1 5200 134 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES. 2016 2 668 57 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 3 4223 37 METHYLATION CHANGES AT NR3C1 IN NEWBORNS ASSOCIATE WITH MATERNAL PRENATAL STRESS EXPOSURE AND NEWBORN BIRTH WEIGHT. EARLY LIFE EXPERIENCES, INCLUDING THOSE IN UTERO, HAVE BEEN LINKED TO INCREASED RISK FOR ADULT-ONSET CHRONIC DISEASE. THE UNDERLYING ASSUMPTION IS THAT THERE IS A CRITICAL PERIOD OF DEVELOPMENTAL PLASTICITY IN UTERO WHEN SELECTION OF THE FETAL PHENOTYPE THAT IS BEST ADAPTED TO THE INTRAUTERINE ENVIRONMENT OCCURS. THE CURRENT STUDY IS THE FIRST TO TEST THE IDEA THAT EXTREME MATERNAL PSYCHOSOCIAL STRESSORS, AS OBSERVED IN THE DEMOCRATIC REPUBLIC OF CONGO, MAY MODIFY LOCUS-SPECIFIC EPIGENETIC MARKS IN THE NEWBORN RESULTING IN ALTERED HEALTH OUTCOMES. HERE WE SHOW A SIGNIFICANT CORRELATION BETWEEN CULTURALLY RELEVANT MEASURES OF MATERNAL PRENATAL STRESS, NEWBORN BIRTH WEIGHT AND NEWBORN METHYLATION IN THE PROMOTER OF THE GLUCOCORTICOID RECEPTOR NR3C1. INCREASED METHYLATION MAY CONSTRAIN PLASTICITY IN SUBSEQUENT GENE EXPRESSION AND RESTRICT THE RANGE OF STRESS ADAPTATION RESPONSES POSSIBLE IN AFFECTED INDIVIDUALS, THUS INCREASING THEIR RISK FOR ADULT-ONSET DISEASES. 2012 4 520 55 ASSOCIATIONS BETWEEN MATERNAL PRENATAL STRESS, METHYLATION CHANGES IN IGF1 AND IGF2, AND BIRTH WEIGHT. MATERNAL STRESS HAS BEEN LINKED TO LOW BIRTH WEIGHT IN NEWBORNS. ONE POTENTIAL PATHWAY INVOLVES EPIGENETIC CHANGES AT CANDIDATE GENES THAT MAY MEDIATE THE EFFECTS OF PRENATAL MATERNAL STRESS ON BIRTH WEIGHT. THIS RELATIONSHIP HAS BEEN DOCUMENTED IN STRESS-RELATED GENES, SUCH AS NR3C1. THERE IS LESS LITERATURE EXPLORING THE EFFECT OF STRESS ON GROWTH-RELATED GENES. IGF1 AND IGF2 HAVE BEEN IMPLICATED IN FETAL GROWTH AND DEVELOPMENT, THOUGH VIA DIFFERENT MECHANISMS AS IGF2 IS UNDER IMPRINTING CONTROL. IN THIS STUDY, WE TESTED FOR ASSOCIATIONS BETWEEN PRENATAL STRESS, METHYLATION OF IGF1 AND IGF2, AND BIRTH WEIGHT. A TOTAL OF 24 MOTHER-NEWBORN DYADS IN THE DEMOCRATIC REPUBLIC OF CONGO WERE ENROLLED. ETHNOGRAPHIC INTERVIEWS WERE CONDUCTED WITH MOTHERS AT DELIVERY TO GATHER CULTURALLY RELEVANT WAR-RELATED AND CHRONIC STRESSORS. DNA METHYLATION DATA WERE GENERATED FROM MATERNAL VENOUS, CORD BLOOD AND PLACENTAL TISSUE SAMPLES. MULTIVARIATE REGRESSIONS WERE USED TO TEST FOR ASSOCIATIONS BETWEEN STRESS MEASURES, DNA METHYLATION AND BIRTH WEIGHT IN EACH OF THE THREE TISSUE TYPES. WE FOUND