1 1927 147 ENVIRONMENTAL EPIGENOMICS AND DISEASE SUSCEPTIBILITY. KEYSTONE SYMPOSIA ON MOLECULAR AND CELLULAR BIOLOGY. THE GROVE PARK HOTEL & SPA, ASHVILLE, NC, USA, 27 MARCH-1 APRIL 2011. THE MAIN OBJECTIVE OF THIS CONFERENCE WAS TO PROVIDE SOLID EVIDENCE THAT ENVIRONMENTAL EXPOSURES DURING EARLY DEVELOPMENT CAN AFFECT FAITHFUL REPRODUCTION OF INDIVIDUAL PARENTAL EPIGENOMES WITHOUT CHANGING DNA SEQUENCE IN THE OFFSPRING. NO DOUBT, THIS IMPORTANT GOAL HAS BEEN SUCCESSFULLY ACHIEVED OWING TO THE HIGH QUALITY OF PRESENTED EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES AND ENGAGING DISCUSSIONS OF MANY YET TO BE PUBLISHED RESULTS. COMPELLING DATA SUGGESTED A STRONG CAUSAL LINK BETWEEN PRENATAL VULNERABILITY OF FUTURE PARENTAL EPIGENOMES TO DAMAGING ENVIRONMENTAL FACTORS AGGRAVATED BY ABNORMAL SOCIO-CULTURAL CONDITIONS (INCLUDING, FOR INSTANCE, MALNUTRITION AND CHRONIC STRESS) AND THE ALARMING RISK OF DEVELOPING HERITABLE COMPLEX MEDICAL CONDITIONS LATER IN LIFE, SUCH AS ASTHMA, AUTISM, CANCER, CARDIOVASCULAR DISEASE, DIABETES, OBESITY, SCHIZOPHRENIA AND A WHOLE RANGE OF RARE NEUROMUSCULAR PATHOLOGIES. IT WAS CONCLUDED THAT MODERN EPIGENETIC RESEARCH PROMISES TO MARKEDLY IMPROVE OUR ABILITY TO DIAGNOSE, PREVENT AND TREAT THESE AND OTHER PATHOLOGICAL CONDITIONS OF HUMANS. HOWEVER, THE COMPLEX HERITABILITY PATTERN OF 'EPIGENETIC SYNDROMES' ALSO INTRODUCES UNIQUE LEGAL AND ETHICAL ISSUES THAT WERE DISCUSSED AT THE END OF THIS OUTSTANDING MEETING. 2011 2 1749 30 EARLY LIFE INTERVENTIONS CAN SHAPE AGING. IT IS WELL DOCUMENTED THAT THE ENVIRONMENT OF THE DEVELOPING FETUS, INCLUDING AVAILABILITY OF NUTRIENTS AND PRESENCE OF TOXINS, CAN HAVE MAJOR IMPACT ON ADULT PHENOTYPE, AGE-RELATED TRAITS AND RISK OF CHRONIC DISEASE. THERE IS ALSO ACCUMULATING EVIDENCE THAT POSTNATAL ENVIRONMENT CAN IMPACT ADULT CHARACTERISTICS RELATED TO EVOLUTIONARY FITNESS, HEALTH, AND AGING. TO DETERMINE WHETHER EARLY LIFE HORMONAL INTERVENTIONS CAN ALTER TRAJECTORY OF AGING, WE HAVE EXAMINED THE EFFECTS OF EARLY LIFE GROWTH HORMONE (GH) REPLACEMENT THERAPY IN PROP1(DF) (AMES DWARF) MICE WHICH ARE GH DEFICIENT AND REMARKABLY LONG LIVED. TWICE-DAILY GH INJECTIONS BETWEEN THE AGES OF TWO AND EIGHT WEEKS COMPLETELY NORMALIZED ("RESCUED") A NUMBER OF ADULT METABOLIC CHARACTERISTICS BELIEVED TO CONTRIBUTE TO EXTENDED LONGEVITY OF THESE MUTANTS. IMPORTANTLY, LONGEVITY OF AMES DWARF MICE WAS REDUCED BY EARLY LIFE GH TREATMENT. THIS WAS ASSOCIATED WITH HISTONE H3 MODIFICATIONS. WE CONCLUDE THAT THE TRAJECTORY OF MAMMALIAN AGING CAN BE MODIFIED BY EARLY LIFE INTERVENTIONS. MECHANISTIC LINKS AMONG INTERVENTIONS DURING POSTNATAL DEVELOPMENT, ADULT METABOLIC CHARACTERISTICS, AGING, AND LONGEVITY, APPARENTLY INVOLVE EPIGENETIC PHENOMENA. 2022 3 4399 43 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS. 2009 4 6350 30 THE ROLE OF EPIGENOMICS IN AQUATIC TOXICOLOGY. OVER THE PAST DECADE, THE FIELD OF MOLECULAR BIOLOGY HAS RAPIDLY INCORPORATED EPIGENETIC STUDIES TO EVALUATE ORGANISM-ENVIRONMENT INTERACTIONS THAT CAN RESULT IN CHRONIC EFFECTS. SUCH RESPONSES ARISE FROM EARLY LIFE STAGE STRESS, THE UTILIZATION OF GENETIC INFORMATION OVER AN INDIVIDUAL'S LIFE TIME, AND TRANSGENERATIONAL INHERITANCE. KNOWLEDGE OF EPIGENETIC MECHANISMS PROVIDES THE POTENTIAL FOR A COMPREHENSIVE EVALUATION OF MULTIGENERATIONAL AND HERITABLE EFFECTS FROM ENVIRONMENTAL STRESSORS, SUCH AS CONTAMINANTS. FOCUSED STUDIES HAVE PROVIDED A GREATER UNDERSTANDING OF HOW MANY RESPONSES TO ENVIRONMENTAL STRESSORS ARE DRIVEN BY EPIGENETIC MODIFIERS. WE DISCUSS THE PROMISE OF EPIGENETICS AND SUGGEST FUTURE RESEARCH DIRECTIONS WITHIN THE FIELD OF AQUATIC TOXICOLOGY, WITH A PARTICULAR FOCUS ON THE POTENTIAL FOR IDENTIFYING KEY HERITABLE MARKS WITH CONSEQUENTIAL IMPACTS AT THE ORGANISM AND POPULATION LEVELS. ENVIRON TOXICOL CHEM 2017;36:2565-2573. (C) 2017 SETAC. 