1 4079 140 MATERNAL L-CARNITINE SUPPLEMENTATION AMELIORATES RENAL UNDERDEVELOPMENT AND EPIGENETIC CHANGES IN MALE MICE OFFSPRING DUE TO MATERNAL SMOKING. OBJECTIVES: EPIDEMIOLOGICAL AND ANIMAL STUDIES SHOWED THAT L-CARNITINE (LC) SUPPLEMENTATION CAN AMELIORATE OXIDATIVE STRESS-INDUCED TISSUES DAMAGE. WE HAVE PREVIOUSLY SHOWN THAT MATERNAL CIGARETTE SMOKE EXPOSURE (SE) CAN INCREASE RENAL OXIDATIVE STRESS IN NEWBORN OFFSPRING WITH POSTNATAL KIDNEY UNDERDEVELOPMENT AND RENAL DYSFUNCTION IN ADULTHOOD, WHICH WERE NORMALISED BY LC ADMINISTRATION IN THE SE DAMS DURING PREGNANCY. EXPOSURE TO AN ADVERSE INTRAUTERINE ENVIRONMENT MAY LEAD TO ALTERATION IN THE EPIGENOME, A MECHANISM BY WHICH ADVERSE PRENATAL CONDITIONS INCREASE THE SUSCEPTIBILITY TO CHRONIC DISEASE LATER IN LIFE. THE CURRENT STUDY AIMED TO DETERMINE WHETHER MATERNAL SE INDUCES EPIGENETIC CHANGES IN THE OFFSPRING'S KIDNEY ARE ASSOCIATED WITH RENAL UNDERDEVELOPMENT, AND THE PROTECTIVE EFFECT OF MATERNAL LC SUPPLEMENTATION. METHOD: FEMALE BALB/C MICE (7 WEEKS) WERE EXPOSED TO CIGARETTE SMOKE (SE) OR AIR (SHAM) FOR 6 WEEKS PRIOR TO MATING, DURING GESTATION AND LACTATION. A SUBGROUP OF THE SE DAMS RECEIVED LC VIA DRINKING WATER (SE + LC, 1.5 MMOL/L) THROUGHOUT GESTATION AND LACTATION. MALE OFFSPRING WERE STUDIED AT POSTNATAL DAY (P)1, P20, AND 13 WEEKS. RESULTS: MATERNAL SE ALTERED THE EXPRESSION OF RENAL DEVELOPMENT MARKERS GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR AND FIBROBLAST GROWTH FACTOR 2, WHICH WERE ASSOCIATED WITH INCREASED RENAL GLOBAL DNA METHYLATION AND DNA METHYLTRANSFERASE 1 MRNA EXPRESSION AT BIRTH. THESE DISORDERS WERE REVERSED BY MATERNAL LC ADMINISTRATION. CONCLUSION: THE EFFECT OF MATERNAL SE ON RENAL UNDERDEVELOPMENT INVOLVES GLOBAL EPIGENETIC ALTERATIONS FROM BIRTH, WHICH CAN BE PREVENTED BY MATERNAL LC SUPPLEMENTATION. 2019 2 5294 45 PROTECTIVE EFFECTS OF MATERNAL METHYL DONOR SUPPLEMENTATION ON ADULT OFFSPRING OF HIGH FAT DIET-FED DAMS. OBESITY HAS BECOME A GLOBAL PUBLIC HEALTH PROBLEM ASSOCIATED WITH METABOLIC DYSFUNCTION AND CHRONIC DISORDERS. IT HAS BEEN SHOWN THAT THE RISK OF OBESITY AND THE DNA METHYLATION PROFILES OF THE OFFSPRING CAN BE AFFECTED BY MATERNAL NUTRITION, SUCH AS HIGH-FAT DIET (HFD) CONSUMPTION. THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER METABOLIC DYSREGULATION AND PHYSIOLOGICAL ABNORMALITIES IN OFFSPRING CAUSED BY MATERNAL HFD CAN BE ALLEVIATED BY THE TREATMENT OF METHYL DONORS DURING PREGNANCY AND LACTATION OF DAMS. FEMALE C57BL/6 MICE WERE ASSIGNED TO SPECIFIC GROUPS AND GIVEN DIFFERENT NUTRIENTS (CONTROL DIET, CONTROL+MET, HFD AND HFD+MET) THROUGHOUT GESTATION AND LACTATION. OFFSPRING OF EACH GROUP WERE WEANED ONTO A CONTROL DIET AT 3 WEEKS OF AGE. PHYSIOLOGICAL (WEIGHT GAIN AND ADIPOSE COMPOSITION) AND METABOLIC (PLASMA BIOCHEMICAL ANALYSES) OUTCOMES WERE ASSESSED IN MALE AND FEMALE ADULT OFFSPRING. EXPRESSION AND DNA METHYLATION PROFILES OF OBESOGENIC-RELATED GENES INCLUDING PPAR GAMMA, FATTY ACID SYNTHASE, LEPTIN AND ADIPONECTIN WERE ALSO DETECTED IN VISCERAL FAT OF OFFSPRING. THE RESULTS SHOWED THAT DIETARY SUPPLEMENTATION WITH METHYL DONORS CAN PREVENT THE ADVERSE EFFECTS OF MATERNAL HFD ON OFFSPRING. CHANGES IN THE EXPRESSION AND DNA METHYLATION OF OBESOGENIC-RELATED GENES INDICATED THAT EPIGENETIC REGULATION MAY CONTRIBUTE TO THE EFFECTS OF MATERNAL DIETARY FACTORS ON OFFSPRING OUTCOMES. 