1 2158 142 EPIGENETIC MECHANISMS FOR NUTRITION DETERMINANTS OF LATER HEALTH OUTCOMES. EPIGENETIC MARKING ON GENES CAN DETERMINE WHETHER OR NOT GENES ARE EXPRESSED. EPIGENETIC REGULATION IS MEDIATED BY THE ADDITION OF METHYL GROUPS TO DNA CYTOSINE BASES, OF METHYL AND ACETYL GROUPS TO PROTEINS (HISTONES) AROUND WHICH DNA IS WRAPPED, AND BY SMALL INTERFERING RNA MOLECULES. SOME COMPONENTS OF EPIGENETIC REGULATION HAVE EVOLVED TO PERMIT CONTROL OF WHETHER MATERNAL OR PATERNAL GENES ARE EXPRESSED. THE EPIGENETIC IMPRINTING OF IGF2 EXPRESSION IS AN EXAMPLE OF MATERNAL AND PATERNAL EPIGENETIC MARKING THAT MODULATES FETAL GROWTH AND FETAL SIZE. HOWEVER, EPIGENETIC REGULATION ALSO PERMITS THE FETUS AND THE INFANT TO ADAPT GENE EXPRESSION TO THE ENVIRONMENT IN WHICH IT IS GROWING; SOMETIMES WHEN THIS ADJUSTMENT GOES AWRY, THE RISK OF CHRONIC DISEASE IS INCREASED. RECENT PROGRESS IN THE UNDERSTANDING OF NUTRITIONAL INFLUENCES ON EPIGENETICS SUGGESTS THAT NUTRIENTS THAT ARE PART OF METHYL-GROUP METABOLISM CAN SIGNIFICANTLY INFLUENCE EPIGENETICS. DURING CRITICAL PERIODS IN DEVELOPMENT, DIETARY METHYL-GROUP INTAKE (CHOLINE, METHIONINE, AND FOLATE) CAN ALTER DNA AND HISTONE METHYLATION, WHICH RESULTS IN LIFELONG CHANGES IN GENE EXPRESSION. IN RODENT MODELS, PREGNANT DAMS THAT WERE FED DIETS HIGH IN METHIONINE, FOLIC ACID, AND CHOLINE PRODUCED OFFSPRING WITH DIFFERENT COAT COLORS OR WITH KINKED TAILS. A NUMBER OF SYNDROMES IN HUMANS CAN BE CAUSED BY DEFECTIVE EPIGENETIC REGULATION, INCLUDING RETT SYNDROME. THERE ARE INTERESTING EXAMPLES OF THE EFFECTS OF NUTRITION IN EARLY LIFE THAT RESULT IN ALTERED HEALTH IN ADULTS, AND SOME OF THESE COULD BE THE RESULT OF ALTERED EPIGENETIC REGULATION OF GENE EXPRESSION. 2009 2 1520 50 DNA METHYLATION AT DIFFERENTIALLY METHYLATED REGIONS OF IMPRINTED GENES IS RESISTANT TO DEVELOPMENTAL PROGRAMMING BY MATERNAL NUTRITION. THE NUTRITIONAL ENVIRONMENT IN WHICH THE MAMMALIAN FETUS OR INFANT DEVELOP IS RECOGNIZED AS INFLUENCING THE RISK OF CHRONIC DISEASES, SUCH AS TYPE 2 DIABETES AND HYPERTENSION, IN A PHENOMENON THAT HAS BECOME KNOWN AS DEVELOPMENTAL PROGRAMMING. THE LATE ONSET OF SUCH DISEASES IN RESPONSE TO EARLIER TRANSIENT EXPERIENCES HAS LED TO THE SUGGESTION THAT DEVELOPMENTAL PROGRAMMING MAY HAVE AN EPIGENETIC COMPONENT, BECAUSE EPIGENETIC MARKS SUCH AS DNA METHYLATION OR HISTONE TAIL MODIFICATIONS COULD PROVIDE A PERSISTENT MEMORY OF EARLIER NUTRITIONAL STATES. ONE CLASS OF GENES THAT HAS BEEN CONSIDERED A POTENTIAL TARGET OR MEDIATOR OF PROGRAMMING EVENTS IS IMPRINTED GENES, BECAUSE THESE GENES CRITICALLY DEPEND UPON EPIGENETIC MODIFICATIONS FOR CORRECT EXPRESSION AND BECAUSE MANY IMPRINTED GENES HAVE ROLES IN CONTROLLING FETAL GROWTH AS WELL AS NEONATAL AND ADULT METABOLISM. IN THIS STUDY, WE HAVE USED AN ESTABLISHED MODEL OF DEVELOPMENTAL PROGRAMMING-ISOCALORIC PROTEIN RESTRICTION