1  3211 205 HEALTH EFFECTS OF EXPOSURE TO DIESEL EXHAUST PARTICLES. DIESEL-POWERED VEHICLES EMIT SUBSTANTIALLY MORE PARTICLES THAN DO GASOLINE-POWERED VEHICLES WITH CONTEMPORARY EMISSION CONTROL SYSTEMS. THE DEP ARE SUBMICRON IN SIZE AND READILY INHALED. APPROXIMATELY ONE-FOURTH OF THE PARTICLE MASS INHALED BY PEOPLE IS DEPOSITED IN THE PULMONARY REGION, SOME OF WHICH IS RETAINED WITH A HALF-LIFE OF SEVERAL HUNDRED DAYS. IN ANIMAL STUDIES, EXPOSURE TO HIGH LEVELS OF DEP OVERWHELMS THE NORMAL CLEARANCE MECHANISMS AND RESULTS IN LUNG BURDENS OF DEP THAT EXCEED THOSE PREDICTED FROM OBSERVATIONS AT LOWER EXPOSURE CONCENTRATIONS. A VARIABLE AMOUNT OF THE MASS OF DEP IS EXTRACTABLE WITH STRONG ORGANIC SOLVENTS. THE EXTRACTED MATERIAL CONTAINS MORE THAN A THOUSAND INDIVIDUAL COMPOUNDS AND IS MUTAGENIC IN A NUMBER OF BACTERIAL AND MAMMALIAN CELL ASSAYS. BIOASSAY-DIRECTED CHEMICAL ANALYSIS OF DEP HAD IDENTIFIED SEVERAL HUNDRED COMPOUNDS. MANY ARE PAHS, SOME OF WHICH ARE CONSIDERED TO HAVE HUMAN CARCINOGENIC POTENTIAL. A NUMBER OF NITRATED COMPOUNDS HAVE BEEN IDENTIFIED THAT ACCOUNT FOR A SIGNIFICANT PORTION OF THE MUTAGENICITY ASSAYED IN BACTERIA. THE MUTAGENICITY OF THE DEPE IS GENERALLY REDUCED BY ADDITION OF AN S-9 CELLULAR FRACTION OR OF SERUM PROTEINS. MACROPHAGES RAPIDLY REDUCE THE RECOVERABLE MUTAGENIC ACTIVITY ASSOCIATED WITH DEP. THESE FINDINGS SUPPORT A HYPOTHESIS THAT DETOXIFICATION OF DEP-ASSOCIATED ORGANICS OCCURS RAPIDLY IN VIVO. THE ASSOCIATION OF BENZO(A)PYRENE AND NITROPYRENE WITH DEP PROLONGS THEIR RETENTION IN THE LUNGS. THIS INCREASED RETENTION SUGGESTS THE NEED TO CLARIFY THE RELATIVE IMPORTANCE OF COMPETING MECHANISMS THAT DETOXIFY PARTICLE-ASSOCIATED COMPOUNDS AND THOSE THAT SERVE TO ENHANCE THE RETENTION OF TOXICOLOGICALLY IMPORTANT COMPOUNDS. SOME EXTRACTS OF DEP EVOKE TUMORIGENIC RESPONSES IN SKIN-TUMOR BIOASSAYS, SUGGESTING THEIR CARCINOGENIC POTENTIAL IN MAMMALS. A NUMBER OF LARGE-SCALE STUDIES HAVE BEEN CONDUCTED WITH LABORATORY RODENTS TO EVALUATE THE EFFECTS OF CHRONIC INHALATION EXPOSURE TO DE. AN INCREASED INCIDENCE OF LUNG TUMORS, SOME OF WHICH WERE DIAGNOSED AS MALIGNANT, WAS OBSERVED IN 5 STUDIES WITH RATS FOLLOWING EXPOSURE FOR 2 OR MORE YEARS TO HIGH LEVELS OF DE. MOST OF THE LUNG TUMORS WERE OBSERVED AFTER 2 YEARS. SIMILAR STUDIES IN SYRIAN HAMSTERS HAVE YIELDED NEGATIVE RESULTS. STUDIES WITH MICE HAVE GIVEN MIXED RESULTS. THE RESULTS OF SOME STUDIES WITH LABORATORY ANIMALS EXPOSED TO DE AND KNOWN CARCINOGENS SUGGEST THAT EXPOSURE TO DE ENHANCES THE EFFECT OF THE KNOWN CARCINOGENS. THE SPECIFIC MECHANISMS OF TUMOR INDUCTION IN THE DE-EXPOSED RATS ARE UNKNOWN. HYPOTHESES AND EXPERIMENTAL DATA HAVE BEEN ADVANCED IN SUPPORT OF BOTH GENETIC AND EPIGENETIC MECHANISMS OF ACTION OF THE DE.(ABSTRACT TRUNCATED AT 400 WORDS)	1987	

2   354  47 ALTERED LONG NON-CODING RNAS EXPRESSION IN NORMAL AND DISEASED PRIMARY HUMAN AIRWAY EPITHELIAL CELLS EXPOSED TO DIESEL EXHAUST PARTICLES. BACKGROUND: EXPOSURE TO DIESEL EXHAUST PARTICLES (DEP) HAS BEEN LINKED TO A VARIETY OF ADVERSE HEALTH EFFECTS, INCLUDING INCREASED MORBIDITY AND MORTALITY FROM CARDIOVASCULAR DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), METABOLIC SYNDROME, AND LUNG CANCER. THE EPIGENETIC CHANGES CAUSED BY AIR POLLUTION HAVE BEEN ASSOCIATED WITH INCREASED HEALTH RISKS. HOWEVER, THE EXACT MOLECULAR MECHANISMS UNDERLYING THE LNCRNA-MEDIATED PATHOGENESIS INDUCED BY DEP EXPOSURE HAVE NOT BEEN REVEALED. METHODS: THROUGH RNA-SEQUENCING AND INTEGRATIVE ANALYSIS OF BOTH MRNA AND LNCRNA PROFILES, THIS STUDY INVESTIGATED THE ROLE OF LNCRNAS IN ALTERED GENE EXPRESSION IN HEALTHY AND DISEASED HUMAN PRIMARY EPITHELIAL CELLS (NHBE AND DHBE-COPD) EXPOSED