1 1885 149 ENDOCRINE DISRUPTORS IN SOIL: EFFECTS OF BISPHENOL A ON GENE EXPRESSION OF THE EARTHWORM EISENIA FETIDA. XENOBIOTICS SUCH AS BISPHENOL A (BPA), ARE PRESENT IN BIOSOLIDS, WHICH ARE APPLIED AS ORGANIC FERTILIZERS IN AGRICULTURAL FIELDS. THEIR EFFECTS ON SOIL LIFE HAVE BEEN POORLY ASSESSED, AND THIS IS PARTICULARLY IMPORTANT IN THE CASE OF EARTHWORMS, WHICH REPRESENT THE MAIN ANIMAL BIOMASS IN THIS MEDIUM. IN THE PRESENT WORK WE STUDY THE IMPACTS OF BPA ON GENE EXPRESSION OF EISENIA FETIDA, A WIDELY USED ECOTOXICOLOGICAL MODEL. CHRONIC SOIL TESTS AND ACUTE CONTACT TESTS WERE PERFORMED, AND GENE EXPRESSION WAS ANALYZED IN TOTAL TISSUE AND IN MASCULINE REPRODUCTIVE ORGANS OF THE EARTHWORMS. THE GENES STUDIED IN THIS RESEARCH PLAYED A ROLE IN ENDOCRINE PATHWAYS, DETOXIFICATION MECHANISMS, STRESS RESPONSE, EPIGENETICS, AND GENOTOXICITY. MOST OF THE GENES WERE IDENTIFIED FOR THE FIRST TIME, PROVIDING POTENTIALLY USEFUL BIOMARKERS FOR FUTURE ASSESSMENTS. FOR CHRONIC EXPOSURES, NO CHANGES WERE DETECTED IN WHOLE-BODY TISSUE; HOWEVER, MASCULINE REPRODUCTIVE ORGANS SHOWED CHANGES IN THE EXPRESSION OF GENES RELATED TO ENDOCRINE FUNCTION (ECR, MAPR, ADIPOR), EPIGENETIC MECHANISMS (DNMTS), GENOTOXICITY (PARP1), AND STRESS RESPONSES (HSC70 4). FOR ACUTE EXPOSURES, THE EXPRESSION OF ONE EPIGENETIC-RELATED GENE WAS ALTERED FOR BOTH WHOLE-BODY TISSUES AND MALE REPRODUCTIVE ORGANS (PIWI2). FURTHER CHANGES WERE DETECTED FOR WHOLE-BODY TISSUES INVOLVED IN DETOXIFICATION (METALLOTHIONEIN), STRESS (HSC70 4), AND GENOTOXICITY (PARP1) MECHANISMS. ACUTE EXPOSURE EFFECTS WERE ALSO TESTED IN WHOLE-BODY TISSUES OF JUVENILES, SHOWING CHANGES IN THE EXPRESSION OF METALLOTHIONEIN AND PIWI2. THE MOLECULAR CHANGES FOUND IN THE ANALYZED EARTHWORMS INDICATE THAT EXPOSURE TO BPA MAY HAVE NEGATIVE IMPLICATIONS IN THEIR POPULATIONS. PARTICULARLY INTERESTING ARE THE ALTERATIONS RELATED TO EPIGENETIC MECHANISMS, WHICH SUGGEST THAT FUTURE GENERATIONS MAY BE IMPACTED. THIS STUDY IS THE FIRST TO EVALUATE THE MOLECULAR EFFECTS OF BPA ON SOIL ORGANISMS, AND FURTHER ASSAYS WILL BE NECESSARY TO BETTER CHARACTERIZE THE TRUE ENVIRONMENTAL REPERCUSSIONS. CAPSULE: LEVELS OF GENE EXPRESSION IN TOTAL-BODY TISSUES AND MASCULINE REPRODUCTIVE ORGANS WERE ANALYZED IN EARTHWORMS AFTER EXPOSURE TO BISPHENOL A AND WE OBSERVED ASSOCIATED CHANGES IN DETOXIFICATION, ENDOCRINE, EPIGENETIC, GENOTOXIC AND STRESS PATHWAYS. 2018 2 4528 29 MULTIGENERATIONAL EFFECTS OF CADMIUM ON THE LIFESPAN AND FERTILITY OF DROSOPHILA MELANOGASTER. ALTHOUGH THE DAMAGE AND TOLERANCE MECHANISMS OF CD STRESS ARE KNOWN, THE DATA ON GENETIC RISK ARE LIMITED. THE AIM OF THIS STUDY WAS TO ASSESS THE CHRONIC TOXICITY OF CD, GENETIC RESPONSES, AND MULTIGENERATIONAL EFFECTS IN FIVE GENERATIONS OF DROSOPHILA MELANOGASTER. FOR EACH GENERATION, LIFESPAN AND FERTILITY WERE STATISTICALLY ANALYSED AND THE EXPRESSION OF APOPTOSIS- (P53 AND CASPASE-3) AND EPIGENESIS-RELATED (DDNMT2 AND DMBD2/3) GENES WAS EXAMINED. LIFESPAN AND FERTILITY SIGNIFICANTLY DECLINED UNDER CD STRESS AND THESE EFFECTS WERE MAINTAINED FOR TWO GENERATIONS AND ONE GENERATION, RESPECTIVELY, WHEN CD STRESS WAS REMOVED. THE EXPRESSION OF P53 AND CASPASE-3 WAS SIGNIFICANTLY UP-REGULATED AFTER EXPOSURE, SUGGESTING THAT APOPTOSIS CONTRIBUTES TO THE RESISTANCE MECHANISM. THEIR ALTERED EXPRESSION WAS RETAINED FOR TWO GENERATIONS. FURTHERMORE, HIGH EXPRESSION OF DDNMT2 AND DMBD2/3 ACCOMPANIED CD EXPOSURE, WHICH WAS PASSED ON TO THREE GENERATIONS, SUGGESTING THAT GENETIC MODIFICATIONS IN APOPTOSIS-RELATED GENES ARE CARRIED TO THE OFFSPRING THROUGH EPIGENETIC REGULATION. 