1 4932 125 PATERNAL ALCOHOL EXPOSURES PROGRAM INTERGENERATIONAL HORMETIC EFFECTS ON OFFSPRING FETOPLACENTAL GROWTH. HORMESIS REFERS TO GRADED ADAPTIVE RESPONSES TO HARMFUL ENVIRONMENTAL STIMULI WHERE LOW-LEVEL TOXICANT EXPOSURES STIMULATE TISSUE GROWTH AND RESPONSIVENESS WHILE, IN CONTRAST, HIGHER-LEVEL EXPOSURES INDUCE TOXICITY. ALTHOUGH THE INTERGENERATIONAL INHERITANCE OF PROGRAMMED HORMETIC GROWTH RESPONSES IS DESCRIBED IN PLANTS AND INSECTS, RESEARCHERS HAVE YET TO OBSERVE THIS PHENOMENON IN MAMMALS. USING A PHYSIOLOGICALLY RELEVANT MOUSE MODEL, WE DEMONSTRATE THAT CHRONIC PRECONCEPTION PATERNAL ALCOHOL EXPOSURES PROGRAM NONLINEAR, DOSE-DEPENDENT CHANGES IN OFFSPRING FETOPLACENTAL GROWTH. OUR STUDIES IDENTIFY AN INVERSE J-SHAPED CURVE WITH A THRESHOLD OF 2.4 G/KG PER DAY; BELOW THIS THRESHOLD, PATERNAL ETHANOL EXPOSURES INDUCE PROGRAMMED INCREASES IN PLACENTAL GROWTH, WHILE DOSES EXCEEDING THIS POINT YIELD COMPARATIVE DECREASES IN PLACENTAL GROWTH. IN MALE OFFSPRING, HIGHER PATERNAL EXPOSURES INDUCE DOSE-DEPENDENT INCREASES IN THE PLACENTAL LABYRINTH LAYER BUT DO NOT IMPACT FETAL GROWTH. IN CONTRAST, THE PLACENTAL HYPERTROPHY INDUCED BY LOW-LEVEL PATERNAL ETHANOL EXPOSURES ASSOCIATE WITH INCREASED OFFSPRING CROWN-RUMP LENGTH, PARTICULARLY IN MALE OFFSPRING. FINALLY, ALTERATIONS IN PLACENTAL PHYSIOLOGY CORRELATE WITH DISRUPTIONS IN BOTH MITOCHONDRIAL-ENCODED AND IMPRINTED GENE EXPRESSION. UNDERSTANDING THE INFLUENCE OF ETHANOL ON THE PATERNALLY-INHERITED EPIGENETIC PROGRAM AND DOWNSTREAM HORMETIC RESPONSES IN OFFSPRING GROWTH MAY HELP EXPLAIN THE ENORMOUS VARIATION OBSERVED IN FETAL ALCOHOL SPECTRUM DISORDER (FASD) PHENOTYPES AND INCIDENCE. 2022 2 5166 48 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 3 3119 38 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 4 5168 31 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 5 4941 24 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 6 4011 27 LOW PATERNAL DIETARY FOLATE ALTERS THE MOUSE SPERM EPIGENOME AND IS ASSOCIATED WITH NEGATIVE PREGNANCY OUTCOMES. EPIDEMIOLOGICAL STUDIES SUGGEST THAT A FATHER'S DIET CAN INFLUENCE OFFSPRING HEALTH. A PROPOSED MECHANISM FOR PATERNAL TRANSMISSION OF ENVIRONMENTAL INFORMATION IS VIA THE SPERM EPIGENOME. THE EPIGENOME INCLUDES HERITABLE INFORMATION SUCH AS DNA METHYLATION. WE HYPOTHESIZE THAT THE DIETARY SUPPLY OF METHYL DONORS WILL ALTER EPIGENETIC REPROGRAMMING IN SPERM. HERE WE FEED MALE MICE EITHER A FOLATE-DEFICIENT OR FOLATE-SUFFICIENT DIET THROUGHOUT LIFE. PATERNAL FOLATE DEFICIENCY IS ASSOCIATED