1 2526 147 EPIGENETICS APPLIED TO PSYCHIATRY: CLINICAL OPPORTUNITIES AND FUTURE CHALLENGES. PSYCHIATRIC DISORDERS ARE CLINICALLY HETEROGENEOUS AND DEBILITATING CHRONIC DISEASES RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENE VARIANTS AND ENVIRONMENTAL FACTORS. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INSTRUCT THE CELL/TISSUE TO CORRECTLY INTERPRET EXTERNAL SIGNALS AND ADJUST ITS FUNCTIONS ACCORDINGLY. GIVEN THAT EPIGENETIC MODIFICATIONS ARE SENSITIVE TO ENVIRONMENT, STABLE, AND REVERSIBLE, EPIGENETIC STUDIES IN PSYCHIATRY COULD REPRESENT A PROMISING APPROACH TO BETTER UNDERSTANDING AND TREATING DISEASE. IN THE PRESENT REVIEW, WE AIM TO DISCUSS THE CLINICAL OPPORTUNITIES AND CHALLENGES ARISING FROM THE EPIGENETIC RESEARCH IN PSYCHIATRY. USING SELECTED EXAMPLES, WE FIRST RECAPITULATE KEY FINDINGS SUPPORTING THE ROLE OF ADVERSE LIFE EVENTS, ALONE OR IN COMBINATION WITH GENETIC RISK, IN EPIGENETIC PROGRAMMING OF NEUROPSYCHIATRIC SYSTEMS. EPIGENETIC STUDIES FURTHER REPORT ENCOURAGING FINDINGS ABOUT THE USE OF METHYLATION CHANGES AS DIAGNOSTIC MARKERS OF DISEASE PHENOTYPE AND PREDICTIVE TOOLS OF PROGRESSION AND RESPONSE TO TREATMENT. THEN WE DISCUSS THE POTENTIAL OF USING TARGETED EPIGENETIC PHARMACOTHERAPY, COMBINED WITH PSYCHOSOCIAL INTERVENTIONS, FOR FUTURE PERSONALIZED MEDICINE FOR PATIENTS. FINALLY, WE REVIEW THE METHODOLOGICAL LIMITATIONS THAT COULD HINDER INTERPRETATION OF EPIGENETIC DATA IN PSYCHIATRY. THEY MAINLY ARISE FROM HETEROGENEITY AT THE INDIVIDUAL AND TISSUE LEVEL AND REQUIRE FUTURE STRATEGIES IN ORDER TO REINFORCE THE BIOLOGICAL RELEVANCE OF EPIGENETIC DATA AND ITS TRANSLATIONAL USE IN PSYCHIATRY. OVERALL, WE SUGGEST THAT EPIGENETICS COULD PROVIDE NEW INSIGHTS INTO A MORE COMPREHENSIVE INTERPRETATION OF MENTAL ILLNESS AND MIGHT EVENTUALLY IMPROVE THE NOSOLOGY, TREATMENT, AND PREVENTION OF PSYCHIATRIC DISORDERS. 2018 2 548 38 AUTISM SPECTRUM DISORDER AT THE CROSSROAD BETWEEN GENES AND ENVIRONMENT: CONTRIBUTIONS, CONVERGENCES, AND INTERACTIONS IN ASD DEVELOPMENTAL PATHOPHYSIOLOGY. THE COMPLEX PATHOPHYSIOLOGY OF AUTISM SPECTRUM DISORDER ENCOMPASSES INTERACTIONS BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. ON THE ONE HAND, HUNDREDS OF GENES, CONVERGING AT THE FUNCTIONAL LEVEL ON SELECTIVE BIOLOGICAL DOMAINS SUCH AS EPIGENETIC REGULATION AND SYNAPTIC FUNCTION, HAVE BEEN IDENTIFIED TO BE EITHER CAUSATIVE OR RISK FACTORS OF AUTISM. ON THE OTHER HAND, EXPOSURE TO CHEMICALS THAT ARE WIDESPREAD IN THE ENVIRONMENT, SUCH AS ENDOCRINE DISRUPTORS, HAS BEEN ASSOCIATED WITH ADVERSE EFFECTS ON HUMAN HEALTH, INCLUDING NEURODEVELOPMENTAL DISORDERS. INTERESTINGLY, EXPERIMENTAL RESULTS SUGGEST AN OVERLAP IN THE REGULATORY PATHWAYS PERTURBED BY GENETIC MUTATIONS AND ENVIRONMENTAL FACTORS, DEPICTING CONVERGENCES AND COMPLEX INTERPLAYS BETWEEN GENETIC SUSCEPTIBILITY AND TOXIC INSULTS. THE PERVASIVE NATURE OF CHEMICAL EXPOSURE POSES PIVOTAL CHALLENGES FOR NEUROTOXICOLOGICAL STUDIES, REGULATORY AGENCIES, AND POLICY MAKERS. THIS HIGHLIGHTS AN EMERGING NEED OF DEVELOPING NEW INTEGRATIVE MODELS, INCLUDING BIOMONITORING, EPIDEMIOLOGY, EXPERIMENTAL, AND COMPUTATIONAL TOOLS, ABLE TO CAPTURE REAL-LIFE SCENARIOS ENCOMPASSING THE INTERACTION BETWEEN CHRONIC EXPOSURE TO MIXTURE OF SUBSTANCES AND INDIVIDUALS' GENETIC BACKGROUNDS. IN THIS REVIEW, WE ADDRESS THE INTERTWINED ROLES OF GENETIC LESIONS AND ENVIRONMENTAL INSULTS. SPECIFICALLY, WE OUTLINE THE TRANSFORMATIVE POTENTIAL OF STEM CELL MODELS, COUPLED WITH OMICS ANALYTICAL APPROACHES AT INCREASINGLY SINGLE CELL RESOLUTION, AS CONVERGING TOOLS TO EXPERIMENTALLY DISSECT THE PATHOGENIC MECHANISMS UNDERLYING NEURODEVELOPMENTAL DISORDERS, AS WELL AS TO IMPROVE DEVELOPMENTAL NEUROTOXICOLOGY RISK ASSESSMENT. 