1 1768 140 EARLY-LIFE LEAD EXPOSURE RESULTS IN DOSE- AND SEX-SPECIFIC EFFECTS ON WEIGHT AND EPIGENETIC GENE REGULATION IN WEANLING MICE. AIMS: EPIDEMIOLOGICAL AND ANIMAL DATA SUGGEST THAT THE DEVELOPMENT OF ADULT CHRONIC CONDITIONS IS INFLUENCED BY EARLY-LIFE EXPOSURE-INDUCED CHANGES TO THE EPIGENOME. THIS STUDY INVESTIGATES THE EFFECTS OF PERINATAL LEAD (PB) EXPOSURE ON DNA METHYLATION AND BODYWEIGHT IN WEANLING MICE. MATERIALS & METHODS: VIABLE YELLOW AGOUTI (A(VY)) MOUSE DAMS WERE EXPOSED TO 0, 2.1, 16 AND 32 PPM PB ACETATE BEFORE CONCEPTION THROUGH WEANING. EPIGENETIC EFFECTS WERE EVALUATED BY SCORING COAT COLOR OF A(VY)/A OFFSPRING AND QUANTITATIVE BISULFITE SEQUENCING OF TWO RETROTRANSPOSON-DRIVEN (A(VY) AND CDK5 ACTIVATOR-BINDING PROTEIN INTRACISTERNAL A PARTICLE ELEMENT) AND TWO IMPRINTED (IGF2 AND IGF2R) LOCI IN TAIL DNA. RESULTS: MATERNAL BLOOD PB LEVELS WERE BELOW THE LIMIT OF DETECTION IN CONTROLS, AND 4.1, 25.1 AND 32.1 MICROG/DL FOR EACH DOSE, RESPECTIVELY. PB EXPOSURE WAS ASSOCIATED WITH A TREND OF INCREASED WEAN BODYWEIGHT IN MALES (P = 0.03) AND ALTERED COAT COLOR IN A(VY)/A OFFSPRING. DNA METHYLATION AT A(VY) AND THE CDK5 ACTIVATOR-BINDING PROTEIN INTRACISTERNAL A-PARTICLE ELEMENT WAS SIGNIFICANTLY DIFFERENT FROM CONTROLS FOLLOWING A CUBIC TREND (P = 0.04; P = 0.01), WITH MALE-SPECIFIC EFFECTS AT THE A(VY) LOCUS. IMPRINTED GENES DID NOT SHIFT IN METHYLATION ACROSS EXPOSURES. CONCLUSION: DOSE- AND SEX-SPECIFIC RESPONSES IN BODYWEIGHT AND DNA METHYLATION INDICATE THAT PB ACTS ON THE EPIGENOME IN A LOCUS-SPECIFIC FASHION, DEPENDENT ON THE GENOMIC FEATURE HOSTING THE CPG SITE OF INTEREST, AND THAT SEX IS A FACTOR IN EPIGENETIC RESPONSE. 2013 2 5131 34 POSTWEANING DIETARY FOLATE DEFICIENCY PROVIDED THROUGH CHILDHOOD TO PUBERTY PERMANENTLY INCREASES GENOMIC DNA METHYLATION IN ADULT RAT LIVER. FOLATE PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SEVERAL CHRONIC DISEASES BY ITS POTENTIAL ABILITY TO MODULATE DNA METHYLATION. WE HYPOTHESIZED THAT THE POSTWEANING PERIOD MIGHT BE A HIGHLY SUSCEPTIBLE PERIOD TO DIETARY FOLATE INTERVENTION FOR DNA METHYLATION PATTERNING. WE DETERMINED THE EFFECTS OF TIMING AND DURATION OF DIETARY FOLATE INTERVENTION PROVIDED DURING THE POSTWEANING PERIOD ON GENOMIC DNA METHYLATION IN ADULT RAT LIVER. IN STUDY 1, WEANLING RATS WERE RANDOMIZED TO RECEIVE AN AMINO ACID-DEFINED DIET CONTAINING 0 (DEFICIENT), 2 (CONTROL), OR 8 (SUPPLEMENTED) MG FOLIC ACID/KG UNTIL 8 WK OF AGE, AFTER WHICH ALL THE RATS WERE FED THE CONTROL DIET UNTIL 30 WK OF AGE. IN STUDY 2, WEANLING RATS WERE FED THE CONTROL DIET UNTIL 8 WK OF AGE AND THEN RANDOMIZED TO RECEIVE THE DIET CONTAINING 0, 2, OR 8 MG FOLIC ACID/KG UNTIL 30 WK OF AGE. IN STUDY 3, WEANLING RATS WERE RANDOMIZED TO RECEIVE THESE DIETS UNTIL 30 WK OF AGE. DIETARY FOLATE DEFICIENCY, BUT NOT SUPPLEMENTATION, PROVIDED DURING THE POSTWEANING PERIOD THROUGH CHILDHOOD TO PUBERTY SIGNIFICANTLY INCREASED GENOMIC DNA METHYLATION BY 34-48% (P < 0.04) IN RAT LIVER THAT PERSISTED INTO ADULTHOOD FOLLOWING A RETURN TO THE CONTROL DIET AT PUBERTY. IN CONTRAST, DIETARY FOLATE DEFICIENCY OR SUPPLEMENTATION CONTINUALLY IMPOSED AT WEANING OR AT PUBERTY DID NOT SIGNIFICANTLY AFFECT GENOMIC DNA METHYLATION IN ADULT RAT LIVER. OUR DATA SUGGEST THAT EARLY FOLATE NUTRITION DURING POSTNATAL DEVELOPMENT PLAYS AN IMPORTANT ROLE IN EPIGENETIC PROGRAMMING THAT CAN HAVE A PERMANENT EFFECT IN ADULTHOOD. 