2016 3 5166 41 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 4 2472 44 EPIGENETIC TRANSMISSION OF THE IMPACT OF EARLY STRESS ACROSS GENERATIONS. BACKGROUND: TRAUMATIC EXPERIENCES IN EARLY LIFE ARE RISK FACTORS FOR THE DEVELOPMENT OF BEHAVIORAL AND EMOTIONAL DISORDERS. SUCH DISORDERS CAN PERSIST THROUGH ADULTHOOD AND HAVE OFTEN BEEN REPORTED TO BE TRANSMITTED ACROSS GENERATIONS. METHODS: TO INVESTIGATE THE TRANSGENERATIONAL EFFECT OF EARLY STRESS, MICE WERE EXPOSED TO CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION FROM POSTNATAL DAY 1 TO 14. RESULTS: WE SHOW THAT CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION INDUCES DEPRESSIVE-LIKE BEHAVIORS AND ALTERS THE BEHAVIORAL RESPONSE TO AVERSIVE ENVIRONMENTS IN THE SEPARATED ANIMALS WHEN ADULT. MOST OF THE BEHAVIORAL ALTERATIONS ARE FURTHER EXPRESSED BY THE OFFSPRING OF MALES SUBJECTED TO MATERNAL SEPARATION, DESPITE THE FACT THAT THESE MALES ARE REARED NORMALLY. CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION ALSO ALTERS THE PROFILE OF DNA METHYLATION IN THE PROMOTER OF SEVERAL CANDIDATE GENES IN THE GERMLINE OF THE SEPARATED MALES. COMPARABLE CHANGES IN DNA METHYLATION ARE ALSO PRESENT IN THE BRAIN OF THE OFFSPRING AND ARE ASSOCIATED WITH ALTERED GENE EXPRESSION. CONCLUSIONS: THESE FINDINGS HIGHLIGHT THE NEGATIVE IMPACT OF EARLY STRESS ON BEHAVIORAL RESPONSES ACROSS GENERATIONS AND ON THE REGULATION OF DNA METHYLATION IN THE GERMLINE. 2010 5 1795 40 EFFECT OF DIFFERENT COMBINATION OF MATERNAL AND POSTNATAL DIET ON ADIPOSE TISSUE MORPHOLOGY IN MALE RAT OFFSPRING. PURPOSE: ADIPOSE TISSUE EXPANSION CAN OCCUR THROUGH SEVERAL DIFFERENT WAYS AND, UNDER CERTAIN CONDITIONS, CAN BE CONNECTED WITH CHRONIC INFLAMMATION. TNF-ALPHA IS ONE OF THE IMPORTANT CYTOKINES INVOLVED IN THIS PROCESS. PROLONGED INFLAMMATION IN OBESITY CAN LEAD TO OBESITY-RELATED INSULIN RESISTANCE AND TISSUE DYSFUNCTION. THE AIM OF OUR STUDY WAS TO INVESTIGATE HOW DIFFERENT COMBINATION OF MATERNAL AND POSTNATAL DIET AFFECTS OFFSPRING ADIPOSE TISSUE MORPHOLOGY AND ADIPOSE TISSUE TNF-ALPHA EXPRESSION. METHODS: TEN FEMALE SPRAGUE DAWLEY RATS, 9 WEEKS OLD, WERE RANDOMLY DIVIDED INTO TWO GROUPS AND FED EITHER STANDARD LABORATORY CHOW OR FOOD RICH IN SATURATED FATTY ACIDS DURING 6 WEEKS AND THEN MATED WITH THE SAME MALE RAT. AFTER BIRTH AND LACTATION MALE RAT OFFSPRING FROM BOTH GROUPS WERE DIVIDED INTO FOUR SUBGROUPS DEPENDING ON THE DIET THEY WERE FED UNTIL 22 WEEKS OLD. SAMPLES OF WHITE ADIPOSE TISSUE WERE TAKEN FROM THE SUBCUTANEOUS, EPIDIDYMAL, AND PERIRENAL FAT PAD. ON TISSUE SECTIONS, HISTOMORPHOMETRIC ANALYSIS WAS CONDUCTED USING CELLPROFILER PROGRAM V 2.1.1, AND IMMUNOHISTOCHEMICAL STAINING FOR TNF-ALPHA WAS PERFORMED. RESULTS: GREATER MEAN SURFACE AREA OF SUBCUTANEOUS AND EPIDIDYMAL ADIPOCYTES WAS FOUND IN GROUPS OF MALE RAT OFFSPRING WITH ALTERED DIET. IN PERIRENAL ADIPOSE TISSUE, THE HIGHEST NUMBER OF ADIPOCYTES WAS MEASURED IN THE GROUP WHERE BOTH MOTHER AND OFFSPRING WERE FED A HIGH-FAT DIET. ADIPOCYTE STAINING INTENSITY FOR TNF-ALPHA DID NOT DIFFER SIGNIFICANTLY BETWEEN THE GROUPS. CONCLUSIONS: TOGETHER WITH OUR PREVIOUSLY PUBLISHED DATA, OUR RESULTS LEAD TO THE CONCLUSION THAT ALTERATION OF POSTNATAL DIET CAN LEAD TO TNF-ALPHA AND ADIPOCYTE MORPHOLOGY CHANGES. 2019 6 2757 45 EXPRESSION OF EPIGENETIC MACHINERY GENES IS SENSITIVE TO MATERNAL OBESITY AND WEIGHT LOSS IN RELATION TO FETAL GROWTH IN MICE. BACKGROUND: MATERNAL OBESITY IMPACTS FETAL GROWTH AND PREGNANCY OUTCOMES. TO COUNTERACT THE DELETERIOUS EFFECTS OF OBESITY ON FERTILITY AND PREGNANCY ISSUE, PRECONCEPTIONAL WEIGHT LOSS IS RECOMMENDED TO OBESE WOMEN. WHETHER THIS WEIGHT LOSS IS BENEFICIAL/DETRIMENTAL FOR OFFSPRING REMAINS POORLY EXPLORED. EPIGENETIC MECHANISMS COULD BE AFFECTED BY MATERNAL WEIGHT CHANGES, PERTURBING EXPRESSION OF KEY DEVELOPMENTAL GENES IN THE PLACENTA OR FETUS. OUR