1  4378 154 MITOCHONDRIAL DNA COPY NUMBER AND EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS. BACKGROUND: INCREASED MITOCHONDRIAL DNA COPY NUMBER (MTDNACN) IS A BIOLOGIC RESPONSE TO MTDNA DAMAGE AND DYSFUNCTION, PREDICTIVE OF LUNG CANCER RISK. POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) ARE ESTABLISHED LUNG CARCINOGENS AND MAY CAUSE MITOCHONDRIAL TOXICITY. WHETHER PAH EXPOSURE AND PAH-RELATED NUCLEAR DNA (NDNA) GENOTOXIC EFFECTS ARE LINKED WITH INCREASED MTDNACN HAS NEVER BEEN EVALUATED. METHODS: WE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO PAHS ON MTDNACN IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) OF 46 POLISH MALE NONCURRENT SMOKING COKE-OVEN WORKERS AND 44 MATCHED CONTROLS, WHO WERE PART OF A GROUP OF 94 STUDY INDIVIDUALS EXAMINED IN OUR PREVIOUS WORK. SUBJECTS' PAH EXPOSURE AND GENETIC ALTERATIONS WERE CHARACTERIZED THROUGH MEASURES OF INTERNAL DOSE (URINARY 1-PYRENOL), TARGET DOSE [ANTI-BENZO[A]PYRENE DIOLEPOXIDE (ANTI-BPDE)-DNA ADDUCT], GENETIC INSTABILITY (MICRONUCLEI AND TELOMERE LENGTH), AND DNA METHYLATION (P53 PROMOTER) IN PBLS. MTDNACN (MT/S) WAS MEASURED USING A VALIDATED REAL-TIME PCR METHOD. RESULTS: WORKERS WITH PAH EXPOSURE ABOVE THE MEDIAN VALUE (>3 MUMOL 1-PYRENOL/MOL CREATININE) SHOWED HIGHER MTDNACN [GEOMETRIC MEANS (GM) OF 1.06 (UNADJUSTED) AND 1.07 (AGE-ADJUSTED)] COMPARED WITH CONTROLS [GM 0.89 (UNADJUSTED); 0.89 (AGE-ADJUSTED); (P = 0.029 AND 0.016)], AS WELL AS HIGHER LEVELS OF GENETIC AND CHROMOSOMAL [I.E., ANTI-BPDE-DNA ADDUCTS (P < 0.001), MICRONUCLEI (P < 0.001), AND TELOMERE LENGTH (P = 0.053)] AND EPIGENETIC [I.E., P53 GENE-SPECIFIC PROMOTER METHYLATION (P < 0.001)] ALTERATIONS IN THE NDNA. IN THE WHOLE STUDY POPULATION, UNADJUSTED AND AGE-ADJUSTED MTDNACN WAS POSITIVELY CORRELATED WITH 1-PYRENOL (P = 0.043 AND 0.032) AND ANTI-BPDE-DNA ADDUCTS (P = 0.046 AND 0.049). CONCLUSIONS: PAH EXPOSURE AND PAH-RELATED NDNA GENOTOXICITY ARE ASSOCIATED WITH INCREASED MTDNACN. IMPACT: THE PRESENT STUDY IS SUGGESTIVE OF POTENTIAL ROLES OF MTDNACN IN PAH-INDUCED CARCINOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  5683  87 SHORTER TELOMERE LENGTH IN PERIPHERAL BLOOD LYMPHOCYTES OF WORKERS EXPOSED TO POLYCYCLIC AROMATIC HYDROCARBONS. SHORTER TELOMERE LENGTH (TL) IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) IS PREDICTIVE OF LUNG CANCER RISK. POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) ARE ESTABLISHED LUNG CARCINOGENS THAT CAUSE CHROMOSOME INSTABILITY. WHETHER PAH EXPOSURE AND ITS MOLECULAR EFFECTS ARE LINKED WITH SHORTER TL HAS NEVER BEEN EVALUATED. IN THE PRESENT STUDY, WE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO PAHS ON TL MEASURED IN PBLS OF POLISH MALE NON-CURRENT SMOKING COKEOVEN WORKERS AND MATCHED CONTROLS. PAH EXPOSURE AND MOLECULAR EFFECTS WERE CHARACTERIZED USING MEASURES OF INTERNAL DOSE (URINARY 1-PYRENOL), EFFECTIVE DOSE [ANTI-BENZO[A]PYRENE DIOLEPOXIDE (ANTI-BPDE)-DNA ADDUCT], GENETIC INSTABILITY (MICRONUCLEI, MN) AND DNA METHYLATION [P53 PROMOTER AND ALU AND LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) REPETITIVE ELEMENTS, AS SURROGATE MEASURES OF GLOBAL METHYLATION] IN PBLS. TL WAS MEASURED BY REAL-TIME POLYMERASE CHAIN REACTION. COKEOVEN WORKERS WERE HEAVILY EXPOSED TO PAHS (79% EXCEEDED THE URINARY 1-PYRENOL BIOLOGICAL EXPOSURE INDEX) AND EXHIBITED LOWER TL (P = 0.038) THAN CONTROLS, AS WELL AS HIGHER LEVELS OF GENETIC AND CHROMOSOMAL ALTERATIONS [I.E. ANTI-BPDE-DNA ADDUCT AND MN (P < 0.0001)] AND EPIGENETIC CHANGES [I.E. P53 GENE-SPECIFIC PROMOTER AND GLOBAL METHYLATION (P <OR= 0.001)]. TL DECREASED WITH LONGER DURATION OF WORK AS COKEOVEN WORKER (P = 0.039) AND IN ALL SUBJECTS WITH HIGHER LEVELS OF ANTI-BPDE-DNA ADDUCT (P = 0.042), P53 HYPOMETHYLATION (P = 0.005) AND MN (P = 0.009). IN MULTIVARIATE ANALYSIS, YEARS OF WORK IN COKERY (P = 0.008) AND P53 HYPOMETHYLATION (P = 0.001) WERE THE PRINCIPAL DETERMINANTS OF SHORTER TL. OUR RESULTS INDICATE THAT SHORTER TL IS ASSOCIATED WITH CHRONIC PAH EXPOSURE. THE INTERRELATIONS WITH OTHER