1 2296 95 EPIGENETIC REGULATION OF ABIOTIC STRESS MEMORY: MAINTAINING THE GOOD THINGS WHILE THEY LAST. AS SESSILE ORGANISMS, PLANTS HAVE EVOLVED SOPHISTICATED WAYS TO CONSTANTLY GAUGE AND ADAPT TO CHANGING ENVIRONMENTAL CONDITIONS INCLUDING EXTREMES THAT MAY BE HARMFUL TO THEIR GROWTH AND DEVELOPMENT AND ARE THUS PERCEIVED AS STRESS. IN NATURE, STRESSFUL EVENTS ARE OFTEN CHRONIC OR RECURRING AND THUS AN INITIAL STRESS MAY PRIME A PLANT TO RESPOND MORE EFFICIENTLY TO A SUBSEQUENT STRESS EVENT. AN EPIGENETIC BASIS OF SUCH STRESS MEMORY WAS LONG POSTULATED AND IN RECENT YEARS IT HAS BEEN SHOWN THAT THIS IS INDEED THE CASE. HIGH TEMPERATURE STRESS HAS PROVEN AN EXCELLENT SYSTEM TO UNPICK THE MOLECULAR BASIS OF SOMATIC STRESS MEMORY, WHICH INCLUDES HISTONE MODIFICATIONS AND NUCLEOSOME OCCUPANCY. THIS REVIEW DISCUSSES RECENT FINDINGS AND PINPOINTS OPEN QUESTIONS IN THE FIELD. 2021 2 4996 26 PERINATAL EPIGENETIC DETERMINANTS OF COGNITIVE AND METABOLIC DISORDERS. MULTIPLE CUES FROM THE ENVIRONMENT OF OUR INDIRECT AND IMMEDIATE ANCESTORS, WHICH OFTEN PERSIST THROUGHOUT THE PRENATAL PERIOD AND ADULTHOOD, ARE SHAPING OUR PHENOTYPES THROUGH EITHER DIRECT, PARENT-TO-CHILD INFLUENCES, OR TRANSGENERATIONAL INHERITANCE. THESE EFFECTS ARE DUE TO GENE-ENVIRONMENT INTERACTIONS, WHICH ARE INTENDED TO BE A PREDICTIVE TOOL AND A MECHANISM OF QUICK ADAPTATION TO THE ENVIRONMENT, AS COMPARED WITH GENETIC VARIATIONS THAT ARE INHERITED OVER MANY GENERATIONS. IN CERTAIN CIRCUMSTANCES THE INFLUENCES INDUCED BY THE GENE-ENVIRONMENT INTERACTIONS CAN HAVE DELETERIOUS EFFECTS UPON THE HEALTH STATUS, IN THE CONTEXT OF A RADICAL CHANGE IN THE ENVIRONMENT THAT DOES NOT FIT WITH THE PREDICTED CONDITIONS, VIA EPIGENETIC ALTERATIONS. CONVERSELY THE BEST FIT TO THE EXPECTED ENVIRONMENT MIGHT HAVE A DELAYED AGING PROCESS AND A LONGER LIFE SPAN. THIS REVIEW WILL TOUCH UPON THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) CONCEPT, WHILE DISCUSSING RECENT ADVANCES IN THE UNDERSTANDING OF METABOLIC AND COGNITIVE DISRUPTIONS, WITH A FOCUS ON EPIGENETIC FACTORS, THEIR TRANSGENERATIONAL EFFECTS, AND THE CONSEQUENCES THEY MIGHT HAVE UPON THE ONSET OF CHRONIC DISEASE AND PREMATURE EXITUS. 2012 3 2184 30 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 4 1364 32 DEVELOPMENTAL NEUROENDOCRINOLOGY OF EARLY-LIFE STRESS: IMPACT ON CHILD DEVELOPMENT AND BEHAVIOR. OUR INTERNAL BALANCE, OR HOMEOSTASIS, IS THREATENED OR PERCEIVED AS THREATENED BY STRESSFUL STIMULI, THE STRESSORS. THE STRESS SYSTEM IS A HIGHLY CONSERVED SYSTEM THAT ADJUSTS HOMEOSTASIS TO THE RESTING STATE. THROUGH THE CONCURRENT ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE LOCUS COERULEUS/NOREPINEPHRINE-AUTONOMIC NERVOUS SYSTEMS, THE STRESS SYSTEM PROVIDES THE APPROPRIATE PHYSICAL AND BEHAVIORAL RESPONSES, COLLECTIVELY TERMED AS "STRESS RESPONSE", TO RESTORE HOMEOSTASIS. IF THE STRESS RESPONSE IS PROLONGED, EXCESSIVE OR EVEN INADEQUATE, SEVERAL ACUTE OR CHRONIC STRESS-RELATED PATHOLOGIC CONDITIONS MAY DEVELOP IN CHILDHOOD, ADOLESCENCE AND ADULT LIFE. ON THE OTHER HAND, EARLY-LIFE EXPOSURE TO STRESSORS HAS BEEN RECOGNIZED AS A MAJOR CONTRIBUTING