1 478 133 ARSENIC TOXICOLOGY: TRANSLATING BETWEEN EXPERIMENTAL MODELS AND HUMAN PATHOLOGY. BACKGROUND: CHRONIC ARSENIC EXPOSURE IS A WORLDWIDE HEALTH PROBLEM. HOW ARSENIC EXPOSURE PROMOTES A VARIETY OF DISEASES IS POORLY UNDERSTOOD, AND SPECIFIC RELATIONSHIPS BETWEEN EXPERIMENTAL AND HUMAN EXPOSURES ARE NOT ESTABLISHED. WE PROPOSE PHENOTYPIC ANCHORING AS A MEANS TO UNIFY EXPERIMENTAL OBSERVATIONS AND DISEASE OUTCOMES. OBJECTIVES: WE EXAMINED THE USE OF PHENOTYPIC ANCHORS TO TRANSLATE EXPERIMENTAL DATA TO HUMAN PATHOLOGY AND INVESTIGATED RESEARCH NEEDS FOR WHICH PHENOTYPIC ANCHORS NEED TO BE DEVELOPED. METHODS: DURING A WORKSHOP, WE DISCUSSED EXPERIMENTAL SYSTEMS INVESTIGATING ARSENIC DOSE/EXPOSURE AND PHENOTYPIC EXPRESSION RELATIONSHIPS AND HUMAN DISEASE RESPONSES TO CHRONIC ARSENIC EXPOSURE AND IDENTIFIED KNOWLEDGE GAPS. IN A LITERATURE REVIEW, WE IDENTIFIED AREAS WHERE DATA EXIST TO SUPPORT PHENOTYPIC ANCHORING OF EXPERIMENTAL RESULTS TO PATHOLOGIES FROM SPECIFIC HUMAN EXPOSURES. DISCUSSION: DISEASE OUTCOME IS LIKELY DEPENDENT ON CELL-TYPE-SPECIFIC RESPONSES AND INTERACTION WITH INDIVIDUAL GENETICS, OTHER TOXICANTS, AND INFECTIOUS AGENTS. POTENTIAL PHENOTYPIC ANCHORS INCLUDE TARGET TISSUE DOSIMETRY, GENE EXPRESSION AND EPIGENETIC PROFILES, AND TISSUE BIOMARKERS. CONCLUSIONS: TRANSLATION TO HUMAN POPULATIONS REQUIRES MORE EXTENSIVE PROFILING OF HUMAN SAMPLES ALONG WITH HIGH-QUALITY DOSIMETRY. ANCHORING RESULTS BY GENE EXPRESSION AND EPIGENETIC PROFILING HAS GREAT PROMISE FOR DATA UNIFICATION. GENETIC PREDISPOSITION OF INDIVIDUALS AFFECTS DISEASE OUTCOME. INTERACTIONS WITH INFECTIOUS AGENTS, PARTICULARLY VIRUSES, MAY EXPLAIN SOME SPECIES-SPECIFIC DIFFERENCES BETWEEN HUMAN PATHOLOGIES AND EXPERIMENTAL ANIMAL PATHOLOGIES. INVERTEBRATE SYSTEMS AMENABLE TO GENETIC MANIPULATION OFFER POTENTIAL FOR ELABORATING IMPACTS OF SPECIFIC BIOCHEMICAL PATHWAYS. ANCHORING EXPERIMENTAL RESULTS TO SPECIFIC HUMAN EXPOSURES WILL ACCELERATE UNDERSTANDING OF MECHANISMS OF ARSENIC-INDUCED HUMAN DISEASE. 2011 2 3418 34 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 3 705 32 BUILDING RISK-ON-A-CHIP MODELS TO IMPROVE BREAST CANCER RISK ASSESSMENT AND PREVENTION. PREVENTIVE ACTIONS FOR CHRONIC DISEASES HOLD THE PROMISE OF IMPROVING LIVES AND REDUCING HEALTHCARE COSTS. FOR SEVERAL DISEASES, INCLUDING BREAST CANCER, MULTIPLE RISK AND PROTECTIVE FACTORS HAVE BEEN IDENTIFIED BY EPIDEMIOLOGISTS. THE IMPACT OF MOST OF THESE FACTORS HAS YET TO BE FULLY UNDERSTOOD AT THE ORGANISM, TISSUE, CELLULAR AND MOLECULAR LEVELS. IMPORTANTLY, COMBINATIONS OF EXTERNAL AND INTERNAL RISK AND PROTECTIVE FACTORS INVOLVE COOPERATIVITY THUS, SYNERGIZING OR ANTAGONIZING DISEASE ONSET. MODELS ARE NEEDED TO MECHANISTICALLY DECIPHER CANCER RISKS UNDER DEFINED CELLULAR AND MICROENVIRONMENTAL CONDITIONS. HERE, WE BRIEFLY REVIEW BREAST CANCER RISK MODELS BASED ON 3D CELL CULTURE AND PROPOSE TO IMPROVE RISK MODELING WITH LAB-ON-A-CHIP APPROACHES. WE SUGGEST EPITHELIAL TISSUE POLARITY, DNA REPAIR AND EPIGENETIC PROFILES AS ENDPOINTS IN RISK ASSESSMENT MODELS AND DISCUSS THE DEVELOPMENT OF 'RISKS-ON-CHIPS' INTEGRATING BIOSENSORS OF THESE ENDPOINTS AND OF GENERAL TISSUE HOMEOSTASIS. RISKS-ON-CHIPS WILL HELP IDENTIFY BIOMARKERS OF RISK, SERVE AS SCREENING PLATFORMS FOR CANCER PREVENTIVE AGENTS, AND PROVIDE A BETTER UNDERSTANDING OF RISK MECHANISMS, HENCE RESULTING IN NOVEL DEVELOPMENTS IN DISEASE PREVENTION. 