2020 3 4736 39 NOVEL EPIGENETIC BIOMARKERS MEDIATING BISPHENOL A EXPOSURE AND METABOLIC PHENOTYPES IN FEMALE MICE. THERE IS COMPELLING EVIDENCE THAT EPIGENETIC MODIFICATIONS LINK DEVELOPMENTAL ENVIRONMENTAL INSULTS TO ADULT DISEASE SUSCEPTIBILITY. ANIMAL STUDIES HAVE ASSOCIATED PERINATAL BISPHENOL A (BPA) EXPOSURE TO ALTERED DNA METHYLATION, BUT THESE STUDIES ARE OFTEN LIMITED TO CANDIDATE GENE AND GLOBAL NON-LOCI-SPECIFIC APPROACHES. BY USING AN EPIGENOME-WIDE DISCOVERY PLATFORM, WE ELUCIDATED EPIGENETIC ALTERATIONS IN LIVER TISSUE FROM ADULT MICE OFFSPRING (10 MONTHS) FOLLOWING PERINATAL BPA EXPOSURE AT HUMAN PHYSIOLOGICALLY RELEVANT DOSES (50-NG, 50-MUG, AND 50-MG BPA/KG DIET). BIOLOGICAL PATHWAY ANALYSIS IDENTIFIED AN ENRICHMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS IN METABOLIC PATHWAYS AMONG FEMALES. FURTHERMORE, THROUGH THE USE OF TOP ENRICHED BIOLOGICAL PATHWAYS, 4 CANDIDATE GENES WERE CHOSEN TO ASSESS DNA METHYLATION AS A MEDIATING FACTOR LINKING THE ASSOCIATION OF PERINATAL BPA EXPOSURE TO METABOLIC PHENOTYPES PREVIOUSLY OBSERVED IN FEMALE OFFSPRING. DNA METHYLATION STATUS AT JANUS KINASE-2 (JAK-2), RETINOID X RECEPTOR (RXR), REGULATORY FACTOR X-ASSOCIATED PROTEIN (RFXAP), AND TRANSMEMBRANE PROTEIN 238 (TMEM238) WAS USED WITHIN A MEDIATIONAL REGRESSION ANALYSIS. DNA METHYLATION IN ALL FOUR OF THE CANDIDATE GENES WAS IDENTIFIED AS A MEDIATOR IN THE MECHANISTIC PATHWAY OF DEVELOPMENTAL BPA EXPOSURE AND FEMALE-SPECIFIC ENERGY EXPENDITURE, BODY WEIGHT, AND BODY FAT PHENOTYPES. DATA GENERATED FROM THIS STUDY ARE CRUCIAL FOR DECIPHERING THE MECHANISTIC ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC DISEASE AND THE DEVELOPMENT OF EPIGENETIC-BASED PREVENTION AND THERAPEUTIC STRATEGIES FOR COMPLEX HUMAN DISEASE. 2017 4 1162 44 CONTRASTING EFFECTS OF ACUTE AND CHRONIC STRESS ON THE TRANSCRIPTOME, EPIGENOME, AND IMMUNE RESPONSE OF ATLANTIC SALMON. STRESS EXPERIENCED DURING EARLY LIFE MAY HAVE LASTING EFFECTS ON THE IMMUNE SYSTEM, WITH IMPACTS ON HEALTH AND DISEASE DEPENDENT ON THE NATURE AND DURATION OF THE STRESSOR. THE EPIGENOME IS ESPECIALLY SENSITIVE TO ENVIRONMENTAL STIMULI DURING EARLY LIFE AND REPRESENTS A POTENTIAL MECHANISM THROUGH WHICH STRESS MAY CAUSE LONG-LASTING HEALTH EFFECTS. HOWEVER, THE EXTENT TO WHICH THE EPIGENOME RESPONDS DIFFERENTLY TO CHRONIC VS ACUTE STRESSORS IS UNCLEAR, ESPECIALLY FOR NON-MAMMALIAN SPECIES. WE EXAMINED THE EFFECTS OF ACUTE STRESS (COLD-SHOCK DURING EMBRYOGENESIS) AND CHRONIC STRESS (ABSENCE OF TANK ENRICHMENT DURING LARVAL-STAGE) ON GLOBAL GENE EXPRESSION (USING RNA-SEQ) AND DNA METHYLATION (USING RRBS) IN THE GILLS OF ATLANTIC SALMON (SALMO SALAR) FOUR MONTHS AFTER HATCHING. CHRONIC STRESS INDUCED PRONOUNCED TRANSCRIPTIONAL DIFFERENCES, WHILE ACUTE STRESS CAUSED FEW LASTING TRANSCRIPTIONAL EFFECTS. HOWEVER, BOTH ACUTE AND CHRONIC STRESS CAUSED LASTING AND CONTRASTING CHANGES IN THE METHYLOME. CRUCIALLY, WE FOUND THAT ACUTE STRESS ENHANCED TRANSCRIPTIONAL IMMUNE RESPONSE TO A PATHOGENIC CHALLENGE (BACTERIAL LIPOPOLYSACCHARIDE, LPS), WHILE CHRONIC STRESS SUPPRESSED IT. WE IDENTIFIED STRESS-INDUCED CHANGES IN PROMOTER AND GENE-BODY METHYLATION THAT WERE ASSOCIATED WITH ALTERED EXPRESSION FOR A SMALL PROPORTION OF IMMUNE-RELATED GENES, AND EVIDENCE OF WIDER EPIGENETIC REGULATION WITHIN SIGNALLING PATHWAYS INVOLVED IN IMMUNE RESPONSE. OUR RESULTS SUGGEST THAT STRESS CAN AFFECT IMMUNO-COMPETENCE THROUGH EPIGENETIC MECHANISMS, AND HIGHLIGHT THE MARKEDLY DIFFERENT EFFECTS OF CHRONIC LARVAL AND ACUTE EMBRYONIC STRESS. THIS KNOWLEDGE COULD BE USED TO HARNESS THE STIMULATORY EFFECTS OF ACUTE STRESS ON IMMUNITY, PAVING THE WAY FOR IMPROVED STRESS AND DISEASE MANAGEMENT THROUGH EPIGENETIC CONDITIONING. 