2008 3 998 24 CHRONIC SUBCONVULSIVE ACTIVITY DURING EARLY POSTNATAL LIFE PRODUCES AUTISTIC BEHAVIOR IN THE ABSENCE OF NEUROTOXICITY IN THE JUVENILE WEANLING PERIOD. THE DIAGNOSIS OF AUTISM SPECTRUM DISORDER (ASD) VARIES FROM VERY MILD TO SEVERE SOCIAL AND COGNITIVE IMPAIRMENTS. WE HYPOTHESIZED THAT EPIGENETIC SUBCONVULSIVE ACTIVITY IN EARLY POSTNATAL LIFE MAY CONTRIBUTE TO THE DEVELOPMENT OF AUTISTIC BEHAVIOR IN A SEX-RELATED MANNER. LOW DOSES OF KAINIC ACID (KA) (25-100 MUG) WERE ADMINISTERED TO RAT PUPS FOR 15 DAYS BEGINNING ON POSTNATAL (P) DAY 6 TO CHRONICALLY ELEVATE NEURONAL ACTIVITY. A BATTERY OF CLASSICAL AND NOVEL BEHAVIORAL TESTS WAS USED, AND SEX DIFFERENCES WERE OBSERVED. OUR NOVEL OPEN HANDLING TEST REVEALED THAT ASD MALES NOSE POKED MORE OFTEN AND ASD FEMALES CLIMBED AND ESCAPED MORE FREQUENTLY WITH AGE. IN THE SOCIAL INTERACTION TEST, ASD MALES WERE LESS SOCIAL THAN ASD FEMALES WHO WERE MORE ANXIOUS IN HANDLING AND ELEVATED PLUS MAZE (EPM) TASKS. TO EVALUATE GROUP DYNAMICS, SIBLING AND NON-SIBLING CONTROL AND EXPERIMENTAL ANIMALS EXPLORED 3 DIFFERENT SHAPED NOVEL SOCIAL ENVIRONMENTS. CONTROL PUPS HUDDLED QUICKLY AND MORE FREQUENTLY IN ALL ENVIRONMENTS WHETHER THEY SOCIALIZED WITH LITTERMATES OR NON-SIBLINGS COMPARED TO ASD GROUPS. NON-SIBLING ASD PUPS WERE ERRATIC AND HUDDLED IN SMALLER GROUPS. IN THE OBJECT RECOGNITION TEST, ONLY ASD MALES SPENT LESS TIME WITH THE NOVEL OBJECT COMPARED TO CONTROL PUPS. DATA SUGGEST THAT CHRONIC SUBCONVULSIVE ACTIVITY IN EARLY POSTNATAL LIFE LEADS TO AN ASD PHENOTYPE IN THE ABSENCE OF CELL DEATH. MALES WERE MORE SUSCEPTIBLE TO DEVELOPING ASOCIAL BEHAVIORS AND COGNITIVE PATHOLOGIES, WHEREAS FEMALES WERE PRONE TO HIGHER LEVELS OF HYPERACTIVITY AND ANXIETY, VALIDATING OUR POSTNATAL ASD MODEL APPARENT IN THE PRE-JUVENILE PERIOD. 2019 4 3649 26 INCREASED STRESS AND ALTERED EXPRESSION OF HISTONE MODIFYING ENZYMES IN BRAIN ARE ASSOCIATED WITH ABERRANT BEHAVIOUR IN VITAMIN B12 DEFICIENT FEMALE MICE. A SUB-OPTIMAL NUTRITIONAL ENVIRONMENT FROM EARLY LIFE CAN BE ENVISAGED AS A STRESSOR THAT TRANSLATES INTO MENTAL HEALTH PROBLEMS IN ADULTHOOD. AFTER CONSIDERING (A) THE WIDESPREAD PREVALENCE OF VITAMIN B12 DEFICIENCY ESPECIALLY AMONGST WOMEN IN DEVELOPING COUNTRIES AND (B) THE IMPORTANCE OF VITAMIN B12 IN NORMAL BRAIN FUNCTION, IN THIS STUDY WE HAVE ELUCIDATED THE BEHAVIOURAL CORRELATES OF CHRONIC SEVERE AND MODERATE VITAMIN B12 DEFICIENCY IN C57BL/6 MICE. FEMALE WEANLING MICE WERE ASSIGNED TO THREE DIETARY GROUPS: (A) CONTROL AIN-76A DIET WITH CELLULOSE AS DIETARY FIBRE (B) VITAMIN B12 RESTRICTED AIN-76A DIET WITH PECTIN AS DIETARY FIBRE (SEVERE DEFICIENCY GROUP) AND (C) VITAMIN B12 RESTRICTED AIN-76A DIET WITH CELLULOSE AS DIETARY FIBRE (MODERATE DEFICIENCY GROUP). THE