2013 4 2279 42 EPIGENETIC REGULATION IN ALLERGIC DISEASES AND RELATED STUDIES. ASTHMA, A CHRONIC INFLAMMATORY DISORDER OF THE AIRWAY, HAS FEATURES OF BOTH HERITABILITY AS WELL AS ENVIRONMENTAL INFLUENCES WHICH CAN BE INTRODUCED IN UTERO EXPOSURES AND MODIFIED THROUGH AGING, AND THE FEATURES MAY ATTRIBUTE TO EPIGENETIC REGULATION. EPIGENETIC REGULATION EXPLAINS THE ASSOCIATION BETWEEN EARLY PRENATAL MATERNAL SMOKING AND LATER ASTHMA-RELATED OUTCOMES. EPIGENETIC MARKS (DNA METHYLATION, MODIFICATIONS OF HISTONE TAILS OR NONCODING RNAS) WORK WITH OTHER COMPONENTS OF THE CELLULAR REGULATORY MACHINERY TO CONTROL THE LEVELS OF EXPRESSED GENES, AND SEVERAL ALLERGY- AND ASTHMA-RELATED GENES HAVE BEEN FOUND TO BE SUSCEPTIBLE TO EPIGENETIC REGULATION, INCLUDING GENES IMPORTANT TO T-EFFECTOR PATHWAYS (IFN-GAMMA, INTERLEUKIN [IL] 4, IL-13, IL-17) AND T-REGULATORY PATHWAYS (FOXP3). THEREFORE, THE MECHANISM BY WHICH EPIGENETIC REGULATION CONTRIBUTES TO ALLERGIC DISEASES IS A CRITICAL ISSUE. IN THE PAST MOST PUBLISHED EXPERIMENTAL WORK, WITH FEW EXCEPTIONS, HAS ONLY COMPRISED SMALL OBSERVATIONAL STUDIES AND MODELS IN CELL SYSTEMS AND ANIMALS. HOWEVER, VERY RECENTLY EXCITING AND ELEGANT EXPERIMENTAL STUDIES AND NOVEL TRANSLATIONAL RESEARCH WORKS WERE PUBLISHED WITH NEW AND ADVANCED TECHNOLOGIES INVESTIGATING EPIGENETIC MARK ON A GENOMIC SCALE AND COMPREHENSIVE APPROACHES TO DATA ANALYSIS. INTERESTINGLY, A POTENTIAL LINK BETWEEN EXPOSURE TO ENVIRONMENTAL POLLUTANTS AND THE OCCURRENCE OF ALLERGIC DISEASES IS REVEALED RECENTLY, PARTICULAR IN DEVELOPED AND INDUSTRIALIZED COUNTRIES, AND ENDOCRINE DISRUPTING CHEMICALS (EDCS) AS ENVIRONMENTAL HORMONE MAY PLAY A KEY ROLE. THIS REVIEW ADDRESSES THE IMPORTANT QUESTION OF HOW EDCS (NONYLPHENOL, 4 OCTYLPHENOL, AND PHTHALATES) INFLUENCES ON ASTHMA-RELATED GENE EXPRESSION VIA EPIGENETIC REGULATION IN IMMUNE CELLS, AND HOW ANTI-ASTHMATIC AGENTS PROHIBIT EXPRESSION OF INFLAMMATORY GENES VIA EPIGENETIC MODIFICATION. THE DISCOVERY AND VALIDATION OF EPIGENETIC BIOMARKERS LINKING EXPOSURE TO ALLERGIC DISEASES MIGHT LEAD TO BETTER EPIGENOTYPING OF RISK, PROGNOSIS, TREATMENT PREDICTION, AND DEVELOPMENT OF NOVEL THERAPIES. 2014 5 1811 37 EFFECTS OF ARSENIC TOXICITY BEYOND EPIGENETIC MODIFICATIONS. WORLDWIDE CHRONIC ARSENIC (AS) POISONING BY ARSENIC-CONTAMINATED GROUNDWATER IS ONE OF THE MOST THREATENING PUBLIC HEALTH PROBLEMS. CHRONIC INORGANIC AS (INAS) EXPOSURE HAS BEEN ASSOCIATED WITH VARIOUS FORMS OF CANCERS AND NUMEROUS OTHER PATHOLOGICAL EFFECTS IN HUMANS, COLLECTIVELY KNOWN AS ARSENICOSIS. OVER THE PAST DECADE, EVIDENCE INDICATED THAT AS-INDUCED EPIGENETIC MODIFICATIONS HAVE A ROLE IN THE ADVERSE EFFECTS ON HUMAN HEALTH. THE MAIN OBJECTIVE OF THIS ARTICLE IS TO REVIEW THE EVIDENCE ON EPIGENETIC MODIFICATIONS INDUCED BY ARSENICALS. THE EPIGENETIC COMPONENTS PLAY A CRUCIAL ROLE IN THE REGULATION OF GENE EXPRESSION, AT BOTH TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL LEVELS. WE SYNTHESIZED THE LARGE BODY OF EXISTING RESEARCH ON ARSENIC EXPOSURE AND EPIGENETIC MECHANISMS OF HEALTH OUTCOMES WITH AN EMPHASIS ON RECENT PUBLICATIONS. CHANGES IN PATTERNS OF DNA METHYLATION, HISTONE POSTTRANSLATIONAL MODIFICATIONS, AND MICRORNAS HAVE BEEN REPEATEDLY OBSERVED AFTER INAS EXPOSURE IN LABORATORY STUDIES AND IN STUDIES OF HUMAN POPULATIONS. SUCH ALTERATIONS HAVE THE POTENTIAL TO DISTURB CELLULAR HOMEOSTASIS, RESULTING IN THE MODULATION OF KEY PATHWAYS IN THE AS-INDUCED CARCINOGENESIS. THE PRESENT ARTICLE REVIEWS RECENT DATA ON AS-INDUCED EPIGENETIC EFFECTS AND CONCLUDES THAT IT IS TIME FOR HEIGHTENED AWARENESS OF PATHOGENIC ARSENIC EXPOSURE, PARTICULARLY FOR PREGNANT WOMEN AND CHILDREN, GIVEN THE POTENTIAL FOR A LONG-LASTING DISTURBED CELLULAR HOMEOSTASIS. 