1 968 119 CHRONIC NICOTINE EXPOSURE SYSTEMICALLY ALTERS MICRORNA EXPRESSION PROFILES DURING POST-EMBRYONIC STAGES IN CAENORHABDITIS ELEGANS. TOBACCO SMOKING IS ASSOCIATED WITH MANY DISEASES. ADDICTION IS OF THE MOST NOTORIOUS TOBACCO-RELATED SYNDROME AND IS MAINLY ATTRIBUTED TO NICOTINE. IN THIS STUDY, WE EMPLOYED CAENORHABDITIS ELEGANS AS A BIOLOGICAL MODEL TO SYSTEMICALLY INVESTIGATE THE EFFECT OF CHRONIC NICOTINE EXPOSURE ON MICRORNA (MIRNA) EXPRESSION PROFILE AND THEIR REGULATED BIOCHEMICAL PATHWAYS. NICOTINE TREATMENT (20 MICROM AND 20 MM) WAS LIMITED TO THE POST-EMBRYONIC STAGE FROM L1 TO L4 ( APPROXIMATELY 31 H) PERIOD AFTER WHICH WORMS WERE COLLECTED FOR GENOME-WIDE MIRNA PROFILING. OUR RESULTS SHOW THAT NICOTINE SIGNIFICANTLY ALTERED THE EXPRESSION PATTERNS OF 40 MIRNAS. THE EFFECT WAS PROPORTIONAL TO THE NICOTINE DOSE AND WAS EXPECTED TO HAVE AN ADDITIVE, MORE ROBUST RESPONSE. BASED ON PATHWAY ENRICHMENT ANALYSES COUPLED WITH NICOTINE-INDUCED MIRNA PATTERNS, WE INFERRED THAT MIRNAS AS A SYSTEM MEDIATES "REGULATORY HORMESIS", MANIFESTED IN BIPHASIC BEHAVIORAL AND PHYSIOLOGICAL PHENOTYPES. WE PROPOSED A MODEL WHERE NICOTINE ADDICTION IS MEDIATED BY MIRNAS' REGULATION OF FOS-1 AND IS MAINTAINED BY EPIGENETIC FACTORS. THUS, OUR STUDY OFFERS NEW INSIGHTS FOR A BETTER UNDERSTANDING OF THE SENSITIVITY OF EARLY DEVELOPMENTAL STAGES TO NICOTINE. 2014 2 4593 27 NATURAL GENETIC VARIATION IN A MULTIGENERATIONAL PHENOTYPE IN C. ELEGANS. ALTHOUGH HEREDITY MOSTLY RELIES ON THE TRANSMISSION OF DNA SEQUENCE, ADDITIONAL MOLECULAR AND CELLULAR FEATURES ARE HERITABLE ACROSS SEVERAL GENERATIONS. IN THE NEMATODE CAENORHABDITIS ELEGANS, INSIGHTS INTO SUCH UNCONVENTIONAL INHERITANCE RESULT FROM TWO LINES OF WORK. FIRST, THE MORTAL GERMLINE (MRT) PHENOTYPE WAS DEFINED AS A MULTIGENERATIONAL PHENOTYPE WHEREBY A SELFING LINEAGE BECOMES STERILE AFTER SEVERAL GENERATIONS, IMPLYING MULTIGENERATIONAL MEMORY [1, 2]. SECOND, CERTAIN RNAI EFFECTS ARE HERITABLE OVER SEVERAL GENERATIONS IN THE ABSENCE OF THE INITIAL TRIGGER [3-5]. BOTH LINES OF WORK CONVERGED WHEN THE SUBSET OF MRT MUTANTS THAT ARE HEAT SENSITIVE WERE FOUND TO CLOSELY CORRESPOND TO MUTANTS DEFECTIVE IN THE RNAI-INHERITANCE MACHINERY, INCLUDING HISTONE MODIFIERS [6-9]. HERE, WE REPORT THE SURPRISING FINDING THAT SEVERAL C. ELEGANS WILD ISOLATES DISPLAY A HEAT-SENSITIVE MORTAL GERMLINE PHENOTYPE IN LABORATORY CONDITIONS: UPON CHRONIC EXPOSURE TO HIGHER TEMPERATURES, SUCH AS 25 DEGREES C, LINES REPRODUCIBLY BECOME STERILE AFTER SEVERAL GENERATIONS. THIS PHENOMENON IS REVERSIBLE, AS IT CAN BE SUPPRESSED BY TEMPERATURE ALTERNATIONS AT EACH GENERATION, SUGGESTING A NON-GENETIC BASIS FOR THE STERILITY. WE TESTED WHETHER NATURAL VARIATION IN THE TEMPERATURE-INDUCED MRT PHENOTYPE WAS OF GENETIC NATURE BY BUILDING RECOMBINANT INBRED LINES BETWEEN THE ISOLATES MY10 (MRT) AND JU1395 (NON-MRT). USING BULK SEGREGANT ANALYSIS, WE DETECTED TWO QUANTITATIVE TRAIT LOCI. AFTER FURTHER RECOMBINANT MAPPING AND GENOME EDITING, WE IDENTIFIED THE MAJOR CAUSAL LOCUS AS A POLYMORPHISM IN THE SET-24 GENE, ENCODING A SET- AND SPK-DOMAIN PROTEIN. WE CONCLUDE THAT C. ELEGANS NATURAL POPULATIONS MAY HARBOR NATURAL GENETIC VARIATION IN EPIGENETIC INHERITANCE PHENOMENA. 