AIM WAS TO INVESTIGATE THE EFFECTS OF CHRONIC MATERNAL OBESITY ON FETO-PLACENTAL GROWTH ALONG WITH THE UNDERLYING EPIGENETIC MECHANISMS. WE ALSO TESTED WHETHER PRECONCEPTIONAL WEIGHT LOSS COULD ALLEVIATE THESE EFFECTS. RESULTS: FEMALE MICE WERE FED EITHER A CONTROL DIET (CTRL GROUP), A HIGH-FAT DIET (OBESE (OB) GROUP), OR A HIGH-FAT DIET SWITCHED TO A CONTROL DIET 2 MONTHS BEFORE CONCEPTION (WEIGHT LOSS (WL) GROUP). AT MATING, OB FEMALES PRESENTED AN OBESE PHENOTYPE WHILE WL FEMALES NORMALIZED METABOLIC PARAMETERS. AT EMBRYONIC DAY 18.5 (E18.5), FETUSES FROM OB FEMALES PRESENTED FETAL GROWTH RESTRICTION (FGR; -13 %) AND 28 % OF THE FETUSES WERE SMALL FOR GESTATIONAL AGE (SGA). FETUSES FROM WL FEMALES NORMALIZED THIS PHENOTYPE. THE EXPRESSION OF 60 EPIGENETIC MACHINERY GENES AND 32 METABOLIC GENES WAS MEASURED IN THE FETAL LIVER, PLACENTAL LABYRINTH, AND JUNCTIONAL ZONE. WE REVEALED 23 GENES ALTERED BY MATERNAL WEIGHT TRAJECTORIES IN AT LEAST ONE OF THREE TISSUES. THE FETAL LIVER AND PLACENTAL LABYRINTH WERE MORE RESPONSIVE TO MATERNAL OBESITY THAN JUNCTIONAL ZONE. ONE THIRD (18/60) OF THE EPIGENETIC MACHINERY GENES WERE DIFFERENTIALLY EXPRESSED BETWEEN AT LEAST TWO MATERNAL GROUPS. INTERESTINGLY, GENES INVOLVED IN THE HISTONE ACETYLATION PATHWAY WERE PARTICULARLY ALTERED (13/18). IN OB GROUP, LYSINE ACETYLTRANSFERASES AND BROMODOMAIN-CONTAINING PROTEIN 2 WERE UPREGULATED, WHILE MOST HISTONE DEACETYLASES WERE DOWNREGULATED. IN WL GROUP, THE EXPRESSION OF ONLY A SUBSET OF THESE GENES WAS NORMALIZED. CONCLUSIONS: THIS STUDY HIGHLIGHTS THE HIGH SENSITIVITY OF THE EPIGENETIC MACHINERY GENE EXPRESSION, AND PARTICULARLY THE HISTONE ACETYLATION PATHWAY, TO MATERNAL OBESITY. THESE OBESITY-INDUCED TRANSCRIPTIONAL CHANGES COULD ALTER THE PLACENTAL AND THE HEPATIC EPIGENOME, LEADING TO FGR. PRECONCEPTIONAL WEIGHT LOSS APPEARS BENEFICIAL TO FETAL GROWTH, BUT SOME EFFECTS OF PREVIOUS OBESITY WERE RETAINED IN OFFSPRING PHENOTYPE. 2016 7 5192 39 PRENATAL ENVIRONMENTAL STRESSORS AND DNA METHYLATION LEVELS IN PLACENTA AND PERIPHERAL TISSUES OF MOTHERS AND NEONATES EVALUATED BY APPLYING ARTIFICIAL NEURAL NETWORKS. EXPOSURE TO ENVIRONMENTAL STRESSORS DURING PREGNANCY PLAYS AN IMPORTANT ROLE IN INFLUENCING SUBSEQUENT SUSCEPTIBILITY TO CERTAIN CHRONIC DISEASES THROUGH THE MODULATION OF EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION. OUR AIM WAS TO EXPLORE THE CONNECTIONS BETWEEN ENVIRONMENTAL EXPOSURES DURING GESTATION WITH DNA METHYLATION OF PLACENTAL CELLS, MATERNAL AND NEONATAL BUCCAL CELLS BY APPLYING ARTIFICIAL NEURAL NETWORKS (ANNS). A TOTAL OF 28 MOTHER-INFANT PAIRS WERE ENROLLED. DATA ON GESTATIONAL EXPOSURE TO ADVERSE ENVIRONMENTAL FACTORS AND ON MOTHER HEALTH STATUS WERE COLLECTED THROUGH THE ADMINISTRATION OF A QUESTIONNAIRE. DNA METHYLATION ANALYSES AT BOTH GENE-SPECIFIC AND GLOBAL LEVEL WERE ANALYZED IN PLACENTAS, MATERNAL AND NEONATAL BUCCAL CELLS. IN THE PLACENTA, THE CONCENTRATIONS OF VARIOUS METALS AND DIOXINS WERE ALSO ANALYZED. ANALYSIS OF ANNS REVEALED THAT SUBOPTIMAL BIRTH WEIGHT IS ASSOCIATED WITH PLACENTAL H19 METHYLATION, MATERNAL STRESS DURING PREGNANCY WITH METHYLATION LEVELS OF NR3C1 AND BDNF IN PLACENTAS AND MOTHER'S BUCCAL DNA, RESPECTIVELY, AND EXPOSURE TO AIR POLLUTANTS WITH MATERNAL MGMT METHYLATION. ASSOCIATIONS WERE ALSO OBSERVED BETWEEN PLACENTAL CONCENTRATIONS OF LEAD, CHROMIUM, CADMIUM AND MERCURY WITH METHYLATION LEVELS OF OXTR IN PLACENTAS, HSD11B2 IN MATERNAL BUCCAL CELLS AND PLACENTAS, MECP2 IN NEONATAL BUCCAL CELLS, AND MTHFR IN MATERNAL BUCCAL CELLS. FURTHERMORE, DIOXIN CONCENTRATIONS WERE ASSOCIATED WITH PLACENTAL RELN, NEONATAL HSD11B2 AND MATERNAL H19 GENE METHYLATION LEVELS. CURRENT RESULTS SUGGEST THAT EXPOSURE OF PREGNANT WOMEN TO ENVIRONMENTAL STRESSORS DURING PREGNANCY COULD INDUCE ABERRANT METHYLATION LEVELS IN GENES LINKED TO SEVERAL PATHWAYS IMPORTANT FOR EMBRYOGENESIS IN BOTH THE PLACENTA, POTENTIALLY AFFECTING FOETAL DEVELOPMENT, AND IN THE PERIPHERAL TISSUES OF MOTHERS AND INFANTS, POTENTIALLY PROVIDING PERIPHERAL BIOMARKERS OF ENVIRONMENTAL EXPOSURE. 