART, WHICH CAN CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC ADULT-ONSET DISEASES, SUCH AS METABOLIC SYNDROME, TYPE 2 DIABETES, AND CARDIOVASCULAR DISEASE. DUE TO HIGH PHENOTYPIC PLASTICITY, ART PREGNANCIES CAN PRODUCE BOTH OFFSPRING WITH ADVERSE HEALTH OUTCOMES, AS WELL AS HEALTHY INDIVIDUALS. WE FURTHER DISCUSS THE SEX-SPECIFIC AND AGE-DEPENDENT METABOLIC ALTERATIONS REFLECTED IN ART OFFSPRING, AND HOW THE DEGREE OF INTERFERENCE OF A GIVEN ART PROCEDURE (FROM MILD TO MORE SEVERE MANIPULATION OF THE EGG) AFFECTS THE OCCURRENCE AND DEGREE OF OFFSPRING ALTERATIONS. OVER THE LAST FEW YEARS, STUDIES HAVE REPORTED SIGNS OF CARDIOMETABOLIC ALTERATIONS IN ART OFFSPRING THAT ARE DETECTABLE AT A YOUNG AGE BUT THAT DO NOT APPEAR TO CONSTITUTE A HIGH RISK OF DISEASE AND MORBIDITY PER SE. THESE ABNORMAL PHENOTYPES COULD BE EARLY INDICATORS OF THE DEVELOPMENT OF CHRONIC DISEASES, INCLUDING METABOLIC SYNDROME, IN ADULTHOOD. THE EARLY DETECTION OF METABOLIC ALTERATIONS COULD CONTRIBUTE TO PREVENTING THE ONSET OF DISEASE IN ADULTHOOD. SUCH EARLY INTERVENTIONS MAY COUNTERACT THE RISK FACTORS AND IMPROVE THE LONG-TERM HEALTH OF THE INDIVIDUAL. 2021 12 6094 35 THE EFFECTS OF MATERNAL AND POSTNATAL DIETARY METHYL NUTRIENTS ON EPIGENETIC CHANGES THAT LEAD TO NON-COMMUNICABLE DISEASES IN ADULTHOOD. THE RISK FOR NON-COMMUNICABLE DISEASES IN ADULTHOOD CAN BE PROGRAMMED BY EARLY NUTRITION. THIS PROGRAMMING IS MEDIATED BY CHANGES IN EXPRESSION OF KEY GENES IN VARIOUS METABOLIC PATHWAYS DURING DEVELOPMENT, WHICH PERSIST INTO ADULTHOOD. THESE DEVELOPMENTAL MODIFICATIONS OF GENES ARE DUE TO EPIGENETIC ALTERATIONS IN DNA METHYLATION PATTERNS. RECENT STUDIES HAVE DEMONSTRATED THAT DNA METHYLATION CAN BE AFFECTED BY MATERNAL OR EARLY POSTNATAL DIETS. BECAUSE METHYL GROUPS FOR METHYLATION REACTIONS COME FROM METHIONINE CYCLE NUTRIENTS (I.E., METHIONINE, CHOLINE, BETAINE, FOLATE), DEFICIENCY OR SUPPLEMENTATION OF THESE METHYL NUTRIENTS CAN DIRECTLY CHANGE EPIGENETIC REGULATION OF GENES PERMANENTLY. ALTHOUGH MANY STUDIES HAVE DESCRIBED THE EARLY PROGRAMMING OF ADULT DISEASES BY MATERNAL AND INFANT NUTRITION, THIS REVIEW DISCUSSES STUDIES THAT HAVE ASSOCIATED EARLY DIETARY METHYL NUTRIENT MANIPULATION WITH DIRECT EFFECTS ON EPIGENETIC PATTERNS THAT COULD LEAD TO CHRONIC DISEASES IN ADULTHOOD. THE MATERNAL SUPPLY OF METHYL NUTRIENTS DURING GESTATION AND LACTATION CAN