1 6894 80 [SOCIAL INEQUALITY AND MENTAL HEALTH]. SOCIAL INEQUALITY REFERS TO THE INEQUITABLE DISTRIBUTION OF SOCIAL PROSPERITY INCLUDING THE RESOURCE OF HEALTH. THE RELATIONSHIP BETWEEN SOCIAL INEQUALITY AND MENTAL HEALTH CAN BE ESTABLISHED BY MEANS OF INDICATORS OF SOCIAL INEQUALITY THROUGHOUT ALL AGE GROUPS IN GERMANY. THERE ARE SOCIAL GRADIENTS OF MENTAL HEALTH ON THE POPULATION LEVEL, I.E. THE LINEAR RELATIONSHIP BETWEEN SOCIAL CLASSES OR STATUS AND STATE OF HEALTH. FUNDAMENTAL DETERMINANTS OF HEALTH DISPARITY ARE CULTURAL, SOCIAL, POLITICAL, AND GEOGRAPHICAL CONDITIONS, WHICH INTERACT WITH THE GENETIC MAKE-UP AND EPIGENETIC PROCESSES. THESE DETERMINANTS ALSO INFLUENCE THE MANAGEMENT OF DEVELOPMENTAL TASKS DURING THE LIFE COURSE AND ARE OF UTMOST IMPORTANCE FOR THE DEVELOPMENT OF MENTAL DISORDERS. THE MALADAPTATION TO CHRONIC STRESS IS AT THE CORE OF HEALTH DISPARITY. INTERVENTIONS AT THE INDIVIDUAL BEHAVIORAL LEVEL SHOULD COMPRISE THE DEVELOPMENT OF STRESS MANAGEMENT AND COPING STRATEGIES. 2019 2 2724 31 EXPERIENCE-SENSITIVE EPIGENETIC MECHANISMS, DEVELOPMENTAL PLASTICITY, AND THE BIOLOGICAL EMBEDDING OF CHRONIC DISEASE RISK. A WIDE RANGE OF DEVELOPMENTAL, NUTRITIONAL, ENVIRONMENTAL, AND SOCIAL FACTORS AFFECT THE BIOLOGICAL ACTIVITIES OF EPIGENETIC MECHANISMS. THESE FACTORS CHANGE SPATIOTEMPORAL PATTERNS OF GENE EXPRESSION IN A VARIETY OF DIFFERENT WAYS AND BRING SIGNIFICANT IMPACTS TO BEAR ON DEVELOPMENT, PHYSIOLOGY, AND DISEASE RISK THROUGHOUT THE LIFE COURSE. ABUNDANT EVIDENCE DEMONSTRATES THAT BEHAVIORAL STRESSORS AND ADVERSE NUTRITIONAL CONDITIONS ARE PARTICULARLY POTENT INDUCERS OF EPIGENETIC CHANGES AND ENHANCERS OF CHRONIC DISEASE RISKS. RECENT INSIGHTS FROM BOTH HUMAN CLINICAL STUDIES AND RESEARCH WITH MODEL ORGANISMS FURTHER INDICATE THAT SUCH EXPERIENCE-DEPENDENT CHANGES TO THE EPIGENOME CAN BE TRANSMITTED THROUGH THE GERMLINE ACROSS MULTIPLE GENERATIONS, WITH IMPORTANT CONSEQUENCES FOR THE HERITABILITY OF BOTH ADAPTIVE AND MALADAPTIVE PHENOTYPES. EPIGENETICS RESEARCH THUS OFFERS MANY POSSIBILITIES FOR DEVELOPING INFORMATIVE BIOMARKERS OF ACQUIRED CHRONIC DISEASE RISK AND DETERMINING THE EFFECTIVENESS OF PREVENTIVE AND THERAPEUTIC INTERVENTIONS. MOREOVER, THE EXPERIENCE-SENSITIVE NATURE OF THESE DISEASE RISKS RAISES IMPORTANT QUESTIONS ABOUT SOCIETAL AND INDIVIDUAL RESPONSIBILITIES FOR THE PREVENTION OF ILL-HEALTH AND THE PROMOTION OF WELL-BEING DURING DEVELOPMENT, ACROSS THE LIFE COURSE AND BETWEEN GENERATIONS. BETTER UNDERSTANDING OF HOW EPIGENETIC MECHANISMS REGULATE DEVELOPMENTAL PLASTICITY AND MEDIATE THE BIOLOGICAL EMBEDDING OF CHRONIC DISEASE RISKS IS THEREFORE LIKELY TO SHED IMPORTANT NEW LIGHT ON THE NATURE OF THE PATHOPHYSIOLOGICAL MECHANISMS LINKING SOCIAL AND HEALTH INEQUALITIES, AND WILL HELP TO INFORM PUBLIC POLICY INITIATIVES IN THIS AREA. CONFLICT OF INTEREST: THE AUTHOR HAS DECLARED NO CONFLICTS OF INTEREST FOR THIS ARTICLE. 2015 3 6822 30 [GENDER MEDICINE. SEX- AND GENDER-SPECIFIC ASPECTS OF CLINICAL MEDICINE]. GENDER MEDICINE STUDIES SEX- AND GENDER-BASED DIFFERENCES IN THE DEVELOPMENT AND PREVENTION OF DISEASES, THE AWARENESS AND PRESENTATION OF SYMPTOMS, AND THE EFFECTIVENESS OF THERAPY. GENDER MEDICINE IS PART OF PERSONALIZED MEDICINE, CONSIDERING DIFFERENCES IN BIOLOGICAL AND PSYCHOSOCIAL FACTORS INDIVIDUALLY. THERE ARE DIFFERENCES IN GENES, CHROMOSOMES, HORMONES, AND METABOLISM AS WELL AS DIFFERENCES IN CULTURE, ENVIRONMENT, AND SOCIETY. LIFELONG INTERACTIONS BETWEEN PHYSICAL AND PSYCHOSOCIAL FACTORS WILL INFLUENCE THE HEALTH AND ILL-HEALTH OF MEN AND WOMEN IN DIFFERENT WAYS. EPIGENETIC MODIFICATIONS PROVIDE EVIDENCE OF THE IMPACT OF ENVIRONMENT AND LIFESTYLE DURING VULNERABLE PHASES ON BIOLOGICAL PROCESSES, EFFECTING FUTURE GENERATIONS. MATERNAL LIFESTYLE AND ENVIRONMENTAL FACTORS DURING PREGNANCY CAN IMPACT THE HEALTH OF OFFSPRING IN LATER LIFE ALREADY IN UTERO IN A