MICE RECEIVED THESE DIETS THROUGHOUT PREGNANCY, LACTATION AND THEREAFTER. NEST-BUILDING, MATERNAL CARE, ANXIETY AND DEPRESSIVE BEHAVIOURS WERE EVALUATED. OXIDATIVE STRESS, ACTIVITIES OF ANTIOXIDANT ENZYMES AND EXPRESSION OF VARIOUS HISTONE MODIFYING ENZYMES IN BRAIN WERE INVESTIGATED TO UNRAVEL THE PROBABLE UNDERLYING MECHANISMS. OUR DATA SUGGESTS THAT BOTH SEVERE AND MODERATE VITAMIN B12 DEFICIENCY INDUCED ANXIETY AND IMPAIRED MATERNAL CARE. HOWEVER, ONLY SEVERE VITAMIN B12 DEFICIENCY INDUCED DEPRESSION. OXIDATIVE STRESS AND POOR ANTIOXIDANT DEFENSE UNDERLIE THE DELETERIOUS EFFECTS OF BOTH SEVERE AND MODERATE VITAMIN B12 DEFICIENCY. ALTERED EXPRESSION OF HISTONE MODIFYING ENZYMES IN THE BRAIN OF SEVERELY DEFICIENT MICE IS SUGGESTIVE OF EPIGENETIC REPROGRAMMING. THIS STUDY SUGGESTS THAT CHRONIC VITAMIN B12 DEFICIENCY LEADS TO BEHAVIOURAL ANOMALIES IN FEMALE C57BL/6 MICE AND THE SEVERITY OF THESE OUTCOMES CAN BE CORRELATED TO THE LEVEL OF DEFICIENCY. 2020 5 73 35 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 6 3785 30 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 7 4068 31 MATERNAL ANDROGEN EXCESS AND OBESITY INDUCE SEXUALLY DIMORPHIC ANXIETY-LIKE BEHAVIOR IN THE OFFSPRING. MATERNAL POLYCYSTIC OVARY SYNDROME (PCOS), A CONDITION ASSOCIATED WITH HYPERANDROGENISM, IS SUGGESTED TO INCREASE ANXIETY-LIKE BEHAVIOR IN THE OFFSPRING. BECAUSE PCOS IS CLOSELY LINKED TO OBESITY, WE INVESTIGATED THE IMPACT OF AN ADVERSE HORMONAL OR METABOLIC MATERNAL ENVIRONMENT AND OFFSPRING OBESITY ON ANXIETY IN THE OFFSPRING. THE OBESE PCOS PHENOTYPE WAS INDUCED BY CHRONIC HIGH-FAT-HIGH-SUCROSE (HFHS) CONSUMPTION TOGETHER WITH PRENATAL DIHYDROTESTOSTERONE EXPOSURE IN MOUSE DAMS. ANXIETY-LIKE BEHAVIOR WAS ASSESSED IN ADULT OFFSPRING WITH THE ELEVATED-PLUS MAZE AND OPEN-FIELD TESTS. THE INFLUENCE OF MATERNAL ANDROGENS AND MATERNAL AND OFFSPRING DIET ON GENES IMPLICATED IN ANXIETY WERE ANALYZED IN THE AMYGDALA AND HYPOTHALAMUS WITH REAL-TIME PCR ( N = 47). INDEPENDENT OF DIET, FEMALE OFFSPRING EXPOSED TO MATERNAL ANDROGENS WERE MORE ANXIOUS AND DISPLAYED UP-REGULATION OF ADRENOCEPTOR ALPHA 1B IN THE AMYGDALA AND UP-REGULATION OF HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE ( CRH). BY CONTRAST, MALE OFFSPRING EXPOSED TO A HFHS MATERNAL DIET HAD INCREASED ANXIETY-LIKE BEHAVIOR AND SHOWED UP-REGULATION OF EPIGENETIC MARKERS IN THE AMYGDALA AND UP-REGULATION OF HYPOTHALAMIC CRH. OVERALL, THERE WERE SUBSTANTIAL SEX DIFFERENCES IN GENE EXPRESSION IN THE BRAIN. THESE FINDINGS PROVIDE NOVEL INSIGHT INTO HOW MATERNAL ANDROGENS AND OBESITY EXERT SEX-SPECIFIC EFFECTS ON BEHAVIOR AND GENE EXPRESSION IN THE OFFSPRING OF A PCOS MOUSE MODEL.-MANTI, M., FORNES, R., QI, X., FOLMERZ, E., LINDEN HIRSCHBERG, A., DE CASTRO BARBOSA, T., MALIQUEO, M., BENRICK, A., STENER-VICTORIN, E. MATERNAL ANDROGEN EXCESS AND OBESITY INDUCE SEXUALLY DIMORPHIC ANXIETY-LIKE BEHAVIOR IN THE OFFSPRING. 