2017 5 6853 38 [NEUROBIOLOGY OF EARLY LIFE TRAUMATIC STRESS AND TRAUMA: PROLONGED NEUROENDOCRINE DYSREGULATION AS A NEURODEVELOPMENTAL RISK FACTOR]. EARLY LIFE STRESSORS DISPLAY A HIGH UNIVERSAL PREVALENCE AND CONSTITUTE A MAJOR PUBLIC HEALTH PROBLEM WITH TWO THIRDS OF YOUTH BEING EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS AND REPRESENTS A DEVELOPMENTAL RISK FACTOR MEDIATING RISK FOR DISEASE. EARLY-LIFE STRESS (ELS) AND CHILDHOOD TRAUMA (CT) CAN BOTH HAVE AN IMPACT ON SENSITIVE NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING LEADING TO CHRONIC HYPER- OR HYPO-ACTIVATION OF THE STRESS SYSTEM. IN ADDITION, ALTERATIONS IN EMOTIONAL AND AUTONOMIC REACTIVITY, CIRCADIAN RHYTHM DISRUPTION, FUNCTIONAL AND STRUCTURAL CHANGES IN THE BRAIN, AS WELL AS IMMUNE AND METABOLIC DYSREGULATION HAVE BEEN LATELY IDENTIFIED AS IMPORTANT RISK FACTORS FOR A CHRONICALLY IMPAIRED HOMEOSTATIC BALANCE AFTER ELS/CT. FURTHERMORE, HUMAN GENETIC BACKGROUND AND EPIGENETIC MODIFICATIONS THROUGH STRESS-RELATED GENE EXPRESSION COULD INTERACT WITH THESE ALTERATIONS AND EXPLAIN INTER-INDIVIDUAL VARIATION IN VULNERABILITY OR RESILIENCE TO STRESS. THIS NARRATIVE REVIEW PRESENTS RELEVANT EVIDENCE FROM MAINLY HUMAN RESEARCH ON THE MOST ACKNOWLEDGED NEUROBIOLOGICAL ALLOSTATIC PATHWAYS EXERTING ENDURING ADVERSE EFFECTS OF ELS/CT EVEN DECADES LATER. FUTURE STUDIES SHOULD PROSPECTIVELY INVESTIGATE POTENTIAL CONFOUNDERS, THEIR TEMPORAL SEQUENCE AND COMBINED EFFECTS AT THE BIOLOGICAL LEVEL, WHILE CONSIDERING THE POTENTIALLY DELAYED TIME-FRAME FOR THE EXPRESSION OF THEIR EFFECTS. FINALLY, SCREENING STRATEGIES FOR ELS/CT AND TRAUMA NEED TO BE IMPROVED. INFORMATION ABOUT ELS/CT HISTORY AND THE NUMBER OF ADVERSE EXPERIENCES COULD HELP TO BETTER IDENTIFY THE INDIVIDUAL RISK FOR DISEASE DEVELOPMENT, PREDICT INDIVIDUAL TREATMENT RESPONSE AND DESIGN PREVENTION STRATEGIES TO REDUCE THE NEGATIVE EFFECTS OF ELS/CT. 2023 6 650 22 BISPHENOL A AND HUMAN CHRONIC DISEASES: CURRENT EVIDENCES, POSSIBLE MECHANISMS, AND FUTURE PERSPECTIVES. BISPHENOL-A (BPA) IS ONE OF THE HIGHEST VOLUME CHEMICALS PRODUCED WORLDWIDE, WITH OVER 6BILLION POUNDS PRODUCED AND OVER 100T RELEASED INTO THE ATMOSPHERE EACH YEAR. RECENT EXTENSIVE LITERATURE HAS RAISED CONCERNS ABOUT ITS POSSIBLE IMPLICATION IN THE ETIOLOGY OF SOME HUMAN CHRONIC DISEASES SUCH AS DIABETES, OBESITY, REPRODUCTIVE DISORDERS, CARDIOVASCULAR DISEASES, BIRTH DEFECTS, CHRONIC RESPIRATORY AND KIDNEY DISEASES AND BREAST CANCER. IN THIS REVIEW, WE PRESENT THE HIGHLIGHTED EVIDENCES ON THE RELATIONSHIP BETWEEN BPA EXPOSURE AND HUMAN CHRONIC DISEASES AND WE DISCUSS ITS EVENTUAL MECHANISMS OF ACTION, ESPECIALLY GENETIC, EPIGENETIC AND ENDOCRINE DISRUPTION MECHANISMS WITH THE POSSIBLE INVOLVEMENT OF OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION AND CELL SIGNALING. 