1   985 63 CHRONIC RADIATION EXPOSURE AS AN ECOLOGICAL FACTOR: HYPERMETHYLATION AND GENETIC DIFFERENTIATION IN IRRADIATED SCOTS PINE POPULATIONS. GENETIC AND EPIGENETIC CHANGES WERE INVESTIGATED IN CHRONICALLY IRRADIATED SCOTS PINE (PINUS SYLVESTRIS L.) POPULATIONS FROM TERRITORIES THAT WERE HEAVILY CONTAMINATED BY RADIONUCLIDES AS RESULT OF THE CHERNOBYL NUCLEAR POWER PLANT ACCIDENT. IN COMPARISON TO THE REFERENCE SITE, THE GENETIC DIVERSITY REVEALED BY ELECTROPHORETIC MOBILITY OF AFLPS WAS FOUND TO BE SIGNIFICANTLY HIGHER AT THE RADIOACTIVELY CONTAMINATED AREAS. IN ADDITION, THE GENOME OF PINE TREES WAS SIGNIFICANTLY HYPERMETHYLATED AT 4 OF THE 7 AFFECTED SITES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  5344 30 RADIOBIOLOGICAL FEATURES IN OFFSPRING OF NATURAL POPULATIONS OF DROSOPHILA MELANOGASTER AFTER CHERNOBYL ACCIDENT. IN THEIR NATURAL HABITATS, POPULATIONS OF ORGANISMS ARE FACED WITH DIFFERENT LEVELS OF CHRONIC LOW-INTENSITY RADIATION, CAUSING A WIDE RANGE OF RADIOBIOLOGICAL EFFECTS (FROM RADIOSENSITIVITY TO RADIOADAPTIVE RESPONSE AND HORMESIS). IN THIS STUDY, SPECIMENS OF DROSOPHILA MELANOGASTER WERE SELECTED FROM TERRITORIES OF THE CHERNOBYL NUCLEAR POWER PLANT WITH DIFFERENT LEVELS OF RADIOACTIVE CONTAMINATION. THE ISOGENIC STOCKS DERIVED FROM THESE SPECIMENS REPRESENT THE GENETIC SYSTEMS OF CURRENT POPULATIONS AND MAKE IT POSSIBLE TO STUDY RADIORESISTANCE AND ITS MECHANISMS IN FUTURE GENERATIONS UNDER CONTROLLED LABORATORY CONDITIONS. PREVIOUS STUDIES HAVE SHOWN THAT TRANSGENERATIONAL RADIATION EFFECTS AT THE LEVEL OF LETHAL MUTATIONS AND SURVIVAL RATE ARE UNSTABLE AND DEPEND NOT ONLY ON THE LEVEL OF CHRONIC LOW-INTENSITY IRRADIATION, BUT ALSO ON OTHER FACTORS. A SINGLE ACUTE IRRADIATION EXPOSURE OF OFFSPRING WHOSE PARENTS INHABITED A SITE WITH A HIGHER LEVEL OF CHRONIC IRRADIATION MADE IT POSSIBLE TO REVEAL PRONOUNCED RADIORESISTANT FEATURES IN THE OFFSPRING. AND THE OFFSPRING WHOSE PARENTS WERE EXPOSED TO RADIATION LEVELS CLOSE TO THE NATURAL RADIATION BACKGROUND, ON THE CONTRARY, ACQUIRED RADIOSENSITIVE FEATURES. THEIR RESPONSE TO ACUTE EXPOSURE INCLUDES A HIGH-FREQUENCY OF LETHAL MUTATIONS AND A SHORT LIFESPAN. THE DIFFERENTIAL RESPONSE TO DIFFERENT LEVELS OF CHRONIC PARENTAL EXPOSURE IS CAUSED BY DIFFERENCES IN THE ACTIVITIES OF CERTAIN TRANSPOSONS THAT DESTABILIZE THE GENOME. OUR DATA CONTRIBUTE TO THE UNDERSTANDING OF GENETIC AND EPIGENETIC MECHANISMS (VIA TRANSPOSON ACTIVITY) OF THE EFFECT OF PARENTAL RADIATION EXPOSURE ON THE HEALTH AND ADAPTIVE POTENTIAL OF POPULATIONS AFFECTED BY THE TECHNOGENICALLY INCREASED RADIATION BACKGROUND.	2022	
                                                                                                                                                                                                                                                                                                                                                                                
3  1835 29 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	
                                                                                                                                                                                                                                                                                                                                                                
