1 2265 124 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 2 1488 54 DNA DAMAGE RECOGNITION IN THE RAT ZYGOTE FOLLOWING CHRONIC PATERNAL CYCLOPHOSPHAMIDE EXPOSURE. THE DETRIMENTAL EFFECTS OF PRECONCEPTIONAL PATERNAL EXPOSURE TO THE ALKYLATING ANTICANCER AGENT, CYCLOPHOSPHAMIDE, INCLUDE ABERRANT EPIGENETIC PROGRAMMING, DYSREGULATED ZYGOTIC GENE ACTIVATION, AND ABNORMALITIES IN THE OFFSPRING THAT ARE TRANSMITTED TO THE NEXT GENERATION. THE ADVERSE DEVELOPMENTAL CONSEQUENCES OF GENOMIC INSTABILITIES TRANSMITTED VIA THE SPERMATOZOON EMPHASIZE THE NEED TO ELUCIDATE THE MECHANISMS BY WHICH THE EARLY EMBRYO RECOGNIZES DNA DAMAGE IN THE PATERNAL GENOME. LITTLE INFORMATION EXISTS ON DNA DAMAGE DETECTION IN THE ZYGOTE. WE ASSESSED THE IMPACT OF PATERNAL CYCLOPHOSPHAMIDE EXPOSURE ON PHOSPHORYLATED H2AX (GAMMAH2AX) AND POLY(ADP-RIBOSE) POLYMERASE-1(PARP-1), BIOMARKERS OF DNA DAMAGE, TO DETERMINE THE CAPACITY IN THE RAT ZYGOTE TO RECOGNIZE GENOMIC DAMAGE AND INITIATE A RESPONSE TO DNA LESIONS. AN AMPLIFIED BIPHASIC GAMMAH2AX RESPONSE WAS TRIGGERED IN THE PATERNAL PRONUCLEUS IN ZYGOTES SIRED BY DRUG-TREATED MALES; THE MATERNAL GENOME WAS NOT AFFECTED. PARP-1 IMMUNOREACTIVITY WAS SUBSTANTIALLY ELEVATED IN BOTH PARENTAL GENOMES, COINCIDENT WITH THE SECOND PHASE OF GAMMAH2AX INDUCTION IN EMBRYOS SIRED BY CYCLOPHOSPHAMIDE-EXPOSED SPERMATOZOA. THUS, PATERNAL EXPOSURE TO A DNA DAMAGING AGENT RAPIDLY ACTIVATES SIGNALS IMPLEMENTAL FOR DNA DAMAGE RECOGNITION IN THE ZYGOTE. INEFFICIENT REPAIR OF DNA LESIONS MAY LEAD TO PERSISTENT ALTERATIONS OF THE HISTONE CODE AND CHROMATIN INTEGRITY, RESULTING IN ABERRANT EMBRYOGENESIS. WE PROPOSE THAT THE RESPONSE OF THE EARLY EMBRYO TO DISTURBANCES IN SPERMATOZOAL GENOMIC INTEGRITY PLAYS A VITAL ROLE IN DETERMINING ITS OUTCOME. 2007 3 6558 34 TRANSGENERATIONAL EPIGENETIC PROGRAMMING VIA SPERM MICRORNA RECAPITULATES EFFECTS OF PATERNAL STRESS. EPIGENETIC SIGNATURES IN GERM CELLS, CAPABLE OF BOTH RESPONDING TO THE PARENTAL ENVIRONMENT AND SHAPING OFFSPRING NEURODEVELOPMENT, ARE UNIQUELY POSITIONED TO MEDIATE TRANSGENERATIONAL OUTCOMES. HOWEVER, MOLECULAR MECHANISMS BY WHICH THESE MARKS MAY COMMUNICATE EXPERIENCE-DEPENDENT INFORMATION ACROSS GENERATIONS ARE CURRENTLY UNKNOWN. IN OUR MODEL OF CHRONIC PATERNAL STRESS, WE PREVIOUSLY IDENTIFIED NINE MICRORNAS (MIRS) THAT WERE INCREASED IN THE SPERM OF STRESSED SIRES AND ASSOCIATED WITH REDUCED HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) STRESS AXIS REACTIVITY IN OFFSPRING. IN THE CURRENT STUDY, WE RIGOROUSLY EXAMINE THE HYPOTHESIS THAT THESE SPERM MIRS FUNCTION POSTFERTILIZATION TO ALTER OFFSPRING STRESS RESPONSIVITY AND, USING ZYGOTE MICROINJECTION OF THE NINE SPECIFIC MIRS, DEMONSTRATED A REMARKABLE RECAPITULATION