AN ASSOCIATION BETWEEN IGF2 METHYLATION IN MATERNAL BLOOD AND BIRTH WEIGHT. PREVIOUS LITERATURE ON THE RELATIONSHIP BETWEEN IGF2 METHYLATION AND BIRTH WEIGHT HAS FOCUSED ON METHYLATION AT KNOWN DIFFERENTIALLY METHYLATED REGIONS IN CORD BLOOD OR PLACENTAL SAMPLES. OUR FINDINGS INDICATE THERE MAY BE LINKS BETWEEN THE MATERNAL EPIGENOME AND LOW BIRTH WEIGHT THAT RELY ON MECHANISMS OUTSIDE KNOWN IMPRINTING PATHWAYS. IT THUS MAY BE IMPORTANT TO CONSIDER THE EFFECT OF MATERNAL EXPOSURES AND EPIGENETIC PROFILES ON BIRTH WEIGHT EVEN IN THE SETTING OF MATERNALLY IMPRINTED GENES SUCH AS IGF2. 2018 5 3462 33 HYPOTHALAMIC NR3C1 DNA METHYLATION IN RATS EXPOSED TO PRENATAL STRESS. BACKGROUND: HUMAN AND ANIMAL STUDIES HAVE INDICATED THAT MATERNAL PRENATAL STRESS (PS) HAS MOLECULAR AND BEHAVIORAL EFFECTS DURING PREGNANCY AND EARLY LIFE. THE PRESENT STUDY AIMED TO EVALUATE THE EPIGENETIC CHANGES OF THE NR3C1 GENE INVOLVED IN THE HPA AXIS IN THE HYPOTHALAMIC TISSUES OF RATS EXPOSED TO PS INDUCED BY CHRONIC UNPREDICTABLE MILD STRESS (CUMS). BEHAVIORAL AND MOLECULAR EFFECTS OF THESE CHANGES ON THE NEXT GENERATION WERE ALSO ASSESSED. METHODS AND RESULTS: CUMS PROTOCOL WAS USED TO GENERATE STRESS IN PREGNANT WISTAR RATS. TO DETERMINE THE EFFECTS OF STRESS ON ANHEDONIA AND MOVEMENT, SUCROSE PREFERENCE TEST, FORCED SWIMMING TEST, AND OPEN FIELD TEST WERE PERFORMED. FOLLOWING THESE BEHAVIORAL EXPERIMENTS, BISULFITE SEQUENCING PCR FOR DNA METHYLATION LEVELS OF THE NR3C1 GENE, RT-QPCR FOR MRNA LEVELS, AND WESTERN BLOT TECHNIQUES FOR PROTEIN ANALYSIS WERE USED IN THE HYPOTHALAMIC TISSUE OF SACRIFICED RATS. DEPRESSION-LIKE BEHAVIORS WERE EVIDENT IN THE BEHAVIORAL TESTS OF STRESS-EXPOSED MOTHERS AND PUPS. IN PS-EXPOSED PUPS, HYPOTHALAMIC NR3C1 PROMOTER METHYLATION WAS HIGHER, AND NR3C1 MRNA LEVELS AND NR3C1 PROTEIN LEVELS WERE LOWER COMPARED WITH CONTROLS, REGARDLESS OF SEX. CONCLUSION: OUR RESULTS CONFIRM THE RELATIONSHIP BETWEEN PS AND EPIGENETIC CHANGES OF HPA AXIS-RELATED GENES AND SHOW THAT NR3C1 GENE METHYLATION STATUS IN PUPS IS SENSITIVE TO PS DURING PREGNANCY. ENVIRONMENTAL MATERNAL STRESS MAY HAVE TRANSGENERATIONAL EFFECTS THAT ARE POTENTIALLY ASSOCIATED WITH ADVERSE OUTCOMES IN THE PUPS. 2022 6 4948 36 PATERNAL STRESS EXPOSURE ALTERS SPERM MICRORNA CONTENT AND REPROGRAMS OFFSPRING HPA STRESS AXIS REGULATION. NEUROPSYCHIATRIC DISEASE FREQUENTLY PRESENTS WITH AN UNDERLYING HYPOREACTIVITY OR HYPERREACTIVITY OF THE HPA STRESS