2020 3 4344 35 MINIREVIEW: TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE: CHALLENGES AND EMERGING OPPORTUNITIES. INCREASING IMPORTANCE IS PLACED ON THE TRANSLATIONAL VALIDITY OF ANIMAL MODELS OF HUMAN MENOPAUSE TO DISCERN RISK VS. BENEFIT FOR PREDICTION OF OUTCOMES AFTER THERAPEUTIC INTERVENTIONS AND TO DEVELOP NEW THERAPEUTIC STRATEGIES TO PROMOTE HEALTH. BASIC DISCOVERY RESEARCH CONDUCTED OVER MANY DECADES HAS BUILT AN EXTENSIVE BODY OF KNOWLEDGE REGARDING REPRODUCTIVE SENESCENCE ACROSS MAMMALIAN SPECIES UPON WHICH TO ADVANCE ANIMAL MODELS OF HUMAN MENOPAUSE. MODIFICATIONS TO EXISTING ANIMAL MODELS COULD RAPIDLY ADDRESS TRANSLATIONAL GAPS RELEVANT TO CLINICAL ISSUES IN HUMAN MENOPAUSAL HEALTH, WHICH INCLUDE THE IMPACT OF 1) CHRONIC OVARIAN HORMONE DEPRIVATION AND HORMONE THERAPY, 2) CLINICALLY RELEVANT HORMONE THERAPY REGIMENS (CYCLIC VS. CONTINUOUS COMBINED), 3) CLINICALLY RELEVANT HORMONE THERAPY FORMULATIONS, AND 4) WINDOWS OF OPPORTUNITY AND OPTIMAL DURATION OF INTERVENTIONS. MODIFICATIONS IN EXISTING ANIMAL MODELS TO MORE ACCURATELY REPRESENT HUMAN MENOPAUSE AND CLINICAL INTERVENTIONS COULD RAPIDLY PROVIDE PRECLINICAL TRANSLATIONAL DATA TO PREDICT OUTCOMES REGARDING UNRESOLVED CLINICAL ISSUES RELEVANT TO WOMEN'S MENOPAUSAL HEALTH. DEVELOPMENT OF THE NEXT GENERATION OF ANIMAL MODELS OF HUMAN MENOPAUSE COULD LEVERAGE ADVANCES IN IDENTIFYING GENOTYPIC VARIATIONS IN ESTROGEN AND PROGESTERONE RECEPTORS TO DEVELOP PERSONALIZED MENOPAUSAL CARE AND TO PREDICT OUTCOMES OF INTERVENTIONS FOR PROTECTION AGAINST OR VULNERABILITY TO DISEASE. KEY TO THE SUCCESS OF THESE MODELS IS THE CLOSE COUPLING BETWEEN THE TRANSLATIONAL TARGET AND THE RANGE OF PREDICTIVE VALIDITY. PRECLINICAL TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE NEED TO KEEP PACE WITH CHANGES IN CLINICAL PRACTICE. WITH FOCUS ON PREDICTIVE VALIDITY AND STRATEGIC USE OF ADVANCES IN GENETIC AND EPIGENETIC SCIENCE, NEW ANIMAL MODELS OF HUMAN MENOPAUSE HAVE THE OPPORTUNITY TO SET NEW DIRECTIONS FOR MENOPAUSAL CLINICAL CARE FOR WOMEN WORLDWIDE. 2012 4 6295 42 THE PROMISES AND CHALLENGES OF TOXICO-EPIGENOMICS: ENVIRONMENTAL CHEMICALS AND THEIR IMPACTS ON THE EPIGENOME. BACKGROUND: IT HAS BEEN ESTIMATED THAT A SUBSTANTIAL PORTION OF CHRONIC AND NONCOMMUNICABLE DISEASES CAN BE CAUSED OR EXACERBATED BY EXPOSURE TO ENVIRONMENTAL CHEMICALS. MULTIPLE LINES OF EVIDENCE INDICATE THAT EARLY LIFE EXPOSURE TO ENVIRONMENTAL CHEMICALS AT RELATIVELY LOW CONCENTRATIONS COULD HAVE LASTING EFFECTS ON INDIVIDUAL AND POPULATION HEALTH. ALTHOUGH THE POTENTIAL ADVERSE EFFECTS OF ENVIRONMENTAL CHEMICALS ARE KNOWN TO THE SCIENTIFIC COMMUNITY, REGULATORY AGENCIES, AND THE PUBLIC, LITTLE IS KNOWN ABOUT THE MECHANISTIC BASIS BY WHICH THESE CHEMICALS CAN INDUCE LONG-TERM OR TRANSGENERATIONAL EFFECTS. TO ADDRESS THIS QUESTION, EPIGENETIC MECHANISMS HAVE EMERGED AS THE POTENTIAL LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS OF HEALTH AND DISEASE. OBJECTIVES: WE PRESENT AN OVERVIEW OF EPIGENETIC REGULATION AND A SUMMARY OF REPORTED EVIDENCE OF ENVIRONMENTAL TOXICANTS AS EPIGENETIC DISRUPTORS. WE ALSO DISCUSS THE ADVANTAGES AND CHALLENGES OF USING EPIGENETIC BIOMARKERS AS AN INDICATOR OF TOXICANT EXPOSURE, USING MEASURES THAT CAN BE TAKEN TO IMPROVE RISK ASSESSMENT, AND OUR PERSPECTIVES ON THE FUTURE ROLE OF EPIGENETICS IN TOXICOLOGY. DISCUSSION: UNTIL RECENTLY, EFFORTS TO APPLY EPIGENOMIC DATA IN TOXICOLOGY AND RISK ASSESSMENT WERE RESTRICTED BY AN INCOMPLETE UNDERSTANDING OF EPIGENOMIC VARIABILITY ACROSS TISSUE TYPES AND POPULATIONS. THIS IS POISED TO CHANGE WITH THE DEVELOPMENT OF NEW TOOLS AND CONCERTED EFFORTS BY RESEARCHERS ACROSS DISCIPLINES THAT HAVE LED TO A BETTER UNDERSTANDING OF EPIGENETIC MECHANISMS AND COMPREHENSIVE MAPS OF EPIGENOMIC VARIATION. WITH THE FOUNDATIONS NOW IN PLACE, WE FORESEE THAT UNPRECEDENTED ADVANCEMENTS WILL TAKE PLACE IN THE FIELD IN THE COMING YEARS. HTTPS://DOI.ORG/10.1289/EHP6104. 