OF THE OFFSPRING STRESS DYSREGULATION PHENOTYPE. FURTHER, WE ASSOCIATED LONG-TERM REPROGRAMMING OF THE HYPOTHALAMIC TRANSCRIPTOME WITH HPA AXIS DYSFUNCTION, NOTING A MARKED DECREASED IN THE EXPRESSION OF EXTRACELLULAR MATRIX AND COLLAGEN GENE SETS THAT MAY REFLECT AN UNDERLYING CHANGE IN BLOOD-BRAIN BARRIER PERMEABILITY. WE CONCLUDE BY INVESTIGATING THE DEVELOPMENTAL IMPACT OF SPERM MIRS IN EARLY ZYGOTES WITH SINGLE-CELL AMPLIFICATION TECHNOLOGY, IDENTIFYING THE TARGETED DEGRADATION OF STORED MATERNAL MRNA TRANSCRIPTS INCLUDING SIRTUIN 1 AND UBIQUITIN PROTEIN LIGASE E3A, TWO GENES WITH ESTABLISHED FUNCTION IN CHROMATIN REMODELING, AND THIS POTENT REGULATORY FUNCTION OF MIRS POSTFERTILIZATION LIKELY INITIATES A CASCADE OF MOLECULAR EVENTS THAT EVENTUALLY ALTERS STRESS REACTIVITY. OVERALL, THESE FINDINGS DEMONSTRATE A CLEAR MECHANISTIC ROLE FOR SPERM MIRS IN THE TRANSGENERATIONAL TRANSMISSION OF PATERNAL LIFETIME EXPERIENCES. 2015 4 4939 29 PATERNAL NICOTINE EXPOSURE IN RATS PRODUCES LONG-LASTING NEUROBEHAVIORAL EFFECTS IN THE OFFSPRING. STUDIES OF INTERGENERATIONAL EFFECTS OF PARENTAL CHEMICAL EXPOSURE HAVE PRINCIPALLY FOCUSED ON MATERNAL EXPOSURE, PARTICULARLY FOR STUDIES OF ADVERSE NEUROBEHAVIORAL CONSEQUENCES ON THE OFFSPRING. MATERNAL NICOTINE EXPOSURE HAS LONG BEEN KNOWN TO CAUSE ADVERSE NEUROBEHAVIORAL EFFECTS ON THE OFFSPRING. HOWEVER, PATERNAL TOXICANT EXPOSURE HAS ALSO BEEN FOUND TO CAUSE NEUROBEHAVIORAL TOXICITY IN THEIR OFFSPRING. RECENT WORK SUGGESTS THAT PATERNAL NICOTINE EXPOSURE CAN HAVE EPIGENETIC EFFECTS, ALTHOUGH IT REMAINS UNCLEAR WHETHER SUCH CHANGES LEAD TO NEUROBEHAVIORAL EFFECTS. IN THE CURRENT STUDY, WE INVESTIGATED THE EFFECTS OF PATERNAL NICOTINE EXPOSURE ON NEUROBEHAVIORAL DEVELOPMENT OF THEIR OFFSPRING. MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO 0 OR 2 MG/KG/DAY NICOTINE (SC) FOR 56 CONSECUTIVE DAYS WITH TWO CONSECUTIVE 2ML4 OSMOTIC MINIPUMPS. FOLLOWING TREATMENT, THESE MALES WERE MATED WITH DRUG-NAIVE FEMALE RATS. OFFSPRING OF BOTH SEXES WERE TESTED IN A BEHAVIORAL BATTERY TO ASSESS LOCOMOTION, EMOTIONAL FUNCTION AND COGNITION. PATERNAL NICOTINE EXPOSURE DID NOT IMPACT OFFSPRING VIABILITY, HEALTH OR GROWTH. HOWEVER, BEHAVIORAL FUNCTION OF THE OFFSPRING WAS SIGNIFICANTLY ALTERED BY PATERNAL NICOTINE EXPOSURE. MALE OFFSPRING WITH PATERNAL NICOTINE EXPOSURE EXHIBITED LOCOMOTOR HYPERACTIVITY IN THE FIGURE-8 APPARATUS WHEN TESTED DURING ADOLESCENCE. WHEN RETESTED IN ADULTHOOD AND REGARDLESS OF SEX, OFFSPRING OF THE NICOTINE EXPOSED FATHER SHOWED SIGNIFICANTLY REDUCED HABITUATION OF LOCOMOTOR ACTIVITY OVER THE COURSE OF THE SESSION. COMPARED TO CONTROLS, FEMALE OFFSPRING OF NICOTINE-EXPOSED FATHERS SHOWED SIGNIFICANTLY REDUCED RESPONSE LATENCY IN THE RADIAL ARM MAZE TEST. IN ADDITION TO LOCOMOTOR HYPERACTIVITY, THE OFFSPRING OF NICOTINE-EXPOSED FATHERS ALSO SHOWED SIGNIFICANTLY DIMINISHED HABITUATION IN THE NOVEL OBJECT RECOGNITION TEST. THESE RESULTS INDICATE THAT CHRONIC PATERNAL NICOTINE EXPOSURE CAN IMPACT THE BEHAVIOR OF OFFSPRING, PRODUCING LOCOMOTOR HYPERACTIVITY AND IMPAIRED HABITUATION. 