2018 6 2901 34 GENDER DIFFERENCES IN GERM-CELL MUTAGENESIS AND GENETIC RISK. CURRENT INTERNATIONAL CLASSIFICATION SYSTEMS FOR CHEMICAL MUTAGENS ARE HAZARD-BASED RATHER THAN AIMED AT ASSESSING RISKS QUANTITATIVELY. IN THE PAST, GERM-CELL TESTS HAVE BEEN MAINLY PERFORMED WITH A LIMITED NUMBER OF SOMATIC CELL MUTAGENS, AND RARELY UNDER CONDITIONS AIMED AT COMPARING GENDER-SPECIFIC DIFFERENCES IN SUSCEPTIBILITY TO MUTAGEN EXPOSURES. THERE ARE PROFOUND DIFFERENCES IN THE GENETIC CONSTITUTION, AND IN HORMONAL, STRUCTURAL, AND FUNCTIONAL ASPECTS OF DIFFERENTIATION AND CONTROL OF GAMETOGENESIS BETWEEN THE SEXES. A CRITICAL REVIEW OF THE LITERATURE SUGGESTS THAT THESE DIFFERENCES MAY HAVE A PROFOUND IMPACT ON THE RELATIVE SUSCEPTIBILITY, STAGE OF HIGHEST SENSITIVITY AND THE RELATIVE RISK FOR THE GENESIS OF GENE MUTATION, AS WELL AS STRUCTURAL AND NUMERICAL CHROMOSOMAL ABERRATIONS IN MALE AND FEMALE GERM CELLS. TRANSMISSION OF GERM-CELL MUTATIONS TO THE OFFSPRING MAY ALSO ENCOUNTER GENDER-SPECIFIC INFLUENCES. GENDER DIFFERENCES IN SUSCEPTIBILITY TO CHEMICALLY DERIVED ALTERATIONS IN IMPRINTING PATTERNS MAY POSE A THREAT FOR THE HEALTH OF THE OFFSPRING AND MAY ALSO BE TRANSMITTED TO FUTURE GENERATIONS. RECENT REPORTS ON DIFFERENT GENETIC EFFECTS FROM HIGH ACUTE AND FROM CHRONIC LOW-DOSE EXPOSURES CHALLENGE THE VALIDITY OF CONCLUSIONS DRAWN FROM STANDARD METHODS OF MUTAGENICITY TESTING. IN CONCLUSION, RESEARCH IS URGENTLY NEEDED TO IDENTIFY GENETIC HAZARDS FOR A LARGER RANGE OF CHEMICAL COMPOUNDS, INCLUDING THOSE SUSPECTED TO DISTURB PROPER CHROMOSOME SEGREGATION. ALTERATIONS IN EPIGENETIC PROGRAMMING AND THEIR HEALTH CONSEQUENCES WILL HAVE TO BE INVESTIGATED. MORE ATTENTION SHOULD BE PAID TO GENDER-SPECIFIC GENETIC EFFECTS. FINALLY, THE DATABASE FOR GERM-CELL MUTAGENS SHOULD BE ENLARGED USING MOLECULAR METHODOLOGIES, AND GENETIC EPIDEMIOLOGY STUDIES SHOULD BE PERFORMED WITH THESE TECHNIQUES TO VERIFY HUMAN GENETIC RISK. 2007 7 761 32 CATEGORIZING THE CHARACTERISTICS OF HUMAN CARCINOGENS: A NEED FOR SPECIFICITY. THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) HAS RECENTLY PROPOSED EMPLOYING "TEN KEY CHARACTERISTICS OF HUMAN CARCINOGENS" (TKCS) TO DETERMINE THE POTENTIAL OF AGENTS FOR HARMFUL EFFECTS. THE TKCS SEEM LIKELY TO CONFUSE THE UNSATISFACTORY CORRELATION FROM TESTING REGIMES THAT HAVE IGNORED THE DIFFERENCES EVIDENT WHEN CELLULAR CHANGES ARE COMPARED IN SHORT AND LONG-LIVED SPECIES, WITH THEIR VERY DIFFERENT STEM CELL AND SOMATIC CELL PHYLOGENIES. THE PROPOSED CHARACTERISTICS ARE SO BROAD THAT THEIR USE WILL LEAD TO AN INCREASE IN THE CURRENT UNACCEPTABLY HIGH RATE OF FALSE POSITIVES. IT COULD BE AN INFORMATIVE EXPERIMENT TO TAKE WELL-ESTABLISHED APPROVED THERAPEUTICS WITH WELL-KNOWN HUMAN SAFETY PROFILES AND TEST THEM AGAINST THIS NEW TKC PARADIGM. CANCERS ARE INITIATED AND DRIVEN BY HERITABLE AND TRANSIENT CHANGES IN GENE EXPRESSION, EXPAND CLONALLY, AND PROGRESS VIA ADDITIONAL ASSOCIATED ACQUIRED MUTATIONS AND EPIGENETIC