1 4923 128 PARENTAL DIURON EXPOSURE CAUSES LOWER HATCHABILITY AND ABNORMAL OVARIAN DEVELOPMENT IN OFFSPRING OF MEDAKA (ORYZIAS MELASTIGMA). DIURON IS ONE OF THE MOST WIDELY USED HERBICIDES WORLDWIDE. IT HAS BEEN WIDELY DETECTED IN VARIOUS AQUATIC ENVIRONMENTS, ESPECIALLY IN MARINE ECOSYSTEMS. ALTHOUGH DIRECT EFFECTS OF DIURON EXPOSURE ON VARIOUS ORGANISMS HAVE BEEN REPORTED, LITTLE IS KNOWN ABOUT ITS EFFECTS ON MARINE FISHES INCLUDING MULTIGENERATIONAL EFFECTS. HEREIN, THE FILIAL GENERATION (F1) OF DIURON-EXPOSED MARINE MEDAKA (ORYZIAS MELASTIGMA) (F0) WAS RAISED IN CLEAN SEAWATER FROM FERTILIZED EGGS TO ADULTHOOD AND USED AS A MARINE FISH MODEL TO STUDY THE POTENTIAL MULTIGENERATIONAL EFFECTS OF DIURON. WE FOUND THAT THE SUCCESSFUL HATCHING OF F1 LARVAE WAS SIGNIFICANTLY REDUCED AND THAT OVARIAN DEVELOPMENT IN F1 FEMALES WAS RETARDED. A SIGNIFICANT INCREASE IN THE PERCENTAGE OF PREVITELLOGENIC OOCYTES, ALONG WITH A VISUAL DECREASE IN THE PERCENTAGE OF VITELLOGENIC AND MATURE OOCYTES IN THE F1 OVARY, WERE OBSERVED. THE HORMONE LEVELS OF THE HYPOTHALAMUS-PITUITARY-GONAD-LIVER AXIS AND VITELLOGENIN-RELATED TRANSCRIPTION WERE DOWNREGULATED. IN ADDITION, THE MRNA LEVELS OF DNA METHYLTRANSFERASE IN THE BRAIN, OVARY AND LIVER OF F1 ADULT FISH EXHIBITED SIGNIFICANT UPREGULATION, SUGGESTING THAT THE PROBABLE UNDERLYING MULTIGENERATIONAL MECHANISM MIGHT BE ASSOCIATED WITH EPIGENETIC MODIFICATIONS. TAKEN TOGETHER, THESE RESULTS DEMONSTRATED THAT CHRONIC ENVIRONMENTAL DIURON EXPOSURE IN F0 MARINE MEDAKA CAN INHIBIT F1 OVARY DEVELOPMENT AND SUGGESTED THAT DIURON MAY AFFECT MARINE FISH THRIVING IN THE OCEAN. 2022 2 3109 34 GENOTOXIC AND EPIGENETIC EFFECTS OF DIURON IN THE PACIFIC OYSTER: IN VITRO EVIDENCE OF INTERACTION BETWEEN DNA DAMAGE AND DNA METHYLATION. RECENTLY, RESEARCH HAS CONTRIBUTED TO BETTER KNOWLEDGE ON THE OCCURRENCE OF PESTICIDES IN COASTAL WATER BY IDENTIFYING FREQUENTLY DETECTED SUBSTANCES, THEIR CONCENTRATION RANGE AND THEIR ACUTE AND CHRONIC TOXICITY FOR ORGANISMS. PESTICIDE POLLUTION IS OF PARTICULAR CONCERN IN FRANCE DUE TO IMPORTANT AGRICULTURAL ACTIVITIES AND PRESENCE OF SEVERAL EXOREIC CATCHMENT AREAS THAT VEHICLE PESTICIDES UP TO COASTAL WATERS, IMPACTING NON-TARGET MARINE SPECIES. SEVERAL ECOTOXICOLOGY QUESTIONS REMAIN TO BE ADDRESSED CONCERNING THE LONG-TERM EFFECTS OF CHRONIC PESTICIDE EXPOSURE AND THE MECHANISMS INVOLVED IN ADAPTATION TO CHEMICAL STRESS. IN THE PRESENT STUDY, WE BROUGHT NEW INSIGHTS ON