2019 5 4932 26 PATERNAL ALCOHOL EXPOSURES PROGRAM INTERGENERATIONAL HORMETIC EFFECTS ON OFFSPRING FETOPLACENTAL GROWTH. HORMESIS REFERS TO GRADED ADAPTIVE RESPONSES TO HARMFUL ENVIRONMENTAL STIMULI WHERE LOW-LEVEL TOXICANT EXPOSURES STIMULATE TISSUE GROWTH AND RESPONSIVENESS WHILE, IN CONTRAST, HIGHER-LEVEL EXPOSURES INDUCE TOXICITY. ALTHOUGH THE INTERGENERATIONAL INHERITANCE OF PROGRAMMED HORMETIC GROWTH RESPONSES IS DESCRIBED IN PLANTS AND INSECTS, RESEARCHERS HAVE YET TO OBSERVE THIS PHENOMENON IN MAMMALS. USING A PHYSIOLOGICALLY RELEVANT MOUSE MODEL, WE DEMONSTRATE THAT CHRONIC PRECONCEPTION PATERNAL ALCOHOL EXPOSURES PROGRAM NONLINEAR, DOSE-DEPENDENT CHANGES IN OFFSPRING FETOPLACENTAL GROWTH. OUR STUDIES IDENTIFY AN INVERSE J-SHAPED CURVE WITH A THRESHOLD OF 2.4 G/KG PER DAY; BELOW THIS THRESHOLD, PATERNAL ETHANOL EXPOSURES INDUCE PROGRAMMED INCREASES IN PLACENTAL GROWTH, WHILE DOSES EXCEEDING THIS POINT YIELD COMPARATIVE DECREASES IN PLACENTAL GROWTH. IN MALE OFFSPRING, HIGHER PATERNAL EXPOSURES INDUCE DOSE-DEPENDENT INCREASES IN THE PLACENTAL LABYRINTH LAYER BUT DO NOT IMPACT FETAL GROWTH. IN CONTRAST, THE PLACENTAL HYPERTROPHY INDUCED BY LOW-LEVEL PATERNAL ETHANOL EXPOSURES ASSOCIATE WITH INCREASED OFFSPRING CROWN-RUMP LENGTH, PARTICULARLY IN MALE OFFSPRING. FINALLY, ALTERATIONS IN PLACENTAL PHYSIOLOGY CORRELATE WITH DISRUPTIONS IN BOTH MITOCHONDRIAL-ENCODED AND IMPRINTED GENE EXPRESSION. UNDERSTANDING THE INFLUENCE OF ETHANOL ON THE PATERNALLY-INHERITED EPIGENETIC PROGRAM AND DOWNSTREAM HORMETIC RESPONSES IN OFFSPRING GROWTH MAY HELP EXPLAIN THE ENORMOUS VARIATION OBSERVED IN FETAL ALCOHOL SPECTRUM DISORDER (FASD) PHENOTYPES AND INCIDENCE. 2022 6 4944 29 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING. 2016 7 2698 31 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 8 3119 34 GESTATIONAL EXPOSURE TO PARTICULATE AIR POLLUTION EXACERBATES THE GROWTH PHENOTYPES INDUCED BY PRECONCEPTION PATERNAL ALCOHOL USE: A MULTIPLEX MODEL OF EXPOSURE. IT IS NOW CLEAR THAT PARENTAL HISTORIES OF DRUG USE, TOXICANT EXPOSURE, AND SOCIAL STRESS ALL HAVE A SIGNIFICANT INFLUENCE ON THE HEALTH AND DEVELOPMENT OF THE NEXT GENERATION. HOWEVER, THE ABILITY OF EPIGENETIC PARENTAL LIFE MEMORIES TO INTERACT WITH SUBSEQUENT GESTATIONAL EXPOSURES AND CUMULATIVELY MODIFY THE DEVELOPMENTAL TRAJECTORY OF THE OFFSPRING REMAINS AN UNEXPLORED PERSPECTIVE IN