FACTOR UNDERLYING THE PATHOGENESIS OF NON-COMMUNICABLE DISORDERS, INCLUDING NEURODEVELOPMENTAL DISORDERS. ACCUMULATING EVIDENCE SUGGESTS THAT EARLY-LIFE STRESS HAS BEEN ASSOCIATED WITH AN INCREASED RISK FOR ATTENTION DEFICIT HYPERACTIVITY DISORDER AND AUTISM SPECTRUM DISORDER IN THE OFFSPRING, ALTHOUGH FINDINGS ARE STILL CONTROVERSIAL. NEVERTHELESS, AT THE MOLECULAR LEVEL, EARLY-LIFE STRESSORS ALTER THE CHEMICAL STRUCTURE OF CYTOSINES LOCAT- ED IN THE REGULATORY REGIONS OF GENES, MOSTLY THROUGH THE ADDITION OF METHYL GROUPS. THESE EPIGENETIC MODIFICATIONS RESULT IN THE SUPPRESSION OF GENE EXPRESSION WITHOUT CHANGING THE DNA SEQUENCE. IN ADDITION TO DNA METHYLATION, SEVERAL LINES OF EVIDENCE SUPPORT THE ROLE OF NON-CODING RNAS IN THE EVOLVING FIELD OF EPIGENETICS. IN THIS REVIEW ARTICLE, WE PRESENT THE ANATOMICAL AND FUNCTIONAL COMPO- NENTS OF THE STRESS SYSTEM, DISCUSS THE PROPER, IN TERMS OF QUALITY AND QUANTITY, STRESS RESPONSE, AND PROVIDE AN UPDATE ON THE IMPACT OF EARLY-LIFE STRESS ON CHILD DEVELOPMENT AND BEHAVIOR. 2023 5 6905 24 [THE ROLE OF EPIGENETIC REGULATIONS IN EARLY CHILDHOOD DISEASES]. WITH THE ACCEPTANCE OF "THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" CONCEPT IN THE 1990S, IT BECAME CLEAR THAT EPIGENETIC INHERITANCE, WHICH DO NOT INVOLVE CHANGES IN THE DNA SEQUENCE HAS IMPORTANT ROLE IN THE PATHOGENESIS OF DISEASES. EPIGENETIC REGULATION SERVES THE ADAPTATION TO THE CHANGING ENVIRONMENT AND MAINTAINS THE REPRODUCTIVE FITNESS EVEN ON THE DRAWBACK OF INCREASED RISK OF DISEASES IN LATER LIFE. THE ROLE OF EPIGENETIC MECHANISMS IN CHRONIC NON-COMMUNICABLE DISEASES HAS BEEN WELL ESTABLISHED. RECENT STUDIES HAVE REVEALED THAT EPIGENETIC CHANGES HAVE ALSO CAUSAL ROLE IN CERTAIN PEDIATRIC DISEASES. THE REVIEW EVALUATES THE RECENT EPIGENETIC FINDINGS IN THE PATHOMECHANISM OF COMMON PEDIATRIC DISEASES. THE WIDE RANGE AND LONG-LASTING DURATION OF EPIGENETIC REGULATIONS GIVE IMPORTANCE TO THE SUBJECT. METHODS ARE ALREADY AVAILABLE TO EVALUATE A PART OF THE EPIGENETIC CHANGES IN THE CLINICAL PRACTICE, PRESENTLY AIMING PRIMARILY THE ESTIMATION OF THE DISEASE RISK OR DEFINITION OF DIAGNOSIS. FURTHERMORE, THERE ARE ALREADY AVAILABLE LIMITED MEANS TO INFLUENCE THE EPIGENETIC REGULATION. 2019 6 1453 17 DISCOVERING HOW ENVIRONMENTAL EXPOSURES ALTER GENES COULD LEAD TO NEW TREATMENTS FOR CHRONIC ILLNESSES. EMERGING RESEARCH DEMONSTRATES THAT DIET, POLLUTION, AND OTHER ENVIRONMENTAL TRIGGERS CAN ALTER BOTH THE FUNCTION AND EXPRESSION OF HUMAN GENES AND LEAD TO A HEIGHTENED DISEASE RISK. THESE ENVIRONMENT-GENE INTERACTIONS CAN CAUSE SO-CALLED EPIGENETIC CHANGES IN GENE EXPRESSION-PATTERNS OF WHICH GENES ARE SWITCHED "ON" OR "OFF"-THAT MAY ACCOUNT FOR THE RISING MORTALITY FROM CHRONIC DISEASES IN INDUSTRIALIZED NATIONS. IN THIS PAPER, WE CALL FOR A NEW TRANSDISCIPLINARY APPROACH TO PUBLIC HEALTH THAT WOULD EXAMINE HOW ENVIRONMENTAL EXPOSURES, BOTH PHYSICAL AND SOCIAL, INFLUENCE GENE EXPRESSION AND A PERSON'S SUSCEPTIBILITY TO CHRONIC DISEASE. THIS INITIATIVE COULD LEAD TO NEW WAYS TO PREVENT AND TREAT SUCH ILLNESSES. 