1 5168 135 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 2 2472 40 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 3 5166 43 PRECONCEPTION PATERNAL ALCOHOL EXPOSURE EXERTS SEX-SPECIFIC EFFECTS ON OFFSPRING GROWTH AND LONG-TERM METABOLIC PROGRAMMING. BACKGROUND: ALTHOUGH CLINICAL DATA SUPPORT AN ASSOCIATION BETWEEN PATERNAL ALCOHOL USE AND DEFICITS IN CHILD NEUROCOGNITIVE DEVELOPMENT, THE RELATIONSHIP BETWEEN PATERNAL DRINKING AND ALCOHOL-INDUCED GROWTH PHENOTYPES REMAINS CHALLENGING TO DEFINE. USING AN ESTABLISHED MOUSE MODEL OF CHRONIC EXPOSURE, PREVIOUS WORK BY OUR GROUP HAS LINKED PRECONCEPTION PATERNAL ALCOHOL USE TO SEX-SPECIFIC PATTERNS OF FETAL GROWTH RESTRICTION AND PLACENTAL DYSFUNCTION. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE THE LONG-TERM IMPACT OF CHRONIC PRECONCEPTION PATERNAL ALCOHOL USE ON OFFSPRING GROWTH AND METABOLIC PROGRAMMING. RESULTS: PRECONCEPTION PATERNAL ALCOHOL EXPOSURE INDUCED A PROLONGED PERIOD OF FETAL GESTATION AND AN INCREASED INCIDENCE OF INTRAUTERINE GROWTH RESTRICTION, WHICH AFFECTED THE MALE OFFSPRING TO A GREATER EXTENT THAN THE FEMALES. WHILE THE FEMALE OFFSPRING OF ETHANOL-EXPOSED MALES WERE ABLE TO MATCH THE BODY WEIGHTS OF THE CONTROLS WITHIN THE FIRST 2 WEEKS OF POSTNATAL LIFE, MALE OFFSPRING CONTINUED TO DISPLAY AN 11% REDUCTION IN WEIGHT AT 5 WEEKS OF AGE AND A 6% REDUCTION AT 8 WEEKS OF AGE. THE OBSERVED GROWTH DEFICITS ASSOCIATED WITH INSULIN HYPERSENSITIVITY IN THE MALE OFFSPRING, WHILE IN CONTRAST, FEMALES DISPLAYED A MODEST LAG IN THEIR GLUCOSE TOLERANCE TEST. THESE METABOLIC DEFECTS WERE ASSOCIATED WITH AN UP-REGULATION OF GENES WITHIN THE PRO-FIBROTIC TGF-BETA SIGNALING PATHWAY AND INCREASED LEVELS OF CELLULAR HYDROXYPROLINE WITHIN THE LIVERS OF THE MALE OFFSPRING. WE OBSERVED SUPPRESSED CYTOKINE PROFILES WITHIN THE LIVER AND PANCREAS OF BOTH THE MALE AND FEMALE OFFSPRING, WHICH CORRELATED WITH THE UP-REGULATION OF GENES IN THE LIVERX/RETINOIDX/FARNESOIDX RECEPTOR PATHWAYS. HOWEVER, PATTERNS OF GENE EXPRESSION WERE HIGHLY VARIABLE BETWEEN THE OFFSPRING OF ALCOHOL-EXPOSED SIRES. IN THE ADULT OFFSPRING OF ALCOHOL-EXPOSED MALES, WE DID NOT OBSERVE ANY DIFFERENCES IN THE ALLELIC EXPRESSION OF IGF2 OR ANY OTHER IMPRINTED GENES. CONCLUSIONS: THE IMPACT OF PATERNAL ALCOHOL USE ON CHILD DEVELOPMENT IS POORLY EXPLORED AND REPRESENTS A SIGNIFICANT GAP IN OUR UNDERSTANDING OF THE TERATOGENIC EFFECTS OF ETHANOL. OUR STUDIES IMPLICATE PATERNAL EXPOSURE HISTORY AS AN ADDITIONAL AND IMPORTANT MODIFIER OF ALCOHOL-INDUCED GROWTH PHENOTYPES AND CHALLENGE THE CURRENT MATERNAL-CENTRIC EXPOSURE PARADIGM. 