SEX-SPECIFIC WAY. PAIN, STRESS, AND COPING STYLES DIFFER BETWEEN MEN AND WOMEN. WOMEN EXPERIENCE MORE DRAMATIC PHYSICAL CHANGES DURING THEIR LIFETIME, WHICH ARE ASSOCIATED WITH SPECIFIC BURDENS AND PSYCHOSOCIAL ALTERATIONS. WOMEN WITH MULTIPLE ROLES AND RESPONSIBILITIES SUFFERING FROM STRESS DEVELOP DEPRESSION MORE FREQUENTLY. HOWEVER, MEN ARE OFTEN NOT DIAGNOSED AND TREATED APPROPRIATELY IN CASES OF DEPRESSION OR OSTEOPOROSIS, DISEASES THAT ARE TYPICALLY CONSIDERED "FEMALE." THERE ARE PROMINENT DIFFERENCES BETWEEN MEN AND WOMEN IN MEDICINE REGARDING THE IMMUNE SYSTEM, INFLAMMATION, AND NONCOMMUNICABLE DISEASES SUCH AS OBESITY, TYPE 2 DIABETES, HYPERTENSION, AND CARDIOVASCULAR DISEASE. WOMEN EXPERIENCE MORE OFTEN AUTOIMMUNE DISEASES AND SUFFER MORE FREQUENTLY FROM (CHRONIC) PAIN, NEURODEGENERATIVE CHANGES, AND FUNCTIONAL DISABILITIES. MEN HAVE SHORTER LIFE EXPECTANCY BUT RELATIVELY MORE HEALTHY YEARS OF LIFE, WHICH IS IN GREATER PART ASCRIBED TO PSYCHOSOCIAL DETERMINANTS. STATE-OF-THE-ART CLINICAL MEDICINE COMPRISES INDIVIDUAL RISK FACTORS BASED ON SEX- AND GENDER-SENSITIVE HEALTH PROGRAMS IN ORDER TO IMPROVE THE HEALTH-RELATED QUALITY OF LIFE FOR MEN AND WOMEN. 2014 4 4985 32 PATHWAYS TO AGING: THE MITOCHONDRION AT THE INTERSECTION OF BIOLOGICAL AND PSYCHOSOCIAL SCIENCES. COMPELLING EVIDENCE SUGGESTS THAT BOTH BIOLOGICAL AND PSYCHOSOCIAL FACTORS IMPACT THE PROCESS OF AGING. HOWEVER, OUR UNDERSTANDING OF THE DYNAMIC INTERPLAY AMONG BIOLOGICAL AND PSYCHOSOCIAL FACTORS ACROSS THE LIFE COURSE IS STILL FRAGMENTARY. FOR EXAMPLE, IT NEEDS TO BE ESTABLISHED HOW THE INTERACTION OF INDIVIDUAL FACTORS (E.G., GENETIC AND EPIGENETIC ENDOWMENT AND PERSONALITY), BEHAVIORAL FACTORS (E.G., PHYSICAL ACTIVITY, DIET, AND STRESS MANAGEMENT), AND PSYCHOSOCIAL EXPERIENCES (E.G., SOCIAL SUPPORT, WELL-BEING, SOCIOECONOMIC STATUS, AND MARRIAGE) IN PERINATAL, CHILDHOOD, AND ADULTHOOD INFLUENCE HEALTH ACROSS THE AGING CONTINUUM. THIS PAPER AIMS TO OUTLINE POTENTIAL INTERSECTION POINTS SERVING AS AN INTERFACE BETWEEN BIOLOGICAL AND PSYCHOSOCIAL FACTORS, WITH AN EMPHASIS ON THE MITOCHONDRION. MITOCHONDRIA ARE CELLULAR ORGANELLES WHICH PLAY A CRITICAL ROLE IN CELLULAR SENESCENCE. BOTH CHRONIC EXPOSURE TO PSYCHOSOCIAL STRESS AND GENETIC-BASED MITOCHONDRIAL DYSFUNCTION HAVE STRIKINGLY SIMILAR BIOLOGICAL CONSEQUENCES; BOTH PREDISPOSE INDIVIDUALS TO ADVERSE AGE-RELATED HEALTH DISORDERS AND EARLY MORTALITY. EXPLORING THE INTERACTIVE NATURE OF THE FACTORS RESULTING IN PATHWAYS TO NORMAL HEALTHY AGING, AS WELL AS THOSE LEADING TO MORBIDITY AND EARLY MORTALITY, WILL CONTINUE TO ENHANCE OUR ABILITY TO TRANSLATE RESEARCH INTO EFFECTIVE PRACTICES THAT CAN BE IMPLEMENTED THROUGHOUT THE LIFE COURSE TO OPTIMISE THE AGING PROCESS. 2011 5 6119 24 THE EPIGENETIC IMPACTS OF SOCIAL STRESS: HOW DOES SOCIAL ADVERSITY BECOME BIOLOGICALLY EMBEDDED? EPIGENETIC MECHANISMS ARE IMPLICATED IN THE PROCESSES THROUGH WHICH SOCIAL STRESSORS ERODE HEALTH IN HUMANS AND OTHER ANIMALS. HERE I REVIEW PROGRESS IN ELUCIDATING THE BIOLOGICAL PATHWAYS UNDERLYING THE SOCIAL GRADIENT IN HEALTH, WITH PARTICULAR EMPHASIS ON HOW BEHAVIORAL STRESSES INFLUENCE EPIGENOMIC VARIATION LINKED TO HEALTH. THE EVIDENCE THAT EPIGENETIC CHANGES ARE INVOLVED IN EMBEDDING OF SOCIAL STATUS-LINKED CHRONIC STRESS IS REVIEWED IN THE CONTEXT OF CURRENT KNOWLEDGE ABOUT BEHAVIOR WITHIN ANIMAL DOMINANCE HIERARCHIES AND THE IMPACTS OF SOCIAL POSITION ON BEHAVIORS THAT AFFECT HEALTH. THE ROLES OF EPIGENETIC MECHANISMS IN RESPONSES TO TRAUMA AND THE EVIDENCE FOR THEIR INVOLVEMENT IN INTERGENERATIONAL TRANSMISSION OF THE BIOLOGICAL IMPACTS OF TRAUMATIC STRESS ARE ALSO CONSIDERED. TAKEN TOGETHER, THE EMERGING INSIGHTS HAVE IMPORTANT IMPLICATIONS FOR DEVELOPMENT OF STRATEGIES TO IMPROVE SOCIETAL HEALTH AND WELL-BEING. 