2011 7 5810 20 STRESS & SLEEP: A RELATIONSHIP LASTING A LIFETIME. STRESS IS AN ADAPTATIVE RESPONSE AIMED AT RESTORING BODY HOMEOSTASIS. THE CLASSICAL NEUROENDOCRINE STRESS RESPONSE INVOLVING THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS MODULATES MANY PHYSIOLOGICAL ASPECTS, SUCH AS THE WAKE-SLEEP CYCLE. IN THE PRESENT REVIEW, WE WILL FIRST REPORT A SERIES OF HUMAN AND RODENT STUDIES SHOWING THAT EACH ACTOR OF THE HPA AXIS HAS THE POTENTIAL TO INTERFERE WITH SLEEP HOMEOSTASIS AND, THEN, WE WILL HIGHLIGHT HOW ACUTE OR CHRONIC STRESS DIFFERENTLY MODULATES THE WAKE-SLEEP CYCLE. MOREOVER, WE WILL PRESENT NEW AND INTERESTING STUDIES DEALING WITH THE RELATIONSHIP BETWEEN SLEEP AND STRESS ON A DIFFERENT (LONGER) TIME SCALE. PARTICULARLY, WE WILL DISCUSS HOW THE EXPOSURE TO PERINATAL STRESS, PROBABLY THROUGH EPIGENETIC MODULATIONS, IS SUFFICIENT TO CAUSE PERSISTENT SLEEP DERANGEMENTS DURING ADULT LIFE. IN LIGHT OF THIS EVIDENCE, THE MAIN MESSAGE OF THE PRESENT REVIEW IS THAT THE COMPLEX RELATIONSHIP BETWEEN SLEEP AND STRESS CHANGES DRAMATICALLY ON THE BASIS OF THE TIME SCALE CONSIDERED AND, CONSEQUENTLY, "TIME" SHOULD BE CONSIDERED AS A CRITICAL FACTOR WHEN FACING THIS TOPIC. 2020 8 1360 27 DEVELOPMENTAL ASPECTS OF A LIFE COURSE APPROACH TO HEALTHY AGEING. WE EXAMINE THE MECHANISTIC BASIS AND WIDER IMPLICATIONS OF ADOPTING A DEVELOPMENTAL PERSPECTIVE ON HUMAN AGEING. PREVIOUS MODELS OF AGEING HAVE CONCENTRATED ON ITS GENETIC BASIS, OR THE DETRIMENTAL EFFECTS OF ACCUMULATED DAMAGE, BUT ALSO HAVE RAISED ISSUES ABOUT WHETHER AGEING CAN BE VIEWED AS ADAPTIVE ITSELF, OR IS A CONSEQUENCE OF OTHER ADAPTIVE PROCESSES, FOR EXAMPLE IF MAINTENANCE AND REPAIR PROCESSES IN THE PERIOD UP TO REPRODUCTION ARE TRADED OFF AGAINST LATER DECLINE IN FUNCTION. A LIFE COURSE MODEL PLACES AGEING IN THE CONTEXT OF THE ATTAINMENT OF PEAK CAPACITY FOR A BODY SYSTEM, STARTING IN EARLY DEVELOPMENT WHEN PLASTICITY PERMITS CHANGES IN STRUCTURE AND FUNCTION INDUCED BY A RANGE OF ENVIRONMENTAL STIMULI, FOLLOWED BY A PERIOD OF DECLINE, THE RATE OF WHICH DEPENDS ON THE PEAK ATTAINED AS WELL AS THE LATER LIFE CONDITIONS. SUCH PATH DEPENDENCY IN THE RATE OF AGEING MAY OFFER NEW INSIGHTS INTO ITS MODIFICATION. FOCUSING ON MUSCULOSKELETAL AND CARDIOVASCULAR FUNCTION, WE DISCUSS THIS MODEL AND THE POSSIBLE UNDERLYING MECHANISMS, INCLUDING ENDOTHELIAL FUNCTION, OXIDATIVE STRESS, STEM CELLS AND NUTRITIONAL FACTORS SUCH AS VITAMIN D STATUS. EPIGENETIC CHANGES INDUCED DURING DEVELOPMENTAL PLASTICITY, AND IMMUNE FUNCTION MAY PROVIDE A COMMON MECHANISTIC PROCESS UNDERLYING A LIFE COURSE MODEL OF AGEING. THE LIFE COURSE TRAJECTORY DIFFERS IN HIGH AND LOW RESOURCE SETTINGS. NEW INSIGHTS INTO THE DEVELOPMENTAL COMPONENTS OF THE LIFE COURSE MODEL OF AGEING MAY LEAD TO THE DESIGN OF BIOMARKERS OF LATER CHRONIC DISEASE RISK AND TO NEW INTERVENTIONS TO PROMOTE HEALTHY AGEING, WITH IMPORTANT IMPLICATIONS FOR PUBLIC HEALTH. 