1 6558 148 TRANSGENERATIONAL EPIGENETIC PROGRAMMING VIA SPERM MICRORNA RECAPITULATES EFFECTS OF PATERNAL STRESS. EPIGENETIC SIGNATURES IN GERM CELLS, CAPABLE OF BOTH RESPONDING TO THE PARENTAL ENVIRONMENT AND SHAPING OFFSPRING NEURODEVELOPMENT, ARE UNIQUELY POSITIONED TO MEDIATE TRANSGENERATIONAL OUTCOMES. HOWEVER, MOLECULAR MECHANISMS BY WHICH THESE MARKS MAY COMMUNICATE EXPERIENCE-DEPENDENT INFORMATION ACROSS GENERATIONS ARE CURRENTLY UNKNOWN. IN OUR MODEL OF CHRONIC PATERNAL STRESS, WE PREVIOUSLY IDENTIFIED NINE MICRORNAS (MIRS) THAT WERE INCREASED IN THE SPERM OF STRESSED SIRES AND ASSOCIATED WITH REDUCED HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) STRESS AXIS REACTIVITY IN OFFSPRING. IN THE CURRENT STUDY, WE RIGOROUSLY EXAMINE THE HYPOTHESIS THAT THESE SPERM MIRS FUNCTION POSTFERTILIZATION TO ALTER OFFSPRING STRESS RESPONSIVITY AND, USING ZYGOTE MICROINJECTION OF THE NINE SPECIFIC MIRS, DEMONSTRATED A REMARKABLE RECAPITULATION OF THE OFFSPRING STRESS DYSREGULATION PHENOTYPE. FURTHER, WE ASSOCIATED LONG-TERM REPROGRAMMING OF THE HYPOTHALAMIC TRANSCRIPTOME WITH HPA AXIS DYSFUNCTION, NOTING A MARKED DECREASED IN THE EXPRESSION OF EXTRACELLULAR MATRIX AND COLLAGEN GENE SETS THAT MAY REFLECT AN UNDERLYING CHANGE IN BLOOD-BRAIN BARRIER PERMEABILITY. WE CONCLUDE BY INVESTIGATING THE DEVELOPMENTAL IMPACT OF SPERM MIRS IN EARLY ZYGOTES WITH SINGLE-CELL AMPLIFICATION TECHNOLOGY, IDENTIFYING THE TARGETED DEGRADATION OF STORED MATERNAL MRNA TRANSCRIPTS INCLUDING SIRTUIN 1 AND UBIQUITIN PROTEIN LIGASE E3A, TWO GENES WITH ESTABLISHED FUNCTION IN CHROMATIN REMODELING, AND THIS POTENT REGULATORY FUNCTION OF MIRS POSTFERTILIZATION LIKELY INITIATES A CASCADE OF MOLECULAR EVENTS THAT EVENTUALLY ALTERS STRESS REACTIVITY. OVERALL, THESE FINDINGS DEMONSTRATE A CLEAR MECHANISTIC ROLE FOR SPERM MIRS IN THE TRANSGENERATIONAL TRANSMISSION OF PATERNAL LIFETIME EXPERIENCES. 2015 2 5774 46 SPERM TRANSCRIPTIONAL STATE ASSOCIATED WITH PATERNAL TRANSMISSION OF STRESS PHENOTYPES. PATERNAL STRESS CAN INDUCE LONG-LASTING CHANGES IN GERM CELLS POTENTIALLY PROPAGATING HERITABLE CHANGES ACROSS GENERATIONS. TO DATE, NO STUDIES HAVE INVESTIGATED DIFFERENCES IN TRANSMISSION PATTERNS BETWEEN STRESS-RESILIENT AND -SUSCEPTIBLE MICE. WE TESTED THE HYPOTHESIS THAT TRANSCRIPTIONAL ALTERATIONS IN SPERM DURING CHRONIC SOCIAL DEFEAT STRESS (CSDS) TRANSMIT INCREASED SUSCEPTIBILITY TO STRESS PHENOTYPES TO THE NEXT GENERATION. WE DEMONSTRATE DIFFERENCES IN OFFSPRING FROM STRESSED FATHERS THAT DEPEND UPON PATERNAL CATEGORY (RESILIENT VS SUSCEPTIBLE) AND OFFSPRING SEX. IMPORTANTLY, ARTIFICIAL INSEMINATION REVEALS THAT SPERM MEDIATES SOME OF THE BEHAVIORAL PHENOTYPES SEEN IN OFFSPRING. USING RNA-SEQUENCING WE REPORT SUBSTANTIAL AND DISTINCT CHANGES IN THE TRANSCRIPTOMIC PROFILES OF SPERM FOLLOWING CSDS IN SUSCEPTIBLE VS RESILIENT FATHERS, WITH ALTERATIONS IN LONG NONCODING RNAS (LNCRNAS) PREDOMINATING ESPECIALLY IN SUSCEPTIBILITY. CORRELATION ANALYSIS REVEALED THAT THESE ALTERATIONS WERE ACCOMPANIED BY A LOSS OF REGULATION OF PROTEIN-CODING GENES BY LNCRNAS IN