ALTERATIONS THAT PROVIDE CELLS WITH AN EVOLUTIONARY ADVANTAGE. THE GENOTOXICITY TESTING PROTOCOLS CURRENTLY EMPLOYED AND REQUIRED BY REGULATION, EMPHASIZE TESTING FOR THE MUTATIONAL POTENTIAL OF THE TEST AGENT. TWO-YEAR, CHRONIC RODENT CANCER BIOASSAYS ARE INTENDED TO TEST FOR THE ENTIRE SPECTRUM OF CARCINOGENIC TRANSFORMATION. THE USE OF CYTOTOXIC DOSES CAUSING INCREASED, SUSTAINED CELL PROLIFERATION THAT FACILITATES ACCUMULATED GENETIC DAMAGE LEADS TO A HIGH FALSE-POSITIVE RATE OF TUMOR INDUCTION. CURRENT CANCER HAZARD ASSESSMENT PROTOCOLS AND WEIGHT-OF-THE-EVIDENCE ANALYSIS OF AGENT-SPECIFIC CANCER RISK ALIGN POORLY WITH THE PATHOGENESIS OF HUMAN CARCINOMA AND SO NEED MODERNIZATION AND IMPROVEMENT IN WAYS SUGGESTED HERE. 2021 8 1524 22 DNA METHYLATION CHANGES IN CYSTIC FIBROSIS: CAUSE OR CONSEQUENCE? TWIN AND SIBLING STUDIES HAVE SHOWN THAT LUNG DISEASE SEVERITY IS VARIABLE AMONG CYSTIC FIBROSIS (CF) PATIENTS AND AFFECTED TO THE SAME EXTENT BY GENETIC AND NONHERITABLE FACTORS. GENETIC FACTORS HAVE BEEN THOROUGHLY ASSESSED, WHEREAS THE MOLECULAR MECHANISMS WHEREBY NONHERITABLE FACTORS CONTRIBUTE TO THE PHENOTYPIC VARIABILITY OF CF PATIENTS ARE STILL UNKNOWN. EPIGENETIC MODIFICATIONS MAY REPRESENT THE MISSING LINK BETWEEN NONHERITABLE FACTORS AND PHENOTYPIC VARIATION IN CF. HEREIN, WE REVIEW RECENT STUDIES SHOWING THAT DNA METHYLATION IS ALTERED IN CF AND WE ADDRESS THREE POSSIBLE FACTORS RESPONSIBLE FOR THESE VARIATIONS: (I) OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DEPLETION OF DNA METHYLATION COFACTORS AND (III) SUSCEPTIBILITY TO ACUTE AND CHRONIC BACTERIAL INFECTIONS. ALSO, WE HYPOTHESIZE THAT THE UNIQUE DNA METHYLATION PROFILE OF EACH PATIENT CAN MODULATE THE PHENOTYPE AND DISCUSS THE INTEREST OF IMPLEMENTING INTEGRATED GENOMIC, EPIGENOMIC AND TRANSCRIPTOMIC STUDIES TO FURTHER UNDERSTAND THE CLINICAL DIVERSITY OF CF PATIENTS (GRAPHICAL ABSTRACT). 2020 9 6459 23 TIME TO CHANGE FROM A SIMPLE LINEAR MODEL TO A COMPLEX SYSTEMS MODEL. A SIMPLE LINEAR MODEL TO TEST THE HYPOTHESIS BASED ON ONE-ON-ONE RELATIONSHIP HAS BEEN USED TO FIND THE CAUSATIVE FACTORS OF DISEASES. HOWEVER, WE NOW KNOW THAT NOT JUST ONE, BUT MANY FACTORS FROM DIFFERENT SYSTEMS SUCH AS CHEMICAL EXPOSURE, GENES, EPIGENETIC CHANGES, AND PROTEINS ARE INVOLVED IN THE PATHOGENESIS OF CHRONIC DISEASES SUCH AS DIABETES MELLITUS. SO, WITH AVAILABILITY OF MODERN TECHNOLOGIES TO UNDERSTAND THE INTRICATE NATURE OF RELATIONS AMONG COMPLEX SYSTEMS, WE NEED TO MOVE FORWARD TO THE FUTURE BY TAKING COMPLEX SYSTEMS MODEL. 2016 10 6740 32 WHEN GETOMICS MEETS AGING AND EXERCISE IN COPD. THE TERM GETOMICS HAS BEEN RECENTLY PROPOSED TO ILLUSTRATE THAT HUMAN HEALTH AND DISEASE ARE ACTUALLY THE FINAL OUTCOME OF MANY DYNAMIC, INTERACTING AND CUMULATIVE GENE (G) - ENVIRONMENT (E) INTERACTIONS THAT OCCUR THROUGH THE LIFETIME (T) OF THE INDIVIDUAL. ACCORDING TO THIS NEW PARADIGM, THE FINAL OUTCOME OF ANY GXE INTERACTIONS DEPENDS ON BOTH THE AGE OF THE INDIVIDUAL AT WHICH SUCH GXE INTERACTION OCCURS AS WELL AS ON THE PREVIOUS, CUMULATIVE HISTORY OF PREVIOUS GXE INTERACTIONS THROUGH THE INDUCTION OF EPIGENETIC CHANGES AND IMMUNE MEMORY (BOTH LASTING OVERTIME). FOLLOWING THIS CONCEPTUAL APPROACH, OUR UNDERSTANDING OF THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) HAS CHANGED DRAMATICALLY. TRADITIONALLY BELIEVED TO BE A SELF-INFLICTED DISEASE INDUCED