2019 4 3119 37 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 5 5397 36 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 2159 37 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 7 4064 37 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 8 4941 31 PATERNAL OBESITY, INTERVENTIONS, AND MECHANISTIC PATHWAYS TO IMPAIRED HEALTH IN OFFSPRING. BACKGROUND: THE GLOBAL RATES OF MALE OVERWEIGHT/OBESITY ARE RISING, APPROACHING 70% OF THE TOTAL ADULT POPULATION IN WESTERN NATIONS. OVERWEIGHT/OBESITY INCREASES THE RISK OF CHRONIC DISEASES; HOWEVER, THERE IS INCREASING AWARENESS THAT MALE OBESITY NEGATIVELY IMPACTS FERTILITY, SUBSEQUENT PREGNANCY, AND THE OFFSPRING HEALTH BURDEN. DEVELOPMENTAL PROGRAMMING IS WELL DEFINED IN MOTHERS; HOWEVER, IT IS BECOMING INCREASINGLY EVIDENT THAT DEVELOPMENTAL PROGRAMMING CAN BE PATERNALLY INITIATED AND MEDIATED THROUGH PATERNAL OBESITY. KEY MESSAGES: BOTH HUMAN AND RODENT MODELS HAVE ESTABLISHED THAT PATERNAL OBESITY IMPAIRS SEX HORMONES, BASIC SPERM FUNCTION, AND MOLECULAR COMPOSITION. THIS RESULTS IN PERTURBED EMBRYO DEVELOPMENT AND HEALTH AND AN INCREASED SUBSEQUENT OFFSPRING DISEASE BURDEN IN BOTH SEXES. THE REVERSIBILITY OF OBESITY-INDUCED PARENTAL PROGRAMMING HAS ONLY RECENTLY RECEIVED ATTENTION. PROMISING RESULTS IN ANIMAL MODELS UTILIZING DIET AND EXERCISE INTERVENTIONS HAVE SHOWN IMPROVEMENTS IN SPERM FUNCTION AND MOLECULAR COMPOSITION, RESULTING IN RESTORATIONS OF BOTH EMBRYO AND FETAL HEALTH AND SUBSEQUENT MALE OFFSPRING FERTILITY. THE DIRECT MODE FOR PATERNAL INHERITANCE IS LIKELY MEDIATED VIA SPERMATOZOA. WE PROPOSE TWO MAIN THEORIES FOR THE ORIGIN OF MALE OBESITY-INDUCED PATERNAL PROGRAMMING: (1) ACCUMULATION OF SPERM DNA DAMAGE RESULTING IN DE NOVO MUTATIONS IN THE EMBRYO AND (2) CHANGES IN SPERM EPIGENETIC MARKS (MICRORNA, METHYLATION, OR ACETYLATION) ALTERING THE ACCESS, TRANSCRIPTION, AND TRANSLATION OF PATERNALLY DERIVED GENES DURING EARLY EMBRYOGENESIS. CONCLUSIONS: PATERNAL OVERWEIGHT/OBESITY INDUCES PATERNAL PROGRAMMING OF OFFSPRING PHENOTYPES LIKELY MEDIATED THROUGH GENETIC AND EPIGENETIC CHANGES IN SPERMATOZOA. THESE PROGRAMMED CHANGES TO OFFSPRING HEALTH APPEAR TO BE PARTIALLY RESTORED VIA DIET/EXERCISE INTERVENTIONS IN OBESE FATHERS PRECONCEPTION, WHICH HAVE BEEN SHOWN TO IMPROVE ASPECTS OF SPERM DNA INTEGRITY. HOWEVER, THE MAJORITY OF DATA SURROUNDING PATERNAL OBESITY AND OFFSPRING PHENOTYPES HAVE COME FROM RODENT MODELS; THEREFORE, WE CONTEND THAT IT WILL BE INCREASINGLY IMPORTANT TO STUDY POPULATION-BASED DATA TO DETERMINE THE LIKELY MODE OF INHERITANCE IN HUMANS. 