SPERM OF SUSCEPTIBLE MALES. WE ALSO IDENTIFY SEVERAL CO-EXPRESSION GENE MODULES THAT ARE ENRICHED IN DIFFERENTIALLY EXPRESSED GENES IN SPERM FROM EITHER RESILIENT OR SUSCEPTIBLE FATHERS. TAKEN TOGETHER, THESE STUDIES ADVANCE OUR UNDERSTANDING OF INTERGENERATIONAL EPIGENETIC TRANSMISSION OF BEHAVIORAL EXPERIENCE.SIGNIFICANCE STATEMENTTHIS MANUSCRIPT CONTRIBUTES TO THE COMPLEX FACTORS THAT INFLUENCE THE PATERNAL TRANSMISSION OF STRESS PHENOTYPES. BY LEVERAGING THE SEGREGATION OF MALES EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS INTO EITHER RESILIENT OR SUSCEPTIBLE CATEGORIES WE WERE ABLE TO IDENTIFY THE PHENOTYPIC DIFFERENCES IN THE PATERNAL TRANSMISSION OF STRESS PHENOTYPES ACROSS GENERATIONS BETWEEN THE TWO LINEAGES. IMPORTANTLY, THIS WORK ALSO ALLUDES TO THE SIGNIFICANCE OF BOTH LONG NONCODING RNAS AND PROTEIN CODING GENES MEDIATING THE PATERNAL TRANSMISSION OF STRESS. THE KNOWLEDGE GAINED FROM THESE DATA IS OF PARTICULAR INTEREST IN UNDERSTANDING THE RISK FOR THE DEVELOPMENT OF PSYCHIATRIC DISORDERS SUCH AS ANXIETY AND DEPRESSION. 2021 3 4948 61 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 4 2472 38 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 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 6 1981 36 EPIGENETIC ALTERATIONS IN DNA AND HISTONE MODIFICATIONS CAUSED BY DEPRESSION AND ANTIDEPRESSANT DRUGS: LESSONS FROM THE RODENT MODELS. EPIGENETIC MODIFICATIONS REGULATE CHROMATIN FOLDING AND FUNCTION. EPIGENETIC MECHANISMS REGULATE TRANSCRIPTION MEDIATING EFFECTS OF VARIOUS STIMULI ON GENE EXPRESSION. THESE MECHANISMS ARE INVOLVED IN TRANSCRIPTIONAL CONTROL IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS INCLUDING NEUROPSYCHIATRIC DISORDERS AND BEHAVIORAL ABNORMALITIES SUCH AS DEPRESSION. IN RODENTS, EXPOSURE TO CHRONIC SOCIAL STRESS WAS SHOWN TO INDUCE BEHAVIORAL IMPAIRMENTS AND MEMORY/LEARNING DEFICITS THAT RESEMBLE DEPRESSIVE-LIKE PHENOTYPE IN HUMANS. THE RODENT MODELS OF CHRONIC STRESS WERE WIDELY USED TO STUDY MOLECULAR MECHANISMS OF DEPRESSION. IN THESE MODELS, EARLY EXPOSURE TO CHRONIC STRESS SUCH AS PRENATAL OR POSTNATAL STRESS INDUCES LONG-TERM HYPERACTIVE STRESS RESPONSES, BEHAVIORAL ABNORMALITIES, AND FUNCTIONAL IMPAIRMENTS IN BRAIN FUNCTION THAT PERSIST IN ADULTHOOD. FURTHERMORE, THESE ALTERATIONS CAN BE TRANSMITTED TO OFFSPRING OF CHRONICALLY STRESSED ANIMALS ACROSS SEVERAL GENERATIONS. MOLECULAR STUDIES IN ANIMAL MODELS SHOWED THAT CHRONIC STRESS INDUCES STABLE EPIGENETIC CHANGES IN SPECIFIC BRAIN REGIONS, PRIMARILY IN THE LIMBIC SYSTEM. THESE CHANGES LEAD TO LONG-LASTING ABNORMALITIES IN BEHAVIOR THAT PERSIST IN ADULTHOOD AND CAN BE TRANSMITTED TO OFFSPRING. TREATMENT WITH EPIGENETICALLY ACTIVE ANTIDEPRESSANTS DISRUPTS THE ABNORMAL STRESS-INDUCED EPIGENETIC PROGRAMMING AND PROVIDES EPIGENETIC PATTERNS THAT RESEMBLE EPIGENETIC BACKGROUND OF STRESS RESILIENT INDIVIDUALS. 