2018 3 947 32 CHRONIC MEHG EXPOSURE MODIFIES THE HISTONE H3K4ME3 EPIGENETIC LANDSCAPE IN CAENORHABDITIS ELEGANS. METHYLMERCURY (MEHG) IS A PERSISTENT ENVIRONMENTAL POLLUTANT THAT OCCURS IN THE FOOD CHAIN, AT OCCUPATIONAL SITES, AND VIA MEDICAL PROCEDURES. EXPOSURE IN HUMANS AND ANIMAL MODELS RESULTS IN RENAL, NEURO, AND REPRODUCTIVE TOXICITIES. IN THIS STUDY, WE DEMONSTRATE THAT CHRONIC EXPOSURE TO MEHG (10MUM) CAUSES EPIGENETIC LANDSCAPE MODIFICATIONS OF HISTONE H3K4 TRIMETHYLATION (H3K4ME3) MARKS IN CAENORHABDITIS ELEGANS USING CHROMATIN IMMUNO-PRECIPITATION SEQUENCING (CHIP-SEQ). THE MODIFICATIONS CORRESPOND TO THE LOCATIONS OF 1467 GENES WITH ENHANCED AND 508 GENES WITH REDUCED SIGNALS. AMONG ENHANCED GENES ARE THOSE ENCODING GLUTATHIONE-S-TRANSFERASES, LIPOCALIN-RELATED PROTEIN AND A CUTICULAR COLLAGEN. CHIP-SEQ ENHANCEMENT OF THESE GENES WAS CONFIRMED WITH INCREASED MRNA EXPRESSION LEVELS REVEALED BY QRT-PCR. FURTHERMORE, WE OBSERVED ENHANCEMENT OF H3K4ME3 MARKS IN THESE GENES IN ANIMALS EXPOSED TO MEHG IN UTERO AND ASSAYED AT L4 STAGE. IN UTERO EXPOSURE ENHANCED MARKS WITHOUT ALTERATIONS IN MRNA EXPRESSION EXCEPT FOR THE LPR-5 GENE. FINALLY, KNOCKDOWN OF LIPOCALIN-RELATED PROTEIN GENE LPR-5, WHICH IS INVOLVED IN INTERCELLULAR SIGNALING, AND CUTICULAR COLLAGEN GENE DPY-7, STRUCTURAL COMPONENT OF THE CUTICLE, BY RNA INTERFERENCE (RNAI) RESULTED IN INCREASED LETHALITY OF ANIMALS AFTER MEHG EXPOSURE. OUR RESULTS PROVIDE NEW DATA ON THE EPIGENETIC LANDSCAPE CHANGES ELICITED BY MEHG EXPOSURE, AS WELL AS DESCRIBE A UNIQUE MODEL FOR STUDYING IN UTERO EFFECTS OF HEAVY METALS. TOGETHER, THESE FINDINGS MAY HELP TO UNDERSTAND THE TOXICOLOGICAL EFFECTS OF MEHG AT THE MOLECULAR LEVEL. 2017 4 1921 34 ENVIRONMENTAL EPIGENETIC INHERITANCE THROUGH GAMETES AND IMPLICATIONS FOR HUMAN REPRODUCTION. BACKGROUND: TRADITIONAL STUDIES FOCUSED ON DNA AS THE HERITABLE INFORMATION CARRIER THAT PASSES THE PHENOTYPE FROM PARENTS TO OFFSPRING. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT INFORMATION, THAT IS INDEPENDENT OF THE DNA SEQUENCE, TERMED EPIGENETIC INFORMATION, CAN BE INHERITED BETWEEN GENERATIONS. RECENTLY, IN OUR LAB, WE FOUND THAT PREDIABETES IN FATHERS INCREASES THE SUSCEPTIBILITY TO DIABETES IN OFFSPRING THROUGH GAMETIC CYTOSINE METHYLATION CHANGES. PATERNAL PREDIABETES CHANGED OVERALL METHYLATION PATTERNS IN SPERM, AND A LARGE PORTION OF DIFFERENTIALLY METHYLATED LOCI CAN BE TRANSMITTED TO PANCREATIC ISLETS OF OFFSPRING UP TO THE SECOND GENERATION. IN THIS REVIEW, WE SURVEY THE EXTENSIVE EXAMPLES OF ENVIRONMENTALLY INDUCED EPIGENETIC INHERITANCE IN VARIOUS SPECIES, RANGING FROM CAENORHABDITIS ELEGANS TO HUMANS. WE FOCUS MAINLY ON ELUCIDATING THE MOLECULAR BASIS OF ENVIRONMENTAL EPIGENETIC INHERITANCE THROUGH GAMETES, WHICH IS AN EMERGING THEME AND HAS IMPORTANT IMPLICATIONS FOR EXPLAINING THE PREVALENCE OF OBESITY, TYPE 2 DIABETES AND OTHER CHRONIC NON-GENETIC DISEASES, WHICH IS ALSO IMPORTANT FOR UNDERSTANDING THE INFLUENCE OF ENVIRONMENTAL EXPOSURES ON REPRODUCTIVE AND OVERALL HEALTH IN OFFSPRING. METHODS: FOR THIS REVIEW, WE INCLUDED RELEVANT DATA AND INFORMATION OBTAINED THROUGH A PUBMED DATABASE SEARCH FOR ALL ENGLISH LANGUAGE ARTICLES PUBLISHED UP TO AUGUST 2014 WHICH INCLUDED THE TERM 'ENVIRONMENTAL EPIGENETIC INHERITANCE' AND 'TRANSGENERATIONAL EPIGENETIC INHERITANCE'. WE FOCUSED ON RESEARCH PAPERS USING ANIMAL MODELS INCLUDING DROSOPHILA, C. ELEGANS, MOUSE AND RAT. HUMAN DATA WERE ALSO INCLUDED. RESULTS: EVIDENCE FROM ANIMAL MODELS SUGGESTS THAT ENVIRONMENTAL EPIGENETIC INHERITANCE THROUGH GAMETES EXISTS IN VARIOUS SPECIES. EXTENSIVE MOLECULAR EVIDENCE SUGGESTS THAT EPIGENETIC INFORMATION CARRIERS INCLUDING DNA METHYLATION, NON-CODING RNAS AND CHROMATIN PROTEINS IN GAMETES PLAY IMPORTANT ROLES IN THE TRANSMISSION OF PHENOTYPES FROM PARENTS TO OFFSPRING. CONCLUSIONS: GIVEN THE LARGE NUMBER OF EXPERIMENTAL