1 2757 167 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	
                                                                             
2 4089  47 MATERNAL OBESITY PROGRAMS SENESCENCE SIGNALING AND GLUCOSE METABOLISM IN OSTEO-PROGENITORS FROM RAT AND HUMAN. NUTRITIONAL STATUS DURING INTRAUTERINE AND EARLY POSTNATAL LIFE IMPACTS THE RISK OF CHRONIC DISEASES, PRESUMABLY VIA EPIGENETIC MECHANISMS. HOWEVER, EVIDENCE ON THE IMPACT OF GESTATIONAL EVENTS ON REGULATION OF EMBRYONIC BONE CELL FATE IS SPARSE. WE INVESTIGATED THE EFFECTS OF MATERNAL OBESITY ON FETAL OSTEOBLAST DEVELOPMENT IN BOTH RODENTS AND HUMANS. FEMALE RATS WERE FED CONTROL OR AN OBESOGENIC HIGH-FAT DIET (HFD) FOR 12 WEEKS AND MATED WITH MALE RATS FED CONTROL DIETS, AND RESPECTIVE MATERNAL DIETS WERE CONTINUED DURING PREGNANCY. EMBRYONIC RAT OSTEOGENIC CALVARIAL CELLS (EOCCS) WERE TAKEN FROM GESTATIONAL DAY 18.5 FETUSES FROM CONTROL AND HFD DAMS. EOCCS FROM HFD OBESE DAMS SHOWED INCREASES IN P53/P21-MEDIATED CELL SENESCENCE SIGNALING BUT DECREASED GLUCOSE METABOLISM. DECREASED AEROBIC GLYCOLYSIS IN HFD-EOCCS WAS ASSOCIATED WITH DECREASED OSTEOBLASTIC CELL DIFFERENTIATION AND PROLIFERATION. UMBILICAL CORD HUMAN MESENCHYMAL STEM CELLS (MSCS) FROM 24 PREGNANT WOMEN (12 OBESE AND 12 LEAN) ALONG WITH PLACENTAS WERE COLLECTED UPON DELIVERY. THE UMBILICAL CORD MSCS OF OBESE MOTHERS DISPLAYED LESS POTENTIAL TOWARD OSTEOBLASTOGENESIS AND MORE TOWARDS ADIPOGENESIS. HUMAN MSCS AND PLACENTA FROM OBESE MOTHERS ALSO EXHIBITED INCREASED CELL SENESCENCE SIGNALING, WHEREAS MSCS SHOWED DECREASED GLUCOSE METABOLISM AND INSULIN RESISTANCE. FINALLY, WE SHOWED THAT OVEREXPRESSION OF P53 LINKED INCREASED CELL SENESCENCE SIGNALING AND DECREASED GLUCOSE METABOLISM IN FETAL OSTEO-PROGENITORS FROM OBESE RATS AND HUMANS. THESE FINDINGS SUGGEST PROGRAMMING OF FETAL PREOSTEOBLASTIC CELL SENESCENCE SIGNALING AND GLUCOSE METABOLISM BY MATERNAL OBESITY.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3 5294  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 1795  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5 5166  56 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	
                                                                                                                                                
6 5773  49 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	
                                                                                                                                                                                                                                                                                   
7 4079  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8 4085  47 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	