TO FEMALE MICE DURING GESTATION OR LACTATION-TO EXAMINE WHETHER THERE ARE EFFECTS ON EXPRESSION AND DNA METHYLATION OF IMPRINTED GENES IN THE OFFSPRING. WE FIND THAT ALTHOUGH EXPRESSION OF SOME IMPRINTED GENES IN LIVER OF OFFSPRING IS ROBUSTLY AND SUSTAINABLY CHANGED, METHYLATION OF THE DIFFERENTIALLY METHYLATED REGIONS (DMRS) THAT CONTROL THEIR MONOALLELIC EXPRESSION REMAINS LARGELY UNALTERED. WE CONCLUDE THAT DEREGULATION OF IMPRINTING THROUGH A GENERAL EFFECT ON DMR METHYLATION IS UNLIKELY TO BE A COMMON FACTOR IN DEVELOPMENTAL PROGRAMMING. 2012 3 6133 46 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 4 6094 50 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 5 4496 41 MORE THAN GENES: THE ADVANCED FETAL PROGRAMMING HYPOTHESIS. MANY LINES OF DATA, INITIAL EPIDEMIOLOGIC STUDIES AS WELL AS SUBSEQUENT EXTENSIVE EXPERIMENTAL STUDIES, INDICATE THAT EARLY-LIFE EVENTS PLAY A POWERFUL ROLE IN INFLUENCING LATER SUCEPTIBILITY TO CERTAIN CHRONIC DISEASES. SUCH EVENTS MIGHT BE OVER- OR UNDERNUTRITION, EXPOSURE TO ENVIRONMENTAL TOXINS, BUT ALSO CHANGES IN HORMONES, IN PARTICULAR STRESS HORMONES. TYPICALLY, THOSE EVENTS ARE TRIGGERED BY THE ENVIRONMENTAL CHALLENGES OF THE MOTHER. HOWEVER, RECENT STUDIES HAVE SHOWN THAT PATERNAL ENVIRONMENTAL OR NUTRITIONAL FACTORS AFFECT THE PHENOTYPE OF THE OFFSPRING AS WELL. THE MATERNAL AND PATERNAL ENVIRONMENTAL FACTORS ACT ON THE PHENOTYPE OF THE OFFSPRING VIA EPIGENETIC MODIFICATION OF ITS GENOME. THE ADVANCED FETAL PROGRAMMING HYPOTHESIS PROPOSES AN ADDITIONAL NON-ENVIRONMENTALLY DRIVEN MECHANISM: MATERNAL AND ALSO PATERNAL GENES MAY INFLUENCE THE MATURATING SPERM, THE OOCYTE, AND LATER THE EMBRYO/FETUS, LEADING TO THEIR EPIGENETIC ALTERATION. THUS, THE OBSERVED PHENOTYPE OF THE OFFSPRING MAY BE ALTERED BY MATERNAL/PATERNAL GENES INDEPENDENT OF THE FETAL GENOME. MEANWHILE, SEVERAL INDEPENDENT ASSOCIATION STUDIES IN HUMANS DEALING WITH METABOLIC AND NEUROLOGICAL TRAITS ALSO SUGGEST THAT MATERNAL GENES MIGHT AFFECT THE OFFSPRING PHENOTYPE INDEPENDENT OF THE TRANSMISSION OF THAT PARTICULAR GENE TO THE OFFSPRING. CONSIDERING THE IMPLICATIONS OF THIS HYPOTHESIS, SOME CONCLUSIONS DRAWN FROM TRANSGENIC OR KNOCKOUT ANIMAL MODELS AND BASED ON THE CAUSALITY BETWEEN A GENETIC ALTERATION AND A PHENOTYPE, NEED TO BE CHALLENGED. POSSIBLE IMPLICATIONS FOR THE DEVELOPMENT, DIAGNOSTIC AND THERAPY OF HUMAN GENETIC DISEASES HAVE TO BE INVESTIGATED. 2014 6 2833 31 FOLATE AND DNA METHYLATION: A REVIEW OF MOLECULAR MECHANISMS AND THE EVIDENCE FOR FOLATE'S ROLE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION CRITICAL TO NORMAL GENOME REGULATION AND DEVELOPMENT. THE VITAMIN FOLATE IS A KEY SOURCE OF THE ONE CARBON GROUP USED TO METHYLATE DNA. BECAUSE NORMAL MAMMALIAN DEVELOPMENT IS DEPENDENT ON DNA METHYLATION, THERE IS ENORMOUS INTEREST IN ASSESSING THE POTENTIAL FOR CHANGES IN FOLATE INTAKE TO MODULATE DNA METHYLATION BOTH AS A BIOMARKER FOR FOLATE STATUS AND AS A MECHANISTIC LINK TO DEVELOPMENTAL DISORDERS AND CHRONIC DISEASES INCLUDING CANCER. THIS REVIEW HIGHLIGHTS THE ROLE OF DNA METHYLATION IN NORMAL GENOME FUNCTION, HOW IT CAN BE ALTERED, AND THE EVIDENCE OF THE ROLE OF FOLATE/FOLIC ACID IN THESE PROCESSES. 