1 4071 155 MATERNAL DIETARY DEFICIENCY OF N-3 FATTY ACIDS AFFECTS METABOLIC AND EPIGENETIC PHENOTYPES OF THE DEVELOPING FETUS. POLYUNSATURATED FATTY ACIDS (PUFAS) PLAY MULTIPLE PHYSIOLOGICAL ROLES. THEY REGULATE THE STRUCTURE AND FUNCTION OF CELL MEMBRANES AND CELL GROWTH AND PROLIFERATION, AND APOPTOSIS. IN ADDITION, PUFAS ARE INVOLVED IN CELLULAR SIGNALING, GENE EXPRESSION AND SERVE AS PRECURSORS TO SECOND MESSENGERS SUCH AS EICOSANOIDS, DOCOSANOIDS ETC. AND REGULATE SEVERAL PHYSIOLOGICAL PROCESSES INCLUDING PLACENTATION, INFLAMMATION, IMMUNITY, ANGIOGENESIS, PLATELET FUNCTION, SYNAPTIC PLASTICITY, NEUROGENESIS, BONE FORMATION, ENERGY HOMEOSTASIS, PAIN SENSITIVITY, STRESS, AND COGNITIVE FUNCTIONS. LINOLEIC ACID, 18:2N-6 (LA) AND ALPHA-LINOLENIC ACID, 18:3N-3 (ALA) ARE THE TWO ESSENTIAL FATTY ACIDS OBTAINED FROM THE DIETS AND SUBSEQUENTLY THEIR LONG-CHAIN POLYUNSATURATED FATTY ACIDS (LCPUFAS) ARE ACCUMULATED IN THE BODY. THE MATERNAL PLASMA LCPUFAS ESPECIALLY ACCUMULATED IN LARGER AMOUNTS IN THE BRAIN DURING THE THIRD TRIMESTER OF PREGNANCY VIA THE PLACENTA AND POSTNATALLY FROM MOTHER'S BREAST MILK. VARIOUS STUDIES, INCLUDING OURS, SUGGEST PUFA'S IMPORTANT ROLE IN PLACENTATION, AS WELL AS IN GROWTH AND DEVELOPMENT OF THE OFFSPRING. HOWEVER, INTAKES OF MATERNAL N-3 PUFAS DURING PREGNANCY AND LACTATION ARE MUCH LOWER IN INDIA COMPARED WITH THE WESTERN POPULATION. IN INDIA, N-3 FATTY ACID STATUS IS FURTHER REDUCED BY HIGHER INTAKE OF N-6 PUFA RICH OILS AND TRANS FATS. MORE DATA ON THE IMPACTS OF LONG TERM MATERNAL N-3 PUFA DEFICIENCY ON PLACENTAL STRUCTURE AND FUNCTION, GENE EXPRESSION, EPIGENETIC CHANGES AND RESULTANT COGNITIVE FUNCTION OF FETUS & INFANTS ARE EMERGING. THIS REVIEW SUMMARIZES THE IMPACTS OF N-3 PUFA DEFICIENCY IN UTERO ON FETAL GROWTH AND DEVELOPMENT, ADIPOSITY, ENERGY METABOLISM, MUSCULOSKELETAL DEVELOPMENT, AND EPIGENETIC CHANGES IN FETO-PLACENTAL AXIS FROM THE RECENTLY AVAILABLE PRE-CLINICAL AND CLINICAL DATA. 2020 2 4110 40 MECHANISMS BY WHICH PLEIOTROPIC AMPHIPHILIC N-3 PUFA REDUCE COLON CANCER RISK. COLORECTAL CANCER IS ONE OF THE MAJOR CAUSES OF CANCER-RELATED MORTALITY IN BOTH MEN AND WOMEN WORLDWIDE. GENETIC SUSCEPTIBILITY AND DIET ARE PRIMARY DETERMINANTS OF CANCER RISK AND TUMOR BEHAVIOR. EXPERIMENTAL, EPIDEMIOLOGICAL, AND CLINICAL DATA SUBSTANTIATE THE BENEFICIAL ROLE OF N-3 POLYUNSATURATED FATTY ACIDS (PUFA) IN PREVENTING CHRONIC INFLAMMATION AND COLON CANCER. FROM A MECHANISTIC PERSPECTIVE, N-3 PUFA ARE PLEIOTROPIC AND MULTIFACETED WITH RESPECT TO THEIR MOLECULAR MECHANISMS OF ACTION. FOR EXAMPLE, THIS CLASS OF DIETARY LIPID UNIQUELY ALTERS MEMBRANE STRUCTURE/ CYTOSKELETAL FUNCTION, IMPACTING MEMBRANE RECEPTOR FUNCTION AND DOWNSTREAM SIGNALING CASCADES, INCLUDING GENE EXPRESSION PROFILES AND CELL PHENOTYPE. IN ADDITION, N-3 PUFA CAN SYNERGIZE WITH OTHER POTENTIAL ANTI-TUMOR AGENTS, SUCH AS FERMENTABLE FIBER AND CURCUMIN. WITH THE RISING PREVALENCE OF DIET-INDUCED OBESITY, THERE IS ALSO AN URGENT NEED TO ELUCIDATE THE LINK BETWEEN CHRONIC INFLAMMATION IN ADIPOSE TISSUE AND COLON CANCER RISK IN OBESITY. IN THIS REVIEW, WE WILL SUMMARIZE RECENT DEVELOPMENTS LINKING N-3 PUFA INTAKE, MEMBRANE ALTERATIONS, EPIGENETIC MODULATION, AND EFFECTS ON OBESITY-ASSOCIATED COLON CANCER RISK. 2014 3 2794 31 FATTY ACIDS, EPIGENETIC MECHANISMS AND CHRONIC DISEASES: A SYSTEMATIC REVIEW. BACKGROUND: CHRONIC ILLNESSES LIKE OBESITY, TYPE 2 DIABETES (T2D) AND CARDIOVASCULAR DISEASES, ARE WORLDWIDE MAJOR CAUSES OF MORBIDITY AND MORTALITY. THESE PATHOLOGICAL CONDITIONS INVOLVE INTERACTIONS BETWEEN ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS. RECENT ADVANCES IN NUTRIEPIGENOMICS ARE CONTRIBUTING TO CLARIFY THE ROLE OF SOME NUTRITIONAL FACTORS, INCLUDING