TO DEP AT A DOSE OF 30 MUG/CM(2). RESULTS: WE IDENTIFIED 503 AND 563 DIFFERENTIALLY EXPRESSED (DE) MRNAS AND A TOTAL OF 10 AND 14 DE LNCRNAS IN NHBE AND DHBE-COPD CELLS EXPOSED TO DEP, RESPECTIVELY. IN BOTH NHBE AND DHBE-COPD CELLS, ENRICHED CANCER-RELATED PATHWAYS WERE IDENTIFIED AT MRNA LEVEL, AND 3 COMMON LNCRNAS OLMALINC, AC069234.2, AND LINC00665 WERE FOUND TO BE ASSOCIATED WITH CANCER INITIATION AND PROGRESSION. IN ADDITION, WE IDENTIFIED TWO CIS-ACTING (TMEM51-AS1 AND TTN-AS1) AND SEVERAL TRANS-ACTING LNCRNAS (E.G. LINC01278, SNHG29, AC006064.4, TMEM51-AS1) ONLY DIFFERENTIALLY EXPRESSED IN COPD CELLS, WHICH COULD POTENTIALLY PLAY A ROLE IN CARCINOGENESIS AND DETERMINE THEIR SUSCEPTIBILITY TO DEP EXPOSURE. CONCLUSIONS: OVERALL, OUR WORK HIGHLIGHTS THE POTENTIAL IMPORTANCE OF LNCRNAS IN REGULATING DEP-INDUCED GENE EXPRESSION CHANGES ASSOCIATED WITH CARCINOGENESIS, AND INDIVIDUALS SUFFERING FROM COPD ARE LIKELY TO BE MORE VULNERABLE TO THESE ENVIRONMENTAL TRIGGERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  4094  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4  2804  23 FETAL EPIGENETIC MECHANISMS AND INNATE IMMUNITY IN ASTHMA. ALLERGY AND ASTHMA ARE CHRONIC INFLAMMATORY DISEASES THAT RESULT FROM COMPLEX GENE-ENVIRONMENT INTERACTIONS. RECENT EVIDENCE POINTS TO THE IMPORTANCE OF PRENATAL AND POSTNATAL DEVELOPMENTAL PROCESSES IN THE MATURATION OF BALANCED IMMUNE RESPONSES. NOVEL DATA INDICATE THAT EPIGENETIC MECHANISMS CONTRIBUTE TO THE DEVELOPMENT OF T-HELPER-CELL FUNCTION. ENVIRONMENTAL FACTORS, INCLUDING DIESEL EXHAUST PARTICLES, VITAMINS, AND TOBACCO SMOKE, OPERATE THROUGH SUCH MECHANISMS. FURTHERMORE, THE ROLE OF ENVIRONMENTAL MICROBES PROVIDES ANOTHER-AND MAYBE AN EVEN MORE IMPORTANT-GROUP OF EXOGENOUS EXPOSURES THAT OPERATE IN THIS CRITICAL TIME FRAME. A BETTER UNDERSTANDING OF FETAL IMMUNO-MATURATION CONDITIONS WILL PROVIDE THE BASIS FOR THE DEVELOPMENT OF NOVEL ALLERGO-PROTECTIVE CLINICAL STRATEGIES.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  2940  49 GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL AND SENSITIVE COPD-DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5). EVEN THOUGH CLINICAL, EPIDEMIOLOGICAL AND TOXICOLOGICAL STUDIES HAVE PROGRESSIVELY PROVIDED A BETTER KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS, FURTHER IN VITRO STUDIES ON RELEVANT CELL SYSTEMS ARE STILL NEEDED. HENCE, AIMING OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS, PRIMARY HUMAN BRONCHIAL EPITHELIAL CELLS DERIVED FROM NORMAL SUBJECTS (NHBE) OR SENSITIVE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED PATIENTS (DHBE) WERE DIFFERENTIATED AT THE AIR-LIQUID INTERFACE. THEREAFTER, THEY WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) TO STUDY THE OCCURRENCE OF SOME RELEVANT GENETIC AND/OR EPIGENETIC ENDPOINTS. CONCENTRATION-, EXPOSURE- AND SEASON-DEPENDENT INCREASES OF OH-B[A]P METABOLITES IN NHBE, AND TO A LESSER EXTENT, COPD-DHBE CELLS WERE REPORTED; HOWEVER, THERE WERE MORE TETRA-OH-B[A]P AND 8-OHDG DNA ADDUCTS IN COPD-DHBE CELLS. NO INCREASE IN PRIMARY DNA STRAND BREAK NOR CHROMOSOMAL ABERRATION WAS OBSERVED IN REPEATEDLY EXPOSED CELLS. TELOMERE LENGTH AND TELOMERASE ACTIVITY WERE MODIFIED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN NHBE AND PARTICULARLY COPD-DHBE CELLS. THERE WERE A GLOBAL DNA HYPOMETHYLATION, A P16 GENE PROMOTER HYPERMETHYLATION, AND A DECREASING DNA METHYLTRANSFERASE ACTIVITY IN NHBE AND NOTABLY COPD-DHBE CELLS REPEATEDLY EXPOSED. CHANGES IN SITE-SPECIFIC METHYLATION, ACETYLATION, AND PHOSPHORYLATION OF HISTONE H3 (I.E., H3K4ME3, H3K9AC, H3K27AC, AND H3S10PH) AND RELATED ENZYME ACTIVITIES OCCURRED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN ALL THE REPEATEDLY EXPOSED CELLS. COLLECTIVELY, THESE RESULTS HIGHLIGHTED THE KEY ROLE PLAYED BY GENETIC AND EVEN EPIGENETIC EVENTS IN NHBE AND PARTICULARLY SENSITIVE COPD-DHBE CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) AND THEIR DIFFERENT RESPONSIVENESS. WHILE THESE SPECIFIC EPIGENETIC CHANGES HAVE BEEN ALREADY DESCRIBED IN COPD AND EVEN LUNG CANCER PHENOTYPES, OUR FINDINGS SUPPORTED THAT, TOGETHER WITH GENETIC EVENTS, THESE EPIGENETIC EVENTS COULD DRAMATICALLY CONTRIBUTE TO THE SHIFT FROM HEALTHY TO DISEASED PHENOTYPES FOLLOWING REPEATED EXPOSURE TO RELATIVELY LOW DOSES OF AIR POLLUTION-DERIVED PM(2.5).	2017	
                                                                                                                                                                                                                                                                                                                                                                                               
6  1443  46 DIFFERENTIAL RESPONSES OF HEALTHY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4). WHILE THE KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS IS STILL INCOMPLETE, DETAILED IN VITRO STUDIES ARE HIGHLY NEEDED. WITH THE AIM OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS AND BETTER INTEGRATING A NUMBER OF FACTORS RELATED TO PRE-EXISTING CHRONIC PULMONARY INFLAMMATORY, WE SOUGHT TO DEVELOP PRIMARY CULTURES OF NORMAL HUMAN BRONCHIAL EPITHELIAL (NHBE) CELLS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED HUMAN BRONCHIAL EPITHELIAL (DHBE) CELLS, GROWN AT THE AIR-LIQUID INTERFACE. PAN-CYTOKERATIN AND MUC5AC IMMUNOSTAINING CONFIRMED THE SPECIFIC CELL-TYPES OF BOTH THESE HEALTHY AND DISEASED CELL MODELS AND SHOWED THEY ARE CLOSED TO HUMAN BRONCHIAL EPITHELIA. THEREAFTER, HEALTHY AND DISEASED CELLS WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4) AT THE NON-CYTOTOXIC CONCENTRATION OF 5 MUG/CM(2). THE DIFFERENCES BETWEEN THE OXIDATIVE AND INFLAMMATORY STATES IN NON-EXPOSED NHBE AND COPD-DHBE CELLS INDICATED THAT DISEASED CELLS CONSERVED THEIR SPECIFIC PHYSIOPATHOLOGICAL CHARACTERISTICS. INCREASES IN BOTH OXIDATIVE DAMAGE AND CYTOKINE SECRETION WERE REPORTED IN REPEATEDLY EXPOSED NHBE CELLS AND PARTICULARLY IN COPD-DHBE CELLS. DISEASED CELLS REPEATEDLY EXPOSED HAD LOWER CAPACITIES TO METABOLIZE THE ORGANIC CHEMICALS-COATED ONTO THE AIR-POLLUTION-DERIVED PM(4), SUCH AS BENZO[A]PYRENE (B[A]P), BUT SHOWED HIGHER SENSIBILITY TO THE FORMATION OF OH-B[A]P DNA ADDUCTS, BECAUSE THEIR DISEASED STATE POSSIBLY AFFECTED THEIR DEFENSES. DIFFERENTIAL PROFILES OF EPIGENETIC HALLMARKS (I.E., GLOBAL DNA HYPOMETHYLATION, P16 PROMOTER HYPERMETHYLATION, TELOMERE LENGTH SHORTENING, TELOMERASE ACTIVATION, AND HISTONE H3 MODIFICATIONS) OCCURRED IN REPEATEDLY EXPOSED NHBE AND PARTICULARLY IN COPD-DHBE CELLS. TAKEN TOGETHER, THESE RESULTS CLOSELY SUPPORTED THE HIGHEST RESPONSIVENESS OF COPD-DHBE CELLS TO A REPEATED EXPOSURE TO AIR POLLUTION-DERIVED PM(4). THE USE OF THESE INNOVATIVE IN VITRO EXPOSURE SYSTEMS SUCH AS NHBE AND COPD-DHBE CELLS COULD THEREFORE BE CONSIDER AS A VERY USEFUL AND POWERFUL PROMISING TOOL IN THE FIELD OF THE RESPIRATORY TOXICOLOGY, TAKING INTO ACCOUNT SENSITIVE INDIVIDUALS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                         