2020 5 6676 39 USING EPIGENETIC TOOLS TO INVESTIGATE ANTIDEPRESSANT RESPONSE. MAJOR DEPRESSIVE DISORDER IS A CHRONIC AND DEBILITATING ILLNESS. IT IS MOST COMMONLY TREATED WITH ANTIDEPRESSANT DRUGS, HOWEVER, AS THE MAJORITY OF PATIENTS DO NOT RESPOND ON THEIR FIRST TRIAL OR FOLLOWING SEVERAL ADEQUATE TRIALS, THERE IS GREAT INTEREST IN IDENTIFYING BIOLOGICAL FACTORS THAT MAY HELP SELECT THE MOST APPROPRIATE TREATMENT FOR EACH PATIENT AND IN UNDERSTANDING BIOLOGICAL PROCESSES THAT MEDIATE TREATMENT RESPONSE. EPIGENETIC FACTORS, SUCH AS NON-CODING RNAS (NCRNAS), HOLD POTENTIAL AS BIOMARKERS OF ANTIDEPRESSANT RESPONSE. IN THIS CHAPTER, WE REVIEW KEY METHODOLOGICAL CONSIDERATIONS WHEN INVESTIGATING NCRNA BIOMARKERS, INCLUDING BIOLOGICAL SAMPLES AND TECHNOLOGIES WHICH HAVE BEEN USED IN THESE STUDIES. SECONDLY, WE SUMMARIZE FINDINGS FROM STUDIES INVESTIGATING NCRNAS IN ANTIDEPRESSANT TREATMENT RESPONSE. FINALLY, WE DISCUSS SOME OF THE FUTURE DIRECTIONS WHICH WILL BE NECESSARY FOR THE DEVELOPMENT OF CLINICALLY RELEVANT EPIGENETIC TOOLS. 2018 6 4591 38 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 7 666 46 BLOOD-BASED DNA METHYLATION BIOMARKERS FOR TYPE 2 DIABETES: POTENTIAL FOR CLINICAL APPLICATIONS. TYPE 2 DIABETES (T2D) IS A LEADING CAUSE OF DEATH AND DISABILITY WORLDWIDE. IT IS A CHRONIC METABOLIC DISORDER THAT DEVELOPS DUE TO AN INTERPLAY OF GENETIC, LIFESTYLE, AND ENVIRONMENTAL FACTORS. THE BIOLOGICAL ONSET OF THE DISEASE OCCURS LONG BEFORE CLINICAL SYMPTOMS DEVELOP, THUS THE SEARCH FOR EARLY DIAGNOSTIC AND PROGNOSTIC BIOMARKERS, WHICH COULD FACILITATE INTERVENTION STRATEGIES TO PREVENT OR DELAY DISEASE PROGRESSION, HAS INCREASED CONSIDERABLY IN RECENT YEARS. EPIGENETIC MODIFICATIONS REPRESENT IMPORTANT LINKS BETWEEN GENETIC, ENVIRONMENTAL AND LIFESTYLE CUES AND INCREASING EVIDENCE IMPLICATE ALTERED EPIGENETIC MARKS SUCH AS DNA METHYLATION, THE MOST CHARACTERIZED AND WIDELY STUDIED EPIGENETIC MECHANISM, IN THE PATHOGENESIS OF T2D. THIS REVIEW PROVIDES AN UPDATE OF THE CURRENT STATUS OF DNA METHYLATION AS A BIOMARKER FOR T2D. FOUR DATABASES, SCOPUS, PUBMED, COCHRANE CENTRAL, AND GOOGLE SCHOLAR WERE SEARCHED FOR STUDIES INVESTIGATING DNA METHYLATION IN BLOOD. THIRTY-SEVEN STUDIES WERE IDENTIFIED, AND ARE SUMMARIZED WITH RESPECT TO POPULATION CHARACTERISTICS, BIOLOGICAL SOURCE, AND METHOD OF DNA METHYLATION QUANTIFICATION (GLOBAL, CANDIDATE GENE OR GENOME-WIDE). WE HIGHLIGHT THAT DIFFERENTIAL METHYLATION OF THE TCF7L2, KCNQ1, ABCG1, TXNIP, PHOSPHO1, SREBF1, SLC30A8, AND FTO GENES IN BLOOD ARE REPRODUCIBLY ASSOCIATED WITH T2D IN DIFFERENT POPULATION GROUPS. THESE GENES SHOULD BE PRIORITIZED AND REPLICATED IN LONGITUDINAL STUDIES ACROSS MORE POPULATIONS IN FUTURE STUDIES. FINALLY, WE DISCUSS THE LIMITATIONS FACED BY DNA METHYLATION STUDIES, WHICH INCLUDE INCLUDING INTERPATIENT VARIABILITY, CELLULAR HETEROGENEITY, AND LACK OF ACCOUNTING FOR STUDY CONFOUNDERS. THESE LIMITATIONS AND CHALLENGES MUST BE OVERCOME BEFORE THE IMPLEMENTATION OF BLOOD-BASED DNA METHYLATION BIOMARKERS INTO A CLINICAL SETTING. WE EMPHASIZE THE NEED FOR LONGITUDINAL PROSPECTIVE STUDIES TO SUPPORT THE ROBUSTNESS OF THE CURRENT FINDINGS OF THIS REVIEW. 