1  3586 278 IMPACT OF THE POLYCARBONATE STRIPPERS USED IN ASSISTED REPRODUCTION TECHNIQUES ON EMBRYONIC DEVELOPMENT. STUDY QUESTION: DO DAILY MANIPULATIONS OF PREIMPLANTATION EMBRYOS WITH POLYCARBONATE (PC)-MADE BISPHENOL A (BPA)-RELEASING STRIPPERS INFLUENCE EMBRYO DEVELOPMENT? SUMMARY ANSWER: COMPARED TO GLASS STRIPPERS, PC STRIPPERS ENHANCE THE BLASTOCYST DEVELOPMENT RATE BUT THIS DOES NOT SEEM TO BE BPA-RELATED. WHAT IS KNOWN ALREADY: PC STRIPPERS HAVE BEEN SHOWN TO RELEASE TINY AMOUNTS (AROUND 0.5 NG/ML BPA) OF BPA IN ROUTINE HUMAN IVF PROCEDURES. A CHRONIC EXPOSURE TO BPA EITHER IN VIVO OR IN VITRO DURING THE PREIMPLANTATION PERIOD CAN IMPACT POST-IMPLANTATION AND POST-NATAL DEVELOPMENT. BPA CAN ACT RAPIDLY BY BINDING TO MEMBRANE RECEPTORS AND INDUCING RAPID NON-GENOMIC EFFECTS. STUDY DESIGN, SIZE, DURATION: THIS EXPERIMENTAL STUDY USING MOUSE EMBRYOS HAD A BALANCED DESIGN AND BLINDED EVALUATIONS OF THE ENDPOINTS. PARTICIPANTS/MATERIALS, SETTING, METHODS: IN VIVO FERTILIZED ZYGOTES WERE OBTAINED FROM OUTBRED SWISS CD1 MICE CROSSINGS AFTER AN OVARIAN STIMULATION. THE ZYGOTES WERE ALLOCATED TO THREE DAILY HANDLING CONDITIONS (HCS) AND CULTURED UNTIL DAY 4 IN A SINGLE HUMAN COMMERCIAL MEDIUM. EACH DAY, THE EMBRYOS WERE HANDLED FOR 20 S EITHER IN A PC STRIPPER (HC1) OR IN A GLASS STRIPPER (HC2). IN HC3, THE EMBRYOS WERE PRE-EXPOSED TO 0.5 NG/ML BPA BEFORE BEING HANDLED FOR 20 S IN A GLASS STRIPPER. HANDLING OPERATIONS WERE REPEATED ON DAYS 1, 2 AND 3. EMBRYO DEVELOPMENT WAS ASSESSED BLINDLY ON DAY 4. EXPANDED BLASTOCYSTS WERE SELECTED FOR A TRANSCRIPTOMIC ANALYSIS USING AGILENT SUREPRINT G3 MOUSE GE V2 MICROARRAYS AND THE RETROTRANSPOSON LINE1-ORF2 EXPRESSION WAS ANALYSED USING QRT-PCR, AS A PROXY FOR A GLOBAL EVALUATION OF THE EPIGENETIC STATUS. MAIN RESULTS AND THE ROLE OF CHANCE: COMPARED TO THE EMBRYOS MANIPULATED IN HC2 (N = 243), THOSE IN HC1 (N = 228) DEVELOPED SIGNIFICANTLY MORE OFTEN TO THE BLASTOCYST STAGE (55 VS 46%; P < 0.05). IT APPEARS THE EFFECT OF THESE PC STRIPPERS WAS NOT BPA-RELATED BECAUSE EMBRYOS PRE-EXPOSED TO BPA (HC3, N = 230) SHOWED NO DIFFERENCE IN THE BLASTOCYST RATE WHEN COMPARED TO HC2 (43 VS 46%). WHEN ANALYSING SAME-STAGE BLASTOCYSTS, WE NOTICED NO DIFFERENCE IN THE EMBRYO GENE EXPRESSION BETWEEN THE THREE HC GROUPS. LARGE SCALE DATA: HTTPS://WWW.NCBI.NLM.NIH.GOV/GEO/QUERY/ACC.CGI?ACC=GSE148868. LIMITATIONS, REASONS FOR CAUTION: OUR RESULTS USING A MOUSE MODEL DESIGNED TO MIMIC HUMAN CONDITIONS (OUTBRED STRAIN, HUMAN COMMERCIAL IVF DISHES AND A UNIQUE COMMERCIAL HUMAN EMBRYONIC CULTURE MEDIA) ARE REASSURING SINCE NO GENE WAS FOUND TO BE DIFFERENTIALLY