1 1096 139 COINCUBATION OF SPERM WITH EPIDIDYMAL EXTRACELLULAR VESICLE PREPARATIONS FROM CHRONIC INTERMITTENT ETHANOL-TREATED MICE IS SUFFICIENT TO IMPART ANXIETY-LIKE AND ETHANOL-INDUCED BEHAVIORS TO ADULT PROGENY. WE PREVIOUSLY REPORTED THAT PATERNAL PRECONCEPTION CHRONIC ETHANOL EXPOSURE IN MICE IMPARTS ADULT MALE OFFSPRING WITH REDUCED ETHANOL DRINKING PREFERENCE AND CONSUMPTION, INCREASED ETHANOL SENSITIVITY, AND ATTENUATED STRESS RESPONSIVITY. THAT SAME CHRONIC ETHANOL EXPOSURE PARADIGM WAS LATER REVEALED TO AFFECT THE SPERM EPIGENOME BY ALTERING THE ABUNDANCE OF SEVERAL SMALL NONCODING RNAS, A MECHANISM THAT MEDIATES THE INTERGENERATIONAL EFFECTS OF NUMEROUS PATERNAL ENVIRONMENTAL EXPOSURES. ALTHOUGH RECENT STUDIES HAVE REVEALED THAT THE UNIQUE RNA SIGNATURE OF SPERM IS SHAPED DURING MATURATION IN THE EPIDIDYMIS VIA EXTRACELLULAR VESICLES (EVS), FORMAL DEMONSTRATION THAT EVS MEDIATE THE EFFECTS OF PATERNAL PRECONCEPTION PERTURBATIONS IS LACKING. THEREFORE, IN THE CURRENT STUDY WE TESTED THE HYPOTHESIS THAT EPIDIDYMAL EV PREPARATIONS ARE SUFFICIENT TO INDUCE INTERGENERATIONAL EFFECTS OF PATERNAL PRECONCEPTION ETHANOL EXPOSURE ON OFFSPRING. TO TEST THIS HYPOTHESIS, SPERM FROM ETHANOL-NAIVE DONORS WERE INCUBATED WITH EPIDIDYMAL EV PREPARATIONS FROM CHRONIC ETHANOL (ETHANOL EV-DONOR) OR CONTROL-TREATED (CONTROL EV-DONOR) MICE PRIOR TO IN VITRO FERTILIZATION (IVF) AND EMBRYO TRANSFER. PROGENY WERE EXAMINED FOR ETHANOL- AND STRESS-RELATED BEHAVIORS IN ADULTHOOD. ETHANOL EV-DONORS IMPARTED REDUCED BODY WEIGHT AT WEANING AND IMPARTED MODESTLY INCREASED LIMITED ACCESS ETHANOL INTAKE TO MALE OFFSPRING. ETHANOL-EV DONORS ALSO IMPARTED INCREASED BASAL ANXIETY-LIKE BEHAVIOR AND REDUCED SENSITIVITY TO ETHANOL-INDUCED ANXIOLYSIS TO FEMALE OFFSPRING. ALTHOUGH ETHANOL EV-DONOR TREATMENT DID NOT RECAPITULATE THE ETHANOL- OR STRESS-RELATED INTERGENERATIONAL EFFECTS OF PATERNAL ETHANOL FOLLOWING NATURAL MATING, THESE RESULTS DEMONSTRATE THAT COINCUBATION OF SPERM WITH EPIDIDYMAL EV PREPARATIONS IS SUFFICIENT TO IMPART INTERGENERATIONAL EFFECTS OF ETHANOL THROUGH THE MALE GERMLINE. THIS MECHANISM MAY GENERALIZE TO THE INTERGENERATIONAL EFFECTS OF A WIDE VARIETY OF PATERNAL PRECONCEPTION PERTURBATIONS. 2020 2 4939 44 PATERNAL NICOTINE EXPOSURE IN RATS PRODUCES LONG-LASTING NEUROBEHAVIORAL EFFECTS IN THE OFFSPRING. STUDIES OF INTERGENERATIONAL EFFECTS OF PARENTAL CHEMICAL EXPOSURE HAVE PRINCIPALLY FOCUSED ON MATERNAL EXPOSURE, PARTICULARLY FOR STUDIES OF ADVERSE NEUROBEHAVIORAL CONSEQUENCES ON THE OFFSPRING. MATERNAL NICOTINE EXPOSURE HAS LONG BEEN KNOWN TO CAUSE ADVERSE NEUROBEHAVIORAL EFFECTS ON THE OFFSPRING. HOWEVER, PATERNAL TOXICANT EXPOSURE HAS ALSO BEEN FOUND TO CAUSE NEUROBEHAVIORAL TOXICITY IN THEIR OFFSPRING. RECENT WORK SUGGESTS THAT PATERNAL NICOTINE EXPOSURE CAN HAVE EPIGENETIC EFFECTS, ALTHOUGH IT REMAINS UNCLEAR WHETHER SUCH CHANGES LEAD TO NEUROBEHAVIORAL EFFECTS. IN THE CURRENT STUDY, WE INVESTIGATED THE EFFECTS OF PATERNAL NICOTINE EXPOSURE ON NEUROBEHAVIORAL DEVELOPMENT OF THEIR OFFSPRING. MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO 0 OR 2 MG/KG/DAY NICOTINE (SC) FOR 56 CONSECUTIVE DAYS WITH TWO CONSECUTIVE 2ML4 OSMOTIC MINIPUMPS. FOLLOWING TREATMENT, THESE MALES WERE MATED WITH