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 2 934 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 3 2741 25 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 4 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 5 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 6 166 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 7 1816 28 EFFECTS OF CHRONIC EXPOSURE TO BENZOPHENONE AND DICLOFENAC ON DNA METHYLATION LEVELS AND REPRODUCTIVE SUCCESS IN A MARINE COPEPOD. THE UV-FILTER BENZOPHENONE AND THE ANTI-INFLAMMATORY DICLOFENAC ARE COMMONLY DETECTED IN THE ENVIRONMENT. THE AIM OF THIS STUDY WAS TO ASSESS THE MULTIGENERATIONAL EFFECTS OF CHRONIC EXPOSURE TO LOW CONCENTRATIONS OF THESE CHEMICALS ON TOXICITY AND DNA METHYLATION LEVELS IN THE COPEPOD GLADIOFERENS PECTINATUS. ACUTE TOXICITY TESTS WERE CONDUCTED TO DETERMINE THE SENSITIVITY OF G. PECTINATUS TO THE CHEMICALS. ALL CHEMICALS IMPACTED BREEDING, HATCHING AND EGG VIABILITY. DICLOFENAC (1 MG.L(-1)) REDUCED THE NUMBER OF EGGS PER GRAVID FEMALE. BENZOPHENONE (0.5 MG.L(-1)) DECREASED EGG HATCHING SUCCESS. EXPOSURE TO THE REFERENCE TOXICANT COPPER (0.02 MG.L(-1)) LED TO UNSUCCESSFUL HATCHING. EFFECTS ON DNA METHYLATION WAS ESTIMATED BY THE PERCENTAGE OF 5- METHYLCYTOSINE. THE TREATMENTS RESULTED IN STRONG DIFFERENCES IN DNA METHYLATION WITH INCREASED METHYLATION IN THE EXPOSED ANIMALS. THE TWO CHEMICALS IMPACTED BOTH EGG VIABILITY AND THE INDUCTION OF DIFFERENTIAL DNA METHYLATION, SUGGESTING POTENTIAL INTRA- AND TRANS-GENERATIONAL EVOLUTIONARY EFFECTS. 2018 8 184 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 9 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 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 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 12 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 13 73 34 A MULTI-GENERATIONAL STUDY ON LOW-DOSE BPA EXPOSURE IN WISTAR RATS: EFFECTS ON MATERNAL BEHAVIOR, FLAVOR INTAKE AND DEVELOPMENT. BISPHENOL A (BPA) IS A COMMON ENDOCRINE DISRUPTOR FOUND AS AN ENVIRONMENTAL AND FOOD CONTAMINANT. IT EXERTS BOTH DEVELOPMENTAL AND BEHAVIORAL EFFECTS, MAINLY WHEN EXPOSURE OCCURS IN EARLY LIFE. THE AIM OF THIS STUDY WAS TO DETERMINE THE MULTI-GENERATIONAL EFFECTS OF CHRONIC, HUMAN-RELEVANT LOW-DOSE EXPOSURE TO BPA ON DEVELOPMENT, MATERNAL BEHAVIOR AND FLAVOR PREFERENCE IN WISTAR RATS. BPA WAS ORALLY ADMINISTERED AT A DAILY DOSE OF 5 MUG/KG BODY WEIGHT TO F0 PREGNANT DAMS FROM THE FIRST DAY OF GESTATION (GD 1) UNTIL THE LAST DAY OF LACTATION (LD 21), AND THEN TO F1 OFFSPRING