1 166 112 ABNORMAL OVARIAN DNA METHYLATION PROGRAMMING DURING GONAD MATURATION IN WILD CONTAMINATED FISH. THERE IS INCREASING EVIDENCE THAT POLLUTANTS MAY CAUSE DISEASES VIA EPIGENETIC MODIFICATIONS. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION PARTICIPATE IN THE REGULATION OF GENE TRANSCRIPTION. SURPRISINGLY, EPIGENETICS RESEARCH IS STILL LIMITED IN ECOTOXICOLOGY. IN THIS STUDY, WE INVESTIGATED WHETHER CHRONIC EXPOSURE TO CONTAMINANTS EXPERIENCED BY WILD FEMALE FISH (ANGUILLA ANGUILLA) THROUGHOUT THEIR JUVENILE PHASE CAN AFFECT THE DNA METHYLATION STATUS OF THEIR OOCYTES DURING GONAD MATURATION. THUS, FISH WERE SAMPLED IN TWO LOCATIONS PRESENTING A LOW OR A HIGH CONTAMINATION LEVEL. THEN, FISH WERE TRANSFERRED TO THE LABORATORY AND ARTIFICIALLY MATURED. BEFORE HORMONAL TREATMENT, THE DNA METHYLATION LEVELS OF THE GENES ENCODING FOR THE AROMATASE AND THE RECEPTOR OF THE FOLLICLE STIMULATING HORMONE WERE HIGHER IN CONTAMINATED FISH THAN IN FISH FROM THE CLEAN SITE. FOR THE HORMONE RECEPTOR, THIS HYPERMETHYLATION WAS POSITIVELY CORRELATED WITH THE CONTAMINATION LEVEL OF FISH AND WAS ASSOCIATED WITH A DECREASE IN ITS TRANSCRIPTION LEVEL. IN ADDITION, WHEREAS GONAD GROWTH WAS ASSOCIATED WITH AN INCREASE IN DNA METHYLATION IN FISH FROM THE CLEAN SITE, NO CHANGES WERE OBSERVED IN CONTAMINATED FISH IN RESPONSE TO HORMONAL TREATMENT. FINALLY, A HIGHER GONAD GROWTH WAS OBSERVED IN FISH FROM THE REFERENCE SITE IN COMPARISON TO CONTAMINATED FISH. 2014 2 1817 41 EFFECTS OF CHRONIC METAL EXPOSURE ON WILD FISH POPULATIONS REVEALED BY HIGH-THROUGHPUT CDNA SEQUENCING. GIVEN THE INHERENT VARIABILITY OF AQUATIC SYSTEMS, PREDICTING THE IN SITU EFFECTS OF CONTAMINANTS ON SUCH ECOSYSTEMS STILL REPRESENTS A MAJOR CHALLENGE FOR ECOTOXICOLOGY. IN THIS CONTEXT, TRANSCRIPTOMIC TOOLS CAN HELP IDENTIFY AND INVESTIGATE THE MECHANISMS OF TOXICITY BEYOND THE TRADITIONAL MORPHOMETRIC, PHYSIOLOGICAL AND POPULATION-LEVEL ENDPOINTS. IN THIS STUDY, WE USED THE 454 SEQUENCING TECHNOLOGY TO EXAMINE THE IN SITU EFFECTS OF CHRONIC METAL (CD, CU) EXPOSURE ON THE YELLOW PERCH (PERCA FLAVESCENS) TRANSCRIPTOME. TOTAL HEPATIC MRNA FROM FISH SAMPLED ALONG A POLYMETALLIC GRADIENT WAS EXTRACTED, REVERSE TRANSCRIBED, LABELED WITH UNIQUE BARCODE SEQUENCES AND SEQUENCED. THIS APPROACH ALLOWED US TO IDENTIFY CORRELATIONS BETWEEN THE TRANSCRIPTION LEVEL OF SINGLE GENES AND THE HEPATIC CONCENTRATIONS OF INDIVIDUAL METALS; 71% OF THE CORRELATIONS ESTABLISHED WERE NEGATIVE. CHRONIC METAL EXPOSURE WAS THUS ASSOCIATED WITH A DECREASE IN THE TRANSCRIPTION LEVELS OF NUMEROUS GENES INVOLVED IN PROTEIN BIOSYNTHESIS, IN THE IMMUNE SYSTEM, AND IN LIPID AND ENERGY METABOLISM. OUR RESULTS SUGGEST THAT THIS MARKED DECREASE COULD RESULT FROM AN IMPAIRMENT OF BILE ACID METABOLISM BY CD AND ENERGY RESTRICTION BUT ALSO FROM THE RECRUITMENT OF SEVERAL GENES INVOLVED IN EPIGENETIC MODIFICATIONS OF HISTONES AND DNA THAT LEAD TO GENE SILENCING. 2011 3 1655 25 DOSE-DEPENDENCE, SEX- AND TISSUE-SPECIFICITY, AND PERSISTENCE OF RADIATION-INDUCED GENOMIC DNA METHYLATION CHANGES. RADIATION IS A WELL-KNOWN GENOTOXIC AGENT AND HUMAN CARCINOGEN THAT GIVES RISE TO A VARIETY OF LONG-TERM EFFECTS. ITS DETRIMENTAL INFLUENCE ON CELLULAR FUNCTION IS ACTIVELY STUDIED NOWADAYS. ONE OF THE MOST ANALYZED, YET LEAST UNDERSTOOD LONG-TERM EFFECTS OF IONIZING RADIATION IS TRANSGENERATIONAL GENOMIC INSTABILITY. THE INHERITANCE OF GENOMIC INSTABILITY SUGGESTS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS, SUCH AS CHANGES OF THE METHYLATION OF CYTOSINE RESIDUES LOCATED WITHIN CPG DINUCLEOTIDES. IN THE CURRENT STUDY WE EVALUATED THE DOSE-DEPENDENCE OF THE RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION CHANGES. WE ALSO ANALYZED THE EFFECTS OF ACUTE AND CHRONIC HIGH DOSE (5GY) EXPOSURE ON DNA METHYLATION IN LIVER, SPLEEN, AND LUNG TISSUES OF MALE AND FEMALE MICE AND EVALUATED THE POSSIBLE PERSISTENCE OF THE RADIATION-INDUCED DNA METHYLATION CHANGES. HERE WE REPORT THAT RADIATION-INDUCED DNA METHYLATION CHANGES WERE SEX- AND TISSUE-SPECIFIC, DOSE-DEPENDENT, AND PERSISTENT. IN PARALLEL WE HAVE STUDIED THE LEVELS OF DNA DAMAGE IN THE EXPOSED TISSUES. BASED ON THE CORRELATION BETWEEN THE LEVELS OF DNA METHYLATION AND DNA DAMAGE WE PROPOSE THAT RADIATION-INDUCED GLOBAL GENOME DNA HYPOMETHYLATION IS DNA REPAIR-RELATED. 2004 4 1511 35 DNA METHYLATION AND POTENTIAL MULTIGENERATIONAL EPIGENETIC EFFECTS LINKED TO URANIUM CHRONIC LOW-DOSE EXPOSURE IN GONADS OF MALES AND FEMALES RATS. INTRODUCTION: AN INCREASED HEALTH PROBLEM IN INDUSTRIALISED COUNTRIES IS THE CONTEMPORARY CONCERN OF PUBLIC AND SCIENTIFIC COMMUNITY AS WELL. THIS HAS BEEN ATTRIBUTED IN PART TO ACCUMULATED ENVIRONMENTAL POLLUTANTS ESPECIALLY RADIOACTIVE SUBSTANCES AND THE USE OF NUCLEAR POWER PLANTS WORLDWIDE. HOWEVER, THE OUTCOME OF CHRONIC EXPOSURE TO LOW DOSES OF A RADIONUCLIDE SUCH AS URANIUM REMAINS UNKNOWN. RECENTLY, A PARADIGM SHIFT IN THE PERCEPTION OF RISK OF RADIOTOXICOLOGY HAS EMERGED THROUGH INVESTIGATING THE POSSIBILITY OF TRANSMISSION OF BIOLOGICAL EFFECTS OVER GENERATIONS, IN PARTICULAR BY EPIGENETIC PATHWAYS. THESE PROCESSES ARE KNOWN FOR THEIR CRUCIAL ROLES ASSOCIATED WITH THE DEVELOPMENT OF SEVERAL DISEASES. OBJECTIVE: THE CURRENT WORK INVESTIGATES THE EPIGENETIC EFFECT OF CHRONIC EXPOSURE TO LOW DOSES OF URANIUM AND ITS INHERITANCE ACROSS GENERATIONS. MATERIALS AND METHODS TO TEST THIS PROPOSITION, A RODENT MULTIGENERATIONAL MODEL, MALES AND FEMALES, WERE EXPOSED TO A NON-TOXIC CONCENTRATION OF URANIUM (40MGL(-1) DRINKING WATER) FOR NINE MONTHS. THE URANIUM EFFECTS ON WERE EVALUATED OVER THREE GENERATIONS (F0, F1 AND F2) BY ANALYSING THE DNA METHYLATION PROFILE AND DNMT GENES EXPRESSION IN OVARIES AND TESTES TISSUES. RESULTS: HERE WE REPORT A SIGNIFICANT HYPERMETHYLATION OF TESTES DNA (P <0.005) WHEREAS OVARIES SHOWED HYPOMETHYLATED DNA (P <0.005). INTERESTINGLY, THIS DNA METHYLATION PROFILE WAS SIGNIFICANTLY MAINTAINED ACROSS GENERATIONS F0, F1 AND F2. FURTHERMORE, QPCR RESULTS OF BOTH TISSUES IMPLY A SIGNIFICANT CHANGE IN THE EXPRESSION OF DNA METHYLTRANSFERASE GENES (DNMT 1 AND DNMT3A/B) AS WELL. CONCLUSION: ALTOGETHER, OUR WORK DEMONSTRATES FOR THE FIRST TIME A SEX-DEPENDANCE AND INHERITANCE OF EPIGENETIC MARKS, DNA METHYLATION, AS A BIOLOGICAL RESPONSE TO THE EXPOSURE TO LOW DOSES OF URANIUM. HOWEVER, IT IS NOT CLEAR WHICH TYPE OF REPRODUCTIVE CELL TYPE IS MORE RESPONSIVE IN THIS CONTEXT. 2018 5 1503 33 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION. 2009 6 891 41 CHRONIC EFFECTS OF CLOFIBRIC ACID IN ZEBRAFISH (DANIO RERIO): A MULTIGENERATIONAL STUDY. CLOFIBRIC ACID (CA) IS AN ACTIVE METABOLITE OF THE BLOOD LIPID LOWERING AGENT CLOFIBRATE, A PHARMACEUTICAL DESIGNED TO WORK AS AGONIST OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA (PPARA). IT IS THE MOST COMMONLY REPORTED FIBRATE IN AQUATIC ENVIRONMENTS WITH LOW DEGRADATION RATE AND POTENTIAL ENVIRONMENTAL PERSISTENCE. PREVIOUS FISH EXPOSURES SHOWED THAT CA MAY IMPACT SPERMATOGENESIS, GROWTH AND THE EXPRESSION OF FAT BINDING PROTEIN GENES. HOWEVER, THERE ARE LIMITED DATA ON THE EFFECTS OF CHRONIC MULTIGENERATIONAL CA EXPOSURES. HERE, WE ASSESSED CHRONIC MULTIGENERATIONAL EFFECTS OF CA EXPOSURE USING ZEBRAFISH (DANIO RERIO) AS A TELEOST MODEL. ZEBRAFISH WERE EXPOSED THROUGH THE DIET TO CA (1 AND 10MG/G) DURING THEIR WHOLE LIFETIME. GROWTH, REPRODUCTION-RELATED