2016 6 1931 21 ENVIRONMENTAL EXPOSURES, THE EPIGENOME, AND AFRICAN AMERICAN WOMEN'S HEALTH. STRESS IS A COMMON FEATURE OF MODERN LIFE, BUT BOTH THE EXTENT OF EXPOSURE TO STRESSORS AND THE DOWNSTREAM EFFECTS OF THESE STRESS EXPOSURES CAN VARY CONSIDERABLY AMONG INDIVIDUALS, COMMUNITIES, AND POPULATIONS. WHEN INDIVIDUALS ARE EXPOSED TO REPEATED OR CHRONIC STRESS, WEAR AND TEAR ON THE BODY CAN ACCUMULATE AND MANIFEST IN MANY WAYS. THE TERM "ALLOSTATIC LOAD" REPRESENTS THE PHYSIOLOGICAL CONSEQUENCES OF REPEATED OR CHRONIC EXPOSURE TO ENVIRONMENTAL STRESSORS AND IS LINKED TO FLUCTUATING AND/OR HEIGHTENED NEURAL OR NEUROENDOCRINE RESPONSES. AFRICAN AMERICAN WOMEN ARE ONE POPULATION SUBGROUP THAT HAS BEEN IDENTIFIED AS POTENTIALLY HAVING BOTH AN ELEVATED ALLOSTATIC LOAD AND AN ENHANCED RESILIENCE TO EXTERNAL FACTORS. ONE MECHANISM BY WHICH ENVIRONMENTAL STRESSORS MAY IMPACT HUMAN HEALTH IS VIA EPIGENETIC REMODELING OF THE GENOME. THIS REVIEW WILL FOCUS ON WHAT IS KNOWN ABOUT HOW DIFFERENT TYPES OF ENVIRONMENTAL STRESSORS MAY AFFECT THE EPIGENOME AND EXPLORE LINKS BETWEEN EPIGENETIC REPROGRAMMING AND ALTERED ALLOSTATIC LOAD AND RESILIENCE AS IT PERTAINS TO AFRICAN AMERICAN WOMEN'S HEALTH. 2019 7 682 29 BRAIN ON STRESS: HOW THE SOCIAL ENVIRONMENT GETS UNDER THE SKIN. STRESS IS A STATE OF THE MIND, INVOLVING BOTH BRAIN AND BODY AS WELL AS THEIR INTERACTIONS; IT DIFFERS AMONG INDIVIDUALS AND REFLECTS NOT ONLY MAJOR LIFE EVENTS BUT ALSO THE CONFLICTS AND PRESSURES OF DAILY LIFE THAT ALTER PHYSIOLOGICAL SYSTEMS TO PRODUCE A CHRONIC STRESS BURDEN THAT, IN TURN, IS A FACTOR IN THE EXPRESSION OF DISEASE. THIS BURDEN REFLECTS THE IMPACT OF NOT ONLY LIFE EXPERIENCES BUT ALSO GENETIC VARIATIONS AND INDIVIDUAL HEALTH BEHAVIORS SUCH AS DIET, PHYSICAL ACTIVITY, SLEEP, AND SUBSTANCE ABUSE; IT ALSO REFLECTS STABLE EPIGENETIC MODIFICATIONS IN DEVELOPMENT THAT SET LIFELONG PATTERNS OF PHYSIOLOGICAL REACTIVITY AND BEHAVIOR THROUGH BIOLOGICAL EMBEDDING OF EARLY ENVIRONMENTS INTERACTING WITH CUMULATIVE CHANGE FROM EXPERIENCES OVER THE LIFESPAN. HORMONES ASSOCIATED WITH THE CHRONIC STRESS BURDEN PROTECT THE BODY IN THE SHORT RUN AND PROMOTE ADAPTATION (ALLOSTASIS), BUT IN THE LONG RUN, THE BURDEN OF CHRONIC STRESS CAUSES CHANGES IN THE BRAIN AND BODY THAT CAN LEAD TO DISEASE (ALLOSTATIC LOAD AND OVERLOAD). BRAIN CIRCUITS ARE PLASTIC AND REMODELED BY STRESS TO CHANGE THE BALANCE BETWEEN ANXIETY, MOOD CONTROL, MEMORY, AND DECISION MAKING. SUCH CHANGES MAY HAVE ADAPTIVE VALUE IN PARTICULAR CONTEXTS, BUT THEIR PERSISTENCE AND LACK OF REVERSIBILITY CAN BE MALADAPTIVE. HOWEVER, THE CAPACITY OF BRAIN PLASTICITY TO EFFECTS OF STRESSFUL EXPERIENCES IN ADULT LIFE HAS ONLY BEGUN TO BE EXPLORED ALONG WITH THE EFFICACY OF TOP-DOWN STRATEGIES FOR HELPING THE BRAIN CHANGE ITSELF, SOMETIMES AIDED BY PHARMACEUTICAL AGENTS AND OTHER TREATMENTS. 2012 8 6483 24 TOXIC STRESS, EPIGENETICS AND CHILD DEVELOPMENT. OBJECTIVES: TO DESCRIBE THE CONCEPT OF TOXIC STRESS, PRESENT THE BASICS OF EPIGENETICS AND DISCUSS THEIR RELATIONSHIP WITH CHILD DEVELOPMENT. DATA SOURCE: NARRATIVE LITERATURE REVIEW THROUGH A SEARCH IN THE SCIELO, LILACS, MEDLINE DATABASES USING THE TERMS ADVERSE CHILDHOOD EXPERIENCE OR EARLY LIFE STRESS, EPIGENOMIC OR EPIGENETIC, CHILD DEVELOPMENT OR INFANT DEVELOPMENT. DATA SYNTHESIS: CONTINUING STRESS RESPONSE, KNOWN AS TOXIC STRESS, CAN OCCUR WHEN A CHILD EXPERIENCES INTENSE, FREQUENT, AND/OR PROLONGED ADVERSITY-SUCH AS PHYSICAL OR EMOTIONAL ABUSE, CHRONIC NEGLECT, FOR EXAMPLE-WITHOUT ADEQUATE ADULT SUPPORT. THIS TOXIC STRESS CAN HAVE HARMFUL EFFECTS ON LEARNING, BEHAVIOR, AND HEALTH THROUGHOUT LIFE. EPIGENETICS, AN EMERGING SCIENTIFIC RESEARCH AREA?, SHOWS HOW ENVIRONMENTAL INFLUENCES AFFECT GENE EXPRESSIONS AND EXPLAINS HOW EARLY EXPERIENCES CAN IMPACT THROUGHOUT LIFE. CONCLUSIONS: TOXIC STRESS CAUSES CHANGES IN THE HUMAN BODY RESPONSE SYSTEMS THAT CAN BE EXPLAINED IN PART BY EPIGENETIC CHANGES, WHICH CAN BE TEMPORARY OR LONG-LASTING. PEDIATRICIANS MUST BE AWARE OF THESE MECHANISMS AND THEIR CONSEQUENCES, SEEKING TO PREVENT THEM AND THUS PROMOTE THE HEALTH, WELL-BEING, AND QUALITY OF LIFE OF CHILDREN, CONTRIBUTING TO THEIR FULL DEVELOPMENT. 