2018 8 4939 38 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 4073 28 MATERNAL EATING DISORDERS AFFECT OFFSPRING CORD BLOOD DNA METHYLATION: A PROSPECTIVE STUDY. BACKGROUND: EATING DISORDERS (ED) ARE CHRONIC PSYCHIATRIC DISORDERS, COMMON AMONGST WOMEN OF REPRODUCTIVE AGE. ED IN PREGNANCY ARE ASSOCIATED WITH POOR NUTRITION AND ABNORMAL INTRAUTERINE GROWTH. INCREASING EVIDENCE ALSO SHOWS OFFSPRING OF WOMEN WITH ED HAVE ADVERSE DEVELOPMENTAL AND BIRTH OUTCOMES. WE SOUGHT TO CARRY OUT THE FIRST STUDY INVESTIGATING DNA METHYLATION IN OFFSPRING OF WOMEN WITH ED. WE COMPARED CORD BLOOD DNA METHYLATION IN OFFSPRING OF WOMEN WITH ACTIVE ED (N = 21), PAST ED (N = 43) AND AGE- AND SOCIAL CLASS-MATCHED CONTROLS (N = 126) AS PART OF THE AVON LONGITUDINAL STUDY OF PARENTS AND CHILDREN. RESULTS: OFFSPRING OF WOMEN WITH BOTH ACTIVE AND PAST ED HAD LOWER WHOLE-GENOME METHYLATION COMPARED TO CONTROLS (ACTIVE ED 49.1% (95% CONFIDENCE INTERVALS 50.5-47.7%), PAST ED 49.2% (95% CI 50.7-47.7.0%), CONTROLS 52.4% (95% CI 53.0%-51.0%)). AMONGST OFFSPRING OF ED WOMEN, THOSE BORN TO WOMEN WITH RESTRICTIVE-TYPE AND PURGING-TYPE ED HAD LOWER METHYLATION LEVELS COMPARED TO THOSE OF CONTROLS. OFFSPRING OF WOMEN WITH AN ACTIVE RESTRICTIVE ED IN PREGNANCY HAD LOWER WHOLE-GENOME METHYLATION COMPARED TO OFFSPRING OF WOMEN WITH PAST RESTRICTIVE ED. WE OBSERVED DECREASED METHYLATION AT THE DHCR24 LOCUS IN OFFSPRING OF WOMEN WITH ACTIVE PREGNANCY ED (EFFECT SIZE (ES) = - 0.124, P = 6.94 X 10(-8)) AND INCREASED METHYLATION AT THE LGALS2 LOCUS IN OFFSPRING OF WOMEN WITH PAST ED (ES = 0.07, P = 3.74 X 10(-7)) COMPARED TO CONTROLS. CONCLUSIONS: MATERNAL ACTIVE AND PAST ED ARE ASSOCIATED WITH DIFFERENCES IN OFFSPRING WHOLE-GENOME METHYLATION. OUR RESULTS SHOW ALTERED DNA METHYLATION IN LOCI RELEVANT TO METABOLISM; THESE MIGHT BE BIOMARKERS OF DISRUPTED METABOLIC PATHWAYS IN OFFSPRING OF ED MOTHERS. FURTHER WORK IS NEEDED TO EXAMINE POTENTIAL MECHANISMS AND FUNCTIONAL OUTCOMES OF THE OBSERVED METHYLATION PATTERNS. 2017 10 4069 34 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 11 4086 28 MATERNAL OBESITY DISRUPTS THE METHIONINE CYCLE IN BABOON PREGNANCY. MATERNAL INTAKE OF DIETARY METHYL-MICRONUTRIENTS (E.G. FOLATE, CHOLINE, BETAINE AND VITAMIN B-12) DURING PREGNANCY IS ESSENTIAL FOR NORMAL MATERNAL AND FETAL METHIONINE METABOLISM, AND IS CRITICAL FOR IMPORTANT METABOLIC PROCESSES INCLUDING THOSE INVOLVED IN DEVELOPMENTAL PROGRAMMING. MATERNAL OBESITY AND NUTRIENT EXCESS DURING PREGNANCY INFLUENCE DEVELOPMENTAL PROGRAMMING POTENTIALLY PREDISPOSING ADULT OFFSPRING TO A VARIETY OF CHRONIC HEALTH PROBLEMS. IN THE PRESENT STUDY, WE HYPOTHESIZED THAT MATERNAL OBESITY WOULD DYSREGULATE THE MATERNAL AND FETAL METHIONINE CYCLE. TO TEST THIS HYPOTHESIS, WE DEVELOPED A NULLIPAROUS BABOON OBESITY MODEL FED A HIGH FAT, HIGH ENERGY DIET (HF-HED) PRIOR TO AND DURING GESTATION, AND EXAMINED METHIONINE CYCLE BIOMARKERS (E.G., CIRCULATING CONCENTRATIONS OF HOMOCYSTEINE, METHIONINE, CHOLINE, BETAINE, KEY AMINO ACIDS, FOLATE, AND VITAMIN B-12). ANIMALS WERE GROUP HOUSED ALLOWING FULL PHYSICAL ACTIVITY AND SOCIAL INTERACTION. MATERNAL PREPREGNANCY PERCENT BODY FAT WAS 5% IN CONTROLS AND 19% IN HF-HED MOTHERS, WHILE FETAL WEIGHT WAS 16% LOWER IN