2023 8 5397 39 REDUCED LEVELS OF MIRNAS 449 AND 34 IN SPERM OF MICE AND MEN EXPOSED TO EARLY LIFE STRESS. EXPOSURE OF MALE MICE TO EARLY LIFE STRESS ALTERS THE LEVELS OF SPECIFIC SPERM MIRNAS THAT PROMOTE STRESS-ASSOCIATED BEHAVIORS IN THEIR OFFSPRING. TO BEGIN TO EVALUATE WHETHER SIMILAR PHENOMENA OCCUR IN MEN, WE SEARCHED FOR SPERM MIRNA CHANGES THAT OCCUR IN BOTH MICE AND MEN EXPOSED TO EARLY LIFE STRESSORS THAT HAVE LONG-LASTING EFFECTS. FOR MEN, WE USED THE ADVERSE CHILDHOOD EXPERIENCE (ACE) QUESTIONNAIRE. IT REVEALS THE DEGREE OF ABUSIVE AND/OR DYSFUNCTIONAL FAMILY EXPERIENCES WHEN YOUNG, WHICH INCREASES RISKS OF DEVELOPING FUTURE PSYCHOLOGICAL AND PHYSICAL DISORDERS. FOR MALE MICE, WE USED ADOLESCENT CHRONIC SOCIAL INSTABILITY (CSI) STRESS, WHICH NOT ONLY ENHANCES SOCIABILITY DEFECTS FOR >1 YEAR, BUT ALSO ANXIETY AND DEFECTIVE SOCIABILITY IN FEMALE OFFSPRING FOR MULTIPLE GENERATIONS THROUGH THE MALE LINEAGE. HERE WE FOUND A STATISTICALLY SIGNIFICANT INVERSE CORRELATION BETWEEN LEVELS OF MULTIPLE MIRNAS OF THE MIR-449/34 FAMILY AND ACE SCORES OF CAUCASIAN MALES. REMARKABLY, WE FOUND MEMBERS OF THE SAME SPERM MIRNA FAMILY ARE ALSO REDUCED IN MICE EXPOSED TO CSI STRESS. THUS, FUTURE STUDIES SHOULD BE DESIGNED TO DIRECTLY TEST WHETHER REDUCED LEVELS OF THESE MIRNAS COULD BE USED AS UNBIASED INDICATORS OF CURRENT AND/OR EARLY LIFE EXPOSURE TO SEVERE STRESS. MOREOVER, AFTER MATING STRESSED MALE MICE, THESE SPERM MIRNA REDUCTIONS PERSIST IN BOTH EARLY EMBRYOS THROUGH AT LEAST THE MORULA STAGE AND IN SPERM OF MALES DERIVED FROM THEM, SUGGESTING THESE MIRNA CHANGES CONTRIBUTE TO TRANSMISSION OF STRESS PHENOTYPES ACROSS GENERATIONS. SINCE OFFSPRING OF MEN EXPOSED TO EARLY LIFE TRAUMA HAVE ELEVATED RISKS FOR PSYCHOLOGICAL DISORDERS, THESE FINDINGS RAISE THE POSSIBILITY THAT A PORTION OF THIS RISK MAY BE DERIVED FROM EPIGENETIC REGULATION OF THESE SPERM MIRNAS. 2018 9 4752 58 NOVEL ROLE OF GESTATIONAL HYDRALAZINE IN LIMITING MATERNAL AND DIETARY OBESITY-RELATED CHRONIC KIDNEY DISEASE. BACKGROUND: MATERNAL OBESITY IS A RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD) IN OFFSPRING, UNDERPINNING THE THEORY OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PROGRAMMING OF ADULT CHRONIC DISEASE BY MATERNAL OBESITY, THEREFORE, DNA DEMETHYLATING AGENTS MAY MITIGATE OFFSPRING RISK OF DISEASE. IN RODENT MODELS, LOW-DOSE HYDRALAZINE HAS PREVIOUSLY BEEN SHOWN TO REDUCE RENAL FIBROSIS VIA DNA DEMETHYLATION. WE USED MOUSE MODELS OF MATERNAL OBESITY AND OFFSPRING OBESITY TO DETERMINE WHETHER ADMINISTRATION OF LOW-DOSE HYDRALAZINE DURING GESTATION CAN PREVENT FETAL PROGRAMMING OF CKD IN OFFSPRING. METHODS: FEMALE C57BL/6 MICE RECEIVED HIGH FAT DIET (HFD) OR CHOW PRIOR TO MATING, DURING GESTATION AND LACTATION. DURING GESTATION, DAMS RECEIVED SUBCUTANEOUS HYDRALAZINE (5 MG/KG) OR SALINE THRICE-WEEKLY. MALE OFFSPRING WEANED TO HFD OR CHOW, WHICH CONTINUED UNTIL ENDPOINT AT 32 WEEKS. BIOMETRIC AND METABOLIC PARAMETERS, RENAL GLOBAL DNA METHYLATION, RENAL FUNCTIONAL AND STRUCTURAL CHANGES, AND RENAL MARKERS OF FIBROSIS, INFLAMMATION AND OXIDATIVE STRESS WERE ASSESSED AT ENDPOINT. RESULTS: OFFSPRING EXPOSED TO MATERNAL OBESITY OR