2014 9 4949 42 PATERNAL TRANSMISSION OF STRESS-INDUCED PATHOLOGIES. BACKGROUND: THERE HAS BEEN RECENT INTEREST IN THE POSSIBILITY THAT EPIGENETIC MECHANISMS MIGHT CONTRIBUTE TO THE TRANSGENERATIONAL TRANSMISSION OF STRESS-INDUCED VULNERABILITY. HERE, WE FOCUSED ON POSSIBLE PATERNAL TRANSMISSION WITH THE SOCIAL DEFEAT STRESS PARADIGM. METHODS: ADULT MALE MICE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS OR CONTROL NONDEFEATED MICE WERE BRED WITH NORMAL FEMALE MICE, AND THEIR OFFSPRING WERE ASSESSED BEHAVIORALLY FOR DEPRESSIVE- AND ANXIETY-LIKE MEASURES. PLASMA LEVELS OF CORTICOSTERONE AND VASCULAR ENDOTHELIAL GROWTH FACTOR WERE ALSO ASSAYED. TO DIRECTLY ASSESS THE ROLE OF EPIGENETIC MECHANISMS, WE USED IN VITRO FERTILIZATION (IVF); BEHAVIORAL ASSESSMENTS WERE CONDUCTED ON OFFSPRING OF MICE FROM IVF-CONTROL AND IVF-DEFEATED FATHERS. RESULTS: WE SHOW THAT BOTH MALE AND FEMALE OFFSPRING FROM DEFEATED FATHERS EXHIBIT INCREASED MEASURES OF SEVERAL DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. THE MALE OFFSPRING OF DEFEATED FATHERS ALSO DISPLAY INCREASED BASELINE PLASMA LEVELS OF CORTICOSTERONE AND DECREASED LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR. HOWEVER, MOST OF THESE BEHAVIORAL CHANGES WERE NOT OBSERVED WHEN OFFSPRING WERE GENERATED THROUGH IVF. CONCLUSIONS: THESE RESULTS SUGGEST THAT, ALTHOUGH BEHAVIORAL ADAPTATIONS THAT OCCUR AFTER CHRONIC SOCIAL DEFEAT STRESS CAN BE TRANSMITTED FROM THE FATHER TO HIS MALE AND FEMALE F1 PROGENY, ONLY VERY SUBTLE CHANGES MIGHT BE TRANSMITTED EPIGENETICALLY UNDER THE CONDITIONS TESTED. 2011 10 5774 39 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 11 4496 36 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 12 2471 33 EPIGENETIC TRANSGENERATIONAL INHERITANCE OF ALTERED STRESS RESPONSES. ANCESTRAL ENVIRONMENTAL EXPOSURES HAVE PREVIOUSLY BEEN SHOWN TO PROMOTE EPIGENETIC TRANSGENERATIONAL INHERITANCE AND INFLUENCE ALL ASPECTS OF AN INDIVIDUAL'S LIFE HISTORY. IN ADDITION, PROXIMATE LIFE EVENTS SUCH AS CHRONIC STRESS HAVE DOCUMENTED EFFECTS ON THE DEVELOPMENT OF PHYSIOLOGICAL, NEURAL, AND BEHAVIORAL PHENOTYPES IN ADULTHOOD. WE USED A SYSTEMS BIOLOGY APPROACH TO INVESTIGATE IN MALE RATS THE INTERACTION OF THE ANCESTRAL MODIFICATIONS CARRIED TRANSGENERATIONALLY IN THE GERM LINE AND THE PROXIMATE MODIFICATIONS INVOLVING CHRONIC RESTRAINT STRESS DURING ADOLESCENCE. WE FIND THAT A SINGLE EXPOSURE TO A COMMON-USE FUNGICIDE (VINCLOZOLIN) THREE GENERATIONS REMOVED ALTERS THE PHYSIOLOGY, BEHAVIOR, METABOLIC ACTIVITY, AND TRANSCRIPTOME IN DISCRETE BRAIN NUCLEI IN DESCENDANT MALES, CAUSING THEM TO RESPOND DIFFERENTLY TO CHRONIC RESTRAINT STRESS. THIS ALTERATION OF BASELINE BRAIN DEVELOPMENT PROMOTES A CHANGE IN NEURAL GENOMIC ACTIVITY THAT CORRELATES WITH CHANGES IN PHYSIOLOGY AND BEHAVIOR, REVEALING THE INTERACTION OF GENETICS, ENVIRONMENT, AND EPIGENETIC TRANSGENERATIONAL INHERITANCE IN THE SHAPING OF THE ADULT PHENOTYPE. THIS IS AN IMPORTANT DEMONSTRATION IN AN ANIMAL THAT ANCESTRAL EXPOSURE TO AN ENVIRONMENTAL COMPOUND MODIFIES HOW DESCENDANTS OF THESE PROGENITOR INDIVIDUALS PERCEIVE AND RESPOND TO A STRESS CHALLENGE EXPERIENCED DURING THEIR OWN LIFE HISTORY. 