1 5827 131 STRESS, BURNOUT AND DEPRESSION: A SYSTEMATIC REVIEW ON DNA METHYLATION MECHANISMS. DESPITE THAT BURNOUT PRESENTS A SERIOUS BURDEN FOR MODERN SOCIETY, THERE ARE NO DIAGNOSTIC CRITERIA. ADDITIONAL DIFFICULTY IS THE DIFFERENTIAL DIAGNOSIS WITH DEPRESSION. CONSEQUENTLY, THERE IS A NEED TO DISPOSE OF A BURNOUT BIOMARKER. EPIGENETIC STUDIES SUGGEST THAT DNA METHYLATION IS A POSSIBLE MEDIATOR LINKING INDIVIDUAL RESPONSE TO STRESS AND PSYCHOPATHOLOGY AND COULD BE CONSIDERED AS A POTENTIAL BIOMARKER OF STRESS-RELATED MENTAL DISORDERS. THUS, THE AIM OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF DNA METHYLATION MECHANISMS IN STRESS, BURNOUT AND DEPRESSION. IN ADDITION TO STATE-OF-THE-ART OVERVIEW, THE GOAL OF THIS REVIEW IS TO PROVIDE A SCIENTIFIC BASE FOR BURNOUT BIOMARKER RESEARCH. WE PERFORMED A SYSTEMATIC LITERATURE SEARCH AND IDENTIFIED 25 PERTINENT ARTICLES. AMONG THESE, 15 FOCUSED ON DEPRESSION, 7 ON CHRONIC STRESS AND ONLY 3 ON WORK STRESS/BURNOUT. THREE EPIGENOME-WIDE STUDIES WERE IDENTIFIED AND THE MAJORITY OF STUDIES USED THE CANDIDATE-GENE APPROACH, ASSESSING 12 DIFFERENT GENES. THE GLUCOCORTICOID RECEPTOR GENE (NR3C1) DISPLAYED DIFFERENT METHYLATION PATTERNS IN CHRONIC STRESS AND DEPRESSION. THE SEROTONIN TRANSPORTER GENE (SLC6A4) METHYLATION WAS SIMILARLY AFFECTED IN STRESS, DEPRESSION AND BURNOUT. WORK-RELATED STRESS AND DEPRESSIVE SYMPTOMS WERE ASSOCIATED WITH DIFFERENT METHYLATION PATTERNS OF THE BRAIN DERIVED NEUROTROPHIC FACTOR GENE (BDNF) IN THE SAME HUMAN SAMPLE. THE TYROSINE HYDROXYLASE (TH) METHYLATION WAS CORRELATED WITH WORK STRESS IN A SINGLE STUDY. ADDITIONAL, THOROUGHLY DESIGNED LONGITUDINAL STUDIES ARE NECESSARY FOR REVEALING THE CAUSE-EFFECT RELATIONSHIP OF WORK STRESS, EPIGENETICS AND BURNOUT, INCLUDING ITS OVERLAP WITH DEPRESSION. 2017 2 2021 38 EPIGENETIC CHANGES ASSOCIATED WITH DIFFERENT TYPES OF STRESSORS AND SUICIDE. STRESS IS ASSOCIATED WITH VARIOUS EPIGENETIC CHANGES. SOME STRESS-INDUCED EPIGENETIC CHANGES ARE HIGHLY DYNAMIC, WHEREAS OTHERS ARE ASSOCIATED WITH LASTING MARKS ON THE EPIGENOME. IN OUR STUDY, A COMPREHENSIVE NARRATIVE REVIEW OF THE LITERATURE WAS PERFORMED BY INVESTIGATING THE EPIGENETIC CHANGES THAT OCCUR WITH ACUTE STRESS, CHRONIC STRESS, EARLY CHILDHOOD STRESS, AND TRAUMATIC STRESS EXPOSURES, ALONG WITH EXAMINING THOSE OBSERVED IN POST-MORTEM BRAINS OR BLOOD SAMPLES OF SUICIDE COMPLETERS AND ATTEMPTERS. IN ADDITION, THE TRANSGENERATIONAL EFFECTS OF THESE CHANGES ARE REPORTED. FOR ALL TYPES OF STRESS STUDIES EXAMINED, THE GENES NR3C1, OXTR, SLC6A4, AND BDNF REPRODUCIBLY SHOWED EPIGENETIC CHANGES, WITH SOME MODIFICATIONS OBSERVED TO BE PASSED DOWN TO SUBSEQUENT GENERATIONS FOLLOWING STRESS EXPOSURES. THE AFOREMENTIONED GENES ARE KNOWN TO BE INVOLVED IN NEURONAL DEVELOPMENT AND HORMONAL REGULATION AND ARE ALL ASSOCIATED WITH SUSCEPTIBILITY TO MENTAL HEALTH DISORDERS INCLUDING DEPRESSION, ANXIETY, PERSONALITY DISORDERS, AND PTSD (POST-TRAUMATIC STRESS DISORDER). FURTHER RESEARCH IS WARRANTED IN ORDER TO DETERMINE THE SCOPE OF EPIGENETIC ACTIONABLE TARGETS IN INDIVIDUALS SUFFERING FROM THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES. 2023 3 2677 31 EVALUATING THE CHALLENGES AND REPRODUCIBILITY OF STUDIES INVESTIGATING DNA METHYLATION SIGNATURES OF PSYCHOLOGICAL STRESS. PSYCHOLOGICAL STRESS CAN INCREASE THE RISK OF A WIDE RANGE OF NEGATIVE HEALTH OUTCOMES. STUDIES HAVE BEEN COMPLETED TO DETERMINE IF DNA METHYLATION CHANGES OCCUR IN THE HUMAN BRAIN BECAUSE OF STRESS AND ARE ASSOCIATED WITH LONG-TERM EFFECTS