PARAMETERS AND EMBRYONIC DEVELOPMENT WERE ASSESSED IN THE EXPOSED FISH (F1 GENERATION) AND THEIR OFFSPRING (F2 GENERATION), TOGETHER WITH MUSCLE TRIGLYCERIDE CONTENT AND GONAD HISTOLOGY. IN ORDER TO STUDY THE POTENTIAL UNDERLYING MECHANISMS, THE TRANSCRIPTION LEVELS OF GENES CODING FOR ENZYMES INVOLVED IN LIPID METABOLISM PATHWAYS WERE DETERMINED. THE RESULTS SHOW THAT CHRONIC LIFE-CYCLE EXPOSURE TO CA INDUCED A SIGNIFICANT REDUCTION IN GROWTH OF F1 GENERATION AND LOWERED TRIGLYCERIDE MUSCLE CONTENT (10MG/G GROUP). ALSO, AN IMPACT IN MALE GONAD DEVELOPMENT WAS OBSERVED TOGETHER WITH A DECREASE IN THE FECUNDITY (10MG/G GROUP) AND HIGHER FREQUENCY OF EMBRYO ABNORMALITIES IN THE OFFSPRING OF FISH EXPOSED TO THE LOWEST CA DOSE. THE PROFILE OF THE TARGET GENES WAS SEX- AND TISSUE-DEPENDENT. IN F1 AN UP-REGULATION OF MALE HEPATIC PPARAA, PPARB AND ACOX TRANSCRIPT LEVELS WAS OBSERVED, SUGGESTING AN ACTIVATION OF THE FATTY ACID METABOLISM (PROVIDED THAT TRANSCRIPT LEVEL CHANGE INDICATES ALSO A PROTEIN LEVEL CHANGE). INTERESTINGLY, THE F2 GENERATION, RAISED WITH CONTROL DIET, DISPLAYED A RESPONSE PATTERN DIFFERENT FROM THAT OBSERVED IN F1, SHOWING AN INCREASE IN WEIGHT IN THE DESCENDANTS OF CA EXPOSED FISH, IN COMPARISON WITH CONTROL ANIMALS, WHICH POINTS TO A MULTIGENERATIONAL EFFECT. 2015 7 904 39 CHRONIC EXPOSURE TO CADMIUM INDUCES DIFFERENTIAL METHYLATION IN MICE SPERMATOZOA. CADMIUM EXPOSURE IS UBIQUITOUS AND HAS BEEN LINKED TO DISEASES INCLUDING CANCERS AND REPRODUCTIVE DEFECTS. SINCE CADMIUM IS NONMUTAGENIC, IT IS THOUGHT TO EXERT ITS GENE DYSREGULATORY EFFECTS THROUGH EPIGENETIC REPROGRAMMING. SEVERAL STUDIES HAVE IMPLICATED GERMLINE EXPOSURE TO CADMIUM IN DEVELOPMENTAL REPROGRAMMING. HOWEVER, MOST OF THESE STUDIES HAVE FOCUSED ON MATERNAL EXPOSURE, WHILE THE IMPACT ON SPERM FERTILITY AND DISEASE SUSCEPTIBILITY HAS RECEIVED LESS ATTENTION. IN THIS STUDY, WE USED REDUCED REPRESENTATION BISULFITE SEQUENCING TO COMPREHENSIVELY INVESTIGATE THE IMPACT OF CHRONIC CADMIUM EXPOSURE ON MOUSE SPERMATOZOA DNA METHYLATION. ADULT MALE C57BL/J6 MICE WERE PROVIDED WATER WITH OR WITHOUT CADMIUM CHLORIDE FOR 9 WEEKS. SPERM, TESTES, LIVER, AND KIDNEY TISSUES WERE COLLECTED AT THE END OF THE TREATMENT PERIOD. CADMIUM EXPOSURE WAS CONFIRMED THROUGH GENE EXPRESSION ANALYSIS OF METALLOTHIONEIN-1 AND 2, 2 WELL-KNOWN CADMIUM-INDUCED GENES. ANALYSIS OF SPERM DNA METHYLATION CHANGES REVEALED 1788 DIFFERENTIALLY METHYLATED SITES PRESENT AT REGULATORY REGIONS IN SPERM OF MICE EXPOSED TO CADMIUM COMPARED WITH VEHICLE (CONTROL) MICE. FURTHERMORE, MOST OF THESE DIFFERENTIAL METHYLATION CHANGES POSITIVELY CORRELATED WITH CHANGES IN GENE EXPRESSION AT BOTH THE TRANSCRIPTION INITIATION STAGE AS WELL AS THE SPLICING LEVELS. INTERESTINGLY, THE GENES TARGETED BY CADMIUM EXPOSURE ARE INVOLVED IN SEVERAL CRITICAL DEVELOPMENTAL PROCESSES. OUR RESULTS PRESENT A COMPREHENSIVE ANALYSIS OF THE SPERM METHYLOME IN RESPONSE TO CHRONIC CADMIUM EXPOSURE. THESE DATA, THEREFORE, HIGHLIGHT A FOUNDATIONAL FRAMEWORK TO STUDY GENE EXPRESSION PATTERNS THAT MAY AFFECT FERTILITY IN THE EXPOSED INDIVIDUAL AS WELL AS THEIR OFFSPRING, THROUGH PATERNAL INHERITANCE. 