2012 13 5773 38 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 14 4942 37 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 15 1823 38 EFFECTS OF EARLY-LIFE STRESS AND HDAC INHIBITION ON MATERNAL BEHAVIOR IN MICE. DESPITE THE WELL-ESTABLISHED FACT THAT MATERNAL CARE PLAYS A PIVOTAL ROLE IN THE OFFSPRING DEVELOPMENT, LITTLE IS KNOWN ABOUT THE EFFECTS OF DISRUPTION OF MATERNAL CARE EARLY IN LIFE ON THE DEVELOPMENT OF THIS BEHAVIOR IN THE OFFSPRING. USING BRIEF REPEATED MATERNAL SEPARATION (45 MIN/DAY ON POSTNATAL DAYS 3-6), WHICH REPRESENTS A MODEL OF EARLY LIFE STRESS, WE FOUND BEHAVIORAL CHANGES IN ADULT FEMALE MICE OFFSPRING. THE DECREASE IN HOME CAGE EXPLORATORY BEHAVIOR (BOTH PUP-DIRECTED AND NONPUP-DIRECTED) WAS REVEALED LATER IN ADULTHOOD WITHOUT CHANGES IN MATERNAL CARE LEVEL. MATERNAL SEPARATION COUPLED WITH PAIN EXPOSURE CAUSED BY SUBCUTANEOUS SALINE INJECTION PROCEDURE HAD A CUMULATIVE RESULTING EFFECT, WHICH WAS MANIFESTED IN THE DECREASED LEVEL OF NURSING ASSOCIATED WITH LICKING-GROOMING IN ADULT FEMALES. THE BEHAVIORAL CHANGES FOUND IN ADULT FEMALE OFFSPRING COULD BE TRIGGERED BY IDENTIFIED CHANGES IN THE BEHAVIOR OF THEIR MOTHERS, WHILE ALTERATIONS OF THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN WERE NOT DETECTED. HISTONE DEACETYLASE INHIBITOR SODIUM VALPROATE WAS USED IN ORDER TO STUDY THE POSSIBILITY OF PREVENTING THE EFFECTS OF EARLY LIFE STRESS THROUGH INVOLVEMENT OF EPIGENETIC MECHANISMS. DESPITE THE INCREASE IN THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN CAUSED BY VALPROATE, ITS BEHAVIORAL EFFECTS WERE BARELY DETECTABLE. THESE EFFECTS WERE REFLECTED IN PREVENTION OF THE REDUCTION OF NURSING ASSOCIATED WITH LICKING-GROOMING INDUCED BY MATERNAL SEPARATION, ACCOMPANIED BY PAIN EXPOSURE. THE DATA ARE DISCUSSED IN TERMS OF THE POSSIBLE APPLICATION TO THE STUDIES OF MECHANISMS UNDERLYING LONG-TERM EFFECTS OF HUMAN EARLY LIFE TRAUMA. (PSYCINFO DATABASE RECORD (C) 2019 APA, ALL RIGHTS RESERVED). 2019 16 586 33 BEHAVIOURAL AND EPIGENETIC EFFECTS OF PATERNAL EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE ON OFFSPRING VULNERABILITY TO STRESS. CHRONIC CANNABINOID EXPOSURE DURING ADOLESCENCE IN MALE RATS INDUCES CHRONIC COGNITIVE AND EMOTIONAL IMPAIRMENTS. HOWEVER, THE IMPACT OF THIS FORM OF EXPOSURE ON OFFSPRING VULNERABILITY TO STRESS IS UNKNOWN. THE AIM OF THIS STUDY WAS TO EVALUATE THE BEHAVIOURAL AND EPIGENETIC EFFECTS OF STRESS IN THE OFFSPRING OF MALE RATS WHOSE FATHERS WERE EXPOSED TO CANNABINOIDS DURING ADOLESCENCE. MALE ADOLESCENT OFFSPRING OF WIN55,212-2 (1.2 MG/KG) TREATED RATS WERE EXPOSED DURING ONE WEEK TO VARIABLE STRESSORS AND SUBJECTED TO BEHAVIOURAL TESTS OF ANXIETY AND EPISODIC-LIKE MEMORY, FOLLOWED BY AN ASSESSMENT