2017 7 997 29 CHRONIC STRESS-DRIVEN GLUCOCORTICOID RECEPTOR ACTIVATION PROGRAMS KEY CELL PHENOTYPES AND FUNCTIONAL EPIGENOMIC PATTERNS IN HUMAN FIBROBLASTS. CHRONIC ENVIRONMENTAL STRESS CAN PROFOUNDLY IMPACT CELL AND BODY FUNCTION. ALTHOUGH THE UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD, EPIGENETICS HAS EMERGED AS A KEY LINK BETWEEN ENVIRONMENT AND HEALTH. THE GENOMIC EFFECTS OF STRESS ARE THOUGHT TO BE MEDIATED BY THE ACTION OF GLUCOCORTICOID STRESS HORMONES, PRIMARILY CORTISOL IN HUMANS, WHICH ACT VIA THE GLUCOCORTICOID RECEPTOR (GR). TO DISSECT HOW CHRONIC STRESS-DRIVEN GR ACTIVATION INFLUENCES EPIGENETIC AND CELL STATES, HUMAN FIBROBLASTS UNDERWENT PROLONGED EXPOSURE TO PHYSIOLOGICAL STRESS LEVELS OF CORTISOL AND/OR A SELECTIVE GR ANTAGONIST. CORTISOL WAS FOUND TO DRIVE ROBUST CHANGES IN CELL PROLIFERATION, MIGRATION, AND MORPHOLOGY, WHICH WERE ABROGATED BY CONCOMITANT GR BLOCKADE. THE GR-DRIVEN CELL PHENOTYPES WERE ACCOMPANIED BY WIDESPREAD, YET GENOMIC CONTEXT-DEPENDENT, CHANGES IN DNA METHYLATION AND MRNA EXPRESSION, INCLUDING GENE LOCI WITH KNOWN ROLES IN CELL PROLIFERATION AND MIGRATION. THESE FINDINGS PROVIDE INSIGHTS INTO HOW CHRONIC STRESS-DRIVEN FUNCTIONAL EPIGENOMIC PATTERNS BECOME ESTABLISHED TO SHAPE KEY CELL PHENOTYPES. 2022 8 4942 30 PATERNAL OBESITY: HOW BAD IS IT FOR SPERM QUALITY AND PROGENY HEALTH? THERE IS SUBSTANTIAL EVIDENCE THAT PATERNAL OBESITY IS ASSOCIATED NOT ONLY WITH AN INCREASED INCIDENCE OF INFERTILITY, BUT ALSO WITH AN INCREASED RISK OF METABOLIC DISTURBANCE IN ADULT OFFSPRING. APPARENTLY, SEVERAL MECHANISMS MAY CONTRIBUTE TO THE SPERM QUALITY ALTERATIONS ASSOCIATED WITH PATERNAL OBESITY, SUCH AS PHYSIOLOGICAL/HORMONAL ALTERATIONS, OXIDATIVE STRESS, AND EPIGENETIC ALTERATIONS. ALONG THESE LINES, MODIFICATIONS OF HORMONAL PROFILES NAMELY REDUCED ANDROGEN LEVELS AND ELEVATED ESTROGEN LEVELS, WERE FOUND ASSOCIATED WITH LOWER SPERM CONCENTRATION AND SEMINAL VOLUME. ADDITIONALLY, OXIDATIVE STRESS IN TESTIS MAY INDUCE AN INCREASE OF THE PERCENTAGE OF SPERM WITH DNA FRAGMENTATION. THE LATTER, RELATE TO OTHER PECULIARITIES SUCH AS ALTERATION OF THE EMBRYONIC DEVELOPMENT, INCREASED RISK OF MISCARRIAGE, AND DEVELOPMENT OF CHRONIC MORBIDITY IN THE OFFSPRING, INCLUDING CHILDHOOD CANCERS. UNDOUBTEDLY, EPIGENETIC ALTERATIONS (IE, DNA METHYLATION, CHROMATIN MODIFICATIONS, AND SMALL RNA DEREGULATION) OF SPERM RELATED TO PATERNAL OBESITY AND THEIR CONSEQUENCES ON THE PROGENY ARE POORLY UNDERSTOOD DETERMINANTS OF PATERNAL OBESITY-INDUCED TRANSMISSION. IN THIS REVIEW, WE SUMMARIZE AND DISCUSS THE DATA AVAILABLE IN THE LITERATURE REGARDING THE BIOLOGICAL, PHYSIOLOGICAL, AND MOLECULAR CONSEQUENCES OF PATERNAL OBESITY ON MALE FERTILITY POTENTIAL AND ULTIMATELY PROGENY HEALTH. 2017 9 1520 36 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 10 2159 30 EPIGENETIC MECHANISMS IMPACTED BY CHRONIC STRESS ACROSS THE RODENT LIFESPAN. EXPOSURES TO STRESS AT ALL STAGES OF DEVELOPMENT CAN LEAD TO LONG-TERM BEHAVIOURAL EFFECTS, IN PART THROUGH CHANGES IN THE EPIGENOME. THIS REVIEW DESCRIBES RODENT RESEARCH SUGGESTING THAT STRESS IN PRENATAL, POSTNATAL, ADOLESCENT AND ADULT STAGES LEADS TO LONG-TERM CHANGES IN EPIGENETIC REGULATION IN THE BRAIN WHICH HAVE CAUSAL IMPACTS ON RODENT BEHAVIOUR. WE FOCUS ON