2021 8 4224 31 METHYLATION CHANGES IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE EXPOSED TO ACUTE AND CHRONIC LOW-DOSE X-RAY-IRRADIATION. THE BIOLOGICAL AND GENETIC EFFECTS OF CHRONIC LOW-DOSE RADIATION (LDR) EXPOSURE AND ITS RELATIONSHIP TO CARCINOGENESIS HAVE RECEIVED A LOT OF ATTENTION IN THE RECENT YEARS. FOR EXAMPLE, RADIATION-INDUCED GENOME INSTABILITY, WHICH IS THOUGHT TO BE A PRECURSOR OF TUMOROGENESIS, WAS SHOWN TO HAVE A TRANSGENERATIONAL NATURE. THIS INDICATES A POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LDR-INDUCED GENOME INSTABILITY. GENOMIC DNA METHYLATION IS ONE OF THE MOST IMPORTANT EPIGENETIC MECHANISMS. EXISTING DATA ON RADIATION EFFECTS ON DNA METHYLATION PATTERNS IS LIMITED, AND NO ONE HAS SPECIFICALLY STUDIED THE EFFECTS OF THE LDR. WE REPORT THE FIRST STUDY OF THE EFFECTS OF WHOLE-BODY LDR EXPOSURE ON GLOBAL GENOME METHYLATION IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE. IN PARALLEL, WE EVALUATED CHANGES IN PROMOTER METHYLATION AND EXPRESSION OF THE TUMOR SUPPRESSOR GENE P16(INKA) AND DNA REPAIR GENE O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT). WE OBSERVED DIFFERENT PATTERNS OF RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION IN THE LIVER AND MUSCLE OF EXPOSED MALES AND FEMALES. WE ALSO FOUND SEX AND TISSUE-SPECIFIC DIFFERENCES IN P16(INKA) PROMOTER METHYLATION UPON LDR EXPOSURE. IN MALE LIVER TISSUE, P16(INKA) PROMOTER METHYLATION WAS MORE PRONOUNCED THAN IN FEMALE TISSUE. IN CONTRAST, NO SIGNIFICANT RADIATION-INDUCED CHANGES IN P16(INKA) PROMOTER METHYLATION WERE NOTED IN THE MUSCLE TISSUE OF EXPOSED MALES AND FEMALES. RADIATION ALSO DID NOT SIGNIFICANTLY AFFECT METHYLATION STATUS OF MGMT PROMOTER. WE ALSO OBSERVED SUBSTANTIAL SEX DIFFERENCES IN ACUTE AND CHRONIC RADIATION-INDUCED EXPRESSION OF P16(INKA) AND MGMT GENES. ANOTHER IMPORTANT OUTCOME OF OUR STUDY WAS THE FACT THAT CHRONIC LOW-DOSE RADIATION EXPOSURE PROVED TO BE A MORE POTENT INDUCER OF EPIGENETIC EFFECTS THAN THE ACUTE EXPOSURE. THIS SUPPORTS PREVIOUS FINDINGS THAT CHRONIC EXPOSURE LEADS TO GREATER GENOME DESTABILIZATION THAN ACUTE EXPOSURE. 2004 9 3042 35 GENOME-WIDE ALTERATION OF HISTONE METHYLATION PROFILES ASSOCIATED WITH COGNITIVE CHANGES IN RESPONSE TO DEVELOPMENTAL ARSENIC EXPOSURE IN MICE. INORGANIC ARSENIC IS A XENOBIOTIC ENTERING THE BODY PRIMARILY THROUGH CONTAMINATED DRINKING WATER AND FOOD. THERE ARE DEFINED MECHANISMS THAT DESCRIBE ARSENIC'S ASSOCIATION WITH INCREASED CANCER INCIDENCE, HOWEVER MECHANISMS EXPLAINING ARSENIC EXPOSURE AND NEURODEVELOPMENTAL OR AGING DISORDERS ARE POORLY DEFINED. IN RECENT YEARS, ARSENIC EFFECTS ON EPIGENOME HAVE BECOME A PARTICULAR FOCUS. WE HYPOTHESIZE THAT HUMAN RELEVANT ARSENIC EXPOSURE DURING PARTICULAR DEVELOPMENTAL WINDOWS, OR LONG-TERM EXPOSURE LATER IN LIFE INDUCE PATHOPHYSIOLOGICAL NEURAL CHANGES THROUGH EPIGENOMIC ALTERATIONS, IN PARTICULAR HISTONE METHYLATION PROFILE, MANIFESTING AS COGNITIVE DECLINE. C57BL/6 WILD-TYPE MICE WERE CONTINUALLY EXPOSED TO SODIUM ARSENITE (100 MICROG/L) IN DRINKING WATER PRIOR TO MATING THROUGH WEANING OF THE EXPERIMENTAL PROGENY. A SECOND COHORT OF AGED APP/PS MICE WERE CHRONICALLY EXPOSED TO THE SAME LEVEL OF ARSENIC. COGNITIVE TESTING, HISTOLOGICAL EXAMINATION OF BRAINS AND GENOME-WIDE METHYLATION LEVELS OF H3K4ME3 AND H3K27ME3 EXAMINED AFTER CHIP-SEQ WERE USED TO DETERMINE THE EFFECTS OF ARSENIC EXPOSURE. DEVELOPMENTAL ARSENIC EXPOSURE CAUSED SIGNIFICANTLY DIMINISHED COGNITION IN WILD-TYPE MICE. THE ANALYSIS OF CHIP-SEQ DATA AND EXPERIMENTS WITH MOUSE EMBRYONIC STEM CELLS DEMONSTRATED THAT EPIGENETIC CHANGES INDUCED BY ARSENIC EXPOSURE TRANSLATED INTO GENE EXPRESSION ALTERATIONS ASSOCIATED WITH NEURONAL DEVELOPMENT AND NEUROLOGICAL DISEASE. INCREASED HIPPOCAMPAL AMYLOID PLAQUES LEVELS OF APP/PS MICE AND COGNITIVE DECLINE PROVIDED EVIDENCE THAT ARSENIC EXPOSURE AGGRAVATED AN EXISTING ALZHEIMER'S DISEASE-LIKE PHENOTYPE. WE SHOW DEVELOPMENTAL ARSENIC EXPOSURE SIGNIFICANTLY IMPACTS HISTONE MODIFICATIONS IN BRAIN WHICH REMAIN PRESENT INTO ADULTHOOD AND PROVIDE A POTENTIAL MECHANISM BY WHICH DEVELOPMENTAL ARSENIC EXPOSURE INFLUENCES COGNITIVE FUNCTIONS. WE ALSO SHOW THAT HUMAN