2018 8 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 9 2595 51 EPIGENETICS OF SPONDYLOARTHRITIS. SPONDYLOARTHRITIS (SPA) IS A CHRONIC INFLAMMATORY DISORDER RESULTING FROM A COMBINATION OF GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. DESPITE RECENT ADVANCES, A SUBSTANTIAL FRACTION OF ITS GENETIC BASIS REMAINS POORLY UNDERSTOOD. SEVERAL MECHANISMS HAVE BEEN PROPOSED TO ACCOUNT FOR THIS UNEXPLAINED HERITABILITY, INCLUDING EPIGENETICS WHICH CAN PLAY A ROLE AT THE INTERFACE BETWEEN GENETIC AND ENVIRONMENTAL SUSCEPTIBILITY FACTORS. EPIGENETICS REFERS TO CHANGES IN GENE EXPRESSION THAT ARE NOT ENCODED IN THE DNA SEQUENCE ITSELF. SUCH MECHANISMS MAY INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS. DISRUPTION OF ONE OF THESE SYSTEMS CAN LEAD TO INAPPROPRIATE GENE EXPRESSION, WHICH IN TURN MIGHT FAVOUR THE DEVELOPMENT OF DISEASE. THANKS TO RECENT TECHNOLOGICAL PROGRESS, THERE HAS BEEN A GROWING INTEREST IN THE FIELD OF EPIGENETICS IN COMPLEX DISEASES, INCLUDING SPA. HOWEVER, EPIGENETIC STUDIES FACE SOME METHODOLOGICAL LIMITATIONS THAT HAMPER INTERPRETATION OF THEIR RESULTS: SMALL SAMPLE SIZE, ABSENCE OF BIOLOGICAL REPLICATION, LACK OF ADEQUATE CONTROLS FOR POTENTIAL CONFOUNDERS, STUDIES NOT PERFORMED IN THE MOST RELEVANT CELL/TISSUES. IN THE FUTURE, INTEGRATION OF EPIGENETICS WITH OTHER "OMICS" DATA WILL PROBABLY BE NECESSARY TO IMPROVE OUR UNDERSTANDING OF SPA PATHOGENESIS. THESE ISSUES NEED TO BE ADDRESSED BEFORE CONSIDERING THE USE OF EPIGENETIC MARKS IN CLINICAL ROUTINE, AS BIOMARKERS OR AS DRUG TARGETS. 2020 10 4266 35 MICRO-RNAS: CROSSROADS BETWEEN THE EXPOSURE TO ENVIRONMENTAL PARTICULATE POLLUTION AND THE OBSTRUCTIVE PULMONARY DISEASE. ENVIRONMENTAL POLLUTION HAS REACHED A GLOBAL ECHO AND REPRESENTS A SERIOUS PROBLEM FOR HUMAN HEALTH. AIR POLLUTION ENCOMPASSES A SET OF HAZARDOUS SUBSTANCES, SUCH AS PARTICULATE MATTER AND HEAVY METALS (E.G., CADMIUM, LEAD, AND ARSENIC), AND HAS A STRONG IMPACT ON THE ENVIRONMENT BY AFFECTING GROUNDWATER, SOIL, AND AIR. AN ADAPTIVE RESPONSE TO ENVIRONMENTAL CUES IS ESSENTIAL FOR HUMAN SURVIVAL, WHICH IS ASSOCIATED WITH THE INDUCTION OF ADAPTIVE PHENOTYPES. THE EPIGENETIC MECHANISMS REGULATING THE EXPRESSION PATTERNS OF SEVERAL GENES ARE PROMISING CANDIDATES TO PROVIDE MECHANISTIC AND PROGNOSTIC INSIGHTS INTO THIS. MICRO-RNAS (MIRNAS) FULFIL THESE FEATURES GIVEN THEIR ABILITY TO RESPOND TO ENVIRONMENTAL FACTORS AND THEIR CRITICAL ROLE IN DETERMINING PHENOTYPES. THESE MOLECULES ARE PRESENT IN EXTRACELLULAR FLUIDS, AND THEIR EXPRESSION PATTERNS ARE ORGAN-, TISSUE-, OR CELL-SPECIFIC. MOREOVER, THE EXPERIMENTAL SETTINGS FOR THEIR QUANTITATIVE AND QUALITATIVE ANALYSIS ARE ROBUST, STANDARDIZED, AND INEXPENSIVE. IN THIS REVIEW, WE PROVIDE AN UPDATE ON THE ROLE OF MIRNAS AS SUITABLE TOOLS FOR UNDERSTANDING THE MECHANISMS BEHIND THE PHYSIOPATHOLOGICAL RESPONSE TO TOXICANTS AND THE PROGNOSTIC VALUE OF THEIR EXPRESSION PATTERN ASSOCIABLE WITH SPECIFIC EXPOSURES. WE LOOK AT THE MECHANISTIC EVIDENCE ASSOCIABLE TO THE ROLE OF MIRNAS IN THE PROCESSES LEADING TO ENVIRONMENTAL-INDUCED PULMONARY DISEASE (I.E., CHRONIC OBSTRUCTIVE PULMONARY DISEASE). 