9 5189  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10 2077  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11 2158  48 EPIGENETIC MECHANISMS FOR NUTRITION DETERMINANTS OF LATER HEALTH OUTCOMES. EPIGENETIC MARKING ON GENES CAN DETERMINE WHETHER OR NOT GENES ARE EXPRESSED. EPIGENETIC REGULATION IS MEDIATED BY THE ADDITION OF METHYL GROUPS TO DNA CYTOSINE BASES, OF METHYL AND ACETYL GROUPS TO PROTEINS (HISTONES) AROUND WHICH DNA IS WRAPPED, AND BY SMALL INTERFERING RNA MOLECULES. SOME COMPONENTS OF EPIGENETIC REGULATION HAVE EVOLVED TO PERMIT CONTROL OF WHETHER MATERNAL OR PATERNAL GENES ARE EXPRESSED. THE EPIGENETIC IMPRINTING OF IGF2 EXPRESSION IS AN EXAMPLE OF MATERNAL AND PATERNAL EPIGENETIC MARKING THAT MODULATES FETAL GROWTH AND FETAL SIZE. HOWEVER, EPIGENETIC REGULATION ALSO PERMITS THE FETUS AND THE INFANT TO ADAPT GENE EXPRESSION TO THE ENVIRONMENT IN WHICH IT IS GROWING; SOMETIMES WHEN THIS ADJUSTMENT GOES AWRY, THE RISK OF CHRONIC DISEASE IS INCREASED. RECENT PROGRESS IN THE UNDERSTANDING OF NUTRITIONAL INFLUENCES ON EPIGENETICS SUGGESTS THAT NUTRIENTS THAT ARE PART OF METHYL-GROUP METABOLISM CAN SIGNIFICANTLY INFLUENCE EPIGENETICS. DURING CRITICAL PERIODS IN DEVELOPMENT, DIETARY METHYL-GROUP INTAKE (CHOLINE, METHIONINE, AND FOLATE) CAN ALTER DNA AND HISTONE METHYLATION, WHICH RESULTS IN LIFELONG CHANGES IN GENE EXPRESSION. IN RODENT MODELS, PREGNANT DAMS THAT WERE FED DIETS HIGH IN METHIONINE, FOLIC ACID, AND CHOLINE PRODUCED OFFSPRING WITH DIFFERENT COAT COLORS OR WITH KINKED TAILS. A NUMBER OF SYNDROMES IN HUMANS CAN BE CAUSED BY DEFECTIVE EPIGENETIC REGULATION, INCLUDING RETT SYNDROME. THERE ARE INTERESTING EXAMPLES OF THE EFFECTS OF NUTRITION IN EARLY LIFE THAT RESULT IN ALTERED HEALTH IN ADULTS, AND SOME OF THESE COULD BE THE RESULT OF ALTERED EPIGENETIC REGULATION OF GENE EXPRESSION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
12  218  42 ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL TOTAL CHANGES IN PLACENTAL EPIGENETIC MODIFICATIONS. PREECLAMPSIA IS A COMMON OBSTETRICAL COMPLICATION, HALLMARKED BY NEW-ONSET HYPERTENSION. BELIEVED TO RESULT FROM PLACENTAL INSUFFICIENCY AND CHRONIC PLACENTAL ISCHEMIA, THE SYMPTOMS OF PREECLAMPSIA ARE CAUSED BY RELEASE OF PATHOGENIC FACTORS FROM THE PLACENTA ITSELF, ALTHOUGH THE MECHANISMS OF THEIR REGULATION ARE IN MANY CASES UNKNOWN. ONE POTENTIAL MECHANISM IS THROUGH CHANGES IN PLACENTAL EPIGENETIC CHROMATIN MODIFICATIONS, PARTICULARLY HISTONE ACETYLATION AND DNA METHYLATION. HERE, WE DETERMINED THE EFFECTS OF CHRONIC ISCHEMIA ON GLOBAL EPIGENETIC MODIFICATIONS IN THE RODENT PLACENTA IN VIVO AND ACUTE HYPOXIA IN BEWO PLACENTAL