STRESS-INDUCED EPIGENETIC CHANGES THAT HAVE BEEN LINKED TO BEHAVIOURAL DEFICITS INCLUDING POOR LEARNING AND MEMORY, AND INCREASED ANXIETY-LIKE AND DEPRESSIVE-LIKE BEHAVIOURS. INTERESTINGLY, ASPECTS OF THESE STRESS-INDUCED BEHAVIOURAL CHANGES CAN BE TRANSMITTED TO OFFSPRING ACROSS SEVERAL GENERATIONS, A PHENOMENON THAT HAS BEEN PROPOSED TO RESULT VIA EPIGENETIC MECHANISMS IN THE GERMLINE. HERE, WE ALSO DISCUSS EVIDENCE FOR THE DIFFERENTIAL IMPACT OF STRESS ON THE EPIGENOME IN MALES AND FEMALES, CONSCIOUS OF THE FACT THAT THE MAJORITY OF PUBLISHED STUDIES HAVE ONLY INVESTIGATED MALES. THIS HAS LED TO A LIMITED PICTURE OF THE EPIGENETIC IMPACT OF STRESS, HIGHLIGHTING THE NEED FOR FUTURE STUDIES TO INVESTIGATE FEMALES AS WELL AS MALES. 2022 11 6729 42 VULNERABILITY TO STROKE: IMPLICATIONS OF PERINATAL PROGRAMMING OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. CHRONIC STRESS IS CAPABLE OF EXACERBATING EACH MAJOR, MODIFIABLE, ENDOGENOUS RISK FACTOR FOR CEREBROVASCULAR AND CARDIOVASCULAR DISEASE. INDEED, EXPOSURE TO STRESS CAN INCREASE BOTH THE INCIDENCE AND SEVERITY OF STROKE, PRESUMABLY THROUGH ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. NOW THAT CHARACTERIZATION OF THE MECHANISMS UNDERLYING EPIGENETIC PROGRAMMING OF THE HPA AXIS IS WELL UNDERWAY, THERE HAS BEEN RENEWED INTEREST IN EXAMINING THE ROLE OF EARLY ENVIRONMENT ON THE EVOLUTION OF HEALTH CONDITIONS ACROSS THE ENTIRE LIFESPAN. INDEED, NEONATAL MANIPULATIONS IN RODENTS THAT REDUCE STRESS RESPONSIVITY, AND SUBSEQUENT LIFE-TIME EXPOSURE TO GLUCOCORTICOIDS, ARE ASSOCIATED WITH A REDUCTION IN THE DEVELOPMENT OF NEUROENDOCRINE, NEUROANATOMICAL, AND COGNITIVE DYSFUNCTIONS THAT TYPICALLY PROGRESS WITH AGE. ALTHOUGH IMPROVED DAY TO DAY REGULATION OF THE HPA AXIS ALSO MAY BE ACCOMPANIED BY A DECREASE IN STROKE RISK, EVIDENCE FROM RODENT STUDIES SUGGEST THAT AN ASSOCIATED COST COULD BE INCREASED SUSCEPTIBILITY TO INFLAMMATION AND NEURONAL DEATH IN THE EVENT THAT A STROKE DOES OCCUR AND THE INDIVIDUAL IS EXPOSED TO PERSISTENTLY ELEVATED CORTICOSTEROIDS. GIVEN ITS IMPORTANCE IN REGULATION OF HEALTH AND DISEASE STATES, ANY LONG-TERM MODULATION OF THE HPA AXIS IS LIKELY TO BE ASSOCIATED WITH BOTH BENEFITS AND POTENTIAL RISKS. THE GOALS OF THIS REVIEW ARTICLE ARE TO EXAMINE (1) THE CLINICAL AND EXPERIMENTAL DATA SUGGESTING THAT NEONATAL EXPERIENCES CAN SHAPE HPA AXIS REGULATION, (2) THE INFLUENCE OF STRESS AND THE HPA AXIS ON STROKE INCIDENCE AND SEVERITY, AND (3) THE POTENTIAL FOR NEONATAL PROGRAMMING OF THE HPA AXIS TO IMPACT ADULT CEREBROVASCULAR HEALTH. 2009 12 4093 32 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 13 4496 37 MORE THAN GENES: THE ADVANCED FETAL PROGRAMMING HYPOTHESIS. MANY LINES OF DATA, INITIAL EPIDEMIOLOGIC STUDIES AS WELL AS SUBSEQUENT EXTENSIVE EXPERIMENTAL STUDIES, INDICATE THAT EARLY-LIFE EVENTS PLAY A POWERFUL ROLE IN INFLUENCING LATER SUCEPTIBILITY TO CERTAIN CHRONIC DISEASES. SUCH EVENTS MIGHT BE OVER- OR UNDERNUTRITION, EXPOSURE TO ENVIRONMENTAL TOXINS, BUT ALSO CHANGES IN HORMONES, IN PARTICULAR STRESS HORMONES. TYPICALLY, THOSE EVENTS