1 1924 126 ENVIRONMENTAL EPIGENETICS AND ITS IMPLICATION ON DISEASE RISK AND HEALTH OUTCOMES. THIS REVIEW FOCUSES ON HOW ENVIRONMENTAL FACTORS THROUGH EPIGENETICS MODIFY DISEASE RISK AND HEALTH OUTCOMES. MAJOR EPIGENETIC EVENTS, SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, AND MICRORNA EXPRESSION, ARE DESCRIBED. THE FUNCTION OF DOSE, DURATION, COMPOSITION, AND WINDOW OF EXPOSURE IN REMODELING THE INDIVIDUAL'S EPIGENETIC TERRAIN AND DISEASE SUSCEPTIBILITY ARE ADDRESSED. THE IDEAS OF LIFELONG EDITING OF EARLY-LIFE EPIGENETIC MEMORIES, TRANSGENERATIONAL EFFECTS THROUGH GERMLINE TRANSMISSION, AND THE POTENTIAL ROLE OF HYDROXYLMETHYLATION OF CYTOSINE IN DEVELOPMENTAL REPROGRAMMING ARE DISCUSSED. FINALLY, THE EPIGENETIC EFFECTS OF SEVERAL MAJOR CLASSES OF ENVIRONMENTAL FACTORS ARE REVIEWED IN THE CONTEXT OF PATHOGENESIS OF DISEASE. THESE INCLUDE ENDOCRINE DISRUPTORS, TOBACCO SMOKE, POLYCYCLIC AROMATIC HYDROCARBONS, INFECTIOUS PATHOGENS, PARTICULATE MATTER, DIESEL EXHAUST PARTICLES, DUST MITES, FUNGI, HEAVY METALS, AND OTHER INDOOR AND OUTDOOR POLLUTANTS. WE CONCLUDE THAT THE SUMMATION OF EPIGENETIC MODIFICATIONS INDUCED BY MULTIPLE ENVIRONMENTAL EXPOSURES, ACCUMULATED OVER TIME, REPRESENTED AS BROAD OR NARROW, ACUTE OR CHRONIC, DEVELOPMENTAL OR LIFELONG, MAY PROVIDE A MORE PRECISE ASSESSMENT OF RISK AND CONSEQUENCES. FUTURE INVESTIGATIONS MAY FOCUS ON THEIR USE AS READOUTS OR BIOMARKERS OF THE TOTALITY OF PAST EXPOSURE FOR THE PREDICTION OF FUTURE DISEASE RISK AND THE PRESCRIPTION OF EFFECTIVE COUNTERMEASURES. 2012 2 1926 48 ENVIRONMENTAL EPIGENETICS OF ASTHMA: AN UPDATE. ASTHMA, A CHRONIC INFLAMMATORY DISORDER OF THE AIRWAY, IS INFLUENCED BY INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS NOW KNOWN TO BE MEDIATED BY EPIGENETICS. ABERRANT DNA METHYLATION, ALTERED HISTONE MODIFICATIONS, SPECIFIC MICRORNA EXPRESSION, AND OTHER CHROMATIN ALTERATIONS ORCHESTRATE A COMPLEX EARLY-LIFE REPROGRAMMING OF IMMUNE T-CELL RESPONSE, DENDRITIC CELL FUNCTION, MACROPHAGE ACTIVATION, AND A BREACH OF AIRWAY EPITHELIAL BARRIER THAT DICTATES ASTHMA RISK AND SEVERITY IN LATER LIFE. ADULT-ONSET ASTHMA IS UNDER ANALOGOUS REGULATION. THE SHARP INCREASE IN ASTHMA PREVALENCE OVER THE PAST 2 OR 3 DECADES AND THE LARGE VARIATIONS AMONG POPULATIONS OF SIMILAR RACIAL/ETHNIC BACKGROUND BUT DIFFERENT ENVIRONMENTAL EXPOSURES FAVORS A STRONG CONTRIBUTION OF ENVIRONMENTAL FACTORS. THIS REVIEW ADDRESSES THE FUNDAMENTAL QUESTION OF WHETHER ENVIRONMENTAL INFLUENCES ON ASTHMA RISK, SEVERITY, AND STEROID RESISTANCE ARE PARTLY DUE TO DIFFERENTIAL EPIGENETIC MODULATIONS. CURRENT KNOWLEDGE ON THE EPIGENETIC EFFECTS OF TOBACCO SMOKE, MICROBIAL ALLERGENS, OXIDANTS, AIRBORNE PARTICULATE MATTER, DIESEL EXHAUST PARTICLES, POLYCYCLIC AROMATIC HYDROCARBONS, DIETARY METHYL DONORS AND OTHER NUTRITIONAL FACTORS, AND DUST MITES IS DISCUSSED. EXCITING FINDINGS HAVE BEEN GENERATED BY RAPID TECHNOLOGICAL ADVANCES AND WELL-DESIGNED EXPERIMENTAL AND POPULATION STUDIES. THE DISCOVERY AND VALIDATION OF EPIGENETIC BIOMARKERS LINKED TO EXPOSURE, ASTHMA, OR BOTH MIGHT LEAD TO BETTER EPIGENOTYPING OF RISK, PROGNOSIS, TREATMENT PREDICTION, AND DEVELOPMENT OF NOVEL THERAPIES. 