DIETARY FATTY ACIDS IN GENE EXPRESSION REGULATION. THIS SYSTEMATIC REVIEW ASSESSES CURRENTLY AVAILABLE INFORMATION CONCERNING THE ROLE OF THE DIFFERENT FATTY ACIDS ON EPIGENETIC MECHANISMS THAT AFFECT THE DEVELOPMENT OF CHRONIC DISEASES OR INDUCE PROTECTIVE EFFECTS ON METABOLIC ALTERATIONS. METHODS: A TARGETED SEARCH WAS CONDUCTED IN THE PUBMED/MEDLINE DATABASES USING THE KEYWORDS "FATTY ACIDS AND EPIGENETIC". THE DATA WERE ANALYZED ACCORDING TO THE PRISMA-P GUIDELINES. RESULTS: CONSUMPTION FATTY ACIDS LIKE N-3 PUFA: EPA AND DHA, AND MUFA: OLEIC AND PALMITOLEIC ACID WAS ASSOCIATED WITH AN IMPROVEMENT OF METABOLIC ALTERATIONS. ON THE OTHER HAND, FATTY ACIDS THAT HAVE BEEN ASSOCIATED WITH THE PRESENCE OR DEVELOPMENT OF OBESITY, T2D, PRO-INFLAMMATORY PROFILE, ATHEROSCLEROSIS AND IR WERE N-6 PUFA, SATURATED FATTY ACIDS (STEARIC AND PALMITIC), AND TRANS FATTY ACIDS (ELAIDIC), HAVE BEEN ALSO LINKED WITH EPIGENETIC CHANGES. CONCLUSIONS: FATTY ACIDS CAN REGULATE GENE EXPRESSION BY MODIFYING EPIGENETIC MECHANISMS AND CONSEQUENTLY RESULT IN POSITIVE OR NEGATIVE IMPACTS ON METABOLIC OUTCOMES. 2019 4 5569 33 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 5 5112 39 POLYUNSATURATED FATTY ACIDS: BIOCHEMICAL, NUTRITIONAL AND EPIGENETIC PROPERTIES. DIETARY POLYUNSATURATED FATTY ACIDS (PUFA) HAVE EFFECTS ON DIVERSE PHYSIOLOGICAL PROCESSES IMPACTING NORMAL HEALTH AND CHRONIC DISEASES, SUCH AS THE REGULATION OF PLASMA LIPID LEVELS, CARDIOVASCULAR AND IMMUNE FUNCTION, INSULIN ACTION AND NEURONAL DEVELOPMENT AND VISUAL FUNCTION. INGESTION OF PUFA WILL LEAD TO THEIR DISTRIBUTION TO VIRTUALLY EVERY CELL IN THE BODY WITH EFFECTS ON MEMBRANE COMPOSITION AND FUNCTION, EICOSANOID SYNTHESIS, CELLULAR SIGNALING AND REGULATION OF GENE EXPRESSION. CELL SPECIFIC LIPID METABOLISM, AS WELL AS THE EXPRESSION OF FATTY ACID-REGULATED TRANSCRIPTION FACTORS, LIKELY PLAY AN IMPORTANT ROLE IN DETERMINING HOW CELLS RESPOND TO CHANGES IN PUFA COMPOSITION. THIS REVIEW WILL FOCUS ON RECENT ADVANCES ON THE ESSENTIALITY OF THESE MOLECULES AND ON THEIR INTERPLAY IN CELL PHYSIOLOGY, LEADING TO NEW PERSPECTIVE IN DIFFERENT THERAPEUTIC FIELDS. 2004 6 4972 33 PATHOPHYSIOLOGICAL BASIS FOR COMPROMISED HEALTH BEYOND GENERATIONS: ROLE OF MATERNAL HIGH-FAT DIET AND LOW-GRADE CHRONIC INFLAMMATION. EARLY EXPOSURE TO A FAT-ENRICHED DIET PROGRAMS THE DEVELOPMENTAL PROFILE AND THUS IS ASSOCIATED WITH DISEASE SUSCEPTIBILITY IN SUBSEQUENT GENERATIONS. CHRONIC LOW-GRADE INFLAMMATION, RESULTING FROM MATERNAL HIGH-FAT DIET, IS ACTIVATED IN THE FETAL ENVIRONMENT AND IN MANY ORGANS OF OFFSPRING, INCLUDING PLACENTA, ADIPOSE, LIVER, VASCULAR SYSTEM AND BRAIN. THE PREVALENCE OF AN INFLAMMATORY RESPONSE IS HIGHLY ASSOCIATED WITH OBESITY INCIDENCE, CARDIOVASCULAR DISEASES, NONALCOHOLIC FATTY LIVER DISEASE AND BRAIN DAMAGE. SUBSTANTIAL STUDIES USING HIGH-FAT MODEL HAVE CONSISTENTLY DEMONSTRATED THE INCIDENCE OF SUCH INFLAMMATORY REACTIONS; HOWEVER, THE POTENTIAL CONTRIBUTION OF ACTIVE INFLAMMATION TOWARD THE PHYSIOLOGICAL OUTCOMES AND DEVELOPMENTAL DISEASES IS NEITHER DISCUSSED IN DEPTH NOR SYSTEMICALLY INTEGRATED. THEREFORE, WE AIM TO SUMMARIZE THE CURRENT FINDINGS IN REGARDS TO HOW A MATERNAL HIGH-FAT DIET INFLUENCES THE INFLAMMATORY STATUS, AND PROBABLE PATHOGENIC EFFECTS ON THE OFFSPRING. MORE IMPORTANTLY, SINCE LIMITED RESEARCH HAS BEEN CONDUCTED TO REVEAL THE EPIGENETIC REGULATION OF THESE INFLAMMATORY MARKERS BY MATERNAL HIGH-FAT DIET, WE SINCERELY HOPE THAT OUR REVIEW WILL NOT ONLY OUTLINE THE PATHOPHYSIOLOGICAL RELEVANCE OF INFLAMMATION BUT ALSO IDENTIFY A FUTURE DIRECTION FOR MECHANISTIC INVESTIGATION AND CLINICAL APPLICATION. 