2016 9 6844 23 [METABOLIC PROGRAMMING: THEORETICAL CONCEPTS AND EXPERIMENTAL EVIDENCE]. IT IS KNOWN THAT THE POOR NUTRITION DURING A FETAL DEVELOPMENT MAY CONTRIBUTE TO AN INCREASED RISK OF CHRONIC DISEASES IN ADULTHOOD. IN A MODERN LITERATURE, THIS PHENOMENON IS CALLED <>. IT IS ASSUMED THAT THE QUALITATIVE OR QUANTITATIVE DEFICIENCY OF CERTAIN NUTRITIONAL COMPONENTS DURING AN EARLY DEVELOPMENT MAY LEAD TO THE ADAPTATIONS THAT CONTRIBUTE TO IMPROVED SURVIVAL DURING THE PRENATAL AND EARLY POSTNATAL PERIODS OF AN ONTOGENESIS. HOWEVER, THE CONSEQUENCE OF SUCH ADAPTIVE CHANGES MAY ALSO BE THE DEVELOPMENT OF VARIOUS PATHOLOGICAL PROCESSES AT THE LATER STAGES OF LIFE. RECENT STUDIES HAVE SHOWN THAT ONE OF THE MAJOR MECHANISMS INVOLVED IN THESE ADAPTATIONS IS THE EPIGENETIC REGULATION OF A GENE ACTIVITY. IN THIS REVIEW, THE EXPERIMENTAL EVIDENCE IS PROVIDED THAT PROCESSES ARISING FROM A QUANTITATIVELY OR QUALITATIVELY RESTRICTED DIET DURING THE EARLY STAGES OF DEVELOPMENT PLAY AN IMPORTANT ROLE IN THE FURTHER LIFE AND CAN GREATLY INFLUENCE RISK OF VARIOUS AGE-RELATED DISEASES AND LIFE SPAN. 2013 10 4126 23 MECHANISMS OF DISEASE: THE DEVELOPMENTAL ORIGINS OF DISEASE AND THE ROLE OF THE EPIGENOTYPE. THERE IS ACCUMULATING EVIDENCE THAT MANY CHRONIC DISEASES SUCH AS TYPE 2 DIABETES AND CORONARY HEART DISEASE MIGHT ORIGINATE DURING EARLY LIFE. THIS EVIDENCE GIVES RISE TO THE DEVELOPMENTAL ORIGINS OF DISEASE HYPOTHESIS, AND IS SUPPORTED BY EPIDEMIOLOGICAL DATA IN HUMANS AND EXPERIMENTAL ANIMAL MODELS. A PERTURBED ENVIRONMENT IN EARLY LIFE IS THOUGHT TO ELICIT A RANGE OF PHYSIOLOGICAL AND CELLULAR ADAPTIVE RESPONSES IN KEY ORGAN SYSTEMS. THESE ADAPTIVE CHANGES RESULT IN PERMANENT ALTERATIONS AND MIGHT LEAD TO PATHOLOGY IN LATER LIFE. AGING ORGANS AND CELLS SEEM THEREFORE TO RETAIN A 'MEMORY' OF THEIR FETAL HISTORY AND ADAPTIVE RESPONSES. THE MECHANISMS UNDERLYING THE DEVELOPMENTAL ORIGINS OF DISEASE REMAIN POORLY DEFINED. EPIGENETIC TAGGING OF GENES, SUCH AS DNA METHYLATION AND HISTONE MODIFICATION, CONTROLS THE FUNCTION OF THE GENOME AT DIFFERENT LEVELS AND MAINTAINS CELLULAR MEMORY AFTER MANY CELLULAR DIVISIONS; IMPORTANTLY, TAGGING CAN BE MODULATED BY THE ENVIRONMENT AND IS INVOLVED IN ONSET OF DISEASES SUCH AS CANCER. HERE WE REVIEW THE EVIDENCE FOR THE DEVELOPMENTAL ORIGINS OF DISEASE AND DISCUSS THE ROLE OF THE EPIGENOTYPE AS A CONTRIBUTING MECHANISM. ENVIRONMENTALLY INDUCED CHANGES IN THE EPIGENOTYPE MIGHT BE KEY PRIMARY EVENTS IN THE DEVELOPMENTAL ORIGINS OF DISEASE, WITH IMPORTANT CLINICAL IMPLICATIONS. 2007 11 2049 20 EPIGENETIC CODE AND POTENTIAL EPIGENETIC-BASED THERAPIES AGAINST CHRONIC DISEASES IN DEVELOPMENTAL ORIGINS. ACCUMULATED FINDINGS HAVE DEMONSTRATED THAT THE EPIGENETIC CODE PROVIDES A POTENTIAL LINK BETWEEN PRENATAL STRESS AND CHANGES IN GENE EXPRESSION THAT COULD BE INVOLVED IN THE DEVELOPMENTAL PROGRAMMING OF VARIOUS CHRONIC DISEASES IN LATER LIFE. MEANWHILE, BASED ON THE FACT THAT EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND CAN BE MANIPULATED, THIS PROVIDES A UNIQUE CHANCE TO DEVELOP MULTIPLE NOVEL EPIGENETIC-BASED THERAPEUTIC STRATEGIES AGAINST MANY CHRONIC DISEASES IN EARLY DEVELOPMENTAL PERIODS. THIS ARTICLE WILL GIVE A SHORT REVIEW OF RECENT FINDINGS OF PRENATAL INSULT-INDUCED EPIGENETIC CHANGES IN DEVELOPMENTAL ORIGINS OF SEVERAL CHRONIC DISEASES, AND WILL ATTEMPT TO PROVIDE AN OVERVIEW OF THE CURRENT EPIGENETIC-BASED STRATEGIES APPLIED IN THE EARLY PREVENTION, DIAGNOSIS AND POSSIBLE THERAPIES FOR HUMAN CHRONIC DISEASES. 