2014 7 5000 27 PERINATAL PROGRAMMING PREVENTION MEASURES. OVER THE PAST 10 YEARS, THERE HAS BEEN OUTSTANDING SCIENTIFIC PROGRESS RELATED TO PERINATAL PROGRAMMING AND ITS EPIGENETIC EFFECTS IN HEALTH, AND WE CAN ANTICIPATE THIS TREND WILL CONTINUE IN THE NEAR FUTURE. WE NEED TO MAKE USE AND APPLY THESE ACHIEVEMENTS TO HUMAN NEURODEVELOPMENT VIA PREVENTION INTERVENTIONS. BASED ON THE CONCEPT OF THE INTERACTION BETWEEN GENOME AND AMBIOME, THIS CHAPTER PROPOSES LOW-COST EASY-IMPLEMENTATION PREVENTIVE STRATEGIES FOR MATERNAL AND INFANT HEALTH INSTITUTIONS.BREASTFEEDING AND HUMAN MILK ADMINISTRATION ARE THE FIRST PREVENTIVE MEASURES, AS HAS BEEN REVIEWED IN THE POLICY STATEMENT OF THE AMERICAN ACADEMY OF PEDIATRICS. ANOTHER STRATEGY IS THE SAFE AND FAMILY-CENTERED MATERNITY HOSPITALS INITIATIVE THAT PROMOTES AND EMPOWERS THE INCLUSION OF THE FAMILIES AND THE RESPECT FOR THEIR RIGHTS, ESPECIALLY DURING PREGNANCY AND BIRTH. (THIS CHANGE OF PARADIGM WAS APPROVED AND IS RECOMMENDED BY BOTH UNITED NATIONS CHILDREN'S FUND, UNICEF, AND PAN AMERICAN HEALTH ORGANIZATION, PAHO.) THEN, THERE IS ALSO AN IMPORTANT EMPHASIS GIVEN TO THE SACRED HOUR-WHICH HIGHLIGHTS THE IMPACT OF BONDING, ATTACHMENT, AND BREASTFEEDING DURING THE FIRST HOUR OF LIFE-THE PAIN PREVENTION AND TREATMENT IN NEWBORNS, THE CONTROL OF THE "NEW MORBIDITY" REPRESENTED BY LATE PRETERM INFANTS, AND FINALLY, THE IMPORTANCE OF AVOIDING INTRAUTERINE AND EXTRAUTERINE GROWTH RESTRICTION. (HOWEVER, THERE ARE NOT YET CLEAR RECOMMENDATIONS ABOUT NUTRITIONAL INTERVENTIONS IN ORDER TO DIMINISH THE POTENTIAL METABOLIC SYNDROME CONSEQUENCE IN THE ADULT.). 2015 8 4995 37 PERINATAL ENVIRONMENT AND ITS INFLUENCES ON METABOLIC PROGRAMMING OF OFFSPRING. THE INTRAUTERINE ENVIRONMENT SUPPORTS THE DEVELOPMENT AND HEALTH OF OFFSPRING. PERTURBATIONS TO THIS ENVIRONMENT CAN HAVE DETRIMENTAL EFFECTS ON THE FETUS THAT HAVE PERSISTENT PATHOLOGICAL CONSEQUENCES THROUGH ADOLESCENCE AND ADULTHOOD. THE DEVELOPMENTAL ORIGINS OF THE HEALTH AND DISEASE CONCEPT, ALSO KNOWN AS THE "BARKER HYPOTHESIS", HAS BEEN PUT FORTH TO DESCRIBE THE INCREASED INCIDENCE OF CHRONIC DISEASE SUCH AS CARDIOVASCULAR DISEASE AND DIABETES IN HUMANS AND ANIMALS EXPOSED TO A LESS THAN IDEAL INTRAUTERINE ENVIRONMENT. MATERNAL INFECTION, POOR OR EXCESS NUTRITION, AND STRESSFUL EVENTS CAN NEGATIVELY INFLUENCE THE DEVELOPMENT OF DIFFERENT CELL TYPES, TISSUES AND ORGAN SYSTEMS ULTIMATELY PREDISPOSING THE ORGANISM TO PATHOLOGICAL CONDITIONS. ALTHOUGH THERE ARE A VARIETY OF CONDITIONS ASSOCIATED TO EXPOSURE TO ALTERED INTRAUTERINE ENVIRONMENTS, THE FOCUS OF THIS REVIEW WILL BE ON THE CONSEQUENCES OF STRESS AND HIGH FAT DIET DURING THE PRE- AND PERINATAL PERIODS AND ASSOCIATED OUTCOMES RELATED TO OBESITY AND OTHER METABOLIC CONDITIONS. WE FURTHER DISCUSS POSSIBLE NEUROENDOCRINE AND EPIGENETIC MECHANISMS RESPONSIBLE FOR THE METABOLIC PROGRAMMING OF OFFSPRING. THE PAPER REPRESENTS AN INVITED REVIEW BY A SYMPOSIUM, AWARD WINNER OR KEYNOTE SPEAKER AT THE SOCIETY FOR THE STUDY OF INGESTIVE BEHAVIOR [SSIB] ANNUAL MEETING IN PORTLAND, JULY 2009. 2010 9 705 32 BUILDING RISK-ON-A-CHIP MODELS TO IMPROVE BREAST CANCER RISK ASSESSMENT AND PREVENTION. PREVENTIVE ACTIONS FOR CHRONIC DISEASES HOLD THE PROMISE OF IMPROVING LIVES AND REDUCING HEALTHCARE COSTS. FOR SEVERAL DISEASES, INCLUDING BREAST CANCER, MULTIPLE RISK AND PROTECTIVE FACTORS HAVE BEEN IDENTIFIED BY EPIDEMIOLOGISTS. THE IMPACT OF MOST OF THESE FACTORS HAS YET TO BE FULLY UNDERSTOOD AT THE ORGANISM, TISSUE, CELLULAR AND MOLECULAR LEVELS. IMPORTANTLY, COMBINATIONS OF EXTERNAL AND INTERNAL RISK AND PROTECTIVE FACTORS INVOLVE COOPERATIVITY THUS, SYNERGIZING OR ANTAGONIZING DISEASE ONSET. MODELS ARE NEEDED TO MECHANISTICALLY DECIPHER CANCER RISKS UNDER DEFINED CELLULAR AND MICROENVIRONMENTAL CONDITIONS. HERE, WE