1 4944 114 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 2 3785 29 INTERGENERATIONAL EFFECTS OF PRE-PREGNANCY CHRONIC LIPOPOLYSACCHARIDE FROM PORPHYROMONAS GINGIVALIS ON THE LEARNING, MEMORY AND SEIZURE SUSCEPTIBILITY OF OFFSPRING. OBJECTIVE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EFFECTS OF PRE-PREGNANCY CHRONIC EXPOSURE TO PORPHYROMONAS GINGIVALIS LPS (PG LPS) ON THE LEARNING, MEMORY, AND SEIZURE SUSCEPTIBILITY OF THE OFFSPRING. DESIGN: TO ACHIEVE PERIODONTITIS, PG LPS (5 MUG/KG) WAS INJECTED INTO THE GINGIVAL OF FIVE FEMALE RATS EVERY 48 H FOR THREE WEEKS. FIVE CONTROL FEMALE RATS RECEIVED SALINE (0.9 %) AND FIVE FEMALE WERE KEPT INTACT. THE CONCENTRATIONS OF TNF-ALPHA AND IL-6 WERE MEASURED IN THE BLOOD SAMPLES. ONE WEEK AFTER THE FINAL INJECTION, FEMALES WERE MATED WITH INTACT MALES. FOLLOWING BIRTH AND WEANING, TWO MALE AND TWO FEMALE OFFSPRING WERE RANDOMLY SELECTED FROM EACH MOTHER, AND NEW GROUPS OF MALE AND FEMALE OFFSPRING WERE DEFINED FOR BEHAVIORAL ASSESSMENTS. MORRIS WATER MAZE WAS USED TO EVALUATE SPATIAL MEMORY, SHUTTLE BOX WAS USED TO INVESTIGATE AVOIDANCE MEMORY AND A PENTYLENETETRAZOLE-INDUCED SEIZURE WAS USED TO EVALUATE SEIZURE SUSCEPTIBILITY IN THE OFFSPRING. RESULTS: SPATIAL LEARNING AND AVOIDANCE MEMORY SIGNIFICANTLY DECREASED IN BOTH MALE AND FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE RATS, COMPARED TO THE CONTROL OFFSPRING. LATENCY TO REACH SEIZURE STAGES 1 AND 2 SIGNIFICANTLY INCREASED IN THE MALE OFFSPRING, BUT NOT THE FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE, COMPARED TO THE CONTROL OFFSPRING. HOWEVER, NO SIGNIFICANT DIFFERENCE WAS FOUND IN LATENCY TO REACH STAGES 3-5. CONCLUSION: PRE-PREGNANCY EXPOSURE TO PG LPS COULD AFFECT SOME BEHAVIORAL FUNCTIONS IN BOTH MALE AND FEMALE OFFSPRING INTERGENERATIONALLY. 2021 3 73 31 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 4 4943 50 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 5 6559 29 TRANSGENERATIONAL INFLUENCE OF PARENTAL MORPHINE EXPOSURE ON PAIN PERCEPTION, ANXIETY-LIKE BEHAVIOR AND PASSIVE AVOIDANCE MEMORY AMONG MALE AND FEMALE OFFSPRING OF WISTAR RATS. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN THE FORMATION AND MAINTENANCE OF MEMORY WITHIN THE BRAIN. MOREOVER, THE EFFECT OF PARENTAL DRUG-EXPOSURE BEFORE GESTATION ON BEHAVIORAL STATE OF OFFSPRING HAS BEEN LITTLE STUDIED. THE MAIN OBJECTIVE OF THE CURRENT STUDY IS TO EVALUATE THE EFFECT OF PARENTAL MORPHINE EXPOSURE ON AVOIDANCE MEMORY, MORPHINE PREFERENCE AND ANXIETY-LIKE BEHAVIOR OF OFFSPRING. THE TOTAL OF 32 MALES AND 32 FEMALES WERE USED FOR MATING. THE ANIMALS WERE TREATED WITH MORPHINE. THE OFFSPRING ACCORDING TO THEIR PARENTAL MORPHINE TREATMENT WAS DIVIDED