2015 7 4977 53 PATHOPHYSIOLOGY AND EVOLUTIONARY ASPECTS OF DIETARY FATS AND LONG-CHAIN POLYUNSATURATED FATTY ACIDS ACROSS THE LIFE CYCLE. DIETARY FAT IS OUR SECOND MOST IMPORTANT ENERGY-PRODUCING MACRONUTRIENT. IT ALSO CONTAINS FATTY ACIDS AND VITAMINS ESSENTIAL FOR GROWTH, DEVELOPMENT, AND MAINTENANCE OF GOOD HEALTH. DIETARY FAT QUANTITY AND QUALITY HAVE BEEN SUBJECT TO TREMENDOUS CHANGE OVER THE PAST 10,000 YEARS. THIS HAS, TOGETHER WITH OTHER MAN-MADE CHANGES IN OUR ENVIRONMENT, CAUSED A CONFLICT WITH OUR SLOWLY ADAPTING GENOME THAT IS IMPLICATED IN "TYPICALLY WESTERN" DISEASES. RATHER THAN REDUCING OUR LIFE EXPECTANCY, THESE DISEASES NOTABLY DIMINISH OUR NUMBER OF YEARS IN HEALTH. IMPORTANT CHANGES IN DIETARY FAT QUALITY ARE THE INCREASED INTAKES OF CERTAIN SATURATED FATTY ACIDS (SAFA) AND LINOLEIC ACID (LA), INTRODUCTION OF INDUSTRIALLY PRODUCED TRANS FATTY ACIDS, AND REDUCED INTAKES OF OMEGA3 FATTY ACIDS, NOTABLY ALPHA-LINOLENIC ACID (ALA) FROM VEGETABLE SOURCES AND EICOSAPENTAENOIC ACID (EPA) AND DOCOSAHEXAENOIC ACID (DHA) FROM FISH. THE PATHOPHYSIOLOGICAL EFFECTS OF THESE CHANGES ARE DIVERSE, BUT ARE INCREASINGLY ASCRIBED TO INDUCTION OF A PROINFLAMMATORY STATE THAT PROGRESSES EASILY TO CHRONIC LOW-GRADE INFLAMMATION. THE LATTER MIGHT AFFECT VIRTUALLY ALL ORGANS AND SYSTEMS, POSSIBLY BEGINNING AT CONCEPTION, AND POSSIBLY EVEN PRIOR TO GAMETOGENESIS THROUGH EPIGENETIC ALTERATIONS. LOW-GRADE INFLAMMATION MIGHT BE A COMMON DENOMINATOR OF THE METABOLIC SYNDROME AND ITS SEQUELAE (E.G., CORONARY ARTERY DISEASE (CAD), DIABETES MELLITUS TYPE 2, SOME TYPES OF CANCER, AND PREGNANCY COMPLICATIONS), SOME PSYCHIATRIC DISEASES (E.G., MAJOR AND POSTPARTUM DEPRESSION, SCHIZOPHRENIA, AND AUTISM), AND NEURODEGENERATIVE DISEASES (E.G., ALZHEIMER'S DISEASE, PARKINSON'S DISEASE). THE LONG-CHAIN POLYUNSATURATED FATTY ACIDS (LCPUFA) ARACHIDONIC ACID (AA), EPA, AND DHA ARE INTIMATELY RELATED TO THE INITIATION AND RESOLUTION OF INFLAMMATORY RESPONSES. THE CURRENT BALANCE BETWEEN AA AND EPA + DHA IS HOWEVER DISTURBED BY THE DOMINANCE OF AA, WHICH ORIGINATES FROM THE DIET OR SYNTHESIS FROM LA. LCPUFA ARE TOGETHER WITH THEIR HIGHLY POTENT METABOLITES (PROSTAGLANDINS, THROMBOXANES, LEUKOTRIENES, RESOLVINS, AND (NEURO)PROTECTINS) INVOLVED IN THE FUNCTIONING OF MEMBRANE-BOUND RECEPTORS, TRANSPORTERS, ION CHANNELS, AND ENZYMES, AND ALSO IN SIGNAL TRANSDUCTION AND GENE EXPRESSION. AMONG THEIR MANY TARGETS ARE NUCLEAR RECEPTORS WHICH, UPON LIGATION WITH LCPUFA AND THEIR METABOLITES, FUNCTION AS TRANSCRIPTION FACTORS OF A VARIETY OF GENES FUNCTIONING IN MANY PATHWAYS. FOR INSTANCE, THE TARGETED PEROXISOME PROLIFERATORS-ACTIVATED RECEPTORS (PPARS) ARE STRATEGIC INTERMEDIATES IN THE COORDINATED EXPRESSION OF PROTEINS WITH FUNCTIONS IN, FOR EXAMPLE, LIPID AND GLUCOSE HOMEOSTASIS AND INFLAMMATORY REACTIONS. MANY INTERVENTIONS HAVE BEEN CONDUCTED WITH LCPUFA, ESPECIALLY EPA AND DHA, AIMING AT PRIMARY AND SECONDARY CAD PREVENTIONS, IMPROVEMENT OF FETAL AND NEWBORN (BRAIN) DEVELOPMENT BY SUPPLEMENTATION DURING PREGNANCY OR EARLY POSTNATAL LIFE, AND IN PSYCHIATRIC DISEASES. CONSENSUS HAS BEEN REACHED THAT THOSE IN CAD AND DEPRESSION ARE POSITIVE, ALTHOUGH MORE LARGE-SCALE TRIALS ARE NEEDED. MANY RECOMMENDATIONS FOR THE INTAKES OF SATURATED FAT, TRANS FAT AND EPA + DHA HAVE BEEN ISSUED, NOTABLY FOR CAD PREVENTION, AND ALSO FOR EPA + DHA INTAKES BY PREGNANT WOMEN AND FOR AA, EPA, AND DHA INTAKES BY NEWBORNS. THE ULTIMATE GOAL MIGHT, HOWEVER, BE TO RETURN TO THE FAT QUALITY OF OUR ANCIENT DIET ON WHICH OUR GENES HAVE EVOLVED DURING THE PAST MILLION YEARS OF EVOLUTION, WHILE THIS ACTUALLY APPLIES FOR OUR ENTIRE DIETARY COMPOSITION AND LIFESTYLE, AS TRANSLATED TO THE CULTURE OF THE CURRENT SOCIETY. 