AND DISEASE, BUT RESULTS HAVE BEEN INCONSISTENT. HUMAN CANDIDATE GENE STUDIES (150) AND EPIGENOME-WIDE ASSOCIATION STUDIES (67) WERE SYSTEMATICALLY EVALUATED TO ASSESS HOW DNA METHYLATION IS IMPACTED BY STRESS DURING THE PRENATAL PERIOD, EARLY CHILDHOOD AND ADULTHOOD. THE ASSOCIATION BETWEEN DNA METHYLATION OF NR3C1 EXON 1F AND CHILD MALTREATMENT AND EARLY LIFE ADVERSITY WAS WELL DEMONSTRATED, BUT OTHER GENES DID NOT EXHIBIT A CLEAR ASSOCIATION. THE REPRODUCIBILITY OF INDIVIDUAL CPG SITES IN EPIGENOME-WIDE ASSOCIATION STUDIES WAS ALSO POOR. HOWEVER, BIOLOGICAL PATHWAYS, INCLUDING STRESS RESPONSE, BRAIN DEVELOPMENT AND IMMUNITY, HAVE BEEN CONSISTENTLY IDENTIFIED ACROSS DIFFERENT STRESSORS THROUGHOUT THE LIFE SPAN. FUTURE STUDIES WOULD BENEFIT FROM THE INCREASED SAMPLE SIZE, LONGITUDINAL DESIGN, STANDARDIZED METHODOLOGY, OPTIMAL QUALITY CONTROL, AND IMPROVED STATISTICAL PROCEDURES. 2022 4 632 44 BIOLOGICAL CORRELATES OF EARLY LIFE STRESSFUL EVENTS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS THE MOST COMMON PSYCHIATRIC DISORDER AND RESPONDS FOR IMPORTANT PSYCHOSOCIAL CONSEQUENCES. STRESSFUL LIFE EVENTS, ESPECIALLY EARLY LIFE STRESS (ELS), CONTRIBUTE TO AN INCREASED PROBABILITY TO DEVELOP MDD, LEADING IN PARTICULAR TO SEVERE AND CHRONIC MANIFESTATION AND UNFAVORABLE TREATMENT OUTCOME. THE ASSOCIATION BETWEEN ELS AND MDD SEEMS TO HAVE BIOLOGICAL BASES, CONSISTING IN DYSREGULATIONS OCCURRING AT DIFFERENT LEVELS. THE AIM OF THIS NARRATIVE REVIEW IS TO PROPOSE AN OVERVIEW OF THE LITERATURE RANGING FROM GENETIC, EPIGENETIC, EXPRESSION AND PROTEIN TO NEUROIMAGING CORRELATES UNDERLYING THIS RELATIONSHIP. A SEARCH ON PUBMED OF STUDIES ASSESSING BIOLOGICAL CORRELATES OF ELS IN MDD DEVELOPMENT, FOCUSING ON HUMAN STUDIES CONDUCTED IN BOTH PERIPHERAL AND BRAIN TISSUES, WAS PERFORMED. EVIDENCE INDICATED THAT THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND THE SEROTONERGIC, DOPAMINERGIC, NEUROTROPHIN AND OXYTOCIN SYSTEMS MIGHT PLAY A ROLE IN THE MEDIATION BETWEEN ELS AND MDD. THE MOST CONSISTENT RESULTS WERE FOUND FOR GENETIC AND EPIGENETIC STUDIES AND INDICATED A JOINT INVOLVEMENT OF THE SYSTEMS MENTIONED. EXPRESSION STUDIES ARE LESS NUMEROUS AND POINT TO AN INVOLVEMENT OF STRESS-RELATED SYSTEMS. CONCERNING PROTEIN STUDIES, THE MAIN MEDIATORS ARE MARKERS RELATED TO THE INFLAMMATORY AND IMMUNE SYSTEMS. NEUROIMAGING STUDIES AIMING AT EVALUATING BRAIN ALTERATIONS CONNECTING ELS AND MDD IN RELATION TO BIOMARKERS INDICATED THE HIPPOCAMPUS, THE AMYGDALA AND THE FRONTAL CORTEX AS IMPORTANT ANATOMICAL MEDIATORS. THESE FINDINGS CAN BUILD THE BASES FOR FUTURE RESEARCH AND CLINICAL INTERVENTIONS; INDEED, THE CLARIFICATION OF BIOLOGICAL MECHANISMS MEDIATING THE RELATIONSHIP BETWEEN ELS AND MDD CAN LEAD TO NEW AND INDIVIDUALIZED PREVENTIVE AND THERAPEUTIC POSSIBILITIES. 2021 5 2918 35 GENE-ENVIRONMENT INTERACTIONS IN MAJOR MENTAL DISORDERS IN THE CZECH REPUBLIC. BACKGROUND: MENTAL DISORDERS AFFECT ABOUT ONE?-THIRD OF THE HUMAN POPULATION, ARE TYPICALLY CHRONIC AND SIGNIFICANTLY DECREASE THE QUALITY OF LIFE. PRESENTLY, THE TREATMENT OF MENTAL ILLNESSES IS FAR FROM ADEQUATE WITH A SUBSTANTIAL PROPORTION OF THE PATIENTS BEING PHARMACORESISTANT AND SUFFERING FROM RELAPSES. ONE OF THE REASONS FOR THIS COMPLICATED SITUATION IS THAT WE DO NOT PRECISELY KNOW ABOUT THE CAUSES OF MENTAL DISORDERS, SO THEIR TREATMENT CANNOT BE CAUSAL. THE ETIOLOGY OF A MENTAL DISORDER IS TYPICALLY BASED ON A COMBINATION OF MOLECULAR (GENETIC) AND ENVIRONMENTAL FACTORS. AIM: THE AIM OF THE PROJECT IS TO DISCOVER