WITH INCREASED BIRTH DEFECTS IN THE OFFSPRING, WHICH INCLUDE CRANIOFACIAL AND MUSCULOSKELETAL MALFORMATIONS. GENOME-WIDE DNA METHYLATION ANALYSIS AND THE SUBSEQUENT FUNCTIONAL ANALYSIS IDENTIFY DIFFERENTIAL METHYLATION IN SPERM OF GENES IMPLICATED IN DEVELOPMENT, CHRONIC DISEASES SUCH AS CANCER, DIABETES, AUTISM AND SCHIZOPHRENIA. WHILE >300 GENES ARE DIFFERENTIALLY EXPRESSED IN OFFSPRING PLACENTA, ONLY TWO CORRESPOND TO GENES WITH DIFFERENTIAL METHYLATION IN SPERM. THIS MODEL SUGGESTS EPIGENETIC TRANSMISSION MAY INVOLVE SPERM HISTONE H3 METHYLATION OR DNA METHYLATION AND THAT ADEQUATE PATERNAL DIETARY FOLATE IS ESSENTIAL FOR OFFSPRING HEALTH. 2013 7 1609 45 DNA METHYLATION-INDEPENDENT GROWTH RESTRICTION AND ALTERED DEVELOPMENTAL PROGRAMMING IN A MOUSE MODEL OF PRECONCEPTION MALE ALCOHOL EXPOSURE. THE PRECONCEPTION ENVIRONMENT IS A SIGNIFICANT MODIFIER OF DYSGENESIS AND THE DEVELOPMENT OF ENVIRONMENTALLY-INDUCED DISEASE. TO DATE, FETAL ALCOHOL SPECTRUM DISORDERS (FASDS) HAVE BEEN EXCLUSIVELY ASSOCIATED WITH MATERNAL EXPOSURES, YET EMERGING EVIDENCE SUGGESTS MALE-INHERITED ALTERATIONS IN THE DEVELOPMENTAL PROGRAM OF SPERM MAY BE RELEVANT TO THE GROWTH-RESTRICTION PHENOTYPES OF THIS CONDITION. USING A MOUSE MODEL OF VOLUNTARY CONSUMPTION, WE FIND CHRONIC PRECONCEPTION MALE ETHANOL EXPOSURE ASSOCIATES WITH FETAL GROWTH RESTRICTION, DECREASED PLACENTAL EFFICIENCY, ABNORMALITIES IN CHOLESTEROL TRAFFICKING, SEX-SPECIFIC ALTERATIONS IN THE GENETIC PATHWAYS REGULATING HEPATIC FIBROSIS, AND DISRUPTIONS IN THE REGULATION OF IMPRINTED GENES. ALTERATIONS IN THE DNA METHYLATION PROFILES OF IMPRINTED LOCI HAVE BEEN IDENTIFIED IN CLINICAL STUDIES OF ALCOHOLIC SPERM, SUGGESTING THE LEGACY OF PATERNAL DRINKING MAY TRANSMIT VIA HERITABLE DISRUPTIONS IN THE REGULATION OF IMPRINTED GENES. HOWEVER, THE CAPACITY OF SPERM-INHERITED CHANGES IN DNA METHYLATION TO BROADLY TRANSMIT ENVIRONMENTALLY-INDUCED PHENOTYPES REMAINS UNCONFIRMED. USING BISULPHITE MUTAGENESIS AND SECOND-GENERATION DEEP SEQUENCING, WE FIND NO EVIDENCE TO SUGGEST THAT THESE PHENOTYPES OR ANY OF THE ASSOCIATED TRANSCRIPTIONAL CHANGES ARE LINKED TO ALTERATIONS IN THE SPERM-INHERITED DNA METHYLATION PROFILE. THESE OBSERVATIONS ARE CONSISTENT WITH RECENT STUDIES EXAMINING THE MALE TRANSMISSION OF DIET-INDUCED PHENOTYPES AND EMPHASIZE THE IMPORTANCE OF EPIGENETIC MECHANISMS OF PATERNAL INHERITANCE BEYOND DNA METHYLATION. THIS STUDY CHALLENGES THE SINGULAR IMPORTANCE OF MATERNAL ALCOHOL EXPOSURES AND SUGGESTS PATERNAL ALCOHOL ABUSE IS A SIGNIFICANT, YET OVERLOOKED EPIDEMIOLOGICAL FACTOR COMPLICIT IN THE GENESIS OF ALCOHOL-INDUCED GROWTH DEFECTS, AND MAY PROVIDE MECHANISTIC INSIGHT INTO THE FAILURE OF FASD CHILDREN TO THRIVE POSTNATALLY. 