RELEVANT, CHRONIC ARSENIC EXPOSURE HAS DELETERIOUS EFFECTS ON ADULT APP/PS MICE AND EXACERBATES EXISTING ALZHEIMER'S DISEASE-LIKE SYMPTOMS. THE RESULTS DEMONSTRATE HOW DEVELOPMENTAL ARSENIC EXPOSURE IMPACTS THE BRAIN EPIGENOME, LEADING TO ALTERED GENE EXPRESSION LATER IN LIFE. 2022 10 3652 31 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION. 2021 11 6845 38 [METHYLATION STATUS OF APOPTOSIS GENES AND INTENSITY OF APOPTOTIC DEATH OF PERIPHERAL BLOOD LYMPHOCYTES IN PERSONS CHRONICALLY EXPOSED TO RADIATION]. METHYLATION OF THE CPG ISLANDS OF GENE PROMOTER REGIONS IS THE MOST COMMON EPIGENETIC MODIFICATION INVOLVED IN THE REGULATION OF GENE EXPRESSION. A NUMBER OF STUDIES HAVE SHOWN THAT IONIZING RADIATION CAN CAUSE BOTH HYPER- AND HYPOMETHYLATION OF DNA. ABERRANT METHYLATION AFFECTS CELLULAR PROCESSES AND CAN LEAD TO THE DEVELOPMENT OF VARIOUS PATHOLOGICAL STATES. IN THE LITERATURE, THERE ARE FEW STUDIES ON THE METHYLATION STATUS OF HUMAN DNA A LONG TIME AFTER RADIATION EXPOSURE. HERE, THE METHYLATION LEVEL OF CPG ISLANDS OF THE PROMOTER REGIONS OF APOPTOSIS GENES (BCL2, ATM, MDM2, CDKN1A, STAT3, AND NFKB1), AND ALSO ITS INFLUENCE ON APOPTOSIS OF PERIPHERAL BLOOD LYMPHOCYTES IN CHRONICALLY EXPOSED PERSONS WERE STUDIED. RESIDENTS OF THE SOUTH URAL REGION WHO WERE CHRONICALLY EXPOSED TO RADIATION (AFTER DISCHARGES OF RADIOACTIVE WASTES INTO THE TECHA RIVER BY THE "MAYAK PRODUCTION ASSOCIATION" IN 1949-1956) WERE INCLUDED IN THE STUDY. IT WAS ESTABLISHED THAT THE PROPORTION OF INDIVIDUALS WITH HYPERMETHYLATED BCL2 GENE PROMOTER AMONG THE EXPOSED PEOPLE WAS STATISTICALLY SIGNIFICANTLY HIGHER THAN IN THE CONTROL GROUP. THE PERCENTAGE OF METHYLATION OF THE ATM GENE PROMOTER WEAKLY POSITIVELY CORRELATED WITH DOSE AND AGE CHARACTERISTICS. DIFFERENCES IN THE FREQUENCY OF LYMPHOCYTE APOPTOSIS IN EXPOSED INDIVIDUALS WITH A HYPO- OR HYPERMETHYLATED ATM GENE PROMOTER WERE ALSO ESTABLISHED. THE DATA INDICATE THAT, IN THE LONG-TERM, AFTER CHRONIC LOW INTENSITY RADIATION EXPOSURE AT LOW AND MEDIUM DOSES, EPIGENETIC MODIFICATIONS OF THE GENOME OCCUR, WHICH ARE MANIFESTED AS CHANGES IN METHYLATION OF PROMOTER REGIONS OF BCL2 AND ATM GENES. 2022 12 6562 27 TRANSIENT AND PERMANENT CHANGES IN DNA METHYLATION PATTERNS IN INORGANIC ARSENIC-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION. CHRONIC LOW DOSE INORGANIC ARSENIC EXPOSURE CAUSES CELLS TO TAKE ON AN EPITHELIAL-TO-MESENCHYMAL PHENOTYPE, WHICH IS A CRUCIAL PROCESS IN CARCINOGENESIS. INORGANIC ARSENIC IS NOT A MUTAGEN AND THUS EPIGENETIC ALTERATIONS HAVE BEEN IMPLICATED IN THIS PROCESS. INDEED, DURING THE EPITHELIAL-TO-MESENCHYMAL TRANSITION, MORPHOLOGIC CHANGES TO CELLS CORRELATE WITH CHANGES IN CHROMATIN STRUCTURE AND GENE EXPRESSION, ULTIMATELY DRIVING THIS PROCESS. HOWEVER, STUDIES ON THE EFFECTS OF INORGANIC ARSENIC EXPOSURE/WITHDRAWAL ON THE EPITHELIAL-TO-MESENCHYMAL TRANSITION AND THE IMPACT OF EPIGENETIC ALTERATIONS IN THIS PROCESS ARE LIMITED. IN THIS STUDY WE USED HIGH-RESOLUTION MICROARRAY ANALYSIS TO MEASURE THE CHANGES IN DNA METHYLATION IN CELLS UNDERGOING INORGANIC ARSENIC-INDUCED EPITHELIAL-TO-MESENCHYMAL TRANSITION, AND ON THE REVERSAL OF THIS PROCESS, AFTER REMOVAL OF THE INORGANIC ARSENIC EXPOSURE. WE FOUND THAT CELLS EXPOSED TO CHRONIC, LOW-DOSE INORGANIC ARSENIC EXPOSURE SHOWED 30,530 SITES WERE DIFFERENTIALLY METHYLATED, AND WITH INORGANIC ARSENIC WITHDRAWAL SEVERAL DIFFERENTIAL METHYLATED SITES WERE REVERSED, ALBEIT NOT COMPLETELY. FURTHERMORE, THESE CHANGES IN DNA METHYLATION MAINLY CORRELATED WITH CHANGES IN GENE EXPRESSION AT MOST SITES TESTED BUT NOT AT ALL. THIS STUDY SUGGESTS THAT DNA METHYLATION CHANGES ON GENE EXPRESSION ARE NOT CLEAR-CUT AND PROVIDE A PLATFORM TO BEGIN TO UNCOVER THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION, SPECIFICALLY WITHIN THE CONTEXT OF INORGANIC ARSENIC TREATMENT. 