2020 11 5164 39 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 12 5263 37 PROMISING BIOMARKERS OF HUMAN AGING: IN SEARCH OF A MULTI-OMICS PANEL TO UNDERSTAND THE AGING PROCESS FROM A MULTIDIMENSIONAL PERSPECTIVE. THE AGING PROCESS HAS BEEN LINKED TO THE OCCURRENCE OF CHRONIC DISEASES AND FUNCTIONAL IMPAIRMENTS, INCLUDING CANCER, SARCOPENIA, FRAILTY, METABOLIC, CARDIOVASCULAR, AND NEURODEGENERATIVE DISEASES. NONETHELESS, AGING IS HIGHLY VARIABLE AND HETEROGENEOUS AND REPRESENTS A CHALLENGE FOR ITS CHARACTERIZATION. IN THIS SENSE, INTRINSIC CAPACITY (IC) STANDS AS A NOVEL PERSPECTIVE BY THE WORLD HEALTH ORGANIZATION, WHICH INTEGRATES THE INDIVIDUAL WELLBEING, ENVIRONMENT, AND RISK FACTORS TO UNDERSTAND AGING. HOWEVER, THERE IS A LACK OF QUANTITATIVE AND QUALITATIVE ATTRIBUTES TO DEFINE IT OBJECTIVELY. THEREFORE, IN THIS REVIEW WE ATTEMPT TO SUMMARIZE THE MOST RELEVANT AND PROMISING BIOMARKERS DESCRIBED IN CLINICAL STUDIES AT DATE OVER DIFFERENT MOLECULAR LEVELS, INCLUDING EPIGENOMICS, TRANSCRIPTOMICS, PROTEOMICS, METABOLOMICS, AND THE MICROBIOME. TO AID GERONTOLOGISTS, GERIATRICIANS, AND BIOMEDICAL RESEARCHERS TO UNDERSTAND THE AGING PROCESS THROUGH THE IC. AGING BIOMARKERS REFLECT THE PHYSIOLOGICAL STATE OF INDIVIDUALS AND THE UNDERLYING MECHANISMS RELATED TO HOMEOSTATIC CHANGES THROUGHOUT AN INDIVIDUAL LIFESPAN; THEY DEMONSTRATED THAT AGING COULD BE MEASURED INDEPENDENTLY OF TIME (THAT MAY EXPLAIN ITS HETEROGENEITY) AND TO BE HELPFUL TO PREDICT AGE-RELATED SYNDROMES AND MORTALITY. IN SUMMARY, WE HIGHLIGHT THE AREAS OF OPPORTUNITY AND GAPS OF KNOWLEDGE THAT MUST BE ADDRESSED TO FULLY INTEGRATE BIOMEDICAL FINDINGS INTO CLINICALLY USEFUL TOOLS AND INTERVENTIONS. 2020 13 5110 34 POLYPHENOLS AND THE MODULATION OF GENE EXPRESSION PATHWAYS: CAN WE EAT OUR WAY OUT OF THE DANGER OF CHRONIC DISEASE? PLANT-DERIVED DIETARY POLYPHENOLS MAY IMPROVE SOME DISEASE STATES AND PROMOTE HEALTH. EXPERIMENTAL EVIDENCE SUGGESTS THAT THIS IS PARTIALLY ATTRIBUTABLE TO CHANGES IN GENE EXPRESSION. THE RATIONAL USE OF BIOACTIVE FOOD COMPONENTS MAY THEREFORE PRESENT AN OPPORTUNITY TO ACTIVATE OR REPRESS SELECTED GENE EXPRESSION PATHWAYS AND, CONSEQUENTLY, TO MANAGE OR PREVENT DISEASE. IT REMAINS TO BE DETERMINED WHETHER THIS USE OF BIOACTIVE FOOD COMPONENTS CAN BE DONE SAFELY. THIS ARTICLE REVIEWS THE ASSOCIATED CONTROVERSIES AND LIMITATIONS OF POLYPHENOL THERAPY. THERE IS A PAUCITY OF CLINICAL DATA ON THE RATIONAL USE OF POLYPHENOLS, INCLUDING A LACK OF KNOWLEDGE ON EFFECTIVE DOSAGE, ACTUAL CHEMICAL FORMULATIONS, BIOAVAILABILITY, DISTRIBUTION IN TISSUES, THE EFFECT OF GENETIC VARIATIONS, DIFFERENCES IN GUT MICROFLORA, THE SYNERGISTIC (OR ANTAGONISTIC) EFFECTS OBSERVED IN EXTRACTS, AND THE POSSIBLE INTERACTION BETWEEN POLYPHENOLS AND LIPID DOMAINS OF CELL MEMBRANES THAT MAY ALTER THE FUNCTION OF RELEVANT RECEPTORS. THE SEMINAL QUESTION OF WHY PLANTS MAKE SUBSTANCES THAT BENEFIT HUMANS REMAINS UNANSWERED, AND THERE IS STILL MUCH TO LEARN IN TERMS OF CORRELATIVE VERSUS CAUSAL EFFECTS OF HUMAN EXPOSURE TO VARIOUS NUTRIENTS. THE AVAILABLE DATA STRONGLY SUGGEST SIGNIFICANT EFFECTS AT THE MOLECULAR LEVEL THAT REPRESENT INTERACTIONS WITH THE EPIGENOME. THE ADVENT OF RELATIVELY SIMPLE TECHNOLOGIES IS HELPING THE FIELD OF EPIGENETICS PROGRESS AND FACILITATING THE ACQUISITION OF MULTIPLE TYPES OF DATA THAT WERE PREVIOUSLY DIFFICULT TO OBTAIN. IN THIS REVIEW, WE SUMMARIZE THE MOLECULAR BASIS OF THE EPIGENETIC REGULATION OF GENE EXPRESSION AND THE EPIGENETIC CHANGES ASSOCIATED WITH THE CONSUMPTION OF POLYPHENOLS THAT ILLUSTRATE HOW MODIFICATIONS IN HUMAN NUTRITION MAY BECOME RELEVANT TO HEALTH AND DISEASE. 