INTO FOUR GROUPS (N=16) INCLUDING PATERNALLY TREATED, MATERNALLY TREATED, BOTH OF PARENTS TREATED AND NAIVE ANIMALS. THE PAIN PERCEPTION, ANXIETY-LIKE BEHAVIOR, AND AVOIDANCE MEMORY WERE EVALUATED IN THE OFFSPRING. IN THE CURRENT STUDY, THE TOTAL OF 256 OFFSPRING WAS USED FOR THE EXPERIMENTS (4 TASKS X 4 GROUPS OF OFFSPRING X 8 FEMALE OFFSPRING X 8 MALE OFFSPRING). THE FINDING REVEALED THAT THE AVOIDANCE MEMORY AND VISCERAL PAIN WERE REDUCED SIGNIFICANTLY IN MALE AND FEMALE OFFSPRING WITH AT LEAST ONE MORPHINE-TREATED PARENT. MOREOVER, ANXIETY-LIKE BEHAVIOR WAS REDUCED SIGNIFICANTLY IN THE MALE OFFSPRING WITH AT LEAST ONE MORPHINE-TREATED PARENT. WHILE ANXIETY-LIKE BEHAVIOR WAS INCREASED SIGNIFICANTLY IN FEMALE OFFSPRING THAT WERE TREATED BY MORPHINE EITHER MATERNALLY OR BOTH OF PARENTS. THE DATA REVEALED THAT THE ENDOGENOUS OPIOID SYSTEM MAY BE ALTERED IN THE OFFSPRING OF MORPHINE-TREATED PARENT(S), AND EPIGENETIC ROLE COULD BE IMPORTANT. HOWEVER, ANALYSIS OF VARIANCE SIGNIFIED THE IMPORTANT ROLE OF MATERNAL INHERITANCE. 2019 6 4939 37 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 7 6545 28 TRANSCRIPTOMIC AND EPIGENETIC CHANGES IN THE HYPOTHALAMUS ARE INVOLVED IN AN INCREASED SUSCEPTIBILITY TO A HIGH-FAT-SUCROSE DIET IN PRENATALLY STRESSED FEMALE RATS. DISTURBANCES IN THE PRENATAL PERIOD ARE LINKED TO METABOLIC DISORDERS IN ADULTHOOD, IMPLYING THE HYPOTHALAMIC SYSTEMS OF APPETITE AND ENERGY BALANCE REGULATION. IN ORDER TO ANALYZE THE CENTRAL EFFECTS OF A HIGH-FAT-SUCROSE (HFS) DIET IN PRENATALLY STRESSED (PNS) FEMALE ADULT RATS, WISTAR DAMS WERE EXPOSED TO CHRONIC-MILD-STRESS DURING THE THIRD WEEK OF GESTATION AND WERE THEN COMPARED WITH UNSTRESSED CONTROLS. ADULT FEMALE OFFSPRING WERE FED A CHOW OR HFS DIET FOR 10 WEEKS. CHANGES IN BODY WEIGHT, ADIPOSITY AS WELL AS EXPRESSION AND METHYLATION LEVELS OF SELECTED HYPOTHALAMIC GENES WERE ANALYZED. PNS INDUCED LOWER BIRTHWEIGHT AND BODY LENGTH WITH NO CHANGES IN BODY FAT MASS. AFTER THE HFS DIET, THE EXPECTED OVERWEIGHT MODEL WAS OBSERVED ACCOMPANIED BY HIGHER ADIPOSITY AND INSULIN RESISTANCE, WHICH WAS WORSENED BY PNS. THE STRESS MODEL INDUCED HIGHER ENERGY INTAKE IN ADULTHOOD. HYPOTHALAMIC GENE EXPRESSION ANALYSIS REVEALED THAT THE HFS DIET DECREASED SLC6A3 (DOPAMINE ACTIVE TRANSPORTER), NPY (NEUROPEPTIDE Y) AND IR (INSULIN RECEPTOR) AND INCREASED POMC (PRO-OPIOMELANOCORTIN). HYPOTHALAMIC DNA METHYLATION LEVELS IN THE PROMOTER REGION OF SLC6A3 REVEALED THAT SLC6A3 WAS HYPERMETHYLATED BY THE HFS DIET IN CPG SITE -53 BP TO THE TRANSCRIPTION START SITE. HFS DIET ALSO HYPERMETHYLATED CPG SITE -167 BP OF THE POMC PROMOTER ONLY IN NONSTRESSED ANIMALS. NO CORRELATIONS WERE FOUND BETWEEN GENE EXPRESSION AND DNA METHYLATION LEVELS. THESE RESULTS IMPLY THAT EARLY-LIFE STRESS IN FEMALES INCREASED PREDISPOSITION TO DIET-INDUCED OBESITY IN ADULTHOOD. 