EXPRESSED, INCLUDING LINE-1 GENES, AS A PROXY FOR A GLOBAL EVALUATION OF THE EPIGENETIC STATUS. HOWEVER, NO GLOBAL EPIGENETIC ANALYSIS OF THE GENOME HAS BEEN PERFORMED. FURTHERMORE, WE DID NOT EVALUATE POST-IMPLANTATION EVENTS, ALTHOUGH BPA EXPOSURE DURING PERI-CONCEPTION COULD AFFECT FOETO-PLACENTAL AND POST-NATAL DEVELOPMENT. WIDER IMPLICATIONS OF THE FINDINGS: BASED ON THE PRECAUTIONARY PRINCIPLE, SEVERAL EUROPEAN COUNTRIES BANNED THE USE OF BPA IN BABY BOTTLES AND FOOD PACKAGING SEVERAL YEARS BEFORE EUROPEAN AGENCIES TOOK AN OFFICIAL POSITION. THE QUESTION OF APPLYING THIS PRINCIPLE TO PLASTICS IN CLOSED CONTACT WITH HUMAN EMBRYOS IS RAISED. FURTHER STUDIES ARE NEEDED FOR A DECISION TO BE MADE. STUDY FUNDING/COMPETING INTEREST(S): THIS STUDY WAS SUPPORTED BY A GRANT FROM THE AGENCE DE BIOMEDECINE (AOR 2016). THE AUTHORS DECLARE NO COMPETING INTEREST.	2021	

2  1488  30 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  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4  6558  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5  4944  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  4948  42 PATERNAL STRESS EXPOSURE ALTERS SPERM MICRORNA CONTENT AND REPROGRAMS OFFSPRING HPA STRESS AXIS REGULATION. NEUROPSYCHIATRIC DISEASE FREQUENTLY PRESENTS WITH AN UNDERLYING HYPOREACTIVITY OR HYPERREACTIVITY OF THE HPA STRESS AXIS, SUGGESTING AN EXCEPTIONAL VULNERABILITY OF THIS CIRCUITRY TO EXTERNAL PERTURBATIONS. PARENTAL LIFETIME EXPOSURES TO ENVIRONMENTAL CHALLENGES ARE ASSOCIATED WITH INCREASED OFFSPRING NEUROPSYCHIATRIC DISEASE RISK, AND LIKELY CONTRIBUTE TO STRESS DYSREGULATION. WHILE MATERNAL INFLUENCES HAVE BEEN EXTENSIVELY EXAMINED, MUCH LESS IS KNOWN REGARDING THE SPECIFIC ROLE OF PATERNAL FACTORS. TO INVESTIGATE THE POTENTIAL MECHANISMS BY WHICH PATERNAL STRESS MAY CONTRIBUTE TO OFFSPRING HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSREGULATION, WE EXPOSED MICE TO 6 WEEKS OF CHRONIC STRESS BEFORE BREEDING. AS EPIDEMIOLOGICAL STUDIES SUPPORT VARIATION IN PATERNAL GERM CELL SUSCEPTIBILITY TO REPROGRAMMING ACROSS THE LIFESPAN, MALE STRESS EXPOSURE OCCURRED EITHER THROUGHOUT PUBERTY OR IN ADULTHOOD. REMARKABLY, OFFSPRING OF SIRES FROM BOTH PATERNAL STRESS GROUPS DISPLAYED SIGNIFICANTLY REDUCED HPA STRESS AXIS RESPONSIVITY. GENE SET ENRICHMENT ANALYSES IN OFFSPRING STRESS REGULATING BRAIN REGIONS, THE PARAVENTRICULAR NUCLEUS (PVN) AND THE BED NUCLEUS OF STRIA TERMINALIS, REVEALED GLOBAL PATTERN CHANGES IN TRANSCRIPTION SUGGESTIVE OF EPIGENETIC REPROGRAMMING AND CONSISTENT WITH ALTERED OFFSPRING STRESS RESPONSIVITY, INCLUDING INCREASED EXPRESSION OF