2010 3 4460 31 MOLECULAR MECHANISMS OF ENVIRONMENTAL EXPOSURES AND HUMAN DISEASE. A SUBSTANTIAL PROPORTION OF DISEASE RISK FOR COMMON COMPLEX DISORDERS IS ATTRIBUTABLE TO ENVIRONMENTAL EXPOSURES AND POLLUTANTS. AN APPRECIATION OF HOW ENVIRONMENTAL POLLUTANTS ACT ON OUR CELLS TO PRODUCE DELETERIOUS HEALTH EFFECTS HAS LED TO ADVANCES IN OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THE PATHOGENESIS OF CHRONIC DISEASES, INCLUDING CANCER AND CARDIOVASCULAR, NEURODEGENERATIVE AND RESPIRATORY DISEASES. HERE, WE DISCUSS EMERGING RESEARCH ON THE INTERPLAY OF ENVIRONMENTAL POLLUTANTS WITH THE HUMAN GENOME AND EPIGENOME. WE REVIEW EVIDENCE SHOWING THE ENVIRONMENTAL IMPACT ON GENE EXPRESSION THROUGH EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNAS. WE ALSO HIGHLIGHT RECENT STUDIES THAT EVALUATE RECENTLY DISCOVERED MOLECULAR PROCESSES THROUGH WHICH THE ENVIRONMENT CAN EXERT ITS EFFECTS, INCLUDING EXTRACELLULAR VESICLES, THE EPITRANSCRIPTOME AND THE MITOCHONDRIAL GENOME. FINALLY, WE DISCUSS CURRENT CHALLENGES WHEN STUDYING THE EXPOSOME - THE CUMULATIVE MEASURE OF ENVIRONMENTAL INFLUENCES OVER THE LIFESPAN - AND ITS INTEGRATION INTO FUTURE ENVIRONMENTAL HEALTH RESEARCH. 2023 4 5434 25 RELATIONSHIP BETWEEN ENVIRONMENTAL EXPOSURES IN CHILDREN AND ADULT LUNG DISEASE: THE CASE FOR OUTDOOR EXPOSURES. THERE IS A GROWING UNDERSTANDING THAT CHRONIC RESPIRATORY DISEASES IN ADULTS HAVE THEIR ORIGINS IN EARLY LIFE. ADVERSE ENVIRONMENTAL EXPOSURES OCCURRING IN VULNERABLE PERIODS DURING LUNG GROWTH AND DEVELOPMENT IN THE FETAL PERIOD AND IN EARLY CHILDHOOD THAT ALTER LUNG STRUCTURE AND LIMIT THE GROWTH IN LUNG FUNCTION MAY HAVE LIFELONG CONSEQUENCES. EVIDENCE IS INCREASING THAT EXPOSURE TO THE AMBIENT ENVIRONMENT, INCLUDING AIR POLLUTANTS, PERSISTENT TOXIC SUBSTANCES, WATER POLLUTANTS AND RESPIRATORY VIRAL INFECTIONS, CAN INHIBIT LUNG FUNCTION GROWTH AND PREDISPOSE TO CHRONIC NON-MALIGNANT LUNG DISEASES. THESE EXPOSURES GENERALLY INTERACT WITH A GENETIC PREDISPOSITION, AND GENE-ENVIRONMENT INTERACTIONS AND EPIGENETIC PHENOMENA ARE ATTRACTING CONSIDERABLE STUDY. AN UNDERSTANDING OF HOW AMBIENT EXPOSURES IMPACT ON NORMAL LUNG GROWTH AND DEVELOPMENT WILL AID IN UNDERSTANDING OF HOW CHRONIC RESPIRATORY DISEASES OF ADULTS DEVELOP AND MAY LEAD TO NEW PREVENTATIVE STRATEGIES. 2010 5 6063 33 THE DEVELOPMENTAL ENVIRONMENT, EPIGENETIC BIOMARKERS AND LONG-TERM HEALTH. EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES HAS SHOWN THAT THE PRENATAL AND EARLY POSTNATAL ENVIRONMENTS INFLUENCE SUSCEPTIBILITY TO CHRONIC DISEASE IN LATER LIFE AND SUGGESTS THAT EPIGENETIC PROCESSES ARE AN IMPORTANT MECHANISM BY WHICH THE ENVIRONMENT ALTERS LONG-TERM DISEASE RISK. EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNAS, PLAY A CENTRAL ROLE IN REGULATING GENE EXPRESSION. THE EPIGENOME IS HIGHLY SENSITIVE TO ENVIRONMENTAL FACTORS IN EARLY LIFE, SUCH AS NUTRITION, STRESS, ENDOCRINE DISRUPTION AND POLLUTION, AND CHANGES IN THE EPIGENOME CAN INDUCE