BRIEFLY REVIEW BREAST CANCER RISK MODELS BASED ON 3D CELL CULTURE AND PROPOSE TO IMPROVE RISK MODELING WITH LAB-ON-A-CHIP APPROACHES. WE SUGGEST EPITHELIAL TISSUE POLARITY, DNA REPAIR AND EPIGENETIC PROFILES AS ENDPOINTS IN RISK ASSESSMENT MODELS AND DISCUSS THE DEVELOPMENT OF 'RISKS-ON-CHIPS' INTEGRATING BIOSENSORS OF THESE ENDPOINTS AND OF GENERAL TISSUE HOMEOSTASIS. RISKS-ON-CHIPS WILL HELP IDENTIFY BIOMARKERS OF RISK, SERVE AS SCREENING PLATFORMS FOR CANCER PREVENTIVE AGENTS, AND PROVIDE A BETTER UNDERSTANDING OF RISK MECHANISMS, HENCE RESULTING IN NOVEL DEVELOPMENTS IN DISEASE PREVENTION. 2013 10 49 27 A CURRENT GENETIC AND EPIGENETIC VIEW ON HUMAN AGING MECHANISMS. THE PROCESS OF AGING IS ONE OF THE MOST COMPLEX AND INTRIGUING BIOLOGICAL PHENOMENONS. AGING IS A GENETICALLY REGULATED PROCESS IN WHICH THE ORGANISM'S MAXIMUM LIFESPAN POTENTIAL IS PRE-DETERMINED, WHILE THE RATE OF AGING IS INFLUENCED BY ENVIRONMENTAL FACTORS AND LIFESTYLE. CONSIDERING THE COMPLEXITY OF MECHANISMS INVOLVED IN THE REGULATION OF AGING PROCESS, UP TO THIS DATE THERE ISN'T A MAJOR, UNIFYING THEORY WHICH COULD EXPLAIN THEM. AS GENETIC/EPIGENETIC AND ENVIRONMENTAL FACTORS BOTH INEVITABLY INFLUENCE THE AGING PROCESS, HERE WE PRESENT A REVIEW ON THE GENETIC AND EPIGENETIC REGULATION OF THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE PROCESS OF AGING. BASED ON THE STUDIES ON OXIDATIVE STRESS, METABOLISM, GENOME STABILITY, EPIGENETIC MODIFICATIONS AND CELLULAR SENESCENCE IN ANIMAL MODELS AND HUMANS, WE GIVE AN OVERVIEW OF KEY GENETIC AND MOLECULAR PATHWAYS RELATED TO AGING. AS MOST OF GENETIC MANIPULATIONS WHICH INFLUENCE THE AGING PROCESS ALSO AFFECT REPRODUCTION, WE DISCUSS AGING IN HUMANS AS A POST-REPRODUCTIVE GENETICALLY DETERMINED PROCESS. AFTER THE AGE OF REPRODUCTIVE SUCCESS, AGING CONTINOUSLY PROGRESSES WHICH CLINICALLY COINCIDES WITH THE ONSET OF MOST CHRONIC DISEASES, CANCERS AND DEMENTIONS. AS EVOLUTION SHAPES THE GENOMES FOR REPRODUCTIVE SUCCESS AND NOT FOR POST-REPRODUCTIVE SURVIVAL, AGING COULD BE DEFINED AS A PROTECTIVE MECHANISM WHICH ENSURES THE PRESERVATION AND PROGRESS OF SPECIES THROUGH THE MODIFICATION, TRASMISSION AND IMPROVEMENT OF GENETIC MATERIAL. 2009 11 2000 24 EPIGENETIC AND NON-CODING REGULATION OF ALCOHOL ABUSE AND ADDICTION. ALCOHOL USE DISORDER IS A CHRONIC DEBILITATED CONDITION ADVERSELY AFFECTING THE LIVES OF MILLIONS OF INDIVIDUALS THROUGHOUT THE MODERN WORLD. INDIVIDUALS SUFFERING FROM AN ALCOHOL USE DISORDER DIAGNOSIS FREQUENTLY HAVE SERIOUS COOCCURRING CONDITIONS, WHICH OFTEN FURTHER EXACERBATES PROBLEMATIC DRINKING BEHAVIOR. COMPREHENDING THE BIOCHEMICAL PROCESSES UNDERLYING THE PROGRESSION AND PERPETUATION OF DISEASE IS ESSENTIAL FOR MITIGATING MALADAPTIVE BEHAVIOR IN ORDER TO RESTORE BOTH PHYSIOLOGICAL AND PSYCHOLOGICAL HEALTH. THE RANGE OF CELLULAR AND BIOLOGICAL SYSTEMS CONTRIBUTING TO, AND AFFECTED BY, ALCOHOL USE DISORDER AND OTHER COMORBID DISORDERS NECESSITATES A FUNDAMENTAL GRASP OF INTRICATE FUNCTIONAL RELATIONSHIPS THAT GOVERN MOLECULAR BIOLOGY. EPIGENETIC FACTORS ARE RECOGNIZED AS ESSENTIAL MEDIATORS OF CELLULAR BEHAVIOR, ORCHESTRATING A SYMPHONY OF GENE EXPRESSION CHANGES WITHIN MULTICELLULAR ENVIRONMENTS THAT ARE ULTIMATELY RESPONSIBLE FOR DIRECTING HUMAN BEHAVIOR. UNDERSTANDING THE EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISMS INVOLVED IN THE PATHOGENESIS OF DISEASE IS IMPORTANT FOR IMPROVING AVAILABLE PHARMACOTHERAPIES AND REDUCING THE INCIDENCE OF ALCOHOL ABUSE AND COOCCURRING CONDITIONS. 