2014 14 1352 43 DEVELOPMENT AND APPLICATION OF THE ADVERSE OUTCOME PATHWAY FRAMEWORK FOR UNDERSTANDING AND PREDICTING CHRONIC TOXICITY: I. CHALLENGES AND RESEARCH NEEDS IN ECOTOXICOLOGY. TO ELUCIDATE THE EFFECTS OF CHEMICALS ON POPULATIONS OF DIFFERENT SPECIES IN THE ENVIRONMENT, EFFICIENT TESTING AND MODELING APPROACHES ARE NEEDED THAT CONSIDER MULTIPLE STRESSORS AND ALLOW RELIABLE EXTRAPOLATION OF RESPONSES ACROSS SPECIES. AN ADVERSE OUTCOME PATHWAY (AOP) IS A CONCEPT THAT PROVIDES A FRAMEWORK FOR ORGANIZING KNOWLEDGE ABOUT THE PROGRESSION OF TOXICITY EVENTS ACROSS SCALES OF BIOLOGICAL ORGANIZATION THAT LEAD TO ADVERSE OUTCOMES RELEVANT FOR RISK ASSESSMENT. IN THIS PAPER, WE FOCUS ON EXPLORING HOW THE AOP CONCEPT CAN BE USED TO GUIDE RESEARCH AIMED AT IMPROVING BOTH OUR UNDERSTANDING OF CHRONIC TOXICITY, INCLUDING DELAYED TOXICITY AS WELL AS EPIGENETIC AND TRANSGENERATIONAL EFFECTS OF CHEMICALS, AND OUR ABILITY TO PREDICT ADVERSE OUTCOMES. A BETTER UNDERSTANDING OF THE INFLUENCE OF SUBTLE TOXICITY ON INDIVIDUAL AND POPULATION FITNESS WOULD SUPPORT A BROADER INTEGRATION OF SUBLETHAL ENDPOINTS INTO RISK ASSESSMENT FRAMEWORKS. DETAILED MECHANISTIC KNOWLEDGE WOULD FACILITATE THE DEVELOPMENT OF ALTERNATIVE TESTING METHODS AS WELL AS HELP PRIORITIZE HIGHER TIER TOXICITY TESTING. WE ARGUE THAT TARGETED DEVELOPMENT OF AOPS SUPPORTS BOTH OF THESE ASPECTS BY PROMOTING THE ELUCIDATION OF MOLECULAR MECHANISMS AND THEIR CONTRIBUTION TO RELEVANT TOXICITY OUTCOMES ACROSS BIOLOGICAL SCALES. WE FURTHER DISCUSS INFORMATION REQUIREMENTS AND CHALLENGES IN APPLICATION OF AOPS FOR CHEMICAL- AND SITE-SPECIFIC RISK ASSESSMENT AND FOR EXTRAPOLATION ACROSS SPECIES. WE PROVIDE RECOMMENDATIONS FOR POTENTIAL EXTENSION OF THE AOP FRAMEWORK TO INCORPORATE INFORMATION ON EXPOSURE, TOXICOKINETICS AND SITUATION-SPECIFIC ECOLOGICAL CONTEXTS, AND DISCUSS COMMON INTERFACES THAT CAN BE EMPLOYED TO COUPLE AOPS WITH COMPUTATIONAL MODELING APPROACHES AND WITH EVOLUTIONARY LIFE HISTORY THEORY. THE EXTENDED AOP FRAMEWORK CAN SERVE AS A VENUE FOR INTEGRATION OF KNOWLEDGE DERIVED FROM VARIOUS SOURCES, INCLUDING EMPIRICAL DATA AS WELL AS MOLECULAR, QUANTITATIVE AND EVOLUTIONARY-BASED MODELS DESCRIBING SPECIES RESPONSES TO TOXICANTS. THIS WILL ALLOW A MORE EFFICIENT APPLICATION OF AOP KNOWLEDGE FOR QUANTITATIVE CHEMICAL- AND SITE-SPECIFIC RISK ASSESSMENT AS WELL AS FOR EXTRAPOLATION ACROSS SPECIES IN THE FUTURE. 2015 15 754 33 CARDIOVASCULAR ADAPTATIONS TO PARTICLE INHALATION EXPOSURE: MOLECULAR MECHANISMS OF THE TOXICOLOGY. AMBIENT AIR, OCCUPATIONAL SETTINGS, AND THE USE AND DISTRIBUTION OF CONSUMER PRODUCTS ALL SERVE AS CONDUITS FOR TOXICANT EXPOSURE THROUGH INHALATION. WHILE THE PULMONARY SYSTEM REMAINS A PRIMARY TARGET FOLLOWING INHALATION EXPOSURE, CARDIOVASCULAR IMPLICATIONS ARE EXCEPTIONALLY CULPABLE FOR INCREASED MORBIDITY AND MORTALITY. THE EPIDEMIOLOGICAL EVIDENCE FOR CARDIOVASCULAR DYSFUNCTION RESULTING FROM ACUTE OR CHRONIC INHALATION EXPOSURE TO PARTICULATE MATTER HAS BEEN WELL DOCUMENTED, BUT THE MECHANISMS DRIVING THE RESULTING DISTURBANCES REMAIN ELUSIVE. IN THE CURRENT REVIEW, WE AIM TO SUMMARIZE THE CELLULAR AND MOLECULAR MECHANISMS THAT ARE DIRECTLY LINKED TO CARDIOVASCULAR HEALTH FOLLOWING EXPOSURE TO A VARIETY OF INHALED TOXICANTS. THE PURPOSE OF THIS REVIEW IS TO PROVIDE A COMPREHENSIVE OVERVIEW OF THE BIOCHEMICAL CHANGES IN THE CARDIOVASCULAR SYSTEM FOLLOWING PARTICLE INHALATION EXPOSURE AND TO HIGHLIGHT POTENTIAL BIOMARKERS THAT EXIST ACROSS MULTIPLE EXPOSURE PARADIGMS. WE ATTEMPT TO INTEGRATE THESE MOLECULAR SIGNATURES IN AN EFFORT TO PROVIDE DIRECTION FOR FUTURE INVESTIGATIONS. THIS REVIEW ALSO CHARACTERIZES HOW MOLECULAR RESPONSES ARE MODIFIED IN AT-RISK POPULATIONS, SPECIFICALLY THE IMPACT OF ENVIRONMENTAL EXPOSURE DURING CRITICAL WINDOWS OF