ARE TRIGGERED BY THE ENVIRONMENTAL CHALLENGES OF THE MOTHER. HOWEVER, RECENT STUDIES HAVE SHOWN THAT PATERNAL ENVIRONMENTAL OR NUTRITIONAL FACTORS AFFECT THE PHENOTYPE OF THE OFFSPRING AS WELL. THE MATERNAL AND PATERNAL ENVIRONMENTAL FACTORS ACT ON THE PHENOTYPE OF THE OFFSPRING VIA EPIGENETIC MODIFICATION OF ITS GENOME. THE ADVANCED FETAL PROGRAMMING HYPOTHESIS PROPOSES AN ADDITIONAL NON-ENVIRONMENTALLY DRIVEN MECHANISM: MATERNAL AND ALSO PATERNAL GENES MAY INFLUENCE THE MATURATING SPERM, THE OOCYTE, AND LATER THE EMBRYO/FETUS, LEADING TO THEIR EPIGENETIC ALTERATION. THUS, THE OBSERVED PHENOTYPE OF THE OFFSPRING MAY BE ALTERED BY MATERNAL/PATERNAL GENES INDEPENDENT OF THE FETAL GENOME. MEANWHILE, SEVERAL INDEPENDENT ASSOCIATION STUDIES IN HUMANS DEALING WITH METABOLIC AND NEUROLOGICAL TRAITS ALSO SUGGEST THAT MATERNAL GENES MIGHT AFFECT THE OFFSPRING PHENOTYPE INDEPENDENT OF THE TRANSMISSION OF THAT PARTICULAR GENE TO THE OFFSPRING. CONSIDERING THE IMPLICATIONS OF THIS HYPOTHESIS, SOME CONCLUSIONS DRAWN FROM TRANSGENIC OR KNOCKOUT ANIMAL MODELS AND BASED ON THE CAUSALITY BETWEEN A GENETIC ALTERATION AND A PHENOTYPE, NEED TO BE CHALLENGED. POSSIBLE IMPLICATIONS FOR THE DEVELOPMENT, DIAGNOSTIC AND THERAPY OF HUMAN GENETIC DISEASES HAVE TO BE INVESTIGATED. 2014 14 6426 43 THE TRANSGENERATIONAL TRANSMISSION OF THE PATERNAL TYPE 2 DIABETES-INDUCED SUBFERTILITY PHENOTYPE. DIABETES IS A CHRONIC METABOLIC DISORDER CHARACTERIZED BY HYPERGLYCEMIA AND ASSOCIATED WITH MANY HEALTH COMPLICATIONS DUE TO THE LONG-TERM DAMAGE AND DYSFUNCTION OF VARIOUS ORGANS. A CONSEQUENTIAL COMPLICATION OF DIABETES IN MEN IS REPRODUCTIVE DYSFUNCTION, REDUCED FERTILITY, AND POOR REPRODUCTIVE OUTCOMES. HOWEVER, THE MOLECULAR MECHANISMS RESPONSIBLE FOR DIABETIC ENVIRONMENT-INDUCED SPERM DAMAGE AND OVERALL DECREASED REPRODUCTIVE OUTCOMES ARE NOT FULLY ESTABLISHED. WE EVALUATED THE EFFECTS OF TYPE 2 DIABETES EXPOSURE ON THE REPRODUCTIVE SYSTEM AND THE REPRODUCTIVE OUTCOMES OF MALES AND THEIR MALE OFFSPRING, USING A MOUSE MODEL. WE DEMONSTRATE THAT PATERNAL EXPOSURE TO TYPE 2 DIABETES MEDIATES INTERGENERATIONAL AND TRANSGENERATIONAL EFFECTS ON THE REPRODUCTIVE HEALTH OF THE OFFSPRING, ESPECIALLY ON SPERM QUALITY, AND ON METABOLIC CHARACTERISTICS. GIVEN THE TRANSGENERATIONAL IMPAIRMENT OF REPRODUCTIVE AND METABOLIC PARAMETERS THROUGH TWO GENERATIONS, THESE CHANGES LIKELY TAKE THE FORM OF INHERITED EPIGENETIC MARKS THROUGH THE GERMLINE. OUR RESULTS EMPHASIZE THE IMPORTANCE OF IMPROVING METABOLIC HEALTH NOT ONLY IN WOMEN OF REPRODUCTIVE AGE, BUT ALSO IN POTENTIAL FATHERS, IN ORDER TO REDUCE THE NEGATIVE IMPACTS OF DIABETES ON SUBSEQUENT GENERATIONS. 