2021 12 1865 38 EMERGING CONCEPTS ON THE ROLE OF EPIGENETICS IN THE RELATIONSHIPS BETWEEN NUTRITION AND HEALTH. UNDERSTANDING THE PHYSIOLOGICAL AND METABOLIC UNDERPINNINGS THAT CONFER INDIVIDUAL DIFFERENCES IN RESPONSES TO DIET AND DIET-RELATED CHRONIC DISEASE IS ESSENTIAL TO ADVANCE THE FIELD OF NUTRITION. THIS INCLUDES ELUCIDATING THE DIFFERENCES IN GENE EXPRESSION THAT ARE MEDIATED THROUGH PROGRAMMING OF THE GENOME THROUGH EPIGENETIC CHROMATIN MODIFICATIONS. EPIGENETIC LANDSCAPES ARE INFLUENCED BY AGE, GENETICS, TOXINS AND OTHER ENVIRONMENTAL FACTORS, INCLUDING DIETARY EXPOSURES AND NUTRITIONAL STATUS. EPIGENETIC MODIFICATIONS INFLUENCE TRANSCRIPTION AND GENOME STABILITY ARE ESTABLISHED DURING DEVELOPMENT WITH LIFE-LONG CONSEQUENCES. THEY CAN BE INHERITED FROM ONE GENERATION TO THE NEXT. THE COVALENT MODIFICATIONS OF CHROMATIN, WHICH INCLUDE METHYLATION AND ACETYLATION, ON DNA NUCLEOTIDE BASES, HISTONE PROTEINS AND RNA ARE DERIVED FROM INTERMEDIATES OF ONE-CARBON METABOLISM AND CENTRAL METABOLISM. THEY INFLUENCE KEY PHYSIOLOGICAL PROCESSES THROUGHOUT LIFE, AND TOGETHER WITH INHERITED DNA PRIMARY SEQUENCE, CONTRIBUTE TO RESPONSIVENESS TO ENVIRONMENTAL STRESSES, DIET AND RISK FOR AGE-RELATED CHRONIC DISEASE. REVEALING DIET-EPIGENETIC RELATIONSHIPS HAS THE POTENTIAL TO TRANSFORM NUTRITION SCIENCE BY INCREASING OUR FUNDAMENTAL UNDERSTANDING OF: (I) THE ROLE OF NUTRIENTS IN BIOLOGICAL SYSTEMS, (II) THE RESILIENCE OF LIVING ORGANISMS IN RESPONDING TO ENVIRONMENTAL PERTURBATIONS, AND (III) THE DEVELOPMENT OF DIETARY PATTERNS THAT PROGRAMME PHYSIOLOGY FOR LIFE-LONG HEALTH. EPIGENETICS MAY ALSO ENABLE THE CLASSIFICATION OF INDIVIDUALS WITH CHRONIC DISEASE FOR SPECIFIC DIETARY MANAGEMENT AND/OR FOR EFFICACIOUS DIET-PHARMACEUTICAL COMBINATION THERAPIES. THESE NEW EMERGING CONCEPTS AT THE INTERFACE OF NUTRITION AND EPIGENETICS WERE DISCUSSED, AND FUTURE RESEARCH NEEDS IDENTIFIED BY LEADING EXPERTS AT THE 26TH MARABOU SYMPOSIUM ENTITLED 'NUTRITION, EPIGENETICS, GENETICS: IMPACT ON HEALTH AND DISEASE'. FOR A COMPILATION OF THE GENERAL DISCUSSION AT THE MARABOU SYMPOSIUM, CLICK HERE HTTP://WWW.MARABOUSYMPOSIUM.ORG/. 2018 13 6334 25 THE ROLE OF DNA METHYLATION AND HYDROXYMETHYLATION IN IMMUNOSENESCENCE. A HEALTHY FUNCTIONING IMMUNE SYSTEM IS CRITICAL TO STAVE OFF INFECTIOUS DISEASES, BUT AS HUMANS AND OTHER ORGANISMS AGE, THEIR IMMUNE SYSTEMS DECLINE. AS A RESULT, DISEASES THAT WERE READILY THWARTED IN EARLY LIFE POSE NONTRIVIAL HARM AND CAN EVEN BE DEADLY IN LATE LIFE. IMMUNOSENESCENCE IS DEFINED AS THE GENERAL DETERIORATION OF THE IMMUNE SYSTEM WITH AGE, AND IT IS CHARACTERIZED BY FUNCTIONAL CHANGES IN HEMATOPOIETIC STEM CELLS (HSCS) AND SPECIFIC BLOOD CELL TYPES AS WELL AS CHANGES IN LEVELS OF NUMEROUS FACTORS, PARTICULARLY THOSE INVOLVED IN INFLAMMATION. POTENTIAL MECHANISMS UNDERLYING IMMUNOSENESCENCE INCLUDE EPIGENETIC CHANGES SUCH AS CHANGES IN DNA METHYLATION (DNAM) AND DNA HYDROXYMETHYLATION (DNAHM) THAT OCCUR WITH AGE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE WHAT IS CURRENTLY KNOWN ABOUT THE RELATIONSHIP BETWEEN IMMUNOSENESCENCE AND THE AGE-RELATED CHANGES TO DNAM AND DNAHM, AND TO DISCUSS EXPERIMENTAL APPROACHES BEST SUITED TO FILL GAPS IN OUR UNDERSTANDING. 