GENETIC AND EPIGENETIC MECHANISMS IN OUR DATA SUGGEST THAT SHORTER TL COULD BE A CENTRAL EVENT IN PAH CARCINOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3  6492  44 TRAFFIC-RELATED AIR POLLUTION AND GROUND-LEVEL OZONE ASSOCIATED GLOBAL DNA HYPOMETHYLATION AND BULKY DNA ADDUCT FORMATION. STUDIES HAVE INDICATED THAT AIR POLLUTION, INCLUDING SURFACE-LEVEL OZONE (O(3)), CAN SIGNIFICANTLY INFLUENCE THE RISK OF CHRONIC DISEASES. TO BETTER UNDERSTAND THE CARCINOGENIC MECHANISMS OF AIR POLLUTANTS AND IDENTIFY PREDICTIVE DISEASE BIOMARKERS, WE EXAMINED THE ASSOCIATION BETWEEN TRAFFIC-RELATED POLLUTANTS WITH DNA METHYLATION ALTERATIONS AND BULKY DNA ADDUCTS, TWO BIOMARKERS OF CARCINOGEN EXPOSURE AND CANCER RISK, IN THE PERIPHERAL BLOOD OF 140 VOLUNTEERS-95 TRAFFIC POLICE OFFICERS, AND 45 UNEXPOSED SUBJECTS. THE DNA METHYLATION AND ADDUCT MEASUREMENTS WERE PERFORMED BY BISULFITE-PCR AND PYROSEQUENCING AND (32)P-POSTLABELING ASSAY. AIRBORNE LEVELS OF BENZO(A)PYRENE [B(A)P], CARBON MONOXIDE, AND TROPOSPHERIC O(3) WERE DETERMINED BY PERSONAL EXPOSURE BIOMONITORING OR BY FIXED MONITORING STATIONS. OVERALL, AIR POLLUTION EXPOSURE WAS ASSOCIATED WITH A SIGNIFICANT REDUCTION (1.41 UNITS) IN GLOBAL DNA METHYLATION (95% C.I. -2.65-0.04, P = 0.026). THE DECREMENT IN ALU REPETITIVE ELEMENTS WAS GREATEST IN THE POLICEMEN WORKING DOWNTOWN (95% C.I. -3.23--0.49, P = 0.008). THE DNA ADDUCTS WERE FOUND TO BE SIGNIFICANTLY INCREASED (0.45 UNITS) IN THE MUNICIPAL OFFICERS WITH RESPECT TO UNEXPOSED SUBJECTS (95% C.I. 0.02-0.88, P = 0.039), MAINLY IN THOSE WHO WERE CONTROLLING TRAFFIC IN DOWNTOWN AREAS (95% C.I. 0.39-1.29, P < 0.001). REGRESSION MODELS INDICATED AN INCREMENT OF ALU METHYLATION AT HIGHER B(A)P CONCENTRATIONS (95% C.I. 0.03-0.60, P = 0.032). MOREOVER, STATISTICAL MODELS SHOWED A DECREMENT IN ALU METHYLATION AND AN INCREMENT OF DNA DAMAGE ONLY ABOVE THE CUT-OFF VALUE OF 30 MICROG/M(3) O(3). A SIGNIFICANT INCREMENT OF 0.73 UNITS OF IL-6 GENE METHYLATION WAS ALSO FOUND IN SMOKERS WITH RESPECT TO NON-SMOKERS. OUR RESULTS HIGHLIGHTED THE ROLE OF AIR POLLUTION ON EPIGENETIC ALTERATIONS AND GENOTOXIC EFFECTS, ESPECIALLY ABOVE THE TARGET VALUE OF 30 MICROG/M(3) SURFACE-LEVEL O(3), SUPPORTING THE NECESSITY FOR DEVELOPING PUBLIC HEALTH STRATEGIES AIMED TO REDUCE TRAFFIC-RELATED AIR POLLUTION MOLECULAR ALTERATIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4   567  28 BASIC PROPERTIES AND MOLECULAR MECHANISMS OF EXOGENOUS CHEMICAL CARCINOGENS. EXOGENOUS CHEMICAL CARCINOGENESIS IS AN EXTREMELY COMPLEX MULTIFACTORIAL PROCESS DURING WHICH GENE-ENVIRONMENT INTERACTIONS INVOLVING CHRONIC EXPOSURE TO EXOGENOUS CHEMICAL CARCINOGENS (ECCS) AND POLYMORPHISMS OF CANCER SUSCEPTIBILITY GENES ADD FURTHER COMPLEXITY. WE DESCRIBE THE PROPERTIES AND MOLECULAR MECHANISMS OF ECCS THAT CONTRIBUTE TO INDUCE AND GENERATE CANCER. A BASIC AND SPECIFIC PROPERTY OF MANY LIPOPHILIC ORGANIC ECCS INCLUDING POLYCYCLIC AROMATIC HYDROCARBONS AND POLYHALOGENATED AROMATIC HYDROCARBONS IS THEIR ABILITY TO BIOACCUMULATE IN THE ADIPOSE TISSUE FROM WHERE THEY MAY BE RELEASED IN THE BLOOD CIRCULATION AND TARGET PERIPHERAL TISSUES FOR CARCINOGENESIS. MANY ORGANIC ECCS ARE PROCARCINOGENS AND CONSEQUENTLY NEED TO BE ACTIVATED BY THE CYTOCHROME P450 (CYP) SYSTEM AND/OR OTHER ENZYMES BEFORE THEY CAN ADDUCT DNA AND PROTEINS. BECAUSE THEY CONTRIBUTE NOT ONLY TO THE COCARCINOGENIC AND PROMOTING EFFECTS OF MANY AROMATIC POLLUTANTS BUT ALSO TO THEIR MUTAGENIC EFFECTS, THE ARYL HYDROCARBON RECEPTOR-ACTIVATING AND THE INDUCIBLE CYP SYSTEMS ARE CENTRAL TO EXOGENOUS CHEMICAL CARCINOGENESIS. ANOTHER BASIC PROPERTY OF ECCS IS THEIR ABILITY TO INDUCE STABLE AND BULKY DNA ADDUCTS THAT CANNOT BE SIMPLY REPAIRED BY THE DIFFERENT REPAIR SYSTEMS. IN ADDITION, FOLLOWING ECC EXPOSURE, MUTAGENESIS MAY ALSO BE CAUSED INDIRECTLY BY FREE-RADICAL PRODUCTION AND BY EPIGENETIC ALTERATIONS. AS A RESULT OF COMPLEX MOLECULAR INTERPLAYS, DIRECT AND/OR INDIRECT MUTAGENESIS MAY ESPECIALLY ACCOUNT FOR THE CARCINOGENIC EFFECTS OF MANY EXOGENOUS METALS AND METALLOIDS. BECAUSE OF THESE MOLECULAR PROPERTIES AND ACTION MECHANISMS, WE CONCLUDE THAT ECCS COULD BE MAJOR CONTRIBUTORS TO HUMAN CANCER, WITH OBVIOUSLY GREAT PUBLIC HEALTH CONSEQUENCES.