2021 15 4276 35 MICROGLIA FROM OFFSPRING OF DAMS WITH ALLERGIC ASTHMA EXHIBIT EPIGENOMIC ALTERATIONS IN GENES DYSREGULATED IN AUTISM. DYSREGULATION IN IMMUNE RESPONSES DURING PREGNANCY INCREASES THE RISK OF A HAVING A CHILD WITH AN AUTISM SPECTRUM DISORDER (ASD). ASTHMA IS ONE OF THE MOST COMMON CHRONIC DISEASES AMONG PREGNANT WOMEN, AND SYMPTOMS OFTEN WORSEN DURING PREGNANCY. WE RECENTLY DEVELOPED A MOUSE MODEL OF MATERNAL ALLERGIC ASTHMA (MAA) THAT INDUCES CHANGES IN SOCIABILITY, REPETITIVE, AND PERSEVERATIVE BEHAVIORS IN THE OFFSPRING. SINCE EPIGENETIC CHANGES HELP A STATIC GENOME ADAPT TO THE MATERNAL ENVIRONMENT, ACTIVATION OF THE IMMUNE SYSTEM MAY EPIGENETICALLY ALTER FETAL MICROGLIA, THE BRAIN'S RESIDENT IMMUNE CELLS. WE THEREFORE TESTED THE HYPOTHESIS THAT EPIGENOMIC ALTERATIONS TO MICROGLIA MAY BE INVOLVED IN BEHAVIORAL ABNORMALITIES OBSERVED IN MAA OFFSPRING. WE USED THE GENOME-WIDE APPROACHES OF WHOLE GENOME BISULFITE SEQUENCING TO EXAMINE DNA METHYLATION AND RNA SEQUENCING TO EXAMINE GENE EXPRESSION IN MICROGLIA FROM JUVENILE MAA OFFSPRING. DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED FOR IMMUNE SIGNALING PATHWAYS AND IMPORTANT MICROGLIAL DEVELOPMENTAL TRANSCRIPTION FACTOR BINDING MOTIFS. DIFFERENTIAL EXPRESSION ANALYSIS IDENTIFIED GENES INVOLVED IN CONTROLLING MICROGLIAL SENSITIVITY TO THE ENVIRONMENT AND SHAPING NEURONAL CONNECTIONS IN THE DEVELOPING BRAIN. DIFFERENTIALLY EXPRESSED GENES SIGNIFICANTLY OVERLAPPED GENES WITH ALTERED EXPRESSION IN HUMAN ASD CORTEX, SUPPORTING A ROLE FOR MICROGLIA IN THE PATHOGENESIS OF ASD. 2018 16 291 31 AGING AND STRESS: PAST HYPOTHESES, PRESENT APPROACHES AND PERSPECTIVES. BRAIN AGING HAS BEEN SUGGESTED TO BE CONDITIONED BY AN EXCESSIVE GLUCOCORTIOID SECRETION LEADING TO DAMAGES ON BRAIN AREAS INVOLVED NOT ONLY IN COGNITIVE AND EMOTIONAL PROCESSES BUT ALSO IN THE CONTROL OF THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY ADRENAL AXIS. THIS REVIEW DESCRIBES SOME OF THE HYPOTHESIS THAT TRY TO EXPLAIN THE RELATION BETWEEN THE DYSREGULATION OF THE STRESS RESPONSE AND BRAIN AGING, FOCUSING ON CORTICOSTERONE BUT ALSO ON NEUROTRANSMISSION IN THE HIPPOCAMPUS, THE PREFRONTAL CORTEX AND THE AMYGDALA. MOREOVER, DIFFERENT MOLECULAR FACTORS CAN ACCOUNT FOR AN ENHANCED VULNERABILITY OF THE AGED BRAIN TO STRESS EXPOSURE, SPECIALLY FOR RESILIENCE. AMONG THEM, GOOD CANDIDATES COULD BE THOSE MECHANISMS DETERMINING THE LEVELS OF CORTICOSTERONE IN THE BRAIN, SEVERAL MOLECULES DOWNSTREAM GLUCOCORTICOID RECEPTOR ACTIVATION (IE: HEAT SHOCK PROTEINS, BAG-1) OR EVEN THE EPIGENETIC PROGRAMMING OF THE HPA AXIS IN EARLY STAGES. IN CONCLUSION, GENETIC AND ENVIRONMENTAL FACTORS (EARLY LIFE STRESS, CHRONIC STRESS DURING ADULTHOOD) CAN PRODUCE AN ENHANCED VULNERABILITY AND A REDUCED RESILIENCE OF THE BRAIN TO SUBSEQUENT STRESS EXPOSURES OR TO METABOLIC CHALLENGES LEADING, IN TURN, TO AN UNSUCCESSFUL AGING OF THE BRAIN. HOWEVER, RESULTS OBTAINED WITH THE USE OF THE ENVIRONMENTAL ENRICHMENT MODEL IN ANIMALS, ADDED TO SEVERAL RESULTS IN HUMANS ALSO DESCRIBED IN THIS REVIEW SUGGEST THAT POSITIVE ENVIRONMENTAL FACTORS (COGNITIVE-DEMANDING TASKS OR PHYSICAL EXERCISE) CAN HELP TO MAINTAIN NEURONAL PLASTICITY DURING AGING AND TO PROTECT THE BRAIN AGAINST THE DAMAGING EFFECTS OF STRESS EXPOSURE. 