2010 8 48 35 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 9 6133 37 THE EPIGENETIC ROLE OF VITAMIN C IN NEURODEVELOPMENT. THE MATERNAL DIET DURING PREGNANCY IS A KEY DETERMINANT OF OFFSPRING HEALTH. EARLY STUDIES HAVE LINKED POOR MATERNAL NUTRITION DURING GESTATION WITH A PROPENSITY FOR THE DEVELOPMENT OF CHRONIC CONDITIONS IN OFFSPRING. THESE CONDITIONS INCLUDE CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND EVEN COMPROMISED MENTAL HEALTH. WHILE MULTIPLE FACTORS MAY CONTRIBUTE TO THESE OUTCOMES, DISTURBED EPIGENETIC PROGRAMMING DURING EARLY DEVELOPMENT IS ONE POTENTIAL BIOLOGICAL MECHANISM. THE EPIGENOME IS PROGRAMMED PRIMARILY IN UTERO, AND DURING THIS TIME, THE DEVELOPING FETUS IS HIGHLY SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS NUTRITIONAL INSULTS. DURING NEURODEVELOPMENT, EPIGENETIC PROGRAMMING COORDINATES THE FORMATION OF PRIMITIVE CENTRAL NERVOUS SYSTEM STRUCTURES, NEUROGENESIS, AND NEUROPLASTICITY. DYSREGULATED EPIGENETIC PROGRAMMING HAS BEEN IMPLICATED IN THE AETIOLOGY OF SEVERAL NEURODEVELOPMENTAL DISORDERS SUCH AS TATTON-BROWN-RAHMAN SYNDROME. ACCORDINGLY, THERE IS GREAT INTEREST IN DETERMINING HOW MATERNAL NUTRIENT AVAILABILITY IN PREGNANCY MIGHT AFFECT THE EPIGENETIC STATUS OF OFFSPRING, AND HOW SUCH INFLUENCES MAY PRESENT PHENOTYPICALLY. IN RECENT YEARS, A NUMBER OF EPIGENETIC ENZYMES THAT ARE ACTIVE DURING EMBRYONIC DEVELOPMENT HAVE BEEN FOUND TO REQUIRE VITAMIN C AS A COFACTOR. THESE ENZYMES INCLUDE THE TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASES (TETS) AND THE JUMONJI C DOMAIN-CONTAINING HISTONE LYSINE DEMETHYLASES THAT CATALYSE THE OXIDATIVE REMOVAL OF METHYL GROUPS ON CYTOSINES AND HISTONE LYSINE RESIDUES, RESPECTIVELY. THESE ENZYMES ARE INTEGRAL TO EPIGENETIC REGULATION AND HAVE FUNDAMENTAL ROLES IN CELLULAR DIFFERENTIATION, THE MAINTENANCE OF PLURIPOTENCY AND DEVELOPMENT. THE DEPENDENCE OF THESE ENZYMES ON VITAMIN C FOR OPTIMAL CATALYTIC ACTIVITY ILLUSTRATES A POTENTIALLY CRITICAL CONTRIBUTION OF THE NUTRIENT DURING MAMMALIAN DEVELOPMENT. THESE INSIGHTS ALSO HIGHLIGHT A POTENTIAL RISK ASSOCIATED WITH VITAMIN C INSUFFICIENCY DURING PREGNANCY. THE LINK BETWEEN VITAMIN C INSUFFICIENCY AND DEVELOPMENT IS PARTICULARLY APPARENT IN THE CONTEXT OF NEURODEVELOPMENT AND HIGH VITAMIN C CONCENTRATIONS IN THE BRAIN ARE INDICATIVE OF IMPORTANT FUNCTIONAL REQUIREMENTS IN THIS ORGAN. ACCORDINGLY, THIS REVIEW CONSIDERS THE EVIDENCE FOR THE POTENTIAL IMPACT OF MATERNAL VITAMIN C STATUS ON NEURODEVELOPMENTAL EPIGENETICS. 2022 10 3801 38 INTERPLAY OF VITAMIN D AND SIRT1 IN TISSUE-SPECIFIC METABOLISM-POTENTIAL ROLES IN PREVENTION AND TREATMENT OF NON-COMMUNICABLE DISEASES INCLUDING CANCER. THE IMPORTANCE OF THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES, INCLUDING OBESITY, METABOLIC SYNDROME, TYPE 2 DIABETES, CARDIOVASCULAR DISEASES, AND CANCER, IS INCREASING AS A REQUIREMENT OF THE AGING POPULATION IN DEVELOPED COUNTRIES AND THE SUSTAINABILITY OF HEALTHCARE. SIMILARLY, THE 2013-2030 ACTION PLAN OF THE WHO FOR THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES SEEKS THESE ACHIEVEMENTS. ADEQUATE LIFESTYLE CHANGES, ALONE OR WITH THE NECESSARY TREATMENTS, COULD REDUCE THE RISK OF MORTALITY OR THE DETERIORATION OF QUALITY OF LIFE. IN OUR RECENT WORK, WE SUMMARIZED THE ROLE OF TWO CENTRAL FACTORS, I.E., APPROPRIATE LEVELS OF VITAMIN D AND SIRT1, WHICH ARE CONNECTED TO ADEQUATE LIFESTYLES WITH BENEFICIAL EFFECTS ON THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES. BOTH OF THESE FACTORS HAVE RECEIVED INCREASED ATTENTION IN RELATION TO THE COVID-19 PANDEMIC AS THEY BOTH TAKE PART IN REGULATION OF THE MAIN METABOLIC PROCESSES, I.E., LIPID/GLUCOSE/ENERGY HOMEOSTASIS, OXIDATIVE STRESS, REDOX BALANCE, AND CELL FATE, AS WELL AS IN THE HEALTHY REGULATION OF THE IMMUNE SYSTEM. VITAMIN D AND SIRT1 