AXIS, SUGGESTING AN EXCEPTIONAL VULNERABILITY OF THIS CIRCUITRY TO EXTERNAL PERTURBATIONS. PARENTAL LIFETIME EXPOSURES TO ENVIRONMENTAL CHALLENGES ARE ASSOCIATED WITH INCREASED OFFSPRING NEUROPSYCHIATRIC DISEASE RISK, AND LIKELY CONTRIBUTE TO STRESS DYSREGULATION. WHILE MATERNAL INFLUENCES HAVE BEEN EXTENSIVELY EXAMINED, MUCH LESS IS KNOWN REGARDING THE SPECIFIC ROLE OF PATERNAL FACTORS. TO INVESTIGATE THE POTENTIAL MECHANISMS BY WHICH PATERNAL STRESS MAY CONTRIBUTE TO OFFSPRING HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSREGULATION, WE EXPOSED MICE TO 6 WEEKS OF CHRONIC STRESS BEFORE BREEDING. AS EPIDEMIOLOGICAL STUDIES SUPPORT VARIATION IN PATERNAL GERM CELL SUSCEPTIBILITY TO REPROGRAMMING ACROSS THE LIFESPAN, MALE STRESS EXPOSURE OCCURRED EITHER THROUGHOUT PUBERTY OR IN ADULTHOOD. REMARKABLY, OFFSPRING OF SIRES FROM BOTH PATERNAL STRESS GROUPS DISPLAYED SIGNIFICANTLY REDUCED HPA STRESS AXIS RESPONSIVITY. GENE SET ENRICHMENT ANALYSES IN OFFSPRING STRESS REGULATING BRAIN REGIONS, THE PARAVENTRICULAR NUCLEUS (PVN) AND THE BED NUCLEUS OF STRIA TERMINALIS, REVEALED GLOBAL PATTERN CHANGES IN TRANSCRIPTION SUGGESTIVE OF EPIGENETIC REPROGRAMMING AND CONSISTENT WITH ALTERED OFFSPRING STRESS RESPONSIVITY, INCLUDING INCREASED EXPRESSION OF GLUCOCORTICOID-RESPONSIVE GENES IN THE PVN. IN EXAMINING POTENTIAL EPIGENETIC MECHANISMS OF GERM CELL TRANSMISSION, WE FOUND ROBUST CHANGES IN SPERM MICRORNA (MIR) CONTENT, WHERE NINE SPECIFIC MIRS WERE SIGNIFICANTLY INCREASED IN BOTH PATERNAL STRESS GROUPS. OVERALL, THESE RESULTS DEMONSTRATE THAT PATERNAL EXPERIENCE ACROSS THE LIFESPAN CAN INDUCE GERM CELL EPIGENETIC REPROGRAMMING AND IMPACT OFFSPRING HPA STRESS AXIS REGULATION, AND MAY THEREFORE OFFER NOVEL INSIGHT INTO FACTORS INFLUENCING NEUROPSYCHIATRIC DISEASE RISK. 2013 7 2677 31 EVALUATING THE CHALLENGES AND REPRODUCIBILITY OF STUDIES INVESTIGATING DNA METHYLATION SIGNATURES OF PSYCHOLOGICAL STRESS. PSYCHOLOGICAL STRESS CAN INCREASE THE RISK OF A WIDE RANGE OF NEGATIVE HEALTH OUTCOMES. STUDIES HAVE BEEN COMPLETED TO DETERMINE IF DNA METHYLATION CHANGES OCCUR IN THE HUMAN BRAIN BECAUSE OF STRESS AND ARE ASSOCIATED WITH LONG-TERM EFFECTS AND DISEASE, BUT RESULTS HAVE BEEN INCONSISTENT. HUMAN CANDIDATE GENE STUDIES (150) AND EPIGENOME-WIDE ASSOCIATION STUDIES (67) WERE SYSTEMATICALLY EVALUATED TO ASSESS HOW DNA METHYLATION IS IMPACTED BY STRESS DURING THE PRENATAL PERIOD, EARLY CHILDHOOD AND ADULTHOOD. THE ASSOCIATION