DEVELOPMENT. MATERNAL EXPOSURE TO PARTICULATE MATTER DURING GESTATION CAN LEAD TO FETAL EPIGENETIC REPROGRAMMING, RESULTING IN LONG-TERM DEFICITS TO THE CARDIOVASCULAR SYSTEM. IN BOTH DIRECT AND INDIRECT (GESTATIONAL) EXPOSURES, CONNECTING THE BIOCHEMICAL MECHANISMS WITH FUNCTIONAL DEFICITS OUTLINES PATHWAYS THAT CAN BE TARGETED FOR FUTURE THERAPEUTIC INTERVENTION. ULTIMATELY, FUTURE INVESTIGATIONS INTEGRATING "OMICS"-BASED APPROACHES WILL BETTER ELUCIDATE THE MECHANISMS THAT ARE ALTERED BY XENOBIOTIC INHALATION EXPOSURE, IDENTIFY BIOMARKERS, AND GUIDE IN CLINICAL DECISION MAKING. 2020 16 6739 36 WHEN ENVIRONMENT MEETS GENETICS: A CLINICAL REVIEW OF THE EPIGENETICS OF PAIN, PSYCHOLOGICAL FACTORS, AND PHYSICAL ACTIVITY. EPIGENETIC MECHANISMS REPRESENT A LINK BETWEEN THE ENVIRONMENT AND GENE FUNCTION. RECENT RESEARCH SHOWS HOW EARLY LIFE STRESS, INFLAMMATION, AND PHYSICAL ACTIVITY CAN INFLUENCE GENE EXPRESSION THROUGH EPIGENETIC MECHANISMS. EPIGENETIC CHANGES-SUCH AS DNA METHYLATION AND MICRORNA INTERFERENCE-CAN BE MEASURED IN HUMANS AND MIGHT SOON BECOME IMPORTANT BIOLOGICAL MARKERS. EPIGENETIC MARKS CAN ACCOMPANY CLINICAL ASSESSMENT TO MEASURE THE EFFECTIVENESS OF VARIOUS INTERVENTIONS, SUCH AS EXERCISE THERAPY. IN ADDITION, EPIGENETICS IS IMPROVING THE UNDERSTANDING OF IMPORTANT UNDERLYING MECHANISMS RELATED TO THE CENTRAL NERVOUS SYSTEM, THE OPIOIDERGIC SYSTEM, AND STRESS RESPONSES. EPIGENETICS IS CLOSING A GAP IN OUR EXPLANATORY ABILITIES AND SHOULD BE IMPLEMENTED TO BROADEN THE FIELD OF REHABILITATION SCIENCES, PROMOTE A MECHANISM-BASED CLINICAL REASONING, AND DEVELOP NEW TREATMENTS. IN THE PRESENT REVIEW, WE FOCUSED ON EPIGENETIC MECHANISMS RELATED TO PAIN, PSYCHOLOGICAL FACTORS (SUCH AS FEAR AND ANXIETY), AND PHYSICAL ACTIVITY, TRANSLATING RELEVANT FINDINGS FROM THESE 3 DIFFERENT, YET RELATED, AREAS OF CARDINAL IMPORTANCE FOR CLINICIANS. 2019 17 6329 40 THE ROLE OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS. THIS REVIEW WILL DISCUSS THE ROLE OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS. RELEVANT STUDIES WERE IDENTIFIED VIA MEDLINE (PUBMED) AND PSYCINFO DATABASES PUBLISHED UP TO AND INCLUDING JULY 2015. THIS REVIEW CONTRIBUTES TO A NEW UNDERSTANDING OF THE NEGATIVE CONSEQUENCES OF EARLY LIFE STRESS, AS WELL AS SETTING CHILDHOOD TRAUMA IN A BIOLOGICAL CONTEXT OF SUSCEPTIBILITY AND DISCUSSING NOVEL LONG-TERM PATHOPHYSIOLOGICAL CONSEQUENCES IN BIPOLAR DISORDERS. CHILDHOOD TRAUMATIC EVENTS ARE RISK FACTORS FOR DEVELOPING BIPOLAR DISORDERS, IN ADDITION TO A MORE SEVERE CLINICAL PRESENTATION OVER TIME (PRIMARILY AN EARLIER AGE AT ONSET AND AN INCREASED RISK OF SUICIDE ATTEMPT AND SUBSTANCE MISUSE). CHILDHOOD TRAUMA LEADS TO ALTERATIONS OF AFFECT REGULATION, IMPULSE CONTROL, AND COGNITIVE FUNCTIONING THAT MIGHT DECREASE THE ABILITY TO COPE WITH LATER STRESSORS. CHILDHOOD TRAUMA INTERACTS WITH SEVERAL GENES BELONGING TO SEVERAL DIFFERENT BIOLOGICAL PATHWAYS [HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, SEROTONERGIC TRANSMISSION, NEUROPLASTICITY, IMMUNITY, CALCIUM SIGNALING, AND CIRCADIAN RHYTHMS] TO DECREASE THE AGE AT THE ONSET OF THE DISORDER OR INCREASE THE RISK OF SUICIDE. EPIGENETIC FACTORS MAY ALSO BE INVOLVED IN THE NEUROBIOLOGICAL CONSEQUENCES OF CHILDHOOD TRAUMA IN BIPOLAR DISORDER. BIOLOGICAL SEQUELAE SUCH AS CHRONIC INFLAMMATION, SLEEP DISTURBANCE, OR TELOMERE SHORTENING ARE POTENTIAL MEDIATORS OF THE NEGATIVE EFFECTS OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS, IN PARTICULAR WITH REGARD TO PHYSICAL HEALTH. THE MAIN CLINICAL IMPLICATION IS TO SYSTEMATICALLY ASSESS CHILDHOOD TRAUMA IN PATIENTS WITH BIPOLAR DISORDERS, OR AT LEAST IN THOSE WITH A SEVERE OR INSTABLE COURSE. THE CHALLENGE FOR THE NEXT YEARS WILL BE TO FILL THE GAP BETWEEN CLINICAL AND FUNDAMENTAL RESEARCH AND ROUTINE PRACTICE, SINCE RECOMMENDATIONS FOR MANAGING THIS SPECIFIC POPULATION ARE LACKING. IN PARTICULAR, LITTLE IS KNOWN ON WHICH PSYCHOTHERAPIES SHOULD BE PROVIDED OR WHICH TARGETS THERAPISTS SHOULD FOCUS ON, AS WELL AS HOW CHILDHOOD TRAUMA COULD EXPLAIN THE RESISTANCE TO MOOD STABILIZERS. 