ALTER EPIGENETICS, BUT PROGRAMMING EFFECTS VARY DEPENDING ON THE TIMING OF DIETARY INTERVENTION, THE TYPE OF METHYL NUTRIENT MANIPULATED, AND THE TISSUE RESPONSIBLE FOR THE PHENOTYPE. MOREOVER, THE POSTNATAL MANIPULATION OF METHYL NUTRIENTS CAN PROGRAM EPIGENETICS, BUT MORE RESEARCH IS NEEDED ON WHETHER THIS APPROACH CAN RESCUE MATERNALLY PROGRAMMED OFFSPRING. 2020 13 2801 35 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 14 2806 39 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 15 1376 31 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 16 1755 37 EARLY NUTRITION AND LATER OUTCOMES IN PRETERM INFANTS. THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE IS AN EMERGING AREA OF INTEREST THAT AMALGAMATES MANY AREAS OF SCIENTIFIC STUDIES AND ENCOMPASSES A WIDE RANGE OF DIVERSE DISCIPLINES FROM EPIDEMIOLOGY TO MOLECULAR BIOLOGY. EVIDENCE HAS ACCUMULATED TO SHOW THAT EARLY LIFE EXPERIENCES, BOTH IN UTERO AND IN INFANCY HAVE LONG-TERM EFFECTS ON MANY BODY SYSTEMS. THERE ARE NOW GOOD DATA TO SHOW THAT SUBOPTIMAL IN UTERO GROWTH, ESPECIALLY WHEN COMBINED WITH RAPID GROWTH ACCELERATION IN EARLY POSTNATAL LIFE MAY INCREASE THE RISK OF LATER LIFE METABOLIC DISEASE. THE MECHANISMS ARE COMPLEX BUT LIKELY TO INVOLVE EPIGENETIC MARKS SUCH AS DNA METHYLATION. PRETERM INFANTS FREQUENTLY EXPERIENCE SUBOPTIMAL NUTRIENT INTAKES IN EARLY POSTNATAL LIFE AND EXHIBIT GROWTH FAILURE WITHIN THE NICU. THEY ALSO RECEIVE PRODUCTS THAT MAY NOT PROVIDE EITHER AN OPTIMAL QUANTITY OR QUALITY OF NUTRIENTS. FOLLOW-UP STUDIES HAVE NOW SHOWN MUCH HIGHER RISKS FOR LONG-TERM CHRONIC DISEASE IN CHILDREN AND ADULTS WHO WERE BORN PRETERM. THERE ARE HIGHER LEVELS OF INSULIN RESISTANCE AND ABNORMAL PARTITIONING OF FAT DEPOSITION. THE ONSET OF PUBERTY SEEMS EARLIER, AVERAGE HEIGHT IS LESS AND BLOOD PRESSURE, MEASURES OF VASCULAR HEALTH AND LIPID PROFILES SUGGEST CARDIOVASCULAR HEALTH IS LIKELY TO DIFFER FROM HEALTHY TERM BORN CONTROLS. DESPITE THIS, THERE ARE NO DATA TO SUGGEST AN OVERALL BENEFIT OF LIMITING NUTRIENT INTAKE, OR RESTRICTING GROWTH IN PRETERM INFANTS. THERE ARE STRONG DATA TO SHOW THAT THE PRETERM BRAIN IS EXQUISITELY VULNERABLE TO UNDERNUTRITION, AND THAT SUBOPTIMAL NUTRIENT INTAKES MAY PERMANENTLY AFFECT LATER COGNITIVE ATTAINMENT. A CLINICAL FOCUS ON EARLY NUTRIENT INTAKES AND BREAST MILK PROVISION IS KEY TO OPTIMISING LONG-TERM HEALTH OUTCOMES. 