7   298  45 AIR POLLUTION AND AIRWAY DISEASE. EPIDEMIOLOGICAL AND TOXICOLOGICAL RESEARCH CONTINUES TO SUPPORT A LINK BETWEEN URBAN AIR POLLUTION AND AN INCREASED INCIDENCE AND/OR SEVERITY OF AIRWAY DISEASE. DETRIMENTAL EFFECTS OF OZONE (O(3)), NITROGEN DIOXIDE (NO(2)) AND PARTICULATE MATTER (PM), AS WELL AS TRAFFIC-RELATED POLLUTION AS A WHOLE, ON RESPIRATORY SYMPTOMS AND FUNCTION ARE WELL DOCUMENTED. NOT ONLY DO WE HAVE STRONG EPIDEMIOLOGICAL EVIDENCE OF A RELATIONSHIP BETWEEN AIR POLLUTION AND EXACERBATION OF ASTHMA AND RESPIRATORY MORBIDITY AND MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT RECENT STUDIES, PARTICULARLY IN URBAN AREAS, HAVE SUGGESTED A ROLE FOR POLLUTANTS IN THE DEVELOPMENT OF BOTH ASTHMA AND COPD. SIMILARLY, WHILE PREVALENCE AND SEVERITY OF ATOPIC CONDITIONS APPEAR TO BE MORE COMMON IN URBAN COMPARED WITH RURAL COMMUNITIES, EVIDENCE IS EMERGING THAT TRAFFIC-RELATED POLLUTANTS MAY CONTRIBUTE TO THE DEVELOPMENT OF ALLERGY. FURTHERMORE, NUMEROUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST AN ASSOCIATION BETWEEN EXPOSURE TO NO(2) , O(3) , PM AND COMBUSTION PRODUCTS OF BIOMASS FUELS AND AN INCREASED SUSCEPTIBILITY TO AND MORBIDITY FROM RESPIRATORY INFECTION. GIVEN THE CONSIDERABLE CONTRIBUTION THAT TRAFFIC EMISSIONS MAKE TO URBAN AIR POLLUTION RESEARCHERS HAVE SOUGHT TO CHARACTERIZE THE RELATIVE TOXICITY OF TRAFFIC-RELATED PM POLLUTANTS. RECENT ADVANCES IN MECHANISMS IMPLICATED IN THE ASSOCIATION OF AIR POLLUTANTS AND AIRWAY DISEASE INCLUDE EPIGENETIC ALTERATION OF GENES BY COMBUSTION-RELATED POLLUTANTS AND HOW POLYMORPHISMS IN GENES INVOLVED IN ANTIOXIDANT PATHWAYS AND AIRWAY INFLAMMATION CAN MODIFY RESPONSES TO AIR POLLUTION EXPOSURES. OTHER INTERESTING EPIDEMIOLOGICAL OBSERVATIONS RELATED TO INCREASED HOST SUSCEPTIBILITY INCLUDE A POSSIBLE LINK BETWEEN CHRONIC PM EXPOSURE DURING CHILDHOOD AND VULNERABILITY TO COPD IN ADULTHOOD, AND THAT INFANTS SUBJECTED TO HIGHER PRENATAL LEVELS OF AIR POLLUTION MAY BE AT GREATER RISK OF DEVELOPING RESPIRATORY CONDITIONS. WHILE THE CHARACTERIZATION OF POLLUTANT COMPONENTS AND SOURCES PROMISE TO GUIDE POLLUTION CONTROL STRATEGIES, THE IDENTIFICATION OF SUSCEPTIBLE SUBPOPULATIONS WILL BE NECESSARY IF TARGETED THERAPY/PREVENTION OF POLLUTION-INDUCED RESPIRATORY DISEASES IS TO BE DEVELOPED.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8  1926  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  3063  40 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10  2605  23 EPIGENETICS-A POTENTIAL MEDIATOR BETWEEN AIR POLLUTION AND PRETERM BIRTH. PRETERM BIRTH IS A MAJOR CAUSE OF INFANT MORBIDITY AND MORTALITY AND A POTENTIAL RISK FACTOR FOR ADULT CHRONIC DISEASE. WITH OVER 15 MILLION INFANTS BORN PRETERM WORLDWIDE EACH YEAR, PRETERM BIRTH POSES A GLOBAL HEALTH CONCERN. THERE IS A POSSIBLE ASSOCIATION BETWEEN AIR POLLUTION AND PRETERM BIRTH, THOUGH STUDIES HAVE BEEN INCONSISTENT, LIKELY DUE TO VARIATION IN STUDY DESIGN. HOW AIR POLLUTION INDUCES HEALTH EFFECTS IS UNCERTAIN; HOWEVER, STUDIES HAVE REPEATEDLY DEMONSTRATED THE EFFECTS OF AIR POLLUTION ON EPIGENETIC MODIFICATIONS. MORE RECENT EVIDENCE SUGGESTS THAT EPIGENETICS MAY, IN TURN, BE LINKED TO PRETERM BIRTH. DISCOVERY OF ENVIRONMENTALLY MODIFIABLE EPIGENETIC PROCESSES CONNECTED TO PRETERM BIRTH MAY HELP TO IDENTIFY WOMEN AT RISK OF PRETERM BIRTH, AND ULTIMATELY LEAD TO DEVELOPMENT OF NEW PRETERM BIRTH PREVENTION MEASURES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11   360  27 AMBIENT AIR POLLUTION AND BIOMARKERS OF HEALTH EFFECT. RECENTLY, THE AIR POLLUTION SITUATION OF OUR COUNTRY IS VERY SERIOUS ALONG WITH THE DEVELOPMENT OF URBANIZATION AND INDUSTRIALIZATION. STUDIES INDICATE THAT THE EXPOSURE OF AIR POLLUTION CAN CAUSE A RISE OF INCIDENCE AND MORTALITY OF MANY DISEASES, SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), ASTHMA, MYOCARDIAL INFARCTION, AND SO ON. HOWEVER, THERE IS NOW GROWING EVIDENCE SHOWING THAT SIGNIFICANT AIR POLLUTION EXPOSURES ARE ASSOCIATED WITH EARLY BIOMARKERS IN VARIOUS