EVIDENCE FROM VARIOUS ORGANISMS, IT IS CLEAR THAT PARENTAL ENVIRONMENTAL ALTERATIONS CAN AFFECT THE PHENOTYPES OF OFFSPRING THROUGH GAMETIC EPIGENETIC ALTERATIONS. THIS MORE RECENT THINKING BASED ON NEW DATA MAY HAVE IMPLICATIONS IN EXPLAINING THE PREVALENCE OF OBESITY, TYPE 2 DIABETES AND OTHER CHRONIC NON-GENETIC DISEASES. THIS ALSO IMPLIES THAT, IN THE NEAR FUTURE, EPIGENETIC FACTORS WHICH ARE HERITABLE SHOULD BE REGARDED IMPORTANT IN DETERMINING THE RISK OF CERTAIN DISEASES. MOREOVER, IDENTIFICATION OF EPIGENETIC MARKERS IN GAMETES (POLAR BODY OR SPERM) MAY HOLD GREAT PROMISE FOR PREDICTING SUSCEPTIBILITY TO AND PREVENTING CERTAIN NON-GENETIC DISEASES IN OFFSPRING, AS WELL AS PROVIDING INDICATIONS ON PARENTAL ENVIRONMENTAL EXPOSURES. 2015 5 4943 27 PATERNAL PRECONCEPTION ALCOHOL EXPOSURE IMPARTS INTERGENERATIONAL ALCOHOL-RELATED BEHAVIORS TO MALE OFFSPRING ON A PURE C57BL/6J BACKGROUND. WHILE ALCOHOL USE DISORDER (AUD) IS A HIGHLY HERITABLE CONDITION, THE BASIS OF AUD IN FAMILIES WITH A HISTORY OF ALCOHOLISM IS DIFFICULT TO EXPLAIN BY GENETIC VARIATION ALONE. EMERGING EVIDENCE SUGGESTS THAT PARENTAL EXPERIENCE PRIOR TO CONCEPTION CAN AFFECT INHERITANCE OF COMPLEX BEHAVIORS IN OFFSPRING VIA NON-GENOMIC (EPIGENETIC) MECHANISMS. FOR INSTANCE, MALE C57BL/6J (B6) MICE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL (CIE) PRIOR TO MATING WITH STRAIN 129S1/SVIMJ ETHANOL-NAIVE FEMALES PRODUCE MALE OFFSPRING WITH REDUCED ETHANOL-DRINKING PREFERENCE, INCREASED ETHANOL SENSITIVITY, AND INCREASED BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION IN THE VENTRAL TEGMENTAL AREA (VTA). IN THE PRESENT STUDY, WE TESTED THE HYPOTHESIS THAT THESE INTERGENERATIONAL EFFECTS OF PATERNAL CIE ARE REPRODUCIBLE IN MALE OFFSPRING ON AN INBRED B6 BACKGROUND. TO THIS END, B6 MALES WERE EXPOSED TO 6 WEEKS OF CIE (OR ROOM AIR AS A CONTROL) BEFORE MATING WITH ETHANOL-NAIVE B6 FEMALES TO PRODUCE ETHANOL (E)-SIRED AND CONTROL (C)-SIRED MALE AND FEMALE OFFSPRING. WE OBSERVED A SEX-SPECIFIC EFFECT, AS E-SIRED MALES EXHIBITED DECREASED TWO-BOTTLE FREE-CHOICE ETHANOL-DRINKING PREFERENCE, INCREASED SENSITIVITY TO THE ANXIOLYTIC EFFECTS OF ETHANOL, AND INCREASED VTA BDNF EXPRESSION; NO DIFFERENCES WERE OBSERVED IN FEMALE OFFSPRING. THESE FINDINGS CONFIRM AND EXTEND OUR PREVIOUS RESULTS BY DEMONSTRATING THAT THE EFFECTS OF PATERNAL PRECONCEPTION ETHANOL ARE REPRODUCIBLE USING GENETICALLY IDENTICAL, INBRED B6 ANIMALS. 2017 6 4944 23 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 4180 34 MERCURY EXPOSURE INDUCES CYTOSKELETON DISRUPTION AND LOSS OF RENAL FUNCTION THROUGH EPIGENETIC MODULATION OF MMP9 EXPRESSION. MERCURY IS ONE OF THE MAJOR HEAVY METAL POLLUTANTS OCCURRING IN ELEMENTAL, INORGANIC AND ORGANIC FORMS. DUE TO BAN ON MOST INORGANIC MERCURY CONTAINING PRODUCTS, HUMAN EXPOSURE TO MERCURY GENERALLY OCCURS AS METHYLMERCURY (MEHG) BY CONSUMPTION OF CONTAMINATED FISH AND OTHER SEA FOOD. ANIMAL AND EPIDEMIOLOGICAL STUDIES INDICATE THAT MEHG AFFECTS NEURAL AND RENAL FUNCTION. OUR STUDY IS FOCUSED ON NEPHROTOXIC POTENTIAL OF MEHG. IN THIS STUDY, WE HAVE SHOWN FOR THE FIRST TIME HOW MEHG COULD EPIGENETICALLY MODULATE MATRIX METALLOPROTEINASE 9(MMP9) TO PROMOTE NEPHROTOXICITY USING AN ANIMAL MODEL OF SUB CHRONIC MEHG EXPOSURE. MEHG CAUSED RENAL TOXICITY AS WAS SEEN BY INCREASED LEVELS OF SERUM CREATININE AND EXPRESSION OF EARLY NEPHROTOXICITY MARKERS (KIM-1, CLUSTERIN, IP-10, AND TIMP). MEHG EXPOSURE ALSO CORRELATED STRONGLY WITH INDUCTION OF MMP9 MRNA AND PROTEIN IN A DOSE DEPENDENT MANNER. FURTHER, WHILE INDUCTION OF