2011 17 904 42 CHRONIC EXPOSURE TO CADMIUM INDUCES DIFFERENTIAL METHYLATION IN MICE SPERMATOZOA. CADMIUM EXPOSURE IS UBIQUITOUS AND HAS BEEN LINKED TO DISEASES INCLUDING CANCERS AND REPRODUCTIVE DEFECTS. SINCE CADMIUM IS NONMUTAGENIC, IT IS THOUGHT TO EXERT ITS GENE DYSREGULATORY EFFECTS THROUGH EPIGENETIC REPROGRAMMING. SEVERAL STUDIES HAVE IMPLICATED GERMLINE EXPOSURE TO CADMIUM IN DEVELOPMENTAL REPROGRAMMING. HOWEVER, MOST OF THESE STUDIES HAVE FOCUSED ON MATERNAL EXPOSURE, WHILE THE IMPACT ON SPERM FERTILITY AND DISEASE SUSCEPTIBILITY HAS RECEIVED LESS ATTENTION. IN THIS STUDY, WE USED REDUCED REPRESENTATION BISULFITE SEQUENCING TO COMPREHENSIVELY INVESTIGATE THE IMPACT OF CHRONIC CADMIUM EXPOSURE ON MOUSE SPERMATOZOA DNA METHYLATION. ADULT MALE C57BL/J6 MICE WERE PROVIDED WATER WITH OR WITHOUT CADMIUM CHLORIDE FOR 9 WEEKS. SPERM, TESTES, LIVER, AND KIDNEY TISSUES WERE COLLECTED AT THE END OF THE TREATMENT PERIOD. CADMIUM EXPOSURE WAS CONFIRMED THROUGH GENE EXPRESSION ANALYSIS OF METALLOTHIONEIN-1 AND 2, 2 WELL-KNOWN CADMIUM-INDUCED GENES. ANALYSIS OF SPERM DNA METHYLATION CHANGES REVEALED 1788 DIFFERENTIALLY METHYLATED SITES PRESENT AT REGULATORY REGIONS IN SPERM OF MICE EXPOSED TO CADMIUM COMPARED WITH VEHICLE (CONTROL) MICE. FURTHERMORE, MOST OF THESE DIFFERENTIAL METHYLATION CHANGES POSITIVELY CORRELATED WITH CHANGES IN GENE EXPRESSION AT BOTH THE TRANSCRIPTION INITIATION STAGE AS WELL AS THE SPLICING LEVELS. INTERESTINGLY, THE GENES TARGETED BY CADMIUM EXPOSURE ARE INVOLVED IN SEVERAL CRITICAL DEVELOPMENTAL PROCESSES. OUR RESULTS PRESENT A COMPREHENSIVE ANALYSIS OF THE SPERM METHYLOME IN RESPONSE TO CHRONIC CADMIUM EXPOSURE. THESE DATA, THEREFORE, HIGHLIGHT A FOUNDATIONAL FRAMEWORK TO STUDY GENE EXPRESSION PATTERNS THAT MAY AFFECT FERTILITY IN THE EXPOSED INDIVIDUAL AS WELL AS THEIR OFFSPRING, THROUGH PATERNAL INHERITANCE. 2021 18 110 31 A ROLE FOR ACTIVITY-DEPENDENT EPIGENETICS IN THE DEVELOPMENT AND TREATMENT OF MAJOR DEPRESSIVE DISORDER. CHRONIC STRESSORS, DURING DEVELOPMENTAL SENSITIVE PERIODS AND BEYOND, CONTRIBUTE TO THE RISK OF DEVELOPING PSYCHIATRIC CONDITIONS, INCLUDING MAJOR DEPRESSIVE DISORDER (MDD). EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, AT KEY STRESS RESPONSE AND NEUROTROPHIN GENES, ARE INCREASINGLY IMPLICATED IN MEDIATING THIS RISK. ALTHOUGH THE EXACT MECHANISMS THROUGH WHICH STRESSFUL ENVIRONMENTAL STIMULI ALTER THE EPIGENOME ARE STILL UNCLEAR, RESEARCH FROM THE LEARNING AND MEMORY FIELDS INDICATES THAT EPIGENOMIC MARKS CAN BE ALTERED, AT LEAST IN PART, THROUGH CALCIUM-DEPENDENT SIGNALING CASCADES IN DIRECT RESPONSE TO NEURONAL ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT KEY FINDINGS FROM THE STRESS, MDD, AND LEARNING AND MEMORY FIELDS TO PROPOSE A MODEL WHERE STRESS REGULATES DOWNSTREAM CELLULAR FUNCTIONING THROUGH ACTIVITY-DEPENDENT EPIGENETIC CHANGES. FURTHERMORE, WE SUGGEST THAT BOTH TYPICAL AND NOVEL ANTIDEPRESSANT TREATMENTS MAY EXERT POSITIVE INFLUENCE THROUGH SIMILAR, ACTIVITY-DEPENDENT PATHWAYS. 