FROM WEANING (PND 21) TO ADULTHOOD (PND 100). F2 OFFSPRING WERE NOT EXPOSED. DEVELOPMENT AND CLINICAL SIGNS OF TOXICITY WERE ASSESSED DAILY. MATERNAL BEHAVIOR WAS EVALUATED BY OBSERVING NURSING AND PUP-CARING ACTIONS, AS WELL AS "NON-MATERNAL" BEHAVIORS IN F0 AND F1 DAMS FROM PARTURITION UNTIL LD 8. THE FLAVOR PREFERENCES OF F1 AND F2 OFFSPRING WERE EVALUATED BASED ON THE INTAKE OF SWEET, SALT AND FAT SOLUTIONS USING THE TWO-BOTTLE CHOICE TEST ON PND 21-34 AND PND 86-99. BPA EXPOSURE: 1) DECREASED MATERNAL BEHAVIOR IN F1 DAMS, 2) CAUSED DEVELOPMENTAL DEFECTS IN BOTH F1 AND F2 OFFSPRING, WITH A NOTICEABLE DECREASE IN ANOGENITAL DISTANCE IN MALE RATS, AND 3) DID NOT AFFECT FLAVORED SOLUTION INTAKE IN F1, BUT INDUCED CHANGES IN SWEET PREFERENCE IN F2 JUVENILES AND IN SALT AND FAT SOLUTION INTAKES IN F2 ADULTS, AND 4) INDUCED A BODY WEIGHT INCREASE IN THE F2 GENERATION ONLY, WHEREAS FOOD INTAKE AND WATER CONSUMPTION DID NOT CHANGE. TAKEN AS A WHOLE, OUR FINDINGS SHOWED THAT BOTH GESTATIONAL (F0) AND LIFELONG (F1) EXPOSURES TO A HUMAN-RELEVANT DOSE OF BPA COULD INDUCE MULTI-GENERATIONAL EFFECTS ON BOTH DEVELOPMENT AND BEHAVIOR. THESE RESULTS SUGGEST POSSIBLE SELECTIVE NEUROENDOCRINE DEFECTS AND/OR EPIGENETIC CHANGES CAUSED BY BPA EXPOSURE. 2014 14 2265 29 EPIGENETIC PROGRAMMING IN THE PREIMPLANTATION RAT EMBRYO IS DISRUPTED BY CHRONIC PATERNAL CYCLOPHOSPHAMIDE EXPOSURE. PRECONCEPTIONAL PATERNAL EXPOSURE TO CYCLOPHOSPHAMIDE, A WIDELY USED ANTICANCER AGENT, LEADS TO INCREASES IN EMBRYO LOSS, MALFORMATIONS, AND BEHAVIORAL DEFICITS IN OFFSPRING; THESE ABNORMALITIES ARE TRANSMISSIBLE TO SUBSEQUENT GENERATIONS [AUROUX, M., DULIOUST, E., SELVA, J. & RINCE, P. (1990) MUTAT. RES. 229, 189-200]. LITTLE INFORMATION EXISTS ON THE MECHANISMS UNDERLYING THIS MALE-MEDIATED DEVELOPMENTAL TOXICITY. WE ASSESSED THE IMPACT OF PATERNAL CYCLOPHOSPHAMIDE EXPOSURE ON THE DYNAMIC REGULATION OF HISTONE H4 ACETYLATION AT LYSINE 5 AND DNA METHYLATION IN PREIMPLANTATION RAT EMBRYOS. ZYGOTES SIRED BY DRUG-TREATED MALES DISPLAYED ADVANCED DEVELOPMENTAL PROGRESSION, INCREASED PRONUCLEAR AREAS, AND DISRUPTION OF THE EPIGENETIC PROGRAMMING OF BOTH PARENTAL GENOMES. EARLY POSTFERTILIZATION ZYGOTIC PRONUCLEI WERE HYPERACETYLATED; BY MID-ZYGOTIC DEVELOPMENT, MALE PRONUCLEI WERE DRAMATICALLY HYPOMETHYLATED, WHEREAS FEMALE PRONUCLEI WERE HYPERMETHYLATED. MICRONUCLEI WERE SUBSTANTIALLY ELEVATED, AND HISTONE H4 ACETYLATION AT LYSINE 5 LOCALIZATION TO THE NUCLEAR PERIPHERY WAS DISRUPTED IN TWO-CELL EMBRYOS FERTILIZED BY CYCLOPHOSPHAMIDE-EXPOSED SPERMATOZOA. THIS FINDING DEMONSTRATES THAT PATERNAL EXPOSURE TO THIS DRUG INDUCES ABERRANT EPIGENETIC PROGRAMMING IN EARLY EMBRYOS. WE HYPOTHESIZE THAT DISTURBANCES IN EPIGENETIC PROGRAMMING CONTRIBUTE TO HERITABLE INSTABILITIES LATER IN DEVELOPMENT, EMPHASIZING THE IMPORTANCE OF EPIGENETIC RISK ASSESSMENT AFTER CHEMOTHERAPY. 