2014 12 3404 21 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 13 2412 33 EPIGENETIC SIDE-EFFECTS OF COMMON PHARMACEUTICALS: A POTENTIAL NEW FIELD IN MEDICINE AND PHARMACOLOGY. THE TERM "EPIGENETICS" REFERS TO DNA AND CHROMATIN MODIFICATIONS THAT PERSIST FROM ONE CELL DIVISION TO THE NEXT, DESPITE A LACK OF CHANGE IN THE UNDERLYING DNA SEQUENCE. THE "EPIGENOME" REFERS TO THE OVERALL EPIGENETIC STATE OF A CELL, AND SERVES AS AN INTERFACE BETWEEN THE ENVIRONMENT AND THE GENOME. THE EPIGENOME IS DYNAMIC AND RESPONSIVE TO ENVIRONMENTAL SIGNALS NOT ONLY DURING DEVELOPMENT, BUT ALSO THROUGHOUT LIFE; AND IT IS BECOMING INCREASINGLY APPARENT THAT CHEMICALS CAN CAUSE CHANGES IN GENE EXPRESSION THAT PERSIST LONG AFTER EXPOSURE HAS CEASED. HERE WE PRESENT THE HYPOTHESIS THAT COMMONLY-USED PHARMACEUTICAL DRUGS CAN CAUSE SUCH PERSISTENT EPIGENETIC CHANGES. DRUGS MAY ALTER EPIGENETIC HOMEOSTASIS BY DIRECT OR INDIRECT MECHANISMS. DIRECT EFFECTS MAY BE CAUSED BY DRUGS WHICH AFFECT CHROMATIN ARCHITECTURE OR DNA METHYLATION. FOR EXAMPLE THE ANTIHYPERTENSIVE HYDRALAZINE INHIBITS DNA METHYLATION. AN EXAMPLE OF AN INDIRECTLY ACTING DRUG IS ISOTRETINOIN, WHICH HAS TRANSCRIPTION FACTOR ACTIVITY. A TWO-TIER MECHANISM IS POSTULATED FOR INDIRECT EFFECTS IN WHICH ACUTE EXPOSURE TO A DRUG INFLUENCES SIGNALING PATHWAYS THAT MAY LEAD TO AN ALTERATION OF TRANSCRIPTION FACTOR ACTIVITY AT GENE PROMOTERS. THIS STIMULATION RESULTS IN THE ALTERED EXPRESSION OF RECEPTORS, SIGNALING MOLECULES, AND OTHER PROTEINS NECESSARY TO ALTER GENETIC REGULATORY CIRCUITS. WITH MORE CHRONIC EXPOSURE, CELLS ADAPT BY AN UNKNOWN HYPOTHETICAL PROCESS THAT RESULTS IN MORE PERMANENT MODIFICATIONS TO DNA METHYLATION AND CHROMATIN STRUCTURE, LEADING TO ENDURING ALTERATION OF A GIVEN EPIGENETIC NETWORK. THEREFORE, ANY EPIGENETIC SIDE-EFFECT CAUSED BY A DRUG MAY PERSIST AFTER THE DRUG IS DISCONTINUED. IT IS FURTHER PROPOSED THAT SOME IATROGENIC DISEASES SUCH AS TARDIVE DYSKINESIA AND DRUG-INDUCED SLE ARE EPIGENETIC IN NATURE. IF THIS HYPOTHESIS IS CORRECT THE CONSEQUENCES FOR MODERN MEDICINE ARE PROFOUND, SINCE IT WOULD IMPLY THAT OUR CURRENT UNDERSTANDING OF PHARMACOLOGY IS AN OVERSIMPLIFICATION. WE PROPOSE THAT EPIGENETIC SIDE-EFFECTS OF PHARMACEUTICALS MAY BE INVOLVED IN THE ETIOLOGY OF HEART DISEASE, CANCER, NEUROLOGICAL AND COGNITIVE DISORDERS, OBESITY, DIABETES, INFERTILITY, AND SEXUAL DYSFUNCTION. IT IS SUGGESTED THAT A SYSTEMS BIOLOGY APPROACH EMPLOYING MICROARRAY ANALYSES OF GENE EXPRESSION AND METHYLATION PATTERNS CAN LEAD TO A BETTER UNDERSTANDING OF LONG-TERM SIDE-EFFECTS OF DRUGS, AND THAT IN THE FUTURE, EPIGENETIC ASSAYS SHOULD BE INCORPORATED INTO THE SAFETY ASSESSMENT OF ALL PHARMACEUTICAL DRUGS. THIS NEW APPROACH TO PHARMACOLOGY HAS BEEN TERMED "PHAMACOEPIGENOMICS", THE IMPACT OF WHICH MAY BE EQUAL TO OR GREATER THAN THAT OF PHARMACOGENETICS. WE PROVIDE HERE AN OVERVIEW OF THIS POTENTIALLY MAJOR NEW FIELD IN PHARMACOLOGY AND MEDICINE. 