4  3040 27 GENOME HYPERMETHYLATION IN PINUS SILVESTRIS OF CHERNOBYL--A MECHANISM FOR RADIATION ADAPTATION? ADAPTATION IS A COMPLEX PROCESS BY WHICH POPULATIONS OF ORGANISMS RESPOND TO LONG-TERM ENVIRONMENTAL STRESSES BY PERMANENT GENETIC CHANGE. HERE WE PRESENT DATA FROM THE NATURAL "OPEN-FIELD" RADIATION ADAPTATION EXPERIMENT AFTER THE CHERNOBYL ACCIDENT AND PROVIDE THE FIRST EVIDENCE OF THE INVOLVEMENT OF EPIGENETIC CHANGES IN ADAPTATION OF A EUKARYOTE-SCOTS PINE (PINUS SILVESTRIS), TO CHRONIC RADIATION EXPOSURE. WE HAVE EVALUATED GLOBAL GENOME METHYLATION OF CONTROL AND RADIATION-EXPOSED PINE TREES USING A METHOD BASED ON CLEAVAGE BY A METHYLATION-SENSITIVE HPAII RESTRICTION ENDONUCLEASE THAT LEAVES A 5' GUANINE OVERHANG AND SUBSEQUENT SINGLE NUCLEOTIDE EXTENSION WITH LABELED [3H] DCTP. WE HAVE FOUND THAT GENOMIC DNA OF EXPOSED PINE TREES WAS CONSIDERABLY HYPERMETHYLATED. MOREOVER, HYPERMETHYLATION APPEARED TO BE DEPENDENT UPON THE RADIATION DOSE ABSORBED BY THE TREES. SUCH HYPERMETHYLATION MAY BE VIEWED AS A DEFENSE STRATEGY OF PLANTS THAT PREVENTS GENOME INSTABILITY AND RESHUFFLING OF THE HEREDITARY MATERIAL, ALLOWING SURVIVAL IN AN EXTREME ENVIRONMENT. FURTHER STUDIES ARE CLEARLY NEEDED TO ANALYZE IN DETAIL THE INVOLVEMENT OF DNA METHYLATION AND OTHER EPIGENETIC MECHANISMS IN THE COMPLEX PROCESS OF RADIATION STRESS AND ADAPTIVE RESPONSE.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  1115 33 COMPARATIVE ANALYSIS OF EPIGENETIC VARIABILITY IN TWO PINE SPECIES EXPOSED TO CHRONIC RADIATION IN THE CHERNOBYL AND FUKUSHIMA AFFECTED ZONES. COMPARATIVE ANALYSIS OF EPIGENETIC VARIABILITY IN TWO PINE SPECIES AFFECTED AS A RESULT OF THE CHERNOBYL AND FUKUSHIMA ACCIDENTS IS PRESENTED. THE ABSORBED DOSE RATE WITHIN THE AFFECTED CHERNOBYL SITES VARIES OVER A WIDER RANGE (1.5-24.6 MUGY/H) THAN WITHIN THE FUKUSHIMA SITES (3.5-6.5 MUGY/H). IT WAS SHOWN THAT CHRONIC IRRADIATION CAN CHANGE THE LEVEL OF WHOLE GENOME METHYLATION IN PINE POPULATIONS, BUT IN DIFFERENT WAYS. THE GENOMES OF JAPANESE RED PINES ARE HYPOMETHYLATED, AND THE DEGREE OF METHYLATION AND HYDROXYMETHYLATION DECREASES WITH AN INCREASE IN THE LEVEL OF RADIATION EXPOSURE. IN CONTRAST, THE PERCENTAGES OF GENOME METHYLATION AND HYDROXYMETHYLATION IN SCOTS PINE POPULATIONS EXCEED THE REFERENCE LEVELS. THE OBSERVED DISCREPANCY IN THE PATTERNS OF GENOME-WIDE DNA METHYLATION CAN BE ATTRIBUTED PARTLY TO THE DESIGN OF THE STUDY (DIFFERENCES IN THE CLIMATE, RADIATION DOSE, AGE AND SPECIES OF THE PINES) WHICH COULD AFFECT THE RESULTS. IN THE FRAME OF IRAP ANALYSIS, A LARGER NUMBER OF DIFFERENT BANDS WAS OBSERVED IN THE CHERNOBYL POPULATIONS COMPARED TO THE JAPANESE POPULATIONS. BOTH THE JAPANESE AND CHERNOBYL POPULATIONS ARE CHARACTERIZED BY SIGNIFICANT GENETIC VARIABILITY. HOWEVER, THE MAIN PART OF THIS VARIABILITY IS OBSERVED WITHIN POPULATIONS. THE DENDROGRAMS, BASED ON PRESENCE/ABSENCE OF IRAP FRAGMENTS AND NEI'S GENETIC DISTANCES, REVEALED SUBDIVISIONS OF THE CHERNOBYL AND JAPANESE POPULATIONS ACCORDING TO THE LEVEL OF RADIOACTIVE CONTAMINATION. ANALYSIS OF THE RESULTS PRESENTED WILL IMPROVE OUR UNDERSTANDING OF THE MECHANISMS UNDERLYING THE RESPONSES OF PINE TREES TO CHRONIC RADIATION EXPOSURE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6  5032 22 PERTURBED TRANSCRIPTIONAL PROFILES AFTER CHRONIC LOW DOSE RATE RADIATION IN MICE. ADVERSE HEALTH OUTCOMES OF