TOXICOLOGY. STUDIES FROM OUR LABORATORY HAVE IDENTIFIED MALE-SPECIFIC POSTNATAL GROWTH RESTRICTION IN A MOUSE MODEL OF CHRONIC, PRECONCEPTION PATERNAL ALCOHOL EXPOSURE. THE GOAL OF THE CURRENT STUDY WAS TO DETERMINE IF PATERNAL ALCOHOL USE, BEFORE CONCEPTION, COULD MODIFY THE SUSCEPTIBILITY OF THE OFFSPRING TO A COMPLETELY SEPARATE EXPOSURE ENCOUNTERED BY THE MOTHER DURING PREGNANCY. IN INDEPENDENT EXPERIMENTS, WE PREVIOUSLY IDENTIFIED ALTERED DEVELOPMENTAL PROGRAMMING AND INCREASED MARKERS OF SEVERE ASTHMA INDUCED BY GESTATIONAL EXPOSURE TO PARTICULATE AIR POLLUTION. IN THIS STUDY, MALE MICE WERE EXPOSED TO EITHER THE CONTROL OR ALCOHOL PRECONCEPTION TREATMENTS, THEN MATED TO NAIVE FEMALES, WHICH WE SUBSEQUENTLY EXPOSED TO AN ULTRAFINE MIXTURE OF PARTICULATE MATTER VIA INHALATION. INDIVIDUALLY, NEITHER PRECONCEPTION PATERNAL DRINKING NOR GESTATIONAL EXPOSURES TO PARTICULATE AIR POLLUTION IMPACTED THE POSTNATAL GROWTH OF FEMALE OFFSPRING. HOWEVER, WHEN BOTH EXPOSURES WERE COMBINED, FEMALES DISPLAYED A 30% REDUCTION IN WEIGHT GAIN. UNEXPECTEDLY, THIS EXPOSURE PARADIGM RESULTED IN A DRAMATIC POSTNATAL INCREASE IN LITTER LOSS DUE TO MATERNAL CANNIBALISM, WHICH PREVENTED ADDITIONAL MEASURES OF OFFSPRING HEALTH. THESE PRELIMINARY STUDIES PROVIDE EVIDENCE OF A COMPLEX INTERPLAY BETWEEN PRECONCEPTION LIFE HISTORY AND INTRAUTERINE ENVIRONMENTAL FACTORS IN THE CONTROL OF POSTNATAL GROWTH. 2020 9 4941 34 PATERNAL OBESITY, INTERVENTIONS, AND MECHANISTIC PATHWAYS TO IMPAIRED HEALTH IN OFFSPRING. BACKGROUND: THE GLOBAL RATES OF MALE OVERWEIGHT/OBESITY ARE RISING, APPROACHING 70% OF THE TOTAL ADULT POPULATION IN WESTERN NATIONS. OVERWEIGHT/OBESITY INCREASES THE RISK OF CHRONIC DISEASES; HOWEVER, THERE IS INCREASING AWARENESS THAT MALE OBESITY NEGATIVELY IMPACTS FERTILITY, SUBSEQUENT PREGNANCY, AND THE OFFSPRING HEALTH BURDEN. DEVELOPMENTAL PROGRAMMING IS WELL DEFINED IN MOTHERS; HOWEVER, IT IS BECOMING INCREASINGLY EVIDENT THAT DEVELOPMENTAL PROGRAMMING CAN BE PATERNALLY INITIATED AND MEDIATED THROUGH PATERNAL OBESITY. KEY MESSAGES: BOTH HUMAN AND RODENT MODELS HAVE ESTABLISHED THAT PATERNAL OBESITY IMPAIRS SEX HORMONES, BASIC SPERM FUNCTION, AND MOLECULAR COMPOSITION. THIS RESULTS IN PERTURBED EMBRYO DEVELOPMENT AND HEALTH AND AN INCREASED SUBSEQUENT OFFSPRING DISEASE BURDEN IN BOTH SEXES. THE REVERSIBILITY OF OBESITY-INDUCED PARENTAL PROGRAMMING HAS ONLY RECENTLY RECEIVED ATTENTION. PROMISING RESULTS IN ANIMAL MODELS UTILIZING DIET AND EXERCISE INTERVENTIONS HAVE SHOWN IMPROVEMENTS IN SPERM FUNCTION AND MOLECULAR COMPOSITION, RESULTING IN RESTORATIONS OF BOTH EMBRYO AND FETAL HEALTH AND SUBSEQUENT MALE OFFSPRING FERTILITY. THE DIRECT MODE FOR PATERNAL INHERITANCE IS LIKELY MEDIATED VIA SPERMATOZOA. WE