MMP9 PROMOTED CYTOSKELETON DISRUPTION AND LOSS OF CELL-CELL ADHESION (LOSS OF F-ACTIN, VIMENTIN AND FIBRONECTIN), INHIBITION OF MMP9 WAS FOUND TO REDUCE THESE DISRUPTIONS. MECHANISTIC STUDIES BY CHIP ANALYSIS SHOWED THAT MEHG MODULATED MMP9 BY PROMOTING DEMETHYLATION OF ITS REGULATORY REGION TO INCREASE ITS EXPRESSION. BISULFITE SEQUENCING IDENTIFIED CRITICAL CPGS IN THE FIRST EXON OF MMP9 WHICH WERE DEMETHYLATED FOLLOWING MEHG EXPOSURE. CHIP STUDIES ALSO SHOWED LOSS OF METHYL BINDING PROTEIN, MECP2 AND TRANSCRIPTION FACTOR PEA3 AT THE DEMETHYLATED SITE CONFIRMING DECREASED CPG METHYLATION. OUR STUDIES THUS SHOW HOW MEHG COULD EPIGENETICALLY MODULATE MMP9 TO PROMOTE CYTOSKELETON DISRUPTION LEADING TO LOSS OF RENAL FUNCTION. 2017 8 502 34 ASSOCIATION OF ARSENIC EXPOSURE WITH WHOLE BLOOD DNA METHYLATION: AN EPIGENOME-WIDE STUDY OF BANGLADESHI ADULTS. BACKGROUND: ARSENIC EXPOSURE AFFECTS [FORMULA: SEE TEXT] PEOPLE WORLDWIDE, INCLUDING [FORMULA: SEE TEXT] IN BANGLADESH. ARSENIC EXPOSURE INCREASES THE RISK OF CANCER AND OTHER CHRONIC DISEASES, AND ONE POTENTIAL MECHANISM OF ARSENIC TOXICITY IS EPIGENETIC DYSREGULATION. OBJECTIVE: WE ASSESSED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENOME-WIDE DNA METHYLATION MEASURED AT BASELINE AMONG 396 BANGLADESHI ADULTS PARTICIPATING IN THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (HEALS) WHO WERE EXPOSED BY DRINKING NATURALLY CONTAMINATED WELL WATER. METHODS: METHYLATION IN WHOLE BLOOD DNA WAS MEASURED AT [FORMULA: SEE TEXT] USING THE ILLUMINA INFINIUMMETHYLATIONEPIC (EPIC) ARRAY. TO ASSESS ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG METHYLATION, WE USED LINEAR REGRESSION MODELS ADJUSTED FOR COVARIATES AND SURROGATE VARIABLES (SVS) (CAPTURING UNKNOWN TECHNICAL AND BIOLOGIC FACTORS). WE ATTEMPTED REPLICATION AND CONDUCTED A META-ANALYSIS USING AN INDEPENDENT DATASET OF [FORMULA: SEE TEXT] FROM 400 BANGLADESHI INDIVIDUALS WITH ARSENICAL SKIN LESIONS. RESULTS: WE IDENTIFIED 34 CPGS ASSOCIATED WITH [FORMULA: SEE TEXT] CREATININE-ADJUSTED URINARY ARSENIC [[FORMULA: SEE TEXT]]. SIXTEEN OF THESE CPGS ANNOTATED TO THE [FORMULA: SEE TEXT] ARRAY, AND 10 ASSOCIATIONS WERE REPLICATED ([FORMULA: SEE TEXT]). THE TOP TWO CPGS ANNOTATED UPSTREAM OF THE ABR GENE (CG01912040, CG10003262 ). ALL URINARY ARSENIC-ASSOCIATED CPGS WERE ALSO ASSOCIATED WITH ARSENIC CONCENTRATION MEASURED IN DRINKING WATER ([FORMULA: SEE TEXT]). META-ANALYSIS ([FORMULA: SEE TEXT] SAMPLES) IDENTIFIED 221 URINARY ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]). THE ARSENIC-ASSOCIATED CPGS FROM THE META-ANALYSIS WERE ENRICHED IN NON-CPG ISLANDS AND SHORES ([FORMULA: SEE TEXT]) AND DEPLETED IN PROMOTER REGIONS ([FORMULA: SEE TEXT]). AMONG THE ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]), WE OBSERVED SIGNIFICANT ENRICHMENT OF GENES ANNOTATING TO THE REACTIVE OXYGEN SPECIES PATHWAY, INFLAMMATORY RESPONSE, AND TUMOR NECROSIS FACTOR [FORMULA: SEE TEXT] ([FORMULA: SEE TEXT]) SIGNALING VIA NUCLEAR FACTOR KAPPA-B ([FORMULA: SEE TEXT]) HALLMARKS ([FORMULA: SEE TEXT]). CONCLUSIONS: THE NOVEL AND REPLICABLE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND DNA METHYLATION AT SPECIFIC CPGS OBSERVED IN THIS WORK SUGGEST THAT EPIGENETIC ALTERATIONS SHOULD BE FURTHER INVESTIGATED AS POTENTIAL MEDIATORS IN ARSENIC TOXICITY AND AS BIOMARKERS OF EXPOSURE AND EFFECT IN EXPOSED POPULATIONS. HTTPS://DOI.ORG/10.1289/EHP3849. 