IONIZING RADIATION GIVEN CHRONICALLY AT LOW DOSE RATES ARE HIGHLY DEBATED, A CONTROVERSY ALSO RELEVANT FOR OTHER STRESSORS. INCREASED KNOWLEDGE IS NEEDED FOR A MORE COMPREHENSIVE UNDERSTANDING OF THE DAMAGING POTENTIAL OF IONIZING RADIATION FROM ALL DOSE RATES AND DOSES. THERE IS A LACK OF RELEVANT LOW DOSE RATE DATA THAT IS PARTLY ASCRIBED TO THE RARITY OF EXPOSURE FACILITIES ALLOWING CHRONIC LOW DOSE RATE EXPOSURES. USING THE FIGARO FACILITY, WE ASSESSED EARLY (ONE DAY POST-RADIATION) AND LATE (RECOVERY TIME OF 100-200 DAYS) HEPATIC GENOME-WIDE TRANSCRIPTIONAL PROFILES IN MALE MICE OF TWO STRAINS (CBA/CAOLAHSD AND C57BL/6NHSD) EXPOSED CHRONICALLY TO A LOW DOSE RATE (2.5 MGY/H; 1200H, LDR), A MID-DOSE RATE (10 MGY/H; 300H, MDR) AND ACUTELY TO A HIGH DOSE RATE (100 MGY/H; 30H, HDR) OF GAMMA IRRADIATION, GIVEN TO AN EQUIVALENT TOTAL DOSE OF 3 GY. DOSE-RATE AND STRAIN-SPECIFIC TRANSCRIPTIONAL RESPONSES WERE IDENTIFIED. DIFFERENTLY MODULATED TRANSCRIPTIONAL RESPONSES ACROSS ALL DOSE RATE EXPOSURE GROUPS WERE EVIDENT BY THE REPRESENTATION OF FUNCTIONAL BIOLOGICAL PATHWAYS. EVIDENCE OF CHANGED EPIGENETIC REGULATION (GLOBAL DNA METHYLATION) WAS NOT DETECTED. A PERIOD OF RECOVERY MARKEDLY REDUCED THE NUMBER OF DIFFERENTIALLY EXPRESSED GENES. USING ENRICHMENT ANALYSIS TO IDENTIFY THE FUNCTIONAL SIGNIFICANCE OF THE MODULATED GENES, PERTURBED SIGNALING PATHWAYS ASSOCIATED WITH BOTH CANCER AND NON-CANCER EFFECTS WERE OBSERVED, SUCH AS LIPID METABOLISM AND INFLAMMATION. THESE PATHWAYS WERE SEEN AFTER CHRONIC LOW DOSE RATE AND WERE NOT RESTRICTED TO THE ACUTE HIGH DOSE RATE EXPOSURE. THE TRANSCRIPTIONAL RESPONSE INDUCED BY CHRONIC LOW DOSE RATE IONIZING RADIATION SUGGESTS CONTRIBUTION TO CONDITIONS SUCH AS CARDIOVASCULAR DISEASES. WE CONTRIBUTE WITH NOVEL GENOME WIDE TRANSCRIPTIONAL DATA HIGHLIGHTING DOSE-RATE-SPECIFIC RADIATION RESPONSES AND EMPHASIZE THE IMPORTANCE OF CONSIDERING BOTH DOSE RATE, DURATION OF EXPOSURE, AND VARIABILITY IN SUSCEPTIBILITY WHEN ASSESSING RISKS FROM IONIZING RADIATION.	2021	
                                                                                                                   
7  6555 23 TRANSGENERATIONAL EFFECTS OF GAMMA RADIATION DOSE AND DOSE RATE ON DROSOPHILA FLIES IRRADIATED AT AN EARLY EMBRYONAL STAGE. IONIZING RADIATION (IR) KILLS CELLS MAINLY THROUGH INDUCTION OF DNA DAMAGES AND THE SURVIVING CELLS MAY SUFFER FROM MUTATIONS. TRANSGENERATIONAL EFFECTS OF IR ARE WELL DOCUMENTED, BUT THE EXACT MECHANISMS UNDERLYING THEM ARE LESS WELL UNDERSTOOD; THEY INCLUDE INDUCTION OF MUTATIONS IN GERM CELLS AND EPIGENETIC INHERITANCE. PREVIOUSLY, EFFECTS IN THE OFFSPRING OF MICE AND ZEBRAFISH EXPOSED TO IR HAVE BEEN REPORTED. A FEW STUDIES ALSO SHOWED INDICATIONS OF TRANSGENERATIONAL EFFECTS OF RADIATION IN HUMANS, PARTICULARLY IN NUCLEAR POWER WORKERS. IN THE PRESENT PROJECT, SHORT- AND LONG-TERM EFFECTS OF LOW-DOSE-RATE (LDR; 50 AND 97 MGY/H) AND HIGH-DOSE-RATE (HDR; 23.4, 47.1 AND 495 GY/H) IR IN DROSOPHILA EMBRYOS WERE INVESTIGATED. THE EMBRYOS WERE IRRADIATED AT DIFFERENT DOSES AND DOSE RATES AND RADIOSENSITIVITY AT DIFFERENT DEVELOPMENTAL STAGES WAS INVESTIGATED. ALSO, THE SURVIVAL OF LARVAE, PUPAE AND ADULTS DEVELOPED FROM EMBRYOS IRRADIATED AT AN EARLY STAGE (30 MIN AFTER EGG LAYING) WERE STUDIED. THE LARVAL CRAWLING AND PUPATION HEIGHT ASSAYS WERE APPLIED TO INVESTIGATE RADIATION EFFECTS ON LARVAL