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  4822  22 OCHRATOXIN A: 50 YEARS OF RESEARCH. SINCE OCHRATOXIN A (OTA) WAS DISCOVERED, IT HAS BEEN UBIQUITOUS AS A NATURAL CONTAMINANT OF MOLDY FOOD AND FEED. THE MULTIPLE TOXIC EFFECTS OF OTA ARE A REAL THREAT FOR HUMAN BEINGS AND ANIMAL HEALTH. FOR EXAMPLE, OTA CAN CAUSE PORCINE NEPHROPATHY BUT CAN ALSO DAMAGE POULTRIES. HUMANS EXPOSED TO OTA CAN DEVELOP (NOTABLY BY INHALATION IN THE DEVELOPMENT OF ACUTE RENAL FAILURE WITHIN 24 H) A RANGE OF CHRONIC DISORDERS SUCH AS UPPER UROTHELIAL CARCINOMA. OTA PLAYS THE MAIN ROLE IN THE PATHOGENESIS OF SOME RENAL DISEASES INCLUDING BALKAN ENDEMIC NEPHROPATHY, KIDNEY TUMORS OCCURRING IN CERTAIN ENDEMIC REGIONS OF THE BALKAN PENINSULA, AND CHRONIC INTERSTITIAL NEPHROPATHY OCCURRING IN NORTHERN AFRICAN COUNTRIES AND LIKELY IN OTHER PARTS OF THE WORLD. OTA LEADS TO DNA ADDUCT FORMATION, WHICH IS KNOWN FOR ITS GENOTOXICITY AND CARCINOGENICITY. THE PRESENT ARTICLE DISCUSSES HOW RENAL CARCINOGENICITY AND NEPHROTOXICITY CAUSE BOTH OXIDATIVE STRESS AND DIRECT GENOTOXICITY. CAREFUL ANALYSES OF THE DATA SHOW THAT OTA CARCINOGENIC EFFECTS ARE DUE TO COMBINED DIRECT AND INDIRECT MECHANISMS (E.G., GENOTOXICITY, OXIDATIVE STRESS, EPIGENETIC FACTORS). ALTOGETHER THIS PROVIDES STRONG EVIDENCE THAT OTA CARCINOGENICITY CAN ALSO OCCUR IN HUMANS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6   846  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  3710  48 INFLUENCES OF POLYCYCLIC AROMATIC HYDROCARBON ON THE EPIGENOME TOXICITY AND ITS APPLICABILITY IN HUMAN HEALTH RISK ASSESSMENT. THE EXISTENCE OF POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) IN AMBIENT AIR IS AN ESCALATING CONCERN WORLDWIDE BECAUSE OF THEIR ABILITY TO CAUSE CANCER AND INDUCE PERMANENT CHANGES IN THE GENETIC MATERIAL. GROWING EVIDENCE IMPLIES THAT DURING EARLY LIFE-SENSITIVE STAGES, THE RISK OF PROGRESSION OF ACUTE AND CHRONIC DISEASES DEPENDS ON EPIGENETIC CHANGES INITIATED BY THE INFLUENCE OF ENVIRONMENTAL CUES. SEVERAL REPORTS DECIPHERED THE RELATIONSHIP BETWEEN EXPOSURE TO ENVIRONMENTAL CHEMICALS AND EPIGENETICS, AND HAVE KNOWN TOXICANTS THAT ALTER THE EPIGENETIC STATES. AMONGST PAHS, BENZO[A]PYRENE (B[A]P) IS ACCEPTED AS A GROUP 1 CANCER-CAUSING AGENT BY THE INTERNATIONAL AGENCY FOR THE RESEARCH ON CANCER (IARC). B[A]P IS A WELL-STUDIED PRO-CARCINOGEN THAT IS METABOLICALLY ACTIVATED BY THE ARYL HYDROCARBON RECEPTOR (AHR)/CYTOCHROME P450 PATHWAY. CYTOCHROME P450 PLAYS A PIVOTAL ROLE IN THE STIMULATION STEP, WHICH IS ESSENTIAL FOR DNA ADDUCT FORMATION. ACCRUING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS ASSUME A FUNDAMENTAL PART IN PAH-PROMOTED CARCINOGENESIS. THIS INTERACTION BETWEEN PAHS AND EPIGENETIC FACTORS RESULTS IN AN ALTERED PROFILE OF THESE MARKS, GLOBALLY AND LOCUS-SPECIFIC. SOME OF THE EPIGENETIC CHANGES DUE TO EXPOSURE TO PAHS LEAD TO INCREASED DISEASE SUSCEPTIBILITY AND PROGRESSION. IT IS WELL UNDERSTOOD THAT EXPOSURE TO ENVIRONMENTAL CARCINOGENS, SUCH AS PAH TRIGGERS DISEASE PATHWAYS THROUGH CHANGES IN THE GENOME. SEVERAL EVIDENCE REPORTED DUE TO THE EPIGENOME-WIDE ASSOCIATION STUDIES, THAT EARLY LIFE ADVERSE ENVIRONMENTAL EVENTS MAY TRIGGER WIDESPREAD AND PERSISTENT VARIATIONS IN TRANSCRIPTIONAL PROFILING. MOREOVER, THESE VARIATIONS RESPOND TO DNA DAMAGE AND/OR A CONSEQUENCE OF EPIGENETIC MODIFICATIONS THAT NEED FURTHER INVESTIGATION. GROWING EVIDENCE HAS ASSOCIATED PAHS WITH EPIGENETIC VARIATIONS INVOLVING ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION, AND MICRO RNA (MIRNA) REGULATION. EPIGENETIC ALTERATIONS TO PAH EXPOSURE WERE RELATED TO CHRONIC DISEASES, SUCH AS PULMONARY DISEASE, CARDIOVASCULAR DISEASE, ENDOCRINE DISRUPTOR, NERVOUS SYSTEM DISORDER, AND CANCER. THIS HORMETIC RESPONSE GIVES A NOVEL PERCEPTION CONCERNING THE TOXICITY OF PAHS AND THE BIOLOGICAL REACTION THAT MAY BE A