2019 14 4809 33 OBESITY PREVENTION. ONCE CONSIDERED A PROBLEM ONLY IN HIGH-INCOME COUNTRIES (HICS), OBESITY HAS BECOME A MAJOR CONTRIBUTOR TO THE GLOBAL DISEASE BURDEN (FINUCANE AND OTHERS 2011; MISRA AND KHURANA 2008). EXCESS ADIPOSITY, PARTICULARLY AROUND THE VISCERAL ABDOMINAL REGION, IS AN IMPORTANT RISK FACTOR FOR MORBIDITY AND MORTALITY FROM TYPE 2 DIABETES, CARDIOVASCULAR DISEASES, AND SOME CANCERS (DANAEI AND OTHERS 2009; WHITLOCK AND OTHERS 2009; WHO 2009). ALTHOUGH SOME STUDIES HAVE SUGGESTED LOWER MORTALITY AMONG OVERWEIGHT OR OBESE PERSONS THAN AMONG HEALTHY-WEIGHT PERSONS (CARNETHON AND OTHERS 2012), THIS OUTCOME HAS NOT BEEN OBSERVED IN STUDIES THAT PROPERLY ACCOUNT FOR THE CONFOUNDING EFFECTS OF SMOKING, PREEXISTING CHRONIC CONDITIONS, AND OTHER BIASES (GLOBAL BMI MORTALITY COLLABORATION 2016; TOBIAS, PAN, AND HU 2014). THE COSTS OF OBESITY AND COMORBID CONDITIONS ARE STAGGERING AS MEASURED BY BOTH HEALTH CARE EXPENDITURES AND QUALITY OF LIFE, UNDERSCORING THE IMPORTANCE OF IMPLEMENTING OBESITY PREVENTION STRATEGIES AND TREATMENT STRATEGIES ON A GLOBAL SCALE. THE CHANGES NEEDED TO REVERSE GLOBAL TRENDS IN OBESITY WILL LIKELY REQUIRE NUMEROUS INTERVENTIONS AND POLICY RECOMMENDATIONS THAT TARGET DIET, LIFESTYLE, ACCESS TO CARE, AND ENVIRONMENTAL RISK FACTORS. IN THIS CHAPTER, WE SUMMARIZE THE GLOBAL BURDEN OF OBESITY AND THE IMPACT OF A SPECTRUM OF OBESITY RISK FACTORS, RANGING FROM SOCIOPOLITICAL AND ECONOMIC FORCES THAT ARE LARGELY BEYOND AN INDIVIDUAL'S CONTROL TO MODIFIABLE LIFESTYLE FACTORS, AND DISCUSS GENETIC AND EPIGENETIC RISKS. WE ALSO REVIEW THE EFFECTIVENESS OF POPULATION-BASED INTERVENTIONS AND POLICIES FOR PREVENTING OBESITY, SOME INDIVIDUAL-LEVEL TREATMENT OPTIONS ACROSS VARIOUS PLATFORMS, AND THE COST-EFFECTIVENESS OF SELECT INTERVENTIONS. 2017 15 6422 24 THE THIN-FAT PHENOTYPE AND GLOBAL METABOLIC DISEASE RISK. PURPOSE OF REVIEW: THERE HAS BEEN A GREAT DEAL OF INTEREST IN THE THIN-FAT PHENOTYPE EVIDENT IN ASIAN INDIANS AND ITS RISK ASSOCIATIONS IN THE EPIDEMIC OF NONCOMMUNICABLE CHRONIC DISEASE ASSOCIATED WITH IT. THE CAUSE OF THIS PHENOTYPE IS PROBABLY RELATED TO LIFESTYLE AND ENVIRONMENT; HOWEVER, GENOTYPIC AND EPIGENETIC MODIFICATIONS IN UTERO ALSO HAVE BEEN CONSIDERED. RECENT FINDINGS: THE THIN-FAT PHENOTYPE OCCURS WHEN FAT IS ADDED TO AN ALREADY THIN FRAME. THIS MAY OCCUR WITH RURAL-URBAN MIGRATION, WHEN POSITIVE ENERGY BALANCE OCCURS IN A MIGRATING POPULATION WHO WERE PREDOMINANTLY THIN AND PHYSICALLY ACTIVE TO BEGIN WITH. THE ROLE OF THE PRE-EXISTING SKELETAL MUSCLE MASS AND ITS INTERACTION WITH NEWLY DEPOSITED FAT MUST BE CONSIDERED. THE THIN-FAT PHENOTYPE MAY BE PROGRAMMED DURING FETAL GROWTH, BUT THE EVIDENCE FOR THIS PHENOMENON IS STILL NOT COMPLETELY CLEAR. FINALLY, ALTHOUGH THERE IS INCREASED CHRONIC DISEASE MORBIDITY AT LOWER BMI AND YOUNGER AGE IN SOUTH ASIAN POPULATIONS, BMI-RELATED MORTALITY DOES NOT APPEAR TO FOLLOW THIS TREND. SUMMARY: AT PRESENT, THE WEIGHT OF EVIDENCE APPEARS TO LINK THE THIN-FAT PHENOTYPE TO AN ENVIRONMENTAL AND LIFESTYLE PHENOMENON OCCURRING IN PREVIOUSLY THIN PEOPLE. THIS IS PARTICULARLY RELEVANT IN INDIA, GIVEN THE PACE OF TRANSITION OVER THE LAST TWO DECADES. 2011 16 4999 31 PERINATAL PROGRAMMING OF CIRCADIAN CLOCK-STRESS CROSSTALK. AN INTACT COMMUNICATION BETWEEN CIRCADIAN CLOCKS AND THE STRESS SYSTEM IS IMPORTANT FOR MAINTAINING PHYSIOLOGICAL HOMEOSTASIS UNDER RESTING CONDITIONS AND IN RESPONSE TO EXTERNAL STIMULI. THERE IS ACCUMULATING EVIDENCE FOR A RECIPROCAL INTERACTION BETWEEN BOTH-FROM THE SYSTEMIC TO THE MOLECULAR LEVEL. DISRUPTION OF THIS INTERACTION BY EXTERNAL FACTORS SUCH AS SHIFTWORK, JETLAG, OR CHRONIC STRESS INCREASES THE RISK OF DEVELOPING METABOLIC, IMMUNE, OR MOOD DISORDERS. FROM