THE GENE-ENVIRONMENT INTERACTIONS (GXE) IN A WIDE SPECTRUM OF MENTAL DISORDERS. METHODS: THE DESIGN OF OUR STUDY IS INNOVATIVE IN THE SENSE THAT WE INTEND TO STUDY LARGE GROUPS OF ASSOCIATED MENTAL DISORDERS AS A WHOLE INSTEAD OF IN ISOLATION. THIS WOULD ENABLE US TO MAP OUT THE POSSIBLE ENVIRONMENTAL CAUSAL FACTORS IN DETAIL IN RELATION TO THEIR CHARACTER, MAGNITUDE AND TIMING. THE PROJECT ALSO ALLOWS A STUDY OF GENETICS (INCLUDING EPIGENETICS AND MICROBIOMES) AS WELL AS THE ENVIRONMENT SIMULTANEOUSLY. WE PLAN ON INVOLVING THREE STUDY GROUPS: THE FIRST GROUP ARE PATIENTS SUFFERING FROM SCHIZOPHRENIA OR A MOOD DISORDER SUCH AS MAJOR DEPRESSION, RECURRENT DEPRESSIVE DISORDER AND BIPOLAR AFFECTIVE DISORDER; THE SECOND GROUP OF PATIENTS HAVE ANXIETY DISORDERS; AND THE THIRD GROUP ARE HEALTHY VOLUNTEERS FROM THE GENERAL POPULATION WHO ARE GENETICALLY UNRELATED. ALL OF THE STUDY SUBJECTS WILL UNDERGO THE FOLLOWING ASSESSMENTS: A PSYCHIATRIC EXAMINATION, THE IDENTIFICATION OF STRESSFUL LIFE EVENTS WITH THE AID OF A QUESTIONNAIRE, THE EXAMINATION OF THEIR REACTION TO STRESS, GENETIC AND EPIGENETIC (MICRORNA) ASSESSMENTS AND THE ANALYSIS OF ORAL AND GUT MICROBIOME. CONCLUSION: WE EXPECT THAT SOME OF THE GENETIC AS WELL AS ENVIRONMENTAL FACTORS IN THE STUDIED MENTAL DISORDERS ARE SHARED, WHILE SOME OTHERS ARE SPECIFIC. WE ALSO EXPECT THAT THE GXE (GENE-ENVIRONMENT INTERACTION) IN SCHIZOPHRENIC AND AFFECTIVE DISORDERS WILL BE DIFFERENT FROM THE GXE IN ANXIETY DISORDERS AND THAT THE GXE IN THE STUDIED MENTAL DISORDERS WILL DIFFER GENERALLY FROM THE GXE IN HEALTHY VOLUNTEERS. OUR RESULTS CAN HELP IN THE PREVENTION AND INDIVIDUALIZED TREATMENT OF A RANGE OF MENTAL DISORDERS. 2020 6 2917 30 GENE-ENVIRONMENT INTERACTIONS IN COMMON MENTAL DISORDERS: AN UPDATE AND STRATEGY FOR A GENOME-WIDE SEARCH. A DECADE OF RESEARCH HAS DEMONSTRATED THE EXPLANATORY POTENTIAL OF INTERPLAY BETWEEN GENETIC VARIANTS AND ENVIRONMENTAL FACTORS IN THE DEVELOPMENT OF COMMON MENTAL DISORDERS. INITIAL FINDINGS HAVE UNDERGONE TESTS OF REPLICABILITY AND SPECIFICITY. SOME GENE-ENVIRONMENT INTERACTIONS HAVE BEEN CONFIRMED, SOME HAVE NOT REPLICATED AND YET OTHER TURNED OUT TO BE MORE SPECIFIC THAN INITIALLY THOUGHT. SPECIFIC AND COMPLEMENTARY ROLES OF GENETIC FACTORS HAVE BEEN DELINEATED: A COMMON FUNCTIONAL LENGTH POLYMORPHISM IN THE SEROTONIN TRANSPORTER GENE (5-HTTLPR) MODERATED THE EFFECT OF CHILDHOOD MALTREATMENT ON CHRONIC DEPRESSION IN ADULTHOOD, BUT DID NOT SUBSTANTIALLY INFLUENCE THE EFFECTS OF ADULT STRESSFUL LIFE EVENTS ON THE ONSET OF NEW DEPRESSIVE EPISODES; IN CONTRAST, A COMMON FUNCTIONAL POLYMORPHISM IN THE BRAIN-DERIVED NEUROTROPHIC FACTOR GENE (BDNF) MODERATED THE EFFECT OF STRESSFUL LIFE EVENTS IN ADULTHOOD IN TRIGGERING NEW DEPRESSIVE EPISODES, BUT DID NOT INFLUENCE THE EFFECTS OF CHILDHOOD MALTREATMENT. MOLECULAR MECHANISMS UNDERLYING GENE-ENVIRONMENT INTERACTIONS ARE BEING UNCOVERED, INCLUDING DNA METHYLATION AND OTHER EPIGENETIC MODIFICATIONS. NEW GENE-ENVIRONMENT INTERACTIONS CONTINUE TO BE REPORTED, STILL LARGELY FROM HYPOTHESIS-DRIVEN RESEARCH. STATISTICAL AND BIOLOGICAL PRIORITIZATION STRATEGIES ARE PROPOSED TO FACILITATE A SYSTEMATIC DISCOVERY OF NOVEL GENE-ENVIRONMENT INTERACTIONS IN GENOME-WIDE ANALYSES. 