DISTINCT RELIANCE ON EXPOSURE. THIS REVIEW SHEDS LIGHT ON UNDERSTANDING THE LATEST EVIDENCE ABOUT HOW PAHS CAN ALTER EPIGENETIC PATTERNS AND HUMAN HEALTH. IN CONCLUSION, AS SEVERAL EPIGENETIC CHANGE MECHANISMS REMAIN UNCLEAR YET, FURTHER ANALYSES DERIVED FROM PAHS EXPOSURE MUST BE PERFORMED TO FIND NEW TARGETS AND DISEASE BIOMARKERS. IN SPITE OF THE CURRENT LIMITATIONS, NUMEROUS EVIDENCE SUPPORTS THE PERCEPTION THAT EPIGENETICS GRIPS SUBSTANTIAL POTENTIAL FOR ADVANCING OUR KNOWLEDGE ABOUT THE MOLECULAR MECHANISMS OF ENVIRONMENTAL TOXICANTS, ALSO FOR PREDICTING HEALTH-ASSOCIATED RISKS DUE TO ENVIRONMENTAL CIRCUMSTANCES EXPOSURE AND INDIVIDUAL SUSCEPTIBILITY.	2022	

8  1916  34 ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO CHEMICALS AND TELOMERE LENGTH IN HUMAN STUDIES. TELOMERES ARE COMPLEXES OF TANDEM REPEATS OF DNA (5'-TTAGGG-3') AND PROTEIN THAT CAP EUKARYOTIC CHROMOSOMES AND PLAY A CRITICAL ROLE IN CHROMOSOME STABILITY. TELOMERES SHORTEN WITH AGING AND THIS PROCESS CAN BE ACCELERATED BY INCREASED OXIDATIVE STRESS AND EPISODES OF INFLAMMATION. EVIDENCE IS RAPIDLY GROWING THAT TELOMERE LENGTH (TL) MAY BE AFFECTED BY ENVIRONMENTAL CHEMICALS THAT HAVE FREQUENTLY BEEN ASSOCIATED WITH CHRONIC DISEASES. IN THIS ARTICLE, WE REVIEW THE PUBLISHED DATA ON TL IN RELATION TO ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO SEVERAL CHEMICALS BASED ON OUR OWN AND OTHERS' STUDIES. THE ENVIRONMENTAL AND OCCUPATIONAL EXPOSURES ASSOCIATED WITH SHORTER TL INCLUDE TRAFFIC-RELATED AIR POLLUTION (IE, PARTICULATE MATTER (PM), BLACK CARBON (BC), AND BENZENE AND TOLUENE), POLYCYCLIC AROMATIC HYDROCARBONS (PAHS), N-NITROSAMINES, PESTICIDES, LEAD, EXPOSURE IN CAR MECHANICAL WORKSHOPS, AND HAZARDOUS WASTE EXPOSURE. ARSENIC, PERSISTENT ORGANIC POLLUTANTS (POPS) AND SHORT-TERM EXPOSURE TO PM ARE ASSOCIATED WITH LONGER TL. WE DISCUSS THE POSSIBLE REASONS FOR THE DIFFERENCES IN RESULTS, INCLUDING TIME- AND DOSE-RELATED ISSUES, STUDY DESIGN, AND POSSIBLE MECHANISMS INVOLVED IN TELOMERE REGULATION. WE ALSO DISCUSS THE FUTURE DIRECTIONS AND CHALLENGES FOR TL-RELATED ENVIRONMENTAL AND OCCUPATIONAL HEALTH RESEARCH, SUCH AS INVESTIGATION OF TL IN SUBPOPULATIONS OF BLOOD LEUKOCYTES, AND THE STUDY OF GENETIC AND EPIGENETIC FACTORS THAT MAY REGULATE TELOMERE INTEGRITY USING LONGITUDINAL DESIGNS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9   974  42 CHRONIC OCCUPATIONAL EXPOSURE ENDURED BY TOBACCO FARMERS FROM BRAZIL AND ASSOCIATION WITH DNA DAMAGE. TOBACCO FARMING IS AN IMPORTANT ECONOMIC INCOME IN BRAZIL, ALTHOUGH IT HAS BEEN CHALLENGED AS REGARD THE OCCUPATIONAL EXPOSURE TO BOTH PESTICIDES AND NICOTINE ENDURED BY FARMERS. CHRONIC OCCUPATIONAL EXPOSURE TO COMPLEX MIXTURES CAN LEAD TO HEALTH HAZARDOUS. WE EXAMINED GENOMIC INSTABILITY AND EPIGENETIC CHANGES IN TOBACCO FARMERS OCCUPATIONALLY EXPOSED TO PESTICIDE MIXTURES AND NICOTINE AT TOBACCO FIELDS. DNA DAMAGE WAS ASSESSED BY ALKALINE COMET ASSAY IN BLOOD CELLS. GENOMIC DNA WAS ISOLATED, AND TELOMERE LENGTH WAS MEASURED USING QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY. WE MEASURED 5-METHYL-2'-DEOXYCYTIDINE, A MARKER OF GLOBAL DNA METHYLATION, AND P16 PROMOTER METHYLATION. THE OXIDATIVE PROFILE WAS EVALUATED BY TROLOX EQUIVALENT ANTIOXIDANT CAPACITY AND LIPID PEROXIDATION (THIOBARBITURIC ACID REACTIVE SUBSTANCES) IN SERUM. EXPOSURE PARAMETERS, PLASMA COTININE AND INORGANIC ELEMENT LEVELS, WERE ALSO MEASURED. DNA DAMAGE WAS SIGNIFICANTLY ELEVATED FOR FARMERS IN RELATION TO UNEXPOSED GROUP (P < 0.001; MANN-WHITNEY TEST) AND POSITIVELY ASSOCIATED WITH YEARS OF EXPOSURE. INVERSE RELATIONSHIP BETWEEN DNA DAMAGE AND TOTAL EQUIVALENT ANTIOXIDANT ACTIVITY WAS DEMONSTRATED FOR EXPOSED AND UNEXPOSED GROUPS. EXPOSED GROUP SHOWED SIGNIFICANTLY SHORTER TELOMERES (P < 0.001; UNPAIRED T-TEST) AND DNA HYPOMETHYLATION (P < 0.001; UNPAIRED T-TEST), AS WELL AS P16 HYPERMETHYLATION (P = 0.003; MANN-WHITNEY TEST). LIPID PEROXIDATION WAS INCREASED FOR EXPOSED GROUP IN RELATION TO UNEXPOSED ONE (P = 0.02; MANN-WHITNEY TEST) AND PRESENTED A POSITIVE