2018 5 4009 38 LOW LEVELS OF CD INDUCE PERSISTING EPIGENETIC MODIFICATIONS AND ACCLIMATION MECHANISMS IN THE EARTHWORM LUMBRICUS TERRESTRIS. TOXIC EFFECTS OF CADMIUM (CD), A COMMON SOIL POLLUTANT, ARE STILL NOT VERY WELL UNDERSTOOD, PARTICULARLY IN REGARD TO ITS EPIGENETIC IMPACT. THEREFORE, THE AIM OF THIS STUDY WAS TO ASSESS DNA METHYLATION CHANGES AND THEIR PERSISTENCE IN THE EARTHWORM LUMBRICUS TERRESTRIS UPON CHRONIC LOW DOSE CD EXPOSURE USING METHYLATION SENSITIVE AMPLIFICATION POLYMORPHISM (MSAP). MOREOVER, THE BIOMARKER RESPONSE AND FITNESS OF THE EARTHWORMS, AS WELL AS THE EXPRESSION OF DETOXIFICATION-RELATED GENES (METALLOTHIONEIN (MT) AND PHYTOCHELATIN SYNTHASE (PCS)) WAS EVALUATED. LOW LEVELS OF CD CAUSED AN INCREASE IN GENOME-WIDE DNA METHYLATION, WHICH REMAINED PARTLY MODIFIED, EVEN AFTER SEVERAL MONTHS OF RECOVERY IN UNPOLLUTED SOIL. INCREASED CELLULAR STRESS SEEMED TO DECREASE AFTER TWO WEEKS OF EXPOSURE WHEREAS FITNESS PARAMETERS REMAINED UNAFFECTED BY CD, PROBABLY AS A RESULT FROM THE ACTIVATION OF DETOXIFICATION MECHANISMS LIKE THE EXPRESSION OF MTS. INTERESTINGLY, EVEN THOUGH THE LEVEL OF CD EXPOSURE WAS VERY LOW, MT EXPRESSION LEVELS INDICATE THE DEVELOPMENT OF ACCLIMATION MECHANISMS. TAKEN TOGETHER, THIS STUDY DEMONSTRATES THAT ACCLIMATION, AS WELL AS EPIGENETIC MODIFICATIONS CAN OCCUR ALREADY IN MODERATELY POLLUTED ENVIRONMENTS. IN ADDITION, THESE EFFECTS CAN HAVE LONG-LASTING IMPACTS ON KEY SPECIES OF SOIL INVERTEBRATES AND MIGHT PERSIST LONG AFTER THE ACTUAL HEAVY METAL CHALLENGE HAS PASSED. 2017 6 2776 36 EXTRAUTERINE GROWTH RESTRICTION ON PULMONARY VASCULAR ENDOTHELIAL DYSFUNCTION IN ADULT MALE RATS: THE ROLE OF EPIGENETIC MECHANISMS. OBJECTIVE: EARLY POSTNATAL LIFE IS CONSIDERED AS A CRITICAL TIME WINDOW FOR THE DETERMINATION OF LONG-TERM METABOLIC STATES AND ORGAN FUNCTIONS. EXTRAUTERINE GROWTH RESTRICTION (EUGR) CAUSES THE DEVELOPMENT OF ADULT-ONSET CHRONIC DISEASES, INCLUDING PULMONARY HYPERTENSION. HOWEVER, THE EFFECTS OF NUTRITIONAL DISADVANTAGES DURING THE EARLY POSTNATAL PERIOD ON PULMONARY VASCULAR CONSEQUENCES IN LATER LIFE ARE NOT FULLY UNDERSTOOD. OUR STUDY WAS DESIGNED TO TEST WHETHER EPIGENETICS DYSREGULATION MEDIATES THE CELLULAR MEMORY OF THIS EARLY POSTNATAL EVENT. METHODS AND RESULTS: TO TEST THIS HYPOTHESIS, WE ISOLATED PULMONARY VASCULAR ENDOTHELIAL CELLS BY MAGNETIC-ACTIVATED CELL SORTING FROM EUGR AND CONTROL RATS. A POSTNATAL INSULT, NUTRITIONAL RESTRICTION-INDUCED EUGR CAUSED DEVELOPMENT OF AN INCREASED PULMONARY ARTERY PRESSURE AT 9 WEEKS OF AGE IN MALE SPRAGUE-DAWLEY RATS. METHYL-DNA IMMUNE PRECIPITATION CHIP, GENOME-SCALE MAPPING STUDIES TO SEARCH FOR DIFFERENTIALLY METHYLATED LOCI BETWEEN CONTROL AND EUGR RATS, REVEALED SIGNIFICANT DIFFERENCE IN CYTOSINE METHYLATION BETWEEN EUGR AND CONTROL RATS. EUGR CHANGES THE CYTOSINE METHYLATION AT APPROXIMATELY 500 LOCI IN MALE RATS AT 9 WEEKS OF AGE, PRECEDING THE DEVELOPMENT OF PULMONARY HYPERTENSION AND THESE REPRESENT THE CANDIDATE LOCI FOR MEDIATING THE PATHOGENESIS OF PULMONARY VASCULAR DISEASE THAT OCCURS LATER IN LIFE. GENE ONTOLOGY ANALYSIS ON DIFFERENTIALLY METHYLATED GENES SHOWED THAT HYPERMETHYLATED GENES IN EUGR ARE VASCULAR DEVELOPMENT-ASSOCIATED GENES AND HYPOMETHYLATED GENES IN EUGR ARE LATE-DIFFERENTIATION-ASSOCIATED AND SIGNAL TRANSDUCTION GENES. WE VALIDATED CANDIDATE DYSREGULATED LOCI WITH THE QUANTITATIVE ASSAYS OF CYTOSINE METHYLATION AND GENE EXPRESSIONS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT EPIGENETICS DYSREGULATION IS A STRONG MECHANISM FOR PROPAGATING THE CELLULAR MEMORY OF EARLY POSTNATAL EVENTS, CAUSING CHANGES IN THE EXPRESSION OF GENES AND LONG-TERM SUSCEPTIBILITY TO PULMONARY HYPERTENSION, AND FURTHER PROVIDING A NEW INSIGHT INTO THE PREVENTION AND TREATMENT OF EUGR-RELATED PULMONARY HYPERTENSION. 