2012 7 48 48 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 8 2183 43 EPIGENETIC MECHANISMS RESPONSIBLE FOR THE TRANSGENERATIONAL INHERITANCE OF INTRAUTERINE GROWTH RESTRICTION PHENOTYPES. A POORLY FUNCTIONING PLACENTA RESULTS IN IMPAIRED EXCHANGES OF OXYGEN, NUTRITION, WASTES AND HORMONES BETWEEN THE MOTHER AND HER FETUS. THIS CAN LEAD TO RESTRICTION OF FETAL GROWTH. THESE GROWTH RESTRICTED BABIES ARE AT INCREASED RISK OF DEVELOPING CHRONIC DISEASES, SUCH AS TYPE-2 DIABETES, HYPERTENSION, AND KIDNEY DISEASE, LATER IN LIFE. ANIMAL STUDIES HAVE SHOWN THAT GROWTH RESTRICTED PHENOTYPES ARE SEX-DEPENDENT AND CAN BE TRANSMITTED TO SUBSEQUENT GENERATIONS THROUGH BOTH THE PATERNAL AND MATERNAL LINEAGES. ALTERED EPIGENETIC MECHANISMS, SPECIFICALLY CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS THAT REGULATE EXPRESSION OF GENES THAT ARE IMPORTANT FOR FETAL DEVELOPMENT HAVE BEEN SHOWN TO BE ASSOCIATED WITH THE TRANSMISSION PATTERN OF GROWTH RESTRICTED PHENOTYPES. THIS REVIEW WILL DISCUSS THE SUBSEQUENT HEALTH OUTCOMES IN THE OFFSPRING AFTER GROWTH RESTRICTION AND THE TRANSMISSION PATTERNS OF THESE DISEASES. EVIDENCE OF ALTERED EPIGENETIC MECHANISMS IN ASSOCIATION WITH FETAL GROWTH RESTRICTION WILL ALSO BE REVIEWED. 2022 9 4788 51 NUTRITION, EPIGENETICS, AND METABOLIC SYNDROME. SIGNIFICANCE: EPIDEMIOLOGICAL AND ANIMAL STUDIES HAVE DEMONSTRATED A CLOSE LINK BETWEEN MATERNAL NUTRITION AND CHRONIC METABOLIC DISEASE IN CHILDREN AND ADULTS. COMPELLING EXPERIMENTAL RESULTS ALSO INDICATE THAT ADVERSE EFFECTS OF INTRAUTERINE GROWTH RESTRICTION ON OFFSPRING CAN BE CARRIED FORWARD TO SUBSEQUENT GENERATIONS THROUGH COVALENT MODIFICATIONS OF DNA AND CORE HISTONES. RECENT ADVANCES: DNA METHYLATION IS CATALYZED BY S-ADENOSYLMETHIONINE-DEPENDENT DNA METHYLTRANSFERASES. METHYLATION, DEMETHYLATION, ACETYLATION, AND DEACETYLATION OF HISTONE PROTEINS ARE PERFORMED BY HISTONE METHYLTRANSFERASE, HISTONE DEMETHYLASE, HISTONE ACETYLTRANSFERASE, AND HISTONE DEACETYLTRANSFERASE, RESPECTIVELY. HISTONE ACTIVITIES ARE ALSO INFLUENCED BY PHOSPHORYLATION, UBIQUITINATION, ADP-RIBOSYLATION, SUMOYLATION, AND GLYCOSYLATION. METABOLISM OF AMINO ACIDS (GLYCINE, HISTIDINE, METHIONINE, AND SERINE) AND VITAMINS (B6, B12, AND FOLATE) PLAYS A KEY ROLE IN PROVISION OF METHYL DONORS FOR DNA AND PROTEIN METHYLATION. CRITICAL ISSUES: DISRUPTION OF EPIGENETIC MECHANISMS CAN RESULT IN OXIDATIVE STRESS, OBESITY, INSULIN RESISTANCE, DIABETES, AND VASCULAR DYSFUNCTION IN ANIMALS AND HUMANS. DESPITE A RECOGNIZED ROLE