2012 8 4069 24 MATERNAL CHRONIC FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET THROUGH METHYLATION ALTERATION OF BDNF AND GRIN2B IN OFFSPRING HIPPOCAMPUS. SCOPE: MATERNAL CONSUMPTION OF A HIGH-FAT DIET (HFD) DURING PREGNANCY INCREASES THE RISK OF BEHAVIORAL PROBLEMS. FOLATE PLAYS AN IMPORTANT ROLE IN NEUROPLASTICITY AND THE PRESERVATION OF NEURONAL INTEGRITY. THIS STUDY AIMS AT DETERMINING THE INFLUENCE OF DIETS SUPPLEMENTED WITH FOLATE ON OFFSPRING BEHAVIOR, AND THE MECHANISMS INVOLVED. METHODS AND RESULTS: FEMALE MICE WERE FED A CONTROL DIET, AN HFD, CONTROL DIET SUPPLEMENTED WITH FOLATE, OR AN HFD SUPPLEMENTED WITH FOLATE FOR 5 WEEKS BEFORE MATING. OPEN FIELD TASK AND ELEVATED PLUS MAZE ARE USED TO EVALUATE THE OFFSPRING BEHAVIORS. RESULTS SHOWED THAT OFFSPRING COGNITIVE PERFORMANCE AND ANXIETY-RELATED BEHAVIORS, INCLUDING THOSE RELATED TO OPEN FIELD EXPLORATION AND ELEVATED PLUS MAZE, WERE SIGNIFICANTLY IMPROVED WHEN DAMS WERE TREATED WITH FOLATE IN PREGNANCY. MOREOVER, THE MATERNAL FOLATE SUPPLEMENT DECREASED BDNF AND GRIN2B METHYLATION AND UPREGULATED THEIR EXPRESSIONS IN THE BRAIN OF OFFSPRING, WHICH WERE ASSOCIATED WITH DECREASING THE EXPRESSION OF DNA METHYLTRANSFERASES COMPARED WITH THOSE DAMS WERE TREATED ONLY HFD IN PREGNANCY. CONCLUSION: MATERNAL FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET. THE BENEFICIAL EFFECTS WERE ASSOCIATED WITH METHYLATION AND EXPRESSION ALTERATION OF BDNF AND GRIN2B GENES. 2017 9 418 33 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 10 4930 36 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 11 4949 36 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 12 4008 30 LOW DOSE OF URANIUM INDUCES MULTIGENERATIONAL EPIGENETIC EFFECTS IN RAT KIDNEY. PURPOSE: A PROTOCOL OF CHRONIC EXPOSURE TO LOW DOSE OF URANIUM WAS ESTABLISHED IN ORDER TO DISTINGUISH THE SEXUAL DIFFERENCES AND THE DEVELOPMENTAL PROCESS THAT ARE CRITICAL WINDOWS FOR EPIGENETIC EFFECTS OVER GENERATIONS. METHODS: BOTH MALE AND FEMALE RATS WERE CONTAMINATED THROUGH THEIR DRINKING WATER WITH A NON-TOXIC SOLUTION OF URANYL NITRATE FOR 9 MONTHS. THE EXPOSED GENERATION (F0) AND THE FOLLOWING TWO GENERATIONS (F1 AND F2) WERE EXAMINED. CLINICAL MONITORING, GLOBAL DNA METHYLATION PROFILE AND DNA METHYLTRANSFERASES (DNMTS) GENE EXPRESSION WERE ANALYZED IN KIDNEYS. RESULTS: WHILE THE BODY WEIGHT OF F1 MALES INCREASED, A SMALL DECREASE IN KIDNEY AND BODY WEIGHT WAS OBSERVED IN F2 MALES. IN ADDITION, GLOBAL DNA HYPERMETHYLATION PROFILE IN KIDNEY CELLS WAS OBSERVED IN F1 AND F2 MALES. QPCR RESULTS REVEAL A