THE GENETIC AND EPIGENETIC EFFECTS OF THE HERBICIDE DIURON IN OYSTER GENITORS. DURING GAMETOGENESIS, WE EXPOSED CRASSOSTREA GIGAS TO ENVIRONMENTALLY REALISTIC HERBICIDE CONCENTRATIONS (0.2-0.3 MUG L(-1) DURING TWO 7-DAY PERIODS AT HALF-COURSE AND END OF GAMETOGENESIS). DIURON EXPOSURE WAS SHOWN TO DECREASE GLOBAL DNA METHYLATION AND TOTAL METHYLTRANSFERASE ACTIVITY IN WHOLE OYSTER TISSUE; THIS IS CONSISTENT WITH THE PREVIOUS OBSERVATION OF A SIGNIFICANT DECREASE IN DNMT1 GENE EXPRESSION. DIURON EFFECT SEEMED TO BE TISSUE-SPECIFIC; HYPERMETHYLATION WAS DETECTED IN THE DIGESTIVE GLAND, WHEREAS DIURON EXPOSURE HAD NO EFFECT ON GILL AND GONAD TISSUE. THE GENOTOXICITY OF DIURON WAS CONFIRMED BY THE DETECTION OF ONE ADDUCT IN GONAD DNA. BY USING IN VITRO APPROACHES AND HUMAN DNMT1 (DNMT1 HAS NOT BEEN PURIFIED YET IN BIVALVES), THE PRESENCE OF DNA LESIONS (ADDUCT, 8-OXODGUO) WAS SHOWN TO INTERFERE WITH DNMT1 ACTIVITY, INDICATING A COMPLEX INTERACTION BETWEEN DNA DAMAGE AND DNA METHYLATION. BASED ON OUR RESULTS, WE PROPOSE MECHANISMS TO EXPLAIN THE EFFECT OF DIURON EXPOSURE ON DNA METHYLATION, A WIDESPREAD EPIGENETIC MARK. 2021 3 891 46 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 4 6594 33 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 5 166 38 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 6 934 27 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 7 6552 33 TRANSGENERATIONAL DNA METHYLATION CHANGES IN DAPHNIA MAGNA EXPOSED TO CHRONIC GAMMA IRRADIATION. OUR AIM WAS TO INVESTIGATE EPIGENETIC CHANGES IN DAPHNIA MAGNA AFTER A 25-DAY CHRONIC EXTERNAL GAMMA IRRADIATION (GENERATION F0 EXPOSED TO 6.5 MUGY.H(-1) OR 41.3 MGY.H(-1)) AND THEIR POTENTIAL INHERITANCE BY SUBSEQUENT RECOVERING GENERATIONS, NAMELY, F2 (EXPOSED AS GERMLINE CELLS IN F1 EMBRYOS) AND F3 (THE FIRST TRULY UNEXPOSED GENERATION). EFFECTS ON SURVIVAL, GROWTH, AND REPRODUCTION WERE OBSERVED AND DNA WAS EXTRACTED FOR WHOLE-GENOME BISULFITE SEQUENCING IN ALL GENERATIONS. RESULTS SHOWED EFFECTS ON REPRODUCTION IN F0 BUT NO EFFECT IN THE SUBSEQUENT GENERATIONS F1, F2, AND F3. IN CONTRAST, WE OBSERVED SIGNIFICANT METHYLATION CHANGES AT SPECIFIC CPG POSITIONS IN EVERY GENERATION INDEPENDENT OF DOSE RATE, WITH A MAJORITY OF HYPOMETHYLATION. SOME OF THESE CHANGES WERE SHARED BETWEEN DOSE RATES AND BETWEEN GENERATIONS. ASSOCIATED GENE FUNCTIONS INCLUDED GENE FAMILIES AND GENES THAT WERE PREVIOUSLY SHOWN TO PLAY ROLES DURING EXPOSURE TO IONIZING