OFFSPRING OF HF-HED MOTHERS AT TERM. MATERNAL AND FETAL HOMOCYSTEINE WERE HIGHER, WHILE MATERNAL AND FETAL VITAMIN B-12 AND BETAINE WERE LOWER IN THE HF-HED GROUP. ELEVATIONS IN CIRCULATING MATERNAL FOLATE WERE EVIDENT IN THE HF-HED GROUP INDICATING IMPAIRED FOLATE METABOLISM (METHYL-TRAP) AS A CONSEQUENCE OF MATERNAL VITAMIN B-12 DEPLETION. FINALLY, FETAL METHIONINE, GLYCINE, SERINE, AND TAURINE WERE LOWER IN THE HF-HED FETUSES. THESE DATA SHOW THAT MATERNAL OBESITY DISTURBS THE METHIONINE CYCLE IN PRIMATE PREGNANCY, PROVIDING A MECHANISM FOR THE EPIGENETIC CHANGES OBSERVED AMONG OBESE PREGNANT WOMEN AND SUGGESTING DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES IN HUMAN PREGNANCIES COMPLICATED BY OBESITY. 2015 12 4061 31 MATERNAL ADVERSITIES DURING PREGNANCY AND CORD BLOOD OXYTOCIN RECEPTOR (OXTR) DNA METHYLATION. THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER MATERNAL ADVERSITIES AND CORTISOL LEVELS DURING PREGNANCY PREDICT CORD BLOOD DNA METHYLATION OF THE OXYTOCIN RECEPTOR (OXTR). WE COLLECTED CORD BLOOD OF 39 BABIES BORN TO MOTHERS PARTICIPATING IN A CROSS-SECTIONAL STUDY (N = 100) CONDUCTED IN BASEL, SWITZERLAND (2007-10). MOTHERS COMPLETED THE INVENTORY OF LIFE EVENTS (SECOND TRIMESTER: T2), THE EDINBURGH POSTNATAL DEPRESSION SCALE (EPDS, THIRD TRIMESTER: T3), THE TRIER INVENTORY OF CHRONIC STRESS (TICS-K, 1-3 WEEKS POSTPARTUM) AND PROVIDED SALIVA SAMPLES (T2, T3) FOR MATERNAL CORTISOL PROFILES, AS COMPUTED BY THE AREA UNDER THE CURVE WITH RESPECT TO GROUND (AUCG) OR INCREASE (AUCI) FOR THE CORTISOL AWAKENING RESPONSE (CAR) AND FOR DIURNAL CORTISOL PROFILES (DAY). OXTR DNA METHYLATION WAS QUANTIFIED USING SEQUENOM EPITYPER. THE NUMBER OF STRESSFUL LIFE EVENTS (P = 0.032), EPDS SCORE (P = 0.007) AND CORTISOL AUCGS AT T2 (CAR: P = 0.020; DAY: P = 0.024) WERE NEGATIVELY ASSOCIATED WITH OXTR DNA METHYLATION. OUR FINDINGS SUGGEST THAT DISTINCT PRENATAL ADVERSITIES PREDICT DECREASED DNA METHYLATION IN A GENE THAT IS RELEVANT FOR CHILDBIRTH, MATERNAL BEHAVIOR AND WELLBEING OF MOTHER AND OFFSPRING. IF A REDUCED OXTR METHYLATION INCREASES OXTR EXPRESSION, OUR FINDINGS COULD SUGGEST AN EPIGENETIC ADAPTATION TO AN ADVERSE EARLY ENVIRONMENT. 2016 13 4916 28 PAIN-RELATED INCREASE IN SEROTONIN TRANSPORTER GENE METHYLATION ASSOCIATES WITH EMOTIONAL REGULATION IN 4.5-YEAR-OLD PRETERM-BORN CHILDREN. AIM: THE MAIN GOAL OF THIS STUDY WAS TO ASSESS THE ASSOCIATION BETWEEN PAIN-RELATED INCREASE IN SEROTONIN TRANSPORTER GENE (SLC6A4) METHYLATION AND EMOTIONAL DYSREGULATION IN 4.5-YEAR-OLD PRETERM CHILDREN COMPARED WITH FULL-TERM MATCHED COUNTERPARTS. METHODS: PRETERM (N = 29) AND FULL-TERM (N = 26) CHILDREN RECRUITED FROM TWO ITALIAN HOSPITALS WERE FOLLOWED-UP FROM OCTOBER 2011 TO DECEMBER 2017. SLC6A4 METHYLATION WAS ASSESSED FROM CORD BLOOD AT BIRTH FROM BOTH GROUPS AND PERIPHERAL BLOOD AT DISCHARGE FOR PRETERM ONES. AT 4.5 YEARS, EMOTIONAL REGULATION (IE, ANGER, FEAR AND SADNESS) WAS ASSESSED THROUGH AN OBSERVATIONAL STANDARDISED PROCEDURE. RESULTS: PRETERM CHILDREN (18 FEMALES; MEAN AGE = 4.5, RANGE = 4.3-4.8) SHOWED GREATER