BY TOBACCO SMOKING OCCURRING IN OLDER MEN AND CHARACTERIZED BY AN ACCELERATED DECLINE OF LUNG FUNCTION WITH AGE, NOW WE UNDERSTAND THAT THERE ARE MANY OTHER RISK FACTORS ASSOCIATED WITH COPD, THAT IT OCCURS ALSO IN FEMALES AND YOUNG INDIVIDUALS, THAT THERE ARE DIFFERENT LUNG FUNCTION TRAJECTORIES THROUGH LIFE, AND THAT COPD IS NOT ALWAYS CHARACTERIZED BY ACCELERATED LUNG FUNCTION DECLINE. IN THIS PAPER WE DISCUSS HOW A GETOMICS APPROACH TO COPD MAY OPEN NEW PERSPECTIVES TO BETTER UNDERSTAND ITS RELATIONSHIP WITH EXERCISE LIMITATION AND THE AGEING PROCESS. 2023 11 2586 26 EPIGENETICS OF PAIN MEDIATORS. PURPOSE OF REVIEW: THE FIELD OF EPIGENETICS CONTINUES ITS INFLUENTIAL RISE AS A MEANS TO BETTER UNDERSTAND AN ORGANISM'S UNIQUE DEVELOPMENTAL IDENTITY OVER A LIFESPAN. WHEREAS A GENOME IS CONSTANT AND UNCHANGING, AN EPIGENOME IS DYNAMIC AND ALTERABLE. EPIGENETIC CHANGES ARE IN RESPONSE TO INNUMERABLE INTERNAL AND EXTERNAL INFLUENCES INCLUDING ENVIRONMENTAL CHANGES SUCH AS DIET, EXERCISE, DISEASE, TOXINS, AND STRESS. EPIGENETICS IS OF PARTICULAR INTEREST IN THE MEDICAL RESEARCH COMMUNITY BOTH FOR THE POTENTIAL TO CAUSE DISEASE AND AS A TARGET FOR THERAPEUTIC INTERVENTIONS. THIS ARTICLE PROVIDES A SUCCINCT EXPLANATION OF THE POTENTIAL FOR EPIGENETICS TO INFLUENCE THE UNDERSTANDING OF PAIN AS WELL AS A REVIEW OF RELEVANT RESEARCH ON THE TOPIC. RECENT FINDINGS: STUDIES ON EPIGENETICS AND PAIN REMAIN LARGELY PRECLINICAL AND INVESTIGATE THE THEORETICAL ABILITY OF EPIGENETICS TO ALTER THE NOCICEPTIVE PATHWAYS BOTH IN THE PERIPHERY AND CENTRALLY. SIGNIFICANT EVIDENCE NOW EXISTS FOR THE ABILITY OF EPIGENETICS TO MODIFY BROADLY CATEGORIZED PAIN TYPES, INCLUDING INFLAMMATORY, NEUROPATHIC, VISCERAL, AND CANCER RELATED. SUMMARY: BOTH PATIENTS AND PROVIDERS RECOGNIZE THAT NOVEL MEDICATIONS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC PAIN CONDITIONS ARE SORELY NEEDED. THE UNDERSTANDING OF EPIGENETICS AND ITS INFLUENCE ON NOCICEPTION REMAINS IN RELATIVE INFANCY BUT EARLY EVIDENCE IS STRONG FOR POTENTIAL THERAPEUTIC BENEFITS TO TREAT THESE CONDITIONS. 2018 12 2059 26 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE LUNG. EPIGENETICS IS TRADITIONALLY DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. THERE ARE THREE MAIN CLASSES OF EPIGENETIC MARKS--DNA METHYLATION, MODIFICATIONS OF HISTONE TAILS, AND NONCODING RNAS--EACH OF WHICH MAY BE INFLUENCED BY THE ENVIRONMENT, DIET, DISEASES, AND AGEING. IMPORTANTLY, EPIGENETIC MARKS HAVE BEEN SHOWN TO INFLUENCE IMMUNE CELL MATURATION AND ARE ASSOCIATED WITH THE RISK OF DEVELOPING VARIOUS FORMS OF CANCER, INCLUDING LUNG CANCER. MOREOVER, THERE IS EMERGING EVIDENCE THAT THESE EPIGENETIC MARKS AFFECT GENE EXPRESSION IN THE LUNG AND ARE ASSOCIATED WITH BENIGN LUNG DISEASES, SUCH AS ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND INTERSTITIAL LUNG DISEASE. TECHNOLOGICAL ADVANCES HAVE MADE IT FEASIBLE TO STUDY EPIGENETIC MARKS IN THE LUNG, AND IT IS ANTICIPATED THAT THIS KNOWLEDGE WILL ENHANCE OUR UNDERSTANDING OF THE DYNAMIC BIOLOGY IN THE LUNG AND LEAD TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES FOR OUR PATIENTS WITH LUNG DISEASE. 