2018 19 6228 30 THE LINKS BETWEEN STRESS AND DEPRESSION: PSYCHONEUROENDOCRINOLOGICAL, GENETIC, AND ENVIRONMENTAL INTERACTIONS. THE ROLE OF STRESS IN THE ORIGIN AND DEVELOPMENT OF DEPRESSION MAY BE CONCEIVED AS THE RESULT OF MULTIPLE CONVERGING FACTORS, INCLUDING THE CHRONIC EFFECT OF ENVIRONMENTAL STRESSORS AND THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES DURING CHILDHOOD, ALL OF WHICH MAY INDUCE PERSISTENT HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THESE CHANGES, INCLUDING INCREASED AVAILABILITY OF CORTICOTROPIN-RELEASING FACTOR AND CORTISOL, ARE ALSO ASSOCIATED WITH HYPERACTIVITY OF THE AMYGDALA, HYPOACTIVITY OF THE HIPPOCAMPUS, AND DECREASED SEROTONERGIC NEUROTRANSMISSION, WHICH TOGETHER RESULT IN INCREASED VULNERABILITY TO STRESS. THE ROLE OF OTHER MONOAMINERGIC NEUROTRANSMITTERS, GENETIC POLYMORPHISMS, EPIGENETIC MECHANISMS, INFLAMMATORY PROCESSES, AND ALTERED COGNITIVE PROCESSING HAS ALSO BEEN CONSIDERED IN THE DEVELOPMENT OF A COMPREHENSIVE MODEL OF THE INTERACTIONS BETWEEN DIFFERENT FACTORS OF VULNERABILITY. FURTHER UNDERSTANDING OF THE UNDERLYING MECHANISMS THAT LINK THESE FACTORS MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND PREVENTIVE STRATEGIES IN THE INTERFACE BETWEEN STRESS AND MOOD DISORDERS. 2016 20 5756 35 SOCIOECONOMIC DEPRIVATION, ADVERSE CHILDHOOD EXPERIENCES AND MEDICAL DISORDERS IN ADULTHOOD: MECHANISMS AND ASSOCIATIONS. SEVERE SOCIOECONOMIC DEPRIVATION (SED) AND ADVERSE CHILDHOOD EXPERIENCES (ACE) ARE SIGNIFICANTLY ASSOCIATED WITH THE DEVELOPMENT IN ADULTHOOD OF (I) ENHANCED INFLAMMATORY STATUS AND/OR HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSFUNCTION AND (II) NEUROLOGICAL, NEUROPROGRESSIVE, INFLAMMATORY AND AUTOIMMUNE DISEASES. THE MECHANISMS BY WHICH THESE ASSOCIATIONS TAKE PLACE ARE DETAILED. THE TWO SETS OF CONSEQUENCES ARE THEMSELVES STRONGLY ASSOCIATED, WITH THE FIRST SET LIKELY CONTRIBUTING TO THE SECOND. MECHANISMS ENABLING BIDIRECTIONAL COMMUNICATION BETWEEN THE IMMUNE SYSTEM AND THE BRAIN ARE DESCRIBED, INCLUDING COMPLEX SIGNALLING PATHWAYS FACILITATED BY FACTORS AT THE LEVEL OF IMMUNE CELLS. ALSO DETAILED ARE MECHANISMS UNDERPINNING THE ASSOCIATION BETWEEN SED, ACE AND THE GENESIS OF PERIPHERAL INFLAMMATION, INCLUDING EPIGENETIC CHANGES TO IMMUNE SYSTEM-RELATED GENE EXPRESSION. THE DURATION AND MAGNITUDE OF INFLAMMATORY RESPONSES CAN BE INFLUENCED BY GENETIC FACTORS, INCLUDING SINGLE NUCLEOTIDE POLYMORPHISMS, AND BY EPIGENETIC FACTORS, WHEREBY PRO-INFLAMMATORY CYTOKINES, REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES AND NUCLEAR FACTOR-KAPPAB AFFECT GENE DNA METHYLATION AND HISTONE ACETYLATION AND ALSO INDUCE SEVERAL MICRORNAS INCLUDING MIR-155, MIR-181B-1 AND MIR-146A. ADULT HPA AXIS ACTIVITY IS REGULATED BY (I) GENETIC FACTORS, SUCH AS GLUCOCORTICOID RECEPTOR POLYMORPHISMS; (II) EPIGENETIC FACTORS AFFECTING GLUCOCORTICOID RECEPTOR FUNCTION OR EXPRESSION, INCLUDING THE METHYLATION STATUS OF ALTERNATIVE PROMOTER REGIONS OF NR3C1 AND THE METHYLATION OF FKBP5 AND HSD11BETA2; (III) CHRONIC INFLAMMATION AND CHRONIC NITROSATIVE AND OXIDATIVE STRESS. FINALLY, IT IS SHOWN HOW SEVERE PSYCHOLOGICAL STRESS ADVERSELY AFFECTS MITOCHONDRIAL STRUCTURE AND FUNCTIONING AND IS ASSOCIATED WITH CHANGES IN BRAIN MITOCHONDRIAL DNA COPY NUMBER AND TRANSCRIPTION; MITOCHONDRIA CAN ACT AS COURIERS OF CHILDHOOD STRESS INTO ADULTHOOD. 2019