GLUCOCORTICOID-RESPONSIVE GENES IN THE PVN. IN EXAMINING POTENTIAL EPIGENETIC MECHANISMS OF GERM CELL TRANSMISSION, WE FOUND ROBUST CHANGES IN SPERM MICRORNA (MIR) CONTENT, WHERE NINE SPECIFIC MIRS WERE SIGNIFICANTLY INCREASED IN BOTH PATERNAL STRESS GROUPS. OVERALL, THESE RESULTS DEMONSTRATE THAT PATERNAL EXPERIENCE ACROSS THE LIFESPAN CAN INDUCE GERM CELL EPIGENETIC REPROGRAMMING AND IMPACT OFFSPRING HPA STRESS AXIS REGULATION, AND MAY THEREFORE OFFER NOVEL INSIGHT INTO FACTORS INFLUENCING NEUROPSYCHIATRIC DISEASE RISK.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7  3119  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  4939  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
9    73  49 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  4932  35 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  4941  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  1096  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14  6672  49 USE OF A MOUSE IN VITRO FERTILIZATION MODEL TO UNDERSTAND THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS. THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS HOLDS THAT ALTERATIONS TO HOMEOSTASIS DURING CRITICAL PERIODS OF DEVELOPMENT CAN PREDISPOSE INDIVIDUALS TO ADULT-ONSET CHRONIC DISEASES SUCH AS DIABETES AND METABOLIC SYNDROME. IT REMAINS CONTROVERSIAL WHETHER PREIMPLANTATION EMBRYO MANIPULATION, CLINICALLY USED TO TREAT PATIENTS WITH INFERTILITY, DISTURBS HOMEOSTASIS AND AFFECTS LONG-TERM GROWTH AND METABOLISM. TO ADDRESS THIS CONTROVERSY, WE HAVE ASSESSED THE EFFECTS OF IN VITRO FERTILIZATION (IVF) ON POSTNATAL PHYSIOLOGY IN MICE. WE DEMONSTRATE THAT IVF AND EMBRYO CULTURE, EVEN UNDER CONDITIONS CONSIDERED OPTIMAL FOR MOUSE EMBRYO CULTURE, ALTER POSTNATAL GROWTH TRAJECTORY, FAT ACCUMULATION, AND GLUCOSE METABOLISM IN ADULT MICE. UNBIASED METABOLIC PROFILING IN SERUM AND MICROARRAY ANALYSIS OF PANCREATIC ISLETS AND INSULIN SENSITIVE TISSUES (LIVER, SKELETAL MUSCLE, AND ADIPOSE TISSUE) REVEALED BROAD CHANGES IN METABOLIC HOMEOSTASIS, CHARACTERIZED BY SYSTEMIC OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION. ADOPTING A CANDIDATE APPROACH, WE IDENTIFY THIOREDOXIN-INTERACTING PROTEIN (TXNIP), A KEY MOLECULE INVOLVED IN INTEGRATING CELLULAR NUTRITIONAL AND OXIDATIVE STATES WITH METABOLIC RESPONSE, AS A MARKER FOR PREIMPLANTATION STRESS AND DEMONSTRATE TISSUE-SPECIFIC EPIGENETIC AND TRANSCRIPTIONAL TXNIP MISREGULATION IN SELECTED ADULT TISSUES. IMPORTANTLY, DYSREGULATION OF TXNIP EXPRESSION IS ASSOCIATED WITH ENRICHMENT FOR H4 ACETYLATION AT THE TXNIP PROMOTER THAT PERSISTS FROM THE BLASTOCYST STAGE THROUGH