BETWEEN DNA METHYLATION OF NR3C1 EXON 1F AND CHILD MALTREATMENT AND EARLY LIFE ADVERSITY WAS WELL DEMONSTRATED, BUT OTHER GENES DID NOT EXHIBIT A CLEAR ASSOCIATION. THE REPRODUCIBILITY OF INDIVIDUAL CPG SITES IN EPIGENOME-WIDE ASSOCIATION STUDIES WAS ALSO POOR. HOWEVER, BIOLOGICAL PATHWAYS, INCLUDING STRESS RESPONSE, BRAIN DEVELOPMENT AND IMMUNITY, HAVE BEEN CONSISTENTLY IDENTIFIED ACROSS DIFFERENT STRESSORS THROUGHOUT THE LIFE SPAN. FUTURE STUDIES WOULD BENEFIT FROM THE INCREASED SAMPLE SIZE, LONGITUDINAL DESIGN, STANDARDIZED METHODOLOGY, OPTIMAL QUALITY CONTROL, AND IMPROVED STATISTICAL PROCEDURES. 2022 8 5192 40 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 9 2472 32 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 10 3973 29 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES. 2008 11 4064 38 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 12 5397 28 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 13 1563 40 DNA METHYLATION OF METHYLATION COMPLEX GENES IN RELATION TO STRESS AND GENOME-WIDE METHYLATION IN MOTHER-NEWBORN DYADS. OBJECTIVES: EARLY LIFE STRESS IS KNOWN TO HAVE ENDURING BIOLOGICAL EFFECTS, PARTICULARLY WITH RESPECT TO HEALTH. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, ARE A POSSIBLE MECHANISM TO MEDIATE THE BIOLOGICAL EFFECT OF STRESS. WE PREVIOUSLY FOUND CORRELATIONS BETWEEN MATERNAL STRESS, NEWBORN BIRTHWEIGHT, AND GENOME-WIDE MEASURES OF DNA METHYLATION. HERE WE INVESTIGATE TEN GENES RELATED TO THE METHYLATION/DEMETHYLATION COMPLEX IN ORDER TO BETTER UNDERSTAND THE IMPACT OF STRESS ON HEALTH. MATERIALS AND METHODS: DNA METHYLATION AND GENETIC VARIANTS AT METHYLATION/DEMETHYLATION GENES WERE ASSAYED. MEAN METHYLATION MEASURES WERE CONSTRUCTED FOR EACH GENE AND TESTED, IN ADDITION TO GENETIC VARIANTS, FOR ASSOCIATION WITH MATERNAL STRESS MEASURES BASED ON INTERVIEW AND SURVEY DATA (CHRONIC STRESS AND WAR TRAUMA), MATERNAL VENOUS, AND NEWBORN CORD GENOME-WIDE MEAN METHYLATION (GMM), AND BIRTHWEIGHT. RESULTS: AFTER CELL TYPE CORRECTION, WE FOUND MULTIPLE PAIRWISE ASSOCIATIONS BETWEEN WAR TRAUMA, MATERNAL GMM, MATERNAL METHYLATION AT DNMT1, DNMT3A, TET3, AND MBD2, AND BIRTHWEIGHT. CONCLUSIONS: THE ASSOCIATION OF MATERNAL GMM AND MATERNAL METHYLATION AT DNMT1, DNMT3A, TET3, AND MBD2 IS CONSISTENT WITH THE ROLE OF THESE GENES IN ESTABLISHING, MAINTAINING AND ALTERING GENOME-WIDE METHYLATION PATTERNS, IN SOME CASES IN RESPONSE TO STRESS. DNMT1 PRODUCES ONE