2022 9 6554 24 TRANSGENERATIONAL EFFECTS OF EARLY ENVIRONMENTAL INSULTS ON AGING AND DISEASE INCIDENCE. ADVERSE EARLY LIFE EXPERIENCES ARE MAJOR INFLUENCES ON DEVELOPMENTAL TRAJECTORIES WITH POTENTIALLY LIFE-LONG CONSEQUENCES. PRENATAL OR EARLY POSTNATAL EXPOSURE TO STRESS, UNDERNUTRITION OR ENVIRONMENTAL TOXICANTS MAY REPROGRAM BRAIN DEVELOPMENT AND INCREASE RISK OF BEHAVIOURAL AND NEUROLOGICAL DISORDERS LATER IN LIFE. NOT ONLY EXPERIENCE WITHIN A SINGLE LIFETIME, BUT ALSO ANCESTRAL EXPERIENCE AFFECTS HEALTH TRAJECTORIES AND CHANCES OF SUCCESSFUL AGING. THE CENTRAL MECHANISM IN TRANSGENERATIONAL PROGRAMMING OF A DISEASE MAY BE THE FORMATION OF EPIGENETIC MEMORY. THIS REVIEW EXPLORES TRANSGENERATIONAL EFFECTS OF EARLY ADVERSE EXPERIENCE ON HEALTH AND DISEASE INCIDENCE IN OLDER AGE. FIRST, WE ADDRESS MECHANISMS OF DEVELOPMENTAL AND TRANSGENERATIONAL PROGRAMMING OF DISEASE AND INHERITANCE. SECOND, WE DISCUSS EXPERIMENTAL AND CLINICAL FINDINGS LINKING EARLY ENVIRONMENTAL DETERMINANTS TO ADVERSE AGING TRAJECTORIES IN ASSOCIATION WITH POSSIBLE PARENTAL CONTRIBUTIONS AND SEX-SPECIFIC EFFECTS. THIRD, WE OUTLINE THE MAIN MECHANISMS OF AGE-RELATED FUNCTIONAL DECLINE AND SUGGEST POTENTIAL INTERVENTIONS TO REVERSE NEGATIVE EFFECTS OF TRANSGENERATIONAL PROGRAMMING. THUS, STRATEGIES THAT SUPPORT HEALTHY DEVELOPMENT AND SUCCESSFUL AGING SHOULD TAKE INTO ACCOUNT THE POTENTIAL INFLUENCES OF TRANSGENERATIONAL INHERITANCE. 2020 10 2638 21 EPIGENOME: BIOSENSOR OF CUMULATIVE EXPOSURE TO CHEMICAL AND NONCHEMICAL STRESSORS RELATED TO ENVIRONMENTAL JUSTICE. UNDERSTANDING DIFFERENTIAL DISEASE SUSCEPTIBILITY REQUIRES NEW TOOLS TO QUANTIFY THE CUMULATIVE EFFECTS OF ENVIRONMENTAL STRESS. EVIDENCE SUGGESTS THAT SOCIAL, PHYSICAL, AND CHEMICAL STRESSORS CAN INFLUENCE DISEASE THROUGH THE ACCUMULATION OF EPIGENETIC MODIFICATIONS. GEOGRAPHICALLY STABLE EPIGENETIC ALTERATIONS COULD IDENTIFY PLAUSIBLE MECHANISMS FOR HEALTH DISPARITIES AMONG THE DISADVANTAGED AND POOR. RELATIONS BETWEEN NEIGHBORHOOD-SPECIFIC EPIGENETIC MARKERS AND DISEASE WOULD IDENTIFY THE MOST APPROPRIATE TARGETS FOR MEDICAL AND ENVIRONMENTAL INTERVENTION. COMPLEX INTERACTIONS AMONG GENES, THE ENVIRONMENT, AND DISEASE REQUIRE THE EXAMINATION OF HOW EPIGENETIC CHANGES REGULATE SUSCEPTIBILITY TO ENVIRONMENTAL STRESSORS. PROGRESS IN UNDERSTANDING DISPARITIES IN DISEASE SUSCEPTIBILITY MAY DEPEND ON ASSESSING THE CUMULATIVE EFFECT OF ENVIRONMENTAL STRESSORS ON GENETIC SUBSTRATES. WE HIGHLIGHT KEY CONCEPTS REGARDING THE INTERFACE BETWEEN ENVIRONMENTAL STRESS, EPIGENETICS, AND CHRONIC DISEASE. 2014 11 380 31 AN EPIGENETIC PERSPECTIVE ON LIFESTYLE MEDICINE FOR DEPRESSION: IMPLICATIONS FOR PRIMARY CARE PRACTICE. DEPRESSION IS THE MOST COMMON PRESENTING MENTAL HEALTH DISORDER IN PRIMARY CARE. IT IS ALSO A MAJOR CONTRIBUTOR TO SOMATIC COMPLAINTS, WORSENING OF CHRONIC MEDICAL CONDITIONS, POOR QUALITY OF LIFE, AND SUICIDE. CURRENT PHARMACOLOGIC AND PSYCHOTHERAPEUTIC APPROACHES AVERT LESS THAN HALF OF DEPRESSION'S CUMULATIVE BURDEN ON SOCIETY. HOWEVER, THERE IS A GROWING BODY OF RESEARCH DESCRIBING BOTH HOW MALADAPTIVE LIFESTYLE CHOICES CONTRIBUTE TO THE DEVELOPMENT AND WORSENING OF DEPRESSION AND HOW LIFESTYLE-ORIENTED MEDICAL INTERVENTIONS CAN REDUCE THE INCIDENCE AND SEVERITY OF DEPRESSION. THIS RESEARCH, LARGELY DERIVED FROM AN EMERGING FIELD CALLED EPIGENETICS, ELUCIDATES THE INTERACTIONS BETWEEN OUR LIFESTYLE CHOICES AND THOSE EPIGENETIC FACTORS WHICH MEDIATE OUR TENDENCIES TOWARD EITHER HEALTH, OR THE ONSET, IF NOT WORSENING OF DISEASE. THE PRESENT REVIEW HIGHLIGHTS HOW LIFESTYLE CHOICES INVOLVING DIET, PHYSICAL ACTIVITY, SLEEP, SOCIAL RELATIONSHIPS, AND STRESS INFLUENCE EPIGENETIC PROCESSES POSITIVELY OR NEGATIVELY, AND THEREBY PLAY A SIGNIFICANT ROLE IN DETERMINING WHETHER ONE DOES OR DOES NOT SUFFER FROM DEPRESSION. THE AUTHORS PROPOSE THAT MEDICAL TRAINING PROGRAMS CONSIDER AND ADOPT LIFESTYLE MEDICINE ORIENTED INSTRUCTIONAL INITIATIVES THAT WILL ENABLE TOMORROW'S PRIMARY CARE PROVIDERS TO MORE EFFECTIVELY IDENTIFY AND THERAPEUTICALLY INTERVENE IN THE MALADAPTIVE CHOICES CONTRIBUTING TO THEIR PATIENTS' DEPRESSION. 