SIGNIFICANT INCREASE OF METHYLTRANSFERASE GENES EXPRESSION (DNMT1 AND DNMT3A) FOR F2 FEMALES. CONCLUSIONS: IN THE FIELD OF PUBLIC HEALTH POLICY AND TO RAISE ATTENTION TO GENERATIONAL EFFECTS FOR THE RISK ASSESSMENT OF THE ENVIRONMENTAL EXPOSURES, LOW DOSES OF URANIUM DO NOT IMPLY CLINICAL EFFECTS ON ADULT EXPOSED RATS. HOWEVER, OUR RESULTS CONFIRM THE IMPORTANCE OF THE DEVELOPMENTAL WINDOWS' SENSITIVITY IN ADDITION TO THE SEXUAL DIMORPHISMS OF THE OFFSPRING. 2018 13 2077 26 EPIGENETIC DISRUPTION OF PLACENTAL GENES BY CHRONIC MATERNAL CAFETERIA DIET IN RATS. MATERNAL DIET HAS IMPACT ON REPRODUCTION, FETAL DEVELOPMENT AND OFFSPRING BEHAVIOR, ALTHOUGH MOLECULAR MECHANISMS REMAINED UNKNOWN. OUR AIMS WERE TO ASSESS (1) THE EFFECTS OF A CAFETERIA (CAF) DIET (WESTERN DIET HABITS) ON FEMALE REPRODUCTIVE PERFORMANCE, FETAL AND PLACENTAL PARAMETERS ON GESTATIONAL DAY 21 AND LITTER SIZE AND PUP WEIGHT AT BIRTH; AND (2) PLACENTAL MESSENGER RNA (MRNA) EXPRESSION AND EPIGENETIC REGULATION OF INSULIN-LIKE GROWTH FACTOR (IGF) AND VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND THEIR RECEPTORS. FEMALE WISTAR RATS WERE FED WITH CONTROL OR CAF DIET FROM WEANING UNTIL PARTURITION. AT WEEK 14 AFTER DIETS STARTED, FEMALES WERE MATED AND HALF OF THE ANIMALS WERE EUTHANIZED ON GESTATIONAL DAY 21 TO EVALUATE REPRODUCTIVE PARAMETERS INCLUDING THE PREGNANCY RATE, NUMBER OF CORPORA LUTEA, IMPLANTATION SITES AND RESORPTION SITES. MOREOVER, FETAL WEIGHT AND LENGTH, PLACENTAL WEIGHT, AND PLACENTAL INDEX WERE RECORDED. PLACENTAS WERE COLLECTED FOR MRNA QUANTIFICATION AND DNA METHYLATION ANALYSIS. THE REMAINING ANIMALS WERE ALLOWED TO GIVE BIRTH AND THE NUMBER AND WEIGHT OF THE PUPS WERE EVALUATED. CAF DIET DID NOT AFFECT REPRODUCTIVE PERFORMANCE OR FETAL WEIGHT AND LENGTH. HOWEVER, CAF-FED ANIMALS SHOWED A DECREASE IN PLACENTAL WEIGHT AND INDEX AND THE PUPS EXHIBITED A LOW BIRTH WEIGHT. ADDITIONALLY, WE FOUND AN UPREGULATION OF IGF2 AND A DOWN REGULATION OF VEGF PLACENTAL MRNA EXPRESSION IN CAF DAMS, ASSOCIATED WITH METHYLATION STATUS CHANGES OF THEIR PROMOTERS. WE CONCLUDE THAT FEMALE CHRONIC CAF DIET CONSUMPTION IMPAIRS FETO-PLACENTAL DEVELOPMENT AND COULD BE EXPLAINED BY AN EPIGENETIC DISRUPTION OF IGF AND VEGF SYSTEMS. 2022 14 5206 32 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 15 5651 26 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD. 2020 16 3462 27 HYPOTHALAMIC NR3C1 DNA METHYLATION IN RATS EXPOSED TO PRENATAL STRESS. BACKGROUND: HUMAN AND ANIMAL STUDIES HAVE INDICATED THAT MATERNAL PRENATAL STRESS (PS) HAS MOLECULAR AND BEHAVIORAL EFFECTS DURING PREGNANCY AND EARLY LIFE. THE PRESENT STUDY AIMED TO EVALUATE THE EPIGENETIC CHANGES OF THE NR3C1 GENE INVOLVED IN THE