2017 8 5773 40 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 9 6426 34 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 10 2958 29 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 11 5397 27 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 12 4942 27 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 13 4064 26 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 14 4496 32 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 15 2472 24 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 16 5774 36 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 17 5294 21 PROTECTIVE EFFECTS OF MATERNAL METHYL DONOR SUPPLEMENTATION ON ADULT OFFSPRING OF HIGH FAT DIET-FED DAMS. OBESITY HAS BECOME A GLOBAL PUBLIC HEALTH PROBLEM ASSOCIATED WITH METABOLIC DYSFUNCTION AND CHRONIC DISORDERS. IT HAS BEEN SHOWN THAT THE RISK OF OBESITY AND THE DNA METHYLATION PROFILES OF THE OFFSPRING CAN BE AFFECTED BY MATERNAL NUTRITION, SUCH AS HIGH-FAT DIET (HFD) CONSUMPTION. THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER METABOLIC DYSREGULATION AND PHYSIOLOGICAL ABNORMALITIES IN OFFSPRING CAUSED BY MATERNAL HFD CAN BE ALLEVIATED BY THE TREATMENT OF METHYL DONORS DURING PREGNANCY AND LACTATION OF DAMS. FEMALE C57BL/6 MICE WERE ASSIGNED TO SPECIFIC GROUPS AND GIVEN DIFFERENT NUTRIENTS (CONTROL DIET, CONTROL+MET, HFD AND HFD+MET) THROUGHOUT GESTATION AND LACTATION. OFFSPRING OF EACH GROUP WERE WEANED ONTO A CONTROL DIET AT 3 WEEKS OF AGE. PHYSIOLOGICAL (WEIGHT GAIN AND ADIPOSE COMPOSITION) AND METABOLIC (PLASMA BIOCHEMICAL ANALYSES) OUTCOMES WERE ASSESSED IN MALE AND FEMALE ADULT OFFSPRING. EXPRESSION AND DNA METHYLATION PROFILES OF OBESOGENIC-RELATED GENES INCLUDING PPAR GAMMA, FATTY ACID SYNTHASE, LEPTIN AND ADIPONECTIN WERE ALSO DETECTED IN VISCERAL FAT OF OFFSPRING. THE RESULTS SHOWED THAT DIETARY SUPPLEMENTATION WITH METHYL DONORS CAN PREVENT THE ADVERSE EFFECTS OF MATERNAL HFD ON OFFSPRING. CHANGES IN THE EXPRESSION AND DNA METHYLATION OF OBESOGENIC-RELATED GENES INDICATED THAT EPIGENETIC REGULATION MAY CONTRIBUTE TO THE EFFECTS OF MATERNAL DIETARY FACTORS ON OFFSPRING OUTCOMES. 