TROPHOBLAST CELLS IN VITRO. PLACENTAL INSUFFICIENCY VIA UTERINE ARTERY RESTRICTION INCREASED MATERNAL BLOOD PRESSURE AND FETAL DEMISE WHILE DECREASING PLACENTAL AND FETAL MASS. GLOBAL PLACENTAL HISTONE H3 ACETYLATION LEVELS WERE SIGNIFICANTLY DECREASED AT H3 K9, K14, K18, K27, AND K56. INTERESTINGLY, WHEN BEWO-IMMORTALIZED PLACENTAL TROPHOBLAST CELLS WERE CULTURED IN OXYGEN CONCENTRATIONS MIMICKING HEALTHY AND ISCHEMIC PLACENTAS, THERE WAS A SIGNIFICANT INCREASE IN ACETYLATED AT K9, K18, K27, AND K56. THIS WAS ASSOCIATED WITH A SMALL BUT SIGNIFICANT DECREASE IN PLACENTAL ACETYL-COA, SUGGESTING DEPLETION IN THE SOURCE OF ACETYL GROUP DONORS. FINALLY, WHILE GLOBAL METHYLATION OF CYTOSINE FROM PLACENTAL DNA WAS LOW IN BOTH GROUPS OF ANIMALS (<1%), THERE WAS APPROXIMATELY 50% INCREASE IN 5-MC IN RESPONSE TO CHRONIC ISCHEMIA. THIS SUGGESTS ACUTE HYPOXIA AND CHRONIC ISCHEMIA INDUCE DIFFERENTIAL GLOBAL CHANGES IN HISTONE ACETYLATION IN THE PLACENTA AND THAT CHRONICALLY ALTERED METABOLIC PROFILES COULD AFFECT HISTONE ACETYLATION IN THE PLACENTA, THEREBY REGULATING PRODUCTION OF PATHOGENIC FACTORS FROM THE PLACENTA DURING PREECLAMPSIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13 1823  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14 1609  31 DNA METHYLATION-INDEPENDENT GROWTH RESTRICTION AND ALTERED DEVELOPMENTAL PROGRAMMING IN A MOUSE MODEL OF PRECONCEPTION MALE ALCOHOL EXPOSURE. THE PRECONCEPTION ENVIRONMENT IS A SIGNIFICANT MODIFIER OF DYSGENESIS AND THE DEVELOPMENT OF ENVIRONMENTALLY-INDUCED DISEASE. TO DATE, FETAL ALCOHOL SPECTRUM DISORDERS (FASDS) HAVE BEEN EXCLUSIVELY ASSOCIATED WITH MATERNAL EXPOSURES, YET EMERGING EVIDENCE SUGGESTS MALE-INHERITED ALTERATIONS IN THE DEVELOPMENTAL PROGRAM OF SPERM MAY BE RELEVANT TO THE GROWTH-RESTRICTION PHENOTYPES OF THIS CONDITION. USING A MOUSE MODEL OF VOLUNTARY CONSUMPTION, WE FIND CHRONIC PRECONCEPTION MALE ETHANOL EXPOSURE ASSOCIATES WITH FETAL GROWTH RESTRICTION, DECREASED PLACENTAL EFFICIENCY, ABNORMALITIES IN CHOLESTEROL TRAFFICKING, SEX-SPECIFIC ALTERATIONS IN THE GENETIC PATHWAYS REGULATING HEPATIC FIBROSIS, AND DISRUPTIONS IN THE REGULATION OF IMPRINTED GENES. ALTERATIONS IN THE DNA METHYLATION PROFILES OF IMPRINTED LOCI HAVE BEEN IDENTIFIED IN CLINICAL STUDIES OF ALCOHOLIC SPERM, SUGGESTING THE LEGACY OF PATERNAL DRINKING MAY TRANSMIT VIA HERITABLE DISRUPTIONS IN THE REGULATION OF IMPRINTED GENES. HOWEVER, THE CAPACITY OF SPERM-INHERITED CHANGES IN DNA METHYLATION TO BROADLY TRANSMIT ENVIRONMENTALLY-INDUCED PHENOTYPES REMAINS UNCONFIRMED. USING BISULPHITE MUTAGENESIS AND SECOND-GENERATION DEEP SEQUENCING, WE FIND NO EVIDENCE TO SUGGEST THAT THESE PHENOTYPES OR ANY OF THE ASSOCIATED TRANSCRIPTIONAL CHANGES