PROPOSE TWO MAIN THEORIES FOR THE ORIGIN OF MALE OBESITY-INDUCED PATERNAL PROGRAMMING: (1) ACCUMULATION OF SPERM DNA DAMAGE RESULTING IN DE NOVO MUTATIONS IN THE EMBRYO AND (2) CHANGES IN SPERM EPIGENETIC MARKS (MICRORNA, METHYLATION, OR ACETYLATION) ALTERING THE ACCESS, TRANSCRIPTION, AND TRANSLATION OF PATERNALLY DERIVED GENES DURING EARLY EMBRYOGENESIS. CONCLUSIONS: PATERNAL OVERWEIGHT/OBESITY INDUCES PATERNAL PROGRAMMING OF OFFSPRING PHENOTYPES LIKELY MEDIATED THROUGH GENETIC AND EPIGENETIC CHANGES IN SPERMATOZOA. THESE PROGRAMMED CHANGES TO OFFSPRING HEALTH APPEAR TO BE PARTIALLY RESTORED VIA DIET/EXERCISE INTERVENTIONS IN OBESE FATHERS PRECONCEPTION, WHICH HAVE BEEN SHOWN TO IMPROVE ASPECTS OF SPERM DNA INTEGRITY. HOWEVER, THE MAJORITY OF DATA SURROUNDING PATERNAL OBESITY AND OFFSPRING PHENOTYPES HAVE COME FROM RODENT MODELS; THEREFORE, WE CONTEND THAT IT WILL BE INCREASINGLY IMPORTANT TO STUDY POPULATION-BASED DATA TO DETERMINE THE LIKELY MODE OF INHERITANCE IN HUMANS. 2014 10 1096 33 COINCUBATION OF SPERM WITH EPIDIDYMAL EXTRACELLULAR VESICLE PREPARATIONS FROM CHRONIC INTERMITTENT ETHANOL-TREATED MICE IS SUFFICIENT TO IMPART ANXIETY-LIKE AND ETHANOL-INDUCED BEHAVIORS TO ADULT PROGENY. WE PREVIOUSLY REPORTED THAT PATERNAL PRECONCEPTION CHRONIC ETHANOL EXPOSURE IN MICE IMPARTS ADULT MALE OFFSPRING WITH REDUCED ETHANOL DRINKING PREFERENCE AND CONSUMPTION, INCREASED ETHANOL SENSITIVITY, AND ATTENUATED STRESS RESPONSIVITY. THAT SAME CHRONIC ETHANOL EXPOSURE PARADIGM WAS LATER REVEALED TO AFFECT THE SPERM EPIGENOME BY ALTERING THE ABUNDANCE OF SEVERAL SMALL NONCODING RNAS, A MECHANISM THAT MEDIATES THE INTERGENERATIONAL EFFECTS OF NUMEROUS PATERNAL ENVIRONMENTAL EXPOSURES. ALTHOUGH RECENT STUDIES HAVE REVEALED THAT THE UNIQUE RNA SIGNATURE OF SPERM IS SHAPED DURING MATURATION IN THE EPIDIDYMIS VIA EXTRACELLULAR VESICLES (EVS), FORMAL DEMONSTRATION THAT EVS MEDIATE THE EFFECTS OF PATERNAL PRECONCEPTION PERTURBATIONS IS LACKING. THEREFORE, IN THE CURRENT STUDY WE TESTED THE HYPOTHESIS THAT EPIDIDYMAL EV PREPARATIONS ARE SUFFICIENT TO INDUCE INTERGENERATIONAL EFFECTS OF PATERNAL PRECONCEPTION ETHANOL EXPOSURE ON OFFSPRING. TO TEST THIS HYPOTHESIS, SPERM FROM ETHANOL-NAIVE DONORS WERE INCUBATED WITH EPIDIDYMAL EV PREPARATIONS FROM CHRONIC ETHANOL (ETHANOL EV-DONOR) OR CONTROL-TREATED (CONTROL EV-DONOR) MICE PRIOR TO IN VITRO FERTILIZATION (IVF) AND EMBRYO TRANSFER. PROGENY WERE EXAMINED FOR ETHANOL- AND STRESS-RELATED BEHAVIORS IN ADULTHOOD. ETHANOL EV-DONORS IMPARTED REDUCED BODY WEIGHT AT WEANING AND IMPARTED MODESTLY INCREASED LIMITED ACCESS ETHANOL INTAKE TO MALE OFFSPRING. ETHANOL-EV DONORS ALSO IMPARTED INCREASED BASAL ANXIETY-LIKE BEHAVIOR AND REDUCED SENSITIVITY TO ETHANOL-INDUCED