HPA AXIS IN THE HYPOTHALAMIC TISSUES OF RATS EXPOSED TO PS INDUCED BY CHRONIC UNPREDICTABLE MILD STRESS (CUMS). BEHAVIORAL AND MOLECULAR EFFECTS OF THESE CHANGES ON THE NEXT GENERATION WERE ALSO ASSESSED. METHODS AND RESULTS: CUMS PROTOCOL WAS USED TO GENERATE STRESS IN PREGNANT WISTAR RATS. TO DETERMINE THE EFFECTS OF STRESS ON ANHEDONIA AND MOVEMENT, SUCROSE PREFERENCE TEST, FORCED SWIMMING TEST, AND OPEN FIELD TEST WERE PERFORMED. FOLLOWING THESE BEHAVIORAL EXPERIMENTS, BISULFITE SEQUENCING PCR FOR DNA METHYLATION LEVELS OF THE NR3C1 GENE, RT-QPCR FOR MRNA LEVELS, AND WESTERN BLOT TECHNIQUES FOR PROTEIN ANALYSIS WERE USED IN THE HYPOTHALAMIC TISSUE OF SACRIFICED RATS. DEPRESSION-LIKE BEHAVIORS WERE EVIDENT IN THE BEHAVIORAL TESTS OF STRESS-EXPOSED MOTHERS AND PUPS. IN PS-EXPOSED PUPS, HYPOTHALAMIC NR3C1 PROMOTER METHYLATION WAS HIGHER, AND NR3C1 MRNA LEVELS AND NR3C1 PROTEIN LEVELS WERE LOWER COMPARED WITH CONTROLS, REGARDLESS OF SEX. CONCLUSION: OUR RESULTS CONFIRM THE RELATIONSHIP BETWEEN PS AND EPIGENETIC CHANGES OF HPA AXIS-RELATED GENES AND SHOW THAT NR3C1 GENE METHYLATION STATUS IN PUPS IS SENSITIVE TO PS DURING PREGNANCY. ENVIRONMENTAL MATERNAL STRESS MAY HAVE TRANSGENERATIONAL EFFECTS THAT ARE POTENTIALLY ASSOCIATED WITH ADVERSE OUTCOMES IN THE PUPS. 2022 17 5166 36 PRECONCEPTION PATERNAL ALCOHOL EXPOSURE EXERTS SEX-SPECIFIC EFFECTS ON OFFSPRING GROWTH AND LONG-TERM METABOLIC PROGRAMMING. BACKGROUND: ALTHOUGH CLINICAL DATA SUPPORT AN ASSOCIATION BETWEEN PATERNAL ALCOHOL USE AND DEFICITS IN CHILD NEUROCOGNITIVE DEVELOPMENT, THE RELATIONSHIP BETWEEN PATERNAL DRINKING AND ALCOHOL-INDUCED GROWTH PHENOTYPES REMAINS CHALLENGING TO DEFINE. USING AN ESTABLISHED MOUSE MODEL OF CHRONIC EXPOSURE, PREVIOUS WORK BY OUR GROUP HAS LINKED PRECONCEPTION PATERNAL ALCOHOL USE TO SEX-SPECIFIC PATTERNS OF FETAL GROWTH RESTRICTION AND PLACENTAL DYSFUNCTION. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE THE LONG-TERM IMPACT OF CHRONIC PRECONCEPTION PATERNAL ALCOHOL USE ON OFFSPRING GROWTH AND METABOLIC PROGRAMMING. RESULTS: PRECONCEPTION PATERNAL ALCOHOL EXPOSURE INDUCED A PROLONGED PERIOD OF FETAL GESTATION AND AN INCREASED INCIDENCE OF INTRAUTERINE GROWTH RESTRICTION, WHICH AFFECTED THE MALE OFFSPRING TO A GREATER EXTENT THAN THE FEMALES. WHILE THE FEMALE OFFSPRING OF ETHANOL-EXPOSED MALES WERE ABLE TO MATCH THE BODY WEIGHTS OF THE CONTROLS WITHIN THE FIRST 2 WEEKS OF POSTNATAL LIFE, MALE OFFSPRING CONTINUED TO DISPLAY AN 11% REDUCTION IN WEIGHT AT 5 WEEKS OF AGE AND A 6% REDUCTION AT 8 WEEKS OF AGE. THE OBSERVED GROWTH DEFICITS ASSOCIATED WITH INSULIN HYPERSENSITIVITY IN THE MALE OFFSPRING, WHILE IN CONTRAST, FEMALES DISPLAYED A MODEST LAG IN THEIR GLUCOSE TOLERANCE