EXPERIMENTS IN RODENTS, WE KNOW THAT BOTH SYSTEMS MATURATE DURING THE PERINATAL PERIOD. DURING THAT TIME, EXOGENOUS FACTORS SUCH AS STRESS OR ALTERATIONS IN THE EXTERNAL PHOTOPERIOD MAY CRITICALLY AFFECT-OR PROGRAM-PHYSIOLOGICAL FUNCTIONS LATER IN LIFE. THIS DEVELOPMENTAL PROGRAMMING PROCESS HAS BEEN ATTRIBUTED TO MATERNAL STRESS SIGNALS REACHING THE EMBRYO, WHICH LASTINGLY CHANGE GENE EXPRESSION THROUGH THE INDUCTION OF EPIGENETIC MECHANISMS. DESPITE THE WELL-KNOWN FUNCTION OF THE ADULT CIRCADIAN SYSTEM IN TEMPORAL COORDINATION OF PHYSIOLOGY AND BEHAVIOR, THE ROLE OF MATERNAL AND EMBRYONIC CIRCADIAN CLOCKS DURING PREGNANCY AND POSTNATAL DEVELOPMENT IS STILL POORLY DEFINED. A BETTER UNDERSTANDING OF THE CIRCADIAN-STRESS CROSSTALK AT DIFFERENT PERIODS OF DEVELOPMENT MAY HELP TO IMPROVE STRESS RESISTANCE AND DEVISE PREVENTIVE AND THERAPEUTIC STRATEGIES AGAINST CHRONIC STRESS-ASSOCIATED DISORDERS. 2018 17 2136 34 EPIGENETIC INFLUENCES IN THE OBESITY/COLORECTAL CANCER AXIS: A NOVEL THERAGNOSTIC AVENUE. THE WORLD HEALTH ORGANIZATION (WHO) CONSIDERS THAT OBESITY HAS REACHED PROPORTIONS OF PANDEMIC. EXPERTS ALSO INSIST ON THE IMPORTANCE OF CONSIDERING OBESITY AS A CHRONIC DISEASE AND ONE OF THE MAIN CONTRIBUTORS TO THE WORLDWIDE BURDEN OF OTHER NONTRANSMISSIBLE CHRONIC DISEASES, WHICH HAVE A GREAT IMPACT ON HEALTH, LIFESTYLE, AND ECONOMIC COST. ONE OF THE MOST CURRENT CHALLENGES OF BIOMEDICAL SCIENCE FACES IS TO UNDERSTAND THE ORIGIN OF THE CHRONIC NONTRANSMISSIBLE DISEASES, SUCH AS OBESITY AND CANCER. THERE IS A LARGE EVIDENCE, BOTH IN EPIDEMIOLOGICAL STUDIES IN HUMANS AND IN ANIMAL MODELS, OF THE ASSOCIATION BETWEEN OBESITY AND AN INCREASED RISK OF CANCER INCIDENCE. IN THE LAST YEARS, THE INITIAL DISCOVERY OF EPIGENETIC MECHANISMS REPRESENTS THE MOST RELEVANT FINDING TO EXPLAIN HOW THE GENOME INTERACTS WITH ENVIRONMENTAL FACTORS AND THE RIPPLE EFFECTS ON DISEASE PATHOGENESES. SINCE THEN, ALL EPIGENETIC PROCESS HAS BEEN INVESTIGATED BY THE SCIENTIFIC COMMUNITIES FOR NEARLY TWO DECADES TO DETERMINE WHICH COMPONENTS ARE INVOLVED IN THIS PROCESS. DNA/RNA METHYLATION AND MIRNA ARE CLASSIFIED AS TWO OF THE MOST IMPORTANT REPRESENTATIVE CLASSES OF SUCH EPIGENETIC MECHANISMS AND DYSREGULATED ACTIVITY OF SUCH MECHANISM CAN CERTAINLY CONTRIBUTE TO DISEASE PATHOGENESIS AND/OR PROGRESSION ESPECIALLY IN TUMORS. THIS REVIEW ARTICLE SERVES TO HIGHLIGHT THE IMPACT OF DNA/RNA METHYLATION AND MIRNA-BASED EPIGENETIC MECHANISM ACTIVITIES IN THE INTERPLAY BETWEEN OBESITY AND THE DEVELOPMENT AND CLINICAL SIGNIFICANCE OF COLORECTAL CANCER. 2019 18 421 29 ANIMAL MODELS IN EPIGENETIC RESEARCH: INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE CONSIDERATIONS ACROSS THE LIFESPAN. THE RAPID EXPANSION AND EVOLUTION OF EPIGENETICS AS A CORE SCIENTIFIC DISCIPLINE HAVE RAISED NEW QUESTIONS ABOUT HOW ENDOGENOUS AND ENVIRONMENTAL FACTORS CAN INFORM THE MECHANISMS THROUGH WHICH BIOLOGICAL FORM AND FUNCTION ARE REGULATED. EXISTING AND PROPOSED ANIMAL MODELS USED FOR EPIGENETIC RESEARCH HAVE TARGETED A MYRIAD OF HEALTH AND DISEASE ENDPOINTS THAT MAY BE ACUTE, CHRONIC, AND TRANSGENERATIONAL IN NATURE. INITIATING EVENTS AND OUTCOMES MAY EXTEND ACROSS THE ENTIRE LIFESPAN TO ELICIT UNANTICIPATED PHENOTYPES THAT ARE OF PARTICULAR CONCERN TO INSTITUTIONAL ANIMAL CARE AND USE COMMITTEES (IACUCS). THE DYNAMICS AND PLASTICITY OF EPIGENETIC MECHANISMS PRODUCE EFFECTS AND CONSEQUENCES THAT ARE MANIFEST DIFFERENTIALLY WITHIN DISCREET SPATIAL AND TEMPORAL CONTEXTS, INCLUDING PRENATAL