LONG-TERM CHANGES IN GENE EXPRESSION AND PHENOTYPE. IN THIS REVIEW WE FOCUS ON HOW THE EARLY LIFE NUTRITIONAL ENVIRONMENT CAN ALTER THE EPIGENOME LEADING TO AN ALTERED SUSCEPTIBILITY TO DISEASE IN LATER LIFE. 2015 6 3771 39 INTER- AND TRANSGENERATIONAL EPIGENETIC INHERITANCE: EVIDENCE IN ASTHMA AND COPD? EVIDENCE IS NOW EMERGING THAT EARLY LIFE ENVIRONMENT CAN HAVE LIFELONG EFFECTS ON METABOLIC, CARDIOVASCULAR, AND PULMONARY FUNCTION IN OFFSPRING, A CONCEPT ALSO KNOWN AS FETAL OR DEVELOPMENTAL PROGRAMMING. IN MAMMALS, DEVELOPMENTAL PROGRAMMING IS THOUGHT TO OCCUR MAINLY VIA EPIGENETIC MECHANISMS, WHICH INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND EXPRESSION OF NON-CODING RNAS. THE EFFECTS OF DEVELOPMENTAL PROGRAMMING CAN BE INDUCED BY THE INTRAUTERINE ENVIRONMENT, LEADING TO INTERGENERATIONAL EPIGENETIC EFFECTS FROM ONE GENERATION TO THE NEXT. TRANSGENERATIONAL EPIGENETIC INHERITANCE MAY BE CONSIDERED WHEN DEVELOPMENTAL PROGRAMMING IS TRANSMITTED ACROSS GENERATIONS THAT WERE NOT EXPOSED TO THE INITIAL ENVIRONMENT WHICH TRIGGERED THE CHANGE. SO FAR, INTER- AND TRANSGENERATIONAL PROGRAMMING HAS BEEN MAINLY DESCRIBED FOR CARDIOVASCULAR AND METABOLIC DISEASE RISK. IN THIS REVIEW, WE DISCUSS AVAILABLE EVIDENCE THAT EPIGENETIC INHERITANCE ALSO OCCURS IN RESPIRATORY DISEASES, USING ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AS EXAMPLES. WHILE MULTIPLE EPIDEMIOLOGICAL AS WELL AS ANIMAL STUDIES DEMONSTRATE EFFECTS OF 'TOXIC' INTRAUTERINE EXPOSURE ON VARIOUS ASTHMA-RELATED PHENOTYPES IN THE OFFSPRING, ONLY FEW STUDIES LINK EPIGENETIC MARKS TO THE OBSERVED PHENOTYPES. AS EPIGENETIC MARKS MAY DISTINGUISH INDIVIDUALS MOST AT RISK OF LATER DISEASE AT EARLY AGE, IT WILL ENABLE EARLY INTERVENTION STRATEGIES TO REDUCE SUCH RISKS. TO ACHIEVE THIS GOAL FURTHER, WELL DESIGNED EXPERIMENTAL AND HUMAN STUDIES ARE NEEDED. 2015 7 1938 38 EPIDEMIOLOGIC EVIDENCE FOR ASSOCIATION BETWEEN ADVERSE ENVIRONMENTAL EXPOSURES IN EARLY LIFE AND EPIGENETIC VARIATION: A POTENTIAL LINK TO DISEASE SUSCEPTIBILITY? A GROWING BODY OF EVIDENCE SUGGESTS THAT THE RISK OF DEVELOPMENT AND PROGRESSION OF A VARIETY OF HUMAN CHRONIC DISEASES DEPENDS ON EPIGENETIC MODIFICATIONS TRIGGERED BY ENVIRONMENTAL CUES DURING EARLY LIFE SENSITIVE STAGES. EXPOSURES TO ENVIRONMENTAL FACTORS SUCH AS ADVERSE NUTRITIONAL, PSYCHOLOGICAL, AND SOCIAL CONDITIONS, AS WELL AS POLLUTANTS AND SUBSTANCE ABUSE IN EARLY LIFE, HAVE BEEN SHOWN TO BE IMPORTANT DETERMINANTS OF EPIGENETIC PROGRAMMING OF CHRONIC PATHOLOGICAL CONDITIONS IN HUMAN POPULATIONS. OVER THE PAST YEARS, IT HAS BECOME INCREASINGLY CLEAR DUE TO THE EPIGENOME-WIDE ASSOCIATION STUDIES (EWASS) THAT EARLY LIFE ADVERSE ENVIRONMENTAL EVENTS MAY TRIGGER WIDESPREAD AND PERSISTENT ALTERATIONS IN TRANSCRIPTIONAL PROFILING. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED UNDERLYING THESE ASSOCIATIONS. IN THIS CONTEXT, DNA METHYLATION IS THE MOST INTENSIVELY STUDIED EPIGENETIC PHENOMENON. IN THIS REVIEW, THE CLINICAL AND EPIDEMIOLOGICAL EVIDENCE FOR THE ROLE OF EPIGENETIC FACTORS IN MEDIATING THE LINK BETWEEN EARLY LIFE EXPERIENCES AND LONG-TERM HEALTH OUTCOMES ARE SUMMARIZED. 