LOCOMOTION AND PUPATION BEHAVIOR, RESPECTIVELY. IN PARALLEL, THE OFFSPRING FROM 3 GY IRRADIATED EARLY-STAGE EMBRYOS WERE FOLLOWED UP TO 12 GENERATIONS AND ABNORMAL PHENOTYPES WERE STUDIED. ACUTE EXPOSURE OF EMBRYOS AT DIFFERENT STAGES OF DEVELOPMENT SHOWED THAT THE EARLY STAGE EMBRYO IS THE MOST SENSITIVE. THE EFFECTS ON LARVAL LOCOMOTION SHOWED NO SIGNIFICANT DIFFERENCES BETWEEN THE DOSE RATES BUT A SIGNIFICANT DECREASE OF LOCOMOTION ACTIVITY ABOVE 7 GY WAS OBSERVED. THE RESULTS INDICATE THAT EMBRYOS EXPOSED TO THE LOW DOSE RATES HAVE SHORTER ECLOSION TIMES. AT THE SAME CUMULATIVE DOSE (1 UP TO 7 GY), HDR IS MORE EMBRYOTOXIC THAN LDR. WE ALSO FOUND A RADIATION-INDUCED DEPIGMENTATION ON MALES (A5 SEGMENT OF THE DORSAL ABDOMEN, A5PIG(-)) THAT CAN BE TRANSMITTED UP TO 12 GENERATIONS. THE PHENOMENON DOES NOT FOLLOW THE CLASSICAL MENDELIAN LAWS OF SEGREGATION.	2022	
                                                                                                                                           
8   934 15 CHRONIC LOW DOSE IRRADIATION ALTERS HEPATIC TRANSCRIPTIONAL PROFILES, BUT NOT GLOBAL DNA METHYLATION IN MEDAKA (ORYZIAS LATIPES). IONIZING RADIATION (IR) RESULTING FROM BOTH NATURAL AND ANTHROPOGENIC SOURCES IS UBIQUITOUS THROUGHOUT THE ENVIRONMENT. HISTORICALLY, STUDIES ON THE BIOLOGICAL IMPACTS OF RADIATION PRIMARILY FOCUSED ON RESPONSES TO ACUTE DOSES OF RADIATION, WITH LITTLE ADVANCEMENT IN OUR UNDERSTANDING OF ENVIRONMENTALLY RELEVANT EXPOSURES. EPIGENETIC MECHANISMS ARE CAPABLE OF MEDIATING ORGANISMAL RESPONSES TO ENVIRONMENTAL STRESSORS AND DNA METHYLATION PLAYS IMPORTANT ROLES IN GENE REGULATION AND PROMOTING CHROMOSOMAL STABILITY. HERE, WE ASSESS BROAD-SCALE TRANSCRIPTIONAL AND EPIGENETIC VARIATION RESULTING FROM CHRONIC EXPOSURE TO LOW DOSES OF IONIZING RADIATION (LDIR; 5.78, 53.76, OR 520.23 MGY/DAY) USING JAPANESE MEDAKA FISH (ORYZIAS LATIPES) IN A REPLICATED MESOCOSM DESIGN. WE OBSERVED SIGNIFICANT CHANGES TO THE HEPATIC TRANSCRIPTOME INDUCED BY A 3-MONTH CHRONIC EXPOSURE TO IR, WHEREAS GLOBAL DNA METHYLATION APPEARED LARGELY UNAFFECTED. OUR FINDINGS REVEAL A SET OF GENES, INCLUDING THOSE INVOLVED IN IMMUNE FUNCTION, RESPONDING TO ENVIRONMENTALLY RELEVANT IR EXPOSURES, WHICH DO NOT APPEAR TO BE MEDIATED BY A SYSTEMIC GLOBAL SHIFT IN DNA METHYLATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9   930 17 CHRONIC IRRADIATION OF HUMAN CELLS REDUCES HISTONE LEVELS AND DEREGULATES GENE EXPRESSION. OVER THE PAST DECADES, THERE HAVE BEEN HUGE ADVANCES IN UNDERSTANDING CELLULAR RESPONSES TO IONISING RADIATION (IR) AND DNA DAMAGE. THESE STUDIES, HOWEVER, WERE MOSTLY EXECUTED WITH CELL LINES AND MICE USING SINGLE OR MULTIPLE ACUTE DOSES OF RADIATION. HENCE, RELATIVELY LITTLE IS KNOWN ABOUT HOW CONTINUOUS EXPOSURE TO LOW DOSE IONISING RADIATION AFFECTS NORMAL CELLS AND ORGANISMS, EVEN THOUGH OUR CELLS ARE CONSTANTLY EXPOSED TO LOW LEVELS OF RADIATION. WE ADDRESSED THIS ISSUE BY EXAMINING THE CONSEQUENCES OF EXPOSING HUMAN PRIMARY CELLS TO CONTINUOUS IONISING GAMMA-RADIATION DELIVERED AT 6-20 MGY/H. ALTHOUGH THESE DOSE RATES ARE ESTIMATED TO INFLICT FEWER THAN A SINGLE DNA DOUBLE-STRAND BREAK (DSB) PER HOUR PER CELL, THEY STILL CAUSED DOSE-DEPENDENT REDUCTIONS IN CELL PROLIFERATION AND INCREASED CELLULAR SENESCENCE. WE CONCOMITANTLY OBSERVED HISTONE PROTEIN LEVELS TO REDUCE BY UP TO 40%, WHICH IN CONTRAST TO PREVIOUS