1 5344 131 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 2 1174 68 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 3 1835 46 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 6550 41 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 5 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 6 5032 40 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 1655 28 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 8 4018 40 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 9 3418 30 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 10 2471 28 EPIGENETIC TRANSGENERATIONAL INHERITANCE OF ALTERED STRESS RESPONSES. ANCESTRAL ENVIRONMENTAL EXPOSURES HAVE PREVIOUSLY BEEN SHOWN TO PROMOTE EPIGENETIC TRANSGENERATIONAL INHERITANCE AND INFLUENCE ALL ASPECTS OF AN INDIVIDUAL'S LIFE HISTORY. IN ADDITION, PROXIMATE LIFE EVENTS SUCH AS CHRONIC STRESS HAVE DOCUMENTED EFFECTS ON THE DEVELOPMENT OF PHYSIOLOGICAL, NEURAL, AND BEHAVIORAL PHENOTYPES IN ADULTHOOD. WE USED A SYSTEMS BIOLOGY APPROACH TO INVESTIGATE IN MALE RATS THE INTERACTION OF THE ANCESTRAL MODIFICATIONS CARRIED TRANSGENERATIONALLY IN THE GERM LINE AND THE PROXIMATE MODIFICATIONS INVOLVING CHRONIC RESTRAINT STRESS DURING ADOLESCENCE. WE FIND THAT A SINGLE EXPOSURE TO A COMMON-USE FUNGICIDE (VINCLOZOLIN) THREE GENERATIONS REMOVED ALTERS THE PHYSIOLOGY, BEHAVIOR, METABOLIC ACTIVITY, AND TRANSCRIPTOME IN DISCRETE BRAIN NUCLEI IN DESCENDANT MALES, CAUSING THEM TO RESPOND DIFFERENTLY TO CHRONIC RESTRAINT STRESS. THIS ALTERATION OF BASELINE BRAIN DEVELOPMENT PROMOTES A CHANGE IN NEURAL GENOMIC ACTIVITY THAT CORRELATES WITH CHANGES IN PHYSIOLOGY AND BEHAVIOR, REVEALING THE INTERACTION OF GENETICS, ENVIRONMENT, AND EPIGENETIC TRANSGENERATIONAL INHERITANCE IN THE SHAPING OF THE ADULT PHENOTYPE. THIS IS AN IMPORTANT DEMONSTRATION IN AN ANIMAL THAT ANCESTRAL EXPOSURE TO AN ENVIRONMENTAL COMPOUND MODIFIES HOW DESCENDANTS OF THESE PROGENITOR INDIVIDUALS PERCEIVE AND RESPOND TO A STRESS CHALLENGE EXPERIENCED DURING THEIR OWN LIFE HISTORY. 2012 11 2901 37 GENDER DIFFERENCES IN GERM-CELL MUTAGENESIS AND GENETIC RISK. CURRENT INTERNATIONAL CLASSIFICATION SYSTEMS FOR CHEMICAL MUTAGENS ARE HAZARD-BASED RATHER THAN AIMED AT ASSESSING RISKS QUANTITATIVELY. IN THE PAST, GERM-CELL TESTS HAVE BEEN MAINLY PERFORMED WITH A LIMITED NUMBER OF SOMATIC CELL MUTAGENS, AND RARELY UNDER CONDITIONS AIMED AT COMPARING GENDER-SPECIFIC DIFFERENCES IN SUSCEPTIBILITY TO MUTAGEN EXPOSURES. THERE ARE PROFOUND DIFFERENCES IN THE GENETIC CONSTITUTION, AND IN HORMONAL, STRUCTURAL, AND FUNCTIONAL ASPECTS OF DIFFERENTIATION AND CONTROL OF GAMETOGENESIS BETWEEN THE SEXES. A CRITICAL REVIEW OF THE LITERATURE SUGGESTS THAT THESE DIFFERENCES MAY HAVE A PROFOUND IMPACT ON THE RELATIVE SUSCEPTIBILITY, STAGE OF HIGHEST SENSITIVITY AND THE RELATIVE RISK FOR THE GENESIS OF GENE MUTATION, AS WELL AS STRUCTURAL AND NUMERICAL CHROMOSOMAL ABERRATIONS IN MALE AND FEMALE GERM CELLS. TRANSMISSION OF GERM-CELL MUTATIONS TO THE OFFSPRING MAY ALSO ENCOUNTER GENDER-SPECIFIC INFLUENCES. GENDER DIFFERENCES IN SUSCEPTIBILITY TO CHEMICALLY DERIVED ALTERATIONS IN IMPRINTING PATTERNS