2015 8 396 33 AN UPDATE ON EPIGENETICS AND CHILDHOOD RESPIRATORY DISEASES. EPIGENETIC MECHANISMS, DEFINED AS CHANGES IN PHENOTYPE OR GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE, HAVE BEEN PROPOSED TO CONSTITUTE A LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THAT AFFECT COMPLEX DISEASES. RECENT STUDIES SHOW THAT DNA METHYLATION, ONE OF THE KEY EPIGENETIC MECHANISMS, IS ALTERED IN CHILDREN EXPOSED TO AIR POLLUTANTS AND ENVIRONMENTAL TOBACCO SMOKE EARLY IN LIFE. SEVERAL CANDIDATE GENE STUDIES ON EPIGENETICS HAVE BEEN PUBLISHED TO DATE, BUT IT IS ONLY RECENTLY THAT GLOBAL METHYLATION ANALYSES HAVE BEEN PERFORMED FOR RESPIRATORY DISORDERS SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, LARGE-SCALE STUDIES WITH ADEQUATE POWER ARE YET TO BE PRESENTED IN CHILDREN, AND IMPLICATIONS FOR CLINICAL USE REMAIN TO BE EVALUATED. IN THIS REVIEW, WE SUMMARIZE THE RECENT ADVANCES IN EPIGENETICS AND RESPIRATORY DISORDERS IN CHILDREN, WITH A MAIN FOCUS ON METHODOLOGICAL CHALLENGES AND ANALYSES RELATED TO PHENOTYPE AND EXPOSURE USING GLOBAL METHYLATION APPROACHES. 2014 9 1453 27 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 10 1936 36 ENVIRONMENTAL RISK FACTORS OF TYPE 2 DIABETES-AN EXPOSOME APPROACH. TYPE 2 DIABETES IS ONE OF THE MAJOR CHRONIC DISEASES ACCOUNTING FOR A SUBSTANTIAL PROPORTION OF DISEASE BURDEN IN WESTERN COUNTRIES. THE MAJORITY OF THE BURDEN OF TYPE 2 DIABETES IS ATTRIBUTED TO ENVIRONMENTAL RISKS AND MODIFIABLE RISK FACTORS SUCH AS LIFESTYLE. THE ENVIRONMENT WE LIVE IN, AND CHANGES TO IT, CAN THUS CONTRIBUTE SUBSTANTIALLY TO THE PREVENTION OF TYPE 2 DIABETES AT A POPULATION LEVEL. THE 'EXPOSOME' REPRESENTS THE (MEASURABLE) TOTALITY OF ENVIRONMENTAL, I.E. NONGENETIC, DRIVERS OF HEALTH AND DISEASE. THE EXTERNAL EXPOSOME COMPRISES ASPECTS OF THE BUILT ENVIRONMENT, THE SOCIAL ENVIRONMENT, THE PHYSICO-CHEMICAL ENVIRONMENT AND THE LIFESTYLE/FOOD ENVIRONMENT. THE INTERNAL EXPOSOME COMPRISES MEASUREMENTS AT THE EPIGENETIC, TRANSCRIPT, PROTEOME, MICROBIOME OR METABOLOME LEVEL TO STUDY EITHER THE EXPOSURES DIRECTLY, THE IMPRINTS THESE EXPOSURES LEAVE IN THE BIOLOGICAL SYSTEM, THE POTENTIAL OF THE BODY TO COMBAT ENVIRONMENTAL INSULTS AND/OR THE BIOLOGY ITSELF. IN THIS REVIEW, WE DESCRIBE THE EVIDENCE FOR ENVIRONMENTAL RISK FACTORS OF TYPE 2 DIABETES, FOCUSING ON BOTH THE GENERAL EXTERNAL EXPOSOME AND IMPRINTS OF THIS ON THE INTERNAL EXPOSOME. STUDIES PROVIDED ESTABLISHED ASSOCIATIONS OF AIR POLLUTION, RESIDENTIAL NOISE AND AREA-LEVEL SOCIOECONOMIC DEPRIVATION WITH AN INCREASED RISK OF TYPE 2 DIABETES, WHILE NEIGHBOURHOOD WALKABILITY AND GREEN SPACE ARE CONSISTENTLY ASSOCIATED WITH A REDUCED RISK OF TYPE 2 DIABETES. THERE IS LITTLE OR INCONSISTENT EVIDENCE ON THE CONTRIBUTION OF THE FOOD ENVIRONMENT, OTHER ASPECTS OF THE SOCIAL ENVIRONMENT AND OUTDOOR TEMPERATURE. THESE ENVIRONMENTAL FACTORS ARE THOUGHT TO AFFECT TYPE 2 DIABETES RISK MAINLY THROUGH MECHANISMS INCORPORATING LIFESTYLE FACTORS SUCH AS PHYSICAL ACTIVITY OR DIET, THE MICROBIOME, INFLAMMATION OR CHRONIC STRESS. TO FURTHER ASSESS CAUSALITY OF THESE ASSOCIATIONS, FUTURE STUDIES SHOULD FOCUS ON INVESTIGATING THE LONGITUDINAL EFFECTS OF OUR ENVIRONMENT (AND CHANGES TO IT) IN RELATION TO TYPE 2 DIABETES RISK AND WHETHER THESE ASSOCIATIONS ARE EXPLAINED BY THESE PROPOSED MECHANISMS. 