ADULTHOOD IN ADIPOSE TISSUE. OUR DATA SUPPORT THE VULNERABILITY OF PREIMPLANTATION EMBRYOS TO ENVIRONMENTAL DISTURBANCE AND DEMONSTRATE THAT CONCEPTION BY IVF CAN REPROGRAM METABOLIC HOMEOSTASIS THROUGH METABOLIC, TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS WITH LASTING EFFECTS FOR ADULT GROWTH AND FITNESS. THIS STUDY HAS WIDE CLINICAL RELEVANCE AND UNDERSCORES THE IMPORTANCE OF CONTINUED FOLLOW-UP OF IVF-CONCEIVED OFFSPRING.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15   418  51 ANCESTRAL EXPOSURE TO STRESS EPIGENETICALLY PROGRAMS PRETERM BIRTH RISK AND ADVERSE MATERNAL AND NEWBORN OUTCOMES. BACKGROUND: CHRONIC STRESS IS CONSIDERED TO BE ONE OF MANY CAUSES OF HUMAN PRETERM BIRTH (PTB), BUT NO DIRECT EVIDENCE HAS YET BEEN PROVIDED. HERE WE SHOW IN RATS THAT STRESS ACROSS GENERATIONS HAS DOWNSTREAM EFFECTS ON ENDOCRINE, METABOLIC AND BEHAVIOURAL MANIFESTATIONS OF PTB POSSIBLY VIA MICRORNA (MIRNA) REGULATION. METHODS: PREGNANT DAMS OF THE PARENTAL GENERATION WERE EXPOSED TO STRESS FROM GESTATIONAL DAYS 12 TO 18. THEIR PREGNANT DAUGHTERS (F1) AND GRAND-DAUGHTERS (F2) EITHER WERE STRESSED OR REMAINED AS NON-STRESSED CONTROLS. GESTATIONAL LENGTH, MATERNAL GESTATIONAL WEIGHT GAIN, BLOOD GLUCOSE AND PLASMA CORTICOSTERONE LEVELS, LITTER SIZE AND OFFSPRING WEIGHT GAIN FROM POSTNATAL DAYS 1 TO 30 WERE RECORDED IN EACH GENERATION, INCLUDING F3. MATERNAL BEHAVIOURS WERE ANALYSED FOR THE FIRST HOUR AFTER COMPLETED PARTURITION, AND OFFSPRING SENSORIMOTOR DEVELOPMENT WAS RECORDED ON POSTNATAL DAY (P) 7. F0 THROUGH F2 MATERNAL BRAIN FRONTAL CORTEX, UTERUS AND PLACENTA MIRNA AND GENE EXPRESSION PATTERNS WERE USED TO IDENTIFY STRESS-INDUCED EPIGENETIC REGULATORY PATHWAYS OF MATERNAL BEHAVIOUR AND PREGNANCY MAINTENANCE. RESULTS: PROGRESSIVELY UP TO THE F2 GENERATION, STRESS GRADUALLY REDUCED GESTATIONAL LENGTH, MATERNAL WEIGHT GAIN AND BEHAVIOURAL ACTIVITY, AND INCREASED BLOOD GLUCOSE LEVELS. REDUCED OFFSPRING GROWTH AND DELAYED BEHAVIOURAL DEVELOPMENT IN THE STRESS COHORT WAS RECOGNIZABLE AS EARLY AS P7, WITH THE GREATEST EFFECT IN THE F3 OFFSPRING OF TRANSGENERATIONALLY STRESSED MOTHERS. FURTHERMORE, STRESS ALTERED MIRNA EXPRESSION PATTERNS IN THE BRAIN AND UTERUS OF F2 MOTHERS, INCLUDING THE MIR-200 FAMILY, WHICH REGULATES PATHWAYS RELATED TO BRAIN PLASTICITY AND PARTURITION, RESPECTIVELY. MAIN MIR-200 FAMILY TARGET GENES IN THE UTERUS, STAT5B, ZEB1 AND ZEB2, WERE DOWNREGULATED BY MULTIGENERATIONAL STRESS IN THE F1 GENERATION. ZEB2 WAS ALSO REDUCED IN THE STRESSED F2 GENERATION, SUGGESTING A CAUSAL MECHANISM FOR DISTURBED PREGNANCY MAINTENANCE. ADDITIONALLY, STRESS