TEST. THESE METABOLIC DEFECTS WERE ASSOCIATED WITH AN UP-REGULATION OF GENES WITHIN THE PRO-FIBROTIC TGF-BETA SIGNALING PATHWAY AND INCREASED LEVELS OF CELLULAR HYDROXYPROLINE WITHIN THE LIVERS OF THE MALE OFFSPRING. WE OBSERVED SUPPRESSED CYTOKINE PROFILES WITHIN THE LIVER AND PANCREAS OF BOTH THE MALE AND FEMALE OFFSPRING, WHICH CORRELATED WITH THE UP-REGULATION OF GENES IN THE LIVERX/RETINOIDX/FARNESOIDX RECEPTOR PATHWAYS. HOWEVER, PATTERNS OF GENE EXPRESSION WERE HIGHLY VARIABLE BETWEEN THE OFFSPRING OF ALCOHOL-EXPOSED SIRES. IN THE ADULT OFFSPRING OF ALCOHOL-EXPOSED MALES, WE DID NOT OBSERVE ANY DIFFERENCES IN THE ALLELIC EXPRESSION OF IGF2 OR ANY OTHER IMPRINTED GENES. CONCLUSIONS: THE IMPACT OF PATERNAL ALCOHOL USE ON CHILD DEVELOPMENT IS POORLY EXPLORED AND REPRESENTS A SIGNIFICANT GAP IN OUR UNDERSTANDING OF THE TERATOGENIC EFFECTS OF ETHANOL. OUR STUDIES IMPLICATE PATERNAL EXPOSURE HISTORY AS AN ADDITIONAL AND IMPORTANT MODIFIER OF ALCOHOL-INDUCED GROWTH PHENOTYPES AND CHALLENGE THE CURRENT MATERNAL-CENTRIC EXPOSURE PARADIGM. 2019 18 1839 26 EFFECTS OF PRENATAL NICOTINE EXPOSURE ON HEPATIC GLUCOSE AND LIPID METABOLISM IN OFFSPRING RATS AND ITS HEREDITABILITY. PRENATAL NICOTINE EXPOSURE (PNE) COULD INDUCE AN INCREASED SUSCEPTIBILITY TO MULTIPLE CHRONIC DISEASES IN ADULT OFFSPRING, THAT MAINLY CAUSED BY INTRAUTERINE MATERNAL GLUCOCORTICOID (GC) OVER-EXPOSURE. WE INVESTIGATED THE CHANGES AND INHERITABILITY OF HEPATIC GLUCOSE AND LIPID METABOLISM CAUSED BY PNE, TO DECIPHER THE POSSIBLE INTRAUTERINE PROGRAMMING MECHANISM. PREGNANT WISTAR RATS WERE ADMINISTERED SUBCUTANEOUSLY WITH 2 MG/KG.D NICOTINE FROM GESTATIONAL DAY (GD) 9 APPROXIMATELY 20, AND SECOND-GENERATION (F2) WERE SET ACCORDING TO THE MATING BETWEEN CONTROL FEMALES AND PNE MALES. THE RESULTS SHOWED THAT SERUM PHENOTYPES AND HEPATIC ENZYMES OF GLUCOSE AND LIPID METABOLISM WERE LOWER IN F1 FETAL RATS OF PNE BUT HIGHER IN THE F1 ADULT RATS. MEANWHILE, THE ACTIVATED STATES OF HEPATIC GLUCOCORTICOID-ACTIVATION SYSTEM, INCLUDING TYPE 1 AND TYPE 2 11BETA-HYDROXYSTEROID DEHYDROGENASES (HSD11B1/2), NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1 (NR3C1) AND CCAAT ENHANCER BINDING PROTEIN ALPHA (CEBPA), WERE POSITIVELY CORRELATED WITH SERUM CORTICOSTERONE LEVELS BUT NEGATIVELY CORRELATED WITH THE HISTONE ACETYLATION (H3K27AC) AND EXPRESSION LEVELS OF INSULIN-LIKE GROWTH FACTOR 1 (IGF1) BEFORE AND AFTER BIRTH. FURTHERMORE, SERUM PHENOTYPES AND HEPATIC ENZYMES OF GLUCOSE AND LIPID METABOLISM WERE LOWER IN BOTH F2 FETAL AND ADULT RATS OF PNE, WHICH WERE CONSISTENT WITH THE HEPATIC CHANGES OF GC-IGF1 AXIS AND THE GLUCOCORTICOID-ACTIVATION SYSTEM. IN CONCLUSION, PNE COULD LEAD TO INHERITABLE CHANGES OF HEPATIC GLUCOSE AND LIPID METABOLISM, WHICH ARE RELATED TO THE INTRAUTERINE PROGRAMMING OF GC-IGF1 AXIS INDUCED BY THE GLUCOCORTICOID-ACTIVATION SYSTEM. 