ANGER DISPLAY COMPARED WITH FULL-TERM CONTROLS (14 FEMALES; MEAN AGE = 4.5, RANGE = 4.4-4.9) IN RESPONSE TO EMOTIONAL STRESS. CONTROLLING FOR ADVERSE LIFE EVENTS OCCURRENCE FROM DISCHARGE TO 4.5 YEARS AND SLC6A4 METHYLATION AT BIRTH, CPG-SPECIFIC SLC6A4 METHYLATION IN THE NEONATAL PERIOD WAS PREDICTIVE OF GREATER ANGER DISPLAY IN PRETERM CHILDREN BUT NOT IN FULL-TERM ONES. CONCLUSION: THESE FINDINGS CONTRIBUTE TO HIGHLIGHT HOW EPIGENETIC REGULATION OF SEROTONIN TRANSPORTER GENE IN RESPONSE TO NICU PAIN EXPOSURE CONTRIBUTES TO LONG-LASTING PROGRAMMING OF ANGER REGULATION IN PRETERM CHILDREN. 2020 14 2265 25 EPIGENETIC PROGRAMMING IN THE PREIMPLANTATION RAT EMBRYO IS DISRUPTED BY CHRONIC PATERNAL CYCLOPHOSPHAMIDE EXPOSURE. PRECONCEPTIONAL PATERNAL EXPOSURE TO CYCLOPHOSPHAMIDE, A WIDELY USED ANTICANCER AGENT, LEADS TO INCREASES IN EMBRYO LOSS, MALFORMATIONS, AND BEHAVIORAL DEFICITS IN OFFSPRING; THESE ABNORMALITIES ARE TRANSMISSIBLE TO SUBSEQUENT GENERATIONS [AUROUX, M., DULIOUST, E., SELVA, J. & RINCE, P. (1990) MUTAT. RES. 229, 189-200]. LITTLE INFORMATION EXISTS ON THE MECHANISMS UNDERLYING THIS MALE-MEDIATED DEVELOPMENTAL TOXICITY. WE ASSESSED THE IMPACT OF PATERNAL CYCLOPHOSPHAMIDE EXPOSURE ON THE DYNAMIC REGULATION OF HISTONE H4 ACETYLATION AT LYSINE 5 AND DNA METHYLATION IN PREIMPLANTATION RAT EMBRYOS. ZYGOTES SIRED BY DRUG-TREATED MALES DISPLAYED ADVANCED DEVELOPMENTAL PROGRESSION, INCREASED PRONUCLEAR AREAS, AND DISRUPTION OF THE EPIGENETIC PROGRAMMING OF BOTH PARENTAL GENOMES. EARLY POSTFERTILIZATION ZYGOTIC PRONUCLEI WERE HYPERACETYLATED; BY MID-ZYGOTIC DEVELOPMENT, MALE PRONUCLEI WERE DRAMATICALLY HYPOMETHYLATED, WHEREAS FEMALE PRONUCLEI WERE HYPERMETHYLATED. MICRONUCLEI WERE SUBSTANTIALLY ELEVATED, AND HISTONE H4 ACETYLATION AT LYSINE 5 LOCALIZATION TO THE NUCLEAR PERIPHERY WAS DISRUPTED IN TWO-CELL EMBRYOS FERTILIZED BY CYCLOPHOSPHAMIDE-EXPOSED SPERMATOZOA. THIS FINDING DEMONSTRATES THAT PATERNAL EXPOSURE TO THIS DRUG INDUCES ABERRANT EPIGENETIC PROGRAMMING IN EARLY EMBRYOS. WE HYPOTHESIZE THAT DISTURBANCES IN EPIGENETIC PROGRAMMING CONTRIBUTE TO HERITABLE INSTABILITIES LATER IN DEVELOPMENT, EMPHASIZING THE IMPORTANCE OF EPIGENETIC RISK ASSESSMENT AFTER CHEMOTHERAPY. 2005 15 1521 42 DNA METHYLATION AT IMPRINT REGULATORY REGIONS IN PRETERM BIRTH AND INFECTION. OBJECTIVE: TO AID IN UNDERSTANDING LONG-TERM HEALTH CONSEQUENCES OF INTRAUTERINE INFECTIONS IN PRETERM BIRTH, WE EVALUATED DNA METHYLATION AT 9 DIFFERENTIALLY METHYLATED REGIONS THAT REGULATE IMPRINTED GENES BY TYPE OF PRETERM BIRTH (SPONTANEOUS PRETERM LABOR, PRETERM PREMATURE RUPTURE OF MEMBRANES, OR MEDICALLY INDICATED [FETAL GROWTH RESTRICTION AND PREECLAMPSIA]) AND INFECTION STATUS (CHORIOAMNIONITIS OR FUNISITIS). STUDY DESIGN: DATA ON TYPE OF PRETERM BIRTH AND INFECTION STATUS WERE ABSTRACTED FROM MEDICAL RECORDS AND STANDARDIZED PATHOLOGY REPORTS IN 73 PRETERM INFANTS ENROLLED IN THE NEWBORN EPIGENETICS STUDY, A PROSPECTIVE COHORT STUDY OF MOTHER-INFANT DYADS IN DURHAM, NC. CORD BLOOD WAS COLLECTED AT BIRTH, AND INFANT DNA METHYLATION LEVELS AT THE