2022 11 6287 43 THE POTENTIAL ROLE OF ENVIRONMENTAL FACTORS IN MODULATING MITOCHONDRIAL DNA EPIGENETIC MARKS. MANY STUDIES IMPLICATE MITOCHONDRIAL DYSFUNCTION IN THE DEVELOPMENT AND PROGRESSION OF NUMEROUS CHRONIC DISEASES. MITOCHONDRIA ARE RESPONSIBLE FOR MOST CELLULAR ENERGY PRODUCTION, AND UNLIKE OTHER CYTOPLASMIC ORGANELLES, MITOCHONDRIA CONTAIN THEIR OWN GENOME. MOST RESEARCH TO DATE, THROUGH INVESTIGATING MITOCHONDRIAL DNA COPY NUMBER, HAS FOCUSED ON LARGER STRUCTURAL CHANGES OR ALTERATIONS TO THE ENTIRE MITOCHONDRIAL GENOME AND THEIR ROLE IN HUMAN DISEASE. USING THESE METHODS, MITOCHONDRIAL DYSFUNCTION HAS BEEN LINKED TO CANCERS, CARDIOVASCULAR DISEASE, AND METABOLIC HEALTH. HOWEVER, LIKE THE NUCLEAR GENOME, THE MITOCHONDRIAL GENOME MAY EXPERIENCE EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION THAT MAY PARTIALLY EXPLAIN SOME OF THE HEALTH EFFECTS OF VARIOUS EXPOSURES. RECENTLY, THERE HAS BEEN A MOVEMENT TO UNDERSTAND HUMAN HEALTH AND DISEASE WITHIN THE CONTEXT OF THE EXPOSOME, WHICH AIMS TO DESCRIBE AND QUANTIFY THE ENTIRETY OF ALL EXPOSURES PEOPLE ENCOUNTER THROUGHOUT THEIR LIVES. THESE INCLUDE, AMONG OTHERS, ENVIRONMENTAL POLLUTANTS, OCCUPATIONAL EXPOSURES, HEAVY METALS, AND LIFESTYLE AND BEHAVIORAL FACTORS. IN THIS CHAPTER, WE SUMMARIZE THE CURRENT RESEARCH ON MITOCHONDRIA AND HUMAN HEALTH, PROVIDE AN OVERVIEW OF THE CURRENT KNOWLEDGE ON MITOCHONDRIAL EPIGENETICS, AND DESCRIBE THE EXPERIMENTAL AND EPIDEMIOLOGIC STUDIES THAT HAVE INVESTIGATED PARTICULAR EXPOSURES AND THEIR RELATIONSHIPS WITH MITOCHONDRIAL EPIGENETIC MODIFICATIONS. WE CONCLUDE THE CHAPTER WITH SUGGESTIONS FOR FUTURE DIRECTIONS IN EPIDEMIOLOGIC AND EXPERIMENTAL RESEARCH THAT IS NEEDED TO ADVANCE THE GROWING FIELD OF MITOCHONDRIAL EPIGENETICS. 2023 12 4094 29 MATERNAL SIGNALS FOR PROGENY PREVENTION AGAINST ALLERGY AND ASTHMA. ALLERGY AND ASTHMA ARE CHRONIC INFLAMMATORY DISEASES WHICH RESULT FROM COMPLEX GENE-ENVIRONMENT INTERACTIONS. RECENT EVIDENCE INDICATES THE IMPORTANCE OF PRENATAL AND POSTNATAL DEVELOPMENTAL PROCESSES IN TERMS OF MATURATION OF BALANCED IMMUNE RESPONSES. ACCORDING TO THE CURRENT VIEW, GENE-ENVIRONMENT INTERACTIONS DURING A RESTRICTED TIME FRAME ARE RESPONSIBLE FOR PROGRAMMING OF THE IMMUNE SYSTEM IN FAVOR OF ALLERGIC IMMUNE MECHANISMS LATER IN LIFE. THE INTERACTION BETWEEN GENES AND ENVIRONMENT IS COMPLEX AND ONLY PARTIALLY UNDERSTOOD; HOWEVER, HERITABLE EPIGENETIC MODIFICATIONS INCLUDING CHEMICAL ADDITIONS IN AND ALTERNATIVE PACKAGING OF THE DNA HAVE BEEN SHOWN TO PLAY A CRUCIAL ROLE IN THIS CONTEXT. NOVEL DATA INDICATE THAT EPIGENETIC MECHANISMS CONTRIBUTE TO THE DEVELOPMENT OF T-HELPER CELL FUNCTION. ENVIRONMENTAL FACTORS, INCLUDING DIESEL EXHAUST PARTICLES (DEP), VITAMINS AND TOBACCO SMOKE, OPERATE THROUGH SUCH MECHANISMS. FURTHERMORE, THE ROLE OF ENVIRONMENTAL MICROBES PROVIDES ANOTHER AND MAYBE EVEN MORE IMPORTANT GROUP OF EXOGENOUS EXPOSURES WHICH OPERATES IN THIS CRITICAL TIME FRAME. 