OF THE PRIMARY ENZYMES THAT REPRODUCES METHYLATION PATTERNS DURING DNA REPLICATION. DNMT3A AND TET3 HAVE BEEN IMPLICATED IN GENOME-WIDE HYPOMETHYLATION IN RESPONSE TO GLUCOCORTICOID HORMONES. ALTHOUGH WE CANNOT DETERMINE THE DIRECTIONALITY OF THE GENIC AND GENOME-WIDE CHANGES IN METHYLATION, OUR RESULTS SUGGEST THAT ALTERED METHYLATION OF SPECIFIC METHYLATION GENES MAY BE PART OF THE MOLECULAR MECHANISM UNDERLYING THE HUMAN BIOLOGICAL RESPONSE TO STRESS. 2018 14 2021 38 EPIGENETIC CHANGES ASSOCIATED WITH DIFFERENT TYPES OF STRESSORS AND SUICIDE. STRESS IS ASSOCIATED WITH VARIOUS EPIGENETIC CHANGES. SOME STRESS-INDUCED EPIGENETIC CHANGES ARE HIGHLY DYNAMIC, WHEREAS OTHERS ARE ASSOCIATED WITH LASTING MARKS ON THE EPIGENOME. IN OUR STUDY, A COMPREHENSIVE NARRATIVE REVIEW OF THE LITERATURE WAS PERFORMED BY INVESTIGATING THE EPIGENETIC CHANGES THAT OCCUR WITH ACUTE STRESS, CHRONIC STRESS, EARLY CHILDHOOD STRESS, AND TRAUMATIC STRESS EXPOSURES, ALONG WITH EXAMINING THOSE OBSERVED IN POST-MORTEM BRAINS OR BLOOD SAMPLES OF SUICIDE COMPLETERS AND ATTEMPTERS. IN ADDITION, THE TRANSGENERATIONAL EFFECTS OF THESE CHANGES ARE REPORTED. FOR ALL TYPES OF STRESS STUDIES EXAMINED, THE GENES NR3C1, OXTR, SLC6A4, AND BDNF REPRODUCIBLY SHOWED EPIGENETIC CHANGES, WITH SOME MODIFICATIONS OBSERVED TO BE PASSED DOWN TO SUBSEQUENT GENERATIONS FOLLOWING STRESS EXPOSURES. THE AFOREMENTIONED GENES ARE KNOWN TO BE INVOLVED IN NEURONAL DEVELOPMENT AND HORMONAL REGULATION AND ARE ALL ASSOCIATED WITH SUSCEPTIBILITY TO MENTAL HEALTH DISORDERS INCLUDING DEPRESSION, ANXIETY, PERSONALITY DISORDERS, AND PTSD (POST-TRAUMATIC STRESS DISORDER). FURTHER RESEARCH IS WARRANTED IN ORDER TO DETERMINE THE SCOPE OF EPIGENETIC ACTIONABLE TARGETS IN INDIVIDUALS SUFFERING FROM THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES. 2023 15 6315 36 THE RELATIONSHIP OF MATERNAL AND CHILD METHYLATION OF THE GLUCOCORTICOID RECEPTOR NR3C1 DURING EARLY CHILDHOOD AND SUBSEQUENT CHILD PSYCHOPATHOLOGY AT SCHOOL-AGE IN THE CONTEXT OF MATERNAL INTERPERSONAL VIOLENCE-RELATED POST-TRAUMATIC STRESS DISORDER. INTRODUCTION: INTERPERSONAL VIOLENT (IPV) EXPERIENCES WHEN THEY BEGIN IN CHILDHOOD AND CONTINUE IN VARIOUS FORMS DURING ADULTHOOD OFTEN LEAD TO CHRONIC POST-TRAUMATIC STRESS DISORDER (PTSD) THAT IS ASSOCIATED IN MULTIPLE STUDIES WITH HYPOCORTISOLISM AND LOWER PERCENTAGE OF METHYLATION OF THE PROMOTER REGION OF THE GENE CODING FOR THE GLUCOCORTICOID RECEPTOR (NR3C1). THIS PROSPECTIVE, LONGITUDINAL STUDY EXAMINED THE RELATIONSHIP OF NR3C1 METHYLATION AMONG MOTHERS WITH IPV-RELATED PTSD AND THEIR TODDLERS AND THEN LOOKED AT THE RELATIONSHIP OF MATERNAL NR3C1 METHYLATION AND CHILD PSYCHOPATHOLOGY AT SCHOOL AGE. METHODS: FORTY-EIGHT MOTHERS WERE EVALUATED FOR LIFE-EVENTS HISTORY AND POST-TRAUMATIC STRESS DISORDER VIA STRUCTURED CLINICAL INTERVIEW WHEN THEIR CHILDREN WERE AGES 12-42 MONTHS (MEAN AGE 26.7 MONTHS, SD 8.8). THEIR CHILDREN'S PSYCHOPATHOLOGY IN TERMS OF INTERNALIZING SYMPTOMS AND EXTERNALIZING BEHAVIORS WAS EVALUATED USING THE CHILD BEHAVIOR CHECKLIST AT AGES 5-9 YEARS (MEAN AGE 7 YEARS, SD 1.1). PERCENTAGE OF METHYLATION FOR THE NR3C1 GENE PROMOTER REGION WAS ASSESSED FROM DNA EXTRACTED FROM MATERNAL AND CHILD SALIVA USING BISULFITE PYROSEQUENCING. DATA ANALYSIS INVOLVED PARAMETRIC AND NON-PARAMETRIC CORRELATIONS AND MULTIPLE LINEAR AND LOGISTIC REGRESSION MODELING. RESULTS: LOGISTIC REGRESSION MODELS USING CHILD NR3C1 METHYLATION AS THE DEPENDENT VARIABLE AND MATERNAL NR3C1 METHYLATION AND PTSD GROUP STATUS AS PREDICTORS, AS WELL AS THE INTERACTION INDICATED THAT ALL THREE OF THESE SIGNIFICANTLY PREDICTED CHILD NR3C1 METHYLATION. THESE FINDINGS REMAINED SIGNIFICANT WHEN CONTROLLING FOR CHILD AGE, SEX AND MATERNAL CHILD ABUSE HISTORY. OVERALL, MATERNAL NR3C1 METHYLATION WHEN CHILDREN WERE TODDLERS WAS NEGATIVELY AND SIGNIFICANTLY ASSOCIATED WITH CHILD EXTERNALIZING BEHAVIOR SEVERITY AT SCHOOL AGE. DISCUSSION: WE FOUND THAT CORRELATIONS BETWEEN MOTHERS AND THEIR CHILDREN OF NR3C1 METHYLATION LEVELS OVERALL AND AT ALL INDIVIDUAL CPG SITES OF INTEREST WERE SIGNIFICANT ONLY IN THE IPV-PTSD GROUP. THE LATTER FINDINGS SUPPORT THAT NR3C1 METHYLATION IN MOTHERS POSITIVELY AND STATISTICALLY SIGNIFICANTLY CORRELATES WITH NR3C1 METHYLATION IN THEIR CHILDREN ONLY IN PRESENCE OF IPV-PTSD IN THE MOTHERS. THIS MATERNAL EPIGENETIC SIGNATURE WITH RESPECT TO THIS GLUCOCORTICOID RECEPTOR IS SIGNIFICANTLY ASSOCIATED WITH CHILD BEHAVIOR THAT MAY WELL POSE A RISK FOR INTERGENERATIONAL TRANSMISSION OF VIOLENCE AND RELATED PSYCHOPATHOLOGY. 