2016 18 4983 29 PATHOPHYSIOLOGY, CELLULAR AND MOLECULAR MECHANISMS OF FOETAL GROWTH RETARDATION. IN MAMMALS, SIZE AT BIRTH IS THE OUTCOME OF LENGTH OF GESTATION AND RATE OF FOETAL GROWTH. IN THE ABSENCE OF PREMATURE DELIVERY, FOETAL SIZE WITHIN SPECIES IS DETERMINED PRINCIPALLY BY FOETAL GROWTH RATE WHICH IS DEPENDENT ON BOTH GENETIC AND EPIGENETIC FACTORS. FAILURE OF EITHER OF THESE MECHANISMS LEADS TO FOETAL GROWTH RETARDATION. IN MAMMALS, INCLUDING HUMAN INFANTS, FOETAL GROWTH RETARDATION CAN OCCUR NATURALLY OR PATHOLOGICALLY. ONE MAJOR CAUSE FOR NATURAL FOETAL GROWTH RETARDATION OR RUNTING IS THE INCREASE IN LITTER SIZE. IN MANY CASES, HOWEVER, THE CAUSE OF RUNTING IS UNKNOWN. PARENTAL GENOTYPE OR ANTIGENIC DIFFERENCES BETWEEN THE MOTHER AND THE DEVELOPING CONCEPTUS MAY BE POTENTIAL CAUSES. PATHOLOGICAL FOETAL GROWTH RETARDATION OR INTRAUTERINE GROWTH RETARDATION (IUGR) IS DUE TO GENETIC CAUSES (CHROMOSOMAL ABNORMALITIES OR INHERITED SYNDROMES) OR EPIGENETIC CAUSES (INTRAUTERINE INFECTIONS, TOXINS AND CHEMICALS, MATERNAL DISEASES OF PREGNANCY AFFECTING THE PLACENTA). THE UNDERLYING PATHOPHYSIOLOGICAL PROCESSES THAT OCCUR AT THE CELLULAR AND MOLECULAR LEVEL IN IUGR ARE STILL UNKNOWN. REDUCTION IN THE SUPPLY OF SUBSTRATES THAT ARE NECESSARY FOR NORMAL CELLULAR FUNCTION, AND ALTERATION IN MEDIATOR MOLECULES THAT REGULATE CELLULAR GROWTH AND DIFFERENTIATION, ARE IMPORTANT MECHANISMS. A DECREASE IN GROWTH PROMOTING FACTORS OR AN INCREASE IN GROWTH INHIBITORY FACTORS MAY LEAD TO GROWTH FAILURE. GROWTH FACTORS AND THEIR RECEPTORS ARE EXPRESSED IN THE DEVELOPING EMBRYO (AS EARLY AS THE 1-2-CELL STAGE), PLACENTA AND MATERNAL UTERINE TISSUES, SUGGESTING THAT THESE MOLECULES MAY PLAY A ROLE IN REGULATING NORMAL GROWTH AND DIFFERENTIATION OF THE CONCEPTUS AS WELL AS MATERNAL REPRODUCTIVE TISSUES. THE LOCAL EXPRESSION WITHIN DEVELOPING TISSUES INDICATES THAT THESE FACTORS ACT IN EITHER AUTOCRINE OR PARACRINE MECHANISM. RECENT STUDIES USING GENE TARGETING TO KNOCK OUT ONE ALLELE OF INSULIN-LIKE GROWTH FACTOR II (IGF II) GENE IN MICE WHICH RESULTED IN GROWTH RETARDED PUPS AT BIRTH, STRONGLY SUPPORT THE IMPORTANCE OF LOCAL IGF II IN REGULATING TISSUE GROWTH. FOETAL GROWTH RETARDATION HAS ALSO BEEN INDUCED EXPERIMENTALLY IN SEVERAL SPECIES USING ONE OF THE FOLLOWING METHODS: (I) MATERNAL UNDERNUTRITION, (II) CHRONIC HYPOXIA, (III) PROLONGED REDUCTION IN UTERINE BLOOD FLOW, (IV) REDUCTION IN PLACENTAL SIZE, AND (V) ENDOCRINE ALTERATIONS. THESE MODELS PROVIDE USEFUL INFORMATION ON THE PHYSIOLOGICAL MECHANISMS UNDERLYING A SPECIFIC TYPE OF GROWTH RETARDATION. THESE IN-VIVO MODELS AND IN-VIVO TISSUE CULTURE MODELS CAN NOW BE ANALYSED BY BIOCHEMICAL AND MOLECULAR BIOLOGICAL TECHNIQUES TO UNRAVEL THE BASIC MECHANISMS THAT UNDERLIE FOETAL GROWTH RETARDATION. 