SYSTEMS OF THE BODY. IN ORDER TO BETTER PREVENT AND CONTROL THE DAMAGE EFFECT OF AIR POLLUTION, THIS ARTICLE SUMMARIZES COMPREHENSIVELY EPIDEMIOLOGICAL STUDIES ABOUT THE BAD EFFECTS ON THE BIOMARKERS OF RESPIRATORY SYSTEM, CARDIOVASCULAR SYSTEM, AND GENETIC AND EPIGENETIC SYSTEM EXPOSURE TO AMBIENT AIR POLLUTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12   363  34 AMBIENT AIR POLLUTION: HEALTH HAZARDS TO CHILDREN. AMBIENT AIR POLLUTION IS PRODUCED BY SOURCES INCLUDING VEHICULAR TRAFFIC, COAL-FIRED POWER PLANTS, HYDRAULIC FRACTURING, AGRICULTURAL PRODUCTION, AND FOREST FIRES. IT CONSISTS OF PRIMARY POLLUTANTS GENERATED BY COMBUSTION AND SECONDARY POLLUTANTS FORMED IN THE ATMOSPHERE FROM PRECURSOR GASES. AIR POLLUTION CAUSES AND EXACERBATES CLIMATE CHANGE, AND CLIMATE CHANGE WORSENS HEALTH EFFECTS OF AIR POLLUTION. INFANTS AND CHILDREN ARE UNIQUELY SENSITIVE TO AIR POLLUTION, BECAUSE THEIR ORGANS ARE DEVELOPING AND THEY HAVE HIGHER AIR PER BODY WEIGHT INTAKE. HEALTH EFFECTS LINKED TO AIR POLLUTION INCLUDE NOT ONLY EXACERBATIONS OF RESPIRATORY DISEASES BUT ALSO REDUCED LUNG FUNCTION DEVELOPMENT AND INCREASED ASTHMA INCIDENCE. ADDITIONAL OUTCOMES OF CONCERN INCLUDE PRETERM BIRTH, LOW BIRTH WEIGHT, NEURODEVELOPMENTAL DISORDERS, IQ LOSS, PEDIATRIC CANCERS, AND INCREASED RISKS FOR ADULT CHRONIC DISEASES. THESE EFFECTS ARE MEDIATED BY OXIDATIVE STRESS, CHRONIC INFLAMMATION, ENDOCRINE DISRUPTION, AND GENETIC AND EPIGENETIC MECHANISMS ACROSS THE LIFE SPAN. NATURAL EXPERIMENTS DEMONSTRATE THAT WITH INITIATIVES SUCH AS INCREASED USE OF PUBLIC TRANSPORTATION, BOTH AIR QUALITY AND COMMUNITY HEALTH IMPROVE. SIMILARLY, THE CLEAN AIR ACT HAS IMPROVED AIR QUALITY, ALTHOUGH EXPOSURE INEQUITIES PERSIST. OTHER EFFECTIVE STRATEGIES FOR REDUCING AIR POLLUTION INCLUDE ENDING RELIANCE ON COAL, OIL, AND GAS; REGULATING INDUSTRIAL EMISSIONS; REDUCING EXPOSURE WITH ATTENTION TO PROXIMITY OF RESIDENCES, SCHOOLS, AND CHILD CARE FACILITIES TO TRAFFIC; AND A GREATER AWARENESS OF THE AIR QUALITY INDEX. THIS POLICY REVIEWS BOTH SHORT- AND LONG-TERM HEALTH CONSEQUENCES OF AMBIENT AIR POLLUTION, ESPECIALLY IN RELATION TO DEVELOPMENTAL EXPOSURES. IT EXAMINES INDIVIDUAL, COMMUNITY, AND LEGISLATIVE STRATEGIES TO MITIGATE AIR POLLUTION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13   300  34 AIR POLLUTION AND INDOOR SETTINGS. INDOOR ENVIRONMENTS CONTRIBUTE SIGNIFICANTLY TO TOTAL HUMAN EXPOSURE TO AIR POLLUTANTS, AS PEOPLE SPEND MOST OF THEIR TIME INDOORS. HOUSEHOLD AIR POLLUTION (HAP) RESULTING FROM COOKING WITH POLLUTING ("DIRTY") FUELS, WHICH INCLUDE COAL, KEROSENE, AND BIOMASS (WOOD, CHARCOAL, CROP RESIDUES, AND ANIMAL MANURE) IS A GLOBAL ENVIRONMENTAL HEALTH PROBLEM. INDOOR POLLUTANTS ARE GASES, PARTICULATES, TOXINS, AND MICROORGANISMS AMONG OTHERS, THAT CAN HAVE AN IMPACT ESPECIALLY ON THE HEALTH OF CHILDREN AND ADULTS THROUGH A COMBINATION OF DIFFERENT MECHANISMS ON OXIDATIVE STRESS AND GENE ACTIVATION, EPIGENETIC, CELLULAR, AND IMMUNOLOGICAL SYSTEMS. AIR POLLUTION IS A MAJOR RISK FACTOR AND CONTRIBUTOR TO MORBIDITY AND MORTALITY FROM MAJOR CHRONIC DISEASES. CHILDREN ARE SIGNIFICANTLY AFFECTED BY THE IMPACT OF THE ENVIRONMENT DUE TO BIOLOGICAL IMMATURITY, PRENATAL AND POSTNATAL LUNG DEVELOPMENT. POOR AIR QUALITY HAS BEEN RELATED TO AN INCREASED PREVALENCE OF CLINICAL MANIFESTATIONS OF ALLERGIC ASTHMA AND RHINITIS. HEALTH PROFESSIONALS SHOULD INCREASE THEIR ROLE IN MANAGING THE EXPOSURE OF CHILDREN AND ADULTS TO AIR POLLUTION WITH BETTER METHODS OF CARE, PREVENTION, AND COLLECTIVE ACTION. INTERVENTIONS TO REDUCE HOUSEHOLD POLLUTANTS MAY PROMOTE HEALTH AND CAN BE ACHIEVED WITH EDUCATION, COMMUNITY, AND HEALTH PROFESSIONAL INVOLVEMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14   361  40 AMBIENT AIR POLLUTION AND THROMBOSIS. AIR POLLUTION IS A GROWING PUBLIC HEALTH CONCERN OF GLOBAL SIGNIFICANCE. ACUTE AND CHRONIC EXPOSURE IS KNOWN TO IMPAIR CARDIOVASCULAR FUNCTION, EXACERBATE DISEASE AND INCREASE CARDIOVASCULAR MORTALITY. SEVERAL PLAUSIBLE BIOLOGICAL MECHANISMS HAVE BEEN PROPOSED FOR THESE ASSOCIATIONS, HOWEVER, AT PRESENT, THE PATHWAYS ARE INCOMPLETE. A SEMINAL REVIEW BY THE AMERICAN HEART ASSOCIATION (2010) CONCLUDED THAT THE THROMBOTIC EFFECTS OF PARTICULATE AIR POLLUTION LIKELY CONTRIBUTED TO THEIR EFFECTS ON CARDIOVASCULAR MORTALITY AND MORBIDITY. THE AIM OF THE CURRENT REVIEW IS TO APPRAISE THE NEWLY ACCUMULATED SCIENTIFIC EVIDENCE (2009-2016) ON CONTRIBUTION OF HAEMOSTASIS AND THROMBOSIS TOWARDS CARDIOVASCULAR DISEASE INDUCED BY EXPOSURE TO BOTH PARTICULATE AND GASEOUS POLLUTANTS.SEVENTY FOUR PUBLICATIONS WERE REVIEWED IN-DEPTH. THE WEIGHT OF EVIDENCE SUGGESTS THAT ACUTE EXPOSURE TO FINE PARTICULATE MATTER (PM(2.5)) INDUCES A SHIFT IN THE HAEMOSTATIC BALANCE TOWARDS A PRO-THROMBOTIC/PRO-COAGULATIVE STATE. INSUFFICIENT DATA WAS AVAILABLE TO ASCERTAIN IF A SIMILAR RELATIONSHIP EXISTS FOR GASEOUS POLLUTANTS, AND VERY FEW STUDIES HAVE ADDRESSED LONG-TERM EXPOSURE TO AMBIENT AIR POLLUTION. PLATELET ACTIVATION, OXIDATIVE STRESS, INTERPLAY BETWEEN INTERLEUKIN-6 AND TISSUE FACTOR, ALL APPEAR TO BE POTENTIALLY IMPORTANT MECHANISMS IN POLLUTION-MEDIATED THROMBOSIS, TOGETHER WITH AN EMERGING ROLE FOR CIRCULATING MICROVESICLES AND EPIGENETIC CHANGES.OVERALL, THE RECENT LITERATURE SUPPORTS, AND ARGUABLY STRENGTHENS, THE CONTENTION THAT AIR POLLUTION CONTRIBUTES TO CARDIOVASCULAR MORBIDITY BY PROMOTING HAEMOSTASIS. THE VOLUME AND DIVERSITY OF THE EVIDENCE HIGHLIGHTS THE COMPLEXITY OF THE PATHOPHYSIOLOGIC MECHANISMS BY WHICH AIR POLLUTION PROMOTES THROMBOSIS; MULTIPLE PATHWAYS ARE PLAUSIBLE AND IT IS MOST LIKELY THEY ACT IN CONCERT. FUTURE RESEARCH SHOULD ADDRESS THE ROLE GASEOUS POLLUTANTS PLAY IN THE CARDIOVASCULAR EFFECTS OF AIR POLLUTION MIXTURE AND DIRECT COMPARISON OF POTENTIALLY SUSCEPTIBLE GROUPS TO HEALTHY INDIVIDUALS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15  1924  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16   529  22 ASTHMA IN URBAN CHILDREN: EPIDEMIOLOGY, ENVIRONMENTAL RISK FACTORS, AND THE PUBLIC HEALTH DOMAIN. ASTHMA IS THE MOST COMMONLY REPORTED CHRONIC CONDITION OF CHILDHOOD IN DEVELOPED COUNTRIES, WITH 6.5 MILLION CHILDREN AFFECTED IN THE USA. A DISPARATE BURDEN OF CHILDHOOD ASTHMA IS SEEN AMONG SOCIOECONOMICALLY DISADVANTAGED YOUTH, OFTEN CONCENTRATED IN URBAN AREAS WITH HIGH POVERTY RATES. HOST FACTORS THAT PREDISPOSE A CHILD TO ASTHMA INCLUDE ATOPY, MALE GENDER, PARENTAL HISTORY OF ASTHMA, AND ALSO RACE, ETHNICITY, AND GENETIC AND EPIGENETIC SUSCEPTIBILITIES. ENVIRONMENTAL FACTORS, SUCH AS IMPROVED HYGIENE, AMBIENT AIR POLLUTION, AND EARLY LIFE EXPOSURES TO MICROBES AND AEROALLERGENS, ALSO INFLUENCE THE DEVELOPMENT OF ASTHMA. WITH GREATER THAN 90% OF TIME SPENT INDOORS, HOME EXPOSURES (SUCH AS COCKROACH, RODENT, AND INDOOR AIR POLLUTION) ARE HIGHLY RELEVANT FOR URBAN ASTHMA. MORBIDITY REDUCTION MAY REQUIRE FOCUSED PUBLIC HEALTH INITIATIVES FOR ENVIRONMENTAL INTERVENTION IN HIGH PRIORITY RISK GROUPS AND THE ADDITION OF IMMUNE MODULATORY AGENTS IN CHILDREN WITH POORLY CONTROLLED DISEASE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17  3119  39 GESTATIONAL EXPOSURE TO PARTICULATE AIR POLLUTION EXACERBATES THE GROWTH PHENOTYPES INDUCED BY PRECONCEPTION PATERNAL ALCOHOL USE: A MULTIPLEX MODEL OF EXPOSURE. IT IS NOW CLEAR THAT PARENTAL HISTORIES OF DRUG USE, TOXICANT EXPOSURE, AND SOCIAL STRESS ALL HAVE A SIGNIFICANT