2011 13 1453 26 DISCOVERING HOW ENVIRONMENTAL EXPOSURES ALTER GENES COULD LEAD TO NEW TREATMENTS FOR CHRONIC ILLNESSES. EMERGING RESEARCH DEMONSTRATES THAT DIET, POLLUTION, AND OTHER ENVIRONMENTAL TRIGGERS CAN ALTER BOTH THE FUNCTION AND EXPRESSION OF HUMAN GENES AND LEAD TO A HEIGHTENED DISEASE RISK. THESE ENVIRONMENT-GENE INTERACTIONS CAN CAUSE SO-CALLED EPIGENETIC CHANGES IN GENE EXPRESSION-PATTERNS OF WHICH GENES ARE SWITCHED "ON" OR "OFF"-THAT MAY ACCOUNT FOR THE RISING MORTALITY FROM CHRONIC DISEASES IN INDUSTRIALIZED NATIONS. IN THIS PAPER, WE CALL FOR A NEW TRANSDISCIPLINARY APPROACH TO PUBLIC HEALTH THAT WOULD EXAMINE HOW ENVIRONMENTAL EXPOSURES, BOTH PHYSICAL AND SOCIAL, INFLUENCE GENE EXPRESSION AND A PERSON'S SUSCEPTIBILITY TO CHRONIC DISEASE. THIS INITIATIVE COULD LEAD TO NEW WAYS TO PREVENT AND TREAT SUCH ILLNESSES. 2011 14 1865 43 EMERGING CONCEPTS ON THE ROLE OF EPIGENETICS IN THE RELATIONSHIPS BETWEEN NUTRITION AND HEALTH. UNDERSTANDING THE PHYSIOLOGICAL AND METABOLIC UNDERPINNINGS THAT CONFER INDIVIDUAL DIFFERENCES IN RESPONSES TO DIET AND DIET-RELATED CHRONIC DISEASE IS ESSENTIAL TO ADVANCE THE FIELD OF NUTRITION. THIS INCLUDES ELUCIDATING THE DIFFERENCES IN GENE EXPRESSION THAT ARE MEDIATED THROUGH PROGRAMMING OF THE GENOME THROUGH EPIGENETIC CHROMATIN MODIFICATIONS. EPIGENETIC LANDSCAPES ARE INFLUENCED BY AGE, GENETICS, TOXINS AND OTHER ENVIRONMENTAL FACTORS, INCLUDING DIETARY EXPOSURES AND NUTRITIONAL STATUS. EPIGENETIC MODIFICATIONS INFLUENCE TRANSCRIPTION AND GENOME STABILITY ARE ESTABLISHED DURING DEVELOPMENT WITH LIFE-LONG CONSEQUENCES. THEY CAN BE INHERITED FROM ONE GENERATION TO THE NEXT. THE COVALENT MODIFICATIONS OF CHROMATIN, WHICH INCLUDE METHYLATION AND ACETYLATION, ON DNA NUCLEOTIDE BASES, HISTONE PROTEINS AND RNA ARE DERIVED FROM INTERMEDIATES OF ONE-CARBON METABOLISM AND CENTRAL METABOLISM. THEY INFLUENCE KEY PHYSIOLOGICAL PROCESSES THROUGHOUT LIFE, AND TOGETHER WITH INHERITED DNA PRIMARY SEQUENCE, CONTRIBUTE TO RESPONSIVENESS TO ENVIRONMENTAL STRESSES, DIET AND RISK FOR AGE-RELATED CHRONIC DISEASE. REVEALING DIET-EPIGENETIC RELATIONSHIPS HAS THE POTENTIAL TO TRANSFORM NUTRITION SCIENCE BY INCREASING OUR FUNDAMENTAL UNDERSTANDING OF: (I) THE ROLE OF NUTRIENTS IN BIOLOGICAL SYSTEMS, (II) THE RESILIENCE OF LIVING ORGANISMS IN RESPONDING TO ENVIRONMENTAL PERTURBATIONS, AND (III) THE DEVELOPMENT OF DIETARY PATTERNS THAT PROGRAMME PHYSIOLOGY FOR LIFE-LONG HEALTH. EPIGENETICS MAY ALSO ENABLE THE CLASSIFICATION OF INDIVIDUALS WITH CHRONIC DISEASE FOR SPECIFIC DIETARY MANAGEMENT AND/OR FOR EFFICACIOUS DIET-PHARMACEUTICAL COMBINATION THERAPIES. THESE NEW EMERGING CONCEPTS AT THE INTERFACE OF NUTRITION AND EPIGENETICS WERE DISCUSSED, AND FUTURE RESEARCH NEEDS IDENTIFIED BY LEADING EXPERTS AT THE 26TH MARABOU SYMPOSIUM ENTITLED 'NUTRITION, EPIGENETICS, GENETICS: IMPACT ON HEALTH AND DISEASE'. FOR A COMPILATION OF THE GENERAL DISCUSSION AT THE MARABOU SYMPOSIUM, CLICK HERE HTTP://WWW.MARABOUSYMPOSIUM.ORG/. 2018 15 49 30 A CURRENT GENETIC AND EPIGENETIC VIEW ON HUMAN AGING MECHANISMS. THE PROCESS OF AGING IS ONE OF THE MOST COMPLEX AND INTRIGUING BIOLOGICAL PHENOMENONS. AGING IS A GENETICALLY REGULATED PROCESS IN WHICH THE ORGANISM'S MAXIMUM LIFESPAN POTENTIAL IS PRE-DETERMINED, WHILE THE RATE OF AGING IS INFLUENCED BY ENVIRONMENTAL FACTORS AND LIFESTYLE. CONSIDERING THE COMPLEXITY OF MECHANISMS INVOLVED IN THE REGULATION OF AGING PROCESS, UP TO THIS DATE THERE ISN'T A MAJOR, UNIFYING THEORY WHICH COULD EXPLAIN THEM. AS GENETIC/EPIGENETIC AND ENVIRONMENTAL FACTORS BOTH INEVITABLY INFLUENCE THE AGING PROCESS, HERE WE