2014 7 6137 28 THE EPIGENETICS OF PSYCHOSIS: A STRUCTURED REVIEW WITH REPRESENTATIVE LOCI. THE EVIDENCE FOR AN ENVIRONMENTAL COMPONENT IN CHRONIC PSYCHOTIC DISORDERS IS STRONG AND RESEARCH ON THE EPIGENETIC MANIFESTATIONS OF THESE ENVIRONMENTAL IMPACTS HAS COMMENCED IN EARNEST. IN REVIEWING THIS RESEARCH, THE FOCUS IS ON THREE GENES AS MODELS FOR DIFFERENTIAL METHYLATION, MCHR1, AKT1 AND TDO2, EACH OF WHICH HAVE BEEN INVESTIGATED FOR GENETIC ASSOCIATION WITH PSYCHOTIC DISORDERS. ENVIRONMENTAL FACTORS ASSOCIATED WITH PSYCHOTIC DISORDERS, AND WHICH INTERACT WITH THESE MODEL GENES, ARE EXPLORED IN DEPTH. THE LOCATION OF TRANSCRIPTION FACTOR MOTIFS RELATIVE TO KEY METHYLATION SITES IS EVALUATED FOR PREDICTED GENE EXPRESSION RESULTS, AND FOR OTHER SITES, EVIDENCE IS PRESENTED FOR METHYLATION DIRECTING ALTERNATIVE SPLICING. EXPERIMENTAL RESULTS FROM KEY STUDIES SHOW DIFFERENTIAL METHYLATION: FOR MCHR1, IN PSYCHOSIS CASES VERSUS CONTROLS; FOR AKT1, AS A PRE-EXISTING METHYLATION PATTERN INFLUENCING BRAIN ACTIVATION FOLLOWING ACUTE ADMINISTRATION OF A PSYCHOSIS-ELICITING ENVIRONMENTAL STIMULUS; AND FOR TDO2, IN A PATTERN ASSOCIATED WITH A DEVELOPMENTAL FACTOR OF RISK FOR PSYCHOSIS, IN ALL CASES THE PREDICTED EXPRESSION IMPACT BEING HIGHLY DEPENDENT ON LOCATION. METHYLATION INDUCED BY SMOKING, A CONFOUNDING VARIABLE, EXHIBITS AN INTRIGUING PATTERN FOR ALL THREE GENES. FINALLY, HOW DIFFERENTIAL METHYLATION MESHES WITH DARWINIAN PRINCIPLES IS EXAMINED, IN PARTICULAR AS IT RELATES TO THE "FLEXIBLE STEM" THEORY OF EVOLUTION. 2022 8 6594 29 TUMOR-AUGMENTING EFFECTS OF GESTATIONAL ARSENIC EXPOSURE ON F1 AND F2 IN MICE. THE CONSEQUENCES OF EARLY-LIFE EXPOSURE TO CHEMICALS IN THE ENVIRONMENT ARE EMERGING CONCERNS. CHRONIC EXPOSURE TO NATURALLY OCCURRING INORGANIC ARSENIC HAS BEEN KNOWN TO CAUSE VARIOUS ADVERSE HEALTH EFFECTS, INCLUDING CANCERS, IN HUMANS. ON THE OTHER HAND, ANIMAL STUDIES BY DR. M. WAALKES' GROUP REPORTED THAT ARSENITE EXPOSURE OF PREGNANT F0 FEMALES, ONLY FROM GESTATIONAL DAY 8 TO 18, INCREASED HEPATIC TUMORS IN THE F1 (ARSENITE-F1) MALES OF C3H MICE, WHOSE MALES TEND TO DEVELOP SPONTANEOUS HEPATIC TUMORS LATER IN LIFE. SINCE THIS MICE MODEL ILLUMINATED NOVEL UNIDENTIFIED CONSEQUENCES OF ARSENIC EXPOSURE, WE WISHED TO FURTHER INVESTIGATE THE BACKGROUND MECHANISMS. IN THE SAME EXPERIMENTAL MODEL, WE IDENTIFIED A VARIETY OF FACTORS THAT WERE AFFECTED BY GESTATIONAL ARSENIC EXPOSURE, INCLUDING EPIGENETIC AND GENETIC CHANGES, AS POSSIBLE CONSTITUENTS OF MULTIPLE STEPS OF LATE-ONSET HEPATIC TUMOR AUGMENTATION IN ARSENITE-F1 MALES. FURTHERMORE, OUR STUDY DISCOVERED THAT THE F2 MALES BORN TO ARSENITE-F1 MALES DEVELOPED HEPATIC TUMORS AT A SIGNIFICANTLY HIGHER RATE THAN THE CONTROL F2 MALES. THE RESULTS IMPLY THAT THE TUMOR AUGMENTING EFFECT IS INHERITED BY ARSENITE-F2 MALES THROUGH THE SPERM OF ARSENITE-F1. IN THIS ARTICLE, WE SUMMARIZED OUR STUDIES ON THE CONSEQUENCES OF GESTATIONAL ARSENITE EXPOSURE IN F1 AND F2 MICE TO DISCUSS NOVEL ASPECTS OF BIOLOGICAL EFFECTS OF GESTATIONAL ARSENIC EXPOSURE. 2017 9 3991 36 LONGITUDINAL EFFECTS OF DEVELOPMENTAL BISPHENOL A, VARIABLE DIET, AND PHYSICAL ACTIVITY ON AGE-RELATED METHYLATION IN BLOOD. RESEARCH INDICATES THAT ENVIRONMENTAL FACTORS CAN ALTER DNA METHYLATION, BUT THE SPECIFIC EFFECTS OF ENVIRONMENTAL EXPOSURES ON EPIGENETIC AGING REMAIN UNCLEAR. HERE, USING A MOUSE MODEL OF HUMAN-RELEVANT EXPOSURES, WE TESTED THE HYPOTHESIS THAT EARLY-LIFE EXPOSURE TO BISPHENOL A (BPA), VARIABLE DIET, AND/OR CHANGES IN PHYSICAL ACTIVITY WOULD MODIFY RATES OF AGE-RELATED METHYLATION AT SEVERAL TARGET REGIONS, AS MEASURED FROM LONGITUDINAL BLOOD SAMPLES (2, 4, AND 10 MONTHS OLD). DNA METHYLATION WAS QUANTIFIED AT TWO REPETITIVE ELEMENTS (LINE-1, IAP), TWO IMPRINTED GENES (IGF2, H19), AND ONE NON-IMPRINTED GENE (ESR1) IN ISOGENIC MICE DEVELOPMENTALLY EXPOSED TO CONTROL, CONTROL + BPA (50 MICROG/KG DIET), WESTERN HIGH-FAT DIET (WHFD), OR WESTERN + BPA DIETS. IN BLOOD SAMPLES, ESR1 DNA METHYLATION INCREASED SIGNIFICANTLY WITH AGE, BUT NO OTHER INVESTIGATED LOCI SHOWED SIGNIFICANT AGE-RELATED METHYLATION. LINE-1 AND IAP BOTH SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE (P < 0.05). ESR1ALSO SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE IN FEMALE MICE (P = 0.02), BUT NOT MALE MICE. PHYSICAL ACTIVITY HAD A NON-SIGNIFICANT POSITIVE EFFECT ON AGE-RELATED ESR1 METHYLATION IN FEMALE BLOOD, SUGGESTING THAT IT MAY PARTIALLY ABROGATE THE EFFECTS OF WHFD ON THE AGING EPIGENOME. THESE RESULTS SUGGEST THAT DEVELOPMENTAL NUTRITIONAL EXPOSURES CAN MODIFY AGE-RELATED DNA METHYLATION PATTERNS AT A GENE RELATED TO GROWTH AND DEVELOPMENT. AS SUCH, ENVIRONMENTAL DEFLECTION OF THE AGING EPIGENOME MAY HELP TO EXPLAIN THE GROWING PREVALENCE OF CHRONIC DISEASES IN HUMAN POPULATIONS. 2018 10 6550 37 TRANSGENERATIONAL ACCUMULATION OF RADIATION DAMAGE IN SMALL MAMMALS CHRONICALLY EXPOSED TO CHERNOBYL FALLOUT. THE PURPOSE OF THIS INVESTIGATION HAS BEEN THE ANALYSIS OF THE LONG-TERM DEVELOPMENT OF BIOLOGICAL DAMAGE IN NATURAL POPULATIONS OF A MODEL MAMMALIAN SPECIES, THE BANK VOLE (CLETHRIONOMYS GLAREOLUS, SCHREBER), WHICH WERE CHRONICALLY EXPOSED TO LOW DOSES OF IONIZING RADIATION OVER 22 ANIMAL GENERATIONS WITHIN 10 YEARS FOLLOWING THE CHERNOBYL ACCIDENT. THE TIME COURSE OF THE BIOLOGICAL END-POINTS (CHROMOSOME ABERRATIONS IN BONE MARROW CELLS AND EMBRYONIC LETHALITY) WAS COMPARED WITH THE TIME COURSE OF THE WHOLE-BODY ABSORBED DOSE RATE FROM EXTERNAL AND INTERNAL EXPOSURE IN THE STUDIED POPULATIONS INHABITING MONITORING SITES IN BELARUS WITH DIFFERENT GROUND DEPOSITION OF RADIONUCLIDES. THE YIELD OF CHROMOSOME ABERRATIONS AND, IN LESSER DEGREE, EMBRYONIC LETHALITY WAS ASSOCIATED WITH THE RADIONUCLIDE CONTAMINATION OF THE MONITORING AREAS IN A DOSE-DEPENDENT MANNER. AS A MAIN FEATURE OF THE LONG-TERM DEVELOPMENT OF BIOLOGICAL DAMAGE UNDER LOW DOSE RATE IRRADIATION, PERMANENTLY ELEVATED LEVELS OF CHROMOSOME ABERRATIONS AND AN INCREASING FREQUENCY OF EMBRYONIC LETHALITY HAVE DEVELOPED OVER 22 ANIMAL GENERATIONS. THIS CONTRASTS WITH THE ASSUMPTION THAT THE BIOLOGICAL DAMAGE WOULD GRADUALLY DISAPPEAR SINCE IN THE SAME PERIOD OF TIME THE WHOLE-BODY ABSORBED DOSE RATE DECREASED EXPONENTIALLY WITH A HALF-VALUE TIME OF ABOUT 2.5-3 YEARS. FURTHERMORE, GRAVID FEMALES WERE CAPTURED, AND THEIR OFFSPRING, BORN AND GROWN UP UNDER CONTAMINATION-FREE LABORATORY CONDITIONS, SHOWED THE SAME ENHANCED LEVEL OF CHROMOSOME ABERRATIONS. THEREFORE THE AUTHORS SUGGEST THAT, ALONG WITH THE BIOLOGICAL DAMAGE ATTRIBUTABLE TO THE INDIVIDUAL EXPOSURE OF EACH ANIMAL, THE OBSERVED CELLULAR AND SYSTEMIC EFFECTS REFLECT THE TRANSGENERATIONAL TRANSMISSION AND ACCUMULATION, VIA GENETIC AND/OR EPIGENETIC PATHWAYS, OF DAMAGE ATTRIBUTABLE TO THE CHRONIC LOW-DOSE RATE EXPOSURE OF THE PRECEDING GENERATIONS OF ANIMALS. THEY ALSO SUGGEST THAT THE LEVEL OF THE ACCUMULATED TRANSMISSIBLE DAMAGE IN THE INVESTIGATED POPULATIONS WILL DECREASE IN FUTURE DUE TO THE FURTHER RECESSION OF THE CHRONIC EXPOSURE AND AS A CONSEQUENCE OF SELECTION PROCESSES. 