2022 12 4591 22 NARRATIVE REVIEW OF THE COMPLEX INTERACTION BETWEEN PAIN AND TRAUMA IN CHILDREN: A FOCUS ON BIOLOGICAL MEMORY, PRECLINICAL DATA, AND EPIGENETIC PROCESSES. THE INCIDENCE AND COLLECTIVE IMPACT OF EARLY ADVERSE EXPERIENCES, TRAUMA, AND PAIN CONTINUE TO INCREASE. THIS UNDERSCORES THE URGENT NEED FOR TRANSLATIONAL EFFORTS BETWEEN CLINICAL AND PRECLINICAL RESEARCH TO BETTER UNDERSTAND THE UNDERLYING MECHANISMS AND DEVELOP EFFECTIVE THERAPEUTIC APPROACHES. AS OUR UNDERSTANDING OF THESE ISSUES IMPROVES FROM STUDIES IN CHILDREN AND ADOLESCENTS, WE CAN CREATE MORE PRECISE PRECLINICAL MODELS AND ULTIMATELY TRANSLATE OUR FINDINGS BACK TO CLINICAL PRACTICE. A MULTIDISCIPLINARY APPROACH IS ESSENTIAL FOR ADDRESSING THE COMPLEX AND WIDE-RANGING EFFECTS OF THESE EXPERIENCES ON INDIVIDUALS AND SOCIETY. THIS NARRATIVE REVIEW AIMS TO (1) DEFINE PAIN AND TRAUMA EXPERIENCES IN CHILDHOOD AND ADOLESCENTS, (2) DISCUSS THE RELATIONSHIP BETWEEN PAIN AND TRAUMA, (3) CONSIDER THE ROLE OF BIOLOGICAL MEMORY, (4) DECIPHER THE RELATIONSHIP BETWEEN PAIN AND TRAUMA USING PRECLINICAL DATA, AND (5) EXAMINE THE ROLE OF THE ENVIRONMENT BY INTRODUCING THE IMPORTANCE OF EPIGENETIC PROCESSES. THE ULTIMATE SCOPE IS TO BETTER UNDERSTAND THE WIDE-RANGING EFFECTS OF TRAUMA, ABUSE, AND CHRONIC PAIN ON CHILDREN AND ADOLESCENTS, HOW THEY OCCUR, AND HOW TO PREVENT OR MITIGATE THEIR EFFECTS AND DEVELOP EFFECTIVE TREATMENT STRATEGIES THAT ADDRESS BOTH THE UNDERLYING CAUSES AND THE ASSOCIATED PHYSIOLOGICAL AND PSYCHOLOGICAL EFFECTS. 2023 13 1911 23 ENVIRONMENT IN CHILDREN'S HEALTH: A NEW CHALLENGE FOR RISK ASSESSMENT. IN THE LAST FEW YEARS, MANY STUDIES HAVE FOCUSED ON THE EFFECTS OF ENVIRONMENTAL CONTAMINANT EXPOSURE DURING THE PRENATAL PERIOD OR INFANCY AS PREDICTORS OF HEALTH OUTCOMES IN THE FUTURE. IN THESE TIME WINDOWS, DUE TO THEIR RAPID GROWTH, AND PHYSIOLOGIC AND METABOLIC DEVELOPMENT, WE CAN OBSERVE A HIGHER VULNERABILITY TO THE EFFECTS OF ENVIRONMENT, WITH RESPECT TO ADULTHOOD. THE EVIDENCE OF POSSIBLE INFLUENCES, PARTLY MEDIATED BY EPIGENETIC MECHANISMS, INVOLVE NEUROBEHAVIORAL RESPONSES AND IMMUNE, ENDOCRINE, AND RESPIRATORY SYSTEMS, ACTING DIRECTLY ON THE CHILD OR INDIRECTLY WHEN MEDIATED BY PLACENTAL TRANSFER OR BREAST FEEDING. IN PARTICULAR, DUE TO A GREATER INTAKE OF AIR, FOOD, AND FLUIDS RELATIVE TO BODY WEIGHT, CRAWLING BEHAVIORS AND SHORT STATURE, THE RISK OF EXCESSIVE EXPOSURE IS GREATER IN CHILDREN. HOWEVER, DATA ON THE LONG-TERM IMPLICATIONS OF EARLY EXPOSURES ARE SCARCE. ADDITIONALLY, SO THAT PHYSICIANS AND INSTITUTIONS FOR CHILD CARE AND ASSISTANCE OF PREGNANT WOMEN CAN TAKE ACTIONS TO COUNTERACT THE EFFECTS OF CHEMICAL POLLUTION (I.E., BY EDUCATIONAL OPPORTUNITIES), A RISK ASSESSMENT PERSPECTIVE THAT RESPONDS TO THE BIOCOMPLEXITY OF THE HUMAN BEING IS NEEDED. THE PRESENT PAPER PROVIDES AN OVERVIEW OF PHYSIOLOGIC AND BEHAVIORAL CHARACTERISTICS DURING THE PERINATAL PERIOD AND IN CHILDHOOD, SUGGESTING IN A MORE INTEGRATED WAY, THE NEED OF A NEW RISK-ASSESSMENT APPROACH TO MANAGING CHRONIC DISEASE IN PEDIATRIC PATIENTS. 