2017 13 1815 29 EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN ON EPIGENETIC REGULATORY GENES EXPRESSION AND EPIGENETIC CODE IN HUMAN PROSTATE EPITHELIAL CELLS. CHRONIC EXPOSURES TO ARSENIC AND ESTROGEN ARE KNOWN RISK FACTORS FOR PROSTATE CANCER. THOUGH THE EVIDENCE SUGGESTS THAT EXPOSURE TO ARSENIC OR ESTROGENS CAN DISRUPT NORMAL DNA METHYLATION PATTERNS AND HISTONE MODIFICATIONS, THE MECHANISMS BY WHICH THESE CHEMICALS INDUCE EPIGENETIC CHANGES ARE NOT FULLY UNDERSTOOD. MOREOVER, THE EPIGENETIC EFFECTS OF CO-EXPOSURE TO THESE TWO CHEMICALS ARE NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN, BOTH ALONE AND IN COMBINATION, ON THE EXPRESSION OF EPIGENETIC REGULATORY GENES, THEIR CONSEQUENCES ON DNA METHYLATION, AND HISTONE MODIFICATIONS. HUMAN PROSTATE EPITHELIAL CELLS, RWPE-1, CHRONICALLY EXPOSED TO ARSENIC AND ESTROGEN ALONE AND IN COMBINATION WERE USED FOR ANALYSIS OF EPIGENETIC REGULATORY GENES EXPRESSION, GLOBAL DNA METHYLATION CHANGES, AND HISTONE MODIFICATIONS AT PROTEIN LEVEL. THE RESULT OF THIS STUDY REVEALED THAT EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION ALTERS THE EXPRESSION OF EPIGENETIC REGULATORY GENES AND CHANGES GLOBAL DNA METHYLATION AND HISTONE MODIFICATION PATTERNS IN RWPE-1 CELLS. THESE CHANGES WERE SIGNIFICANTLY GREATER IN ARSENIC AND ESTROGEN COMBINATION TREATED GROUP THAN INDIVIDUALLY TREATED GROUP. THE FINDINGS OF THIS STUDY WILL HELP EXPLAIN THE EPIGENETIC MECHANISM OF ARSENIC- AND/OR ESTROGEN-INDUCED PROSTATE CARCINOGENESIS. 2012 14 4528 23 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 15 5628 31 SEMEN ABNORMALITIES, SPERM DNA DAMAGE AND GLOBAL HYPERMETHYLATION IN HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION. BACKGROUND: CYTOGENETIC STUDIES HAVE DEMONSTRATED THAT LOW LEVELS OF CHRONIC RADIATION EXPOSURE CAN POTENTIALLY INCREASE THE FREQUENCY OF CHROMOSOMAL ABERRATIONS AND ANEUPLOIDY IN SOMATIC CELLS. EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION BEAR AN INCREASED RISK OF HEMATOLOGICAL MALIGNANCIES. OBJECTIVES: TO FIND THE INFLUENCE OF OCCUPATIONAL RADIATION EXPOSURE ON SEMEN CHARACTERISTICS, INCLUDING GENETIC AND EPIGENETIC INTEGRITY OF SPERMATOZOA IN A CHRONICALLY EXPOSED POPULATION. METHODS: THIS CROSS SECTIONAL STUDY INCLUDED 134 MALE VOLUNTEERS OF WHICH 83 WERE OCCUPATIONALLY EXPOSED TO IONIZING RADIATION AND 51 WERE NON-EXPOSED CONTROL SUBJECTS. SEMEN CHARACTERISTICS, SPERM DNA FRAGMENTATION, ANEUPLOIDY AND INCIDENCE OF GLOBAL HYPERMETHYLATION IN THE SPERMATOZOA WERE DETERMINED AND COMPARED BETWEEN THE NON-EXPOSED AND THE EXPOSED GROUP. RESULTS: DIRECT COMPARISON OF THE SEMEN CHARACTERISTICS BETWEEN THE NON-EXPOSED AND THE EXPOSED POPULATION REVEALED SIGNIFICANT DIFFERENCES IN MOTILITY CHARACTERISTICS, VIABILITY, AND MORPHOLOGICAL ABNORMALITIES (P<0.05-0.0001). ALTHOUGH, THE LEVEL OF SPERM DNA FRAGMENTATION WAS SIGNIFICANTLY HIGHER IN THE EXPOSED GROUP AS COMPARED TO THE NON-EXPOSED GROUP (P<0.05-0.0001), THE INCIDENCE OF SPERM ANEUPLOIDY WAS NOT STATISTICALLY DIFFERENT BETWEEN THE TWO GROUPS. HOWEVER, A SIGNIFICANT NUMBER OF HYPERMETHYLATED SPERMATOZOA WERE OBSERVED IN THE EXPOSED GROUP IN COMPARISON TO NON-EXPOSED GROUP (P<0.05). CONCLUSIONS: WE PROVIDE THE FIRST EVIDENCE ON THE DETRIMENTAL EFFECTS OF OCCUPATIONAL RADIATION EXPOSURE ON FUNCTIONAL, GENETIC AND EPIGENETIC INTEGRITY OF SPERM IN HEALTH WORKERS. HOWEVER, FURTHER STUDIES ARE REQUIRED TO CONFIRM THE POTENTIAL DETRIMENTAL EFFECTS OF IONIZING RADIATION IN THESE SUBJECTS. 