2020 19 3812 32 INTRAUTERINE ENDOGENOUS HIGH GLUCOCORTICOIDS PROGRAM OVARIAN DYSFUNCTION IN FEMALE OFFSPRING SECONDARY TO PRENATAL CAFFEINE EXPOSURE. OVARIAN DYSFUNCTION HAS AN INTRAUTERINE ORIGIN, AND PRENATAL CAFFEINE EXPOSURE (PCE) COULD LEAD TO ABNORMAL FOLLICLE COUNTS IN OFFSPRING AFTER BIRTH. HOWEVER, THE EFFECT OF PCE ON OFFSPRING OVARIAN FUNCTION AND ITS MECHANISM OF INTRAUTERINE PROGRAMMING HAVE NOT BEEN REPORTED THUS FAR. IN THIS STUDY, PREGNANT WISTAR RATS WERE INTRAGASTRICALLY ADMINISTERED CAFFEINE (30 AND 120 MG/KG.D) AT GESTATIONAL DAYS 9-20 (GD9-20). CERTAIN TESTS WERE PERFORMED ON THE BLOOD, OVARIES AND HYPOTHALAMUS OF FEMALE OFFSPRING AT DIFFERENT TIME POINTS. PCE FEMALE OFFSPRING HAD OVARIAN DYSFUNCTION IN ADULTHOOD COMPARED WITH THE CONTROL. FURTHER RESULTS SHOWED THAT IN UTERO OVARIAN MORPHOLOGICAL DEVELOPMENT AND ESTRADIOL SYNTHESIS WERE INHIBITED BUT RAPIDLY INCREASED DURING PUBERTY IN THE PCE GROUP. THE HISTONE 3 LYSINE 27 ACETYLATION (H3K27AC) LEVEL OF THE INSULIN-LIKE GROWTH FACTOR 1 (IGF1) PROMOTER REGION AND ITS EXPRESSION WERE DECREASED IN THE OVARY, WHICH WAS DUE TO EXPOSURE TO HIGH LEVELS OF FETAL BLOOD CORTICOSTERONE, AND THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION SHIFTED TO INCREASE AFTER BIRTH WITH A DECREASE IN SERUM CORTICOSTERONE LEVELS. CHRONIC STRESS LED TO INCREASED SERUM CORTICOSTERONE LEVELS IN ADULT OFFSPRING, WHEREAS OVARIAN MORPHOLOGICAL DEVELOPMENT, THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION, AND ESTRADIOL SYNTHESIS WERE SIGNIFICANTLY INHIBITED. MOREOVER, THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-OVARIAN (HPO) AXIS WAS INCREASED IN THE EARLY POSTNATAL PERIOD OF PCE OFFSPRING, AND CHRONIC STRESS REVERSED THESE CHANGES. IN THE KGN CELL LINE, IT WAS FOUND THAT CORTISOL COULD PROMOTE THE TRANSLOCATION OF THE GLUCOCORTICOID RECEPTOR (GR) INTO THE NUCLEUS AND UPREGULATE HISTONE DEACETYLASE 10 (HDAC10) TO INHIBIT THE H3K27AC LEVEL OF IGF1 AND ITS EXPRESSION AND ESTRADIOL SYNTHESIS. IN SUMMARY, PCE IS ASSOCIATED WITH OVARIAN DYSFUNCTION IN FEMALE ADULT OFFSPRING, AND THE POTENTIAL MECHANISM IS RELATED TO INTRAUTERINE HIGH GLUCOCORTICOID EXPOSURE BY ACTIVATING THE GR AND RECRUITING HDAC10 TO AFFECT OVARIAN GLUCOCORTICOID-IGF1 AXIS PROGRAMMING AND TO INHIBIT ESTRADIOL SYNTHESIS. 