2021 14 585 23 BEHAVIORAL PERINATOLOGY: BIOBEHAVIORAL PROCESSES IN HUMAN FETAL DEVELOPMENT. BEHAVIORAL PERINATOLOGY IS AS AN INTERDISCIPLINARY AREA OF RESEARCH THAT INVOLVES CONCEPTUALIZATION OF THEORETICAL MODELS AND CONDUCT OF EMPIRICAL STUDIES OF THE DYNAMIC TIME-, PLACE-, AND CONTEXT-DEPENDENT INTERPLAY BETWEEN BIOLOGICAL AND BEHAVIORAL PROCESSES IN FETAL, NEONATAL, AND INFANT LIFE USING AN EPIGENETIC FRAMEWORK OF DEVELOPMENT. THE BIOBEHAVIORAL PROCESSES OF PARTICULAR INTEREST TO OUR RESEARCH GROUP RELATE TO THE EFFECTS OF MATERNAL PRE- AND PERINATAL STRESS AND MATERNAL-PLACENTAL-FETAL STRESS PHYSIOLOGY. WE PROPOSE THAT BEHAVIORAL PERINATOLOGY RESEARCH MAY HAVE IMPORTANT IMPLICATIONS FOR A BETTER UNDERSTANDING OF THE PROCESSES THAT UNDERLIE OR CONTRIBUTE TO THE RISK OF THREE SETS OF OUTCOMES: PREMATURITY, ADVERSE NEURODEVELOPMENT, AND CHRONIC DEGENERATIVE DISEASES IN ADULTHOOD. BASED ON OUR UNDERSTANDING OF THE ONTOGENY OF HUMAN FETAL DEVELOPMENT AND THE PHYSIOLOGY OF PREGNANCY AND FETAL DEVELOPMENT, WE HAVE ARTICULATED A NEUROBIOLOGICAL MODEL OF PRE- AND PERINATAL STRESS. OUR MODEL PROPOSES THAT CHRONIC MATERNAL STRESS MAY EXERT A SIGNIFICANT INFLUENCE ON FETAL DEVELOPMENTAL OUTCOMES. MATERNAL STRESS MAY ACT VIA ONE OR MORE OF THREE MAJOR PHYSIOLOGICAL PATHWAYS: NEUROENDOCRINE, IMMUNE/INFLAMMATORY, AND VASCULAR. WE FURTHER SUGGEST THAT PLACENTAL CORTICOTROPIN-RELEASING HORMONE (CRH) MAY PLAY A CENTRAL ROLE IN COORDINATING THE EFFECTS OF ENDOCRINE, IMMUNE/INFLAMMATORY, AND VASCULAR PROCESSES ON FETAL DEVELOPMENTAL OUTCOMES. FINALLY, WE HYPOTHESIZE THAT THE EFFECTS OF MATERNAL STRESS ARE MODULATED BY THE NATURE, DURATION, AND TIMING OF OCCURRENCE OF STRESS DURING GESTATION. IN THIS PAPER, WE ELABORATE ON THE CONCEPTUAL AND EMPIRICAL BASIS FOR THIS MODEL, HIGHLIGHT SOME RELEVANT ISSUES AND QUESTIONS, AND MAKE RECOMMENDATIONS FOR FUTURE RESEARCH IN THIS AREA. 2002 15 5316 21 PSYCHOLOGICAL STRESS IN EARLY LIFE AS A PREDISPOSING FACTOR FOR THE DEVELOPMENT OF CHRONIC PAIN: CLINICAL AND PRECLINICAL EVIDENCE AND NEUROBIOLOGICAL MECHANISMS. A WEALTH OF RESEARCH OVER THE PAST 2 DECADES HAS EXPANDED OUR UNDERSTANDING OF THE IMPACT OF EARLY-LIFE ADVERSITY ON PHYSIOLOGICAL FUNCTION AND, CONSEQUENTLY, HEALTH AND WELLBEING IN LATER LIFE. EARLY-LIFE ADVERSITY INCREASES THE RISK OF DEVELOPING A NUMBER OF DISORDERS, SUCH AS CHRONIC PAIN, FIBROMYALGIA, AND IRRITABLE BOWEL SYNDROME. ALTHOUGH MUCH OF THE RESEARCH HAS EXAMINED THE IMPACT OF PHYSICAL MALTREATMENT, AN INCREASING NUMBER OF STUDIES HAVE BEEN PUBLISHED OVER THE PAST FEW YEARS EXAMINING THE EFFECT OF CHILDHOOD PSYCHOLOGICAL STRESS AND TRAUMA ON THE DEVELOPMENT OF VARIOUS TYPES OF CHRONIC PAIN CONDITIONS. WE REVIEW THE CLINICAL AND PRECLINICAL DATA EXAMINING THE LINK AMONG EARLY-LIFE PSYCHOLOGICAL STRESS, ALTERED NOCICEPTIVE BEHAVIOR, AND CHRONIC PAIN IN LATER LIFE. EVIDENCE SUPPORTING A ROLE FOR CERTAIN KEY NEUROBIOLOGICAL SUBSTRATES, INCLUDING THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS; MONOAMINERGIC, OPIOIDERGIC, ENDOCANNABINOID AND IMMUNE SYSTEMS; AND EPIGENETIC MECHANISMS IN THE ASSOCIATION BETWEEN EARLY-LIFE PSYCHOLOGICAL STRESS AND CHRONIC PAIN, IS PROVIDED. GREATER UNDERSTANDING OF THE IMPACT OF EARLY-LIFE STRESS MAY INFORM THE DEVELOPMENT OF PERSONALIZED TREATMENTS FOR CHRONIC PAIN IN LATER LIFE AND STRATEGIES TO PREVENT ITS ONSET IN SUSCEPTIBLE INDIVIDUALS. (C) 2016 WILEY PERIODICALS, INC. 2017 16 1779 31 EDITORIAL: MATERNAL INFLAMMATION DURING PREGNANCY: A MODIFIABLE PATHWAY TOWARD IMPROVING OFFSPRING SOCIOEMOTIONAL OUTCOMES IN CHILDHOOD AND ADOLESCENCE. CHILDHOOD PSYCHOPATHOLOGY IS A WELL-ESTABLISHED PREDICTOR OF POOR ADULT LIFE-COURSE OUTCOMES INCLUDING LOWER RATES OF EDUCATIONAL ATTAINMENT AND REDUCED FAMILY INCOME, WITH A TOTAL ECONOMIC LOSS OF $2.1 TRILLION IN THE UNITED STATES.(1) GIVEN THIS HIGH LEVEL OF INDIVIDUAL AND SOCIETAL BURDEN, MUCH EFFORT HAS BEEN DEVOTED TO IDENTIFYING THE MODIFIABLE RISK FACTORS THAT CONFER RISK FOR PSYCHIATRIC DISORDERS DURING EARLY CHILDHOOD. INDEED, NUMEROUS ASPECTS OF EARLY LIFE ADVERSITY, SUCH AS SOCIOECONOMIC DISADVANTAGE, STRESSFUL/TRAUMATIC LIFE EVENTS, AND DISRUPTED PARENT-CHILD RELATIONSHIPS, DEMONSTRATE STRONG ASSOCIATIONS WITH SOCIOEMOTIONAL PROBLEMS AND PSYCHIATRIC DISORDERS INTO ADOLESCENCE.