RADIATION. COMMON METHYLATION CHANGES DETECTED BETWEEN GENERATIONS F2 AND F3 CLEARLY SHOWED THAT EPIGENETIC MODIFICATIONS CAN BE TRANSMITTED TO UNEXPOSED GENERATIONS, MOST LIKELY THROUGH THE GERMLINE, WITH POTENTIAL IMPLICATIONS FOR ENVIRONMENTAL RISK. 2018 8 6553 39 TRANSGENERATIONAL EFFECTS IN DNA METHYLATION, GENOTOXICITY AND REPRODUCTIVE PHENOTYPE BY CHRONIC ARSENIC EXPOSURE. AN EMERGING CONCERN IS THE INFLUENCES OF EARLY LIFE EXPOSURE TO ENVIRONMENTAL TOXICANTS ON OFFSPRING CHARACTERISTICS IN LATER LIFE. SINCE RECENT EVIDENCE SUGGESTS A TRANSGENERATIONAL TRANSFERENCE OF ABERRANT PHENOTYPES FROM EXPOSED-PARENTS TO NON-EXPOSED OFFSPRING RELATED TO ADULT-ONSET DISEASES INCLUDING REPRODUCTIVE PHENOTYPE. THE TRANSGENERATIONAL POTENTIAL OF ARSENIC A WELL KNOW GENOTOXIC AND EPIGENETIC MODIFIER AGENT HAS NOT BEEN ASSESSED IN MAMMALS UNTIL NOW. IN THIS EXPERIMENTAL STUDY, WE EVALUATED THE TRANSGENERATIONAL EFFECTS OF ARSENIC IN A RAT MODEL WITH CHRONIC EXPOSURE TO ARSENIC. RATS CHRONICALLY EXPOSED TO ARSENIC IN DRINKING WATER (1 MG AS(2)O(3)/ML) (F0) WERE MATED TO PRODUCE THE ARSENIC LINEAGE (F1, F2, AND F3). THE ARSENIC TOXIC EFFECTS ON WERE EVALUATED OVER THE FOUR GENERATIONS BY ANALYZING THE DNA METHYLATION PERCENTAGE, GENOTOXICITY IN WBC AND PHYSICAL AND REPRODUCTIVE PARAMETERS, INCLUDING SPERM QUALITY PARAMETERS AND HISTOPATHOLOGICAL EVALUATION OF THE GONADS. CHRONIC EXPOSURE TO ARSENIC CAUSED GENOTOXIC DAMAGE (F0-F3) DIFFERENT METHYLATION PATTERNS, ALTERATIONS IN PHYSICAL AND REPRODUCTIVE PARAMETERS, ABERRANT MORPHOLOGY IN THE OVARIES (F0 AND F1) AND TESTICLES (F1-F3), AND A DECREASE IN THE QUALITY OF SPERM (F0-F3, EXCEPT F2). PARENTAL CHRONIC ARSENIC EXPOSURE CAUSES TRANSGENERATIONAL GENOTOXICITY AND CHANGES IN GLOBAL DNA METHYLATION WHICH MIGHT BE ASSOCIATED WITH REPRODUCTIVE DEFECTS IN RATS. COMBINED WITH RECENT STUDIES REVEAL THAT DISTURBANCES IN THE EARLY LIFE OF AN INDIVIDUAL CAN AFFECT THE HEALTH OF LATER GENERATIONS. 2021 9 184 41 ACCOUNTING FOR TRANSGENERATIONAL EFFECTS OF TOXICANT EXPOSURE IN POPULATION MODELS ALTERS THE PREDICTED LONG-TERM POPULATION STATUS. ACUTE ENVIRONMENTAL STRESSORS SUCH AS SHORT-TERM EXPOSURE TO POLLUTANTS CAN HAVE LASTING EFFECTS ON ORGANISMS, POTENTIALLY IMPACTING FUTURE GENERATIONS. PARENTAL EXPOSURE TO TOXICANTS CAN RESULT IN CHANGES TO THE EPIGENOME (E.G., DNA METHYLATION) THAT ARE PASSED DOWN TO SUBSEQUENT, UNEXPOSED GENERATIONS. HOWEVER, IT IS DIFFICULT TO GAUGE THE CUMULATIVE