CORRELATION WITH GLOBAL DNA METHYLATION (P = 0.0264). FARMERS HAVE INCREASED PLASMA COTININE LEVELS (P < 0.001) AND INORGANIC ELEMENTS (PHOSPHORUS, SULPHUR AND CHLORINE) IN RELATION TO UNEXPOSED GROUP. ELEVATED OXIDATIVE STRESS LEVELS DUE TO CHRONIC OCCUPATIONAL PESTICIDE MIXTURES AND NICOTINE EXPOSURE IN TOBACCO FARMERS WERE ASSOCIATED WITH HIGHER DNA DAMAGE, SHORTER TELOMERES AND ALTERED DNA METHYLATION. TELOMERE-ACCELERATED ATTRITION DUE TO EXPOSURE MAY BE POTENTIAL INTERMEDIATE STEP BEFORE A DISEASE STATE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10   298  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11  6903  17 [THE NEED OF PRENATAL PUBLIC HEALTH INITIATIVES IN POLAND]. THE AUTHOR EMPHASIZES THE ACHIEVEMENTS OF THE POLISH GYNECOLOGICAL SOCIETY IN THE FIELD OF IMPROVING THE HEALTH INDICATORS CONCERNING PERINATAL MORTALITY AMONG INFANTS DURING THE LAST TWO DECADES IN POLAND. ATTENTION IS PAID TO THE CONTRIBUTION OF THE MEMBERS OF THE SOCIETY TO ORGANIZATIONAL CHANGE IN POLISH HEALTH CARE AFTER 1990, WHICH RESULTED IN THE IMPROVEMENT OF THE CARE OF MOTHER AND CHILD. IT IS ALSO UNDERLINED THAT THE MEMBERS OF THE SOCIETY CONTRIBUTED TO THE CREATION OF EARLY DETECTION SYSTEM OF BREAST AND CERVICAL CANCER IN POLAND. HOWEVER IT IS NOTEWORTHY THAT IN 'POLISH GYNECOLOGY' - THE PUBLICATION OF THE POLISH GYNECOLOGICAL SOCIETY - THE NUMBER OF REPORTS DEVOTED TO RISKY HEALTH BEHAVIORS OF WOMEN DURING PERICONCEPTIONAL PERIOD AND PREGNANCY IS SCARCE. THE AUTHOR DRAWS ATTENTION TO THE PERCENTAGE OF WOMEN WHO SMOKE CIGARETTES AND CONSUME ALCOHOL BEFORE AND DURING PREGNANCY EMPHASIS IS ALSO PLACED ON THE PROBLEM OF NUTRITIONAL DISORDERS (MAINLY PATHOLOGICAL METHODS OF DIETING) AMONG POLISH WOMEN DURING THE REPRODUCTIVE PERIOD AND IN THE FIRST WEEKS OF PREGNANCY (BEFORE THE PREGNANCY IS CONFIRMED). THESE ASPECTS MAY RESULT IN EPIGENETIC CHANGES SHAPING THE PHENOTYPE OF THE OFFSPRING. THE AUTHOR REFERS TO THE BARKER'S THEORY OF DEVELOPMENTAL ORIGINS OF ADULT DISEASES AND WARNS THAT THE ABOVE-MENTIONED HEALTH BEHAVIORS OF WOMEN MAY BRING ABOUT NEGATIVE EFFECTS FOR THE OFFSPRING AND FUTURE GENERATIONS, NAMELY SUSCEPTIBILITY TO CHRONIC DISEASES: ARTERIAL HYPERTENSION, OBESITY TYPE 2 DIABETES AND METABOLIC SYNDROME. NEGATIVE EFFECTS FOR THE HEALTH OF OFFSPRING MAY ALSO RESULT FROM LOW LEVEL OF PHYSICAL ACTIVITY OF WOMEN BEFORE AND DURING PREGNANCY THE AUTHOR CONCLUDES THAT IT IS NECESSARY TO INTENSIFY THE EFFORTS OF THE POLISH GYNECOLOGICAL SOCIETY IN THE AREA OF PRENATAL PUBLIC HEALTH.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  2961  33 GENETIC AND EPIGENETIC MECHANISMS IN METAL CARCINOGENESIS AND COCARCINOGENESIS: NICKEL, ARSENIC, AND CHROMIUM. CHRONIC EXPOSURE TO NICKEL(II), CHROMIUM(VI), OR INORGANIC ARSENIC (IAS) HAS LONG BEEN KNOWN TO INCREASE CANCER INCIDENCE AMONG AFFECTED INDIVIDUALS. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND THAT CARCINOGENIC RISKS ASSOCIATED WITH CHROMATE AND IAS EXPOSURES WERE SUBSTANTIALLY HIGHER THAN PREVIOUSLY THOUGHT, WHICH LED TO MAJOR REVISIONS OF THE FEDERAL STANDARDS REGULATING AMBIENT AND DRINKING WATER LEVELS. GENOTOXIC EFFECTS OF CR(VI) AND IAS ARE STRONGLY INFLUENCED BY THEIR INTRACELLULAR METABOLISM, WHICH CREATES SEVERAL REACTIVE INTERMEDIATES AND BYPRODUCTS. TOXIC METALS ARE CAPABLE OF POTENT AND SURPRISINGLY SELECTIVE ACTIVATION OF STRESS-SIGNALING PATHWAYS, WHICH ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF HUMAN CANCERS. DEPENDING ON THE METAL, ASCORBATE (VITAMIN C) HAS BEEN FOUND TO ACT EITHER AS A STRONG ENHANCER OR SUPPRESSOR OF TOXIC RESPONSES IN HUMAN CELLS. IN ADDITION TO GENETIC DAMAGE VIA BOTH OXIDATIVE AND NONOXIDATIVE (DNA ADDUCTS) MECHANISMS, METALS CAN ALSO CAUSE SIGNIFICANT CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS, LEADING TO EPIGENETIC SILENCING OR REACTIVATION OF GENE EXPRESSION. IN VITRO GENOTOXICITY EXPERIMENTS AND RECENT ANIMAL CARCINOGENICITY STUDIES PROVIDED STRONG SUPPORT FOR THE IDEA THAT METALS CAN ACT AS COCARCINOGENS IN COMBINATION WITH NONMETAL CARCINOGENS. COCARCINOGENIC AND COMUTAGENIC EFFECTS OF METALS ARE LIKELY TO STEM FROM THEIR ABILITY TO INTERFERE WITH DNA REPAIR PROCESSES. OVERALL, METAL CARCINOGENESIS APPEARS TO REQUIRE THE FORMATION OF SPECIFIC METAL COMPLEXES, CHROMOSOMAL DAMAGE, AND ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS PROMOTING SURVIVAL AND EXPANSION OF GENETICALLY/EPIGENETICALLY ALTERED CELLS.