2014 7 5164 31 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017 8 6159 44 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010 9 1736 32 EARLY DETECTION AND PREVENTION OF SCHIZOPHRENIC PSYCHOSIS-A REVIEW. PSYCHOTIC DISORDERS OFTEN RUN A CHRONIC COURSE AND ARE ASSOCIATED WITH A CONSIDERABLE EMOTIONAL AND SOCIAL IMPACT FOR PATIENTS AND THEIR RELATIVES. THEREFORE, EARLY RECOGNITION, COMBINED WITH THE POSSIBILITY OF PREVENTIVE INTERVENTION, IS URGENTLY WARRANTED SINCE THE DURATION OF UNTREATED PSYCHOSIS (DUP) SIGNIFICANTLY DETERMINES THE FURTHER COURSE OF THE DISEASE. IN ADDITION TO ESTABLISHED DIAGNOSTIC TOOLS, NEUROBIOLOGICAL FACTORS IN THE DEVELOPMENT OF SCHIZOPHRENIC PSYCHOSES ARE INCREASINGLY BEING INVESTIGATED. IT IS SHOWN THAT NUMEROUS MOLECULAR ALTERATIONS ALREADY EXIST BEFORE THE CLINICAL ONSET OF THE DISEASE. AS SCHIZOPHRENIC PSYCHOSES ARE NOT ELICITED BY A SINGLE MUTATION IN THE DEOXYRIBONUCLEIC ACID (DNA) SEQUENCE, EPIGENETICS LIKELY CONSTITUTE THE MISSING LINK BETWEEN ENVIRONMENTAL INFLUENCES AND DISEASE DEVELOPMENT AND COULD POTENTIALLY SERVE AS A BIOMARKER. THE RESULTS FROM TRANSCRIPTOMIC AND PROTEOMIC STUDIES POINT TO A DYSREGULATED IMMUNE SYSTEM, LIKELY EVOKED BY EPIGENETIC ALTERATIONS. DESPITE THE INCREASING KNOWLEDGE OF THE NEUROBIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF PSYCHOTIC DISORDERS, FURTHER RESEARCH EFFORTS WITH LARGE POPULATION-BASED STUDY DESIGNS ARE NEEDED TO IDENTIFY SUITABLE BIOMARKERS. IN CONCLUSION, A COMBINATION OF BLOOD EXAMINATIONS, FUNCTIONAL IMAGING TECHNIQUES, ELECTROENCEPHALOGRAPHY (EEG) INVESTIGATIONS AND POLYGENIC RISK SCORES SHOULD BE CONSIDERED AS THE BASIS FOR PREDICTING HOW SUBJECTS WILL TRANSITION INTO MANIFEST PSYCHOSIS. 2021 10 1971 41 EPIGENETIC ALTERATIONS ASSOCIATED WITH CHILDHOOD TRAUMA AND ADULT MENTAL HEALTH OUTCOMES: A SYSTEMATIC REVIEW. OBJECTIVES: MULTIPLE, CHRONIC AND REPEATED TRAUMA EXPOSURE IN CHILDHOOD IS ASSOCIATED WITH ADVERSE MENTAL HEALTH OUTCOMES IN ADULTHOOD. IN THIS PAPER WE SYNTHESISE THE LITERATURE ON EPIGENETIC MODIFICATIONS IN CHILDHOOD TRAUMA (CT) AND THE MEDIATING EFFECTS OF DIFFERENTIAL EPIGENETIC MECHANISMS ON THE ASSOCIATION BETWEEN CT AND THE LATER ONSET OF PSYCHIATRIC DISORDERS.METHODS: WE REVIEWED THE LITERATURE UP TO MARCH 2018 IN FOUR DATABASES: PUBMED, WEB OF SCIENCE, EBSCOHOST AND SCOPUS. NON-HUMAN STUDIES WERE EXCLUDED. ALL STUDIES INVESTIGATING CT EXPOSURE BOTH IN HEALTHY ADULTS (18 YEARS AND OLDER) AND ADULTS WITH PSYCHIATRIC DISORDERS WERE INCLUDED.RESULTS: THIRTY-SIX PUBLICATIONS WERE INCLUDED. FOR MOOD DISORDERS, METHYLATION OF THE GLUCOCORTICOID RECEPTOR NR3C1 GENE, SPECIFICALLY AT THE NGFI-A BINDING SITE IN EXON 1F, AND CORRELATION WITH CT WAS A ROBUST FINDING. SEVERAL STUDIES DOCUMENTED DIFFERENTIAL METHYLATION OF SLC6A4, BDNF, OXTR AND FKBP5 IN ASSOCIATION WITH CT. COMMON PATHWAYS IDENTIFIED INCLUDE NEURONAL FUNCTIONING AND MAINTENANCE, IMMUNE AND INFLAMMATORY PROCESSES, CHROMATIN AND HISTONE MODIFICATION, AND TRANSCRIPTION FACTOR BINDING.CONCLUSIONS: A VARIETY OF EPIGENETIC MEDIATORS THAT LIE ON A COMMON PATHWAY BETWEEN CT AND PSYCHIATRIC DISORDERS HAVE BEEN IDENTIFIED, ALTHOUGH LONGITUDINAL STUDIES AND CONSISTENCY IN METHODOLOGICAL APPROACH ARE NEEDED TO DISENTANGLE CAUSE AND EFFECT ASSOCIATIONS. 2020 11 6458 38 TIME COURSE OF DNA METHYLATION IN PAIN CONDITIONS: FROM EXPERIMENTAL MODELS TO HUMANS. BACKGROUND AND OBJECTIVE: THROUGHOUT THE LAST DECADE, RESEARCH HAS UNCOVERED ASSOCIATIONS BETWEEN PAIN AND EPIGENETIC ALTERATIONS CAUSED BY ENVIRONMENTAL FACTORS. SPECIFICALLY, STUDIES HAVE DEMONSTRATED CORRELATIONS BETWEEN PAIN CONDITIONS AND ALTERED DNA METHYLATION PATTERNS. THUS, DNA METHYLATION HAS BEEN REVEALED AS A POSSIBLE MODULATOR OR CONTRIBUTOR TO PAIN CONDITIONS, PROVIDING A POTENTIAL THERAPEUTIC TARGET FOR TREATMENT BY DNA METHYLATION