ANXIOLYSIS TO FEMALE OFFSPRING. ALTHOUGH ETHANOL EV-DONOR TREATMENT DID NOT RECAPITULATE THE ETHANOL- OR STRESS-RELATED INTERGENERATIONAL EFFECTS OF PATERNAL ETHANOL FOLLOWING NATURAL MATING, THESE RESULTS DEMONSTRATE THAT COINCUBATION OF SPERM WITH EPIDIDYMAL EV PREPARATIONS IS SUFFICIENT TO IMPART INTERGENERATIONAL EFFECTS OF ETHANOL THROUGH THE MALE GERMLINE. THIS MECHANISM MAY GENERALIZE TO THE INTERGENERATIONAL EFFECTS OF A WIDE VARIETY OF PATERNAL PRECONCEPTION PERTURBATIONS. 2020 11 6681 29 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 12 4935 25 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 13 3300 25 HIGH-FAT DIET REPROGRAMS THE EPIGENOME OF RAT SPERMATOZOA AND TRANSGENERATIONALLY AFFECTS METABOLISM OF THE OFFSPRING. OBJECTIVES: CHRONIC AND HIGH CONSUMPTION OF FAT CONSTITUTES AN ENVIRONMENTAL STRESS THAT LEADS TO METABOLIC DISEASES. WE HYPOTHESIZED THAT HIGH-FAT DIET (HFD) TRANSGENERATIONALLY REMODELS THE EPIGENOME OF SPERMATOZOA AND METABOLISM OF THE OFFSPRING. METHODS: F0-MALE RATS FED EITHER HFD OR CHOW DIET FOR 12 WEEKS WERE MATED WITH CHOW-FED DAMS TO GENERATE F1 AND F2 OFFSPRING. MOTILE SPERMATOZOA WERE ISOLATED FROM F0 AND F1 BREEDERS TO DETERMINE DNA METHYLATION AND SMALL NON-CODING RNA (SNCRNA) EXPRESSION PATTERN BY DEEP SEQUENCING. RESULTS: NEWBORN OFFSPRING OF HFD-FED FATHERS HAD REDUCED BODY WEIGHT AND PANCREATIC BETA-CELL MASS. ADULT FEMALE, BUT NOT MALE, OFFSPRING OF HFD-FED FATHERS WERE GLUCOSE INTOLERANT AND RESISTANT TO HFD-INDUCED WEIGHT GAIN. THIS PHENOTYPE WAS PERPETUATED IN THE F2 PROGENY, INDICATING TRANSGENERATIONAL EPIGENETIC INHERITANCE. THE EPIGENOME OF SPERMATOZOA FROM HFD-FED F0 AND THEIR F1 MALE OFFSPRING SHOWED COMMON DNA METHYLATION AND SMALL NON-CODING RNA EXPRESSION SIGNATURES. ALTERED EXPRESSION OF SPERM MIRNA LET-7C WAS PASSED DOWN TO METABOLIC TISSUES OF THE OFFSPRING, INDUCING A TRANSCRIPTOMIC SHIFT OF THE LET-7C PREDICTED TARGETS. CONCLUSION: OUR RESULTS PROVIDE INSIGHT INTO MECHANISMS BY WHICH HFD TRANSGENERATIONALLY REPROGRAMS THE EPIGENOME OF SPERM CELLS, THEREBY AFFECTING METABOLIC TISSUES OF OFFSPRING THROUGHOUT TWO GENERATIONS. 2016 14 4011 29 LOW PATERNAL DIETARY FOLATE ALTERS THE MOUSE SPERM EPIGENOME AND IS ASSOCIATED WITH NEGATIVE PREGNANCY OUTCOMES. EPIDEMIOLOGICAL STUDIES SUGGEST THAT A FATHER'S DIET CAN INFLUENCE OFFSPRING HEALTH. A PROPOSED MECHANISM FOR PATERNAL TRANSMISSION OF ENVIRONMENTAL INFORMATION IS VIA THE SPERM EPIGENOME. THE EPIGENOME INCLUDES HERITABLE INFORMATION SUCH AS DNA METHYLATION. WE HYPOTHESIZE THAT THE DIETARY SUPPLY OF METHYL DONORS WILL ALTER EPIGENETIC REPROGRAMMING IN SPERM. HERE WE FEED MALE MICE EITHER A FOLATE-DEFICIENT OR FOLATE-SUFFICIENT DIET THROUGHOUT LIFE. PATERNAL FOLATE DEFICIENCY