DIET-INDUCED OBESITY HAD SIGNIFICANTLY INCREASED RENAL GLOBAL DNA METHYLATION, TOGETHER WITH OTHER ADVERSE RENAL EFFECTS INCLUDING ALBUMINURIA, GLOMERULOSCLEROSIS, RENAL FIBROSIS, AND OXIDATIVE STRESS. OFFSPRING EXPOSED TO GESTATIONAL HYDRALAZINE HAD SIGNIFICANTLY REDUCED RENAL GLOBAL DNA METHYLATION. IN OBESE OFFSPRING OF OBESE MOTHERS, GESTATIONAL HYDRALAZINE SIGNIFICANTLY DECREASED ALBUMINURIA, GLOMERULOSCLEROSIS, AND SERUM CREATININE. OBESE OFFSPRING OF HYDRALAZINE-TREATED LEAN MOTHERS DISPLAYED REDUCED MARKERS OF RENAL FIBROSIS AND OXIDATIVE STRESS. CONCLUSION: GESTATIONAL HYDRALAZINE DECREASED RENAL GLOBAL DNA METHYLATION AND EXERTED RENOPROTECTIVE EFFECTS IN OFFSPRING. THIS SUPPORTS A POTENTIAL THERAPEUTIC EFFECT OF HYDRALAZINE IN PREVENTING MATERNAL OBESITY OR DIETARY OBESITY-RELATED CKD, THROUGH AN EPIGENETIC MECHANISM. 2021 10 5168 36 PRECONCEPTIONAL PATERNAL EXPOSURE TO A SINGLE TRAUMATIC EVENT AFFECTS POSTNATAL GROWTH OF FEMALE BUT NOT MALE OFFSPRING. ALTHOUGH PRECONCEPTIONAL AND PERICONCEPTIONAL MATERNAL STRESS IS A RECOGNIZED RISK FACTOR FOR OFFSPRING NEURODEVELOPMENTAL DISTURBANCES, LESS IS KNOWN ABOUT THE RELEVANCE OF PATERNAL EXPOSURES. THESE HAVE HITHERTO BEEN INVESTIGATED MAINLY WITH RESPECT TO SUBSTANCE-INDUCED IMPAIRMENT IN THE PROGENY. IN RECENT YEARS, EXPERIENTIAL INFLUENCES ON OFFSPRING HAVE COME INTO FOCUS THROUGH GROWING INSIGHT INTO EPIGENETIC MECHANISMS SUCH AS NONGENETIC MODES OF TRANSMISSION. THE EFFECT OF CHRONIC AND/OR EARLY MANIPULATIONS IN MALES HAS BEEN STUDIED BUT MUCH LESS IS KNOWN ABOUT THE POTENTIAL IMPACT OF SINGULAR MANIPULATIONS IN OLDER INDIVIDUALS. WE INVESTIGATED THE INFLUENCE OF A STRONG STRESSOR EXPOSURE, REMINISCENT OF A TRAUMATIC EVENT, IN ADULT MALE MICE ON OFFSPRING BEHAVIOR. MALE MICE, 6 WEEKS OF AGE, RECEIVED A STRONG FOOTSHOCK AND WERE MATED TO NAIVE FEMALES SEVERAL WEEKS LATER. MALE AND FEMALE OFFSPRING WERE INVESTIGATED IN A VARIETY OF TESTS FOR ANXIETY-LIKE AND DEPRESSION-LIKE BEHAVIORS. IN ADDITION, BODYWEIGHT DEVELOPMENT WAS ASSESSED. ALTHOUGH WE DID NOT OBSERVE ANY ALTERATIONS IN ANXIETY-LIKE AND DEPRESSIVE-LIKE BEHAVIORAL INDICES, WE RECORDED REDUCED BODYWEIGHT DEVELOPMENT IN THE FEMALE OFFSPRING. OUR DATA EMPHASIZE THE RELEVANCE OF SEX AS A (CO)DETERMINANT OF OUTCOMES IN THE WAKE OF PARENTAL MANIPULATIONS. THEY FURTHER SUGGEST THAT THE WINDOW OF VULNERABILITY FOR THE INDUCTION OF PATRILINEAR EFFECTS MIGHT BE WIDER THAN THAT CURRENTLY ASSUMED. 2013 11 4085 48 MATERNAL OBESITY AND GESTATIONAL DIABETES REPROGRAM THE METHYLOME OF OFFSPRING BEYOND BIRTH BY INDUCING EPIGENETIC SIGNATURES IN METABOLIC AND DEVELOPMENTAL PATHWAYS. BACKGROUND: OBESITY IS A NEGATIVE CHRONIC METABOLIC HEALTH CONDITION THAT REPRESENTS AN ADDITIONAL RISK FOR THE DEVELOPMENT OF MULTIPLE PATHOLOGIES. EPIDEMIOLOGICAL STUDIES HAVE SHOWN HOW MATERNAL OBESITY OR GESTATIONAL DIABETES MELLITUS DURING PREGNANCY CONSTITUTE SERIOUS RISK FACTORS IN RELATION TO THE APPEARANCE OF CARDIOMETABOLIC DISEASES IN THE OFFSPRING. FURTHERMORE, EPIGENETIC REMODELLING MAY HELP EXPLAIN THE MOLECULAR MECHANISMS THAT UNDERLIE THESE EPIDEMIOLOGICAL FINDINGS. THUS, IN THIS STUDY WE EXPLORED THE DNA METHYLATION LANDSCAPE OF CHILDREN BORN TO MOTHERS WITH OBESITY AND GESTATIONAL DIABETES DURING THEIR FIRST YEAR OF LIFE. METHODS: WE USED ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS TO PROFILE MORE THAN 770,000 GENOME-WIDE CPG SITES IN BLOOD SAMPLES FROM A PAEDIATRIC LONGITUDINAL COHORT CONSISTING OF 26 CHILDREN BORN TO MOTHERS WHO SUFFERED FROM OBESITY OR OBESITY WITH GESTATIONAL DIABETES MELLITUS DURING PREGNANCY AND 13 HEALTHY CONTROLS (MEASUREMENTS