POPULATION-SCALE IMPACTS OF EPIGENETIC EFFECTS FROM LABORATORY EXPERIMENTS ALONE. HERE, WE DEVELOPED A SIZE- AND AGE-STRUCTURED DELAY-COORDINATE POPULATION MODEL TO EVALUATE THE LONG-TERM CONSEQUENCES OF EPIGENETIC MODIFICATIONS ON POPULATION SUSTAINABILITY. THE MODEL EMULATED CHANGES IN GROWTH, MORTALITY, AND FECUNDITY IN THE F0, F1, AND F2 GENERATIONS OBSERVED IN EXPERIMENTS IN WHICH LARVAL MENIDIA BERYLLINA WERE EXPOSED TO ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF BIFENTHRIN (BIF), ETHINYLESTRADIOL (EE2), LEVONORGESTREL (LV), OR TRENBOLONE (TB) IN THE PARENT GENERATION (F0) AND REARED IN CLEAN WATER UP TO THE F2 GENERATION. OUR ANALYSIS SUGGESTS POTENTIALLY DRAMATIC POPULATION-LEVEL EFFECTS OF REPEATED, CHRONIC EXPOSURES OF EARLY-LIFE STAGE FISH THAT ARE NOT CAPTURED BY MODELS NOT ACCOUNTING FOR THOSE EFFECTS. SIMULATED EXPOSURES LED TO SUBSTANTIAL DECLINES IN POPULATION ABUNDANCE (LV AND BIF) OR NEAR-EXTINCTION (EE2 AND TB) WITH THE EXACT TRAJECTORY AND TIMELINE OF POPULATION DECLINE DEPENDENT ON THE COMBINATION OF F0, F1, AND F2 EFFECTS PRODUCED BY EACH COMPOUND. EVEN ACUTE ONE-TIME EXPOSURES OF EACH COMPOUND LED TO DECLINES AND RECOVERY OVER MULTIPLE YEARS DUE TO LAGGED EPIGENETIC EFFECTS. THESE RESULTS DEMONSTRATE THE POTENTIAL FOR ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF COMMONLY USED COMPOUNDS TO IMPACT THE POPULATION DYNAMICS AND SUSTAINABILITY OF AN ECOLOGICALLY RELEVANT SPECIES AND MODEL ORGANISM. 2022 10 6681 32 USING ZEBRAFISH EMBRYO BIOASSAYS TO IDENTIFY CHEMICALS MODULATING THE REGULATION OF THE EPIGENOME: A CASE STUDY WITH SIMVASTATIN. CONTAMINANTS OF EMERGING CONCERN HAVE BEEN INCREASINGLY ASSOCIATED WITH THE MODULATION OF THE EPIGENOME, LEADING TO POTENTIALLY INHERITED AND PERSISTENT IMPACTS ON APICAL ENDPOINTS. HERE, WE ADDRESS THE PERFORMANCE OF THE OECD TEST NO. 236 FET (FISH EMBRYO ACUTE TOXICITY) IN THE IDENTIFICATION OF CHEMICALS ABLE TO MODULATE THE EPIGENOME. USING ZEBRAFISH (DANIO RERIO) EMBRYOS, ACUTE AND CHRONIC EXPOSURES WERE PERFORMED WITH THE PHARMACEUTICAL, SIMVASTATIN (SIM), A WIDELY PRESCRIBED HYPOCHOLESTEROLEMIC DRUG REPORTED TO INDUCE INTER AND TRANSGENERATIONAL EFFECTS. IN THE PRESENT STUDY, THE EPIGENETIC EFFECTS OF ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF SIM (FROM 8 NG/L TO 2000 NG/L) WERE ADDRESSED FOLLOWING (1) AN ACUTE EMBRYO ASSAY BASED ON OECD TEST NO. 236 FET, (2) A CHRONIC PARTIAL LIFE-CYCLE EXPOSURE USING ADULT ZEBRAFISH (90 DAYS), AND (3) F1 EMBRYOS OBTAINED FROM PARENTAL EXPOSED ANIMALS. SIMVASTATIN INDUCED SIGNIFICANT EFFECTS IN GENE EXPRESSION OF KEY EPIGENETIC BIOMARKERS (DNA METHYLATION AND HISTONE ACETYLATION/DEACETYLATION) IN THE GONADS OF EXPOSED ADULT ZEBRAFISH AND IN 80 HPF ZEBRAFISH EMBRYOS (ACUTE AND CHRONIC PARENTAL INTERGENERATIONAL EXPOSURE), ALBEIT WITH DISTINCT EFFECT PROFILES BETWEEN BIOLOGICAL SAMPLES. IN THE CHRONIC EXPOSURE, SIM IMPACTED PARTICULARLY DNA METHYLTRANSFERASE GENES IN MALES AND FEMALE GONADS, WHEREAS IN F1 EMBRYOS SIM AFFECTED MOSTLY GENES ASSOCIATED WITH HISTONE ACETYLATION/DEACETYLATION. IN THE EMBRYO ACUTE DIRECT EXPOSURE, SIM MODULATED THE EXPRESSION OF BOTH GENES INVOLVED IN DNA METHYLATION AND HISTONE DEACETYLASE. THESE FINDINGS FURTHER SUPPORT THE USE OF EPIGENETIC BIOMARKERS IN ZEBRAFISH EMBRYOS IN A HIGH THROUGHPUT APPROACH TO IDENTIFY AND PRIORITIZE EPIGENOME-MODULATING CHEMICALS. 2023 11 4528 26 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 12 4538 32 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 13 2698 37 EXAMINING MULTI- AND TRANSGENERATIONAL BEHAVIORAL AND MOLECULAR ALTERATIONS RESULTING FROM PARENTAL EXPOSURE TO AN ENVIRONMENTAL PCB AND PBDE MIXTURE. POLYCHLORINATED BIPHENYLS (PCBS) AND POLYBROMINATED DIPHENYL ETHERS (PBDES) ARE PERSISTENT ORGANIC POLLUTANTS EXTENSIVELY USED DURING THE 20(TH) CENTURY AND STILL PRESENT IN AQUATIC ENVIRONMENTS DESPITE THEIR BAN. EFFECTS OF EXPOSURE TO THESE COMPOUNDS OVER GENERATIONS ARE POORLY DOCUMENTED. THEREFORE, OUR AIMS WERE TO CHARACTERIZE BEHAVIORAL RESPONSES AND UNDERLYING MOLECULAR MECHANISMS IN ZEBRAFISH EXPOSED TO AN ENVIRONMENTALLY RELEVANT MIXTURE OF PCBS AND PBDES AS WELL AS IN FOUR UNEXPOSED OFFSPRING GENERATIONS. ZEBRAFISH (F0) WERE CHRONICALLY EXPOSED FROM THE FIRST MEAL ONWARD TO A DIET SPIKED WITH A MIXTURE CONTAINING 22 PCB AND 7 PBDE CONGENERS IN PROPORTIONS AND CONCENTRATIONS REFLECTING ENVIRONMENTAL SITUATIONS (SIGMAPCBS = 1991 AND SIGMAPBDES = 411 NG/G). FOUR OFFSPRING GENERATIONS (F1 TO F4) WERE OBTAINED FROM THIS F0 AND WERE NOT FURTHER EXPOSED. BEHAVIOR WAS ASSESSED AT BOTH LARVAL AND ADULT STAGES. MECHANISMS RELATED TO BEHAVIORAL DEFECTS (HABENULA MATURATION AND C-FOS TRANSCRIPTION) AND METHYLATION (DNMTS TRANSCRIPTION) WERE MONITORED IN LARVAE. EXPOSED ADULT F0 AS WELL AS F1 AND F3 ADULTS DISPLAYED NO BEHAVIORAL CHANGE WHILE F2 EXPRESSED ANXIETY-LIKE BEHAVIOR. LARVAL BEHAVIOR WAS ALSO DISRUPTED, I.E. HYPERACTIVE AFTER LIGHT