INFLUENCE ON THE HEALTH AND DEVELOPMENT OF THE NEXT GENERATION. HOWEVER, THE ABILITY OF EPIGENETIC PARENTAL LIFE MEMORIES TO INTERACT WITH SUBSEQUENT GESTATIONAL EXPOSURES AND CUMULATIVELY MODIFY THE DEVELOPMENTAL TRAJECTORY OF THE OFFSPRING REMAINS AN UNEXPLORED PERSPECTIVE IN TOXICOLOGY. STUDIES FROM OUR LABORATORY HAVE IDENTIFIED MALE-SPECIFIC POSTNATAL GROWTH RESTRICTION IN A MOUSE MODEL OF CHRONIC, PRECONCEPTION PATERNAL ALCOHOL EXPOSURE. THE GOAL OF THE CURRENT STUDY WAS TO DETERMINE IF PATERNAL ALCOHOL USE, BEFORE CONCEPTION, COULD MODIFY THE SUSCEPTIBILITY OF THE OFFSPRING TO A COMPLETELY SEPARATE EXPOSURE ENCOUNTERED BY THE MOTHER DURING PREGNANCY. IN INDEPENDENT EXPERIMENTS, WE PREVIOUSLY IDENTIFIED ALTERED DEVELOPMENTAL PROGRAMMING AND INCREASED MARKERS OF SEVERE ASTHMA INDUCED BY GESTATIONAL EXPOSURE TO PARTICULATE AIR POLLUTION. IN THIS STUDY, MALE MICE WERE EXPOSED TO EITHER THE CONTROL OR ALCOHOL PRECONCEPTION TREATMENTS, THEN MATED TO NAIVE FEMALES, WHICH WE SUBSEQUENTLY EXPOSED TO AN ULTRAFINE MIXTURE OF PARTICULATE MATTER VIA INHALATION. INDIVIDUALLY, NEITHER PRECONCEPTION PATERNAL DRINKING NOR GESTATIONAL EXPOSURES TO PARTICULATE AIR POLLUTION IMPACTED THE POSTNATAL GROWTH OF FEMALE OFFSPRING. HOWEVER, WHEN BOTH EXPOSURES WERE COMBINED, FEMALES DISPLAYED A 30% REDUCTION IN WEIGHT GAIN. UNEXPECTEDLY, THIS EXPOSURE PARADIGM RESULTED IN A DRAMATIC POSTNATAL INCREASE IN LITTER LOSS DUE TO MATERNAL CANNIBALISM, WHICH PREVENTED ADDITIONAL MEASURES OF OFFSPRING HEALTH. THESE PRELIMINARY STUDIES PROVIDE EVIDENCE OF A COMPLEX INTERPLAY BETWEEN PRECONCEPTION LIFE HISTORY AND INTRAUTERINE ENVIRONMENTAL FACTORS IN THE CONTROL OF POSTNATAL GROWTH.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18   299  41 AIR POLLUTION AND DNA METHYLATION: EFFECTS OF EXPOSURE IN HUMANS. AIR POLLUTION EXPOSURE IS ESTIMATED TO CONTRIBUTE TO APPROXIMATELY SEVEN MILLION EARLY DEATHS EVERY YEAR WORLDWIDE AND MORE THAN 3% OF DISABILITY-ADJUSTED LIFE YEARS LOST. AIR POLLUTION HAS NUMEROUS HARMFUL EFFECTS ON HEALTH AND CONTRIBUTES TO THE DEVELOPMENT AND MORBIDITY OF CARDIOVASCULAR DISEASE, METABOLIC DISORDERS, AND A NUMBER OF LUNG PATHOLOGIES, INCLUDING ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). EMERGING DATA INDICATE THAT AIR POLLUTION EXPOSURE MODULATES THE EPIGENETIC MARK, DNA METHYLATION (DNAM), AND THAT THESE CHANGES MIGHT IN TURN INFLUENCE INFLAMMATION, DISEASE DEVELOPMENT, AND EXACERBATION RISK. SEVERAL TRAFFIC-RELATED AIR POLLUTION (TRAP) COMPONENTS, INCLUDING PARTICULATE MATTER (PM), BLACK CARBON (BC), OZONE (O(3)), NITROGEN OXIDES (NO(X)), AND POLYAROMATIC HYDROCARBONS (PAHS), HAVE BEEN ASSOCIATED WITH CHANGES IN DNAM; TYPICALLY LOWERING DNAM AFTER EXPOSURE. EFFECTS OF AIR POLLUTION ON DNAM HAVE BEEN OBSERVED ACROSS THE HUMAN LIFESPAN, BUT IT IS NOT YET CLEAR WHETHER EARLY LIFE DEVELOPMENTAL SENSITIVITY OR THE ACCUMULATION OF EXPOSURES HAVE THE MOST SIGNIFICANT EFFECTS ON HEALTH. AIR POLLUTION EXPOSURE-ASSOCIATED DNAM PATTERNS ARE OFTEN CORRELATED WITH LONG-TERM NEGATIVE RESPIRATORY HEALTH OUTCOMES, INCLUDING THE DEVELOPMENT OF LUNG DISEASES, A FOCUS IN THIS REVIEW. RECENTLY, INTERVENTIONS SUCH AS EXERCISE AND B VITAMINS HAVE BEEN PROPOSED TO REDUCE THE IMPACT OF AIR POLLUTION ON DNAM AND HEALTH. ULTIMATELY, IMPROVED KNOWLEDGE OF HOW EXPOSURE-INDUCED CHANGE IN DNAM IMPACTS HEALTH, BOTH ACUTELY AND CHRONICALLY, MAY ENABLE PREVENTATIVE AND REMEDIAL STRATEGIES TO REDUCE MORBIDITY IN POLLUTED ENVIRONMENTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19   846  36 CHILDHOOD EXPOSURE TO AMBIENT POLYCYCLIC AROMATIC HYDROCARBONS IS LINKED TO EPIGENETIC MODIFICATIONS AND IMPAIRED SYSTEMIC IMMUNITY IN T CELLS. BACKGROUND: EVIDENCE SUGGESTS THAT EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) INCREASES ATOPY; IT IS UNCLEAR HOW PAH EXPOSURE IS LINKED TO INCREASED SEVERITY OF ATOPIC DISEASES. OBJECTIVE: WE HYPOTHESIZED THAT AMBIENT PAH EXPOSURE IS LINKED TO IMPAIRMENT OF IMMUNITY IN ATOPIC CHILDREN (DEFINED AS CHILDREN WITH ASTHMA AND/OR ALLERGIC RHINITIS) FROM FRESNO, CALIFORNIA, AN AREA WITH ELEVATED AMBIENT PAHS. METHODS: WE RECRUITED 256 SUBJECTS FROM FRESNO, CA. AMBIENT PAH CONCENTRATIONS (NG/M(3) ) WERE MEASURED USING A SPATIAL-TEMPORAL REGRESSION MODEL OVER MULTIPLE TIME PERIODS. ASTHMA DIAGNOSIS WAS DETERMINED BY CURRENT NHLBI CRITERIA. PHENOTYPING AND FUNCTIONAL IMMUNE MEASUREMENTS WERE PERFORMED FROM ISOLATED CELLS. FOR EPIGENETIC MEASUREMENTS, DNA WAS ISOLATED AND PYROSEQUENCED. RESULTS: WE SHOW THAT HIGHER AVERAGE PAH EXPOSURE WAS SIGNIFICANTLY ASSOCIATED WITH IMPAIRED TREG FUNCTION AND INCREASED METHYLATION IN THE FORKHEAD BOX PROTEIN 3 (FOXP3) LOCUS (P < 0.05), CONDITIONAL ON ATOPIC STATUS. THESE EPIGENETIC MODIFICATIONS WERE SIGNIFICANTLY LINKED TO DIFFERENTIAL PROTEIN EXPRESSION OF FOXP3 (P < 0.001). METHYLATION WAS ASSOCIATED WITH CELLULAR FUNCTIONAL CHANGES, SPECIFICALLY TREG DYSFUNCTION, AND AN INCREASE IN TOTAL PLASMA IGE LEVELS. PROTEIN EXPRESSION OF IL-10 DECREASED AND IFN-GAMMA INCREASED AS THE EXTENT OF PAH EXPOSURE INCREASED. THE STRENGTH OF THE ASSOCIATIONS GENERALLY INCREASED AS THE TIME WINDOW FOR AVERAGE PAH EXPOSURE INCREASED FROM 24 HR TO 1 YEAR, SUGGESTING MORE OF A CHRONIC RESPONSE. SIGNIFICANT ASSOCIATIONS WITH CHRONIC PAH EXPOSURE AND IMMUNE OUTCOMES WERE ALSO OBSERVED IN SUBJECTS WITH ALLERGIC RHINITIS. CONCLUSIONS AND CLINICAL RELEVANCE: COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT INCREASED AMBIENT PAH EXPOSURE IS ASSOCIATED WITH IMPAIRED SYSTEMIC IMMUNITY AND EPIGENETIC MODIFICATIONS IN A KEY LOCUS INVOLVED IN ATOPY: FOXP3, WITH A HIGHER IMPACT ON ATOPIC CHILDREN. THE RESULTS SUGGEST THAT INCREASED ATOPIC CLINICAL SYMPTOMS IN CHILDREN COULD BE LINKED TO INCREASED PAH EXPOSURE IN AIR POLLUTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20   178  35 ACCELERATED EPIGENETIC AGING AS A RISK FACTOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND DECREASED LUNG FUNCTION IN TWO PROSPECTIVE COHORT STUDIES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A FREQUENT DIAGNOSIS IN OLDER INDIVIDUALS AND CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY. GIVEN THE LINK BETWEEN LUNG DISEASE AND AGING, WE NEED TO UNDERSTAND HOW MOLECULAR INDICATORS OF AGING RELATE TO LUNG FUNCTION AND DISEASE. USING DATA FROM THE POPULATION-BASED KORA (COOPERATIVE HEALTH RESEARCH IN THE REGION OF AUGSBURG) SURVEYS, WE ASSOCIATED BASELINE EPIGENETIC (DNA METHYLATION) AGE ACCELERATION WITH INCIDENT COPD AND LUNG FUNCTION. MODELS WERE ADJUSTED FOR AGE, SEX, SMOKING, HEIGHT, WEIGHT, AND BASELINE LUNG DISEASE AS APPROPRIATE. ASSOCIATIONS WERE REPLICATED IN THE NORMATIVE AGING STUDY. OF 770 KORA PARTICIPANTS, 131 DEVELOPED INCIDENT COPD OVER 7 YEARS. BASELINE ACCELERATED EPIGENETIC AGING WAS SIGNIFICANTLY ASSOCIATED WITH INCIDENT COPD. THE CHANGE IN AGE ACCELERATION (FOLLOW-UP - BASELINE) WAS MORE STRONGLY ASSOCIATED WITH COPD THAN BASELINE AGING ALONE. THE ASSOCIATION BETWEEN THE CHANGE IN AGE ACCELERATION BETWEEN BASELINE AND FOLLOW-UP AND INCIDENT COPD REPLICATED IN THE NORMATIVE AGING STUDY. ASSOCIATIONS WITH SPIROMETRIC LUNG FUNCTION PARAMETERS WERE WEAKER THAN THOSE WITH COPD, BUT A META-ANALYSIS OF BOTH COHORTS PROVIDE SUGGESTIVE EVIDENCE OF ASSOCIATIONS. ACCELERATED EPIGENETIC AGING, BOTH BASELINE MEASURES AND CHANGES OVER TIME, MAY BE A RISK FACTOR FOR COPD AND REDUCED LUNG FUNCTION.	2020