2011 13 6378 36 THE ROLE OF NUTRITION ON EPIGENETIC MODIFICATIONS AND THEIR IMPLICATIONS ON HEALTH. NUTRITION PLAYS A KEY ROLE IN MANY ASPECTS OF HEALTH AND DIETARY IMBALANCES ARE MAJOR DETERMINANTS OF CHRONIC DISEASES INCLUDING CARDIOVASCULAR DISEASE, OBESITY, DIABETES AND CANCER. ADEQUATE NUTRITION IS PARTICULARLY ESSENTIAL DURING CRITICAL PERIODS IN EARLY LIFE (BOTH PRE- AND POSTNATAL). IN THIS REGARD, THERE IS EXTENSIVE EPIDEMIOLOGIC AND EXPERIMENTAL DATA SHOWING THAT EARLY SUB-OPTIMAL NUTRITION CAN HAVE HEALTH CONSEQUENCES SEVERAL DECADES LATER. THE HYPOTHESIS THAT EPIGENETIC MECHANISMS MAY LINK SUCH NUTRITIONAL IMBALANCES WITH ALTERED DISEASE RISK HAS BEEN GAINING ACCEPTANCE OVER RECENT YEARS. EPIGENETICS CAN BE DEFINED AS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION THAT DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE. EPIGENETIC MARKS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND A VARIETY OF NON-CODING RNAS. STRIKINGLY, THEY ARE PLASTIC AND RESPOND TO ENVIRONMENTAL SIGNALS, INCLUDING DIET. HERE WE WILL REVIEW HOW DIETARY FACTORS MODULATE THE ESTABLISHMENT AND MAINTENANCE OF EPIGENETIC MARKS, THEREBY INFLUENCING GENE EXPRESSION AND, HENCE, DISEASE RISK AND HEALTH. 2012 14 3404 36 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 15 2282 37 EPIGENETIC REGULATION IN EXPOSOME-INDUCED TUMORIGENESIS: EMERGING ROLES OF NCRNAS. ENVIRONMENTAL FACTORS, INCLUDING POLLUTANTS AND LIFESTYLE, CONSTITUTE A SIGNIFICANT ROLE IN SEVERE, CHRONIC PATHOLOGIES WITH AN ESSENTIAL SOCIETAL, ECONOMIC BURDEN. THE MEASUREMENT OF ALL ENVIRONMENTAL EXPOSURES AND ASSESSING THEIR CORRELATION WITH EFFECTS ON INDIVIDUAL HEALTH IS DEFINED AS THE EXPOSOME, WHICH INTERACTS WITH OUR UNIQUE CHARACTERISTICS SUCH AS GENETICS, PHYSIOLOGY, AND EPIGENETICS. EPIGENETICS INVESTIGATES MODIFICATIONS IN THE EXPRESSION OF GENES THAT DO NOT DEPEND ON THE UNDERLYING DNA SEQUENCE. SOME STUDIES HAVE CONFIRMED THAT ENVIRONMENTAL FACTORS MAY PROMOTE DISEASE IN INDIVIDUALS OR SUBSEQUENT PROGENY THROUGH EPIGENETIC ALTERATIONS. VARIATIONS IN THE EPIGENETIC MACHINERY CAUSE A SPECTRUM OF DIFFERENT DISORDERS SINCE THESE MECHANISMS ARE MORE SENSITIVE TO THE ENVIRONMENT THAN THE GENOME, DUE TO THE INHERENT REVERSIBLE NATURE OF THE EPIGENETIC LANDSCAPE. SEVERAL EPIGENETIC MECHANISMS, INCLUDING MODIFICATIONS IN DNA (E.G., METHYLATION), HISTONES, AND NONCODING RNAS CAN CHANGE GENOME EXPRESSION UNDER THE EXOGENOUS INFLUENCE. NOTABLY, THE ROLE OF LONG NONCODING RNAS IN EPIGENETIC PROCESSES HAS NOT BEEN WELL EXPLORED IN THE CONTEXT OF EXPOSOME-INDUCED TUMORIGENESIS. IN THE PRESENT REVIEW, OUR SCOPE IS TO PROVIDE RELEVANT EVIDENCE INDICATING THAT EPIGENETIC ALTERATIONS MEDIATE THOSE DETRIMENTAL EFFECTS CAUSED BY EXPOSURE TO ENVIRONMENTAL TOXICANTS, FOCUSING MAINLY ON A MULTI-STEP REGULATION BY DIVERSE NONCODING RNAS SUBTYPES. 