2019 9 3971 28 LONG-LASTING NEUROTOXIC EFFECTS OF EXPOSURE TO METHYLMERCURY DURING DEVELOPMENT. AMONGST ENVIRONMENTAL CHEMICAL CONTAMINANTS, METHYLMERCURY (MEHG) REMAINS A MAJOR CONCERN BECAUSE OF ITS DETRIMENTAL EFFECTS ON DEVELOPING ORGANISMS, WHICH APPEAR TO BE PARTICULARLY SUSCEPTIBLE TO ITS TOXICITY. HERE, WE INVESTIGATED THE EFFECTS OF LOW MEHG LEVELS ON THE DEVELOPMENT OF THE NERVOUS SYSTEM USING BOTH IN VITRO AND IN VIVO EXPERIMENTAL MODELS. IN NEURAL STEM CELLS (NSCS), MEHG DECREASED PROLIFERATION AND NEURONAL DIFFERENTIATION AND INDUCED CELLULAR SENESCENCE ASSOCIATED WITH IMPAIRMENT IN MITOCHONDRIAL FUNCTION AND A CONCOMITANT DECREASE IN GLOBAL DNA METHYLATION. INTERESTINGLY, THE EFFECTS WERE HERITABLE AND COULD BE OBSERVED IN DAUGHTER NSCS NEVER DIRECTLY EXPOSED TO MEHG. BY CHRONICALLY EXPOSING PREGNANT/LACTATING MICE TO MEHG, WE FOUND PERSISTENT BEHAVIOURAL CHANGES IN THE MALE OFFSPRING, WHICH EXHIBITED DEPRESSION-LIKE BEHAVIOUR THAT COULD BE REVERSED BY CHRONIC TREATMENT WITH THE ANTIDEPRESSANT FLUOXETINE. THE BEHAVIOURAL ALTERATIONS WERE ASSOCIATED WITH A DECREASED NUMBER OF PROLIFERATING CELLS AND LOWER EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA IN THE HIPPOCAMPAL DENTATE GYRUS. MEHG EXPOSURE ALSO INDUCED LONG-LASTING DNA HYPERMETHYLATION, INCREASED HISTONE H3-K27 TRI-METHYLATION AND DECREASED H3 ACETYLATION AT THE BDNF PROMOTER IV, INDICATING THAT EPIGENETIC MECHANISMS PLAY A CRITICAL ROLE IN MEDIATING THE LONG-LASTING EFFECTS OF PERINATAL EXPOSURE TO MEHG. FLUOXETINE TREATMENT RESTORED THE BDNF MRNA EXPRESSION LEVELS, AS WELL AS THE NUMBER OF PROLIFERATING CELLS IN THE GRANULE CELL LAYER OF THE DENTATE GYRUS, WHICH FURTHER SUPPORTS THE HYPOTHESIS THAT LINKS DEPRESSION TO IMPAIRED NEUROGENESIS. ALTOGETHER, OUR FINDINGS HAVE SHOWN THAT LOW CONCENTRATIONS OF MEHG INDUCE LONG-LASTING EFFECTS IN NSCS THAT CAN POTENTIALLY PREDISPOSE INDIVIDUALS TO DEPRESSION, WHICH WE HAVE REPORTED EARLIER TO OCCUR IN EXPERIMENTAL ANIMALS EXPOSED TO MEHG DURING PRENATAL AND EARLY POSTNATAL DEVELOPMENT. 2013 10 4932 28 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 11 3119 32 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 12 3300 27 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 13 2484 39 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 14 4949 20 PATERNAL TRANSMISSION OF STRESS-INDUCED PATHOLOGIES. BACKGROUND: THERE HAS BEEN RECENT INTEREST IN THE POSSIBILITY THAT EPIGENETIC MECHANISMS MIGHT CONTRIBUTE TO THE TRANSGENERATIONAL TRANSMISSION OF STRESS-INDUCED VULNERABILITY. HERE, WE FOCUSED ON POSSIBLE PATERNAL TRANSMISSION WITH THE SOCIAL DEFEAT STRESS PARADIGM. METHODS: ADULT MALE MICE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS OR CONTROL NONDEFEATED MICE WERE BRED WITH NORMAL FEMALE MICE, AND THEIR OFFSPRING WERE ASSESSED BEHAVIORALLY FOR DEPRESSIVE- AND ANXIETY-LIKE MEASURES. PLASMA LEVELS OF CORTICOSTERONE AND VASCULAR ENDOTHELIAL GROWTH FACTOR WERE ALSO ASSAYED. TO DIRECTLY ASSESS THE ROLE OF EPIGENETIC MECHANISMS, WE USED IN VITRO FERTILIZATION (IVF); BEHAVIORAL ASSESSMENTS WERE CONDUCTED ON OFFSPRING OF MICE FROM IVF-CONTROL AND IVF-DEFEATED FATHERS. RESULTS: WE SHOW THAT BOTH MALE AND FEMALE OFFSPRING FROM DEFEATED FATHERS EXHIBIT INCREASED MEASURES OF SEVERAL DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. THE MALE OFFSPRING OF DEFEATED FATHERS ALSO DISPLAY INCREASED BASELINE PLASMA LEVELS OF CORTICOSTERONE AND DECREASED LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR. HOWEVER, MOST OF THESE BEHAVIORAL CHANGES WERE NOT OBSERVED WHEN OFFSPRING WERE GENERATED THROUGH IVF. CONCLUSIONS: THESE RESULTS SUGGEST THAT, ALTHOUGH BEHAVIORAL ADAPTATIONS THAT OCCUR AFTER CHRONIC SOCIAL DEFEAT STRESS CAN BE TRANSMITTED FROM THE FATHER TO HIS MALE AND FEMALE F1 PROGENY, ONLY VERY SUBTLE CHANGES MIGHT BE TRANSMITTED EPIGENETICALLY UNDER THE CONDITIONS TESTED. 