2022 16 5166 32 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 17 5160 34 PREADOLESCENT ADVERSITY PROGRAMS A DISRUPTED MATERNAL STRESS REACTIVITY IN HUMANS AND MICE. BACKGROUND: ADVERSE CHILDHOOD EXPERIENCES (ACES) ARE ONE OF THE GREATEST PREDICTORS OF AFFECTIVE DISORDERS FOR WOMEN. PERIODS OF DYNAMIC HORMONAL FLUX, INCLUDING PREGNANCY, EXACERBATE THE RISK FOR AFFECTIVE DISTURBANCE AND PROMOTE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSREGULATION, A KEY FEATURE OF AFFECTIVE DISORDERS. LITTLE IS UNDERSTOOD AS TO HOW STRESS EXPERIENCED IN LATE CHILDHOOD, DEFINED AS PREADOLESCENCE, ALTERS THE PROGRAMMING UNIQUE TO THIS PERIOD OF BRAIN MATURATION AND ITS INTERACTION WITH THE HORMONAL CHANGES OF PREGNANCY AND POSTPARTUM. METHODS: PREADOLESCENT FEMALE MICE WERE EXPOSED TO CHRONIC STRESS AND EXAMINED FOR CHANGES IN THEIR HPA AXIS DURING PREGNANCY AND POSTPARTUM, INCLUDING ASSESSMENT OF MATERNAL-SPECIFIC STRESS RESPONSIVENESS AND TRANSCRIPTOMICS OF THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS. TRANSLATIONALLY, PREGNANT WOMEN WITH LOW OR HIGH ACES WERE EXAMINED FOR THEIR MATERNAL STRESS RESPONSIVENESS. RESULTS: AS PREDICTED, PREADOLESCENT STRESS IN MICE RESULTED IN A SIGNIFICANT BLUNTING OF THE CORTICOSTERONE RESPONSE DURING PREGNANCY. TRANSCRIPTOMIC ANALYSIS OF THE PARAVENTRICULAR NUCLEUS REVEALED WIDESPREAD CHANGES IN EXPRESSION OF IMMEDIATE EARLY GENES AND THEIR TARGETS, SUPPORTING THE LIKELY INVOLVEMENT OF AN UPSTREAM EPIGENETIC MECHANISM. CRITICALLY, IN OUR HUMAN STUDIES, THE HIGH ACE WOMEN SHOWED A SIGNIFICANT BLUNTING OF THE HPA RESPONSE. CONCLUSIONS: THIS UNIQUE MOUSE MODEL RECAPITULATES A CLINICAL OUTCOME OF A HYPORESPONSIVE HPA STRESS AXIS, AN IMPORTANT FEATURE OF AFFECTIVE DISORDERS, DURING A DYNAMIC HORMONAL PERIOD, AND SUGGESTS INVOLVEMENT OF TRANSCRIPTIONAL REGULATION IN THE HYPOTHALAMUS. THESE STUDIES IDENTIFY A NOVEL MOUSE MODEL OF FEMALE ACES THAT CAN BE USED TO EXAMINE HOW ADDITIONAL LIFE ADVERSITY MAY PROVOKE DISEASE RISK OR RESILIENCE. 2017 18 5662 27 SEXUAL DIMORPHISM IN GLUCOCORTICOID STRESS RESPONSE. CHRONIC STRESS IS ENCOUNTERED IN OUR EVERYDAY LIFE AND IS THOUGHT TO CONTRIBUTE TO A NUMBER OF DISEASES. MANY OF THESE STRESS-RELATED DISORDERS DISPLAY A SEX BIAS. BECAUSE GLUCOCORTICOID HORMONES ARE THE MAIN BIOLOGICAL MEDIATOR OF CHRONIC STRESS, RESEARCHERS HAVE BEEN INTERESTED IN UNDERSTANDING THE SEXUAL DIMORPHISM IN GLUCOCORTICOID STRESS RESPONSE TO BETTER EXPLAIN THE SEX BIAS IN STRESS-RELATED DISEASES. ALTHOUGH NOT YET DEMONSTRATED FOR GLUCOCORTICOID REGULATION, SEX CHROMOSOMES DO INFLUENCE SEX-SPECIFIC BIOLOGY AS SOON AS CONCEPTION. THEN A TRANSIENT RISE IN TESTOSTERONE START TO SHAPE THE MALE BRAIN DURING THE PRENATAL PERIOD DIFFERENTLY TO THE FEMALE BRAIN. THESE ORGANIZATIONAL EFFECTS ARE COMPLETED JUST