TO DARK TRANSITION IN F1 OR HYPOACTIVE IN F2, F3 AND F4. BEHAVIORAL DISRUPTIONS MAY BE RELATED TO DEFECT IN HABENULA MATURATION (OBSERVED IN F1) AND CHANGE IN C-FOS TRANSCRIPTION (OBSERVED IN F1 AND F2). TRANSCRIPTION OF THE GENE ENCODING DNA METHYLTRANSFERASE (DNMT3BA) WAS ALSO MODIFIED IN ALL GENERATIONS. OUR RESULTS LEAD US TO HYPOTHESIZE THAT CHRONIC DIETARY EXPOSURE TO AN ENVIRONMENTALLY RELEVANT MIXTURE OF PCB AND PBDE TRIGGERS MULTIGENERATIONAL AND TRANSGENERATIONAL MOLECULAR AND BEHAVIORAL DISRUPTIONS IN A VERTEBRATE MODEL. 2019 14 1325 26 DEPLETED URANIUM INDUCES SEX- AND TISSUE-SPECIFIC METHYLATION PATTERNS IN ADULT ZEBRAFISH. WE EXAMINED THE EFFECTS OF CHRONIC EXPOSURE TO DIFFERENT CONCENTRATIONS (2 AND 20 MUG L(-)(1)) OF ENVIRONMENTALLY RELEVANT WATERBORNE DEPLETED URANIUM (DU) ON THE DNA METHYLATION PATTERNS BOTH AT HPAII RESTRICTION SITES (5'-CCGG-3') AND ACROSS THE WHOLE GENOME IN THE ZEBRAFISH BRAIN, GONADS, AND EYES. WE FIRST IDENTIFIED SEX-DEPENDENT DIFFERENCES IN THE METHYLATION LEVEL OF HPAII SITES AFTER EXPOSURE. IN MALES, THESE EFFECTS WERE PRESENT AS EARLY AS 7 DAYS AFTER EXPOSURE TO 20 MUG L(-)(1) DU, AND WERE EVEN MORE PRONOUNCED IN THE BRAIN, GONADS, AND EYES AFTER 24 DAYS. HOWEVER, IN FEMALES, HYPOMETHYLATION WAS ONLY OBSERVED IN THE GONADS AFTER EXPOSURE TO 20 MUG L(-)(1) DU FOR 24 DAYS. SEX-SPECIFIC EFFECTS OF DU WERE ALSO APPARENT AT THE WHOLE-GENOME LEVEL, BECAUSE IN MALES, EXPOSURE TO 20 MUG L(-)(1) DU FOR 24 DAYS RESULTED IN CYTOSINE HYPERMETHYLATION IN THE BRAIN AND EYES AND HYPOMETHYLATION IN THE GONADS. IN CONTRAST, IN FEMALES, HYPERMETHYLATION WAS OBSERVED IN THE BRAIN AFTER EXPOSURE TO BOTH CONCENTRATIONS OF DU FOR 7 DAYS. BASED ON OUR CURRENT KNOWLEDGE OF URANIUM TOXICITY, SEVERAL HYPOTHESES ARE PROPOSED TO EXPLAIN THESE FINDINGS, INCLUDING THE INVOLVEMENT OF OXIDATIVE STRESS, ALTERATION OF DEMETHYLATION ENZYMES AND THE CALCIUM SIGNALING PATHWAY. THIS STUDY REPORTS, FOR THE FIRST TIME, THE SEX- AND TISSUE-SPECIFIC EPIGENETIC CHANGES THAT OCCUR IN A NONHUMAN ORGANISM AFTER EXPOSURE TO ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF URANIUM, WHICH COULD INDUCE TRANSGENERATIONAL EPIGENETIC EFFECTS. 