2013 16 477 31 ARSENIC PROJECTS IN SE ASIA. EARLY LIFE EXPOSURE TO INORGANIC ARSENIC IS ASSOCIATED WITH A WIDE RANGE OF MALIGNANT AND CHRONIC DISEASE OUTCOMES IN HUMANS. PRENATAL ARSENIC EXPOSURE MAY GIVE RISE TO ADVERSE EFFECTS ON CHILD HEALTH AND DEVELOPMENT AS ARSENIC READILY PASSES THROUGH THE PLACENTA IN HUMAN BEINGS. THE IMPACT OF MATERNAL ARSENIC EXPOSURE ON FETAL GENE EXPRESSION WAS CONDUCTED IN PREGNANT WOMEN LIVING IN SOUTHERN THAILAND. ARSENIC EXPOSED NEWBORNS HAD SIGNIFICANTLY HIGHER LEVELS OF ARSENIC IN CORD BLOOD, AND A SET OF GENES ASSOCIATED WITH NUMEROUS BIOLOGICAL PATHWAYS, INCLUDING CELL SIGNALING, APOPTOSIS, INFLAMMATORY AND STRESS RESPONSE. A SLIGHT INCREASE IN PROMOTER METHYLATION OF P53 IN CORD BLOOD LYMPHOCYTES WHICH CORRELATED WITH ARSENIC ACCUMULATION IN NAILS WAS OBSERVED IN THESE EXPOSED NEWBORNS. A FOLLOW-UP STUDY ON THESE EXPOSED CHILDREN SHOWED A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE, MEASURED AS 8-HYDROXYDEOXYGUANOSINE (8-OHDG) IN SALIVA. IN ADDITION, LEVELS OF URINARY 8-OHDG EXCRETION AND SALIVARY HOGG1 EXPRESSION WERE SIGNIFICANTLY DECREASED IN EXPOSED CHILDREN SUGGESTING A DEFECT IN REPAIR OF 8-OHDG IN ARSENIC-EXPOSED CHILDREN. OUR STUDY INDICATES THAT PRENATAL ARSENIC AND CONTINUED EXPOSURE THROUGH EARLY CHILDHOOD CAN TRIGGER VARIOUS GENETIC AND EPIGENETIC ALTERATIONS THAT MAY LEAD TO DISEASE DEVELOPMENT LATER IN LIFE. 2016 17 4093 35 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 18 990 30 CHRONIC SOCIAL STRESS INDUCES DNA METHYLATION CHANGES AT AN EVOLUTIONARY CONSERVED INTERGENIC REGION IN CHROMOSOME X. CHRONIC STRESS RESULTING FROM PROLONGED EXPOSURE TO NEGATIVE LIFE EVENTS INCREASES THE RISK OF MOOD AND ANXIETY DISORDERS. ALTHOUGH CHRONIC STRESS CAN CHANGE GENE EXPRESSION RELEVANT FOR BEHAVIOR, MOLECULAR REGULATORS OF THIS CHANGE HAVE NOT BEEN FULLY DETERMINED. ONE PROCESS THAT COULD PLAY A ROLE IS DNA METHYLATION, AN EPIGENETIC PROCESS WHEREBY A METHYL GROUP IS ADDED ONTO NUCLEOTIDES, PREDOMINANTLY CYTOSINE IN THE CPG CONTEXT, AND WHICH CAN BE INDUCED BY CHRONIC STRESS. IT IS UNKNOWN TO WHAT EXTENT CHRONIC SOCIAL DEFEAT, A MODEL OF HUMAN SOCIAL STRESS, INFLUENCES DNA METHYLATION PATTERNS ACROSS THE GENOME. OUR STUDY ADDRESSED THIS QUESTION BY USING A TARGETED-CAPTURE APPROACH CALLED METHYL-SEQ TO INVESTIGATE DNA METHYLATION PATTERNS OF THE DENTATE GYRUS AT PUTATIVE REGULATORY REGIONS ACROSS THE MOUSE GENOME FROM MICE EXPOSED TO 14 DAYS OF SOCIAL DEFEAT. FINDINGS WERE REPLICATED IN INDEPENDENT COHORTS BY BISULFITE-PYROSEQUENCING. TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) WERE IDENTIFIED. ONE DMR WAS LOCATED AT INTRON 9 OF DROSHA, AND IT SHOWED REDUCED METHYLATION IN STRESSED MICE. THIS OBSERVATION REPLICATED IN ONE OF TWO INDEPENDENT COHORTS. A SECOND DMR WAS IDENTIFIED AT AN INTERGENIC REGION OF CHROMOSOME X, AND METHYLATION IN THIS REGION WAS INCREASED IN STRESSED MICE. THIS METHYLATION DIFFERENCE REPLICATED IN TWO INDEPENDENT COHORTS AND IN MAJOR DEPRESSIVE DISORDER (MDD) POSTMORTEM BRAINS. THESE RESULTS HIGHLIGHT A REGION NOT PREVIOUSLY KNOWN TO BE DIFFERENTIALLY METHYLATED BY CHRONIC SOCIAL DEFEAT STRESS AND WHICH MAY BE INVOLVED IN MDD. 2018 19 1835 30 EFFECTS OF NON-HUMAN SPECIES IRRADIATION AFTER THE CHERNOBYL NPP ACCIDENT. THE AREA AFFECTED BY THE CHERNOBYL NUCLEAR POWER PLANT ACCIDENT IN 1986 HAS BECOME A UNIQUE TEST SITE WHERE LONG-TERM ECOLOGICAL AND BIOLOGICAL CONSEQUENCES OF A DRASTIC CHANGE IN A RANGE OF ENVIRONMENTAL FACTORS AS WELL AS TRENDS AND INTENSITY OF SELECTION ARE STUDIED IN NATURAL SETTINGS. THE CONSEQUENCES OF THE CHERNOBYL ACCIDENT FOR BIOTA VARIED FROM AN ENHANCED RATE OF MUTAGENESIS TO DAMAGE AT THE ECOSYSTEM