BEFORE PUBERTY. THE CEREBRAL REGIONS IMPLICATED IN GLUCOCORTICOID REGULATION AT REST AND AFTER STRESS ARE THEREBY IMPACTED IN A SEX-SPECIFIC MANNER. AFTER PUBERTY, THE HIGH LEVELS OF ALL GONADAL HORMONES WILL INTERACT WITH GLUCOCORTICOID HORMONES IN SPECIFIC CROSSTALK THROUGH THEIR RESPECTIVE NUCLEAR RECEPTORS. IN ADDITION, STRESS OCCURRING EARLY IN LIFE, IN PARTICULAR DURING THE PRENATAL PERIOD AND IN ADOLESCENCE WILL PRIME IN THE LONG-TERM GLUCOCORTICOID STRESS RESPONSE THROUGH EPIGENETIC MECHANISMS, AGAIN IN A SEX-SPECIFIC MANNER. ALTOGETHER, VARIOUS MOLECULAR MECHANISMS EXPLAIN SEX-SPECIFIC GLUCOCORTICOID STRESS RESPONSES THAT DO NOT EXCLUDE IMPORTANT GENDER EFFECTS IN HUMANS. 2021 19 886 39 CHRONIC CORTICOSTERONE EXPOSURE INCREASES EXPRESSION AND DECREASES DEOXYRIBONUCLEIC ACID METHYLATION OF FKBP5 IN MICE. THERE IS EVIDENCE FOR HYPERCORTISOLEMIA PLAYING A ROLE IN THE GENERATION OF PSYCHIATRIC SYMPTOMS AND FOR EPIGENETIC VARIATION WITHIN HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS GENES MEDIATING BEHAVIORAL CHANGES. WE TESTED THE HYPOTHESIS THAT EXPRESSION CHANGES WOULD BE INDUCED IN FKBP5 AND OTHER HPA AXIS GENES BY CHRONIC EXPOSURE TO CORTICOSTERONE AND THAT THESE CHANGES WOULD OCCUR THROUGH THE EPIGENETIC MECHANISM OF LOSS OR GAIN OF DNA METHYLATION (DNAM). WE ADMINISTERED CORTICOSTERONE (CORT) TO C57BL/6J MICE VIA THEIR DRINKING WATER FOR 4 WK AND TESTED FOR BEHAVIORAL AND PHYSIOLOGICAL CHANGES AND CHANGES IN GENE EXPRESSION LEVELS USING RNA EXTRACTED FROM HIPPOCAMPUS, HYPOTHALAMUS, AND BLOOD FOR THE FOLLOWING HPA GENES: FKBP5, NR3C1, HSP90, CRH, AND CRHR1. THE CORT MICE EXHIBITED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE TEST. CHRONIC EXPOSURE TO CORT ALSO CAUSED A SIGNIFICANT DECREASE IN THE HIPPOCAMPAL AND BLOOD MRNA LEVELS OF NR3C1 AND A DECREASE IN HSP90 IN BLOOD AND CAUSED AN INCREASE IN FKBP5 FOR ALL TISSUES. DIFFERENCES WERE SEEN IN FKBP5 METHYLATION IN HIPPOCAMPUS AND HYPOTHALAMUS. TO ISOLATE A SINGLE-CELL TYPE, WE FOLLOWED UP WITH AN HT-22 MOUSE HIPPOCAMPAL NEURONAL CELL LINE EXPOSED TO CORT. AFTER 7 D, WE OBSERVED A 2.4-FOLD INCREASE IN FKBP5 EXPRESSION AND A DECREASE IN DNAM. IN THE CORT-TREATED MICE, WE ALSO OBSERVED CHANGES IN BLOOD DNAM IN FKBP5. OUR RESULTS SUGGEST DNAM PLAYS A ROLE IN MEDIATING EFFECTS OF GLUCOCORTICOID EXPOSURE ON FKBP5 FUNCTION, WITH POTENTIAL CONSEQUENCES FOR BEHAVIOR. 2010 20 3119 32 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