IS ASSOCIATED WITH INCREASED BIRTH DEFECTS IN THE OFFSPRING, WHICH INCLUDE CRANIOFACIAL AND MUSCULOSKELETAL MALFORMATIONS. GENOME-WIDE DNA METHYLATION ANALYSIS AND THE SUBSEQUENT FUNCTIONAL ANALYSIS IDENTIFY DIFFERENTIAL METHYLATION IN SPERM OF GENES IMPLICATED IN DEVELOPMENT, CHRONIC DISEASES SUCH AS CANCER, DIABETES, AUTISM AND SCHIZOPHRENIA. WHILE >300 GENES ARE DIFFERENTIALLY EXPRESSED IN OFFSPRING PLACENTA, ONLY TWO CORRESPOND TO GENES WITH DIFFERENTIAL METHYLATION IN SPERM. THIS MODEL SUGGESTS EPIGENETIC TRANSMISSION MAY INVOLVE SPERM HISTONE H3 METHYLATION OR DNA METHYLATION AND THAT ADEQUATE PATERNAL DIETARY FOLATE IS ESSENTIAL FOR OFFSPRING HEALTH. 2013 15 4923 29 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 16 4529 26 MULTIGENERATIONAL GRAPHENE OXIDE INTOXICATION RESULTS IN REPRODUCTION DISORDERS AT THE MOLECULAR LEVEL OF VITELLOGENIN PROTEIN EXPRESSION IN ACHETA DOMESTICUS. THE ANTHROPOGENIC ACTIVITIES MAY LEAD TO ACCUMULATION OF GRAPHENE OXIDE (GO) POLLUTION IN THE ENVIRONMENT. ORGANISMS EXPOSED TO CHRONIC OR MULTIGENERATIONAL GO INTOXICATION CAN PRESENT REPRODUCTION DEPLETION. VITELLOGENIN (VG) HAS BEEN USED AS A PARAMETER FOR EVALUATING FEMALE FERTILITY DUE TO ITS IMPORTANCE IN EMBRYO NUTRITION. IN THIS STUDY, WE USED A PROMISING MODEL ORGANISM, ACHETA DOMESTICUS, WHICH WAS INTOXICATED WITH GO IN FOOD FOR THREE GENERATIONS. THE AIM OF THE STUDY WAS TO INVESTIGATE THE PROCESS OF VG SYNTHESIS IN CRICKETS DEPENDING ON THE EXPOSURE TIME, GO CONCENTRATION, AND AGE OF THE FEMALES. THE RESULTS REVEALED THAT CHRONIC GO INTOXICATION HAD ADVERSE EFFECTS ON THE VG EXPRESSION PATTERN. THE 1ST GENERATION OF INSECTS SHOWING LOW VG EXPRESSION WAS MOST AFFECTED. THE 2ND GENERATION OF A. DOMESTICUS PRESENTED A HIGH VG EXPRESSION. THE LAST INVESTIGATED GENERATION SEEMED TO COPE WITH STRESS CAUSED BY GO, AND THE VG EXPRESSION WAS BALANCED. WE SUGGEST THAT THE EPIGENETIC MECHANISMS MAY PLAY A ROLE IN THE INFORMATION TRANSFER TO THE NEXT GENERATIONS ON HOW TO REACT TO THE RISK FACTOR AND KEEP REPRODUCTION AT A HIGH RATE. WE SUSPECT THAT CHRONIC GO INTOXICATION CAN DISTURB THE REGULAR FORMATION OF THE VG QUATERNARY STRUCTURE, RESULTING IN CONSEQUENCES FOR DEVELOPING AN EMBRYO. 2021 17 4930 27 PATERNAL ALCOHOL EXPOSURE REDUCES ACQUISITION OF OPERANT ALCOHOL SELF-ADMINISTRATION AND AFFECTS BDNF DNA METHYLATION IN MALE AND FEMALE OFFSPRING. FAMILIAL TRANSMISSION OF ALCOHOL USE DISORDER REFLECTS GENETIC AND ENVIRONMENTAL FACTORS. PATERNAL ALCOHOL EXPOSURE MAY AFFECT RODENT OFFSPRING VIA EPIGENETIC MODIFICATIONS TRANSMITTED THROUGH THE MALE GERM LINE. WHILE SUCH EXPOSURE ALTERS ALCOHOL SENSITIVITY IN MOUSE OFFSPRING, NO STUDIES EXAMINED IF IT IMPACTS THE DEVELOPMENT OF OPERANT ALCOHOL