MAY POSE A THREAT FOR THE HEALTH OF THE OFFSPRING AND MAY ALSO BE TRANSMITTED TO FUTURE GENERATIONS. RECENT REPORTS ON DIFFERENT GENETIC EFFECTS FROM HIGH ACUTE AND FROM CHRONIC LOW-DOSE EXPOSURES CHALLENGE THE VALIDITY OF CONCLUSIONS DRAWN FROM STANDARD METHODS OF MUTAGENICITY TESTING. IN CONCLUSION, RESEARCH IS URGENTLY NEEDED TO IDENTIFY GENETIC HAZARDS FOR A LARGER RANGE OF CHEMICAL COMPOUNDS, INCLUDING THOSE SUSPECTED TO DISTURB PROPER CHROMOSOME SEGREGATION. ALTERATIONS IN EPIGENETIC PROGRAMMING AND THEIR HEALTH CONSEQUENCES WILL HAVE TO BE INVESTIGATED. MORE ATTENTION SHOULD BE PAID TO GENDER-SPECIFIC GENETIC EFFECTS. FINALLY, THE DATABASE FOR GERM-CELL MUTAGENS SHOULD BE ENLARGED USING MOLECULAR METHODOLOGIES, AND GENETIC EPIDEMIOLOGY STUDIES SHOULD BE PERFORMED WITH THESE TECHNIQUES TO VERIFY HUMAN GENETIC RISK. 2007 12 77 34 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 13 6594 37 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 14 4538 33 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 15 4224 36 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 16 1162 30 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 17 1817 29 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 18 3714 29 INHERITANCE OF SOCIAL DOMINANCE IS ASSOCIATED WITH GLOBAL SPERM DNA METHYLATION IN INBRED MALE MICE. DOMINANCE RELATIONSHIPS BETWEEN MALES AND THEIR ASSOCIATED TRAITS ARE USUALLY HERITABLE AND HAVE IMPLICATIONS FOR SEXUAL SELECTION IN ANIMALS. IN PARTICULAR, SOCIAL DOMINANCE AND ITS RELATED MALE PHEROMONES ARE HERITABLE IN INBRED MICE; THUS, WE WONDERED WHETHER EPIGENETIC CHANGES DUE TO ALTERED LEVELS OF DNA METHYLATION DETERMINE INHERITANCE. HERE, WE USED C57BL/6 MALE MICE TO ESTABLISH A SOCIAL DOMINANCE-SUBORDINATION RELATIONSHIP THROUGH CHRONIC DYADIC ENCOUNTERS, AND THIS RELATIONSHIP AND PHEROMONE COVARIATION OCCURRED IN THEIR OFFSPRING, INDICATIVE OF HERITABILITY. THROUGH TRANSCRIPTOME SEQUENCING AND WHOLE-GENOME DNA METHYLATION PROFILING OF THE SPERM OF BOTH GENERATIONS, WE FOUND THAT DIFFERENTIAL METHYLATION OF MANY GENES WAS INDUCED BY SOCIAL DOMINANCE-SUBORDINATION IN SIRES AND COULD BE PASSED ON TO THE OFFSPRING. THESE METHYLATED GENES WERE MAINLY RELATED TO GROWTH AND DEVELOPMENT PROCESSES, NEURODEVELOPMENT, AND CELLULAR TRANSPORTATION. THE EXPRESSION OF THE GENES WITH SIMILAR FUNCTIONS IN WHOLE-GENOME METHYLATION/BISULFITE SEQUENCING WAS ALSO DIFFERENTIATED BY SOCIAL DOMINANCE-SUBORDINATION, AS REVEALED BY RNA-SEQ. IN PARTICULAR, THE GENE DENND1A, WHICH REGULATES NEURAL SIGNALING, WAS DIFFERENTIALLY METHYLATED AND EXPRESSED IN THE SPERM AND MEDIAL PREFRONTAL CORTEX IN PAIRED MALES BEFORE AND AFTER DOMINANCE-SUBORDINATION ESTABLISHMENT, SUGGESTING THE POTENTIAL EPIGENETIC CONTROL AND INHERITANCE OF SOCIAL DOMINANCE-RELATED AGGRESSION. WE SUGGEST THAT SOCIAL DOMINANCE MIGHT BE PASSED ON TO MALE OFFSPRING THROUGH SPERM DNA METHYLATION AND THAT THE DIFFERENCES COULD POTENTIALLY AFFECT MALE COMPETITION IN OFFSPRING BY AFFECTING THE DEVELOPMENT OF THE NERVOUS SYSTEM. 