2011 15 3715 34 INHERITED EFFECTS OF LOW-DOSE EXPOSURE TO METHYLMERCURY IN NEURAL STEM CELLS. METHYLMERCURY (MEHG) IS AN ENVIRONMENTAL CONTAMINANT WITH RECOGNIZED NEUROTOXIC EFFECTS, PARTICULARLY TO THE DEVELOPING NERVOUS SYSTEM. IN THE PRESENT STUDY, WE SHOW THAT NANOMOLAR CONCENTRATIONS OF MEHG CAN INDUCE LONG-LASTING EFFECTS IN NEURAL STEM CELLS (NSCS). WE INVESTIGATED SHORT-TERM DIRECT AND LONG-TERM INHERITED EFFECTS OF EXPOSURE TO MEHG (2.5 OR 5.0 NM) USING PRIMARY CULTURES OF RAT EMBRYONIC CORTICAL NSCS. WE FOUND THAT MEHG HAD NO ADVERSE EFFECT ON CELL VIABILITY BUT REDUCED NSC PROLIFERATION AND ALTERED THE EXPRESSION OF CELL CYCLE REGULATORS (P16 AND P21) AND SENESCENCE-ASSOCIATED MARKERS. IN ADDITION, WE DEMONSTRATED A DECREASE IN GLOBAL DNA METHYLATION IN THE EXPOSED CELLS, INDICATING THAT EPIGENETIC CHANGES MAY BE INVOLVED IN THE MECHANISMS UNDERLYING THE MEHG-INDUCED EFFECTS. THESE CHANGES WERE OBSERVED IN CELLS DIRECTLY EXPOSED TO MEHG (PARENT CELLS) AND IN THEIR DAUGHTER CELLS CULTURED UNDER MEHG-FREE CONDITIONS. IN AGREEMENT WITH OUR IN VITRO DATA, A TREND WAS FOUND FOR DECREASED CELL PROLIFERATION IN THE SUBGRANULAR ZONE IN THE HIPPOCAMPI OF ADULT MICE EXPOSED TO LOW DOSES OF MEHG DURING THE PERINATAL PERIOD. INTERESTINGLY, THIS IMPAIRED PROLIFERATION HAD A MEASURABLE IMPACT ON THE TOTAL NUMBER OF NEURONS IN THE HIPPOCAMPAL DENTATE GYRUS. IMPORTANTLY, THIS EFFECT COULD BE REVERSED BY CHRONIC ANTIDEPRESSANT TREATMENT. OUR STUDY PROVIDES NOVEL EVIDENCE FOR PROGRAMMING EFFECTS INDUCED BY MEHG IN NSCS AND SUPPORTS THE IDEA THAT DEVELOPMENTAL EXPOSURE TO LOW LEVELS OF MEHG MAY RESULT IN LONG-TERM CONSEQUENCES PREDISPOSING TO NEURODEVELOPMENTAL DISORDERS AND/OR NEURODEGENERATION. 2012 16 910 30 CHRONIC EXPOSURE TO ETHANOL OF MALE MICE BEFORE MATING PRODUCES ATTENTION DEFICIT HYPERACTIVITY DISORDER-LIKE PHENOTYPE ALONG WITH EPIGENETIC DYSREGULATION OF DOPAMINE TRANSPORTER EXPRESSION IN MOUSE OFFSPRING. PRECONCEPTION EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE MAY AFFECT NEUROBEHAVIORAL AND DEVELOPMENTAL FEATURES OF OFFSPRING. THIS STUDY INVESTIGATES THE EFFECTS OF PATERNAL EXPOSURE TO ETOH BEFORE CONCEPTION ON THE HYPERACTIVITY, INATTENTION, AND IMPULSIVITY BEHAVIOR OF MALE OFFSPRING IN MICE. SIRE MICE WERE TREATED WITH ETOH IN A CONCENTRATION RANGE APPROXIMATING HUMAN BINGE DRINKING (0-4 G/KG/DAY ETOH) FOR 7 WEEKS AND MATED WITH UNTREATED FEMALES MICE TO PRODUCE OFFSPRING. ETOH EXPOSURE TO SIRE MICE INDUCED ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)-LIKE HYPERACTIVE, INATTENTIVE, AND IMPULSIVE BEHAVIORS IN OFFSPRING. AS A MECHANISTIC LINK, BOTH PROTEIN AND MRNA EXPRESSION OF DOPAMINE TRANSPORTER (DAT), A KEY DETERMINANT OF ADHD-LIKE PHENOTYPES IN EXPERIMENTAL ANIMALS AND HUMANS, WERE SIGNIFICANTLY DECREASED BY PATERNAL ETOH EXPOSURE IN CEREBRAL CORTEX AND STRIATUM OF OFFSPRING MICE ALONG WITH INCREASED METHYLATION OF A CPG REGION OF THE DAT GENE PROMOTER. THE INCREASE IN METHYLATION OF DAT GENE PROMOTER WAS ALSO OBSERVED IN THE SPERM OF SIRE MICE, SUGGESTING GERMLINE CHANGES IN THE EPIGENETIC METHYLATION SIGNATURE OF DAT GENE BY ETOH EXPOSURE. IN ADDITION, THE EXPRESSION OF TWO KEY REGULATORS OF METHYLATION-DEPENDENT EPIGENETIC REGULATION OF FUNCTIONAL GENE EXPRESSION, NAMELY, MECP2 AND DNMT1, WAS MARKEDLY DECREASED IN OFFSPRING CORTEX AND STRIATUM SIRED BY ETOH-EXPOSED MICE. THESE RESULTS SUGGEST THAT PRECONCEPTIONAL EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE INDUCES BEHAVIORAL CHANGES IN OFFSPRING, POSSIBLY VIA EPIGENETIC CHANGES IN GENE EXPRESSION, WHICH IS ESSENTIAL FOR THE REGULATION OF ADHD-LIKE BEHAVIORS. 