(2) HOWEVER, THE UNDERLYING BIOLOGICAL MECHANISMS THAT ALSO CONTRIBUTE TO THIS RISK TRAJECTORY REMAIN LESS WELL UNDERSTOOD. ONE PROPOSED BIOLOGICAL MECHANISM THAT IS RAPIDLY GAINING MOMENTUM IN THE FIELD OF DEVELOPMENTAL PSYCHOPATHOLOGY CONCERNS EXCESSIVE IMMUNE SYSTEM ACTIVATION AND/OR PROINFLAMMATORY RESPONSES IN THE ORIGINS OF HEALTH AND DISEASE.(3) OF PARTICULAR INTEREST IS THE PRENATAL PERIOD, REPRESENTING A WINDOW OF VULNERABILITY IN WHICH PRENATAL EXPOSURES PREPARE OR PROGRAM THE FETUS FOR THE EXPECTED POSTNATAL ENVIRONMENT.(3-5) MORE SPECIFICALLY, FETAL PROGRAMMING POSITS THAT THE EFFECTS OF MATERNAL ADVERSITY DURING PREGNANCY ARE, AT LEAST IN PART, TRANSMITTED TO THE FETUS VIA MULTIPLE RELATED PATHWAYS INCLUDING CHRONIC MATERNAL INFLAMMATION AND/OR OVERACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, RESULTING IN ABERRANT MATERNAL-FETAL IMMUNE/GLUCOCORTICOID SYSTEMS AND DOWNSTREAM EPIGENETIC ALTERATIONS IN THE DEVELOPING FETUS. TOGETHER, THESE FACTORS WORK TO INCREASE THE SUSCEPTIBILITY OF OFFSPRING TO ADVERSITY IN THE POSTNATAL ENVIRONMENT AND, IN TURN, ENHANCE RISK FOR PSYCHIATRIC DISORDERS.(3-6) HOWEVER, MUCH OF THE EXISTING LITERATURE IS BASED ON PRECLINICAL ANIMAL MODELS WITH COMPARATIVELY FEWER CLINICAL STUDIES.(3) AS SUCH, THERE REMAINS A PAUCITY OF LARGE, PROSPECTIVELY DESIGNED CLINICAL STUDIES EXAMINING MATERNAL PROINFLAMMATORY CONDITIONS DURING PREGNANCY IN RELATION TO PSYCHOPATHOLOGY IN OFFSPRING. AS PART OF THE LANDMARK NATIONAL INSTITUTES OF HEALTH-FUNDED ECHO (ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOMES) CONSORTIUM, THE STUDY BY FRAZIER ET AL.(7) REPRESENTS ONE OF THE LARGEST INVESTIGATIONS LINKING PERINATAL MATERNAL PROINFLAMMATORY CONDITIONS WITH CO-OCCURRING PSYCHIATRIC SYMPTOMS IN CHILDREN AND ADOLESCENTS. 2023 17 3001 21 GENETIC, EPIGENETIC AND ENVIRONMENTAL IMPACT ON SEX DIFFERENCES IN SOCIAL BEHAVIOR. THE FIELD OF BEHAVIORAL NEUROENDOCRINOLOGY HAS GENERATED THOUSANDS OF STUDIES THAT INDICATE DIFFERENCES IN BRAIN STRUCTURE AND REACTIVITY TO GONADAL STEROIDS THAT PRODUCE SEX-SPECIFIC PATTERNS OF SOCIAL BEHAVIOR. HOWEVER, RAPIDLY EMERGING EVIDENCE SHOWS THAT GENETIC POLYMORPHISMS AND RESULTING DIFFERENCES IN THE EXPRESSION OF NEUROACTIVE PEPTIDES AND RECEPTORS AS WELL AS EARLY-LIFE EXPERIENCE AND EPIGENETIC CHANGES ARE IMPORTANT MODIFIERS OF SOCIAL BEHAVIOR. FURTHERMORE, DUE TO ITS INHERENT COMPLEXITY, THE NEUROCHEMICAL MECHANISMS UNDERLYING SEX DIFFERENCES IN SOCIAL BEHAVIOR ARE USUALLY STUDIED IN A TIGHTLY REGULATED LABORATORY SETTING RATHER THAN IN COMPLEX ENVIRONMENTS. IMPORTANTLY, SPECIFIC HORMONES MAY ELICIT A RANGE OF DIFFERENT BEHAVIORS DEPENDING ON THE CUES PRESENT IN THESE ENVIRONMENTS. FOR EXAMPLE, INDIVIDUALS EXPOSED TO A PSYCHOSOCIAL STRESSOR MAY RESPOND DIFFERENTLY TO THE EFFECTS OF A GONADAL STEROID THAN THOSE NOT EXPOSED TO CHRONIC STRESS. THE OBJECTIVE OF THIS REVIEW IS NOT TO RE-EXAMINE THE ACTIVATIONAL EFFECTS OF HORMONES ON SEX DIFFERENCES IN SOCIAL BEHAVIOR BUT RATHER TO CONSIDER HOW GENETIC AND ENVIRONMENTAL FACTORS MODIFY THE EFFECTS OF HORMONES ON BEHAVIOR. WE WILL FOCUS ON ESTROGEN AND ITS RECEPTORS BUT CONSIDERATION IS ALSO GIVEN TO THE ROLE OF ANDROGENS. FURTHERMORE, WE HAVE LIMITED OUR DISCUSSIONS TO THE IMPORTANCE OF OXYTOCIN AND VASOPRESSIN AS TARGETS OF GONADAL STEROIDS AND HOW THESE EFFECTS ARE MODIFIED BY GENETIC AND EXPERIENTIAL SITUATIONS. TAKEN TOGETHER, THE DATA CLEARLY UNDERSCORE THE NEED TO EXPAND RESEARCH INITIATIVES TO CONSIDER GENE-ENVIRONMENT INTERACTIONS FOR BETTER UNDERSTANDING OF THE NEUROBIOLOGY OF SEX DIFFERENCES IN SOCIAL BEHAVIOR. 