FOR EPIGENETICS IN FETAL PROGRAMMING OF METABOLIC SYNDROME, RESEARCH ON THERAPIES IS STILL IN ITS INFANCY. POSSIBLE INTERVENTIONS INCLUDE: 1) INHIBITION OF DNA METHYLATION, HISTONE DEACETYLATION, AND MICRORNA EXPRESSION; 2) TARGETING EPIGENETICALLY DISTURBED METABOLIC PATHWAYS; AND 3) DIETARY SUPPLEMENTATION WITH FUNCTIONAL AMINO ACIDS, VITAMINS, AND PHYTOCHEMICALS. FUTURE DIRECTIONS: MUCH WORK IS NEEDED WITH ANIMAL MODELS TO UNDERSTAND THE BASIC MECHANISMS RESPONSIBLE FOR THE ROLES OF SPECIFIC NUTRIENTS IN FETAL AND NEONATAL PROGRAMMING. SUCH NEW KNOWLEDGE IS CRUCIAL TO DESIGN EFFECTIVE THERAPEUTIC STRATEGIES FOR PREVENTING AND TREATING METABOLIC ABNORMALITIES IN OFFSPRING BORN TO MOTHERS WITH A PREVIOUS EXPERIENCE OF MALNUTRITION. 2012 10 315 41 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS. 2013 11 4767 43 NUCLEAR AND MITOCHONDRIAL DNA ALTERATIONS IN NEWBORNS WITH PRENATAL EXPOSURE TO CIGARETTE SMOKE. NEWBORNS EXPOSED TO MATERNAL CIGARETTE SMOKE (CS) IN UTERO HAVE AN INCREASED RISK OF DEVELOPING CHRONIC DISEASES, CANCER, AND ACQUIRING DECREASED COGNITIVE FUNCTION IN ADULTHOOD. ALTHOUGH THE LITERATURE REPORTS MANY DELETERIOUS EFFECTS ASSOCIATED WITH MATERNAL CIGARETTE SMOKING ON THE FETUS, THE MOLECULAR ALTERATIONS AND MECHANISMS OF ACTION ARE NOT YET CLEAR. SMOKING MAY ACT DIRECTLY ON NUCLEAR DNA BY INDUCING MUTATIONS OR EPIGENETIC MODIFICATIONS. RECENT STUDIES ALSO INDICATE THAT SMOKING MAY ACT ON MITOCHONDRIAL DNA BY INDUCING A CHANGE IN THE NUMBER OF COPIES TO MAKE UP FOR THE DAMAGE CAUSED BY SMOKING ON THE RESPIRATORY CHAIN AND LACK OF ENERGY. IN ADDITION, INDIVIDUAL GENETIC SUSCEPTIBILITY PLAYS A SIGNIFICANT ROLE IN DETERMINING THE EFFECTS OF SMOKING DURING DEVELOPMENT. FURTHERMORE, PRIOR EXPOSURE OF PATERNAL AND MATERNAL GAMETES TO CIGARETTE SMOKE MAY AFFECT THE HEALTH OF THE DEVELOPING INDIVIDUAL, NOT ONLY THE IN UTERO EXPOSURE. THIS REVIEW EXAMINES THE GENETIC AND EPIGENETIC ALTERATIONS IN NUCLEAR AND MITOCHONDRIAL DNA ASSOCIATED WITH SMOKE EXPOSURE DURING THE MOST SENSITIVE PERIODS OF DEVELOPMENT (PRIOR TO CONCEPTION, PRENATAL AND EARLY POSTNATAL) AND ASSESSES HOW SUCH CHANGES MAY HAVE CONSEQUENCES FOR BOTH FETAL GROWTH AND DEVELOPMENT. 2015 12 6063 38 THE DEVELOPMENTAL ENVIRONMENT, EPIGENETIC BIOMARKERS AND LONG-TERM HEALTH. EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES HAS SHOWN THAT THE PRENATAL AND EARLY POSTNATAL ENVIRONMENTS INFLUENCE SUSCEPTIBILITY TO CHRONIC DISEASE IN LATER LIFE AND SUGGESTS THAT EPIGENETIC PROCESSES ARE AN IMPORTANT MECHANISM BY WHICH THE ENVIRONMENT ALTERS LONG-TERM DISEASE RISK. EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNAS, PLAY A CENTRAL ROLE IN REGULATING GENE EXPRESSION. THE EPIGENOME IS HIGHLY SENSITIVE TO ENVIRONMENTAL FACTORS IN EARLY LIFE, SUCH AS NUTRITION, STRESS, ENDOCRINE DISRUPTION AND POLLUTION, AND CHANGES IN THE EPIGENOME