2016 15 1174 28 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 16 5100 24 POLYCHLORINATED BIPHENYLS (PCBS) ALTER DNA METHYLATION AND GENOMIC INTEGRITY OF SHEEP FETAL CELLS IN A SIMPLIFIED IN VITRO MODEL OF PREGNANCY EXPOSURE. POLYCHLORINATED BIPHENYLS (PCBS) ARE PERSISTENT ORGANIC POLLUTANTS UBIQUITOUSLY DETECTABLE IN THE ENVIRONMENT AND IN THE FOOD CHAIN. PRENATAL EXPOSURE TO PCBS NEGATIVELY AFFECTS FETAL DEVELOPMENT AND PRODUCES LONG-TERM DETRIMENTAL EFFECTS ON CHILD HEALTH. THE PRESENT STUDY SOUGHT TO EVALUATE THE CYTOTOXIC AND GENOTOXIC EFFECTS OF CHRONIC PCB EXPOSURE ON FETAL CELLS DURING PREGNANCY. TO THIS AIM, SHEEP EMBRYONIC FIBROBLASTS (SEF) AND AMNIOCYTES (SA) WERE CULTURED IN VITRO IN THE PRESENCE OF LOW DOSES OF PCBS FOR A PERIOD OF 120DAYS, COMPARABLE TO THE FULL TERM OF OVINE PREGNANCY. CELLULAR PROLIFERATION RATES, GLOBAL DNA METHYLATION, CHROMOSOME INTEGRITY, AND MARKERS OF DNA DAMAGE WERE EVALUATED AT DIFFERENT TIME POINTS. MOREOVER, SEF TREATED WITH PCBS FOR 60DAYS WERE LEFT UNTREATED FOR ONE FURTHER MONTH AND THEN EXAMINED IN ORDER TO EVALUATE THE REVERSIBILITY OF PCB-INDUCED EPIGENETIC DEFECTS. PCB-TREATED SEF WERE MORE SENSITIVE THAN SA TREATED WITH PCBS, IN TERMS OF LOW CELL PROLIFERATION, AND INCREASED DNA DAMAGE AND GLOBAL DNA METHYLATION, WHICH WERE STILL DETECTABLE AFTER INTERRUPTION OF PCB TREATMENT. THESE DATA INDICATE THAT CHRONIC EXPOSURE OF FETAL CELLS TO PCBS CAUSES PERMANENT GENOMIC AND EPIGENETIC INSTABILITY, WHICH MAY INFLUENCE BOTH PRENATAL AND POST-NATAL GROWTH UP TO ADULTHOOD. OUR IN VITRO MODEL OFFER A SIMPLE AND CONTROLLED MEANS OF STUDYING THE EFFECTS OF DIFFERENT CONTAMINANTS ON FETAL CELLS - ONE THAT COULD SET THE STAGE FOR TARGETED IN VIVO STUDIES. 2018 17 903 29 CHRONIC EXPOSURE TO BISPHENOL A RESULTED IN ALTERATIONS OF REPRODUCTIVE FUNCTIONS VIA IMMUNE DEFENSE, OXIDATIVE DAMAGE AND DISRUPTION DNA/HISTONE METHYLATION IN MALE RARE MINNOW GOBIOCYPRIS RARUS. BISPHENOL A (BPA) IS A WIDELY USED CHEMICAL THAT REPRESENTS A REPRODUCTIVE HAZARD IN FISH. HOWEVER, THE MOLECULAR PATHWAYS MEDIATING REPRODUCTIVE TOXICITY UNDER CHRONIC BPA EXPOSURE REMAIN UNCLEAR. TO STUDY THE REPRODUCTIVE HAZARDS ASSOCIATED WITH CHRONIC BPA EXPOSURE, ADULT MALE RARE MINNOWS (GOBIOCYPRIS RARUS) WERE TREATED WITH 15 MUG L (-) (1) AND 225 MUG L (-) (1) BPA FOR 90 DAYS. RESULTS SHOWED THAT CHRONIC BPA TREATMENT INDUCED REPRODUCTIVE IMPAIRMENTS WITH DECREASED FERTILIZATION CAPACITY AND MOVEMENT TIME OF SPERM. TRANSCRIPTOME ANALYSIS INDICATED 1421 TRANSCRIPTS THAT WERE DIFFERENTIALLY EXPRESSED IN RESPONSE TO BPA EXPOSURE, WHICH ARE INVOLVED IN THE BIOLOGICAL PROCESS OF OXIDATIVE STRESS, IMMUNE RESPONSES AND DNA/HISTONE METHYLATION. BPA CAUSED THE OXIDATIVE STRESS VIA SIGNIFICANTLY