2021 20 4075 36 MATERNAL HIGH-FAT DIET IMPAIRS LEPTIN SIGNALING AND UP-REGULATES TYPE-1 CANNABINOID RECEPTOR WITH SEX-SPECIFIC EPIGENETIC CHANGES IN THE HYPOTHALAMUS OF NEWBORN RATS. MATERNAL NUTRITIONAL IMBALANCES TRIGGER DEVELOPMENTAL ADAPTATIONS INVOLVING EARLY EPIGENETIC MECHANISMS ASSOCIATED WITH ADULT CHRONIC DISEASE. MATERNAL HIGH-FAT (HF) DIET PROMOTES OBESITY AND HYPOTHALAMIC LEPTIN RESISTANCE IN MALE RAT OFFSPRING AT WEANING AND ADULTHOOD. LEPTIN RESISTANCE IS ASSOCIATED WITH OVER ACTIVATION OF THE ENDOCANNABINOID SYSTEM (ECS). THE ECS MAINLY CONSISTS OF ENDOCANNABINOIDS DERIVED FROM N-6 FATTY ACIDS AND CANNABINOID RECEPTORS (CB1 CODED BY CNR1 AND CB2 CODED BY CNR2). THE CB1 ACTIVATION IN HYPOTHALAMUS STIMULATES FEEDING AND APPETITE FOR FAT WHILE CB2 ACTIVATION SEEMS TO PLAY AN IMMUNOMODULATORY ROLE. WE DEMONSTRATED THAT MATERNAL HF DIET INCREASES HYPOTHALAMIC CB1 IN MALE OFFSPRING WHILE INCREASES CB2 IN FEMALE OFFSPRING AT BIRTH, PRIOR TO OBESITY DEVELOPMENT. HOWEVER, THE MOLECULAR MECHANISMS BEHIND THESE CHANGES REMAIN UNEXPLORED. WE HYPOTHESIZED THAT MATERNAL HF DIET WOULD DOWN-REGULATE LEPTIN SIGNALING AND UP-REGULATE CNR1 MRNA LEVELS IN THE HYPOTHALAMUS OF THE OFFSPRING AT BIRTH, ASSOCIATED WITH SEX-SPECIFIC CHANGES IN EPIGENETIC MARKERS AND SEX STEROID SIGNALING. TO TEST OUR HYPOTHESIS, WE USED PROGENITOR FEMALE RATS THAT RECEIVED CONTROL DIET (C, 9% FAT) OR ISOCALORIC HIGH-FAT DIET (HF, 28% FAT) FROM 8 WEEKS BEFORE MATING UNTIL DELIVERY. BLOOD, HYPOTHALAMUS AND CARCASS FROM C AND HF MALE AND FEMALE OFFSPRING WERE COLLECTED FOR BIOCHEMICAL AND MOLECULAR ANALYSES AT BIRTH. MATERNAL HF DIET DOWN-REGULATED THE TRANSCRIPTIONAL FACTOR STAT3 IN THE HYPOTHALAMUS OF MALE AND FEMALE OFFSPRING, BUT INDUCED HYPOLEPTINEMIA ONLY IN MALES AND DECREASED PHOSPHORYLATED STAT3 ONLY IN FEMALE OFFSPRING. BECAUSE LEPTIN ACTS THROUGH STAT3 PATHWAY TO INHIBIT CENTRAL ECS, OUR RESULTS SUGGEST THAT LEPTIN PATHWAY IMPAIRMENT MIGHT CONTRIBUTE TO INCREASED LEVELS OF CRN1 MRNA IN HYPOTHALAMUS OF BOTH SEX OFFSPRING. BESIDES, MATERNAL HF DIET INCREASED THE HISTONE ACETYLATION PERCENTAGE OF CNR1 PROMOTER IN MALE OFFSPRING AND INCREASED THE ANDROGEN RECEPTOR BINDING TO THE CNR1 PROMOTER, WHICH CAN CONTRIBUTE TO HIGHER EXPRESSION OF CNR1 IN NEWBORN HF OFFSPRING. MATERNAL HF DIET INCREASED PLASMA N6 TO N3 FATTY ACID RATIO IN MALE OFFSPRING, WHICH IS AN IMPORTANT RISK FACTOR TO METABOLIC DISEASES AND MIGHT INDICATE AN OVER ACTIVATION OF ENDOCANNABINOID SIGNALING. THUS, ALTHOUGH MATERNAL HF DIET PROGRAMS A SIMILAR PHENOTYPE IN ADULT OFFSPRING OF BOTH SEXES (OBESITY, HYPERPHAGIA AND HIGHER PREFERENCE FOR FAT), HERE WE SHOWED THAT MOLECULAR MECHANISMS INVOLVING LEPTIN SIGNALING, ECS, EPIGENETIC MARKERS AND SEX HORMONE SIGNALING WERE MODIFIED PRIOR TO OBESITY DEVELOPMENT AND CAN DIFFER BETWEEN NEWBORN MALE AND FEMALE OFFSPRING. THESE OBSERVATIONS MAY PROVIDE MOLECULAR INSIGHTS INTO SEX-SPECIFIC TARGETS FOR ANTI-OBESITY THERAPIES. 2019