OBSERVATIONS, WAS NOT MAINLY DUE TO PROTEIN DEGRADATION BUT INSTEAD CORRELATED WITH REDUCED HISTONE GENE EXPRESSION. HISTONE REDUCTIONS WERE ACCOMPANIED BY ENLARGED NUCLEAR SIZE PARALLELED BY AN INCREASE IN GLOBAL TRANSCRIPTION, INCLUDING THAT OF PRO-INFLAMMATORY GENES. THUS, CHRONIC IRRADIATION, EVEN AT LOW DOSE-RATES, CAN INDUCE CELL SENESCENCE AND ALTER GENE EXPRESSION VIA A HITHERTO UNCHARACTERISED EPIGENETIC ROUTE. THESE FEATURES OF CHRONIC RADIATION REPRESENT A NEW ASPECT OF RADIATION BIOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10  5628 23 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	
                                                                                                                                                                                                                                                                                                          
11    77 20 A NEW ERA OF LOW-DOSE RADIATION EPIDEMIOLOGY. THE LAST DECADE HAS INTRODUCED A NEW ERA OF EPIDEMIOLOGIC STUDIES OF LOW-DOSE RADIATION FACILITATED BY ELECTRONIC RECORD LINKAGE AND POOLING OF COHORTS THAT ALLOW FOR MORE DIRECT AND POWERFUL ASSESSMENTS OF CANCER AND OTHER STOCHASTIC EFFECTS AT DOSES BELOW 100 MGY. SUCH STUDIES HAVE PROVIDED ADDITIONAL EVIDENCE REGARDING THE RISKS OF CANCER, PARTICULARLY LEUKEMIA, ASSOCIATED WITH LOWER-DOSE RADIATION EXPOSURES FROM MEDICAL, ENVIRONMENTAL, AND OCCUPATIONAL RADIATION SOURCES, AND HAVE QUESTIONED THE PREVIOUS FINDINGS WITH REGARD TO POSSIBLE THRESHOLDS FOR CARDIOVASCULAR DISEASE AND CATARACTS. INTEGRATED ANALYSIS OF NEXT GENERATION GENOMIC AND EPIGENETIC SEQUENCING OF GERMLINE AND SOMATIC TISSUES COULD SOON PROPEL OUR UNDERSTANDING FURTHER REGARDING DISEASE RISK THRESHOLDS, RADIOSENSITIVITY OF POPULATION SUBGROUPS AND INDIVIDUALS, AND THE MECHANISMS OF RADIATION CARCINOGENESIS. THESE ADVANCES IN LOW-DOSE RADIATION EPIDEMIOLOGY ARE CRITICAL TO OUR UNDERSTANDING OF CHRONIC DISEASE RISKS FROM THE BURGEONING USE OF NEWER AND EMERGING MEDICAL IMAGING TECHNOLOGIES, AND THE CONTINUED POTENTIAL THREAT OF NUCLEAR POWER PLANT ACCIDENTS OR OTHER RADIOLOGICAL EMERGENCIES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  1399 19 DIET-INDUCED OBESITY MODULATES EPIGENETIC RESPONSES TO IONIZING RADIATION IN MICE. BOTH EXPOSURE TO IONIZING RADIATION AND OBESITY HAVE BEEN ASSOCIATED WITH VARIOUS PATHOLOGIES INCLUDING CANCER. THERE IS A CRUCIAL NEED IN BETTER UNDERSTANDING THE INTERACTIONS BETWEEN IONIZING RADIATION EFFECTS (ESPECIALLY AT LOW DOSES) AND OTHER RISK FACTORS, SUCH AS OBESITY. IN ORDER TO EVALUATE RADIATION RESPONSES IN OBESE ANIMALS, C3H AND C57BL/6J MICE FED A CONTROL NORMAL FAT OR A HIGH FAT (HF) DIET WERE EXPOSED TO FRACTIONATED DOSES OF X-RAYS (0.75 GY X4). BONE MARROW MICRONUCLEUS ASSAYS DID NOT SUGGEST A MODULATION OF RADIATION-INDUCED GENOTOXICITY BY HF DIET. USING MSP, WE OBSERVED THAT THE PROMOTERS OF P16 AND DAPK GENES WERE METHYLATED IN THE LIVERS OF C57BL/6J MICE FED A HF DIET (IRRADIATED AND NON-IRRADIATED); MGMT PROMOTER WAS METHYLATED IN IRRADIATED AND/OR HF DIET-FED MICE. IN ADDITION, METHYLATION PCR ARRAYS IDENTIFIED EP300 AND SOCS1 (WHOSE PROMOTERS EXHIBITED HIGHER METHYLATION LEVELS IN NON-IRRADIATED HF DIET-FED MICE) AS POTENTIAL TARGETS FOR FURTHER STUDIES. WE THEN COMPARED MICRORNA REGULATIONS AFTER RADIATION EXPOSURE IN THE LIVERS OF C57BL/6J MICE FED A NORMAL