MODIFICATION. TO DEVELOP SUCH TREATMENTS, IT IS NECESSARY TO CLARIFY A WIDE NUMBER OF ASPECTS ON HOW DNA METHYLATION AFFECTS PAIN PERCEPTION; FIRST AND FOREMOST, THE TEMPORAL DYNAMICS. THE OBJECTIVE OF THE PRESENT REVIEW IS TO PROVIDE AN OVERVIEW OF CURRENT KNOWLEDGE ON TEMPORAL DYNAMICS OF DNA METHYLATION IN RESPONSE TO PAIN, AND TO INVESTIGATE IF A TIMEFRAME CAN BE ESTABLISHED BASED ON THE DATA OF CURRENTLY PUBLISHED STUDIES. DATABASES AND DATA TREATMENT: PUBMED, MEDLINE, GOOGLE SCHOLAR AND EMBASE WERE SEARCHED COMPREHENSIVELY FOR STUDIES OF DNA METHYLATION IN NEUROPATHIC, INFLAMMATORY AND ALTERNATIVE ANIMAL PAIN MODELS, AND IN CHRONIC PAIN PATIENTS INCLUDING COMPLEX REGIONAL PAIN SYNDROME, CHRONIC POSTSURGICAL PAIN, CHRONIC WIDESPREAD PAIN, FIBROMYALGIA AND CROHN'S DISEASE. RESULTS: WE IDENTIFIED 34 ARTICLES HIGHLIGHTING VARIATIONS IN TEMPORAL DYNAMICS OF DNA METHYLATION ACROSS SPECIES AND BETWEEN DIFFERENT TYPES OF PAIN. THESE STUDIES REPRESENT A STARTING POINT TO UNCOVER NEW INSIGHTS IN THE DNA METHYLATION TIME COURSE IN PAIN. CONCLUSIONS: NO TIMEFRAME CAN CURRENTLY BE MADE FOR THE DNA METHYLATION RESPONSE TO PAIN IN ANY OF THE REVIEWED CONDITIONS, HIGHLIGHTING AN IMPORTANT FOCUS AREA FOR FUTURE RESEARCH. 2021 12 38 29 A COMMON ROLE FOR PSYCHOTROPIC MEDICATIONS: MEMORY IMPAIRMENT. THE PSYCHOPATHOLOGIC PROFILE OF MENTAL DISORDERS IS VERY DIVERSE AND PSYCHOTROPIC MEDICATIONS USED TO TREAT THEM DIFFER IN THEIR CHEMICAL STRUCTURE. NEVERTHELESS, THESE DRUGS SHARE THESE FOUR CHARACTERISTICS: DELAYED ONSET OF CLINICAL RESPONSE, NOT ONE OF THEM CAN BE SAID TO CURE, THERE IS A HIGH NUMBER OF NON-RESPONDERS, AND THE MECHANISM RESPONSIBLE FOR THEIR THERAPEUTIC ACTION IS NOT KNOWN. IT IS HYPOTHESIZED THAT THE ACTION OF PSYCHOTROPIC MEDICATIONS IS MEMORY IMPAIRMENT, UNDERSTANDING MEMORY AS THE TRACE LEFT IN THE NERVOUS SYSTEM NOT ONLY BY INDIVIDUAL EXPERIENCES BUT ALSO BY GENETIC AND EPIGENETIC PHENOMENA. IT IS SUGGESTED THAT IT WOULD BE BENEFICIAL TO TRANSLATE SOME RESEARCH STRATEGIES FROM THE NEUROBIOLOGY OF LEARNING AND MEMORY TO THE STUDY OF THE EFFECTS OF PSYCHOTROPIC MEDICATIONS. THE HYPOTHESIS IS BRIEFLY ASSESSED ACCORDING TO THE FOLLOWING THREE CRITERIA: (A). THE COMPARISON BETWEEN THE MOLECULAR EFFECTS OF PSYCHOTROPIC MEDICATIONS AND THE SO-CALLED MOLECULAR BIOLOGY OF LEARNING AND MEMORY, (B). THE EFFECTS OF THESE DRUGS, PREFERENTIALLY AFTER CHRONIC USE, ON MEMORY TESTS, AND (C). THE EFFECTS OF DRUGS THAT IMPAIR MEMORY ON TESTS USED FOR SCREENING PSYCHOTROPIC MEDICATIONS. FINALLY, SOME GENERAL SUGGESTIONS FOR FUTURE RESEARCH ARE POINTED OUT. 2003 13 1203 38 COULD EPIGENETICS HELP EXPLAIN RACIAL DISPARITIES IN CHRONIC PAIN? AFRICAN AMERICANS DISPROPORTIONATELY SUFFER MORE SEVERE AND DEBILITATING MORBIDITY FROM CHRONIC PAIN THAN DO NON-HISPANIC WHITES. THESE DIFFERENCES MAY ARISE FROM DIFFERENTIAL EXPOSURE TO PSYCHOSOCIAL AND ENVIRONMENTAL FACTORS SUCH AS ADVERSE CHILDHOOD EXPERIENCES, RACIAL DISCRIMINATION, LOW SOCIOECONOMIC STATUS, AND DEPRESSION, ALL OF WHICH HAVE BEEN ASSOCIATED WITH CHRONIC STRESS AND CHRONIC PAIN. RACE, AS A SOCIAL CONSTRUCT, MAKES IT SUCH THAT AFRICAN AMERICANS ARE MORE LIKELY TO EXPERIENCE DIFFERENT EARLY LIFE CONDITIONS, WHICH MAY INDUCE EPIGENETIC CHANGES THAT SUSTAIN RACIAL DIFFERENCES IN CHRONIC PAIN. EPIGENETICS IS ONE MECHANISM BY WHICH ENVIRONMENTAL FACTORS SUCH AS CHILDHOOD STRESS, RACIAL DISCRIMINATION, ECONOMIC HARDSHIP, AND DEPRESSION CAN AFFECT GENE EXPRESSION WITHOUT ALTERING THE UNDERLYING GENETIC SEQUENCE. THIS ARTICLE PROVIDES A NARRATIVE