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  5960  41 TELOMERE LENGTH IN HEPATOCELLULAR CARCINOMA AND PAIRED ADJACENT NON-TUMOR TISSUES BY QUANTITATIVE PCR. TELOMERE SHORTENING LIMITS THE PROLIFERATIVE CAPACITY OF HUMAN CELLS, RESTRAINS THE REGENERATIVE CAPACITY OF ORGAN SYSTEMS DURING CHRONIC DISEASES AND AGING AND ALSO INDUCES CHROMOSOMAL INSTABILITY AS WELL AS INITIATION OF CANCER. PREVIOUS STUDIES DEMONSTRATED THAT TELOMERES ARE OFTEN SIGNIFICANTLY SHORTER IN TUMOR TISSUE, INCLUDING HEPATOCELLULAR CARCINOMA (HCC), COMPARED TO THE SURROUNDING TISSUE, BUT TELOMERE LENGTH IN HCC TISSUES WAS NOT CORRELATED WITH SEVERAL CLINICAL PARAMETERS, SUCH AS AGE, SEX, HBV OR HCV INFECTIONS AND TUMOR SIZE. IN THE PRESENT STUDY, THE TELOMERE LENGTH RATIO OF 36 PAIRED HCC, AND THEIR ADJACENT NON-TUMOR TISSUES WAS MEASURED BY QUANTITATIVE PCR (Q-PCR). THE MEAN TELOMERE LENGTHS (SD) FOR HCC AND ADJACENT NON-TUMOR TISSUES WERE 0.26 (0.10) AND 0.47 (0.20) RESPECTIVELY (T = 6.22, P < 0.0001). THERE WAS A LARGE DIFFERENCE IN THE DISTRIBUTION OF SUBJECTS BASED ON TELOMERE LENGTH IN TUMOR AND ADJACENT NON-TUMOR TISSUES. THE NUMBER OF TUMORS WITH TELOMERE LENGTH SHORTER THAN 0.50 WAS MUCH HIGHER THAN THAT OF ADJACENT NON-TUMOR TISSUES; MORE THAN 90% OF THE TISSUES WITH TELOMERE LENGTH > OR = 0.50 WERE ADJACENT NON-TUMOR TISSUES. THE CORRELATIONS BETWEEN TELOMERE LENGTH AND AFLATOXIN B1- AND POLYCYCLIC AROMATIC HYDROCARBON-DNA ADDUCTS LEVEL, P53 MUTATIONS AND P16 HYPERMETHYLATION STATUS WERE ALSO TESTED, BUT NO SIGNIFICANT ASSOCIATIONS WERE FOUND. THE RELATIONSHIP BETWEEN TELOMERE LENGTH SHORTENING, CHEMICAL CARCINOGEN EXPOSURE, AND GENETIC AND EPIGENETIC CHANGES IN HEPATOCARCINOGENESIS NEEDS FURTHER INVESTIGATION.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14  3063  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15  3109  32 GENOTOXIC AND EPIGENETIC EFFECTS OF DIURON IN THE PACIFIC OYSTER: IN VITRO EVIDENCE OF INTERACTION BETWEEN DNA DAMAGE AND DNA METHYLATION. RECENTLY, RESEARCH HAS CONTRIBUTED TO BETTER KNOWLEDGE ON THE OCCURRENCE OF PESTICIDES IN COASTAL WATER BY IDENTIFYING FREQUENTLY DETECTED SUBSTANCES, THEIR CONCENTRATION RANGE AND THEIR ACUTE AND CHRONIC TOXICITY FOR ORGANISMS. PESTICIDE POLLUTION IS OF PARTICULAR CONCERN IN FRANCE DUE TO IMPORTANT AGRICULTURAL ACTIVITIES AND PRESENCE OF SEVERAL EXOREIC CATCHMENT AREAS THAT VEHICLE PESTICIDES UP TO COASTAL WATERS, IMPACTING NON-TARGET MARINE SPECIES. SEVERAL ECOTOXICOLOGY QUESTIONS REMAIN TO BE ADDRESSED CONCERNING THE LONG-TERM EFFECTS OF CHRONIC PESTICIDE EXPOSURE AND THE MECHANISMS INVOLVED IN ADAPTATION TO CHEMICAL STRESS. IN THE PRESENT STUDY, WE BROUGHT NEW INSIGHTS ON THE GENETIC AND EPIGENETIC EFFECTS OF THE HERBICIDE DIURON IN OYSTER GENITORS. DURING GAMETOGENESIS, WE EXPOSED CRASSOSTREA GIGAS TO ENVIRONMENTALLY REALISTIC HERBICIDE CONCENTRATIONS (0.2-0.3 MUG L(-1) DURING TWO 7-DAY PERIODS AT HALF-COURSE AND END OF GAMETOGENESIS). DIURON EXPOSURE WAS SHOWN TO DECREASE GLOBAL DNA METHYLATION AND TOTAL METHYLTRANSFERASE ACTIVITY IN WHOLE OYSTER TISSUE; THIS IS CONSISTENT WITH THE PREVIOUS OBSERVATION OF A SIGNIFICANT DECREASE IN DNMT1 GENE EXPRESSION. DIURON EFFECT SEEMED TO BE TISSUE-SPECIFIC; HYPERMETHYLATION WAS DETECTED IN THE DIGESTIVE GLAND, WHEREAS DIURON EXPOSURE HAD NO EFFECT ON GILL AND GONAD TISSUE. THE GENOTOXICITY OF DIURON WAS CONFIRMED BY THE DETECTION OF ONE ADDUCT IN GONAD DNA. BY USING IN VITRO APPROACHES AND HUMAN DNMT1 (DNMT1 HAS NOT BEEN PURIFIED YET IN BIVALVES), THE PRESENCE OF DNA LESIONS (ADDUCT, 8-OXODGUO) WAS SHOWN TO INTERFERE WITH DNMT1 ACTIVITY, INDICATING A COMPLEX INTERACTION BETWEEN DNA DAMAGE AND DNA METHYLATION. BASED ON OUR RESULTS, WE PROPOSE MECHANISMS TO EXPLAIN THE EFFECT OF DIURON EXPOSURE ON DNA METHYLATION, A WIDESPREAD EPIGENETIC MARK.