INCREASING HYDROGEN PEROXIDE (H(2)O(2)) LEVELS AND INHIBITING THE ACTIVITIES OF ANTIOXIDANT-RELATED ENZYMES (CATALASE, CAT). BPA CAUSED AN INFLAMMATORY RESPONSE IN THE TESTES BY SIGNIFICANTLY INCREASING IL-1BETA LEVELS AND INDUCING INFILTRATION OF INFLAMMATORY CELLS. MOREOVER, EXPOSURE TO 15 MUG L (-) (1) BPA SIGNIFICANTLY DECREASED THE GENOMIC DNA METHYLATION LEVEL. THESE DATA REVEALED THAT CHRONIC BPA EXPOSURE HAD ADVERSE EFFECTS ON MALE REPRODUCTION. OXIDATIVE STRESS, INFLAMMATORY RESPONSE AND DNA/HISTONE METHYLATION MIGHT ACCOUNT FOR THE DECREASED SPERM QUALITY. 2021 18 6555 36 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 19 3991 29 LONGITUDINAL EFFECTS OF DEVELOPMENTAL BISPHENOL A, VARIABLE DIET, AND PHYSICAL ACTIVITY ON AGE-RELATED METHYLATION IN BLOOD. RESEARCH INDICATES THAT ENVIRONMENTAL FACTORS CAN ALTER DNA METHYLATION, BUT THE SPECIFIC EFFECTS OF ENVIRONMENTAL EXPOSURES ON EPIGENETIC AGING REMAIN UNCLEAR. HERE, USING A MOUSE MODEL OF HUMAN-RELEVANT EXPOSURES, WE TESTED THE HYPOTHESIS THAT EARLY-LIFE EXPOSURE TO BISPHENOL A (BPA), VARIABLE DIET, AND/OR CHANGES IN PHYSICAL ACTIVITY WOULD MODIFY RATES OF AGE-RELATED METHYLATION AT SEVERAL TARGET REGIONS, AS MEASURED FROM LONGITUDINAL BLOOD SAMPLES (2, 4, AND 10 MONTHS OLD). DNA METHYLATION WAS QUANTIFIED AT TWO REPETITIVE ELEMENTS (LINE-1, IAP), TWO IMPRINTED GENES (IGF2, H19), AND ONE NON-IMPRINTED GENE (ESR1) IN ISOGENIC MICE DEVELOPMENTALLY EXPOSED TO CONTROL, CONTROL + BPA (50 MICROG/KG DIET), WESTERN HIGH-FAT DIET (WHFD), OR WESTERN + BPA DIETS. IN BLOOD SAMPLES, ESR1 DNA METHYLATION INCREASED SIGNIFICANTLY WITH AGE, BUT NO OTHER INVESTIGATED LOCI SHOWED SIGNIFICANT AGE-RELATED METHYLATION. LINE-1 AND IAP BOTH SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE (P < 0.05). ESR1ALSO SHOWED SIGNIFICANT NEGATIVE ENVIRONMENTAL DEFLECTION BY WHFD EXPOSURE IN FEMALE MICE (P = 0.02), BUT NOT MALE MICE. PHYSICAL ACTIVITY HAD A NON-SIGNIFICANT POSITIVE EFFECT ON AGE-RELATED ESR1 METHYLATION IN FEMALE BLOOD, SUGGESTING THAT IT MAY PARTIALLY ABROGATE THE EFFECTS OF WHFD ON THE AGING EPIGENOME. THESE RESULTS SUGGEST THAT DEVELOPMENTAL NUTRITIONAL EXPOSURES CAN MODIFY AGE-RELATED DNA METHYLATION PATTERNS AT A GENE RELATED TO GROWTH AND DEVELOPMENT. AS SUCH, ENVIRONMENTAL DEFLECTION OF THE AGING EPIGENOME MAY HELP TO EXPLAIN THE GROWING PREVALENCE OF CHRONIC DISEASES IN HUMAN POPULATIONS. 2018 20 6550 30 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