OR AN HF DIET, USING MICRORNA ARRAYS. INTERESTINGLY, RADIATION-TRIGGERED MICRORNA REGULATIONS OBSERVED IN NORMAL MICE WERE NOT OBSERVED IN OBESE MICE. MIR-466E WAS UPREGULATED IN NON-IRRADIATED OBESE MICE. IN VITRO FREE FATTY ACID (PALMITIC ACID, OLEIC ACID) ADMINISTRATION SENSITIZED AML12 MOUSE LIVER CELLS TO IONIZING RADIATION, BUT THE INHIBITION OF MIR-466E COUNTERACTED THIS RADIO-SENSITIZATION, SUGGESTING THAT THE MODULATION OF RADIATION RESPONSES BY DIET-INDUCED OBESITY MIGHT INVOLVE MIR-466E EXPRESSION. ALL TOGETHER, OUR RESULTS SUGGESTED THE EXISTENCE OF DIETARY EFFECTS ON RADIATION RESPONSES (ESPECIALLY EPIGENETIC REGULATIONS) IN MICE, POSSIBLY IN RELATIONSHIP WITH OBESITY-INDUCED CHRONIC OXIDATIVE STRESS.	2014	
                                                                                                                                                                                                                                                                                                                                              
13  2741 17 EXPOSURE TO IONIZING RADIATION DISRUPTS NORMAL EPIGENETIC AGING IN JAPANESE MEDAKA. ALTERATIONS TO THE EPIGENOME ARE A HALLMARK OF BIOLOGICAL AGING AND AGE-DEPENDENT PATTERNING OF THE DNA METHYLOME ("EPIGENETIC AGING") CAN BE MODELED TO PRODUCE EPIGENETIC AGE PREDICTORS. RATES OF EPIGENETIC AGING VARY AMONGST INDIVIDUALS AND CORRELATE TO THE ONSET OF AGE-RELATED DISEASE AND ALL-CAUSE MORTALITY. YET, THE ORIGINS OF EPIGENETIC-TO-CHRONOLOGICAL AGE DISCORDANCE ARE NOT EMPIRICALLY RESOLVED. HERE, WE INVESTIGATE THE RELATIONSHIP BETWEEN AGING, DNA METHYLATION, AND ENVIRONMENTAL EXPOSURES IN JAPANESE MEDAKA (ORYZIAS LATIPES). WE FIND AGE-ASSOCIATED DNA METHYLATION PATTERNING ENRICHED IN GENOMIC REGIONS OF LOW CPG DENSITY AND THAT, SIMILAR TO MAMMALS, MOST AGE-RELATED CHANGES OCCUR DURING EARLY LIFE. WE CONSTRUCT AN EPIGENETIC CLOCK CAPABLE OF PREDICTING CHRONOLOGICAL AGE WITH A MEAN ERROR OF 61.1 DAYS (~8.4% OF AVERAGE LIFESPAN). TO TEST THE ROLE OF ENVIRONMENTAL FACTORS IN DRIVING EPIGENETIC AGE VARIATION, WE EXPOSED MEDAKA TO CHRONIC, ENVIRONMENTALLY RELEVANT DOSES OF IONIZING RADIATION. BECAUSE MOST ORGANISMS SHARE AN EVOLUTIONARY HISTORY WITH IONIZING RADIATION, WE HYPOTHESIZED THAT EXPOSURE WOULD REVEAL FUNDAMENTAL INSIGHTS INTO ENVIRONMENT-BY-EPIGENETIC AGING INTERACTIONS. RADIATION EXPOSURE DISRUPTED EPIGENETIC AGING BY ACCELERATING AND DECELERATING NORMAL AGE-ASSOCIATED PATTERNING AND WAS MOST PRONOUNCED IN CYTOSINES THAT WERE MODERATELY ASSOCIATED WITH AGE. THESE FINDINGS EMPIRICALLY DEMONSTRATE THE ROLE OF DNA METHYLATION IN INTEGRATING ENVIRONMENTAL FACTORS INTO AGING TRAJECTORIES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  4018 18 LOW-DOSE IONIZING RADIATION: INDUCTION OF DIFFERENTIAL INTRACELLULAR SIGNALLING POSSIBLY AFFECTING INTERCELLULAR COMMUNICATION. GIVEN THE COMPLEXITY OF THE CARCINOGENIC PROCESS AND THE LACK OF ANY MECHANISTIC UNDERSTANDING OF HOW IONIZING RADIATION AT LOW-LEVEL EXPOSURES AFFECTS THE MULTISTAGE, MULTIMECHANISM PROCESSES OF CARCINOGENESIS, IT IS IMPERATIVE THAT CONCEPTS AND PARADIGMS BE REEXAMINED WHEN EXTRAPOLATING FROM HIGH DOSE TO LOW DOSE. ANY HEALTH EFFECT DIRECTLY LINKED TO LOW-DOSE RADIATION EXPOSURE MUST HAVE MOLECULAR/BIOCHEMICAL AND BIOLOGICAL BASES. ON THE OTHER HAND, DEMONSTRATING SOME MOLECULAR/BIOCHEMICAL OR CELLULAR