HAVE DIRECT AND INDIRECT INFLUENCE OF THE REGULATION OF TRANSCRIPTION AND EPIGENETIC CHANGES AND ARE RELATED TO CYTOPLASMIC SIGNALING PATHWAYS SUCH AS PLC/DAG/IP3/PKC/MAPK, MEK/ERK, INSULIN/MTOR/CELL GROWTH, PROLIFERATION; LEPTIN/PI3K-AKT-MTORC1, AKT/NFKB/COX-2, NFKB/TNFALPHA, IL-6, IL-8, IL-1BETA, AND AMPK/PGC-1ALPHA/GLUT4, AMONG OTHERS. THROUGH THEIR PROPER REGULATION, THEY MAINTAIN NORMAL BODY WEIGHT, LIPID PROFILE, INSULIN SECRETION AND SENSITIVITY, BALANCE BETWEEN THE PRO- AND ANTI-INFLAMMATORY PROCESSES UNDER NORMAL CONDITIONS AND INFECTIONS, MAINTAIN ENDOTHELIAL HEALTH; BALANCE CELL DIFFERENTIATION, PROLIFERATION, AND FATE; AND BALANCE THE CIRCADIAN RHYTHM OF THE CELLULAR METABOLISM. THE ROLE OF THESE TWO MOLECULES IS INTERCONNECTED IN THE MOLECULAR NETWORK, AND THEY REGULATE EACH OTHER IN SEVERAL LAYERS OF THE HOMEOSTASIS OF ENERGY AND THE CELLULAR METABOLISM. BOTH HAVE A CENTRAL ROLE IN THE MAINTENANCE OF HEALTHY AND BALANCED IMMUNE REGULATION AND REDOX REACTIONS; THEREFORE, THEY COULD CONSTITUTE PROMISING TARGETS EITHER FOR PREVENTION OR AS COMPLEMENTARY THERAPIES TO ACHIEVE A BETTER QUALITY OF LIFE, AT ANY AGE, FOR HEALTHY PEOPLE AND PATIENTS UNDER CHRONIC CONDITIONS. 2023 11 6819 29 [FETAL PROGRAMMING OF METABOLIC DISORDERS]. OUR KNOWLEDGE OF FETAL PROGRAMMING HAS DEVELOPED NOTABLY OVER THE YEARS AND RECENT DATA SUGGEST THAT AN UNBALANCED DIET PRIOR AND DURING PREGNANCY CAN HAVE EARLY-ONSET AND LONG-LASTING CONSEQUENCES ON THE HEALTH OF THE OFFSPRING. SPECIFIC NEGATIVE INFLUENCES OF HIGH DIETARY GLUCOSE AND LIPID CONSUMPTION, AS WELL AS UNDERNUTRITION, ARE ASSOCIATED WITH DEVELOPMENT OF METABOLIC SYNDROME, INSULIN RESISTANCE AND DIABETES IN THE OFFSPRING. THE MECHANISMS UNDERLYING THE EFFECTS OF MATERNAL HYPERGLYCEMIA ON THE FETUS MAY INVOLVE STRUCTURAL, METABOLIC AND EPIGENETIC CHANGES. THE AIM OF THIS REVIEW IS TO ILLUSTRATE HOW ADVERSE INTRAUTERINE ENVIRONMENT MAY INFLUENCE MOLECULAR MODIFICATIONS IN THE FETUS AND CAUSE EPIGENETIC ALTERATIONS IN PARTICULAR. IT HAS BEEN DEMONSTRATED THAT PRENATAL EPIGENETIC MODIFICATIONS MAY BE LINKED TO THE PATHOGENESIS AND PROGRESSION OF THE ADULT CHRONIC DISORDERS. STUDIES ON EPIGENETIC ALTERATIONS WILL CONTRIBUTE TO A BETTER UNDERSTANDING OF THE LONG-TERM EFFECTS OF IN UTERO EXPOSURE AND MAY OPEN NEW PERSPECTIVES FOR DISEASE PREVENTION AND TREATMENT. 2015 12 4802 26 OBESITY AND LIFESPAN HEALTH--IMPORTANCE OF THE FETAL ENVIRONMENT. A MARKED INCREASE IN THE FREQUENCY OF OBESITY AT THE POPULATION LEVEL HAS RESULTED IN AN INCREASING NUMBER OF OBESE WOMEN ENTERING PREGNANCY. THE INCREASING REALIZATION OF THE IMPORTANCE OF THE FETAL ENVIRONMENT IN RELATION TO CHRONIC DISEASE ACROSS THE LIFESPAN HAS FOCUSED ATTENTION ON THE ROLE OF MATERNAL OBESITY IN FETAL DEVELOPMENT. PREVIOUS STUDIES HAVE DEMONSTRATED THAT OBESITY DURING ADOLESCENCE AND ADULTHOOD CAN BE TRACED BACK TO FETAL AND EARLY CHILDHOOD EXPOSURES. THIS REVIEW FOCUSES ON FACTORS THAT CONTRIBUTE TO EARLY DEVELOPMENTAL EVENTS, SUCH AS EPIGENETIC MODIFICATIONS, THE POTENTIAL FOR AN INCREASE IN INFLAMMATORY BURDEN, EARLY DEVELOPMENTAL PROGRAMMING CHANGES SUCH AS THE VARIABLE DEVELOPMENT OF WHITE VERSUS BROWN ADIPOSE TISSUE, AND ALTERATIONS IN ORGAN ONTOGENY. WE HYPOTHESIZE THAT THESE MECHANISMS PROMOTE AN UNFAVORABLE FETAL ENVIRONMENT AND CAN HAVE A LONG-STANDING IMPACT, WITH EARLY MANIFESTATIONS OF CHRONIC DISEASE THAT CAN RESULT IN AN INCREASED DEMAND FOR FUTURE HEALTH CARE. IN ORDER TO IDENTIFY APPROPRIATE PREVENTIVE MEASURES, ATTENTION NEEDS TO BE PLACED BOTH ON REDUCING MATERNAL OBESITY AS WELL AS UNDERSTANDING THE MOLECULAR, CELLULAR, AND EPIGENETIC MECHANISMS THAT MAY BE RESPONSIBLE FOR THE PRENATAL ONSET OF CHRONIC DISEASE. 