H19, IGF2, MEG3, MEST, SGCE/PEG10, PEG3, NNAT, AND PLAGL1 DIFFERENTIALLY METHYLATED REGIONS WERE MEASURED USING BISULFITE PYROSEQUENCING. ONE-WAY ANALYSES OF VARIANCE AND LOGISTIC REGRESSION MODELS WERE USED TO COMPARE DNA METHYLATION LEVELS BY TYPE OF PRETERM BIRTH AND INFECTION STATUS. RESULTS: DNA METHYLATION LEVELS DID NOT DIFFER AT ANY OF THE REGIONS (P > .20) BETWEEN INFANTS BORN VIA SPONTANEOUS PRETERM LABOR (AVERAGE N = 29), PRETERM PREMATURE RUPTURE OF MEMBRANES (AVERAGE N = 17), OR MEDICALLY INDICATED PRETERM BIRTH (AVERAGE N = 40). LEVELS WERE SIGNIFICANTLY INCREASED AT PLAGL1 IN INFANTS WITH CHORIOAMNIONITIS (N = 10, 64.4%) COMPARED WITH INFANTS WITHOUT CHORIOAMNIONITIS (N = 63, 57.9%), P < .01. DNA METHYLATION LEVELS WERE ALSO INCREASED AT PLAGL1 FOR INFANTS WITH FUNISITIS (N = 7, 63.3%) COMPARED WITH INFANTS WITHOUT FUNISITIS (N = 66, 58.3%), P < .05. CONCLUSION: DYSREGULATION OF PLAGL1 HAS BEEN ASSOCIATED WITH ABNORMAL DEVELOPMENT AND CANCER. EARLY-LIFE EXPOSURES, INCLUDING INFECTION/INFLAMMATION, MAY AFFECT EPIGENETIC CHANGES THAT INCREASE SUSCEPTIBILITY TO LATER CHRONIC DISEASE. 2013 16 853 31 CHOLINE, OTHER METHYL-DONORS AND EPIGENETICS. CHOLINE DIETARY INTAKE VARIES SUCH THAT MANY PEOPLE DO NOT ACHIEVE ADEQUATE INTAKES. DIET INTAKE OF CHOLINE CAN MODULATE METHYLATION BECAUSE, VIA BETAINE HOMOCYSTEINE METHYLTRANSFERASE (BHMT), THIS NUTRIENT (AND ITS METABOLITE, BETAINE) REGULATE THE CONCENTRATIONS OF S-ADENOSYLHOMOCYSTEINE AND S-ADENOSYLMETHIONINE. SOME OF THE EPIGENETIC MECHANISMS THAT MODIFY GENE EXPRESSION WITHOUT MODIFYING THE GENETIC CODE DEPEND ON THE METHYLATION OF DNA OR OF HISTONES; AND DIET AVAILABILITY OF CHOLINE AND OTHER METHYL-GROUP DONORS INFLUENCES BOTH OF THESE METHYLATIONS. EXAMPLES OF METHYL-DONOR MEDIATED EPIGENETIC EFFECTS INCLUDE THE CHANGES IN COAT COLOR AND BODY WEIGHT IN OFFSPRING WHEN PREGNANT AGOUTI MICE ARE FED HIGH CHOLINE, HIGH METHYL DIETS; THE CHANGES IN TAIL KINKING IN OFFSPRING WHEN PREGNANT AXIN(FU) MICE ARE FED HIGH CHOLINE, HIGH METHYL DIETS; THE CHANGES IN CDKN3 METHYLATION AND ALTERED BRAIN DEVELOPMENT THAT OCCURS IN OFFSPRING WHEN PREGNANT RODENTS ARE FED LOW CHOLINE DIETS. WHEN CHOLINE METABOLISM IS DISRUPTED BY DELETING THE GENE BHMT, DNA METHYLATION IS AFFECTED (ESPECIALLY IN A REGION OF CHROMOSOME 13), EXPRESSION OF SPECIFIC GENES IS SUPPRESSED, AND LIVER CANCERS DEVELOP. BETTER UNDERSTANDING OF HOW NUTRIENTS SUCH AS CHOLINE AND METHYL-DONORS INFLUENCE EPIGENETIC PROGRAMS HAS IMPORTANCE FOR OUR UNDERSTANDING OF NOT ONLY DEVELOPMENTAL ABNORMALITIES BUT ALSO FOR UNDERSTANDING THE ORIGINS OF CHRONIC DISEASES. 2017 17 4944 33 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 18 4077 32 MATERNAL INFLAMMATION INDUCES SPATIAL LEARNING AND MEMORY IMPAIRMENT IN THE F1 AND F2 GENERATIONS OF MICE VIA SEX-SPECIFIC EPIGENETIC MECHANISMS. MOUNTING EVIDENCE INDICATES THAT HISTONE MODIFICATIONS ARE INVOLVED IN AGING-ASSOCIATED COGNITIVE DECLINE (AACD) AND CAN BE TRANSMITTED TO OFFSPRING OVER MULTIPLE GENERATIONS UNDER CONDITIONS OF STRESS. HERE, WE INVESTIGATED THE EFFECTS OF MATERNAL