CAN INDUCE LONG-TERM CHANGES IN GENE EXPRESSION AND PHENOTYPE. IN THIS REVIEW WE FOCUS ON HOW THE EARLY LIFE NUTRITIONAL ENVIRONMENT CAN ALTER THE EPIGENOME LEADING TO AN ALTERED SUSCEPTIBILITY TO DISEASE IN LATER LIFE. 2015 13 1155 46 CONSIDERING MATERNAL DIETARY MODULATORS FOR EPIGENETIC REGULATION AND PROGRAMMING OF THE FETAL EPIGENOME. FETAL LIFE IS CHARACTERIZED BY A TREMENDOUS PLASTICITY AND ABILITY TO RESPOND TO VARIOUS ENVIRONMENTAL AND LIFESTYLE FACTORS, INCLUDING MATERNAL NUTRITION. IDENTIFICATION OF THE ROLE OF DIETARY FACTORS THAT CAN MODULATE AND RESHAPE THE CELLULAR EPIGENOME DURING DEVELOPMENT, INCLUDING METHYL GROUP DONORS (E.G., FOLATE, CHOLINE) AND BIOACTIVE COMPOUNDS (E.G., POLYPHENOLS) IS OF GREAT IMPORTANCE; HOWEVER, THERE IS INSUFFICIENT KNOWLEDGE OF A PARTICULAR EFFECT OF EACH TYPE OF MODULATOR AND/OR THEIR COMBINATION ON FETAL LIFE. TO ENHANCE THE QUALITY AND SAFETY OF FOOD PRODUCTS FOR PROPER FETAL HEALTH AND DISEASE PREVENTION IN LATER LIFE, A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS OF DIETARY EPIGENETIC MODULATORS DURING THE CRITICAL PRENATAL PERIOD IS NECESSARY. THIS REVIEW FOCUSES ON THE INFLUENCE OF MATERNAL DIETARY COMPONENTS ON DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS, AND SUMMARIZES CURRENT KNOWLEDGE OF THE EFFECT AND IMPORTANCE OF DIETARY COMPONENTS ON EPIGENETIC MECHANISMS THAT CONTROL THE PROPER EXPRESSION OF GENETIC INFORMATION. EVIDENCE REVEALS THAT SOME COMPONENTS IN THE MATERNAL DIET CAN DIRECTLY OR INDIRECTLY AFFECT EPIGENETIC MECHANISMS. UNDERSTANDING THE UNDERLYING MECHANISMS OF HOW EARLY-LIFE NUTRITIONAL ENVIRONMENT AFFECTS THE EPIGENOME DURING DEVELOPMENT IS OF GREAT IMPORTANCE FOR THE SUCCESSFUL PREVENTION OF ADULT CHRONIC DISEASES THROUGH OPTIMAL MATERNAL NUTRITION. 2015 14 3210 37 HEALTH EFFECTS ASSOCIATED WITH PRE- AND PERINATAL EXPOSURE TO ARSENIC. INORGANIC ARSENIC IS A WELL-ESTABLISHED HUMAN CARCINOGEN, ABLE TO INDUCE GENETIC AND EPIGENETIC ALTERATIONS. MORE THAN 200 MILLION PEOPLE WORLDWIDE ARE EXPOSED TO ARSENIC CONCENTRATIONS IN DRINKING WATER EXCEEDING THE RECOMMENDED WHO THRESHOLD (10MUG/L). ADDITIONALLY, CHRONIC EXPOSURE TO LEVELS BELOW THIS THRESHOLD IS KNOWN TO RESULT IN LONG-TERM HEALTH EFFECTS IN HUMANS. THE ARSENIC-RELATED HEALTH EFFECTS IN HUMANS ARE ASSOCIATED WITH ITS BIOTRANSFORMATION PROCESS, WHEREBY THE RESULTING METABOLITES CAN INDUCE MOLECULAR DAMAGE THAT ACCUMULATES OVER TIME. THE EFFECTS DERIVED FROM THESE ALTERATIONS INCLUDE GENOMIC INSTABILITY ASSOCIATED WITH OXIDATIVE DAMAGE, ALTERATION OF GENE EXPRESSION (INCLUDING CODING AND NON-CODING RNAS), GLOBAL AND LOCALIZED EPIGENETIC REPROGRAMMING, AND HISTONE POSTTRANSLATIONAL MODIFICATIONS. THESE ALTERATIONS DIRECTLY AFFECT MOLECULAR PATHWAYS INVOLVED IN THE ONSET AND PROGRESSION OF MANY CONDITIONS THAT CAN ARISE EVEN DECADES AFTER THE EXPOSURE