INCREASED PLACENTAL MIR-181A, A MARKER OF HUMAN PTB. CONCLUSIONS: THE FINDINGS INDICATE THAT A FAMILY HISTORY OF STRESS MAY PROGRAM CENTRAL AND PERIPHERAL PATHWAYS REGULATING GESTATIONAL LENGTH AND MATERNAL AND NEWBORN HEALTH OUTCOMES IN THE MATERNAL LINEAGE. THIS NEW PARADIGM MAY MODEL THE ORIGIN OF MANY HUMAN PTB CAUSES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16  4930  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17   301  37 AIR POLLUTION ASSOCIATED EPIGENETIC MODIFICATIONS: TRANSGENERATIONAL INHERITANCE AND UNDERLYING MOLECULAR MECHANISMS. AIR POLLUTION IS ONE OF THE LEADING CAUSES OF DEATHS IN SOUTHEAST ASIAN COUNTRIES INCLUDING INDIA. EXPOSURE TO AIR POLLUTANTS AFFECTS VITAL CELLULAR MECHANISMS AND IS INTIMATELY LINKED WITH THE ETIOLOGY OF A NUMBER OF CHRONIC DISEASES. EARLIER WORK FROM OUR LABORATORY HAS SHOWN THAT AIRBORNE PARTICULATE MATTER DISTURBS THE MITOCHONDRIAL MACHINERY AND CAUSES SIGNIFICANT DAMAGE TO THE EPIGENOME. MITOCHONDRIAL REACTIVE OXYGEN SPECIES POSSESS THE ABILITY TO TRIGGER REDOX-SENSITIVE SIGNALING MECHANISMS AND INDUCE IRREVERSIBLE EPIGENOMIC CHANGES. THE ELECTROPHILIC NATURE OF REACTIVE METABOLITES CAN DIRECTLY RESULT IN DEPROTONATION OF CYTOSINE AT C-5 POSITION OR INTERFERE WITH THE DNA METHYLTRANSFERASES ACTIVITY TO CAUSE ALTERATIONS IN DNA METHYLATION. IN ADDITION, IT ALSO PERTURBS LEVEL OF CELLULAR METABOLITES CRITICALLY INVOLVED IN DIFFERENT EPIGENETIC PROCESSES LIKE ACETYLATION AND METHYLATION OF HISTONE CODE AND DNA HYPO OR HYPERMETHYLATION. INTERESTINGLY, THESE MODIFICATIONS MAY PERSIST THROUGH DOWNSTREAM GENERATIONS AND RESULT IN THE TRANSGENERATIONAL EPIGENOMIC INHERITANCE. THIS PHENOMENON OF SUBSEQUENT TRANSFER OF EPIGENETIC MODIFICATIONS IS MAINLY ASSOCIATED WITH THE GERM CELLS AND RELIES ON THE GERMLINE STABILITY OF THE EPIGENETIC STATES. OVERALL, THE RECENT LITERATURE SUPPORTS, AND ARGUABLY STRENGTHENS, THE CONTENTION THAT AIR POLLUTION MIGHT CONTRIBUTE TO TRANSMISSION OF EPIMUTATIONS FROM GAMETES TO ZYGOTES BY INVOLVING MITOCHONDRIAL DNA, PARENTAL ALLELE IMPRINTING, HISTONE WITHHOLDING AND NON-CODING RNAS. HOWEVER, LARGER PROSPECTIVE STUDIES USING INNOVATIVE, INTEGRATED EPIGENOME-WIDE METABOLOMIC STRATEGY ARE HIGHLY WARRANTED TO ASSESS THE AIR POLLUTION INDUCED TRANSGENERATIONAL EPIGENETIC INHERITANCE AND ASSOCIATED HUMAN HEALTH EFFECTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  1930  41 ENVIRONMENTAL EXPOSURES AROUND CONCEPTION: DEVELOPMENTAL PATHWAYS LEADING TO LIFETIME DISEASE RISK. ENVIRONMENT AROUND CONCEPTION CAN INFLUENCE THE DEVELOPMENTAL PROGRAMME WITH LASTING EFFECTS ON GESTATIONAL AND POSTNATAL