TAKEN AT 0, 6 AND 12 MONTH; TOTAL N = 90). WE CARRIED OUT CROSS-SECTIONAL AND LONGITUDINAL ANALYSES TO DERIVE DNA METHYLATION ALTERATIONS ASSOCIATED WITH DEVELOPMENTAL AND PATHOLOGY-RELATED EPIGENOMICS. RESULTS: WE IDENTIFIED ABUNDANT DNA METHYLATION CHANGES DURING CHILD DEVELOPMENT FROM BIRTH TO 6 MONTHS AND, TO A LESSER EXTENT, UP TO 12 MONTHS OF AGE. USING CROSS-SECTIONAL ANALYSES, WE DISCOVERED DNA METHYLATION BIOMARKERS MAINTAINED ACROSS THE FIRST YEAR OF LIFE THAT COULD DISCRIMINATE CHILDREN BORN TO MOTHERS WHO SUFFERED FROM OBESITY OR OBESITY WITH GESTATIONAL DIABETES. IMPORTANTLY, ENRICHMENT ANALYSES SUGGESTED THAT THESE ALTERATIONS CONSTITUTE EPIGENETIC SIGNATURES THAT AFFECT GENES AND PATHWAYS INVOLVED IN THE METABOLISM OF FATTY ACIDS, POSTNATAL DEVELOPMENTAL PROCESSES AND MITOCHONDRIAL BIOENERGETICS, SUCH AS CPT1B, SLC38A4, SLC35F3 AND FN3K. FINALLY, WE OBSERVED EVIDENCE OF AN INTERACTION BETWEEN DEVELOPMENTAL DNA METHYLATION CHANGES AND MATERNAL METABOLIC CONDITION ALTERATIONS. CONCLUSIONS: OUR OBSERVATIONS HIGHLIGHT THE FIRST SIX MONTHS OF DEVELOPMENT AS BEING THE MOST CRUCIAL FOR EPIGENETIC REMODELLING. FURTHERMORE, OUR RESULTS SUPPORT THE EXISTENCE OF SYSTEMIC INTRAUTERINE FOETAL PROGRAMMING LINKED TO OBESITY AND GESTATIONAL DIABETES THAT AFFECTS THE CHILDHOOD METHYLOME BEYOND BIRTH, WHICH INVOLVES ALTERATIONS RELATED TO METABOLIC PATHWAYS, AND WHICH MAY INTERACT WITH ORDINARY POSTNATAL DEVELOPMENT PROGRAMMES. 2023 12 249 42 ADVANCED AGING PHENOTYPE IS REVEALED BY EPIGENETIC MODIFICATIONS IN RAT LIVER AFTER IN UTERO MALNUTRITION. ADVERSE ENVIRONMENTAL EXPOSURES OF MOTHERS DURING FETAL PERIOD PREDISPOSE OFFSPRING TO A RANGE OF AGE-RELATED DISEASES EARLIER IN LIFE. HERE, WE SET TO DETERMINE WHETHER A DEREGULATED EPIGENETIC PATTERN IS SIMILAR IN YOUNG ANIMALS WHOSE MOTHERS' NUTRITION WAS MODULATED DURING FETAL GROWTH TO THAT ACQUIRED DURING NORMAL AGING IN ANIMALS. USING A RODENT MODEL OF MATERNAL UNDERNUTRITION (UN) OR OVERNUTRITION (ON), WE EXAMINED CYTOSINE METHYLATION PROFILES OF LIVER FROM YOUNG FEMALE OFFSPRING AND COMPARED THEM TO AGE-MATCHED YOUNG CONTROLS AND AGED (20-MONTH-OLD) ANIMALS. HELP-TAGGING, A GENOMEWIDE RESTRICTION ENZYME AND SEQUENCING ASSAY DEMONSTRATES THAT FETAL EXPOSURE TO TWO DIFFERENT MATERNAL DIETS IS ASSOCIATED WITH NONRANDOM DYSREGULATION OF METHYLATION LEVELS WITH PROFILES SIMILAR TO THOSE SEEN IN NORMAL AGING ANIMALS AND OCCUR IN REGIONS MAPPED TO GENES RELEVANT TO METABOLIC DISEASES AND AGING. FUNCTIONAL CONSEQUENCES WERE ASSESSED BY GENE EXPRESSION AT 9 WEEKS OLD WITH MORE SIGNIFICANT CHANGES AT 6 MONTHS OF AGE. EARLY DEVELOPMENTAL EXPOSURES TO UNFAVORABLE MATERNAL DIETS RESULT IN ALTERED METHYLATION PROFILES AND TRANSCRIPTIONAL DYSREGULATION IN PRKCB, PC, NCOR2, AND SMAD3 THAT IS ALSO SEEN WITH NORMAL AGING. THESE NOTCH PATHWAY AND LIPOGENESIS GENES MAY BE USEFUL FOR PREDICTION OF LATER SUSCEPTIBILITY TO CHRONIC DISEASE. 2016 13 5189 41 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE. 2022 14 1823 38 EFFECTS OF EARLY-LIFE STRESS AND HDAC INHIBITION ON MATERNAL BEHAVIOR IN MICE. DESPITE THE WELL-ESTABLISHED FACT THAT MATERNAL CARE PLAYS A PIVOTAL ROLE IN THE OFFSPRING DEVELOPMENT, LITTLE IS KNOWN ABOUT THE EFFECTS OF DISRUPTION OF MATERNAL CARE EARLY IN LIFE ON THE DEVELOPMENT OF THIS BEHAVIOR IN THE OFFSPRING. USING BRIEF REPEATED MATERNAL SEPARATION (45 MIN/DAY ON POSTNATAL DAYS 3-6), WHICH REPRESENTS A MODEL OF EARLY LIFE STRESS, WE FOUND BEHAVIORAL CHANGES IN ADULT FEMALE MICE OFFSPRING. THE DECREASE IN HOME CAGE EXPLORATORY BEHAVIOR (BOTH PUP-DIRECTED AND NONPUP-DIRECTED) WAS REVEALED LATER IN ADULTHOOD