REVIEW OF THE LITERATURE ON EPIGENETICS AS A MECHANISM BY WHICH DIFFERENTIAL ENVIRONMENTAL EXPOSURE COULD EXPLAIN RACIAL DIFFERENCES IN CHRONIC PAIN. MOST STUDIES OF EPIGENETIC CHANGES IN CHRONIC PAIN EXAMINE DNA METHYLATION. DNA METHYLATION IS ALTERED IN THE GLUCOCORTICOID (STRESS RESPONSE) RECEPTOR GENE, NR3C1, WHICH HAS BEEN ASSOCIATED WITH DEPRESSION, CHILDHOOD STRESS, LOW SOCIOECONOMIC STATUS, AND CHRONIC PAIN. SIMILARLY, DNA METHYLATION PATTERNS OF IMMUNE CYTOKINE GENES HAVE BEEN ASSOCIATED WITH CHRONIC STRESS STATES. THUS, DNA METHYLATION CHANGES MAY PLAY AN ESSENTIAL ROLE IN THE EPIGENETIC MODULATION OF CHRONIC PAIN IN DIFFERENT RACES WITH A HIGHER INCIDENCE OF EPIGENETIC ALTERATIONS CONTRIBUTING TO MORE SEVERE AND DISABLING CHRONIC PAIN IN AFRICAN AMERICANS. 2019 14 2472 28 EPIGENETIC TRANSMISSION OF THE IMPACT OF EARLY STRESS ACROSS GENERATIONS. BACKGROUND: TRAUMATIC EXPERIENCES IN EARLY LIFE ARE RISK FACTORS FOR THE DEVELOPMENT OF BEHAVIORAL AND EMOTIONAL DISORDERS. SUCH DISORDERS CAN PERSIST THROUGH ADULTHOOD AND HAVE OFTEN BEEN REPORTED TO BE TRANSMITTED ACROSS GENERATIONS. METHODS: TO INVESTIGATE THE TRANSGENERATIONAL EFFECT OF EARLY STRESS, MICE WERE EXPOSED TO CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION FROM POSTNATAL DAY 1 TO 14. RESULTS: WE SHOW THAT CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION INDUCES DEPRESSIVE-LIKE BEHAVIORS AND ALTERS THE BEHAVIORAL RESPONSE TO AVERSIVE ENVIRONMENTS IN THE SEPARATED ANIMALS WHEN ADULT. MOST OF THE BEHAVIORAL ALTERATIONS ARE FURTHER EXPRESSED BY THE OFFSPRING OF MALES SUBJECTED TO MATERNAL SEPARATION, DESPITE THE FACT THAT THESE MALES ARE REARED NORMALLY. CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION ALSO ALTERS THE PROFILE OF DNA METHYLATION IN THE PROMOTER OF SEVERAL CANDIDATE GENES IN THE GERMLINE OF THE SEPARATED MALES. COMPARABLE CHANGES IN DNA METHYLATION ARE ALSO PRESENT IN THE BRAIN OF THE OFFSPRING AND ARE ASSOCIATED WITH ALTERED GENE EXPRESSION. CONCLUSIONS: THESE FINDINGS HIGHLIGHT THE NEGATIVE IMPACT OF EARLY STRESS ON BEHAVIORAL RESPONSES ACROSS GENERATIONS AND ON THE REGULATION OF DNA METHYLATION IN THE GERMLINE. 2010 15 5649 24 SEX DIFFERENCES IN PSYCHOSTIMULANT ABUSE: IMPLICATIONS FOR ESTROGEN RECEPTORS AND HISTONE DEACETYLASES. SUBSTANCE ABUSE IS A CHRONIC PATHOLOGICAL DISORDER THAT NEGATIVELY AFFECTS MANY HEALTH AND NEUROLOGICAL PROCESSES. A GROWING BODY OF LITERATURE HAS REVEALED GENDER DIFFERENCES IN SUBSTANCE USE. COMPARED TO MEN, WOMEN DISPLAY DISTINCT DRUG-USE PHENOTYPES ACCOMPANIED BY RECOVERY AND REHABILITATION DISPARITIES. THESE OBSERVATIONS HAVE LED TO THE NOTION THAT SEX-DEPENDENT SUSCEPTIBILITIES EXIST ALONG THE PROGRESSION TO ADDICTION. WITHIN THIS SCOPE, NEUROADAPTATIONS FOLLOWING PSYCHOSTIMULANT EXPOSURE ARE THOUGHT TO BE DISTINCT FOR EACH SEX. THIS REVIEW SUMMARIZES CLINICAL FINDINGS AND ANIMAL RESEARCH REPORTING SEX DIFFERENCES IN THE SUBJECTIVE AND BEHAVIORAL RESPONSES TO COCAINE, METHAMPHETAMINE, AND NICOTINE. THIS DISCUSSION IS FOLLOWED BY AN EXAMINATION OF EPIGENETIC AND MOLECULAR ALTERATIONS IMPLICATED IN THE ADDICTION PROCESS. SPECIAL CONSIDERATION IS GIVEN TO HISTONE DEACETYLASES AND ESTROGEN RECEPTOR-MEDIATED GENE EXPRESSION. 