2005 15 5032 29 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 16 4924 27 PARENTAL HYPOXIC EXPOSURE CONFERS OFFSPRING HYPOXIA RESISTANCE IN ZEBRAFISH (DANIO RERIO). PARENTAL INFLUENCES ARE A POTENTIALLY IMPORTANT COMPONENT OF TRANSGENERATIONAL TRANSFER OF PHENOTYPE IN VERTEBRATES. THIS STUDY EXAMINED HOW CHRONIC HYPOXIC EXPOSURE ON ADULT ZEBRAFISH (DANIO RERIO) AFFECTED THE PHENOTYPE OF THEIR OFFSPRING. SEPARATE ADULT POPULATIONS WERE EXPOSED TO HYPOXIA (13.1 KPA O(2)) OR NORMOXIA (21.1 KPA O(2)) FOR PERIODS RANGING FROM 1 TO 12 WEEKS. ADULTS WERE THEN RETURNED TO NORMOXIA AND BRED WITHIN EXPERIMENTAL GROUPS. ADULT FECUNDITY AND EGG CHARACTERISTICS (VOLUME OF EGG, YOLK AND PERIVITELLINE FLUID) WERE ASSESSED. SUBSEQUENTLY, LARVAL BODY LENGTH, TIME TO LOSS OF EQUILIBRIUM IN SEVERE HYPOXIA (~4 KPA O(2)), AND CRITICAL THERMAL MINIMA (CT(MIN)) AND MAXIMA (CT(MAX)) WERE MEASURED AT 6, 9, 12, 15, 18, 21 AND 60 DAYS POST-FERTILIZATION (D.P.F.). ADULT FECUNDITY WAS DEPRESSED BY HYPOXIC EXPOSURE. EGG COMPONENT VOLUMES WERE ALSO DEPRESSED IN ADULTS EXPOSED TO 1-2 WEEKS OF HYPOXIA, BUT RETURNED TO CONTROL LEVELS FOLLOWING LONGER HYPOXIC EXPOSURE. ADULT HYPOXIC EXPOSURES OF >1 WEEK RESULTED IN LONGER BODY LENGTHS IN THEIR LARVAL OFFSPRING. TIME TO LOSS OF EQUILIBRIUM IN SEVERE HYPOXIA (I.E. HYPOXIC RESISTANCE) IN CONTROL LARVAE DECREASED FROM 6 TO 12 D.P.F., REMAINING CONSTANT THEREAFTER. NOTABLY, HYPOXIC RESISTANCE FROM 6 TO 18 D.P.F. WAS ~15% LOWER IN LARVAE WHOSE PARENTS WERE EXPOSED TO JUST 1 WEEK OF CHRONIC HYPOXIA, BUT RESISTANCE WAS SIGNIFICANTLY INCREASED BY ~24-30% IN 6-18 D.P.F. LARVAE FROM ADULTS EXPOSED TO 2, 3 OR 4 WEEKS OF HYPOXIA. CT(MIN) (~10-12 DEGREES C) AND CT(MAX) (~39.5 DEGREES C) WERE UNCHANGED BY PARENTAL HYPOXIC EXPOSURE. THIS STUDY DEMONSTRATES THAT PARENTAL HYPOXIC EXPOSURE IN ADULT ZEBRAFISH HAS PROFOUND EPIGENETIC EFFECTS ON THE MORPHOLOGICAL AND PHYSIOLOGICAL PHENOTYPE OF THEIR OFFSPRING. 