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16  5187  29 PRENATAL AIRBORNE POLYCYCLIC AROMATIC HYDROCARBON EXPOSURE, ALTERED REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR)GAMMA, AND LINKS WITH MAMMARY CANCER. ENVIRONMENTAL EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS (PAH) HAS BEEN SHOWN TO BE ASSOCIATED WITH CHRONIC DISEASE OUTCOMES THROUGH MULTIPLE MECHANISMS INCLUDING ALTERED REGULATION OF THE TRANSCRIPTION FACTOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR) GAMMA. BECAUSE PAH EXPOSURE AND PPARGAMMA EACH HAVE BEEN ASSOCIATED WITH MAMMARY CANCER, WE ASKED WHETHER PAH WOULD INDUCE ALTERED REGULATION OF PPARGAMMA IN MAMMARY TISSUE, AND WHETHER THIS ASSOCIATION MAY UNDERLIE THE ASSOCIATION BETWEEN PAH AND MAMMARY CANCER. PREGNANT MICE WERE EXPOSED TO AEROSOLIZED PAH AT PROPORTIONS THAT MIMIC EQUIVALENT HUMAN EXPOSURES IN NEW YORK CITY AIR. WE HYPOTHESIZED THAT PRENATAL PAH EXPOSURE WOULD ALTER PPARGAMMA DNA METHYLATION AND GENE EXPRESSION AND INDUCE THE EPITHELIAL TO MESENCHYMAL TRANSITION (EMT) IN MAMMARY TISSUE OF OFFSPRING (F1) AND GRANDOFFSPRING (F2) MICE. WE ALSO HYPOTHESIZED THAT ALTERED REGULATION OF PPARGAMMA IN MAMMARY TISSUE WOULD ASSOCIATE WITH BIOMARKERS OF EMT, AND EXAMINED ASSOCIATIONS WITH WHOLE BODY WEIGHT. WE FOUND THAT PRENATAL PAH EXPOSURE LOWERED PPARGAMMA MAMMARY TISSUE METHYLATION AMONG GRANDOFFSPRING MICE AT POSTNATAL DAY (PND) 28. HOWEVER, PAH EXPOSURE DID NOT ASSOCIATE WITH ALTERED PPARGAMMA GENE EXPRESSION OR CONSISTENTLY WITH BIOMARKERS OF EMT. FINALLY, LOWER PPARGAMMA METHYLATION, BUT NOT GENE EXPRESSION, WAS ASSOCIATED WITH HIGHER BODY WEIGHT AMONG OFFSPRING AND GRANDOFFSPRING MICE AT PND28 AND PND60. FINDINGS SUGGEST ADDITIONAL EVIDENCE OF MULTI-GENERATIONAL ADVERSE EPIGENETIC EFFECTS OF PRENATAL PAH EXPOSURE AMONG GRANDOFFSPRING MICE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17   935  37 CHRONIC LOW-DOSE EXPOSURE TO XENOESTROGEN AMBIENT AIR POLLUTANTS AND BREAST CANCER RISK: XENAIR PROTOCOL FOR A CASE-CONTROL STUDY NESTED WITHIN THE FRENCH E3N COHORT. BACKGROUND: BREAST CANCER IS THE MOST FREQUENT CANCER IN WOMEN IN INDUSTRIALIZED COUNTRIES. LIFESTYLE AND ENVIRONMENTAL FACTORS, PARTICULARLY ENDOCRINE-DISRUPTING POLLUTANTS, HAVE BEEN SUGGESTED TO PLAY A ROLE IN BREAST CANCER RISK. CURRENT EPIDEMIOLOGICAL STUDIES, ALTHOUGH NOT FULLY CONSISTENT, SUGGEST A POSITIVE ASSOCIATION OF BREAST CANCER RISK WITH EXPOSURE TO SEVERAL INTERNATIONAL AGENCY FOR RESEARCH ON CANCER GROUP 1 AIR-POLLUTANT CARCINOGENS, SUCH AS PARTICULATE MATTER, POLYCHLORINATED BIPHENYLS (PCB), DIOXINS, BENZO[A]PYRENE (BAP), AND CADMIUM. HOWEVER, EPIDEMIOLOGICAL STUDIES REMAIN SCARCE AND INCONSISTENT. IT HAS BEEN PROPOSED THAT THE MENOPAUSAL STATUS COULD MODIFY THE RELATIONSHIP BETWEEN POLLUTANTS AND BREAST CANCER AND THAT THE ASSOCIATION VARIES WITH HORMONE RECEPTOR STATUS. OBJECTIVE: THE XENAIR PROJECT WILL INVESTIGATE THE ASSOCIATION OF BREAST CANCER RISK (OVERALL AND BY HORMONE RECEPTOR STATUS) WITH CHRONIC EXPOSURE TO SELECTED AIR POLLUTANTS, INCLUDING PARTICULATE MATTER, NITROGEN DIOXIDE (NO2), OZONE (O3), BAP, DIOXINS, PCB-153, AND CADMIUM. METHODS: OUR RESEARCH IS BASED ON A CASE-CONTROL STUDY NESTED WITHIN THE FRENCH NATIONAL E3N COHORT OF 5222 INVASIVE BREAST CANCER CASES IDENTIFIED DURING FOLLOW-UP FROM 1990 TO 2011, AND 5222 MATCHED CONTROLS. A QUESTIONNAIRE WAS SENT TO ALL PARTICIPANTS TO COLLECT THEIR LIFETIME RESIDENTIAL ADDRESSES AND INFORMATION ON INDOOR POLLUTION. WE WILL ASSESS THESE EXPOSURES USING COMPLEMENTARY MODELS OF LAND-USE REGRESSION, ATMOSPHERIC DISPERSION, AND REGIONAL CHEMISTRY-TRANSPORT (CHIMERE) MODELS, VIA A GEOGRAPHIC INFORMATION SYSTEM. ASSOCIATIONS WITH BREAST CANCER RISK WILL BE MODELED USING CONDITIONAL LOGISTIC REGRESSION MODELS. WE WILL ALSO STUDY THE IMPACT OF EXPOSURE ON DNA METHYLATION AND INTERACTIONS WITH GENETIC POLYMORPHISMS. APPROPRIATE