2014 17 1346 35 DETECTION OF TRANSGENERATIONAL SPERMATOGENIC INHERITANCE OF ADULT MALE ACQUIRED CNS GENE EXPRESSION CHARACTERISTICS USING A DROSOPHILA SYSTEMS MODEL. AVAILABLE INSTANCES OF INHERITANCE OF EPIGENETIC TRANSGENERATIONAL PHENOTYPE ARE LIMITED TO ENVIRONMENTAL EXPOSURES DURING EMBRYONIC AND ADULT GONADAL DEVELOPMENT. ADULT EXPOSURES CAN ALSO AFFECT GAMETOGENESIS AND THEREBY POTENTIALLY RESULT IN REPROGRAMMING OF THE GERMLINE. ALTHOUGH EXAMPLES OF EPIGENETIC EFFECTS ON GAMETOGENESIS EXIST, IT IS NOTABLE THAT TRANSGENERATIONAL INHERITANCE OF ENVIRONMENT-INDUCED ADULT PHENOTYPE HAS NOT YET BEEN REPORTED. EPIGENETIC CODES ARE CONSIDERED TO BE CRITICAL IN NEURAL PLASTICITY. A DROSOPHILA SYSTEMS MODEL OF PENTYLENETETRAZOLE (PTZ) INDUCED LONG-TERM BRAIN PLASTICITY HAS RECENTLY BEEN DESCRIBED. IN THIS MODEL, CHRONIC PTZ TREATMENT OF ADULT MALES CAUSES ALTERATIONS IN CNS TRANSCRIPTOME. HERE, WE DESCRIBE OUR SEARCH FOR TRANSGENERATIONAL SPERMATOGENIC INHERITANCE OF PTZ INDUCED GENE EXPRESSION PHENOTYPE ACQUIRED BY ADULT DROSOPHILA MALES. WE GENERATED CNS TRANSCRIPTOMIC PROFILES OF F(1) ADULTS AFTER TREATING F(0) ADULT MALES WITH PTZ AND OF F(2) ADULTS RESULTING FROM A CROSS BETWEEN F(1) MALES AND NORMAL FEMALES. SURPRISINGLY, MICROARRAY CLUSTERING SHOWED F(1) MALE PROFILE AS CLOSEST TO F(1) FEMALE AND F(0) MALE PROFILE CLOSEST TO F(2) MALE. DIFFERENTIALLY EXPRESSED GENES IN F(1) MALES, F(1) FEMALES AND F(2) MALES SHOWED SIGNIFICANT OVERLAP WITH THOSE CAUSED BY PTZ. INTERESTINGLY, MICROARRAY EVIDENCE ALSO LED TO THE IDENTIFICATION OF UPREGULATED RRNA IN F(2) MALES. NEXT, WE GENERATED MICROARRAY EXPRESSION PROFILES OF ADULT TESTIS FROM F(0) AND F(1) MALES. FURTHER SURPRISING, CLUSTERING OF CNS AND TESTIS PROFILES AND MATCHING OF DIFFERENTIALLY EXPRESSED GENES IN THEM PROVIDED EVIDENCE OF A SPERMATOGENIC MECHANISM IN THE TRANSGENERATIONAL EFFECT OBSERVED. TO OUR KNOWLEDGE, WE REPORT FOR THE FIRST TIME DETECTION OF TRANSGENERATIONAL SPERMATOGENIC INHERITANCE OF ADULT ACQUIRED SOMATIC GENE EXPRESSION CHARACTERISTIC. THE DROSOPHILA SYSTEMS MODEL OFFERS AN EXCELLENT OPPORTUNITY TO UNDERSTAND THE EPIGENETIC MECHANISMS UNDERLYING THE PHENOMENON. THE FINDING THAT ADULT ACQUIRED TRANSCRIPTOMIC ALTERATION IN SOMA IS SPERMATOGENICALLY INHERITED ACROSS GENERATIONS HAS POTENTIAL IMPLICATIONS IN HUMAN HEALTH AND EVOLUTION. 2009 18 5774 35 SPERM TRANSCRIPTIONAL STATE ASSOCIATED WITH PATERNAL TRANSMISSION OF STRESS PHENOTYPES. PATERNAL STRESS CAN INDUCE LONG-LASTING CHANGES IN GERM CELLS POTENTIALLY PROPAGATING HERITABLE CHANGES ACROSS GENERATIONS. TO DATE, NO STUDIES HAVE INVESTIGATED DIFFERENCES IN TRANSMISSION PATTERNS BETWEEN STRESS-RESILIENT AND -SUSCEPTIBLE MICE. WE TESTED THE HYPOTHESIS THAT TRANSCRIPTIONAL ALTERATIONS IN SPERM DURING CHRONIC SOCIAL DEFEAT STRESS (CSDS) TRANSMIT INCREASED SUSCEPTIBILITY TO STRESS PHENOTYPES TO THE NEXT GENERATION. WE DEMONSTRATE DIFFERENCES IN OFFSPRING FROM STRESSED FATHERS THAT DEPEND UPON PATERNAL CATEGORY (RESILIENT VS SUSCEPTIBLE) AND OFFSPRING SEX. IMPORTANTLY, ARTIFICIAL INSEMINATION REVEALS THAT SPERM MEDIATES SOME OF THE BEHAVIORAL PHENOTYPES SEEN IN OFFSPRING. USING RNA-SEQUENCING WE REPORT SUBSTANTIAL AND DISTINCT CHANGES IN THE TRANSCRIPTOMIC PROFILES OF SPERM FOLLOWING CSDS IN SUSCEPTIBLE VS RESILIENT FATHERS, WITH ALTERATIONS IN LONG