PHENOTYPE AND WITH CONSEQUENCES FOR ADULT HEALTH AND DISEASE RISK. PERI-CONCEPTION EXPOSURE COMPRISES A CRUCIAL PART OF THE 'DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE' (DOHAD) CONCEPT. IN THIS REVIEW, WE CONSIDER THE EFFECTS OF MATERNAL UNDERNUTRITION EXPERIENCED DURING THE PERI-CONCEPTION PERIOD IN SELECT HUMAN MODELS AND IN A MOUSE EXPERIMENTAL MODEL OF PROTEIN RESTRICTION. HUMAN DATASETS INDICATE THAT MACRONUTRIENT DEPRIVATION AROUND CONCEPTION AFFECT THE EPIGENOME, WITH ENDURING EFFECTS ON CARDIOMETABOLIC AND NEUROLOGICAL HEALTH. THE MOUSE MODEL, COMPRISING MATERNAL LOW PROTEIN DIET EXCLUSIVELY DURING THE PERI-CONCEPTION PERIOD, HAS REVEALED A STEPWISE PROGRESSION IN ALTERED DEVELOPMENTAL PROGRAMMING FOLLOWING INDUCTION THROUGH MATERNAL METABOLITE DEFICIENCY. THIS PROGRESSION INCLUDES DIFFERENTIAL EFFECTS IN EXTRA-EMBRYONIC AND EMBRYONIC CELL LINEAGES AND TISSUES, LEADING TO MALADAPTATION IN THE GROWTH TRAJECTORY AND INCREASED CHRONIC DISEASE COMORBIDITIES. THE TIMELINE EMBRACES AN ARRAY OF MECHANISMS ACROSS NUTRIENT SENSING AND SIGNALLING, CELLULAR, METABOLIC, EPIGENETIC AND PHYSIOLOGICAL PROCESSES WITH A COORDINATING ROLE FOR MTORC1 SIGNALLING PROPOSED. EARLY EMBRYOS APPEAR ACTIVE PARTICIPANTS IN ENVIRONMENTAL SENSING TO OPTIMISE THE DEVELOPMENTAL PROGRAMME FOR SURVIVAL BUT WITH THE TRADE-OFF OF LATER DISEASE. SIMILAR ADVERSE HEALTH OUTCOMES MAY DERIVE FROM OTHER PERI-CONCEPTION ENVIRONMENTAL EXPERIENCES, INCLUDING MATERNAL OVERNUTRITION, MICRONUTRIENT AVAILABILITY, POLLUTANT EXPOSURE AND ASSISTED REPRODUCTIVE TREATMENTS (ART) AND SUPPORT THE NEED FOR PRECONCEPTION HEALTH BEFORE PREGNANCY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19   899  37 CHRONIC EXPOSURE TO A LOW CONCENTRATION OF BISPHENOL A DURING FOLLICLE CULTURE AFFECTS THE EPIGENETIC STATUS OF GERMINAL VESICLES AND METAPHASE II OOCYTES. OBJECTIVE: TO DETERMINE WHETHER EXPOSURE TO LOW CONCENTRATIONS OF THE ENDOCRINE DISRUPTING CHEMICAL BISPHENOL A (BPA) DURING FOLLICLE CULTURE AND OOCYTE GROWTH ALTERS THE METHYLATION STATUS OF DIFFERENTIALLY METHYLATED REGIONS (DMRS) OF IMPRINTED GENES AND HISTONE POSTTRANSLATIONAL MODIFICATION PATTERNS IN MAMMALIAN OOCYTES. DESIGN: COMPARATIVE AND CONTROL STUDY. SETTING: EXPERIMENTAL LABORATORY. ANIMAL(S): C57/BL6JXCBA/CA MICE. INTERVENTION(S): EXPOSURE OF OOCYTES TO 3 NM OR 300 NM BPA DURING FOLLICLE CULTURE FROM PREANTRAL TO ANTRAL STAGE. MAIN OUTCOME MEASURE(S): METHYLATION STATUS OF DMRS OF MATERNALLY IMPRINTED (SNRPN, IGF2R, AND MEST) AND PATERNALLY IMPRINTED GENE(S) (H19) IN MOUSE GERMINAL VESICLE OOCYTES; TRIMETHYLATION OF HISTONE H3K9, ACETYLATION OF