2006 11 1567 38 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D. 2018 12 3418 34 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 13 903 39 CHRONIC EXPOSURE TO BISPHENOL A RESULTED IN ALTERATIONS OF REPRODUCTIVE FUNCTIONS VIA IMMUNE DEFENSE, OXIDATIVE DAMAGE AND DISRUPTION DNA/HISTONE METHYLATION IN MALE RARE MINNOW GOBIOCYPRIS RARUS. BISPHENOL A (BPA) IS A WIDELY USED CHEMICAL THAT REPRESENTS A REPRODUCTIVE HAZARD IN FISH. HOWEVER, THE MOLECULAR PATHWAYS MEDIATING REPRODUCTIVE TOXICITY UNDER CHRONIC BPA EXPOSURE REMAIN UNCLEAR. TO STUDY THE REPRODUCTIVE HAZARDS ASSOCIATED WITH CHRONIC BPA EXPOSURE, ADULT MALE RARE MINNOWS (GOBIOCYPRIS RARUS) WERE TREATED WITH 15 MUG L (-) (1) AND 225 MUG L (-) (1) BPA FOR 90 DAYS. RESULTS SHOWED THAT CHRONIC BPA TREATMENT INDUCED REPRODUCTIVE IMPAIRMENTS WITH DECREASED FERTILIZATION CAPACITY AND MOVEMENT TIME OF SPERM. TRANSCRIPTOME ANALYSIS INDICATED 1421 TRANSCRIPTS THAT WERE DIFFERENTIALLY EXPRESSED IN RESPONSE TO BPA EXPOSURE, WHICH ARE INVOLVED IN THE BIOLOGICAL PROCESS OF OXIDATIVE STRESS, IMMUNE RESPONSES AND DNA/HISTONE METHYLATION. BPA CAUSED THE OXIDATIVE STRESS VIA SIGNIFICANTLY INCREASING HYDROGEN PEROXIDE (H(2)O(2)) LEVELS AND INHIBITING THE ACTIVITIES OF ANTIOXIDANT-RELATED ENZYMES (CATALASE, CAT). BPA CAUSED AN INFLAMMATORY RESPONSE IN THE TESTES BY SIGNIFICANTLY INCREASING IL-1BETA LEVELS AND INDUCING INFILTRATION OF INFLAMMATORY CELLS. MOREOVER, EXPOSURE TO 15 MUG L (-) (1) BPA SIGNIFICANTLY DECREASED THE GENOMIC DNA METHYLATION LEVEL. THESE DATA REVEALED THAT CHRONIC BPA EXPOSURE HAD ADVERSE EFFECTS ON MALE REPRODUCTION. OXIDATIVE STRESS, INFLAMMATORY RESPONSE AND DNA/HISTONE METHYLATION MIGHT ACCOUNT FOR THE DECREASED SPERM QUALITY. 2021 14 1545 44 DNA METHYLATION IN LIVER TUMORIGENESIS IN FISH FROM THE ENVIRONMENT. THE LINK BETWEEN ENVIRONMENT, ALTERATION IN DNA METHYLATION AND CANCER HAS BEEN WELL ESTABLISHED IN HUMANS; YET, IT IS UNDER-STUDIED IN UNSEQUENCED NON-MODEL ORGANISMS. THE OCCURRENCE OF LIVER TUMORS IN THE FLATFISH DAB COLLECTED AT CERTAIN UK SAMPLING SITES EXCEEDS 20%, YET THE CAUSATIVE AGENTS AND THE MOLECULAR MECHANISMS OF TUMOR FORMATION ARE NOT KNOWN, ESPECIALLY REGARDING THE BALANCE BETWEEN EPIGENETIC AND GENETIC FACTORS. METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) COMBINED WITH DE NOVO HIGH-THROUGHPUT DNA SEQUENCING WERE USED TO INVESTIGATE DNA METHYLATION CHANGES IN DAB HEPATOCELLULAR ADENOMA TUMORS FOR THE FIRST TIME IN AN UNSEQUENCED SPECIES. NOVEL CUSTOM-MADE DAB GENE EXPRESSION ARRAYS WERE DESIGNED AND USED TO DETERMINE THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION. IN ADDITION, THE CONFIRMATORY TECHNIQUES OF BISULFITE SEQUENCING PCR (BSP) AND RT-PCR WERE APPLIED. GENES INVOLVED IN PATHWAYS RELATED TO CANCER, INCLUDING APOPTOSIS, WNT/BETA-CATENIN SIGNALING AND GENOMIC AND NON-GENOMIC ESTROGEN RESPONSES, WERE ALTERED BOTH IN METHYLATION AND TRANSCRIPTION. GLOBAL METHYLATION WAS STATISTICALLY SIGNIFICANTLY 1.8-FOLD REDUCED IN HEPATOCELLULAR ADENOMA AND NON-CANCEROUS SURROUNDING TISSUES COMPARED WITH LIVER FROM NON-CANCER BEARING DAB. BASED ON THE IDENTIFIED CHANGES AND CHEMICAL EXPOSURE DATA, OUR STUDY SUPPORTS THE EPIGENETIC MODEL OF CANCER. WE HYPOTHESIZE THAT CHRONIC EXPOSURE TO A MIXTURE OF ENVIRONMENTAL CONTAMINANTS CONTRIBUTES TO A GLOBAL HYPOMETHYLATION FOLLOWED BY FURTHER EPIGENETIC AND GENOMIC CHANGES. THE FINDINGS SUGGEST A LINK BETWEEN ENVIRONMENT, EPIGENETICS AND CANCER IN FISH TUMORS IN THE WILD AND SHOW THE UTILITY OF THIS METHODOLOGY FOR STUDIES IN NON-MODEL ORGANISMS. 2011 15 6794 36 [EFFECT OF BENZO(A)PYRENE ON THE EXPRESSION OF AHR-REGULATED MICRORNA IN FEMALE AND MALE RAT LUNGS]. SMOKING IS THE MAIN RISK FACTOR FOR LUNG CANCER, MAINLY DUE TO PRESENCE OF NITROSAMINES AND POLYCYCLIC AROMATIC HYDROCARBONS, INCLUDING BENZO[A]PYRENE (BP) IN TOBACCO SMOKE COMPOSITION. THE GENOTOXIC EFFECT OF BP IS BASED ON THE HIGH DNA-BINDING ABILITY OF ITS METABOLITES, WHILE THE EPIGENETIC EFFECTS ARE MEDIATED BY A CHANGE IN THE EXPRESSION OF CANCER RELATED GENES OR REGULATORY RNAS. IT HAS BEEN SHOWN THAT WOMEN HAVE A HIGHER RISK TO