DEVELOPMENT, STEM CELLS, ASSISTED REPRODUCTIVE TECHNOLOGIES, PRODUCTION OF SEXUAL DIMORPHISMS, SENESCENCE, AND OTHERS. MANY DIETARY AND NUTRITIONAL INTERVENTIONS HAVE ALSO BEEN SHOWN TO HAVE A SIGNIFICANT IMPACT ON BIOLOGICAL FUNCTIONS AND DISEASE SUSCEPTIBILITIES THROUGH ALTERED EPIGENETIC PROGRAMMING. THE ENVIRONMENTAL, CHEMICAL, TOXIC, THERAPEUTIC, AND PSYCHOSOCIAL STRESSORS USED IN ANIMAL STUDIES TO ELICIT EPIGENETIC CHANGES CAN BECOME EXTREME AND SHOULD RAISE IACUC CONCERNS FOR THE WELL-BEING AND PROPER CARE OF ALL RESEARCH ANIMALS INVOLVED. EPIGENETICS RESEARCH IS RAPIDLY BECOMING AN INTEGRAL PART OF THE SEARCH FOR MECHANISMS IN EVERY MAJOR AREA OF BIOMEDICAL AND BEHAVIORAL RESEARCH AND WILL FOSTER THE CONTINUED DEVELOPMENT OF NEW ANIMAL MODELS. FROM THE IACUC PERSPECTIVE, CARE MUST BE TAKEN TO ACKNOWLEDGE THE PARTICULAR NEEDS AND CONCERNS CREATED BY SUPERIMPOSITION OF EPIGENETIC MECHANISMS OVER DIVERSE FIELDS OF INVESTIGATION TO ENSURE THE PROPER CARE AND USE OF ANIMALS WITHOUT IMPEDING SCIENTIFIC PROGRESS. 2012 19 3777 20 INTERACTOME OF OBESITY: OBESIDOME : GENETIC OBESITY, STRESS INDUCED OBESITY, PATHOGENIC OBESITY INTERACTION. OBESITY IS A CHRONIC DISEASE OF INCREASING PREVALENCE REACHING EPIDEMIC PROPORTIONS. GENETIC DEFECTS AS WELL AS EPIGENETIC EFFECTS CONTRIBUTE TO THE OBESITY PHENOTYPE. INVESTIGATING GENE (E.G. MC4R DEFECTS)-ENVIRONMENT (BEHAVIOR, INFECTIOUS AGENTS, STRESS) INTERACTIONS IS A RELATIVE NEW FIELD OF GREAT RESEARCH INTEREST. IN THIS STUDY, WE HAVE MADE AN EFFORT TO CREATE AN INTERACTOME (HENCEFORTH REFERRED TO AS "OBESIDOME"), WHERE EXTRINSIC STRESSORS RESPONSE, INTRINSIC PREDISPOSITION, IMMUNITY RESPONSE TO INFLAMMATION AND AUTONOMOUS NERVOUS SYSTEM IMPLICATIONS ARE INTEGRATED. THESE PATHWAYS ARE PRESENTED IN ONE INTERACTOME NETWORK FOR THE FIRST TIME. IN OUR STUDY, OBESITY-RELATED GENES/GENE PRODUCTS WERE FOUND TO FORM A COMPLEX INTERACTIONS NETWORK. 2017 20 14 27 3RD COLLEGE OF PAEDIATRICS AND CHILD HEALTH LECTURE--THE PAST, THE PRESENT AND THE SHAPE OF THINGS TO COME.. THE GROWTH TRENDS OF SINGAPORE CHILDREN SPANNING 5 DECADES ARE REVIEWED, BASED ON 8 ANTHROPOMETRIC STUDIES FROM 1957 TILL 2002. THE HEIGHTS OF PRE-SCHOOL CHILDREN AND SCHOOL AGE CHILDREN APPEAR TO HAVE OPTIMISED ACCORDING TO THEIR GENETIC POTENTIAL, BUT THE WEIGHTS AND BODY MASS INDICES OF CHILDREN STILL APPEAR TO BE INCREASING FROM 6 TO 18 YEARS FOR BOTH SEXES, PROBABLY AS A CONSEQUENCE OF INCREASING AFFLUENCE. THIS TREND IS REFLECTED IN THE INCREASING OBESITY PREVALENCE IN SCHOOL CHILDREN OVER THE PAST 30 YEARS, AND THE CONCOMITANT INCREASED MORBIDITY ASSOCIATED WITH THE METABOLIC SYNDROME, NECESSITATES FURTHER RESEARCH INTO THE CAUSES OF OBESITY. BARKER'S HYPOTHESIS FIRST SUGGESTED THAT CHANGES IN THE INTRA-UTERINE ENVIRONMENT CAN CAUSE FETAL ADAPTATIONS WHICH PERSIST INTO ADULTHOOD, AND ARE RESPONSIBLE FOR MANY CHRONIC DISEASES OF ADULT LIFE. MORE RECENTLY, INTENSE RESEARCH IN THE FIELD OF EPIGENETICS SUGGESTS THAT THE ENVIRONMENT CAN ALSO INFLUENCE THE PHENOTYPE THROUGH GENE EXPRESSION, THROUGH MODIFICATION OF DNA METHYLATION AND HISTONES WHICH, IN TURN, INFLUENCES GENE EXPRESSION. THE CHALLENGE FOR THE FUTURE IS TO DETERMINE IF THERE ARE CLEAR EPIGENETIC CHANGES, WHICH ARE RESPONSIBLE FOR THE INCREASED PREVALENCE OF CHILDHOOD AND ADOLESCENT OBESITY, AND WHETHER THESE CHANGES ARE TRANSMITTED THROUGH GENERATIONS. UNRAVELLING THESE EPIGENETIC MECHANISMS MAY BE THE KEY TO THE PREVENTION OF OBESITY AND THE METABOLIC SYNDROME. 2008