PRESENT A REVIEW ON THE GENETIC AND EPIGENETIC REGULATION OF THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE PROCESS OF AGING. BASED ON THE STUDIES ON OXIDATIVE STRESS, METABOLISM, GENOME STABILITY, EPIGENETIC MODIFICATIONS AND CELLULAR SENESCENCE IN ANIMAL MODELS AND HUMANS, WE GIVE AN OVERVIEW OF KEY GENETIC AND MOLECULAR PATHWAYS RELATED TO AGING. AS MOST OF GENETIC MANIPULATIONS WHICH INFLUENCE THE AGING PROCESS ALSO AFFECT REPRODUCTION, WE DISCUSS AGING IN HUMANS AS A POST-REPRODUCTIVE GENETICALLY DETERMINED PROCESS. AFTER THE AGE OF REPRODUCTIVE SUCCESS, AGING CONTINOUSLY PROGRESSES WHICH CLINICALLY COINCIDES WITH THE ONSET OF MOST CHRONIC DISEASES, CANCERS AND DEMENTIONS. AS EVOLUTION SHAPES THE GENOMES FOR REPRODUCTIVE SUCCESS AND NOT FOR POST-REPRODUCTIVE SURVIVAL, AGING COULD BE DEFINED AS A PROTECTIVE MECHANISM WHICH ENSURES THE PRESERVATION AND PROGRESS OF SPECIES THROUGH THE MODIFICATION, TRASMISSION AND IMPROVEMENT OF GENETIC MATERIAL. 2009 16 2528 27 EPIGENETICS AS A KEY LINK BETWEEN PSYCHOSOCIAL STRESS AND AGING: CONCEPTS, EVIDENCE, MECHANISMS . PSYCHOSOCIAL STRESS-ESPECIALLY WHEN CHRONIC, EXCESSIVE, OR OCCURRING EARLY IN LIFE-HAS BEEN ASSOCIATED WITH ACCELERATED AGING AND INCREASED DISEASE RISK. WITH RAPID AGING OF THE WORLD POPULATION, THE NEED TO ELUCIDATE THE UNDERLYING MECHANISMS IS PRESSING, NOW MORE SO THAN EVER. AMONG MOLECULAR MECHANISMS LINKING STRESS AND AGING, THE PRESENT ARTICLE REVIEWS EVIDENCE ON THE ROLE OF EPIGENETICS, BIOCHEMICAL PROCESSES THAT CAN BE SET INTO MOTION BY STRESSORS AND IN TURN INFLUENCE GENOMIC FUNCTION AND COMPLEX PHENOTYPES, INCLUDING AGING-RELATED OUTCOMES. THE ARTICLE FURTHER PROVIDES A CONCEPTUAL MECHANISTIC FRAMEWORK ON HOW STRESS MAY DRIVE EPIGENETIC CHANGES AT SUSCEPTIBLE GENOMIC SITES, THEREBY EXERTING SYSTEMS-LEVEL EFFECTS ON THE AGING EPIGENOME WHILE ALSO REGULATING THE EXPRESSION OF MOLECULES IMPLICATED IN AGING-RELATED PROCESSES. THIS EMERGING EVIDENCE, TOGETHER WITH WORK EXAMINING RELATED BIOLOGICAL PROCESSES, BEGINS TO SHED LIGHT ON THE EPIGENETIC AND, MORE BROADLY, MOLECULAR UNDERPINNINGS OF THE LONG-HYPOTHESIZED CONNECTION BETWEEN STRESS AND AGING. . 2019 17 3653 25 INDIVIDUAL EPIGENETIC VARIATION: WHEN, WHY, AND SO WHAT? EPIGENETICS PROVIDES A POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL FACTORS MODIFY THE RISK FOR COMMON DISEASES AMONG INDIVIDUALS. INTERINDIVIDUAL VARIATION IN DNA METHYLATION AND EPIGENETIC REGULATION HAS BEEN REPORTED AT SPECIFIC GENOMIC REGIONS INCLUDING TRANSPOSABLE ELEMENTS, GENOMICALLY IMPRINTED GENES AND THE 'INACTIVE' X CHROMOSOMES IN FEMALES. WE CURRENTLY HAVE A VERY POOR UNDERSTANDING OF THE FACTORS THAT CONTRIBUTE TO INTERINDIVIDUAL EPIGENETIC VARIATION. IN PARTICULAR, IT IS IMPORTANT TO UNDERSTAND WHEN DURING THE LIFE CYCLE EPIGENETIC VARIATION ARISES, WHY EPIGENETIC REGULATION VARIES AMONG INDIVIDUALS, AND WHETHER EPIGENETIC INTERINDIVIDUALITY AFFECTS SUSCEPTIBILITY TO DIET-RELATED CHRONIC DISEASE. IN THIS REVIEW WE WILL SUMMARIZE CURRENT PROGRESS TOWARD ANSWERING THESE QUESTIONS. 