DEVELOP LUNG CANCER UPON SMOKING RATHER THAN MEN. WE HYPOTHESIZED THAT CROSSTALK BETWEEN SIGNALING PATHWAYS ACTIVATED BY BP AND ESTROGENS COULD UNDERLIE THE SEX-DEPENDENT DIFFERENCES IN MIRNAS EXPRESSION. TO TEST THIS HYPOTHESIS, MALE AND FEMALE RATS WERE SUBJECTED TO SHORT-TERM OR LONG-TERM BP EXPOSURE. USING IN SILICO ANALYSIS, MIRNAS CONTAINING THE ER- AND AHR-BINDING SITES IN THE PROMOTERS OF THE GENES (OR HOST GENES) WERE SELECTED. DURING CHRONIC EXPOSURE OF BP THE EXPRESSION OF MIR-22-3P, -29A-3P, -126A-3P, -193B-5P IN THE LUNGS OF MALE RATS WERE SIGNIFICANTLY INCREASED, WHILE THE LEVEL OF MIRNA-483-3P WERE DECREASED. EXPRESSION OF MIRNA-483-3P WAS UP-REGULATED DURING CHRONIC BP EXPOSURE IN THE LUNGS OF FEMALE RATS AND THE LEVELS OF OTHER STUDIED MIRNAS WERE UNCHANGED. IN TURN, CHANGES IN THE EXPRESSION OF MIRNAS WERE FOLLOWED BY CHANGES IN THE EXPRESSION OF THEIR TARGET GENES, INCLUDING PTEN, EMP2, IGF1, ITGA6, SLC34A2, AND THE OBSERVED CHANGES IN FEMALE AND MALE RAT LUNGS WERE VARIED. THUS, OUR RESULTS SUGGEST THAT SEX-DEPENDENT EPIGENETIC EFFECTS OF BP MAY BE BASED ON DIFFERENT EXPRESSION OF AHR- AND ER- REGULATED MIRNAS. 2020 16 1584 28 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS. 2017 17 4209 40 METALLOTHIONEIN 2A GENE POLYMORPHISMS IN RELATION TO DISEASES AND TRACE ELEMENT LEVELS IN HUMANS. HUMAN METALLOTHIONEINS ARE A SUPERFAMILY OF LOW MOLECULAR WEIGHT INTRACELLULAR PROTEINS, WHOSE SYNTHESIS CAN BE INDUCED BY ESSENTIAL ELEMENTS (PRIMARILY ZN AND CU), TOXIC ELEMENTS AND CHEMICAL AGENTS, AND STRESS-PRODUCING CONDITIONS. OF THE FOUR KNOWN ISOFORMS IN THE HUMAN BODY MT2 IS THE MOST COMMON. THE EXPRESSION OF METALLOTHIONEINS IS ENCODED BY A MULTIGENE FAMILY OF LINKED GENES AND CAN BE INFLUENCED BY SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN THESE GENES. TO DATE, 24 SNPS IN THE MT2A GENE HAVE BEEN IDENTIFIED WITH THE INCIDENCE OF ABOUT 1 % IN VARIOUS POPULATION GROUPS, AND THREE OF THEM WERE SHOWN TO AFFECT PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL PROCESSES. THIS REVIEW SUMMARISES CURRENT KNOWLEDGE ABOUT THESE THREE SNPS IN THE MT2A GENE AND THEIR ASSOCIATIONS WITH ELEMENT CONCENTRATIONS IN THE BODY OF HEALTHY AND DISEASED PERSONS. THE MOST INVESTIGATED SNP IS RS28366003 (MT2A -5 A/G). REPORTS ASSOCIATE IT WITH LONGEVITY, CANCER (BREAST, PROSTATE, LARYNGEAL, AND IN PARANASAL SINUSES), AND CHRONIC RENAL DISEASE. THE SECOND MOST INVESTIGATED SNP, RS10636 (MT2A +838G/C), IS ASSOCIATED WITH BREAST CANCER, CARDIOVASCULAR DISEASE, AND TYPE 2 DIABETES. BOTH ARE ALSO ASSOCIATED WITH SEVERAL METAL/METALLOID CONCENTRATIONS IN THE ORGANISM. THE THIRD SNP, RS1610216 (MT2A -209A/G), HAS BEEN STUDIED FOR ASSOCIATION WITH TYPE 2 DIABETES, CARDIOMYOPATHY, HYPERGLYCAEMIA, AND ZN CONCENTRATIONS. METALLOTHIONEIN CONCENTRATIONS AND MT2A POLYMORPHISMS HAVE A POTENTIAL TO BE USED AS BIOMARKERS OF METAL EXPOSURE AND CLINICAL MARKERS OF A NUMBER OF CHRONIC DISEASES. THIS POTENTIAL NEEDS TO BE STUDIED AND VERIFIED IN A LARGE NUMBER OF WELL-DEFINED GROUPS OF PARTICIPANTS (SEVERAL HUNDREDS AND THOUSANDS) WITH A FOCUS ON PARTICULAR PHYSIOLOGICAL OR PATHOLOGICAL CONDITION AND TAKING INTO CONSIDERATION OTHER CONTRIBUTING FACTORS, SUCH AS ENVIRONMENTAL EXPOSURE AND INDIVIDUAL GENETIC AND EPIGENETIC MAKEUP. 