2022 16 6811 35 [EPIGENETICS, ENVIRONMENT AND ASTHMA]. ASTHMA IS A CHRONIC INFLAMMATORY DISEASE OF THE RESPIRATORY TRACT WITH A COMPLEX GENETIC BACKGROUND INFLUENCED BY THE EXPOSITION TO A SERIES OF ENVIRONMENTAL FACTORS. GENETIC STUDIES CAN ONLY ELUCIDATE PART OF THE HERITABILITY AND SUSCEPTIBILITY OF ASTHMA AND EVEN THOUGH SEVERAL DISEASES HAVE AN EVIDENT GENETIC ETIOLOGY, ONLY A FRACTION OF THE GENES INVOLVED IN THEIR PATHOGENICITY HAVE BEEN IDENTIFIED. THE EPIGENETIC REGULATION OF THE LATTER IS A FACT ONE SHOULD BEAR IN MIND IN ORDER TO EXPLAIN THE MAJOR TRIGGERS OF DISEASES WHOSE UNDERSTANDING IS COMPLICATED, SUCH AS ALLERGIES AND ASTHMA. EXTERNAL STIMULUS SUCH AS NOURISHMENT, STRESS, PHYSICAL ACTIVITY, ATMOSPHERIC POLLUTION, TOBACCO SMOKING AND ALCOHOL DRINKING CAN INDUCE EITHER GENE SILENCING OR GENE EXPRESSION. IN THIS REGARD, EPIGENETICS CAN EXPLAIN HOW THESE ENVIRONMENTAL FACTORS INFLUENCE OUR GENETIC INHERITANCE. THERE IS GROWING EVIDENCE THAT BACKS-UP THE FACT THAT DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATION AND MICRORNA EXPRESSION ARE INFLUENCED BY THE ENVIRONMENT. THIS HELPS EXPLAINING HOW SEVERAL OF THE RISK FACTORS MENTIONED CONTRIBUTE TO THE DEVELOPMENT AND INHERITANCE OF ASTHMA. IN THIS REVIEW, DIFFERENT ENVIRONMENTAL FACTORS AND THEIR RELATION WITH THE MAIN EPIGENETIC REGULATORY MECHANISMS WILL BE ANALYZED, AS WELL AS THEIR POSSIBLE ROLE IN THE DEVELOPMENT OF ASTHMA. 2014 17 5254 31 PROGRAMMING OF RESPIRATORY HEALTH IN CHILDHOOD: INFLUENCE OF OUTDOOR AIR POLLUTION. PURPOSE OF REVIEW: THIS OVERVIEW HIGHLIGHTS RECENT EXPERIMENTAL AND EPIDEMIOLOGICAL EVIDENCE FOR THE PROGRAMMING EFFECTS OF OUTDOOR AIR POLLUTION EXPOSURES DURING EARLY DEVELOPMENT ON LUNG FUNCTION AND CHRONIC RESPIRATORY DISORDERS, SUCH AS ASTHMA AND RELATED ALLERGIC DISORDERS. RECENT FINDINGS: AIR POLLUTANTS MAY IMPACT ANATOMY AND/OR PHYSIOLOGICAL FUNCTIONING OF THE LUNG AND INTERRELATED SYSTEMS. PROGRAMMING EFFECTS MAY RESULT FROM POLLUTANT-INDUCED SHIFTS IN A NUMBER OF MOLECULAR, CELLULAR, AND PHYSIOLOGICAL STATES AND THEIR INTERACTING SYSTEMS. SPECIFIC KEY REGULATORY SYSTEMS SUSCEPTIBLE TO PROGRAMMING MAY INFLUENCE LUNG DEVELOPMENT AND VULNERABILITY TO RESPIRATORY DISEASES, INCLUDING BOTH CENTRAL AND PERIPHERAL COMPONENTS OF NEUROENDOCRINE PATHWAYS AND AUTONOMIC NERVOUS SYSTEM (ANS) FUNCTIONING WHICH, IN TURN, INFLUENCE THE IMMUNE SYSTEM. STARTING IN UTERO, ENVIRONMENTAL FACTORS, INCLUDING AIR POLLUTANTS, MAY PERMANENTLY ORGANIZE THESE SYSTEMS TOWARD TRAJECTORIES OF ENHANCED PEDIATRIC (E.G., ASTHMA, ALLERGY) AS WELL AS ADULT DISEASE RISK (E.G., CHRONIC OBSTRUCTIVE PULMONARY DISEASE). EVIDENCE SUPPORTS A CENTRAL ROLE OF OXIDATIVE STRESS IN THE TOXIC EFFECTS OF AIR POLLUTION. ADDITIONAL RESEARCH SUGGESTS XENOBIOTIC METABOLISM AND SUBCELLULAR COMPONENTS, SUCH AS MITOCHONDRIA ARE TARGETS OF AMBIENT AIR POLLUTION AND PLAY A ROLE IN ASTHMA AND ALLERGY PROGRAMMING. MECHANISMS OPERATING AT THE LEVEL OF THE PLACENTA ARE BEING ELUCIDATED. EPIGENETIC MECHANISMS MAY BE AT THE ROOTS OF ADAPTIVE DEVELOPMENTAL PROGRAMMING. SUMMARY: OPTIMAL COORDINATED FUNCTIONING OF MANY COMPLEX PROCESSES AND THEIR NETWORKS OF INTERACTION ARE NECESSARY FOR NORMAL LUNG DEVELOPMENT AND THE MAINTENANCE OF RESPIRATORY HEALTH. OUTDOOR AIR POLLUTION MAY PLAY AN IMPORTANT ROLE IN EARLY PROGRAMMING OF RESPIRATORY HEALTH AND IS POTENTIALLY AMENABLE TO INTERVENTION. 