OF GLOBAL DNA METHYLATION AND EXPRESSION OF DNA METHYLTRANSFERASES ENZYMES DNMT1 AND DNMT3A MRNA IN THE PREFRONTAL CORTEX. STRESS EXPOSURE INDUCED A SIGNIFICANT ANXIOGENIC-LIKE EFFECT BUT DID NOT AFFECT THE EPISODIC-LIKE MEMORY IN THE OFFSPRING OF WIN55,212-2 EXPOSED FATHERS IN COMPARISON TO THE OFFSPRING OF NON-EXPOSED FATHERS. THESE BEHAVIOURAL CHANGES WERE SUBSEQUENT TO A SIGNIFICANT INCREASE IN GLOBAL DNA METHYLATION AND DNMT1 AND DNMTA3 TRANSCRIPTION IN THE PREFRONTAL CORTEX. THESE DATA SUGGEST THAT THE DELETERIOUS EFFECT OF CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE ARE NOT LIMITED TO THE EXPOSED INDIVIDUALS BUT MAY INCREASE THE VULNERABILITY TO STRESS-INDUCED ANXIETY IN THE OFFSPRING AND ALTER THEIR EPIGENETIC PROGRAMMING. 2019 17 6426 33 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 18 6554 34 TRANSGENERATIONAL EFFECTS OF EARLY ENVIRONMENTAL INSULTS ON AGING AND DISEASE INCIDENCE. ADVERSE EARLY LIFE EXPERIENCES ARE MAJOR INFLUENCES ON DEVELOPMENTAL TRAJECTORIES WITH POTENTIALLY LIFE-LONG CONSEQUENCES. PRENATAL OR EARLY POSTNATAL EXPOSURE TO STRESS, UNDERNUTRITION OR ENVIRONMENTAL TOXICANTS MAY REPROGRAM BRAIN DEVELOPMENT AND INCREASE RISK OF BEHAVIOURAL AND NEUROLOGICAL DISORDERS LATER IN LIFE. NOT ONLY EXPERIENCE WITHIN A SINGLE LIFETIME, BUT ALSO ANCESTRAL EXPERIENCE AFFECTS HEALTH TRAJECTORIES AND CHANCES OF SUCCESSFUL AGING. THE CENTRAL MECHANISM IN TRANSGENERATIONAL PROGRAMMING OF A DISEASE MAY BE THE FORMATION OF EPIGENETIC MEMORY. THIS REVIEW EXPLORES TRANSGENERATIONAL EFFECTS OF EARLY ADVERSE EXPERIENCE ON HEALTH AND DISEASE INCIDENCE IN OLDER AGE. FIRST, WE ADDRESS MECHANISMS OF DEVELOPMENTAL AND TRANSGENERATIONAL PROGRAMMING OF DISEASE AND INHERITANCE. SECOND, WE DISCUSS EXPERIMENTAL AND CLINICAL FINDINGS LINKING EARLY ENVIRONMENTAL DETERMINANTS TO ADVERSE AGING TRAJECTORIES IN ASSOCIATION WITH POSSIBLE PARENTAL CONTRIBUTIONS AND SEX-SPECIFIC EFFECTS. THIRD, WE OUTLINE THE MAIN MECHANISMS OF AGE-RELATED FUNCTIONAL DECLINE AND SUGGEST POTENTIAL INTERVENTIONS TO REVERSE NEGATIVE EFFECTS OF TRANSGENERATIONAL PROGRAMMING. THUS, STRATEGIES THAT SUPPORT HEALTHY DEVELOPMENT AND SUCCESSFUL AGING SHOULD TAKE INTO ACCOUNT THE POTENTIAL INFLUENCES OF TRANSGENERATIONAL INHERITANCE. 2020 19 2958 40 GENETIC AND EPIGENETIC INSIGHTS INTO FETAL ALCOHOL SPECTRUM DISORDERS. THE MAGNITUDE OF THE DETRIMENTAL EFFECTS FOLLOWING IN UTERO ALCOHOL EXPOSURE, INCLUDING FETAL ALCOHOL SYNDROME AND OTHER FETAL ALCOHOL SPECTRUM DISORDERS (FASD), IS GLOBALLY UNDERESTIMATED. THE EFFECTS INCLUDE IRREVERSIBLE COGNITIVE AND BEHAVIORAL DISABILITIES AS A RESULT OF ABNORMAL BRAIN DEVELOPMENT, PRE- AND POSTNATAL GROWTH RETARDATION AND FACIAL DYSMORPHISM. PARENTAL ALCOHOL EXPOSURE AND ITS EFFECT ON OFFSPRING HAS BEEN RECOGNIZED