2016 18 4914 30 PAIN VULNERABILITY: A NEUROBIOLOGICAL PERSPECTIVE. THERE ARE MANY KNOWN RISK FACTORS FOR CHRONIC PAIN CONDITIONS, YET THE BIOLOGICAL UNDERPINNINGS THAT LINK THESE FACTORS TO ABNORMAL PROCESSING OF PAINFUL SIGNALS ARE ONLY JUST BEGINNING TO BE EXPLORED. THIS REVIEW WILL DISCUSS THE POTENTIAL MECHANISMS THAT HAVE BEEN PROPOSED TO UNDERLIE VULNERABILITY AND RESILIENCE TOWARD DEVELOPING CHRONIC PAIN. PARTICULAR FOCUS WILL BE GIVEN TO GENETIC AND EPIGENETIC PROCESSES, PRIMING EFFECTS ON A CELLULAR LEVEL, AND ALTERATIONS IN BRAIN NETWORKS CONCERNED WITH REWARD, MOTIVATION/LEARNING AND DESCENDING MODULATORY CONTROL. ALTHOUGH RESEARCH IN THIS AREA IS STILL IN ITS INFANCY, A BETTER UNDERSTANDING OF HOW PAIN VULNERABILITY EMERGES HAS THE POTENTIAL TO HELP IDENTIFY INDIVIDUALS AT RISK AND MAY OPEN UP NEW THERAPEUTIC AVENUES. 2014 19 2917 34 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 20 1928 44 ENVIRONMENTAL EXPOSURE MEASUREMENT IN CANCER EPIDEMIOLOGY. ENVIRONMENTAL EXPOSURES, USED IN THE BROADEST SENSE OF LIFESTYLE, INFECTIONS, RADIATION, NATURAL AND MAN-MADE CHEMICALS AND OCCUPATION, ARE A MAJOR CAUSE OF HUMAN CANCER. HOWEVER, THE PRECISE CONTRIBUTION OF SPECIFIC RISK FACTORS AND THEIR INTERACTION, BOTH WITH EACH OTHER AND WITH GENOTYPE, CONTINUES TO BE DIFFICULT TO ELUCIDATE. THIS IS PARTIALLY DUE TO LIMITATIONS IN ACCURATELY MEASURING EXPOSURE WITH THE SUBSEQUENT RISK OF MISCLASSIFICATION. ONE OF THE PRIMARY CHALLENGES OF MOLECULAR CANCER EPIDEMIOLOGY THEREFORE IS TO IMPROVE EXPOSURE ASSESSMENT. PROGRESS HAS BEEN MADE WITH BIOMARKERS SUCH AS CARCINOGENS AND THEIR METABOLITES, DNA AND PROTEIN ADDUCTS AND MUTATIONS MEASURED IN VARIOUS TISSUES AND BODY FLUIDS. NEVERTHELESS, MUCH REMAINS TO BE ACCOMPLISHED IN ORDER TO ESTABLISH AETIOLOGY AND PROVIDE THE EVIDENCE BASE FOR PUBLIC HEALTH DECISIONS. THIS REVIEW CONSIDERS SOME OF THE PRINCIPLES BEHIND THE APPLICATION OF EXPOSURE BIOMARKERS IN CANCER EPIDEMIOLOGY. IT ALSO DEMONSTRATES HOW THE SAME BIOMARKERS CAN CONTRIBUTE BOTH TO ESTABLISHING THE BIOLOGICAL PLAUSIBILITY OF ASSOCIATIONS BETWEEN EXPOSURE AND DISEASE AND BE VALUABLE ENDPOINTS IN INTERVENTION STUDIES. THE POTENTIAL OF NEW TECHNOLOGIES SUCH AS TRANSCRIPTOMICS, PROTEOMICS AND METABONOMICS TO PROVIDE A STEP CHANGE IN ENVIRONMENTAL EXPOSURE ASSESSMENT IS DISCUSSED. AN INCREASING RECOGNITION OF THE ROLE OF EPIGENETIC CHANGES IN CARCINOGENESIS PRESENTS A FRESH CHALLENGE AS ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA IN RESPONSE TO ENVIRONMENTAL EXPOSURES DEMAND A NEW GENERATION OF EXPOSURE BIOMARKER. THE OVERALL IMPORTANCE OF THIS AREA OF RESEARCH IS BROUGHT INTO SHARP RELIEF BY THE LARGE PROSPECTIVE COHORT STUDIES (E.G. UK BIOBANK) WHICH NEED ACCURATE EXPOSURE MEASUREMENT IN ORDER TO SHED LIGHT ON THE COMPLEX GENE:ENVIRONMENT INTERACTIONS UNDERLYING COMMON CHRONIC DISORDERS INCLUDING CANCER. IT IS SUGGESTED THAT A CONCERTED EFFORT IS NOW REQUIRED, WITH APPROPRIATE FUNDING, TO DEVELOP AND VALIDATE THE REQUIRED EXPOSURE ASSESSMENT METHODOLOGY BEFORE THESE COHORTS COME TO MATURITY. 2009