2009 18 1229 25 CRITICAL WINDOWS: EXPLORING THE ASSOCIATION BETWEEN PERINATAL TRAUMA, EPIGENETICS, AND CHRONIC PAIN. CHRONIC PAIN IS HIGHLY PREVALENT AND BURDENSOME, AFFECTING MILLIONS OF PEOPLE WORLDWIDE. ALTHOUGH IT EMERGES AT ANY POINT IN LIFE, IT OFTEN MANIFESTS IN ADOLESCENCE. GIVEN THAT ADOLESCENCE IS A UNIQUE DEVELOPMENTAL PERIOD, ADDITIONAL STRAINS ASSOCIATED WITH PERSISTENT AND OFTEN IDIOPATHIC PAIN LEAD TO SIGNIFICANT LONG-TERM CONSEQUENCES. WHILE THERE IS NO SINGULAR CAUSE FOR THE CHRONIFICATION OF PAIN, EPIGENETIC MODIFICATIONS THAT LEAD TO NEURAL REORGANIZATION MAY UNDERPIN CENTRAL SENSITIZATION AND SUBSEQUENT MANIFESTATION OF PAIN HYPERSENSITIVITY. EPIGENETIC PROCESSES ARE PARTICULARLY ACTIVE DURING THE PRENATAL AND EARLY POSTNATAL YEARS. WE DEMONSTRATE HOW EXPOSURE TO VARIOUS TRAUMAS, SUCH AS INTIMATE PARTNER VIOLENCE WHILE IN UTERO OR ADVERSE CHILDHOOD EXPERIENCES, CAN SIGNIFICANTLY INFLUENCE EPIGENETIC REGULATION WITHIN THE BRAIN AND IN TURN MODIFY PAIN-RELATED PROCESSES. WE PROVIDE COMPELLING EVIDENCE THAT THE BURDEN OF CHRONIC PAIN IS LIKELY INITIATED EARLY IN LIFE, OFTEN BEING TRANSMITTED FROM MOTHER TO OFFSPRING. WE ALSO HIGHLIGHT TWO PROMISING PROPHYLACTIC STRATEGIES, OXYTOCIN ADMINISTRATION AND PROBIOTIC USE, THAT HAVE THE POTENTIAL TO ATTENUATE THE EPIGENETIC CONSEQUENCES OF EARLY ADVERSITY. OVERALL, WE ADVANCE UNDERSTANDING OF THE CAUSAL RELATIONSHIP BETWEEN TRAUMA AND ADOLESCENT CHRONIC PAIN BY HIGHLIGHTING EPIGENETIC MECHANISMS THAT UNDERLIE THIS TRANSMISSION OF RISK, ULTIMATELY INFORMING HOW TO PREVENT THIS RISING EPIDEMIC. 2023 19 6478 18 TOPICAL REVIEW: THE EMERGING FIELD OF EPIGENETICS: INFORMING MODELS OF PEDIATRIC TRAUMA AND PHYSICAL HEALTH. OBJECTIVE: TRAUMA EXPERIENCED DURING CHILDHOOD AND ADOLESCENCE HAS BEEN LINKED TO A NUMBER OF CHRONIC MEDICAL CONCERNS. WE HIGHLIGHT MAJOR FINDINGS FROM THE PEDIATRIC TRAUMA LITERATURE TO PROVIDE A MODEL FOR UNDERSTANDING THIS ASSOCIATION. METHODS: STUDIES EXAMINING THE EFFECTS OF TRAUMA WERE SYSTEMATICALLY REVIEWED AND SYNTHESIZED INTO A MODEL PROPOSING A CENTRAL ROLE FOR EPIGENETICS IN THE WAYS THAT CHILDHOOD EXPERIENCES CAN AFFECT HEALTH. RESULTS: EARLY HYPOTHALAMIC PITUITARY ADRENAL (HPA) AXIS RESPONSE MAY IMPACT INITIAL TRAUMA EXPERIENCE, WITH DOWNSTREAM EFFECTS ON POSTTRAUMA ADJUSTMENT REFLECTED IN POSTTRAUMA NEUROBIOLOGY, PSYCHOLOGICAL HEALTH, AND PHYSICAL HEALTH. CONCLUSIONS: PROSPECTIVE RESEARCH WITH CHILDREN AND ADOLESCENTS EXPOSED TO TRAUMA IS NEEDED TO BETTER CHARACTERIZE THE GENETIC AND EPIGENETIC INFLUENCES ON THE COURSE OF HPA AND IMMUNE PROCESSES AS RELATED TO POSTTRAUMA PSYCHOLOGICAL AND PHYSICAL HEALTH OUTCOMES. 2016 20 6026 26 THE BIOLOGY OF STRESS INTOLERANCE IN PATIENTS WITH CHRONIC PAIN-STATE OF THE ART AND FUTURE DIRECTIONS. STRESS HAS BEEN CONSISTENTLY LINKED TO NEGATIVE IMPACTS ON PHYSICAL AND MENTAL HEALTH. MORE SPECIFICALLY, PATIENTS WITH CHRONIC PAIN EXPERIENCE STRESS INTOLERANCE, WHICH IS AN EXACERBATION OR OCCURRENCE OF SYMPTOMS IN RESPONSE TO ANY TYPE OF STRESS. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING THIS PHENOMENON REMAIN UNSOLVED. IN THIS STATE-OF-THE-ART PAPER, WE SUMMARISED THE ROLE OF THE AUTONOMIC NERVOUS SYSTEM (ANS) AND HYPOTHALAMUS-PITUITARY-ADRENAL (HPA) AXIS, THE TWO MAJOR STRESS RESPONSE SYSTEMS IN STRESS INTOLERANCE. WE PROVIDED INSIGHTS INTO SUCH MECHANISMS BASED ON EVIDENCE FROM CLINICAL STUDIES IN BOTH PATIENTS WITH CHRONIC PAIN, SHOWING DYSREGULATED STRESS SYSTEMS, AND HEALTHY CONTROLS SUPPORTED BY PRECLINICAL STUDIES, HIGHLIGHTING THE LINK BETWEEN THESE SYSTEMS AND SYMPTOMS OF STRESS INTOLERANCE. FURTHERMORE, WE EXPLORED THE POSSIBLE REGULATING ROLE FOR (EPI)GENETIC MECHANISMS INFLUENCING THE ANS AND HPA AXIS. THE LINK BETWEEN STRESS AND CHRONIC PAIN HAS BECOME AN IMPORTANT AREA OF RESEARCH AS IT HAS THE POTENTIAL TO INFORM THE DEVELOPMENT OF INTERVENTIONS TO IMPROVE THE QUALITY OF LIFE FOR INDIVIDUALS LIVING WITH CHRONIC PAIN. AS STRESS HAS BECOME A PREVALENT CONCERN IN MODERN SOCIETY, UNDERSTANDING THE CONNECTION BETWEEN STRESS, HPA AXIS, ANS, AND CHRONIC HEALTH CONDITIONS SUCH AS CHRONIC PAIN IS CRUCIAL TO IMPROVE PUBLIC HEALTH AND WELL-BEING. 2023