2012 17 891 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 18 2484 47 EPIGENETIC, TRANSCRIPTIONAL AND PHENOTYPIC RESPONSES IN TWO GENERATIONS OF DAPHNIA MAGNA EXPOSED TO THE DNA METHYLATION INHIBITOR 5-AZACYTIDINE. THE WATER FLEA DAPHNIA MAGNA IS A KEYSTONE SPECIES IN FRESHWATER ECOSYSTEMS AND HAS BEEN WIDELY USED AS A MODEL ORGANISM IN ENVIRONMENTAL ECOTOXICOLOGY. THIS AQUATIC CRUSTACEAN IS SENSITIVE TO ENVIRONMENTAL STRESSORS AND DISPLAYS CONSIDERABLE PLASTICITY IN ADAPTING TO CHANGING ENVIRONMENTAL CONDITIONS. PART OF THIS PLASTICITY MAY BE DUE TO EPIGENETIC REGULATION OF GENE EXPRESSION, INCLUDING CHANGES TO DNA METHYLATION AND HISTONE MODIFICATIONS. BECAUSE OF THE GENERALLY HYPOMETHYLATED GENOME OF THIS SPECIES, WE HYPOTHESIZED THAT THE HISTONE CODE MAY HAVE AN ESSENTIAL ROLE IN THE EPIGENETIC CONTROL AND THAT HISTONE MODIFICATIONS MIGHT BE AN EARLY MARKER FOR STRESS. THIS STUDY AIMS TO CHARACTERIZE THE EPIGENETIC, TRANSCRIPTIONAL AND PHENOTYPIC RESPONSES AND THEIR CAUSAL LINKAGES IN DIRECTLY EXPOSED ADULT (F0) DAPHNIA AND PERITONEAL EXPOSED NEONATES (F1) AFTER A CHRONIC (7-DAY) EXPOSURE TO A SUBLETHAL CONCENTRATION (10 MG/L) OF 5-AZACYTIDINE, A WELL-STUDIED VERTEBRATE DNA METHYLATION INHIBITOR. EXPOSURE OF THE F0 GENERATION SIGNIFICANTLY REDUCED THE CUMULATIVE FECUNDITY, ACCOMPANIED WITH DIFFERENTIAL EXPRESSION OF GENES IN THE ONE-CARBON-CYCLE METABOLIC PATHWAY. IN THE EPIGENOME OF THE F0 GENERATION, A DECREASE IN GLOBAL DNA METHYLATION, BUT NO SIGNIFICANT CHANGES ON H3K4ME3 OR H3K27ME3, WERE OBSERVED. IN THE F1 OFFSPRING GENERATION, CHANGES IN GENE EXPRESSION, A SIGNIFICANT REDUCTION IN GLOBAL DNA METHYLATION AND CHANGES IN HISTONE MODIFICATIONS WERE IDENTIFIED. THE RESULTS INDICATE THAT EXPOSURE DURING ADULTHOOD MAY RESULT IN MORE PRONOUNCED EFFECTS ON EARLY DEVELOPMENT IN THE OFFSPRING GENERATION, THOUGH INTERPRETATION OF THE DATA SHOULD BE CAREFULLY DONE SINCE BOTH THE EXPOSURE REGIME AND DEVELOPMENTAL PERIOD IS DIFFERENT IN THE TWO GENERATIONS EXAMINED. THE OBTAINED RESULTS IMPROVE OUR UNDERSTANDING OF CRUSTACEAN EPIGENETICS AND THE TOOLS DEVELOPED MAY PROMOTE USE OF EPIGENETIC MARKERS IN HAZARD ASSESSMENT OF ENVIRONMENTAL STRESSORS. 2019 19 648 23 BIRTH WEIGHT AND MATERNAL ENERGY STATUS DURING PREGNANCY AS PREDICTORS OF EPIGENETIC AGE ACCELERATION IN YOUNG ADULTS FROM METROPOLITAN CEBU, PHILIPPINES. EPIGENETIC CLOCKS QUANTIFY REGULAR CHANGES IN DNA METHYLATION THAT OCCUR WITH AGE, OR IN RELATION TO BIOMARKERS OF AGEING, AND ARE STRONG PREDICTORS OF MORBIDITY AND MORTALITY. HERE, WE ASSESS WHETHER MEASURES OF FETAL NUTRITION AND GROWTH THAT PREDICT ADULT CHRONIC DISEASE ALSO PREDICT ACCELERATED BIOLOGICAL AGEING IN YOUNG ADULTHOOD USING A SUITE OF COMMONLY USED EPIGENETIC CLOCKS. DATA COME FROM THE CEBU LONGITUDINAL HEALTH AND NUTRITION SURVEY (CLHNS), A LONG-RUNNING COHORT FOLLOWED