WITHOUT CHANGES IN MATERNAL CARE LEVEL. MATERNAL SEPARATION COUPLED WITH PAIN EXPOSURE CAUSED BY SUBCUTANEOUS SALINE INJECTION PROCEDURE HAD A CUMULATIVE RESULTING EFFECT, WHICH WAS MANIFESTED IN THE DECREASED LEVEL OF NURSING ASSOCIATED WITH LICKING-GROOMING IN ADULT FEMALES. THE BEHAVIORAL CHANGES FOUND IN ADULT FEMALE OFFSPRING COULD BE TRIGGERED BY IDENTIFIED CHANGES IN THE BEHAVIOR OF THEIR MOTHERS, WHILE ALTERATIONS OF THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN WERE NOT DETECTED. HISTONE DEACETYLASE INHIBITOR SODIUM VALPROATE WAS USED IN ORDER TO STUDY THE POSSIBILITY OF PREVENTING THE EFFECTS OF EARLY LIFE STRESS THROUGH INVOLVEMENT OF EPIGENETIC MECHANISMS. DESPITE THE INCREASE IN THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN CAUSED BY VALPROATE, ITS BEHAVIORAL EFFECTS WERE BARELY DETECTABLE. THESE EFFECTS WERE REFLECTED IN PREVENTION OF THE REDUCTION OF NURSING ASSOCIATED WITH LICKING-GROOMING INDUCED BY MATERNAL SEPARATION, ACCOMPANIED BY PAIN EXPOSURE. THE DATA ARE DISCUSSED IN TERMS OF THE POSSIBLE APPLICATION TO THE STUDIES OF MECHANISMS UNDERLYING LONG-TERM EFFECTS OF HUMAN EARLY LIFE TRAUMA. (PSYCINFO DATABASE RECORD (C) 2019 APA, ALL RIGHTS RESERVED). 2019 15 4064 35 MATERNAL AND EARLY-LIFE CIRCADIAN DISRUPTION HAVE LONG-LASTING NEGATIVE CONSEQUENCES ON OFFSPRING DEVELOPMENT AND ADULT BEHAVIOR IN MICE. MODERN LIFE INVOLVES CHRONIC CIRCADIAN DISRUPTION THROUGH ARTIFICIAL LIGHT AND THESE DISRUPTIONS ARE ASSOCIATED WITH NUMEROUS MENTAL AND PHYSICAL HEALTH MALADIES. BECAUSE THE DEVELOPING NERVOUS SYSTEM IS PARTICULARLY VULNERABLE TO PERTURBATION, WE HYPOTHESIZED THAT EARLY-LIFE CIRCADIAN DISRUPTION WOULD NEGATIVELY IMPACT OFFSPRING DEVELOPMENT AND ADULT FUNCTION. PREGNANT MICE WERE SUBJECTED TO CHRONIC CIRCADIAN DISRUPTION FROM THE TIME OF UTERINE IMPLANTATION THROUGH WEANING. TO DISSOCIATE IN UTERO FROM POSTNATAL EFFECTS, A SUBSET OF LITTERS WAS CROSS-FOSTERED AT BIRTH FROM DISRUPTED DAMS TO CONTROL DAMS AND VICE VERSA. POSTNATAL CIRCADIAN DISRUPTION WAS ASSOCIATED WITH REDUCED ADULT BODY MASS, SOCIAL AVOIDANCE, AND HYPERACTIVITY. IN UTERO DISRUPTION RESULTED IN MORE PRONOUNCED SOCIAL AVOIDANCE AND HYPERACTIVITY, PHENOTYPES NOT ABROGATED BY CROSS-FOSTERING TO CONTROL MOTHERS. TO EXAMINE WHETHER CIRCADIAN DISRUPTION AFFECTS DEVELOPMENT BY ACTING AS AN EARLY LIFE STRESSOR, WE EXAMINED BIRTHWEIGHT, LITTER SIZE, MATERNAL CANNIBALISM, AND EPIGENETIC MODIFICATIONS. NONE OF THESE VARIABLES DIFFERED BETWEEN CONTROL AND DISRUPTED DAMS, OR RESEMBLED PATTERNS SEEN FOLLOWING EARLY-LIFE STRESS. OUR FINDINGS INDICATE THAT DEVELOPMENTAL CHRONIC CIRCADIAN DISRUPTION PERMANENTLY AFFECTS SOMATIC AND BEHAVIORAL DEVELOPMENT IN A STAGE-OF-LIFE-DEPENDENT MANNER, INDEPENDENT OF EARLY LIFE STRESS MECHANISMS, UNDERSCORING THE IMPORTANCE OF TEMPORAL STRUCTURE DURING DEVELOPMENT, BOTH IN UTERO AND EARLY POSTNATAL LIFE. 2017 16 5206 40 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 17 668 40 BNDF METHYLATION IN MOTHERS AND NEWBORNS IS ASSOCIATED WITH MATERNAL EXPOSURE TO WAR TRAUMA. BACKGROUND: THE BDNF GENE CODES FOR BRAIN-DERIVED NEUROTROPHIC FACTOR, A GROWTH FACTOR INVOLVED IN NEURAL DEVELOPMENT, CELL DIFFERENTIATION, AND SYNAPTIC PLASTICITY. PRESENT IN BOTH THE BRAIN AND PERIPHERY, BDNF PLAYS CRITICAL ROLES THROUGHOUT THE BODY AND IS ESSENTIAL FOR PLACENTAL AND FETAL DEVELOPMENT. RODENT STUDIES SHOW THAT EARLY LIFE STRESS, INCLUDING PRENATAL STRESS, BROADLY ALTERS BDNF METHYLATION, WITH PRESUMED CHANGES IN GENE EXPRESSION. NO STUDIES HAVE ASSESSED PRENATAL EXPOSURE TO MATERNAL TRAUMATIC STRESS AND BDNF METHYLATION IN HUMANS. THIS