NONCODING RNAS (LNCRNAS) PREDOMINATING ESPECIALLY IN SUSCEPTIBILITY. CORRELATION ANALYSIS REVEALED THAT THESE ALTERATIONS WERE ACCOMPANIED BY A LOSS OF REGULATION OF PROTEIN-CODING GENES BY LNCRNAS IN SPERM OF SUSCEPTIBLE MALES. WE ALSO IDENTIFY SEVERAL CO-EXPRESSION GENE MODULES THAT ARE ENRICHED IN DIFFERENTIALLY EXPRESSED GENES IN SPERM FROM EITHER RESILIENT OR SUSCEPTIBLE FATHERS. TAKEN TOGETHER, THESE STUDIES ADVANCE OUR UNDERSTANDING OF INTERGENERATIONAL EPIGENETIC TRANSMISSION OF BEHAVIORAL EXPERIENCE.SIGNIFICANCE STATEMENTTHIS MANUSCRIPT CONTRIBUTES TO THE COMPLEX FACTORS THAT INFLUENCE THE PATERNAL TRANSMISSION OF STRESS PHENOTYPES. BY LEVERAGING THE SEGREGATION OF MALES EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS INTO EITHER RESILIENT OR SUSCEPTIBLE CATEGORIES WE WERE ABLE TO IDENTIFY THE PHENOTYPIC DIFFERENCES IN THE PATERNAL TRANSMISSION OF STRESS PHENOTYPES ACROSS GENERATIONS BETWEEN THE TWO LINEAGES. IMPORTANTLY, THIS WORK ALSO ALLUDES TO THE SIGNIFICANCE OF BOTH LONG NONCODING RNAS AND PROTEIN CODING GENES MEDIATING THE PATERNAL TRANSMISSION OF STRESS. THE KNOWLEDGE GAINED FROM THESE DATA IS OF PARTICULAR INTEREST IN UNDERSTANDING THE RISK FOR THE DEVELOPMENT OF PSYCHIATRIC DISORDERS SUCH AS ANXIETY AND DEPRESSION. 2021 19 4011 25 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 20 4947 31 PATERNAL SEPSIS INDUCES ALTERATIONS OF THE SPERM METHYLOME AND DAMPENS OFFSPRING IMMUNE RESPONSES-AN ANIMAL STUDY. BACKGROUND: SEPSIS REPRESENTS THE UTMOST SEVERE CONSEQUENCE OF INFECTION, INVOLVING A DYSREGULATED AND SELF-DAMAGING IMMUNE RESPONSE OF THE HOST. WHILE DIFFERENT ENVIRONMENTAL EXPOSURES LIKE CHRONIC STRESS OR MALNUTRITION HAVE BEEN WELL DESCRIBED TO REPROGRAM THE GERMLINE AND SUBSEQUENTLY OFFSPRING ATTRIBUTES, THE INTERGENERATIONAL IMPACT OF SEPSIS AS A TREMENDOUS IMMUNOLOGICAL STRESSOR HAS NOT BEEN EXAMINED YET. METHODS: POLYMICROBIAL SEPSIS IN 12-WEEK-OLD MALE C57BL/6 MICE WAS INDUCED BY CECAL LIGATION AND PUNCTURE (CLP), FOLLOWED BY A MATING OF THE MALE SURVIVORS (OR APPROPRIATE SHAM CONTROL ANIMALS) 6 WEEKS LATER WITH HEALTHY FEMALES. ALVEOLAR MACROPHAGES OF OFFSPRING ANIMALS WERE ISOLATED AND STIMULATED WITH EITHER LPS OR ZYMOSAN, AND SUPERNATANT LEVELS OF TNF-ALPHA WERE QUANTIFIED BY ELISA. FURTHERMORE, SYSTEMIC CYTOKINE RESPONSE TO INTRAPERITONEALLY INJECTED LPS WAS ASSESSED AFTER 24 H. ALSO, MORPHOLOGY, MOTILITY, AND GLOBAL DNA METHYLATION OF THE SEPSIS SURVIVORS' SPERM WAS EXAMINED. RESULTS: COMPARATIVE REDUCED REDUCTION BISULFITE SEQUENCING (RRBS) OF SPERM REVEALED CHANGES OF DNA METHYLATION (N = 381), MOST PRONOUNCED IN THE INTERGENIC GENOME AS WELL AS WITHIN INTRONS OF DEVELOPMENTALLY RELEVANT GENES. OFFSPRING OF SEPSIS FATHERS EXHIBITED A SLIGHT DECREASE IN BODY WEIGHT, WITH A MORE PRONOUNCED WEIGHT DIFFERENCE IN MALE ANIMALS (CLP VS. SHAM). MALE DESCENDANTS OF SEPSIS FATHERS, BUT NOT FEMALE DESCENDANTS, EXHIBITED LOWER PLASMA CONCENTRATIONS OF IL-6, TNF-ALPHA, AND IL-10 24 H AFTER INJECTION OF LPS. IN LINE, ONLY ALVEOLAR MACROPHAGES OF MALE DESCENDANTS OF SEPSIS FATHERS PRODUCED LESS TNF-ALPHA UPON ZYMOSAN STIMULATION COMPARED TO SHAM DESCENDANTS, WHILE LPS RESPONSES KEPT UNCHANGED. CONCLUSION: WE CAN PROVE THAT MALE-BUT SURPRISINGLY NOT FEMALE-DESCENDANTS OF POST-SEPSIS FATHERS SHOW A DAMPENED SYSTEMIC AS WELL AS PULMONARY IMMUNE RESPONSE. BASED ON THIS OBSERVATION OF AN IMMUNE HYPO-RESPONSIVITY, WE PROPOSE THAT MALE DESCENDANTS OF SEPSIS FATHERS ARE AT RISK TO DEVELOP FUNGAL AND BACTERIAL INFECTIONS AND MIGHT BENEFIT FROM THERAPEUTIC IMMUNE MODULATION. 2018