LEVEL. THE REVIEW COMPREHENSIVELY BRINGS TOGETHER KEY DATA OF THE LONG-TERM STUDIES OF BIOLOGICAL EFFECTS IN PLANTS AND ANIMALS INHABITING OVER 20 YEARS THE CHERNOBYL NPP ZONE. THE SEVERITY OF RADIATION EFFECTS WAS STRONGLY DEPENDENT ON THE DOSE RECEIVED IN THE EARLY PERIOD AFTER THE ACCIDENT. THE MOST EXPOSED PHYTOCENOSES AND SOIL ANIMALS' COMMUNITIES EXHIBITED DOSE DEPENDENT ALTERATIONS IN THE SPECIES COMPOSITION AND REDUCTION IN BIOLOGICAL DIVERSITY. ON THE OTHER HAND, NO DECREASE IN NUMBERS OR TAXONOMIC DIVERSITY OF SMALL MAMMALS EVEN IN THE MOST RADIOACTIVE HABITAT WAS SHOWN. IN A MAJORITY OF THE STUDIES, IN BOTH PLANT AND ANIMAL POPULATIONS FROM THE CHERNOBYL ZONE, IN THE FIRST YEARS AFTER THE ACCIDENT HIGH INCREASES IN MUTATION RATES WERE DOCUMENTED. IN MOST CASES THE DOSE-EFFECT RELATIONSHIPS WERE NONLINEAR AND THE MUTATION RATES PER UNIT DOSE WERE HIGHER AT LOW DOSES AND DOSE RATES. IN SUBSEQUENT YEARS A DECLINE IN THE RADIATION BACKGROUND RATE OCCURRED FASTER THAN REDUCTION IN THE MUTATION RATE. PLANT AND ANIMAL POPULATIONS HAVE SHOWN SIGNS OF ADAPTATION TO CHRONIC EXPOSURE. IN ADAPTATION TO THE ENHANCED LEVEL OF EXPOSURE AN ESSENTIAL ROLE OF EPIGENETIC MECHANISMS OF GENE EXPRESSION REGULATION WAS SHOWN. BASED ON THE CHERNOBYL NPP ACCIDENT STUDIES, IN THE PRESENT REVIEW ATTEMPTS WERE MADE TO ASSESS MINIMUM DOSES AT WHICH ECOLOGICAL AND BIOLOGICAL EFFECTS WERE OBSERVED. 2008 20 457 35 APPLYING A MULTISCALE SYSTEMS BIOLOGY APPROACH TO STUDY THE EFFECT OF CHRONIC LOW-DOSE EXPOSURE TO URANIUM IN RAT KIDNEYS. PURPOSE: TO EXAMINE THE EFFECTS OF LOW-DOSE EXPOSURE TO URANIUM WITH A SYSTEMS BIOLOGY APPROACH, A MULTISCALE HIGH-THROUGHPUT MULTI-OMICS ANALYSIS WAS APPLIED WITH A PROTOCOL FOR CHRONIC EXPOSURE TO THE RAT KIDNEY. METHODS: MALE AND FEMALE RATS WERE CONTAMINATED FOR NINE MONTHS THROUGH THEIR DRINKING WATER WITH A NONTOXIC SOLUTION OF URANYL NITRATE. A MULTISCALE APPROACH ENABLED CLINICAL MONITORING ASSOCIATED WITH METABOLOMIC AND TRANSCRIPTOMIC (MRNA AND MICRORNA) ANALYSES. RESULTS: A SEX-INTERACTION EFFECT WAS OBSERVED IN THE KIDNEY, URINE, AND PLASMA METABOLOMES OF CONTAMINATED RATS. MOREOVER, URINE AND KIDNEY METABOLIC PROFILES CORRELATED AND CONFIRMED THAT THE PRIMARY DYSREGULATED METABOLISMS ARE THOSE OF NICOTINATE-NICOTINAMIDE AND OF UNSATURATED FATTY ACID BIOSYNTHESIS. UPSTREAM OF THE METABOLIC PATHWAYS, TRANSCRIPTOMIC PROFILES OF THE KIDNEY REVEAL GENE ACTIVITY FOCUSED ON GENE REGULATION MECHANISMS, CELL SIGNALING, CELL STRUCTURE, DEVELOPMENTAL PROCESSES, AND CELL PROLIFERATION. EXAMINATION OF EPIGENETIC POST-TRANSCRIPTIONAL GENE REGULATION PROCESSES SHOWED SIGNIFICANT DYSREGULATION OF 70 MICRO-RNAS. THE MULTI-OMICS APPROACH HIGHLIGHTED THE ACTIVITIES OF THE CELLS' BIOLOGICAL PROCESSES ON MULTIPLE SCALES THROUGH ANALYSIS OF GENE EXPRESSION, CONFIRMED BY CHANGES OBSERVED IN THE METABOLOME. CONCLUSION: OUR RESULTS SHOWED CHANGES IN MULTI-OMIC PROFILES OF RATS EXPOSED TO LOW DOSES OF URANIUM CONTAMINATION, COMPARED WITH CONTROLS. THESE CHANGES INVOLVED GENE EXPRESSION AS WELL AS MODIFICATIONS IN THE TRANSCRIPTOME AND THE METABOLOME. THE METABOLOMIC PROFILE CONFIRMED THAT THE MAIN MOLECULAR TARGETS OF URANIUM IN KIDNEY CELLS ARE THE METABOLISM OF NICOTINATE-NICOTINAMIDE AND THE BIOSYNTHESIS OF UNSATURATED FATTY ACIDS. ADDITIONALLY, GENE EXPRESSION ANALYSIS SHOWED THAT THE METABOLISM OF FATTY ACIDS IS TARGETED BY PROCESSES ASSOCIATED WITH CELL FUNCTION. THESE RESULTS DEMONSTRATE THAT MULTISCALE SYSTEMS BIOLOGY IS USEFUL IN ELUCIDATING THE MOST DISCRIMINATIVE PATHWAYS FROM GENOMIC TO METABOLOMIC LEVELS FOR ASSESSING THE BIOLOGICAL IMPACT OF THIS LOW-LEVEL ENVIRONMENTAL EXPOSURE, I.E. THE EXPOSOME. 2019