2009 14 2586 26 EPIGENETICS OF PAIN MEDIATORS. PURPOSE OF REVIEW: THE FIELD OF EPIGENETICS CONTINUES ITS INFLUENTIAL RISE AS A MEANS TO BETTER UNDERSTAND AN ORGANISM'S UNIQUE DEVELOPMENTAL IDENTITY OVER A LIFESPAN. WHEREAS A GENOME IS CONSTANT AND UNCHANGING, AN EPIGENOME IS DYNAMIC AND ALTERABLE. EPIGENETIC CHANGES ARE IN RESPONSE TO INNUMERABLE INTERNAL AND EXTERNAL INFLUENCES INCLUDING ENVIRONMENTAL CHANGES SUCH AS DIET, EXERCISE, DISEASE, TOXINS, AND STRESS. EPIGENETICS IS OF PARTICULAR INTEREST IN THE MEDICAL RESEARCH COMMUNITY BOTH FOR THE POTENTIAL TO CAUSE DISEASE AND AS A TARGET FOR THERAPEUTIC INTERVENTIONS. THIS ARTICLE PROVIDES A SUCCINCT EXPLANATION OF THE POTENTIAL FOR EPIGENETICS TO INFLUENCE THE UNDERSTANDING OF PAIN AS WELL AS A REVIEW OF RELEVANT RESEARCH ON THE TOPIC. RECENT FINDINGS: STUDIES ON EPIGENETICS AND PAIN REMAIN LARGELY PRECLINICAL AND INVESTIGATE THE THEORETICAL ABILITY OF EPIGENETICS TO ALTER THE NOCICEPTIVE PATHWAYS BOTH IN THE PERIPHERY AND CENTRALLY. SIGNIFICANT EVIDENCE NOW EXISTS FOR THE ABILITY OF EPIGENETICS TO MODIFY BROADLY CATEGORIZED PAIN TYPES, INCLUDING INFLAMMATORY, NEUROPATHIC, VISCERAL, AND CANCER RELATED. SUMMARY: BOTH PATIENTS AND PROVIDERS RECOGNIZE THAT NOVEL MEDICATIONS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC PAIN CONDITIONS ARE SORELY NEEDED. THE UNDERSTANDING OF EPIGENETICS AND ITS INFLUENCE ON NOCICEPTION REMAINS IN RELATIVE INFANCY BUT EARLY EVIDENCE IS STRONG FOR POTENTIAL THERAPEUTIC BENEFITS TO TREAT THESE CONDITIONS. 2018 15 4192 27 METABOLIC MEMORY AND CHRONIC DIABETES COMPLICATIONS: POTENTIAL ROLE FOR EPIGENETIC MECHANISMS. RECENT ESTIMATES INDICATE THAT DIABETES MELLITUS CURRENTLY AFFECTS MORE THAN 10 % OF THE WORLD'S POPULATION. EVIDENCE FROM BOTH THE LABORATORY AND LARGE SCALE CLINICAL TRIALS HAS REVEALED THAT PROLONGED HYPERGLYCEMIA INDUCES CHRONIC COMPLICATIONS WHICH PERSIST AND PROGRESS UNIMPEDED EVEN WHEN GLYCEMIC CONTROL IS PHARMACEUTICALLY ACHIEVED VIA THE PHENOMENON OF METABOLIC MEMORY. THE EPIGENOME IS COMPRISED OF ALL CHROMATIN MODIFICATIONS INCLUDING POST TRANSLATIONAL HISTONE MODIFICATION, EXPRESSION CONTROL VIA MIRNAS AND THE METHYLATION OF CYTOSINE WITHIN DNA. MODIFICATIONS OF THESE EPIGENETIC MARKS NOT ONLY ALLOW CELLS AND ORGANISMS TO QUICKLY RESPOND TO CHANGING ENVIRONMENTAL STIMULI BUT ALSO CONFER THE ABILITY OF THE CELL TO "MEMORIZE" THESE ENCOUNTERS. AS SUCH, THESE PROCESSES HAVE GAINED MUCH ATTENTION AS POTENTIAL MOLECULAR MECHANISMS UNDERLYING METABOLIC MEMORY AND CHRONIC DIABETIC COMPLICATIONS. HERE WE PRESENT A REVIEW OF THE VERY RECENT LITERATURE PUBLISHED PERTAINING TO THIS SUBJECT. 2012 16 5650 19 SEX DIFFERENCES IN THE DEVELOPMENT OF PHYSICAL AGGRESSION: AN INTERGENERATIONAL PERSPECTIVE AND IMPLICATIONS FOR PREVENTIVE INTERVENTIONS. THIS ARTICLE REVIEWS THE STATE OF KNOWLEDGE ON THE DEVELOPMENT OF CHRONIC PHYSICAL AGGRESSION (CPA), WITH THE AIM OF IDENTIFYING THE MOST EFFECTIVE PREVENTION STRATEGIES. WE SPECIFICALLY FOCUS ON THE EARLY DEVELOPMENT OF PHYSICAL AGGRESSION, ON SEX DIFFERENCES IN THE USE OF PHYSICAL AGGRESSION, AND ON THE TRANSMISSION OF BEHAVIOR PROBLEMS FROM ONE GENERATION TO THE OTHER. THE BODY OF RESEARCH ON THE