2008 18 2136 34 EPIGENETIC INFLUENCES IN THE OBESITY/COLORECTAL CANCER AXIS: A NOVEL THERAGNOSTIC AVENUE. THE WORLD HEALTH ORGANIZATION (WHO) CONSIDERS THAT OBESITY HAS REACHED PROPORTIONS OF PANDEMIC. EXPERTS ALSO INSIST ON THE IMPORTANCE OF CONSIDERING OBESITY AS A CHRONIC DISEASE AND ONE OF THE MAIN CONTRIBUTORS TO THE WORLDWIDE BURDEN OF OTHER NONTRANSMISSIBLE CHRONIC DISEASES, WHICH HAVE A GREAT IMPACT ON HEALTH, LIFESTYLE, AND ECONOMIC COST. ONE OF THE MOST CURRENT CHALLENGES OF BIOMEDICAL SCIENCE FACES IS TO UNDERSTAND THE ORIGIN OF THE CHRONIC NONTRANSMISSIBLE DISEASES, SUCH AS OBESITY AND CANCER. THERE IS A LARGE EVIDENCE, BOTH IN EPIDEMIOLOGICAL STUDIES IN HUMANS AND IN ANIMAL MODELS, OF THE ASSOCIATION BETWEEN OBESITY AND AN INCREASED RISK OF CANCER INCIDENCE. IN THE LAST YEARS, THE INITIAL DISCOVERY OF EPIGENETIC MECHANISMS REPRESENTS THE MOST RELEVANT FINDING TO EXPLAIN HOW THE GENOME INTERACTS WITH ENVIRONMENTAL FACTORS AND THE RIPPLE EFFECTS ON DISEASE PATHOGENESES. SINCE THEN, ALL EPIGENETIC PROCESS HAS BEEN INVESTIGATED BY THE SCIENTIFIC COMMUNITIES FOR NEARLY TWO DECADES TO DETERMINE WHICH COMPONENTS ARE INVOLVED IN THIS PROCESS. DNA/RNA METHYLATION AND MIRNA ARE CLASSIFIED AS TWO OF THE MOST IMPORTANT REPRESENTATIVE CLASSES OF SUCH EPIGENETIC MECHANISMS AND DYSREGULATED ACTIVITY OF SUCH MECHANISM CAN CERTAINLY CONTRIBUTE TO DISEASE PATHOGENESIS AND/OR PROGRESSION ESPECIALLY IN TUMORS. THIS REVIEW ARTICLE SERVES TO HIGHLIGHT THE IMPACT OF DNA/RNA METHYLATION AND MIRNA-BASED EPIGENETIC MECHANISM ACTIVITIES IN THE INTERPLAY BETWEEN OBESITY AND THE DEVELOPMENT AND CLINICAL SIGNIFICANCE OF COLORECTAL CANCER. 2019 19 1923 21 ENVIRONMENTAL EPIGENETIC MODIFICATIONS AND REPROGRAMMING-RECALCITRANT GENES. THE TERM "ENVIRONMENTAL EPIGENETIC MODIFICATIONS" REFERS TO ALTERATIONS IN PHENOTYPE TRIGGERED BY ENVIRONMENTAL STIMULI VIA EPIGENETIC MECHANISMS. EPIDEMIOLOGIC AND ANIMAL MODEL STUDIES SHOW THAT A SUBSET OF SUCH ENVIRONMENTAL EPIGENETIC MARKS MAY AFFECT SUSCEPTIBILITY TO CHRONIC DISEASES. A GROWING BODY OF EVIDENCE REGARDING INCOMPLETENESS OF REPROGRAMMING INDICATES THAT THE POTENTIAL RETENTION OF PATHOGENIC ENVIRONMENTAL EPIGENETICS IN HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSCS) SHOULD BE SERIOUSLY CONSIDERED. GIVEN THIS POSSIBILITY, THE OPTIMIZATION OF METHODS FOR THE GENERATION OF HUMAN INDUC PLURIPOTENT STEM CELLS MAY REQUIRE THE IDENTIFICATION OF EPIGENETICALLY APPROPRIATE SOMATIC CELL SOURCES. SIMILARLY, TECHNIQUES FOR CONTROLLING EPIGENETIC MODIFICATION BY ENVIRONMENTAL FACTORS MAY ALSO PLAY A CRITICAL ROLE IN THE DEVELOPMENT OF EPIGENETICALLY STABLE SOURCES OF PLURIPOTENT STEM CELLS. 2010 20 6350 32 THE ROLE OF EPIGENOMICS IN AQUATIC TOXICOLOGY. OVER THE PAST DECADE, THE FIELD OF MOLECULAR BIOLOGY HAS RAPIDLY INCORPORATED EPIGENETIC STUDIES TO EVALUATE ORGANISM-ENVIRONMENT INTERACTIONS THAT CAN RESULT IN CHRONIC EFFECTS. SUCH RESPONSES ARISE FROM EARLY LIFE STAGE STRESS, THE UTILIZATION OF GENETIC INFORMATION OVER AN INDIVIDUAL'S LIFE TIME, AND TRANSGENERATIONAL INHERITANCE. KNOWLEDGE OF EPIGENETIC MECHANISMS PROVIDES THE POTENTIAL FOR A COMPREHENSIVE EVALUATION OF MULTIGENERATIONAL AND HERITABLE EFFECTS FROM ENVIRONMENTAL STRESSORS, SUCH AS CONTAMINANTS. FOCUSED STUDIES HAVE PROVIDED A GREATER UNDERSTANDING OF HOW MANY RESPONSES TO ENVIRONMENTAL STRESSORS ARE DRIVEN BY EPIGENETIC MODIFIERS. WE DISCUSS THE PROMISE OF EPIGENETICS AND SUGGEST FUTURE RESEARCH DIRECTIONS WITHIN THE FIELD OF AQUATIC TOXICOLOGY, WITH A PARTICULAR FOCUS ON THE POTENTIAL FOR IDENTIFYING KEY HERITABLE MARKS WITH CONSEQUENTIAL IMPACTS AT THE ORGANISM AND POPULATION LEVELS. ENVIRON TOXICOL CHEM 2017;36:2565-2573. (C) 2017 SETAC. 2017