OCCURS. IMPORTANTLY, ARSENIC METABOLITES GENERATED DURING ITS BIOTRANSFORMATION CAN ALSO PASS THROUGH THE PLACENTAL BARRIER, RESULTING IN FETAL EXPOSURE TO THIS CARCINOGEN AT SIMILAR LEVELS TO THOSE OF THE MOTHER. AS SUCH, MORE IMMEDIATE EFFECTS OF THE ARSENIC-INDUCED MOLECULAR DAMAGE CAN BE OBSERVED AS DETRIMENTAL EFFECTS ON FETAL DEVELOPMENT, PREGNANCY, AND BIRTH OUTCOMES. IN THIS REVIEW, WE FOCUS ON THE GENETIC AND EPIGENETIC DAMAGE ASSOCIATED WITH EXPOSURE TO LOW LEVELS OF ARSENIC, PARTICULARLY THOSE AFFECTING EARLY DEVELOPMENTAL STAGES. WE ALSO PRESENT HOW THESE ALTERATIONS OCCURRING DURING EARLY LIFE CAN IMPACT THE DEVELOPMENT OF CERTAIN DISEASES IN ADULT LIFE. 2021 15 3848 34 IS EPIGENETICS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE? BACKGROUND: EPIGENETIC MECHANISMS PROVIDE ONE POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL INFLUENCES IN EARLY LIFE CAUSE LONG-TERM CHANGES IN CHRONIC DISEASE SUSCEPTIBILITY. WHEREAS EPIGENETIC DYSREGULATION IS INCREASINGLY IMPLICATED IN VARIOUS RARE DEVELOPMENTAL SYNDROMES AND CANCER, THE ROLE OF EPIGENETICS IN COMPLEX CHRONIC DISEASES, SUCH AS CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND OBESITY, REMAINS LARGELY UNCHARACTERIZED. EXTENSIVE WORK IN ANIMAL MODELS IS REQUIRED TO DEVELOP SPECIFIC HYPOTHESES THAT CAN BE PRACTICABLY TESTED IN HUMANS. ANIMAL MODELS: WE HAVE DEVELOPED A MOUSE MODEL SHOWING THAT METHYL DONOR SUPPLEMENTATION PREVENTS TRANSGENERATIONAL AMPLIFICATION OF OBESITY, SUGGESTING A ROLE FOR DNA METHYLATION IN THE DEVELOPMENTAL ESTABLISHMENT OF BODY WEIGHT REGULATION. CONCLUSIONS: COUPLING SUCH MODELS WITH RECENTLY DEVELOPED EPIGENOMIC TECHNOLOGIES SHOULD ULTIMATELY ENABLE US TO DETERMINE IF EPIGENETICS IS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE. 2009 16 1609 36 DNA METHYLATION-INDEPENDENT GROWTH RESTRICTION AND ALTERED DEVELOPMENTAL PROGRAMMING IN A MOUSE MODEL OF PRECONCEPTION MALE ALCOHOL EXPOSURE. THE PRECONCEPTION ENVIRONMENT IS A SIGNIFICANT MODIFIER OF DYSGENESIS AND THE DEVELOPMENT OF ENVIRONMENTALLY-INDUCED DISEASE. TO DATE, FETAL ALCOHOL SPECTRUM DISORDERS (FASDS) HAVE BEEN EXCLUSIVELY ASSOCIATED WITH MATERNAL EXPOSURES, YET EMERGING EVIDENCE SUGGESTS MALE-INHERITED ALTERATIONS IN THE DEVELOPMENTAL PROGRAM OF SPERM MAY BE RELEVANT TO THE GROWTH-RESTRICTION PHENOTYPES OF THIS CONDITION. USING A MOUSE MODEL OF VOLUNTARY CONSUMPTION, WE FIND CHRONIC PRECONCEPTION MALE ETHANOL EXPOSURE ASSOCIATES WITH FETAL GROWTH RESTRICTION, DECREASED PLACENTAL EFFICIENCY, ABNORMALITIES IN CHOLESTEROL TRAFFICKING, SEX-SPECIFIC ALTERATIONS IN THE GENETIC PATHWAYS REGULATING HEPATIC FIBROSIS, AND DISRUPTIONS IN THE REGULATION OF IMPRINTED GENES. ALTERATIONS IN THE DNA METHYLATION PROFILES OF IMPRINTED LOCI HAVE BEEN IDENTIFIED IN CLINICAL STUDIES OF ALCOHOLIC SPERM, SUGGESTING THE LEGACY OF PATERNAL DRINKING MAY TRANSMIT VIA