DEVELOPMENT OF CPA FROM THE PAST THREE DECADES THAT WE REVIEW SHOWS INCREASING EVIDENCE THAT ITS PREVENTION REQUIRES A LONG-TERM BIOPSYCHOSOCIAL DEVELOPMENTAL APPROACH WHICH ALSO MUST INCLUDE AN INTERGENERATIONAL PERSPECTIVE. RECENT GENETIC AND EPIGENETIC RESEARCH HAS INDICATED THAT THERE ARE BOTH IMPORTANT GENETIC AND ENVIRONMENTAL EFFECTS ON GENE EXPRESSION WHICH START AT CONCEPTION. WE CONCLUDE THAT ONE OF THE MOST EFFECTIVE STRATEGIES TO BREAK THE INTERGENERATIONAL TRANSMISSION OF CPA INVOLVES GIVING LONG-TERM SUPPORT TO PREGNANT WOMEN WITH A HISTORY OF BEHAVIOR PROBLEMS, THEIR SPOUSE, AND THEIR OFFSPRING. 2019 17 5829 26 STRESS, PSYCHIATRIC DISORDERS, MOLECULAR TARGETS, AND MORE. MENTAL HEALTH IS CENTRAL TO NORMAL HEALTH OUTCOMES. A WIDELY ACCEPTED THEORY IS THAT CHRONIC PERSISTENT STRESS DURING ADULTHOOD AS WELL AS DURING EARLY LIFE TRIGGERS ONSET OF NEUROPSYCHIATRIC AILMENTS. HOWEVER, QUESTIONS RELATED TO HOW THAT OCCURS, AND WHY ARE SOME INDIVIDUALS RESISTANT TO STRESS WHILE OTHERS ARE NOT, REMAIN UNANSWERED. AN INTEGRATED, MULTISYSTEMIC STRESS RESPONSE INVOLVING NEUROINFLAMMATORY, NEUROENDOCRINE, EPIGENETIC AND METABOLIC CASCADES HAVE BEEN SUGGESTED TO HAVE CAUSATIVE LINKS. SEVERAL THEORIES HAVE BEEN PROPOSED OVER THE YEARS TO CONCEPTUALIZE THIS LINK INCLUDING THE CYTOKINE HYPOTHESIS, THE ENDOCRINE HYPOTHESIS, THE OXIDATIVE STRESS HYPOTHESIS AND THE OXIDO-NEUROINFLAMMATION HYPOTHESIS. THE DATA DISCUSSED IN THIS REVIEW DESCRIBES POTENTIAL BIOCHEMICAL BASIS OF THE LINK BETWEEN STRESS, AND STRESS-INDUCED NEURONAL, BEHAVIORAL AND EMOTIONAL DEFICITS, PROVIDING INSIGHTS INTO POTENTIALLY NOVEL DRUG TARGETS. 2019 18 357 29 ALTERNATIVE MODELS FOR TRANSGENERATIONAL EPIGENETIC INHERITANCE: MOLECULAR PSYCHIATRY BEYOND MICE AND MAN. MENTAL ILLNESS REMAINS THE GREATEST CHRONIC HEALTH BURDEN GLOBALLY WITH FEW IN-ROADS HAVING BEEN MADE DESPITE SIGNIFICANT ADVANCES IN GENOMIC KNOWLEDGE IN RECENT DECADES. THE FIELD OF PSYCHIATRY IS CONSTANTLY CHALLENGED TO BRING NEW APPROACHES AND TOOLS TO ADDRESS AND TREAT THE NEEDS OF VULNERABLE INDIVIDUALS AND SUBPOPULATIONS, AND THAT HAS TO BE SUPPORTED BY A CONTINUOUS GROWTH IN KNOWLEDGE. THE MAJORITY OF NEUROPSYCHIATRIC SYMPTOMS REFLECT COMPLEX GENE-ENVIRONMENT INTERACTIONS, WITH EPIGENETICS BRIDGING THE GAP BETWEEN GENETIC SUSCEPTIBILITY AND ENVIRONMENTAL STRESSORS THAT TRIGGER DISEASE ONSET AND DRIVE THE ADVANCEMENT OF SYMPTOMS. IT HAS MORE RECENTLY BEEN DEMONSTRATED IN PRECLINICAL MODELS THAT EPIGENETICS UNDERPINS THE TRANSGENERATIONAL INHERITANCE OF STRESS-RELATED BEHAVIOURAL PHENOTYPES IN BOTH PATERNAL AND MATERNAL LINEAGES, PROVIDING FURTHER SUPPORTING EVIDENCE FOR HERITABILITY IN HUMANS. HOWEVER, UNBIASED PROSPECTIVE STUDIES OF THIS NATURE ARE PRACTICALLY IMPOSSIBLE TO CONDUCT IN HUMANS SO PRECLINICAL MODELS REMAIN OUR BEST OPTION FOR RESEARCHING THE MOLECULAR PATHOPHYSIOLOGIES UNDERLYING MANY NEUROPSYCHIATRIC CONDITIONS. WHILE RODENTS WILL REMAIN THE DOMINANT MODEL SYSTEM FOR PRECLINICAL STUDIES (ESPECIALLY FOR ADDRESSING COMPLEX BEHAVIOURAL PHENOTYPES), THERE IS SCOPE TO EXPAND CURRENT RESEARCH OF THE MOLECULAR AND EPIGENETIC PATHOLOGIES BY USING INVERTEBRATE MODELS. HERE, WE WILL DISCUSS THE UTILITY AND ADVANTAGES OF TWO ALTERNATIVE MODEL ORGANISMS-CAENORHABDITIS ELEGANS AND DROSOPHILA MELANOGASTER-AND SUMMARISE THE COMPELLING INSIGHTS OF THE EPIGENETIC REGULATION OF TRANSGENERATIONAL INHERITANCE THAT ARE POTENTIALLY RELEVANT TO HUMAN PSYCHIATRY. 