SELF-ADMINISTRATION IN RATS. WE EXPOSED MALE (SIRES) WISTAR RATS TO CHRONIC INTERMITTENT ETHANOL IN VAPOUR CHAMBERS (16 H/DAY; 5 DAYS/WEEK) OR TO AIR FOR 6 WEEKS. EIGHT WEEKS LATER, RATS WERE MATED WITH ALCOHOL-NAIVE FEMALES. ADULT ALCOHOL- AND CONTROL-SIRED F1 OFFSPRING WERE ASSESSED IN ACQUISITION OF ALCOHOL SELF-ADMINISTRATION IN WHICH INCREASING ALCOHOL CONCENTRATIONS (2.5%, 5% AND 10%, V/V) WERE DELIVERED AFTER ONE LEVER PRESS (FIXED RATIO 1 OR FR1). PRIOR TO ALCOHOL SESSIONS, RATS WERE TRAINED TO LEVER PRESS FOR FOOD DELIVERY UNDER AN FR1 SCHEDULE OF REINFORCEMENT. DNA METHYLATION LEVELS OF THE BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) GENE WERE MEASURED IN SPERM, NUCLEUS ACCUMBENS (NAC) AND MEDIAL PREFRONTAL CORTEX (MPFC) IN SIRES AND IN OFFSPRING. ALCOHOL-EXPOSED SIRES HAD LOWER BDNF DNA METHYLATION LEVELS IN NAC AND GREATER METHYLATION LEVELS IN MPFC. ALTHOUGH THIS PATTERN WAS NOT RECAPITULATED IN OFFSPRING, ALCOHOL-SIRED OFFSPRING OF BOTH SEXES DID SHOW ABERRANT BDNF DNA METHYLATION PATTERNS COMPARED TO CONTROL-SIRED OFFSPRING. ALCOHOL-SIRED OFFSPRING SELF-ADMINISTERED LESS ALCOHOL (5% AND 10%) WITH NO GROUP DIFFERENCES IN FOOD RESPONDING. RESULTS INDICATE THAT PATERNAL ALCOHOL EXPOSURE PRIOR TO CONCEPTION PROTECTS AGAINST ALCOHOL'S INITIAL REINFORCING EFFECTS BUT THE PATTERN OF DYSREGULATED BDNF METHYLATION IN REWARD-RELATED CIRCUITRY DID NOT MIMIC CHANGES SEEN IN SIRES. 2022 18 341 21 ALTERATIONS IN SPERM-INHERITED NONCODING RNAS ASSOCIATE WITH LATE-TERM FETAL GROWTH RESTRICTION INDUCED BY PRECONCEPTION PATERNAL ALCOHOL USE. USING A MOUSE MODEL, OUR GROUP RECENTLY DESCRIBED AN ASSOCIATION BETWEEN CHRONIC PATERNAL ALCOHOL USE PRIOR TO CONCEPTION AND DEFICITS IN OFFSPRING GROWTH. HERE, WE SOUGHT TO DETERMINE THE IMPACT OF ALCOHOL EXPOSURE ON MALE REPRODUCTIVE PHYSIOLOGY AND THE ASSOCIATION OF SPERM-INHERITED NONCODING RNAS WITH THE TRANSMISSION OF THE OBSERVED GROWTH DEFECTS. ALCOHOL EXPOSURE DID NOT APPRECIABLY ALTER MALE REPRODUCTIVE PHYSIOLOGY OR FERTILITY. HOWEVER, CHRONIC ALCOHOL USE REPRODUCIBLY INDUCED LATE-TERM FETAL GROWTH RESTRICTION IN THE OFFSPRING, WHICH CORRELATED WITH A SHIFT IN THE PROPORTIONAL RATIO OF TRANSFER RNA-DERIVED SMALL RNAS TO PIWI-INTERACTING RNAS, AS WELL AS ALTERED ENRICHMENT OF MICRORNAS MIR21, MIR30, AND MIR142 IN ALCOHOL-EXPOSED SPERM. ALTHOUGH OUR DATASET SHARE SIMILARITIES TO PRIOR WORKS EXAMINING THE IMPACT OF PATERNAL STRESS ON OFFSPRING PHENOTYPE, WE WERE UNABLE TO IDENTIFY ANY CHANGES IN PLASMA CORTICOSTERONE, INDICATING ALCOHOL MAY ALTER SPERM-INHERITED NONCODING RNAS THROUGH DISTINCT MECHANISMS. 2019 19 4924 25 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 20 6555 31 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