STATISTICAL METHODS, INCLUDING BAYESIAN MODELING, PRINCIPAL COMPONENT ANALYSIS, AND CLUSTER ANALYSIS, WILL BE USED TO ASSESS THE IMPACT OF MULTIPOLLUTANT EXPOSURE. THE FRACTION OF BREAST CANCER CASES ATTRIBUTABLE TO AIR POLLUTION WILL BE ESTIMATED. RESULTS: THE XENAIR PROJECT WILL CONTRIBUTE TO CURRENT KNOWLEDGE ON THE HEALTH EFFECTS OF AIR POLLUTION AND IDENTIFY AND UNDERSTAND ENVIRONMENTAL MODIFIABLE RISK FACTORS RELATED TO BREAST CANCER RISK. CONCLUSIONS: THE RESULTS WILL PROVIDE RELEVANT EVIDENCE TO GOVERNMENTS AND POLICY-MAKERS TO IMPROVE EFFECTIVE PUBLIC HEALTH PREVENTION STRATEGIES ON AIR POLLUTION. THE XENAIR DATASET CAN BE USED IN FUTURE EFFORTS TO STUDY THE EFFECTS OF EXPOSURE TO AIR POLLUTION ASSOCIATED WITH OTHER CHRONIC CONDITIONS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15167.	2020	
                                                                                                                                                                                                           
18   299  30 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  1140  29 CONCENTRATION OF FOLIC ACID (FA) IN SERUM OF JAPANESE PREGNANT WOMEN. OBJECTIVES EXPOSURE TO INORGANIC ARSENIC (IAS) IS A WORLD-WIDE HEALTH CONCERN. WE REPORTED THAT JAPANESE CHILDREN AND PREGNANT WOMEN ARE EXPOSED TO MODERATE LEVELS OF IAS THROUGH FOOD. REDUCING IAS CONTAMINATION FROM FOODS OF HIGH IAS IS AN IMPORTANT ISSUE UNIQUE IN JAPAN. INTEGRATED IAS IS METHYLATED TO LESS TOXIC ORGANIC FORMS, AND S-ADENOSYL-L-METHYONINE (SAM), A COMMON METHYL-DONOR OF DNA AND HISTONES, IS UTILIZED IN THIS PROCESS. CHRONIC CONSUMPTION OF SAM BY IAS METABOLISM DUE TO EXPOSURE TO IAS MIGHT ALTER THE EPIGENETIC MODIFICATION OF GENOME. THE SAM BIOSYNTHESIS PATHWAY IS DEPENDENT ON FOLATE CYCLE, AND IT IS POSSIBLE THAT INGESTION OF SUFFICIENT FOLIC ACID (FA) IS PROTECTIVE TO IAS INDUCED TOXICITY. METHODS IN THE COURSE OF OUR CROSS-SECTIONAL BODY BURDEN ANALYSES OF PB AND IAS IN JAPANESE CHILDREN AND PREGNANT WOMEN, TERMED "PBAS STUDY", FA CONCENTRATION IN SERUM OF 104 PREGNANT WOMEN WAS MEASURED. RESULTS MEAN (+/-SEM) OF SERUM FA CONCENTRATION WAS 15.8 +/- 1.3 (NG/ML). THERE ARE SIGNIFICANT NUMBER OF PEOPLE SHOWING VERY HIGH FA (>30 NG/ ML), AND LARGE FRACTION OF THEM WERE TAKING SUPPLEMENTS DAILY. CONCLUSIONS THESE RESULTS SUGGESTED THAT LEVEL OF FA INGESTION OF JAPANESE PREGNANT WOMEN IS HIGH FOR SUPPORTING NORMAL FETAL DEVELOPMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  5957  28 TELOMERE LENGTH AND EPIGENETIC AGE ACCELERATION IN ADOLESCENTS WITH ANXIETY DISORDERS. EVIDENCE ON THE RELATIONSHIP BETWEEN GENETICS AND MENTAL HEALTH ARE FLOURISHING. HOWEVER, FEW STUDIES ARE EVALUATING EARLY BIOMARKERS THAT MIGHT LINK GENES, ENVIRONMENT, AND PSYCHOPATHOLOGY. WE AIMED TO STUDY TELOMERE LENGTH (TL) AND EPIGENETIC AGE ACCELERATION (AA) IN A COHORT OF ADOLESCENTS WITH AND WITHOUT ANXIETY DISORDERS (N = 234). WE EVALUATED A REPRESENTATIVE SUBSAMPLE OF PARTICIPANTS AT BASELINE AND AFTER 5 YEARS (N = 76) AND CATEGORIZED THEM ACCORDING TO THEIR ANXIETY DISORDER DIAGNOSIS AT BOTH TIME POINTS: (1) CONTROL GROUP (NO ANXIETY DISORDER, N = 18), (2) VARIABLE GROUP (ANXIETY DISORDER IN ONE EVALUATION, N = 38), AND (3) PERSISTENT GROUP (ANXIETY DISORDER AT BOTH TIME POINTS, N = 20). WE ASSESSED RELATIVE MEAN TL BY REAL-TIME QUANTITATIVE PCR AND DNA METHYLATION BY INFINIUM HUMANMETHYLATION450 BEADCHIP. WE CALCULATED AA USING THE HORVATH AGE ESTIMATION ALGORITHM AND ANALYZED DIFFERENCES AMONG GROUPS USING GENERALIZED LINEAR MIXED MODELS. THE PERSISTENT GROUP OF ANXIETY DISORDER DID NOT CHANGE TL OVER TIME (P = 0.495). THE VARIABLE GROUP HAD HIGHER BASELINE TL (P = 0.003) BUT NO ACCELERATED TL EROSION IN COMPARISON TO THE NON-ANXIETY CONTROL GROUP (P = 0.053). FURTHERMORE, THERE WERE NO DIFFERENCES IN AA AMONG GROUPS OVER TIME. OUR FINDINGS SUGGEST THAT ADOLESCENTS WITH CHRONIC ANXIETY DID NOT CHANGE TELOMERE LENGTH OVER TIME, WHICH COULD BE RELATED TO A DELAY IN NEURONAL DEVELOPMENT IN THIS PERIOD OF LIFE.	2021