HERITABLE DISRUPTIONS IN THE REGULATION OF IMPRINTED GENES. HOWEVER, THE CAPACITY OF SPERM-INHERITED CHANGES IN DNA METHYLATION TO BROADLY TRANSMIT ENVIRONMENTALLY-INDUCED PHENOTYPES REMAINS UNCONFIRMED. USING BISULPHITE MUTAGENESIS AND SECOND-GENERATION DEEP SEQUENCING, WE FIND NO EVIDENCE TO SUGGEST THAT THESE PHENOTYPES OR ANY OF THE ASSOCIATED TRANSCRIPTIONAL CHANGES ARE LINKED TO ALTERATIONS IN THE SPERM-INHERITED DNA METHYLATION PROFILE. THESE OBSERVATIONS ARE CONSISTENT WITH RECENT STUDIES EXAMINING THE MALE TRANSMISSION OF DIET-INDUCED PHENOTYPES AND EMPHASIZE THE IMPORTANCE OF EPIGENETIC MECHANISMS OF PATERNAL INHERITANCE BEYOND DNA METHYLATION. THIS STUDY CHALLENGES THE SINGULAR IMPORTANCE OF MATERNAL ALCOHOL EXPOSURES AND SUGGESTS PATERNAL ALCOHOL ABUSE IS A SIGNIFICANT, YET OVERLOOKED EPIDEMIOLOGICAL FACTOR COMPLICIT IN THE GENESIS OF ALCOHOL-INDUCED GROWTH DEFECTS, AND MAY PROVIDE MECHANISTIC INSIGHT INTO THE FAILURE OF FASD CHILDREN TO THRIVE POSTNATALLY. 2017 17 1974 42 EPIGENETIC ALTERATIONS CAUSED BY NUTRITIONAL STRESS DURING FETAL PROGRAMMING OF THE ENDOCRINE PANCREAS. NUTRITION DURING CRITICAL PERIODS OF DEVELOPMENT IS ONE OF THE PIVOTAL FACTORS IN ESTABLISHING A LIFELONG HEALTHY METABOLISM. DIFFERENT NUTRITIONAL DEFICIENCIES SUCH AS A LOW AVAILABILITY OF PROTEINS IN THE MATERNAL DIET PRODUCE ALTERATIONS IN OFFSPRING THAT INCLUDE CHANGES IN INSULIN AND GLUCOSE METABOLISM, A DECREASE IN THE SIZE AND NUMBER OF CELLS OF PANCREATIC ISLETS OF LANGERHANS, AND PREMATURE AGEING OF THE SECRETORY FUNCTION OF PANCREATIC BETA CELLS. MOREOVER, IT HAS BEEN REPORTED THAT CHRONIC NUTRITIONAL STRESS IS ASSOCIATED WITH EPIGENETIC ALTERATIONS IN MECHANISMS OF GENE REGULATION DURING PANCREATIC DEVELOPMENT AND FUNCTION. THESE ALTERATIONS CAN LEAD TO DYSFUNCTIONAL STATES IN PANCREATIC BETA CELLS, WHICH IN THE LONG RUN ARE RESPONSIBLE FOR THE ONSET OF METABOLIC DISEASES LIKE TYPE 2 DIABETES. THE PRESENT REVIEW SUMMARIZES THE MOST IMPORTANT EVIDENCE IN RELATION TO THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE REGULATION OF GENE EXPRESSION DURING THE INTRAUTERINE PROGRAMMING OF THE ENDOCRINE PANCREAS IN ANIMAL MODELS. SUCH MECHANISMS INCLUDE DNA METHYLATION AS WELL AS MODIFICATIONS OF HISTONES AND MICRORNAS (MIRNAS). 2015 18 5569 44 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 19 1929 44 ENVIRONMENTAL EXPOSURE, DNA METHYLATION, AND GENE REGULATION: LESSONS FROM DIETHYLSTILBESTEROL-INDUCED CANCERS. DNA METHYLATION IS AN EPIGENETIC MECHANISM THAT REGULATES CHROMOSOMAL STABILITY AND GENE EXPRESSION. ABNORMAL DNA METHYLATION PATTERNS HAVE BEEN OBSERVED IN MANY TYPES OF HUMAN TUMORS, INCLUDING THOSE OF THE BREAST, PROSTATE, COLON, THYROID, STOMACH, UTERUS, AND CERVIX. WE AND OTHERS HAVE SHOWN THAT EXPOSURE TO A WIDE VARIETY OF XENOBIOTICS DURING CRITICAL PERIODS OF MAMMALIAN DEVELOPMENT CAN PERSISTENTLY