EFFECT, USING SURROGATE SYSTEMS FOR THE HUMAN BEING, DOES NOT NECESSARILY IMPLY A CORRESPONDING HEALTH EFFECT. GIVEN THE GENERAL ACCEPTANCE OF AN EXTRAPOLATED LNT MODEL, OUR CURRENT UNDERSTANDING OF CARCINOGENESIS CRIES OUT FOR A RESOLUTION OF A REAL PROBLEM. HOW CAN A LOW-LEVEL ACUTE, OR EVEN A CHRONIC, EXPOSURE OF IONIZING RADIATION BRING ABOUT ALL THE DIFFERENT MECHANISMS (MUTAGENIC, CYTOTOXIC, AND EPIGENETIC) AND GENOTYPIC/PHENOTYPIC CHANGES NEEDED TO CONVERT NORMAL CELLS TO AN INVASIVE, MALIGNANT CELL, GIVEN ALL THE PROTECTIVE, REPAIR, AND SUPPRESSIVE SYSTEMS KNOWN TO EXIST IN THE HUMAN BODY? UNTIL RECENTLY, THE PREVAILING PARADIGM THAT IONIZING RADIATION BRINGS ABOUT CANCER PRIMARILY BY DNA DAMAGE AND ITS CONVERSION TO GENE AND CHROMOSOMAL MUTATIONS, DROVE OUR INTERPRETATION OF RADIATION CARCINOGENESIS. TODAY, OUR KNOWLEDGE INCLUDES THE FACTS BOTH THAT EPIGENETIC EVENTS PLAY A MAJOR ROLE IN CARCINOGENESIS AND THAT LOW-DOSE RADIATION CAN ALSO INDUCE EPIGENETIC EVENTS IN AND BETWEEN CELLS IN TISSUES. THIS CHALLENGES ANY SIMPLE EXTRAPOLATION OF THE LNT MODEL. ALTHOUGH A RECENT DELINEATION OF "HALLMARKS" OF THE CANCER PROCESS HAS HELPED TO FOCUS ON HOW IONIZING RADIATION MIGHT CONTRIBUTE TO THE INDUCTION OF CANCERS, SEVERAL OTHER HALLMARKS, PREVIOUSLY IGNORED--NAMELY, THE STEM CELLS IN TISSUES AS TARGETS FOR CARCINOGENESIS AND THE ROLE OF CELL-CELL COMMUNICATION PROCESSES IN MODULATING THE RADIATION EFFECTS ON THE TARGET CELL--MUST BE CONSIDERED, PARTICULARLY FOR THE ADAPTIVE RESPONSE, BYSTANDER EFFECTS, AND GENOMIC INSTABILITY PHENOMENA.	2005	
                                       
15  5342 20 RADIATION-INDUCED LATE EFFECTS IN TWO AFFECTED INDIVIDUALS OF THE LILO RADIATION ACCIDENT. RADIATION EXPOSURE LEADS TO A RISK FOR LONG-TERM DETERMINISTIC AND STOCHASTIC LATE EFFECTS. TWO INDIVIDUALS EXPOSED TO PROTRACTED PHOTON RADIATION IN THE RADIOLOGICAL ACCIDENT AT THE LILO MILITARY SITE IN GEORGIA IN 1997 RECEIVED FOLLOW-UP TREATMENT AND RESECTION OF SEVERAL CHRONIC RADIATION ULCERS IN THE BUNDESWEHR HOSPITAL ULM, GERMANY, IN 2003. MULTI-PARAMETER ANALYSIS REVEALED THAT SPERMATOGENETIC ARREST AND SERUM HORMONE LEVELS IN BOTH PATIENTS HAD RECOVERED COMPARED TO THE STATUS IN 1997. HOWEVER, WE OBSERVED A PERSISTENCE OF ALTERED T-CELL RATIOS, INCREASED ICAM1 AND BETA1-INTEGRIN EXPRESSION, AND ABERRANT BONE MARROW CELLS AND LYMPHOCYTES WITH SIGNIFICANTLY INCREASED TRANSLOCATIONS 6 YEARS AFTER THE ACCIDENT. THIS INVESTIGATION THUS IDENTIFIED ALTERED END POINTS STILL DETECTABLE YEARS AFTER THE ACCIDENT THAT SUGGEST PERSISTENT GENOMIC DAMAGE AS WELL AS EPIGENETIC EFFECTS IN THESE INDIVIDUALS, WHICH MAY BE ASSOCIATED WITH AN ELEVATED RISK FOR THE DEVELOPMENT OF FURTHER LATE EFFECTS. OUR OBSERVATIONS FURTHER SUGGEST THE DEVELOPMENT OF A CHRONIC RADIATION SYNDROME AND INDICATE FOLLOW-UP PARAMETERS IN RADIATION VICTIMS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16  6550 27 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	

17  1655 14 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  4224 19 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	
                                                                                                                                                                           