ARE LINKED TO ALTERATIONS IN THE SPERM-INHERITED DNA METHYLATION PROFILE. THESE OBSERVATIONS ARE CONSISTENT WITH RECENT STUDIES EXAMINING THE MALE TRANSMISSION OF DIET-INDUCED PHENOTYPES AND EMPHASIZE THE IMPORTANCE OF EPIGENETIC MECHANISMS OF PATERNAL INHERITANCE BEYOND DNA METHYLATION. THIS STUDY CHALLENGES THE SINGULAR IMPORTANCE OF MATERNAL ALCOHOL EXPOSURES AND SUGGESTS PATERNAL ALCOHOL ABUSE IS A SIGNIFICANT, YET OVERLOOKED EPIDEMIOLOGICAL FACTOR COMPLICIT IN THE GENESIS OF ALCOHOL-INDUCED GROWTH DEFECTS, AND MAY PROVIDE MECHANISTIC INSIGHT INTO THE FAILURE OF FASD CHILDREN TO THRIVE POSTNATALLY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15 1503  42 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16  249  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17 5168  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18 1520  46 DNA METHYLATION AT DIFFERENTIALLY METHYLATED REGIONS OF IMPRINTED GENES IS RESISTANT TO DEVELOPMENTAL PROGRAMMING BY MATERNAL NUTRITION. THE NUTRITIONAL ENVIRONMENT IN WHICH THE MAMMALIAN FETUS OR INFANT DEVELOP IS RECOGNIZED AS INFLUENCING THE RISK OF CHRONIC DISEASES, SUCH AS TYPE 2 DIABETES AND HYPERTENSION, IN A PHENOMENON THAT HAS BECOME KNOWN AS DEVELOPMENTAL PROGRAMMING. THE LATE ONSET OF SUCH DISEASES IN RESPONSE TO EARLIER TRANSIENT EXPERIENCES HAS LED TO THE SUGGESTION THAT DEVELOPMENTAL PROGRAMMING MAY HAVE AN EPIGENETIC COMPONENT, BECAUSE EPIGENETIC MARKS SUCH AS DNA METHYLATION OR HISTONE TAIL MODIFICATIONS COULD PROVIDE A PERSISTENT MEMORY OF EARLIER NUTRITIONAL STATES. ONE CLASS OF GENES THAT HAS BEEN CONSIDERED A POTENTIAL TARGET OR MEDIATOR OF PROGRAMMING EVENTS IS IMPRINTED GENES, BECAUSE THESE GENES CRITICALLY DEPEND UPON EPIGENETIC MODIFICATIONS FOR CORRECT EXPRESSION AND BECAUSE MANY IMPRINTED GENES HAVE ROLES IN CONTROLLING FETAL GROWTH AS WELL AS NEONATAL AND ADULT METABOLISM. IN THIS STUDY, WE HAVE USED AN ESTABLISHED MODEL OF DEVELOPMENTAL PROGRAMMING-ISOCALORIC PROTEIN RESTRICTION TO FEMALE MICE DURING GESTATION OR LACTATION-TO EXAMINE WHETHER THERE ARE EFFECTS ON EXPRESSION AND DNA METHYLATION OF IMPRINTED GENES IN THE OFFSPRING. WE FIND THAT ALTHOUGH EXPRESSION OF SOME IMPRINTED GENES IN LIVER OF OFFSPRING IS ROBUSTLY AND SUSTAINABLY CHANGED, METHYLATION OF THE DIFFERENTIALLY METHYLATED REGIONS (DMRS) THAT CONTROL THEIR MONOALLELIC EXPRESSION REMAINS LARGELY UNALTERED. WE CONCLUDE THAT DEREGULATION OF IMPRINTING THROUGH A GENERAL EFFECT ON DMR METHYLATION IS UNLIKELY TO BE A COMMON FACTOR IN DEVELOPMENTAL PROGRAMMING.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19 5192  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20 5397  30 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