2022 16 6065 36 THE DEVELOPMENTAL ORIGINS OF CHRONIC PHYSICAL AGGRESSION: BIOLOGICAL PATHWAYS TRIGGERED BY EARLY LIFE ADVERSITY. LONGITUDINAL EPIDEMIOLOGICAL STUDIES WITH BIRTH COHORTS HAVE SHOWN THAT PHYSICAL AGGRESSION IN HUMANS DOES NOT APPEAR SUDDENLY IN ADOLESCENCE AS COMMONLY THOUGHT. IN FACT, PHYSICALLY AGGRESSIVE BEHAVIOUR IS OBSERVED AS EARLY AS 12 MONTHS AFTER BIRTH, ITS FREQUENCY PEAKS AROUND 2-4 YEARS OF AGE AND DECREASES IN FREQUENCY UNTIL EARLY ADULTHOOD. HOWEVER, A MINORITY OF CHILDREN (3-7%) MAINTAIN A HIGH FREQUENCY OF PHYSICAL AGGRESSION FROM CHILDHOOD TO ADOLESCENCE AND DEVELOP SERIOUS SOCIAL ADJUSTMENT PROBLEMS DURING ADULTHOOD. GENETIC FACTORS AND EARLY SOCIAL EXPERIENCES, AS WELL AS THEIR INTERACTION, HAVE BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF CHRONIC AGGRESSIVE BEHAVIOUR. HOWEVER, THE BIOLOGICAL MECHANISMS UNDERLYING THESE ASSOCIATIONS ARE JUST BEGINNING TO BE UNCOVERED. RECENT EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS ARE RESPONSIVE TO ADVERSE ENVIRONMENTS AND COULD BE INVOLVED IN THE DEVELOPMENT OF CHRONIC AGGRESSION. USING BOTH GENE CANDIDATE AND GENOMIC APPROACHES, RECENT STUDIES HAVE IDENTIFIED EPIGENETIC MARKS, SUCH AS DNA METHYLATION ALTERATIONS IN GENES INVOLVED IN THE STRESS RESPONSE AND THE SEROTONIN AND IMMUNE SYSTEMS TO BE PARTLY RESPONSIBLE FOR THE LONG-LASTING EFFECTS OF EARLY ADVERSITY. FURTHER LONGITUDINAL STUDIES WITH BIOLOGICAL, ENVIRONMENTAL AND BEHAVIOURAL ASSESSMENTS FROM BIRTH ONWARDS ARE NEEDED TO ELUCIDATE THE SEQUENCE OF EVENTS THAT LEADS TO THESE LONG-LASTING EPIGENETIC MARKS ASSOCIATED WITH EARLY ADVERSITY AND AGGRESSION. 2015 17 247 35 ADULTHOOD ASTHMA AS A CONSEQUENCE OF CHILDHOOD ADVERSITY: A SYSTEMATIC REVIEW OF EPIGENETICALLY AFFECTED GENES. THERE IS AN ACCUMULATING DATA THAT SHOWS RELATION BETWEEN CHILDHOOD ADVERSITY AND VULNERABILITY TO CHRONIC DISEASES AS WELL AS EPIGENETIC INFLUENCES THAT IN TURN GIVE RISE TO THESE DISEASES. ASTHMA IS ONE OF THE CHRONIC DISEASES THAT IS INFLUENCED FROM GENETIC REGULATION OF THE INFLAMMATORY BIOMOLECULES AND THEREFORE THE HYPOTHESIS IN THIS RESEARCH WAS CHILDHOOD ADVERSITY MIGHT HAVE CAUSED EPIGENETIC DIFFERENTIATION IN THE ASTHMA-RELATED GENES IN THE POPULATION WHO HAD CHILDHOOD TRAUMA. TO TEST THIS HYPOTHESIS, THE LITERATURE WAS SYSTEMATICALLY REVIEWED TO EXTRACT EPIGENETICALLY MODIFIED GENE DATA OF THE ADULTS WHO HAD CHILDHOOD ADVERSITY, AND AFFECTED GENES WERE FURTHER EVALUATED FOR THEIR ASSOCIATION WITH ASTHMA. PRISMA GUIDELINES WERE ADOPTED AND PUBMED AND GOOGLE SCHOLAR WERE INCLUDED IN THE SEARCHED DATABASES, TO EVALUATE EPIGENETIC MODIFICATIONS IN ASTHMA-RELATED GENES OF PHYSICALLY, EMOTIONALLY OR SEXUALLY ABUSED CHILDREN. AFTER RETRIEVING A TOTAL OF 5245 ARTICLES, 36 OF THEM WERE INCLUDED IN THE STUDY. SEVERAL GENES AND PATHWAYS THAT MAY CONTRIBUTE TO PATHOGENESIS OF ASTHMA DEVELOPMENT, INCREASED INFLAMMATION, OR RESPONSE TO ASTHMA TREATMENT WERE FOUND EPIGENETICALLY AFFECTED BY CHILDHOOD TRAUMAS. CHILDHOOD ADVERSITY, CAUSING EPIGENETIC CHANGES IN DNA, MAY LEAD TO ASTHMA DEVELOPMENT OR INFLUENCE THE COURSE OF THE DISEASE AND THEREFORE SHOULD BE TAKEN INTO ACCOUNT FOR THE PROLONGED HEALTH CONSEQUENCES. 2022 18 2075 32 EPIGENETIC DIFFERENCES IN INFLAMMATION GENES OF MONOZYGOTIC TWINS ARE RELATED TO PARENT-CHILD EMOTIONAL AVAILABILITY AND HEALTH. THE INFLAMMATORY RESPONSE IS AN IMMUNE DEFENSE ENGAGED IMMEDIATELY AFTER INJURY OR INFECTION. CHRONIC INFLAMMATION CAN BE DELETERIOUS FOR VARIOUS HEALTH OUTCOMES AND IS CHARACTERIZED BY HIGH LEVELS OF PRO-INFLAMMATORY MARKERS SUCH AS C-REACTIVE PROTEIN (CRP), INTERLEUKIN 6 (IL-6), AND TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA). A LARGE BODY OF RESEARCH DEMONSTRATES THESE INFLAMMATORY MARKERS ARE RESPONSIVE TO STRESS AND QUALITY OF SOCIAL RELATIONSHIPS THROUGHOUT THE LIFESPAN. FOR EXAMPLE, THE QUALITY OF THE EARLY PARENTAL BOND PREDICTS VARIOUS HEALTH OUTCOMES AND MAY BE DRIVEN BY CHANGES IN IMMUNE FUNCTION. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, MAY BE ONE MECHANISM BY WHICH EARLY SOCIAL EXPERIENCES SHAPE IMMUNE FUNCTIONING. THE PRESENT STUDY USED A MONOZYGOTIC TWIN DIFFERENCE DESIGN TO ASSESS IF MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR AND 2.5 YEARS PREDICTED IMMUNE GENE METHYLATION AT 8 YEARS OF AGE. FURTHER, WE ASSESSED IF INFLAMMATION GENE METHYLATION WAS RELATED TO GENERAL HEALTH PROBLEMS (E.G. INFECTIONS, ALLERGIES, ETC.). WE FOUND THAT MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR, BUT NOT 2.5 YEARS, WAS RELATED TO METHYLATION OF VARIOUS IMMUNE GENES IN MONOZYGOTIC TWINS. FURTHERMORE, TWIN PAIRS DISCORDANT IN HEALTH PROBLEMS HAVE MORE DIFFERENCE IN IMMUNE GENE METHYLATION COMPARED TO TWIN PAIRS CONCORDANT FOR HEALTH PROBLEMS, SUGGESTING THAT METHYLATION OF IMMUNE GENES MAY HAVE FUNCTIONAL CONSEQUENCES FOR GENERAL HEALTH. THESE RESULTS SUGGEST THAT THE EMOTIONAL COMPONENT OF ATTACHMENT QUALITY DURING INFANCY CONTRIBUTES TO IMMUNE EPIGENETIC PROFILES IN CHILDHOOD, WHICH MAY INFLUENCE GENERAL HEALTH. 2020 19 1599 34 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES. 2014 20 228 36 ADAPTATION OF THE HUMAN POPULATION TO THE ENVIRONMENT: CURRENT KNOWLEDGE, CLUES FROM CZECH CYTOGENETIC AND "OMICS" BIOMONITORING STUDIES AND POSSIBLE MECHANISMS. THE HUMAN POPULATION IS CONTINUALLY EXPOSED TO NUMEROUS HARMFUL ENVIRONMENTAL STRESSORS, CAUSING NEGATIVE HEALTH EFFECTS AND/OR DEREGULATION OF BIOMARKER LEVELS. HOWEVER, STUDIES REPORTING NO OR EVEN POSITIVE IMPACTS OF SOME STRESSORS ON HUMANS ARE ALSO SOMETIMES PUBLISHED. THE MAIN AIM OF THIS REVIEW IS TO PROVIDE A COMPREHENSIVE OVERVIEW OF THE LAST DECADE OF CZECH BIOMONITORING RESEARCH, CONCERNING THE EFFECT OF VARIOUS LEVELS OF AIR POLLUTION (BENZO[A]PYRENE) AND RADIATION (URANIUM, X-RAY EXAMINATION AND NATURAL RADON BACKGROUND), ON THE DIFFERENTLY EXPOSED POPULATION GROUPS. BECAUSE SOME RESULTS OBTAINED FROM CYTOGENETIC STUDIES WERE OPPOSITE THAN HYPOTHESIZED, WE HAVE SEARCHED FOR A MEANINGFUL INTERPRETATION IN GENOMIC/EPIGENETIC STUDIES. A DETAILED ANALYSIS OF OUR DATA SUPPORTED BY THE STUDIES OF OTHERS AND CURRENT EPIGENETIC KNOWLEDGE, LEADS TO A HYPOTHESIS OF THE VERSATILE MECHANISM OF ADAPTATION TO ENVIRONMENTAL STRESSORS VIA DNA METHYLATION SETTINGS WHICH MAY EVEN ORIGINATE IN PRENATAL DEVELOPMENT, AND HELP TO REDUCE THE RESULTING DNA DAMAGE LEVELS. THIS HYPOTHESIS IS FULLY IN AGREEMENT WITH UNEXPECTED DATA FROM OUR STUDIES (E.G. LOWER LEVELS OF DNA DAMAGE IN SUBJECTS FROM HIGHLY POLLUTED REGIONS THAN IN CONTROLS OR IN SUBJECTS EXPOSED REPEATEDLY TO A POLLUTANT THAN IN THOSE WITHOUT PREVIOUS EXPOSURE), AND IS ALSO SUPPORTED BY DIFFERENCES IN DNA METHYLATION PATTERNS IN GROUPS FROM REGIONS WITH VARIOUS LEVELS OF POLLUTION. IN LIGHT OF THE ADAPTATION HYPOTHESIS, THE FOLLOWING POINTS MAY BE SUGGESTED FOR FUTURE RESEARCH: (I) THE CHRONIC AND ACUTE EXPOSURE OF STUDY SUBJECTS SHOULD BE DISTINGUISHED; (II) THE EXPOSURE HISTORY SHOULD BE MAPPED INCLUDING PLACE OF RESIDENCE DURING THE LIFE AND PRENATAL DEVELOPMENT; (III) CHANGES OF EPIGENETIC MARKERS SHOULD BE MONITORED OVER TIME. IN SUMMARY, INVESTIGATION OF HUMAN ADAPTATION TO THE ENVIRONMENT, ONE OF THE MOST IMPORTANT PROCESSES OF SURVIVAL, IS A NEW CHALLENGE FOR FUTURE RESEARCH IN THE FIELD OF HUMAN BIOMONITORING THAT MAY CHANGE OUR VIEW ON THE RESULTS OF BIOMARKER ANALYSES AND POTENTIAL NEGATIVE HEALTH IMPACTS OF THE ENVIRONMENT. 2017