2014 13 1992 25 EPIGENETIC AND DEVELOPMENTAL INFLUENCES ON THE RISK OF OBESITY, DIABETES, AND METABOLIC SYNDROME. METABOLIC SYNDROME IS A GROWING CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. METABOLIC SYNDROME IS CHARACTERIZED BY THE PRESENCE OF A VARIETY OF METABOLIC DISTURBANCES INCLUDING OBESITY, HYPERLIPIDEMIA, HYPERTENSION, AND ELEVATED FASTING BLOOD SUGAR. ALTHOUGH THE RISK FOR METABOLIC SYNDROME HAS LARGELY BEEN ATTRIBUTED TO ADULT LIFESTYLE FACTORS SUCH AS POOR NUTRITION, LACK OF EXERCISE, AND SMOKING, THERE IS NOW STRONG EVIDENCE SUGGESTING THAT PREDISPOSITION TO THE DEVELOPMENT OF METABOLIC SYNDROME BEGINS IN UTERO. FIRST POSITED BY HALES AND BARKER IN 1992, THE "THRIFTY PHENOTYPE" HYPOTHESIS PROPOSES THAT SUSCEPTIBILITY TO ADULT CHRONIC DISEASES CAN OCCUR IN RESPONSE TO EXPOSURES IN THE PRENATAL AND PERINATAL PERIODS. THIS HYPOTHESIS HAS BEEN CONTINUALLY SUPPORTED BY EPIDEMIOLOGIC STUDIES AND STUDIES INVOLVING ANIMAL MODELS. IN THIS REVIEW, WE DESCRIBE THE STRUCTURAL, METABOLIC AND EPIGENETIC CHANGES THAT OCCUR IN RESPONSE TO ADVERSE INTRAUTERINE ENVIRONMENTS INCLUDING PRENATAL AND POSTNATAL DIET, MATERNAL OBESITY, AND PREGNANCY COMPLICATIONS. GIVEN THE INCREASING PREVALENCE OF METABOLIC SYNDROME IN BOTH THE DEVELOPED AND DEVELOPING WORLDS, A GREATER UNDERSTANDING AND APPRECIATION FOR THE ROLE OF THE INTRAUTERINE ENVIRONMENT IN ADULT CHRONIC DISEASE ETIOLOGY IS IMPERATIVE. 2015 14 2958 35 GENETIC AND EPIGENETIC INSIGHTS INTO FETAL ALCOHOL SPECTRUM DISORDERS. THE MAGNITUDE OF THE DETRIMENTAL EFFECTS FOLLOWING IN UTERO ALCOHOL EXPOSURE, INCLUDING FETAL ALCOHOL SYNDROME AND OTHER FETAL ALCOHOL SPECTRUM DISORDERS (FASD), IS GLOBALLY UNDERESTIMATED. THE EFFECTS INCLUDE IRREVERSIBLE COGNITIVE AND BEHAVIORAL DISABILITIES AS A RESULT OF ABNORMAL BRAIN DEVELOPMENT, PRE- AND POSTNATAL GROWTH RETARDATION AND FACIAL DYSMORPHISM. PARENTAL ALCOHOL EXPOSURE AND ITS EFFECT ON OFFSPRING HAS BEEN RECOGNIZED FOR CENTURIES, BUT ONLY RECENTLY HAVE WE BEGUN TO GAIN MOLECULAR INSIGHT INTO THE MECHANISMS INVOLVED IN ALCOHOL TERATOGENESIS. GENETIC ATTRIBUTES (SUSCEPTIBILITY AND PROTECTIVE ALLELES) OF THE MOTHER AND THE FETUS CONTRIBUTE TO THE RISK OF DEVELOPING FASD AND SPECIFIC ADDITIONAL ENVIRONMENTAL CONDITIONS, INCLUDING MALNUTRITION, HAVE AN IMPORTANT ROLE. THE SEVERITY OF FASD DEPENDS ON THE LEVEL OF ALCOHOL EXPOSURE, THE DEVELOPMENTAL STAGE AT WHICH EXPOSURE OCCURS AND THE NATURE OF THE EXPOSURE (CHRONIC OR ACUTE), AND ALTHOUGH THE MOST VULNERABLE PERIOD IS DURING THE FIRST TRIMESTER, DAMAGE CAN OCCUR THROUGHOUT GESTATION. PRECONCEPTION ALCOHOL EXPOSURE CAN ALSO HAVE A DETRIMENTAL EFFECT ON THE OFFSPRING. SEVERAL DEVELOPMENTAL PATHWAYS ARE AFFECTED IN FASD, INCLUDING NERVOUS SYSTEM DEVELOPMENT, GROWTH AND REMODELING OF TISSUES, AS WELL AS METABOLIC PATHWAYS THAT REGULATE GLUCOCORTICOID SIGNALING AND BALANCED LEVELS OF RETINOL, INSULIN AND NITRIC OXIDE. A BODY OF KNOWLEDGE HAS ACCUMULATED TO SUPPORT THE ROLE OF ENVIRONMENTALLY INDUCED EPIGENETIC REMODELING DURING GAMETOGENESIS AND AFTER CONCEPTION AS A KEY MECHANISM FOR THE TERATOGENIC EFFECTS OF FASD THAT PERSIST INTO ADULTHOOD. TRANSGENERATIONAL EFFECTS ARE LIKELY TO CONTRIBUTE TO THE GLOBAL BURDEN OF ALCOHOL-RELATED DISEASE. FASD RESULTS IN LIFELONG DISABILITY AND PREVENTATIVE PROGRAMS SHOULD INCLUDE BOTH MATERNAL ALCOHOL ABSTENTION AND PRECONCEPTION ALCOHOL AVOIDANCE. 2010 15 2424 30 EPIGENETIC SIGNATURES UNDERLYING INFLAMMATION: AN INTERPLAY OF NUTRITION, PHYSICAL ACTIVITY, METABOLIC DISEASES, AND ENVIRONMENTAL FACTORS FOR PERSONALIZED NUTRITION. AIM AND OBJECTIVE: EMERGING TRANSLATIONAL EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS (DNA METHYLATION, MIRNA EXPRESSION, AND HISTONE MODIFICATIONS) OCCUR AFTER EXTERNAL STIMULI AND MAY CONTRIBUTE TO EXACERBATED INFLAMMATION AND THE RISK OF SUFFERING SEVERAL DISEASES INCLUDING DIABETES, CARDIOVASCULAR DISEASES, CANCER, AND NEUROLOGICAL DISORDERS. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE ABOUT THE HARMFUL EFFECTS OF HIGH-FAT/HIGH-SUGAR DIETS, MICRONUTRIENT DEFICIENCIES (FOLATE, MANGANESE, AND CAROTENOIDS), OBESITY AND ASSOCIATED COMPLICATIONS, BACTERIAL/VIRAL INFECTIONS, SMOKING, EXCESSIVE ALCOHOL CONSUMPTION, SLEEP DEPRIVATION, CHRONIC STRESS, AIR POLLUTION, AND CHEMICAL EXPOSURE ON INFLAMMATION THROUGH EPIGENETIC MECHANISMS. ADDITIONALLY, THE EPIGENETIC PHENOMENA UNDERLYING THE ANTI-INFLAMMATORY POTENTIAL OF CALORIC RESTRICTION, N-3 PUFA, MEDITERRANEAN DIET, VITAMIN D, ZINC, POLYPHENOLS (I.E., RESVERATROL, GALLIC ACID, EPICATECHIN, LUTEOLIN, CURCUMIN), AND THE ROLE OF SYSTEMATIC EXERCISE ARE DISCUSSED. METHODS: ORIGINAL AND REVIEW ARTICLES ENCOMPASSING EPIGENETICS AND INFLAMMATION WERE SCREENED FROM MAJOR DATABASES (INCLUDING PUBMED, MEDLINE, SCIENCE DIRECT, SCOPUS, ETC.) AND ANALYZED FOR THE WRITING OF THE REVIEW PAPER. CONCLUSION: ALTHOUGH CAUTION SHOULD BE EXERCISED, RESEARCH ON EPIGENETIC MECHANISMS IS CONTRIBUTING TO UNDERSTAND PATHOLOGICAL PROCESSES INVOLVING INFLAMMATORY RESPONSES, THE PREDICTION OF DISEASE RISK BASED ON THE EPIGENOTYPE, AS WELL AS THE PUTATIVE DESIGN OF THERAPEUTIC INTERVENTIONS TARGETING THE EPIGENOME. 2021 16 5097 35 PLASTICS DERIVED ENDOCRINE-DISRUPTING COMPOUNDS AND THEIR EFFECTS ON EARLY DEVELOPMENT. DESPITE THE FACT THAT THE ESTROGENIC EFFECTS OF BISPHENOLS WERE FIRST DESCRIBED 80 YEARS AGO, RECENT DATA ABOUT ITS POTENTIAL NEGATIVE IMPACT ON BIRTH OUTCOME PARAMETERS RAISES A STRONG RATIONALE TO INVESTIGATE FURTHER. THE ADVERSE HEALTH EFFECTS OF PLASTICS RECOMMEND TO MEASURE THE IMPACTS OF ENDOCRINE-DISRUPTING COMPOUNDS (EDCS) SUCH AS BISPHENOLS (BPA, BPS, BPF), BIS(2-ETHYLHEXYL) PHTHALATE, AND DIBUTYL PHTHALATE (DBP) IN HUMAN HEALTH. EXPOSURE TO THESE COMPOUNDS IN UTERO MAY PROGRAM THE DISEASES OF THE TESTIS, PROSTATE, KIDNEY AND ABNORMALITIES IN THE IMMUNE SYSTEM, AND CAUSE TUMORS, UTERINE HEMORRHAGE DURING PREGNANCY AND POLYCYSTIC OVARY. THESE COMPOUNDS ALSO CONTROL THE PROCESSES OF EPIGENETIC TRANSGENERATIONAL INHERITANCE OF ADULT-ONSET DISEASES BY MODULATING DNA METHYLATION AND EPIMUTATIONS IN REPRODUCTIVE CELLS. THE EARLY DEVELOPMENTAL STAGE IS THE MOST SUSCEPTIBLE WINDOW FOR DEVELOPMENTAL AND GENOMIC PROGRAMMING. THE CRITICAL STAGES OF THE EVENTS FOR A NORMAL HUMAN BIRTH LIE BETWEEN THE MANY TRANSITIONS OCCURRING BETWEEN SPERMATOGENESIS, EGG FERTILIZATION AND THE FULLY FORMED FETUS. AS THE CELLS BEGIN TO GROW AND DIFFERENTIATE, THERE ARE CRITICAL BALANCES OF HORMONES, AND PROTEIN SYNTHESIS. DATA ARE EMERGING ON HOW THESE PLASTIC-DERIVED COMPOUNDS AFFECT EMBRYOGENESIS, PLACENTATION AND FETO-PLACENTAL DEVELOPMENT SINCE PREGNANT WOMEN AND UNBORN FETUSES ARE OFTEN EXPOSED TO THESE FACTORS DURING PRECONCEPTION AND THROUGHOUT GESTATION. IMPAIRED EARLY DEVELOPMENT THAT ULTIMATELY INFLUENCES FETAL OUTCOMES IS AT THE CENTER OF MANY DEVELOPMENTAL DISORDERS AND CONTRIBUTES AN INDEPENDENT RISK FACTOR FOR ADULT CHRONIC DISEASES. THIS REVIEW WILL SUMMARIZE THE CURRENT STATUS ON THE IMPACT OF EXPOSURE TO PLASTIC DERIVED EDCS ON THE GROWTH, GENE EXPRESSION, EPIGENETIC AND ANGIOGENIC ACTIVITIES OF THE EARLY FETAL DEVELOPMENT PROCESS AND THEIR POSSIBLE EFFECTS ON BIRTH OUTCOMES. 