1993 19 2183 25 EPIGENETIC MECHANISMS RESPONSIBLE FOR THE TRANSGENERATIONAL INHERITANCE OF INTRAUTERINE GROWTH RESTRICTION PHENOTYPES. A POORLY FUNCTIONING PLACENTA RESULTS IN IMPAIRED EXCHANGES OF OXYGEN, NUTRITION, WASTES AND HORMONES BETWEEN THE MOTHER AND HER FETUS. THIS CAN LEAD TO RESTRICTION OF FETAL GROWTH. THESE GROWTH RESTRICTED BABIES ARE AT INCREASED RISK OF DEVELOPING CHRONIC DISEASES, SUCH AS TYPE-2 DIABETES, HYPERTENSION, AND KIDNEY DISEASE, LATER IN LIFE. ANIMAL STUDIES HAVE SHOWN THAT GROWTH RESTRICTED PHENOTYPES ARE SEX-DEPENDENT AND CAN BE TRANSMITTED TO SUBSEQUENT GENERATIONS THROUGH BOTH THE PATERNAL AND MATERNAL LINEAGES. ALTERED EPIGENETIC MECHANISMS, SPECIFICALLY CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS THAT REGULATE EXPRESSION OF GENES THAT ARE IMPORTANT FOR FETAL DEVELOPMENT HAVE BEEN SHOWN TO BE ASSOCIATED WITH THE TRANSMISSION PATTERN OF GROWTH RESTRICTED PHENOTYPES. THIS REVIEW WILL DISCUSS THE SUBSEQUENT HEALTH OUTCOMES IN THE OFFSPRING AFTER GROWTH RESTRICTION AND THE TRANSMISSION PATTERNS OF THESE DISEASES. EVIDENCE OF ALTERED EPIGENETIC MECHANISMS IN ASSOCIATION WITH FETAL GROWTH RESTRICTION WILL ALSO BE REVIEWED. 2022 20 4767 32 NUCLEAR AND MITOCHONDRIAL DNA ALTERATIONS IN NEWBORNS WITH PRENATAL EXPOSURE TO CIGARETTE SMOKE. NEWBORNS EXPOSED TO MATERNAL CIGARETTE SMOKE (CS) IN UTERO HAVE AN INCREASED RISK OF DEVELOPING CHRONIC DISEASES, CANCER, AND ACQUIRING DECREASED COGNITIVE FUNCTION IN ADULTHOOD. ALTHOUGH THE LITERATURE REPORTS MANY DELETERIOUS EFFECTS ASSOCIATED WITH MATERNAL CIGARETTE SMOKING ON THE FETUS, THE MOLECULAR ALTERATIONS AND MECHANISMS OF ACTION ARE NOT YET CLEAR. SMOKING MAY ACT DIRECTLY ON NUCLEAR DNA BY INDUCING MUTATIONS OR EPIGENETIC MODIFICATIONS. RECENT STUDIES ALSO INDICATE THAT SMOKING MAY ACT ON MITOCHONDRIAL DNA BY INDUCING A CHANGE IN THE NUMBER OF COPIES TO MAKE UP FOR THE DAMAGE CAUSED BY SMOKING ON THE RESPIRATORY CHAIN AND LACK OF ENERGY. IN ADDITION, INDIVIDUAL GENETIC SUSCEPTIBILITY PLAYS A SIGNIFICANT ROLE IN DETERMINING THE EFFECTS OF SMOKING DURING DEVELOPMENT. FURTHERMORE, PRIOR EXPOSURE OF PATERNAL AND MATERNAL GAMETES TO CIGARETTE SMOKE MAY AFFECT THE HEALTH OF THE DEVELOPING INDIVIDUAL, NOT ONLY THE IN UTERO EXPOSURE. THIS REVIEW EXAMINES THE GENETIC AND EPIGENETIC ALTERATIONS IN NUCLEAR AND MITOCHONDRIAL DNA ASSOCIATED WITH SMOKE EXPOSURE DURING THE MOST SENSITIVE PERIODS OF DEVELOPMENT (PRIOR TO CONCEPTION, PRENATAL AND EARLY POSTNATAL) AND ASSESSES HOW SUCH CHANGES MAY HAVE CONSEQUENCES FOR BOTH FETAL GROWTH AND DEVELOPMENT. 2015