2013 18 2103 29 EPIGENETIC EPIDEMIOLOGY OF THE DEVELOPMENTAL ORIGINS HYPOTHESIS. EXTENSIVE HUMAN EPIDEMIOLOGIC AND ANIMAL MODEL DATA INDICATE THAT DURING CRITICAL PERIODS OF PRENATAL AND POSTNATAL MAMMALIAN DEVELOPMENT, NUTRITION AND OTHER ENVIRONMENTAL STIMULI INFLUENCE DEVELOPMENTAL PATHWAYS AND THEREBY INDUCE PERMANENT CHANGES IN METABOLISM AND CHRONIC DISEASE SUSCEPTIBILITY. THE BIOLOGIC MECHANISMS UNDERLYING THIS "DEVELOPMENTAL ORIGINS HYPOTHESIS" ARE POORLY UNDERSTOOD. THIS REVIEW FOCUSES ON THE LIKELY INVOLVEMENT OF EPIGENETIC MECHANISMS IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD). WE DESCRIBE PERMANENT EFFECTS OF TRANSIENT ENVIRONMENTAL INFLUENCES ON THE DEVELOPMENTAL ESTABLISHMENT OF EPIGENETIC GENE REGULATION AND EVIDENCE LINKING EPIGENETIC DYSREGULATION WITH HUMAN DISEASE. WE PROPOSE A DEFINITION OF "EPIGENETIC EPIDEMIOLOGY" AND DELINEATE HOW THIS EMERGING FIELD PROVIDES A BASIS FROM WHICH TO EXPLORE THE ROLE OF EPIGENETIC MECHANISMS IN DOHAD. WE SUGGEST STRATEGIES FOR FUTURE HUMAN EPIDEMIOLOGIC STUDIES TO IDENTIFY CAUSAL ASSOCIATIONS BETWEEN EARLY EXPOSURES, LONG-TERM CHANGES IN EPIGENETIC REGULATION, AND DISEASE, WHICH MAY ULTIMATELY ENABLE SPECIFIC EARLY-LIFE INTERVENTIONS TO IMPROVE HUMAN HEALTH. 2007 19 754 36 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 20 4382 33 MITOCHONDRIAL EPIGENETICS AND ENVIRONMENTAL EXPOSURE. THE RISING TOLL OF CHRONIC AND DEBILITATING DISEASES BROUGHT ABOUT BY THE EXPOSURE TO AN EVER EXPANDING NUMBER OF ENVIRONMENTAL POLLUTANTS AND SOCIO-ECONOMIC FACTORS IS CALLING FOR ACTION. THE UNDERSTANDING OF THE MOLECULAR MECHANISMS BEHIND THE EFFECTS OF ENVIRONMENTAL EXPOSURES CAN LEAD TO THE DEVELOPMENT OF BIOMARKERS THAT CAN SUPPORT THE PUBLIC HEALTH FIELDS OF BOTH EARLY DIAGNOSIS AND INTERVENTION TO LIMIT THE BURDEN OF ENVIRONMENTAL DISEASES. THE STUDY OF MITOCHONDRIAL EPIGENETICS CARRIES HIGH HOPES TO PROVIDE IMPORTANT BIOMARKERS OF EXPOSURE AND DISEASE. MITOCHONDRIA ARE IN FACT ON THE FRONTLINE OF THE CELLULAR RESPONSE TO THE ENVIRONMENT. MODIFICATIONS OF THE EPIGENETIC FACTORS REGULATING THE MITOCHONDRIAL ACTIVITY ARE EMERGING AS INFORMATIVE TOOLS THAT CAN EFFECTIVELY REPORT ON THE EFFECTS OF THE ENVIRONMENT ON THE PHENOTYPE. HERE, WE WILL DISCUSS THE EMERGING FIELD OF MITOCHONDRIAL EPIGENETICS. THIS REVIEW DESCRIBES THE MAIN EPIGENETIC PHENOMENA THAT MODIFY THE ACTIVITY OF THE MITOCHONDRIAL DNA INCLUDING DNA METHYLATION, LONG AND SHORT NON-CODING RNAS. WE WILL DISCUSS THE UNIQUE PATTERN OF MITOCHONDRIAL DNA METHYLATION, DESCRIBE THE CHALLENGES OF CORRECTLY MEASURING IT, AND REPORT ON THE EXISTING STUDIES THAT HAVE ANALYSED THE CORRELATION BETWEEN ENVIRONMENTAL EXPOSURES AND MITOCHONDRIAL DNA METHYLATION. FINALLY, WE PROVIDE A BRIEF ACCOUNT OF THE THERAPEUTIC APPROACHES TARGETING MITOCHONDRIA CURRENTLY UNDER CONSIDERATION. 2016