STUDY EXAMINED ASSOCIATIONS OF PRENATAL EXPOSURE TO MATERNAL STRESS AND BDNF METHYLATION AT CPG SITES ACROSS THE BDNF GENE. RESULTS: AMONG 24 MOTHERS AND NEWBORNS IN THE EASTERN DEMOCRATIC REPUBLIC OF CONGO, A REGION WITH EXTREME CONFLICT AND VIOLENCE TO WOMEN, MATERNAL EXPERIENCES OF WAR TRAUMA AND CHRONIC STRESS WERE ASSOCIATED WITH BDNF METHYLATION IN UMBILICAL CORD BLOOD, PLACENTAL TISSUE, AND MATERNAL VENOUS BLOOD. ASSOCIATIONS OF MATERNAL STRESS AND BDNF METHYLATION SHOWED HIGH TISSUE SPECIFICITY. THE MAJORITY OF SIGNIFICANT ASSOCIATIONS WERE OBSERVED IN PUTATIVE TRANSCRIPTION FACTOR BINDING REGIONS. CONCLUSIONS: THIS IS THE FIRST STUDY IN HUMANS TO EXAMINE BDNF METHYLATION IN RELATION TO PRENATAL EXPOSURE TO MATERNAL STRESS IN THREE TISSUES SIMULTANEOUSLY AND THE FIRST IN ANY MAMMALIAN SPECIES TO REPORT ASSOCIATIONS OF PRENATAL STRESS AND BDNF METHYLATION IN PLACENTAL TISSUE. THE FINDINGS ADD TO THE GROWING BODY OF EVIDENCE HIGHLIGHTING THE IMPORTANCE OF CONSIDERING EPIGENETIC EFFECTS WHEN EXAMINING THE IMPACTS OF TRAUMA AND STRESS, NOT ONLY FOR ADULTS BUT ALSO FOR OFFSPRING EXPOSED VIA EFFECTS TRANSMITTED BEFORE BIRTH. 2017 18 5773 42 SPERM MICRORNA CONTENT IS ALTERED IN A MOUSE MODEL OF MALE OBESITY, BUT THE SAME SUITE OF MICRORNAS ARE NOT ALTERED IN OFFSPRING'S SPERM. THE PREVALENCE OF OBESITY IS INCREASING WORLDWIDE AND HAS TRIPLED IN MEN OF REPRODUCTIVE AGE SINCE THE 1970S. CONCERNINGLY, OBESITY IS NOT ONLY COMORBID WITH OTHER CHRONIC DISEASES, BUT THERE IS MOUNTING EVIDENCE THAT IT INCREASES THE NON-COMMUNICABLE DISEASE LOAD IN THEIR CHILDREN (EG MORTALITY, OBESITY, AUTISM). ANIMAL STUDIES HAVE DEMONSTRATED THAT PATERNAL OBESITY INCREASES THE RISK OF METABOLIC (EG GLUCOSE METABOLISM DEFECTS, OBESITY) AND REPRODUCTIVE DISORDERS IN OFFSPRING. EPIGENETIC CHANGES WITHIN SPERM ARE CLEAR MECHANISTIC CANDIDATES THAT ARE ASSOCIATED WITH BOTH CHANGES TO THE FATHER'S ENVIRONMENT AND OFFSPRING PHENOTYPE. SPECIFICALLY THERE IS EMERGING EVIDENCE THAT A FATHER'S SPERM MICRORNA CONTENT BOTH RESPONDS TO PATERNAL ENVIRONMENTAL CUES AND ALTERS THE GENE EXPRESSION PROFILE AND SUBSEQUENT DEVELOPMENT OF THE EARLY EMBRYO. WE USED A MOUSE MODEL OF HIGH FAT DIET (HFD) INDUCED OBESITY TO INVESTIGATE WHETHER MALE OBESITY COULD MODULATE SPERM MICRORNA CONTENT. WE ALSO INVESTIGATED WHETHER THIS ALTERATION TO A FATHER'S SPERM MICRORNA CONTENT LEAD TO A SIMILAR CHANGE IN THE SPERM OF MALE OFFSPRING. OUR INVESTIGATIONS WERE INITIALLY GUIDED BY A TAQMAN PCR ARRAY, WHICH INDICATED THE DIFFERENTIAL ABUNDANCE OF 28 SPERM BORNE MICRORNAS IN HFD MICE. QPCR CONFIRMATION IN A MUCH LARGER COHORT OF FOUNDER MALES DEMONSTRATED THAT 13 OF THESE MICRORNAS WERE DIFFERENTIALLY ABUNDANT (11 UP-REGULATED; 2 DOWN-REGULATED) DUE TO HFD FEEDING. DESPITE METABOLIC AND REPRODUCTIVE PHENOTYPES ALSO BEING OBSERVED IN GRAND-OFFSPRING FATHERED VIA THE MALE OFFSPRING LINEAGE, THERE WAS NO EVIDENCE THAT ANY OF THE 13 MICRORNAS WERE ALSO DYSREGULATED IN MALE OFFSPRING SPERM. THIS WAS PRESUMABLY DUE TO THE VARIATION SEEN WITHIN BOTH GROUPS OF OFFSPRING AND SUGGESTS OTHER MECHANISMS MIGHT ACT BETWEEN OFFSPRING AND GRAND-OFFSPRING. THUS 13 SPERM BORNE MICRORNAS ARE MODULATED BY A FATHER'S HFD AND THE PRESUMED TRANSFER OF THIS ALTERED MICRORNA PAYLOAD TO THE EMBRYO AT FERTILISATION POTENTIALLY ACTS TO ALTER THE EMBRYONIC MOLECULAR MAKEUP POST-FERTILISATION, ALTERING ITS GROWTH TRAJECTORY, ULTIMATELY AFFECTING ADULT OFFSPRING PHENOTYPE AND MAY CONTRIBUTE TO PATERNAL PROGRAMMING. 2016 19 3119 52 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 20 4069 46 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