HISTONE H4K12, AND DISTANCE BETWEEN CENTROMERES OF SISTER CHROMATIDS IN METAPHASE II OOCYTES. RESULT(S): EXPOSURE TO 3 NM BPA WAS ASSOCIATED WITH SLIGHTLY ACCELERATED FOLLICLE DEVELOPMENT, STATISTICALLY SIGNIFICANT INCREASES IN ALLELE METHYLATION ERRORS IN DMRS OF MATERNALLY IMPRINTED GENES, AND STATISTICALLY SIGNIFICANT DECREASES IN HISTONE H3K9 TRIMETHYLATION AND INTERKINETOCHORE DISTANCE. CONCLUSION(S): THE DISTURBANCES IN OOCYTE GENOMIC IMPRINTING AND MODIFICATION OF POSTTRANSLATIONAL HISTONE AND CENTROMERE ARCHITECTURE PROVIDE THE FIRST LINK BETWEEN LOW BPA EXPOSURES AND INDUCTION OF EPIGENETIC CHANGES THAT MAY CONTRIBUTE TO CHROMOSOME CONGRESSION FAILURES AND MEIOTIC ERRORS, AND TO ALTERED GENE EXPRESSION THAT MIGHT AFFECT HEALTH OF THE OFFSPRING.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20  5206  44 PRENATAL STRESS INDUCES LONG-TERM BEHAVIORAL SEX-DEPENDENT CHANGES IN RATS OFFSPRING: THE ROLE OF THE HPA AXIS AND EPIGENETICS. PRECLINICAL GENETIC STUDIES HAVE RELATED STRESS EARLY EXPOSURES WITH CHANGES IN GENE REGULATORY MECHANISMS, INCLUDING EPIGENETIC ALTERATIONS, SUCH AS MODIFICATIONS OF DNA METHYLATION, HISTONE DEACETYLATION, AND HISTONES ACETYLATION. THIS STUDY EVALUATES THE EFFECTS OF PRENATAL STRESS ON THE BEHAVIOR, HYPOTHALAMUS-PITUITARY-ADRENAL (HPA)-AXIS, AND EPIGENETIC PARAMETERS IN STRESSED DAMS AND THEIR OFFSPRING. THE RATS WERE SUBJECTED TO A PROTOCOL OF CHRONIC UNPREDICTABLE MILD STRESS ON THE FOURTEENTH DAY OF PREGNANCY UNTIL THE BIRTH OF OFFSPRING. AFTER BIRTH, MATERNAL CARE WAS EVALUATED FOR SIX DAYS. FOLLOWING WEANING, THE LOCOMOTOR AND DEPRESSIVE-LIKE BEHAVIORS OF THE DAMS AND THEIR OFFSPRING (60 DAYS OLD) WERE ASSESSED. THE HPA AXIS PARAMETERS WERE EVALUATED IN SERUM FROM DAMS AND OFFSPRING, AND EPIGENETIC PARAMETERS (HISTONE ACETYLTRANSFERASE (HAT), HISTONE DEACETYLASE (HDAC), DNA METHYLTRANSFERASE (DNMT) ACTIVITIES, AND THE LEVELS OF HISTONE H3 ACETYLATED AT LYSINE RESIDUE 9 (H3K9AC) AND HISTONE 3 ACETYLATED AT LYSINE RESIDUE 14 (H3K14AC)) WERE ASSESSED IN DAMS' AND OFFSPRING' BRAINS. PRENATAL STRESS DID NOT SIGNIFICANTLY INFLUENCE MATERNAL CARE; HOWEVER, IT INDUCED MANIC BEHAVIOR IN FEMALE OFFSPRING. THESE BEHAVIORAL ALTERATIONS IN THE OFFSPRING WERE ACCOMPANIED BY HYPERACTIVITY OF THE HPA-AXIS, EPIGENETIC ADAPTATIONS IN THE ACTIVITY OF HDAC AND DNMT, AND ACETYLATION IN THE HISTONES H3K9 AND H3K14. IN ADDITION, THE PRENATAL STRESSED FEMALE OFFSPRING SHOWED INCREASED LEVELS OF ACTH COMPARED TO THEIR MALE COUNTERPART. OUR FINDINGS REINFORCE THE IMPACT OF PRENATAL STRESS ON BEHAVIOR, STRESS RESPONSE, AND EPIGENETIC PROFILE OF OFFSPRING.	2023