2020 18 4538 36 MULTISCALE APPROACH TO DECIPHERING THE MOLECULAR MECHANISMS INVOLVED IN THE DIRECT AND INTERGENERATIONAL EFFECT OF IBUPROFEN ON MOSQUITO AEDES AEGYPTI. THE ANTI-INFLAMMATORY IBUPROFEN IS A UBIQUITOUS SURFACE WATER CONTAMINANT. HOWEVER, THE CHRONIC IMPACT OF THIS PHARMACEUTICAL ON AQUATIC INVERTEBRATE POPULATIONS REMAINS POORLY UNDERSTOOD. IN MODEL INSECT AEDES AEGYPTI, WE INVESTIGATED THE INTERGENERATIONAL CONSEQUENCES OF PARENTAL CHRONIC EXPOSURE TO AN ENVIRONMENTALLY RELEVANT CONCENTRATION OF IBUPROFEN. WHILE EXPOSED INDIVIDUALS DID NOT SHOW ANY PHENOTYPIC CHANGES, THEIR PROGENY SHOWED ACCELERATED DEVELOPMENT AND AN INCREASED TOLERANCE TO STARVATION. IN ORDER TO UNDERSTAND THE MECHANISTIC PROCESSES UNDERPINNING THE DIRECT AND INTERGENERATIONAL IMPACTS OF IBUPROFEN, WE COMBINED TRANSCRIPTOMIC, METABOLOMICS, AND HORMONE KINETICS STUDIES AT SEVERAL LIFE STAGES IN EXPOSED INDIVIDUALS AND THEIR PROGENY. THIS INTEGRATIVE APPROACH REVEALED MODERATE TRANSCRIPTIONAL CHANGES IN EXPOSED LARVAE CONSISTENT WITH THE PHARMACOLOGICAL MODE OF ACTION OF IBUPROFEN. PARENTAL EXPOSURE LED TO LOWER LEVELS OF SEVERAL POLAR METABOLITES IN PROGENY EGGS AND TO MAJOR TRANSCRIPTIONAL CHANGES IN THE FOLLOWING LARVAL STAGE. THESE TRANSCRIPTIONAL CHANGES, MOST LIKELY DRIVEN BY CHANGES IN THE EXPRESSION OF NUMEROUS TRANSCRIPTION FACTORS AND EPIGENETIC REGULATORS, LED TO ECDYSONE SIGNALING AND STRESS RESPONSE POTENTIATION. OVERALL, THE PRESENT STUDY ILLUSTRATES THE COMPLEXITY OF THE MOLECULAR BASIS OF THE INTERGENERATIONAL POLLUTANT RESPONSE IN INSECTS AND THE IMPORTANCE OF CONSIDERING THE ENTIRE LIFE CYCLE OF EXPOSED ORGANISMS AND OF THEIR PROGENY IN ORDER TO FULLY UNDERSTAND THE MODE OF ACTION OF POLLUTANTS AND THEIR IMPACT ON ECOSYSTEMS. 2018 19 1174 35 CONTRIBUTION OF TRANSPOSABLE ELEMENTS TO TRANSGENERATIONAL EFFECTS OF CHRONIC RADIOACTIVE EXPOSURE OF NATURAL POPULATIONS OF DROSOPHILA MELANOGASTER LIVING FOR A LONG TIME IN THE ZONE OF THE CHERNOBYL NUCLEAR DISASTER. THE ACCIDENT AT THE CHERNOBYL NUCLEAR POWER PLANT (CHNPP) LED TO THE NEGATIVE IMPACT OF CHRONIC RADIOACTIVE CONTAMINATION ON POPULATIONS OF ORGANISMS ASSOCIATED WITH THE TRANSGENERATIONAL TRANSMISSION OF GENOME INSTABILITY. WHEN THE DESTABILIZATION OF GENOME, DIFFERENT GENETIC DAMAGES OCCUR, THE ACCUMULATION OF WHICH LEADS TO THE FORMATION OF MUTATIONS, MORPHOLOGICAL ANOMALIES, AND MORTALITY IN THE OFFSPRING. THE MECHANISMS UNDERLYING THE MANIFESTATION OF TRANSGENERATIONAL EVENTS IN THE OFFSPRING OF IRRADIATED PARENTS ARE NOT WELL UNDERSTOOD. IN THIS STUDY, FOR THE FIRST TIME, THE FEATURES OF THE INFLUENCE OF TRANSPOSABLE ELEMENTS (TES) ON THE LONG-TERM BIOLOGICAL CONSEQUENCES OF THE CHNPP ARE CONSIDERED. IN THIS WORK, SPECIMENS OF D. MELANOGASTER OBTAINED FROM NATURAL POPULATIONS IN 2007 IN THE AREAS OF THE CHNPP WITH HETEROGENEOUS RADIOACTIVE CONTAMINATION WERE STUDIED. THE DESCENDANTS FROM THESE POPULATIONS WERE MAINTAINED IN LABORATORY (INBRED) CONDITIONS FOR 160 GENERATIONS. A STABLE TRANSGENERATIONAL TRANSMISSION OF DOMINANT LETHAL MUTATIONS (DLMS) TO THE OFFSPRING OF ALL STUDIED POPULATIONS WAS SHOWN. THE DLM FREQUENCIES STRONGLY WERE CORRELATED WITH THE LEVEL OF SURVIVAL OF OFFSPRING. THE MEAN FREQUENCIES OF RECESSIVE SEX-LINKED LETHAL MUTATIONS VARIED AT THE LEVEL OF SPONTANEOUS POINT MUTATIONS. THE SIMULTANEOUS PRESENCE OF P, HOBO AND I ELEMENTS INDICATES THAT THE STUDIED POPULATIONS DO NOT HAVE A DEFINITE CYTOTYPE, THEIR PHENOTYPIC STATUS IS UNSTABLE. THE BEHAVIOR OF TES IN THE GENOMES OF OFFSPRING DEPENDS NOT ONLY ON PARENTAL EXPOSURE, BUT ALSO ON ORIGIN OF POPULATION, DISTANCE TO THE CHNPP, AND INBRED CONDITIONS. THE OBTAINED RESULTS CONFIRM THE HYPOTHESIS THAT TES ARE INVOLVED IN TRANSGENERATIONAL TRANSMISSION AND ACCUMULATION OF MUTATIONS BY THE OFFSPRING OF IRRADIATED PARENTS. THE TES PATTERN PRESENT IN THE CHERNOBYL GENOMES OF D. MELANOGASTER IS A PECULIAR OF EPIGENETIC MECHANISM FOR THE REGULATION OF PLASTICITY AND ADAPTATION OF POPULATIONS LIVING FOR MANY GENERATIONS UNDER CONDITIONS OF A TECHNOGENICALLY CAUSED RADIATION BACKGROUND. 2022 20 6720 34 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN. 2023