2020 17 5091 32 PLACENTAL DISEASES ASSOCIATED WITH ASSISTED REPRODUCTIVE TECHNOLOGY. THE PLACENTA DEVELOPS FROM THE OUTER TROPHOBLASTIC LAYER FOLLOWING THE DIFFERENTIATION OF THE FERTILIZED OVUM AND IS THEREFORE MORE SUSCEPTIBLE TO EPIGENETIC REGULATORY CHANGES CAUSED BY ENVIRONMENTAL INTERVENTIONS AND INFLUENCES DURING ASSISTED REPRODUCTIVE TECHNOLOGY. FURTHERMORE, THE PLACENTA REGULATES THE DEVELOPMENT OF THE FETAL HEART, BRAIN, KIDNEYS, BONES, AND OTHER TISSUES AND ORGANS [1]. PLACENTAL DYSPLASIA LEADS TO POOR PERINATAL OUTCOMES AS WELL AS LONG-TERM HEALTH RISKS LATER IN LIFE, INCLUDING NEURODEVELOPMENTAL DISORDERS, TUMORS, AND ADULT METABOLIC SYNDROME [2,3]. IN VIEW OF THE DECISIVE ROLE OF THE PLACENTA DURING INTRAUTERINE FETAL DEVELOPMENT, GRAHAM J. BURTON, AN EXPERT IN PLACENTOLOGY FROM THE UNIVERSITY OF CAMBRIDGE, FORMALLY PROPOSED THE THEORY OF "PLACENTA-DERIVED CHRONIC DISEASES" IN 2018 BASED ON EMBRYONIC-DERIVED DISEASES [4]. IN THIS REVIEW, WE SUMMARIZED THE CHANGES IN PLACENTAL MORPHOLOGY AND STRUCTURE, GROWTH DYNAMICS, IMPRINTED AND NON-IMPRINTED GENES, AND OTHER ASPECTS ATTRIBUTABLE TO ASSISTED REPRODUCTION TECHNOLOGY. OUR REVIEW PROVIDES A THEORETICAL BASIS FOR FURTHER RESEARCH ON PLACENTAL CHANGES CAUSED BY ASSISTED REPRODUCTIVE TECHNOLOGY THAT ARE MOST STRONGLY ASSOCIATED WITH AN INCREASED RISK OF NEONATAL LONG-TERM DISEASES. 2021 18 167 28 ABNORMAL PLACENTATION ASSOCIATED WITH INFERTILITY AS A MARKER OF OVERALL HEALTH. INFERTILITY AND THE FERTILITY TREATMENTS UTILIZED ARE ASSOCIATED WITH ABNORMAL PLACENTATION LEADING TO ADVERSE PREGNANCY OUTCOMES RELATED TO PLACENTATION, INCLUDING PRETERM BIRTH, LOW BIRTH WEIGHT, PLACENTA ACCRETE AND PLACENTA PREVIA. THIS MAY BE DUE TO THE UNDERLYING GENETICS PREDISPOSING TO INFERTILITY OR THE EPIGENETIC CHANGES ASSOCIATED WITH THE FERTILITY TREATMENTS UTILIZED, AS SPECIFIC DISEASE STATES LEADING TO INFERTILITY ARE AT INCREASED RISK OF ADVERSE OUTCOMES, INCLUDING PLACENTAL ABRUPTION, FETAL LOSS, GDM, AND OUTCOMES RELATED TO PLACENTATION, AS WELL AS THE TREATMENTS UTILIZED INCLUDING IN VITRO FERTILIZATION (IVF) AND NIFT (NON-IVF FERTILITY TREATMENT). PLACENTATION DEFECTS, LEADING TO ADVERSE MATERNAL AND FETAL OUTCOMES, WHICH ARE MORE PRONOUNCED IN THE INFERTILE POPULATION, OCCUR DUE TO CHANGES IN TROPHOBLAST INVASION, VASCULAR DEFECTS, CHANGES IN THE ENVIRONMENTAL MILIEU, CHRONIC INFLAMMATION AND OXIDATIVE STRESS. THESE SIMILAR PROCESSES ARE RECOGNIZED AS MAJOR CONTRIBUTORS TO LIFELONG RISK OF CARDIOVASCULAR AND METABOLIC DISEASE FOR BOTH THE MOTHER AND HER OFFSPRING. THUS, ABNORMAL PLACENTATION, FOUND TO BE MORE PREVALENT IN THE INFERTILE POPULATION, MAY BE THE KEY TO BETTER UNDERSTAND HOW INFERTILITY AFFECTS OVERALL AND LONG TERM HEALTH. 2017 19 2807 24 FETAL PROGRAMMING OF CHRONIC KIDNEY DISEASE: THE ROLE OF MATERNAL SMOKING, MITOCHONDRIAL DYSFUNCTION, AND EPIGENETIC MODFIFICATION. THE ROLE OF AN ADVERSE IN UTERO ENVIRONMENT IN THE PROGRAMMING OF CHRONIC KIDNEY DISEASE IN THE ADULT OFFSPRING IS INCREASINGLY RECOGNIZED. THE CELLULAR AND MOLECULAR MECHANISMS LINKING THE IN UTERO ENVIRONMENT AND FUTURE DISEASE SUSCEPTIBILITY REMAIN UNKNOWN. MATERNAL SMOKING IS A COMMON MODIFIABLE ADVERSE IN UTERO EXPOSURE, POTENTIALLY ASSOCIATED WITH BOTH MITOCHONDRIAL DYSFUNCTION AND EPIGENETIC MODIFICATION IN THE OFFSPRING. WHILE STUDIES ARE EMERGING THAT POINT TOWARD A KEY ROLE OF MITOCHONDRIAL DYSFUNCTION IN ACUTE AND CHRONIC KIDNEY DISEASE, IT MAY HAVE ITS ORIGIN IN EARLY DEVELOPMENT, BECOMING CLINICALLY APPARENT WHEN SECONDARY INSULTS OCCUR. ABERRANT EPIGENETIC PROGRAMMING MAY ADD AN ADDITIONAL LAYER OF COMPLEXITY TO ORCHESTRATE FIBROGENESIS IN THE KIDNEY AND SUSCEPTIBILITY TO CHRONIC KIDNEY DISEASE IN LATER LIFE. IN THIS REVIEW, WE EXPLORE THE EVIDENCE FOR MITOCHONDRIAL DYSFUNCTION AND EPIGENETIC MODIFICATION THROUGH ABERRANT DNA METHYLATION AS KEY MECHANISTIC ASPECTS OF FETAL PROGRAMMING OF CHRONIC KIDNEY DISEASE AND DISCUSS THEIR POTENTIAL USE IN DIAGNOSTICS AND TARGETS FOR THERAPY. 2015 20 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