2023 19 266 37 ADVERSE OUTCOME PATHWAYS FOR IONIZING RADIATION AND BREAST CANCER INVOLVE DIRECT AND INDIRECT DNA DAMAGE, OXIDATIVE STRESS, INFLAMMATION, GENOMIC INSTABILITY, AND INTERACTION WITH HORMONAL REGULATION OF THE BREAST. KNOWLEDGE ABOUT ESTABLISHED BREAST CARCINOGENS CAN SUPPORT IMPROVED AND MODERNIZED TOXICOLOGICAL TESTING METHODS BY IDENTIFYING KEY MECHANISTIC EVENTS. IONIZING RADIATION (IR) INCREASES THE RISK OF BREAST CANCER, ESPECIALLY FOR WOMEN AND FOR EXPOSURE AT YOUNGER AGES, AND EVIDENCE OVERALL SUPPORTS A LINEAR DOSE-RESPONSE RELATIONSHIP. WE USED THE ADVERSE OUTCOME PATHWAY (AOP) FRAMEWORK TO OUTLINE AND EVALUATE THE EVIDENCE LINKING IONIZING RADIATION WITH BREAST CANCER FROM MOLECULAR INITIATING EVENTS TO THE ADVERSE OUTCOME THROUGH INTERMEDIATE KEY EVENTS, CREATING A QUALITATIVE AOP. WE IDENTIFIED KEY EVENTS BASED ON REVIEW ARTICLES, SEARCHED PUBMED FOR RECENT LITERATURE ON KEY EVENTS AND IR, AND IDENTIFIED ADDITIONAL PAPERS USING REFERENCES. WE MANUALLY CURATED PUBLICATIONS AND EVALUATED DATA QUALITY. IONIZING RADIATION DIRECTLY AND INDIRECTLY CAUSES DNA DAMAGE AND INCREASES PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES (RONS). RONS LEAD TO DNA DAMAGE AND EPIGENETIC CHANGES LEADING TO MUTATIONS AND GENOMIC INSTABILITY (GI). PROLIFERATION AMPLIFIES THE EFFECTS OF DNA DAMAGE AND MUTATIONS LEADING TO THE AO OF BREAST CANCER. SEPARATELY, RONS AND DNA DAMAGE ALSO INCREASE INFLAMMATION. INFLAMMATION CONTRIBUTES TO DIRECT AND INDIRECT EFFECTS (EFFECTS IN CELLS NOT DIRECTLY REACHED BY IR) VIA POSITIVE FEEDBACK TO RONS AND DNA DAMAGE, AND SEPARATELY INCREASES PROLIFERATION AND BREAST CANCER THROUGH PRO-CARCINOGENIC EFFECTS ON CELLS AND TISSUE. FOR EXAMPLE, GENE EXPRESSION CHANGES ALTER INFLAMMATORY MEDIATORS, RESULTING IN IMPROVED SURVIVAL AND GROWTH OF CANCER CELLS AND A MORE HOSPITABLE TISSUE ENVIRONMENT. ALL OF THESE EVENTS OVERLAP AT MULTIPLE POINTS WITH EVENTS CHARACTERISTIC OF "BACKGROUND" INDUCTION OF BREAST CARCINOGENESIS, INCLUDING HORMONE-RESPONSIVE PROLIFERATION, OXIDATIVE ACTIVITY, AND DNA DAMAGE. THESE OVERLAPS MAKE THE BREAST PARTICULARLY SUSCEPTIBLE TO IONIZING RADIATION AND REINFORCE THAT THESE BIOLOGICAL ACTIVITIES ARE IMPORTANT CHARACTERISTICS OF CARCINOGENS. AGENTS THAT INCREASE THESE BIOLOGICAL PROCESSES SHOULD BE CONSIDERED POTENTIAL BREAST CARCINOGENS, AND PREDICTIVE METHODS ARE NEEDED TO IDENTIFY CHEMICALS THAT INCREASE THESE PROCESSES. TECHNIQUES ARE AVAILABLE TO MEASURE RONS, DNA DAMAGE AND MUTATION, CELL PROLIFERATION, AND SOME INFLAMMATORY PROTEINS OR PROCESSES. IMPROVED ASSAYS ARE NEEDED TO MEASURE GI AND CHRONIC INFLAMMATION, AS WELL AS THE INTERACTION WITH HORMONALLY DRIVEN DEVELOPMENT AND PROLIFERATION. SEVERAL METHODS MEASURE DIVERSE EPIGENETIC CHANGES, BUT IT IS NOT CLEAR WHICH CHANGES ARE RELEVANT TO BREAST CANCER. IN ADDITION, MOST TOXICOLOGICAL ASSAYS ARE NOT CONDUCTED IN MAMMARY TISSUE, AND SO IT IS A PRIORITY TO EVALUATE IF RESULTS FROM OTHER TISSUES ARE GENERALIZABLE TO BREAST, OR TO CONDUCT ASSAYS IN BREAST TISSUE. DEVELOPING AND APPLYING THESE ASSAYS TO IDENTIFY EXPOSURES OF CONCERN WILL FACILITATE EFFORTS TO REDUCE SUBSEQUENT BREAST CANCER RISK. 2020 20 3042 30 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