2021 19 2007 22 EPIGENETIC BASIS FOR FETAL ORIGINS OF AGE-RELATED DISEASE. THE CURRENT CONCEPT OF FETAL ORIGINS OF ADULT DISEASES DESCRIBES IN UTERO PROGRAMMING, OR ADAPTATION TO A SPECTRUM OF ADVERSE ENVIRONMENTAL CONDITIONS THAT ULTIMATELY LEADS TO INCREASED SUSCEPTIBILITY TO AGE-RELATED DISEASES (E.G., TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE) LATER IN LIFE. ALTHOUGH THE PRECISE MECHANISM OF THIS BIOLOGICAL MEMORY REMAINS UNCLEAR, MOUNTING EVIDENCE SUGGESTS AN EPIGENETIC BASIS. THE INCREASED SUSCEPTIBILITY TO CHRONIC DISEASE AND INVOLVEMENT OF MULTIPLE ORGAN SYSTEMS THAT IS OBSERVED IS ANALOGOUS TO THE DECLINE IN RESISTANCE TO DISEASE THAT IS TYPICAL OF NORMAL AGING. ALTHOUGH THE CUMULATIVE ENVIRONMENT OVER THE COURSE OF A LIFETIME CAN INDUCE INCREASING EPIGENETIC DYSREGULATION, WE PROPOSE THAT ADVERSE EVENTS THAT OCCUR DURING EARLY DEVELOPMENT CAN INDUCE SIGNIFICANT ADDITIONAL DYSREGULATION OF THE EPIGENOME. HERE, WE DESCRIBE THE CURRENT EVIDENCE FOR FETAL ORIGINS OF ADULT DISEASE AND THE ASSOCIATED ROLE OF EPIGENETIC DYSREGULATION. IN ADDITION, WE PRESENT A NEW PERSPECTIVE ON THE INDUCTION OF EPIGENETIC ALTERATIONS IN UTERO, WHICH SUBSEQUENTLY LEAD TO AN AGING PHENOTYPE MARKED BY INCREASED SUSCEPTIBILITY TO AGE-RELATED DISEASES. 2010 20 2137 26 EPIGENETIC INHERITANCE AND EVOLUTION: A PATERNAL PERSPECTIVE ON DIETARY INFLUENCES. THE EARLIEST INDICATIONS FOR PATERNALLY INDUCED TRANSGENERATIONAL EFFECTS FROM THE ENVIRONMENT TO FUTURE GENERATIONS WERE BASED ON A SMALL NUMBER OF LONG-TERM EPIDEMIOLOGICAL STUDIES AND SOME EMPIRICAL OBSERVATIONS. ONLY RECENTLY HAVE EXPERIMENTAL ANIMAL MODELS AND A FEW ANALYSES ON HUMAN DATA EXPLORED THE TRANSGENERATIONAL NATURE OF PHENOTYPIC CHANGES OBSERVED IN OFFSPRING. CHANGES INCLUDE MULTIPLE METABOLIC DISORDERS, CANCER AND OTHER CHRONIC DISEASES. THESE PHENOTYPES CANNOT ALWAYS BE EXPLAINED BY MENDELIAN INHERITANCE, DNA MUTATIONS OR GENETIC DAMAGE. HENCE, A NEW COMPELLING THEORY ON EPIGENETIC INHERITANCE IS GAINING INTEREST, PROVIDING NEW CONCEPTS THAT EXTEND DARWIN'S EVOLUTIONARY THEORY. EPIGENETIC ALTERATIONS OR "EPIMUTATIONS" ARE BEING CONSIDERED TO EXPLAIN TRANSGENERATIONAL INHERITANCE OF PARENTALLY ACQUIRED TRAITS. THE RESPONSIBLE MECHANISMS FOR THESE EPIMUTATIONS INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND RNA-MEDIATED EFFECTS. THIS REVIEW EXPLORES THE LITERATURE ON A NUMBER OF TIME-DEPENDENT ENVIRONMENTALLY INDUCED EPIGENETIC ALTERATIONS, SPECIFICALLY THOSE FROM DIETARY EXPOSURES. WE SUGGEST A ROLE FOR THE MALE GERM LINE AS ONE OF NATURE'S TOOLS TO CAPTURE MESSAGES FROM OUR CONTINUOUSLY CHANGING ENVIRONMENT AND TO TRANSFER THIS INFORMATION TO SUBSEQUENT GENERATIONS. FURTHER, WE OPEN THE DISCUSSION THAT THE PATERNALLY INHERITED EPIGENETIC INFORMATION MAY CONTRIBUTE TO EVOLUTIONARY ADAPTATION. 2015