19  5341 12 RADIATION-HORMESIS PHENOTYPES, THE RELATED MECHANISMS AND IMPLICATIONS FOR DISEASE PREVENTION AND THERAPY. HUMANS ARE CONTINUOUSLY EXPOSED TO IONIZING RADIATION THROUGHOUT LIFE FROM NATURAL SOURCES THAT INCLUDE COSMIC, SOLAR, AND TERRESTRIAL. MUCH HARSHER NATURAL RADIATION AND CHEMICAL ENVIRONMENTS EXISTED DURING OUR PLANET'S EARLY YEARS. MAMMALS SURVIVED THE HARSHER ENVIRONMENTS VIA EVOLUTIONARILY-CONSERVED GIFTS ? A CONTINUOUSLY EVOLVING SYSTEM OF STRESS-INDUCED NATURAL PROTECTIVE MEASURES (I.E., ACTIVATED NATURAL PROTECTION [ANP]). THE CURRENT PROTECTIVE SYSTEM IS DIFFERENTIALLY ACTIVATED BY STOCHASTIC (I.E., VARIABLE) LOW-RADIATION-DOSE THRESHOLDS AND WHEN OPTIMALLY ACTIVATED IN MAMMALS INCLUDES ANTIOXIDANTS, DNA DAMAGE REPAIR, P53-RELATED APOPTOSIS OF SEVERELY-DAMAGED CELLS, REACTIVE-OXYGEN-SPECIES (ROS)/REACTIVE-NITROGEN-SPECIES (RNS)- AND CYTOKINE-REGULATED AUXILIARY APOPTOSIS THAT SELECTIVELY REMOVES ABERRANT CELLS (E.G., PRECANCEROUS CELLS), SUPPRESSION OF DISEASE PROMOTING INFLAMMATION, AND IMMUNITY AGAINST CANCER CELLS. THE INTERCELLULAR-SIGNALING-BASED PROTECTIVE SYSTEM IS REGULATED AT LEAST IN PART VIA EPIGENETIC REPROGRAMMING OF ADAPTIVE-RESPONSE GENES. WHEN THE SYSTEM IS OPTIMALLY ACTIVATED, IT PROTECTS AGAINST CANCER AND SOME OTHER DISEASES, THEREBY LEADING TO HORMETIC PHENOTYPES (E.G., REDUCED DISEASE INCIDENCE TO BELOW THE BASELINE LEVEL; REDUCED PAIN FROM INFLAMMATION-RELATED PROBLEMS). HERE, SOME EXPRESSED RADIATION HORMESIS PHENOTYPES AND RELATED MECHANISMS ARE DISCUSSED ALONG WITH THEIR IMPLICATIONS FOR DISEASE PREVENTION AND THERAPY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20  5942 15 TARGETING OF CELLULAR REDOX METABOLISM FOR MITIGATION OF RADIATION INJURY. ACCIDENTAL EXPOSURE TO IONIZING RADIATION IS A SERIOUS CONCERN TO HUMAN LIFE. STUDIES ON THE MITIGATION OF SIDE EFFECTS FOLLOWING EXPOSURE TO ACCIDENTAL RADIATION EVENTS ARE ONGOING. RECENT STUDIES HAVE SHOWN THAT RADIATION CAN ACTIVATE SEVERAL SIGNALING PATHWAYS, LEADING TO CHANGES IN THE METABOLISM OF FREE RADICALS INCLUDING REACTIVE OXYGEN SPECIES (ROS) AND NITRIC OXIDE (NO). CELLULAR AND MOLECULAR MECHANISMS SHOW THAT RADIATION CAN CAUSE DISRUPTION OF NORMAL REDUCTION/OXIDATION (REDOX) SYSTEM. MITOCHONDRIA MALFUNCTION FOLLOWING EXPOSURE TO RADIATION AND MUTATIONS IN MITOCHONDRIA DNA (MTDNA) HAVE A KEY ROLE IN CHRONIC OXIDATIVE STRESS. FURTHERMORE, EXPOSURE TO RADIATION LEADS TO INFILTRATION OF INFLAMMATORY CELLS SUCH AS MACROPHAGES, LYMPHOCYTES AND MAST CELLS, WHICH ARE IMPORTANT SOURCES OF ROS AND NO. THESE CELLS GENERATE FREE RADICALS VIA UPREGULATION OF SOME PRO-OXIDANT ENZYMES SUCH AS NADPH OXIDASES, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) AND CYCLOOXYGENASE-2 (COX-2). EPIGENETIC CHANGES ALSO HAVE A KEY ROLE IN A SIMILAR WAY. OTHER MEDIATORS SUCH AS MAMMALIAN TARGET OF RAPAMYCIN (MTOR) AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR), WHICH ARE INVOLVED IN THE NORMAL METABOLISM OF CELLS HAVE ALSO BEEN SHOWN TO REGULATE CELL DEATH FOLLOWING EXPOSURE TO RADIATION. THESE MECHANISMS ARE TISSUE SPECIFIC. INHIBITION OR ACTIVATION OF EACH OF THESE TARGETS CAN BE SUGGESTED FOR MITIGATION OF RADIATION INJURY IN A SPECIFIC TISSUE. IN THE CURRENT PAPER, WE REVIEW THE CELLULAR AND MOLECULAR CHANGES IN THE METABOLISM OF CELLS AND ROS/NO FOLLOWING EXPOSURE TO RADIATION. FURTHERMORE, THE POSSIBLE STRATEGIES FOR MITIGATION OF RADIATION INJURY THROUGH MODULATION OF CELLULAR METABOLISM IN IRRADIATED ORGANS WILL BE DISCUSSED.	2020