SINCE BIRTH IN METROPOLITAN CEBU, PHILIPPINES. PAST WORK HAS SHOWN THAT BIRTH WEIGHT (BW) AND THE MOTHER'S ARM FAT DURING PREGNANCY (A MEASURE OF PREGNANCY ENERGY STATUS) RELATE INVERSELY TO HEALTH OUTCOMES IN THE CLHNS BUT PRIMARILY IN MALES. GENOME-WIDE DNA METHYLATION WAS ASSESSED IN WHOLE BLOOD USING THE INFINIUM EPIC ARRAY. PARTICIPANTS INCLUDED MALES (N=895) AND FEMALES (N=803) MEASURED IN 2005 (20.8-22.5 YEARS). CLOCKS INCLUDED THE HANNUM AND HORVATH CLOCKS TRAINED ON CHRONOLOGICAL AGE, THE DNAMPHENOAGE AND DNAMGRIMAGE CLOCKS TRAINED ON CLINICAL BIOMARKERS, THE DUNEDIN PACE OF AGEING (DUNEDINPACE) CLOCK TRAINED ON LONGITUDINAL CHANGES IN AGEING BIOMARKERS, AND THE DNAMTL CLOCK TRAINED ON LEUKOCYTE TELOMERE LENGTH. IN MALES, LOWER BW PREDICTED ADVANCED BIOLOGICAL AGEING USING THE HANNUM, DNAMPHENOAGE, DUNEDINPOAM, AND DNAMTL CLOCKS. IN CONTRAST, BW DID NOT PREDICT ANY CLOCK IN FEMALE PARTICIPANTS. PARTICIPANTS' MOTHERS' PREGNANCY ARM FAT ONLY PREDICTED DNAMTL IN MALES. THESE FINDINGS SUGGEST THAT EPIGENETIC CLOCKS ARE A USEFUL TOOL FOR GAUGING LONG-TERM OUTCOMES PREDICTED BY FETAL GROWTH, AND ADD TO EXISTING EVIDENCE IN THE CLHNS FOR SEX DIFFERENCES IN THESE RELATIONSHIPS. 2022 20 4935 31 PATERNAL COCAINE TAKING ELICITS EPIGENETIC REMODELING AND MEMORY DEFICITS IN MALE PROGENY. PATERNAL ENVIRONMENTAL PERTURBATIONS INCLUDING EXPOSURE TO DRUGS OF ABUSE CAN PRODUCE PROFOUND EFFECTS ON THE PHYSIOLOGY AND BEHAVIOR OF OFFSPRING VIA EPIGENETIC MODIFICATIONS. HERE WE SHOW THAT ADULT DRUG-NAIVE MALE OFFSPRING OF COCAINE-EXPOSED SIRES HAVE MEMORY FORMATION DEFICITS AND ASSOCIATED REDUCTIONS IN NMDA RECEPTOR-MEDIATED HIPPOCAMPAL SYNAPTIC PLASTICITY. REDUCED LEVELS OF THE ENDOGENOUS NMDA RECEPTOR CO-AGONIST D-SERINE WERE ACCOMPANIED BY INCREASED EXPRESSION OF THE D-SERINE DEGRADING ENZYME D-AMINO ACID OXIDASE (DAO1) IN THE HIPPOCAMPUS OF COCAINE-SIRED MALE PROGENY. INCREASED DAO1 TRANSCRIPTION WAS ASSOCIATED WITH ENRICHMENT OF PERMISSIVE EPIGENETIC MARKS ON HISTONE PROTEINS IN THE HIPPOCAMPUS OF MALE COCAINE-SIRED PROGENY, SOME OF WHICH WERE ENHANCED NEAR THE DAO1 LOCUS. FINALLY, HIPPOCAMPAL ADMINISTRATION OF D-SERINE REVERSED BOTH THE MEMORY FORMATION AND SYNAPTIC PLASTICITY DEFICITS. COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT PATERNAL COCAINE EXPOSURE PRODUCES EPIGENETIC REMODELING IN THE HIPPOCAMPUS LEADING TO NMDA RECEPTOR-DEPENDENT MEMORY FORMATION AND SYNAPTIC PLASTICITY IMPAIRMENTS ONLY IN MALE PROGENY, WHICH HAS SIGNIFICANT IMPLICATIONS FOR THE MALE DESCENDANTS OF CHRONIC COCAINE USERS. 2017