2013 17 1153 43 CONSEQUENCES OF PATERNAL NUTRITION ON OFFSPRING HEALTH AND DISEASE. IT IS WELL ESTABLISHED THAT THE MATERNAL DIET DURING THE PERICONCEPTIONAL PERIOD AFFECTS THE PROGENY'S HEALTH. A GROWING BODY OF EVIDENCE SUGGESTS THAT THE PATERNAL DIET ALSO INFLUENCES DISEASE ONSET IN OFFSPRING. FOR MANY YEARS, SPERM WAS CONSIDERED ONLY TO CONTRIBUTE HALF OF THE PROGENY'S GENOME. IT NOW APPEARS THAT IT ALSO PLAYS A CRUCIAL ROLE IN HEALTH AND DISEASE IN OFFSPRING'S ADULT LIFE. THE NUTRITIONAL STATUS AND ENVIRONMENTAL EXPOSURE OF FATHERS DURING THEIR CHILDHOOD AND/OR THE PERICONCEPTIONAL PERIOD HAVE SIGNIFICANT TRANSGENERATIONAL CONSEQUENCES. THIS REVIEW AIMS TO DESCRIBE THE EFFECTS OF VARIOUS HUMAN AND RODENT PATERNAL FEEDING PATTERNS ON PROGENY'S METABOLISM AND HEALTH, INCLUDING FASTING OR INTERMITTENT FASTING, LOW-PROTEIN AND FOLIC ACID DEFICIENT FOOD, AND OVERNUTRITION IN HIGH-FAT AND HIGH-SUGAR DIETS. THE IMPACT ON PREGNANCY OUTCOME, METABOLIC PATHWAYS, AND CHRONIC DISEASE ONSET WILL BE DESCRIBED. THE BIOLOGICAL AND EPIGENETIC MECHANISMS UNDERLYING THE TRANSMISSION FROM FATHERS TO THEIR PROGENY WILL BE DISCUSSED. ALL THESE DATA PROVIDE EVIDENCE OF THE IMPACT OF PATERNAL NUTRITION ON PROGENY HEALTH WHICH COULD LEAD TO PREVENTIVE DIET RECOMMENDATIONS FOR FUTURE FATHERS. 2021 18 3775 30 INTERACTIONS BETWEEN ARSENIC-INDUCED TOXICITY AND NUTRITION IN EARLY LIFE. EXPOSURE TO ARSENIC THROUGH DRINKING WATER IS A MAJOR PUBLIC HEALTH PROBLEM AFFECTING MOST COUNTRIES, ALTHOUGH THE SITUATION IS PARTICULARLY SEVERE IN LOW-INCOME NATIONS. THE HEALTH CONSEQUENCES OF CHRONIC ARSENIC EXPOSURE INCLUDE INCREASED RISK FOR VARIOUS FORMS OF CANCER AND NUMEROUS NONCANCER EFFECTS, INCLUDING DIABETES, SKIN DISEASES, CHRONIC COUGH, AND TOXIC EFFECTS ON LIVER, KIDNEY, CARDIOVASCULAR SYSTEM, AND PERIPHERAL AND CENTRAL NERVOUS SYSTEMS. IN RECENT YEARS INCREASING REPORTS OF EFFECTS ON FETAL AND CHILD DEVELOPMENT HAVE APPEARED. THERE SEEMS TO BE A WIDE VARIATION IN SUSCEPTIBILITY TO ARSENIC TOXICITY, WHICH IS LIKELY TO BE RELATED TO FACTORS SUCH AS VARIATION IN ARSENIC METABOLISM, NUTRITION, HOST-RELATED DEFENSE MECHANISMS, AND GENETIC PREDISPOSITION. THE MAIN MECHANISMS OF ARSENIC-NUTRITION INTERACTIONS INCLUDE ARSENIC-INDUCED OXIDATIVE STRESS, WHICH REQUIRES NUTRIENT-DEPENDENT DEFENSE SYSTEMS, AND ARSENIC METABOLISM (METHYLATION) VIA 1-CARBON METABOLISM, WHICH