FOR CENTURIES, BUT ONLY RECENTLY HAVE WE BEGUN TO GAIN MOLECULAR INSIGHT INTO THE MECHANISMS INVOLVED IN ALCOHOL TERATOGENESIS. GENETIC ATTRIBUTES (SUSCEPTIBILITY AND PROTECTIVE ALLELES) OF THE MOTHER AND THE FETUS CONTRIBUTE TO THE RISK OF DEVELOPING FASD AND SPECIFIC ADDITIONAL ENVIRONMENTAL CONDITIONS, INCLUDING MALNUTRITION, HAVE AN IMPORTANT ROLE. THE SEVERITY OF FASD DEPENDS ON THE LEVEL OF ALCOHOL EXPOSURE, THE DEVELOPMENTAL STAGE AT WHICH EXPOSURE OCCURS AND THE NATURE OF THE EXPOSURE (CHRONIC OR ACUTE), AND ALTHOUGH THE MOST VULNERABLE PERIOD IS DURING THE FIRST TRIMESTER, DAMAGE CAN OCCUR THROUGHOUT GESTATION. PRECONCEPTION ALCOHOL EXPOSURE CAN ALSO HAVE A DETRIMENTAL EFFECT ON THE OFFSPRING. SEVERAL DEVELOPMENTAL PATHWAYS ARE AFFECTED IN FASD, INCLUDING NERVOUS SYSTEM DEVELOPMENT, GROWTH AND REMODELING OF TISSUES, AS WELL AS METABOLIC PATHWAYS THAT REGULATE GLUCOCORTICOID SIGNALING AND BALANCED LEVELS OF RETINOL, INSULIN AND NITRIC OXIDE. A BODY OF KNOWLEDGE HAS ACCUMULATED TO SUPPORT THE ROLE OF ENVIRONMENTALLY INDUCED EPIGENETIC REMODELING DURING GAMETOGENESIS AND AFTER CONCEPTION AS A KEY MECHANISM FOR THE TERATOGENIC EFFECTS OF FASD THAT PERSIST INTO ADULTHOOD. TRANSGENERATIONAL EFFECTS ARE LIKELY TO CONTRIBUTE TO THE GLOBAL BURDEN OF ALCOHOL-RELATED DISEASE. FASD RESULTS IN LIFELONG DISABILITY AND PREVENTATIVE PROGRAMS SHOULD INCLUDE BOTH MATERNAL ALCOHOL ABSTENTION AND PRECONCEPTION ALCOHOL AVOIDANCE. 2010 20 1765 30 EARLY-LIFE ADVERSITY-INDUCED LONG-TERM EPIGENETIC PROGRAMMING ASSOCIATED WITH EARLY ONSET OF CHRONIC PHYSICAL AGGRESSION: STUDIES IN HUMANS AND ANIMALS. OBJECTIVES: TO EXAMINE WHETHER CHRONIC PHYSICAL AGGRESSION (CPA) IN ADULTHOOD CAN BE EPIGENETICALLY PROGRAMMED EARLY IN LIFE DUE TO EXPOSURE TO EARLY-LIFE ADVERSITY. METHODS: LITERATURE SEARCH OF PUBLIC DATABASES SUCH AS PUBMED/MEDLINE AND SCOPUS. RESULTS: CHILDREN/ADOLESCENTS SUSCEPTIBLE FOR CPA AND EXPOSED TO EARLY-LIFE ABUSE FAIL TO EFFICIENTLY COPE WITH STRESS THAT IN TURN RESULTS IN THE DEVELOPMENT OF CPA LATER IN LIFE. THIS PHENOMENON WAS OBSERVED IN HUMANS AND ANIMAL MODELS OF AGGRESSION. THE SUSCEPTIBILITY TO AGGRESSION IS A COMPLEX TRAIT THAT IS REGULATED BY THE INTERACTION BETWEEN ENVIRONMENTAL AND GENETIC FACTORS. EPIGENETIC MECHANISMS MEDIATE THIS INTERACTION. SUBJECTS EXPOSED TO STRESS EARLY IN LIFE EXHIBITED LONG-TERM EPIGENETIC PROGRAMMING THAT CAN INFLUENCE THEIR BEHAVIOUR IN ADULTHOOD. THIS PROGRAMMING AFFECTS EXPRESSION OF MANY GENES NOT ONLY IN THE BRAIN BUT ALSO IN OTHER SYSTEMS SUCH AS NEUROENDOCRINE AND IMMUNE. CONCLUSIONS: THE PROPENSITY TO ADULT CPA BEHAVIOUR IN SUBJECTS EXPERIENCED TO EARLY-LIFE ADVERSITY IS MEDIATED BY EPIGENETIC PROGRAMMING THAT INVOLVES LONG-TERM SYSTEMIC EPIGENETIC ALTERATIONS IN A WHOLE GENOME. 2019