SUB-CHRONIC INFLAMMATION CAUSED BY LIPOPOLYSACCHARIDE (LPS) ON AACD AND HISTONE MODIFICATIONS IN THE F1 AND F2 GENERATIONS OF EXPERIMENTAL MICE AS WELL AS THE POTENTIAL SEX SPECIFICITY OF INTERGENERATIONAL EFFECTS. IN BRIEF, F0-GENERATION CD-1 DAMS WERE EXPOSED TO LPS (50 MICROG/KG) OR SALINE (CON) DURING LATE PREGNANCY. SUBSEQUENTLY, F1 MALES AND FEMALES (AT 2 MONTHS-OF-AGE) FROM THE LPS TREATMENT GROUP WERE MATED WITH NON-LITTERMATES FROM THE LPS GROUP OR WILD-TYPE MICE TO PRODUCE F2 GENERATIONS OF PARENTAL- (F2-LPS(2)), PATERNAL- (F2M-LPS(1)) AND MATERNAL-ORIGIN (F2F-LPS(1)) MICE. THEN, CON-F1 MALES AND FEMALES WERE MATED WITH WILD-TYPE MICE TO GENERATE F2 GENERATIONS OF PATERNAL- (F2M-CON(1)) AND MATERNAL-ORIGIN (F2F-CON(1)). NEXT, WE EVALUATED THE COGNITIVE ABILITY AND LEVELS OF HIPPOCAMPAL H4K12AC AND H3K9ME3 IN THE F1 AND F2 OFFSPRING AT 3- AND 13 MONTHS-OF-AGE. OVERALL, F1 MALE AND FEMALE LPS GROUPS PRESENTED WITH ELEVATED CORTICOSTERONE (P < 0.001, P = 0.036, P = 0.025, 0.012, RESPECTIVELY) AND CYTOKINE RESPONSES, POORER COGNITIVE PERFORMANCE (ALL P < 0.05) AND H3K9 HYPERMETHYLATION AND H4K12 HYPOACETYLATION IN THE DORSAL HIPPOCAMPUS (ALL P < 0.05); THESE ISSUES WERE CARRIED OVER TO THE F2 GENERATION VIA THE PARENTS, PREDOMINANTLY IN THE PATERNAL LINEAGE. MOREOVER, THE LEVELS OF H3K9ME3 AND H4K12AC WERE SIGNIFICANT CORRELATED WITH COGNITIVE PERFORMANCE (ALL P < 0.05), REGARDLESS OF WHETHER INFLAMMATORY INSULTS HAD BEEN INCURRED DIRECTLY OR INDIRECTLY. THESE FINDINGS INDICATED THAT GESTATIONAL INFLAMMATORY INSULTS IN THE F0 GENERATION ACCELERATED AACD IN THE F2 GENERATION, ALONG WITH H3K9 HYPERMETHYLATION AND H4K12 HYPOACETYLATION IN THE HIPPOCAMPUS, AND THAT THESE ISSUES WERE DERIVED FROM THE F1 PARENTS, ESPECIALLY FROM THE F1 FATHERS. 2022 19 2077 35 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 20 3301 26 HIGH-FAT OR ETHINYL-OESTRADIOL INTAKE DURING PREGNANCY INCREASES MAMMARY CANCER RISK IN SEVERAL GENERATIONS OF OFFSPRING. MATERNAL EXPOSURES TO ENVIRONMENTAL FACTORS DURING PREGNANCY INFLUENCE THE RISK OF MANY CHRONIC ADULT-ONSET DISEASES IN THE OFFSPRING. HERE WE INVESTIGATE WHETHER FEEDING PREGNANT RATS A HIGH-FAT (HF)- OR ETHINYL-OESTRADIOL (EE2)-SUPPLEMENTED DIET AFFECTS CARCINOGEN-INDUCED MAMMARY CANCER RISK IN DAUGHTERS, GRANDDAUGHTERS AND GREAT-GRANDDAUGHTERS. WE SHOW THAT MAMMARY TUMOURIGENESIS IS HIGHER IN DAUGHTERS AND GRANDDAUGHTERS OF HF RAT DAMS AND IN DAUGHTERS AND GREAT-GRANDDAUGHTERS OF EE2 RAT DAMS. OUTCROSS EXPERIMENTS SUGGEST THAT THE INCREASE IN MAMMARY CANCER RISK IS TRANSMITTED TO HF GRANDDAUGHTERS EQUALLY THROUGH THE FEMALE OR MALE GERM LINES, BUT IT IS ONLY TRANSMITTED TO EE2 GRANDDAUGHTERS THROUGH THE FEMALE GERM LINE. THE EFFECTS OF MATERNAL EE2 EXPOSURE ON OFFSPRING'S MAMMARY CANCER RISK ARE ASSOCIATED WITH CHANGES IN THE DNA METHYLATION MACHINERY AND METHYLATION PATTERNS IN MAMMARY TISSUE OF ALL THREE EE2 GENERATIONS. WE CONCLUDE THAT DIETARY AND OESTROGENIC EXPOSURES IN PREGNANCY INCREASE BREAST CANCER RISK IN MULTIPLE GENERATIONS OF OFFSPRING, POSSIBLY THROUGH EPIGENETIC MEANS. 2012