REQUIRES METHYL GROUPS, FOLIC ACID, VITAMIN B-12, AND BETAINE FOR THE REMETHYLATION OF HOMOCYSTEINE TO METHIONINE. AN EFFICIENT FIRST METHYLATION STEP IN COMBINATION WITH A SLOW SECOND METHYLATION STEP SEEMS TO BE MOST CRITICAL FROM A TOXICOLOGICAL POINT OF VIEW. A THIRD MODE OF ARSENIC-NUTRITION INTERACTION INVOLVES EPIGENETIC EFFECTS AND FETAL PROGRAMMING VIA DNA METHYLATION. 2007 19 3311 44 HIGHLIGHTING THE TRAJECTORY FROM INTRAUTERINE GROWTH RESTRICTION TO FUTURE OBESITY. DURING THE LAST DECADES SEVERAL LINES OF EVIDENCE REPORTED THE ASSOCIATION OF AN ADVERSE INTRAUTERINE ENVIRONMENT, LEADING TO INTRAUTERINE RESTRICTION, WITH FUTURE DISEASE, SUCH AS OBESITY AND METABOLIC SYNDROME, BOTH LEADING TO INCREASED CARDIOVASCULAR AND CANCER RISK. THE UNDERLYING EXPLANATION FOR THIS ASSOCIATION HAS FIRSTLY BEEN EXPRESSED BY THE BARKER'S HYPOTHESIS, THE "THRIFTY PHENOTYPE HYPOTHESIS". ACCORDING TO THIS HYPOTHESIS, A FETUS FACING AN ADVERSE INTRAUTERINE ENVIRONMENT ADAPTS TO THIS ENVIRONMENT THROUGH A REPROGRAMMING OF ITS ENDOCRINE-METABOLIC STATUS, DURING THE CRUCIAL WINDOW OF DEVELOPMENTAL PLASTICITY TO SAVE ENERGY FOR SURVIVAL, PROVIDING LESS ENERGY AND NUTRIENTS TO THE ORGANS THAT ARE NOT ESSENTIAL FOR SURVIVAL. THIS THEORY EVOLVED TO THE CONCEPT OF THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE (DOHAD). THUS, IN THE SETTING OF AN ADVERSE, F. EX. PROTEIN RESTRICTED INTRAUTERINE ENVIRONMENT, WHILE THE ENERGY IS MAINLY DIRECTED TO THE BRAIN, THE PERIPHERAL ORGANS, F.EX. THE MUSCLES AND THE LIVER UNDERGO AN ADAPTATION THAT IS EXPRESSED THROUGH INSULIN RESISTANCE. THE ADAPTATION AT THE HEPATIC LEVEL PREDISPOSES TO FUTURE DYSLIPIDEMIA, THE MODIFICATIONS AT THE VASCULAR LEVEL TO ENDOTHELIAL DAMAGE AND FUTURE HYPERTENSION AND, OVERALL, THROUGH THE INSULIN RESISTANCE TO THE DEVELOPMENT OF METABOLIC SYNDROME. ALL THESE ADAPTATIONS ARE SUGGESTED TO TAKE PLACE THROUGH EPIGENETIC MODIFICATIONS OF THE EXPRESSION OF GENES WITHOUT CHANGE OF THEIR AMINO-ACID SEQUENCE. THE EPIGENETIC MODIFICATIONS LEADING TO FUTURE OBESITY AND CARDIOVASCULAR RISK ARE THOUGHT TO INDUCE APPETITE DYSREGULATION, PROMOTING FOOD INTAKE AND ADIPOGENESIS, FACILITATING OBESITY DEVELOPMENT. THE EPIGENETIC MODIFICATIONS MAY EVEN PERSIST INTO THE NEXT GENERATION EVEN THOUGH THE SUBSEQUENT GENERATION HAS NOT BEEN EXPOSED TO AN ADVERSE INTRAUTERINE ENVIRONMENT, A NOTION DEFINED AS THE "TRANSGENERATIONAL TRANSFER OF ENVIRONMENTAL INFORMATION". AS A CONSEQUENCE, IF THE INCREASED PUBLIC HEALTH BURDEN AND COSTS OF NON-COMMUNICABLE CHRONIC DISEASES SUCH AS OBESITY, HYPERTENSION, METABOLIC SYNDROME AND TYPE 2 DIABETES HAVE TO BE MINIMIZED, SPECIAL ATTENTION SHOULD BE LAID TO THE HEALTHY LIFESTYLE HABITS OF WOMEN OF REPRODUCTIVE AGE, INCLUDING HEALTHY DIET AND PHYSICAL ACTIVITY TO BE ESTABLISHED LONG BEFORE ANY PREGNANCY TAKES PLACE IN ORDER TO PROVIDE THE BEST CONDITIONS FOR BOTH SOMATIC AND MENTAL HEALTH OF FUTURE GENERATIONS. 2022 20 397 41 AN UPDATE ON FETAL ALCOHOL SYNDROME-PATHOGENESIS, RISKS, AND TREATMENT. ALCOHOL IS A WELL-ESTABLISHED TERATOGEN THAT CAN CAUSE VARIABLE PHYSICAL AND BEHAVIORAL EFFECTS ON THE FETUS. THE MOST SEVERE CONDITION IN THIS SPECTRUM OF DISEASES IS KNOWN AS FETAL ALCOHOL SYNDROME (FAS). THE DIFFERENCES IN MATERNAL AND FETAL ENZYMES, IN TERMS OF ABUNDANCE AND EFFICIENCY, IN ADDITION TO REDUCED ELIMINATION, ALLOW FOR ALCOHOL TO HAVE A PROLONGED EFFECT ON THE FETUS. THIS CAN ACT AS A TERATOGEN THROUGH NUMEROUS METHODS INCLUDING REACTIVE OXYGEN SPECIES (GENERATED AS BY PRODUCTS OF CYP2E1), DECREASED ENDOGENOUS ANTIOXIDANT LEVELS, MITOCHONDRIAL DAMAGE, LIPID PEROXIDATION, DISRUPTED NEURONAL CELL-CELL ADHESION, PLACENTAL VASOCONSTRICTION, AND INHIBITION OF COFACTORS REQUIRED FOR FETAL GROWTH AND DEVELOPMENT. MORE RECENTLY, ALCOHOL HAS ALSO BEEN SHOWN TO HAVE EPIGENETIC EFFECTS. INCREASED FETAL EXPOSURE TO ALCOHOL AND SUSTAINED ALCOHOL INTAKE DURING ANY TRIMESTER OF PREGNANCY IS ASSOCIATED WITH AN INCREASED RISK OF FAS. OTHER RISK FACTORS INCLUDE GENETIC INFLUENCES, MATERNAL CHARACTERISTICS, FOR EXAMPLE, LOWER SOCIOECONOMIC STATUSES AND SMOKING, AND PATERNAL CHRONIC ALCOHOL USE. THE TREATMENT OPTIONS FOR FAS HAVE RECENTLY STARTED TO BE EXPLORED ALTHOUGH NONE ARE CURRENTLY APPROVED CLINICALLY. THESE INCLUDE PRENATAL ANTIOXIDANT ADMINISTRATION FOOD SUPPLEMENTS, FOLIC ACID, CHOLINE, NEUROACTIVE PEPTIDES, AND NEUROTROPHIC GROWTH FACTORS. TACKLING THE WIDER IMPACTS OF FAS, SUCH AS COMORBIDITIES, AND THE FAMILY SYSTEM HAVE BEEN SHOWN TO IMPROVE THE QUALITY OF LIFE OF FAS PATIENTS. THIS REVIEW AIMED TO FOCUS ON THE PATHOGENESIS, ESPECIALLY MECHANISMS OF ALCOHOL TERATOGENICITY, AND RISKS OF DEVELOPING FAS. RECENT DEVELOPMENTS IN POTENTIAL MANAGEMENT STRATEGIES, INCLUDING PRENATAL INTERVENTIONS, ARE DISCUSSED. 2016