ALTER THE PATTERN OF DNA METHYLATION, RESULTING IN POTENTIALLY ADVERSE BIOLOGICAL EFFECTS SUCH AS ABERRANT GENE EXPRESSION. THUS, THIS EPIGENETIC MECHANISM MAY UNDERLIE THE OBSERVED INCREASED RISK IN ADULTHOOD OF SEVERAL CHRONIC DISEASES, INCLUDING CANCER, IN RESPONSE TO XENOBIOTIC EXPOSURES EARLY IN LIFE. WE PRESENT HERE THE LESSONS LEARNED FROM STUDIES ON THE EFFECTS OF PERINATAL DIETHYLSTILBESTEROL (DES) EXPOSURE ON THE METHYLATION PATTERN OF THE PROMOTERS OF SEVERAL ESTROGEN-RESPONSIVE GENES ASSOCIATED WITH THE DEVELOPMENT OF REPRODUCTIVE ORGANS. PERINATAL DES EXPOSURE, WHICH INDUCES EPITHELIAL TUMORS OF THE UTERUS IN MICE AND IS ASSOCIATED WITH SEVERAL REPRODUCTIVE TRACT ABNORMALITIES AND INCREASED VAGINAL AND CERVICAL CANCER RISK IN WOMEN, PROVIDES A CLEAR EXAMPLE OF HOW ESTROGENIC XENOBIOTIC EXPOSURE DURING A CRITICAL PERIOD OF DEVELOPMENT CAN ABNORMALLY DEMETHYLATE DNA SEQUENCES DURING ORGAN DEVELOPMENT AND POSSIBLY INCREASE CANCER RISK LATER IN LIFE. IN ADDITION, NUTRITIONAL FACTORS AND STRESS MAY ALSO ALTER DNA METHYLATION DURING EARLY LIFE AND MODULATE THE RISK OF CANCER AND OTHER CHRONIC DISEASES IN ADULTHOOD. WE SUGGEST THAT DNA METHYLATION STATUS MAY BE INFLUENCED BY ENVIRONMENTAL EXPOSURES IN EARLY LIFE, LEADING TO INCREASED RISK OF CANCER IN ADULTHOOD. 2003 20 2184 39 EPIGENETIC MECHANISMS THAT UNDERPIN METABOLIC AND CARDIOVASCULAR DISEASES. CELLULAR COMMITMENT TO A SPECIFIC LINEAGE IS CONTROLLED BY DIFFERENTIAL SILENCING OF GENES, WHICH IN TURN DEPENDS ON EPIGENETIC PROCESSES SUCH AS DNA METHYLATION AND HISTONE MODIFICATION. DURING EARLY EMBRYOGENESIS, THE MAMMALIAN GENOME IS 'WIPED CLEAN' OF MOST EPIGENETIC MODIFICATIONS, WHICH ARE PROGRESSIVELY RE-ESTABLISHED DURING EMBRYONIC DEVELOPMENT. THUS, THE EPIGENOME OF EACH MATURE CELLULAR LINEAGE CARRIES THE RECORD OF ITS DEVELOPMENTAL HISTORY. THE SUBSEQUENT TRAJECTORY AND PATTERN OF DEVELOPMENT ARE ALSO RESPONSIVE TO ENVIRONMENTAL INFLUENCES, AND SUCH PLASTICITY IS LIKELY TO HAVE AN EPIGENETIC BASIS. EPIGENETIC MARKS MAY BE TRANSMITTED ACROSS GENERATIONS, EITHER DIRECTLY BY PERSISTING THROUGH MEIOSIS OR INDIRECTLY THROUGH REPLICATION IN THE NEXT GENERATION OF THE CONDITIONS IN WHICH THE EPIGENETIC CHANGE OCCURRED. DEVELOPMENTAL PLASTICITY EVOLVED TO MATCH AN ORGANISM TO ITS ENVIRONMENT, AND A MISMATCH BETWEEN THE PHENOTYPIC OUTCOME OF ADAPTIVE PLASTICITY AND THE CURRENT ENVIRONMENT INCREASES THE RISK OF METABOLIC AND CARDIOVASCULAR DISEASE. THESE CONSIDERATIONS POINT TO EPIGENETIC PROCESSES AS A KEY MECHANISM THAT UNDERPINS THE DEVELOPMENTAL ORIGINS OF CHRONIC NONCOMMUNICABLE DISEASE. HERE, WE REVIEW THE EVIDENCE THAT ENVIRONMENTAL INFLUENCES DURING MAMMALIAN DEVELOPMENT LEAD TO STABLE CHANGES IN THE EPIGENOME THAT ALTER THE INDIVIDUAL'S SUSCEPTIBILITY TO CHRONIC METABOLIC AND CARDIOVASCULAR DISEASE, AND DISCUSS THE CLINICAL IMPLICATIONS. 2009