DRUG-NAIVE FEMALE RATS. OFFSPRING OF BOTH SEXES WERE TESTED IN A BEHAVIORAL BATTERY TO ASSESS LOCOMOTION, EMOTIONAL FUNCTION AND COGNITION. PATERNAL NICOTINE EXPOSURE DID NOT IMPACT OFFSPRING VIABILITY, HEALTH OR GROWTH. HOWEVER, BEHAVIORAL FUNCTION OF THE OFFSPRING WAS SIGNIFICANTLY ALTERED BY PATERNAL NICOTINE EXPOSURE. MALE OFFSPRING WITH PATERNAL NICOTINE EXPOSURE EXHIBITED LOCOMOTOR HYPERACTIVITY IN THE FIGURE-8 APPARATUS WHEN TESTED DURING ADOLESCENCE. WHEN RETESTED IN ADULTHOOD AND REGARDLESS OF SEX, OFFSPRING OF THE NICOTINE EXPOSED FATHER SHOWED SIGNIFICANTLY REDUCED HABITUATION OF LOCOMOTOR ACTIVITY OVER THE COURSE OF THE SESSION. COMPARED TO CONTROLS, FEMALE OFFSPRING OF NICOTINE-EXPOSED FATHERS SHOWED SIGNIFICANTLY REDUCED RESPONSE LATENCY IN THE RADIAL ARM MAZE TEST. IN ADDITION TO LOCOMOTOR HYPERACTIVITY, THE OFFSPRING OF NICOTINE-EXPOSED FATHERS ALSO SHOWED SIGNIFICANTLY DIMINISHED HABITUATION IN THE NOVEL OBJECT RECOGNITION TEST. THESE RESULTS INDICATE THAT CHRONIC PATERNAL NICOTINE EXPOSURE CAN IMPACT THE BEHAVIOR OF OFFSPRING, PRODUCING LOCOMOTOR HYPERACTIVITY AND IMPAIRED HABITUATION. 2019 3 1153 30 CONSEQUENCES OF PATERNAL NUTRITION ON OFFSPRING HEALTH AND DISEASE. IT IS WELL ESTABLISHED THAT THE MATERNAL DIET DURING THE PERICONCEPTIONAL PERIOD AFFECTS THE PROGENY'S HEALTH. A GROWING BODY OF EVIDENCE SUGGESTS THAT THE PATERNAL DIET ALSO INFLUENCES DISEASE ONSET IN OFFSPRING. FOR MANY YEARS, SPERM WAS CONSIDERED ONLY TO CONTRIBUTE HALF OF THE PROGENY'S GENOME. IT NOW APPEARS THAT IT ALSO PLAYS A CRUCIAL ROLE IN HEALTH AND DISEASE IN OFFSPRING'S ADULT LIFE. THE NUTRITIONAL STATUS AND ENVIRONMENTAL EXPOSURE OF FATHERS DURING THEIR CHILDHOOD AND/OR THE PERICONCEPTIONAL PERIOD HAVE SIGNIFICANT TRANSGENERATIONAL CONSEQUENCES. THIS REVIEW AIMS TO DESCRIBE THE EFFECTS OF VARIOUS HUMAN AND RODENT PATERNAL FEEDING PATTERNS ON PROGENY'S METABOLISM AND HEALTH, INCLUDING FASTING OR INTERMITTENT FASTING, LOW-PROTEIN AND FOLIC ACID DEFICIENT FOOD, AND OVERNUTRITION IN HIGH-FAT AND HIGH-SUGAR DIETS. THE IMPACT ON PREGNANCY OUTCOME, METABOLIC PATHWAYS, AND CHRONIC DISEASE ONSET WILL BE DESCRIBED. THE BIOLOGICAL AND EPIGENETIC MECHANISMS UNDERLYING THE TRANSMISSION FROM FATHERS TO THEIR PROGENY WILL BE DISCUSSED. ALL THESE DATA PROVIDE EVIDENCE OF THE IMPACT OF PATERNAL NUTRITION ON PROGENY HEALTH WHICH COULD LEAD TO PREVENTIVE DIET RECOMMENDATIONS FOR FUTURE FATHERS. 2021 4 5168 40 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 4944 46 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING. 2016 6 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 7 4092 34 MATERNAL REPETITIVE HYPOXIA PRIOR TO MATING CONFERS EPIGENETIC RESILIENCE TO MEMORY IMPAIRMENT IN MALE PROGENY. WE SHOWED PREVIOUSLY IN A MOUSE MODEL OF VASCULAR COGNITIVE IMPAIRMENT AND DEMENTIA INVOLVING CHRONIC CEREBRAL HYPOPERFUSION (CCH) THAT REPETITIVE HYPOXIC CONDITIONING (RHC) OF BOTH PARENTS RESULTS IN THE EPIGENETIC, INTERGENERATIONAL TRANSMISSION OF RESILIENCE TO RECOGNITION MEMORY LOSS IN ADULT PROGENY, AS ASSESSED BY THE NOVEL OBJECT RECOGNITION TEST. THE PRESENT STUDY WAS UNDERTAKEN IN THE SAME MODEL TO DETERMINE WHETHER RHC TREATMENT OF ONE OR BOTH PARENTS IS REQUIRED TO CONFER DEMENTIA RESILIENCE INTERGENERATIONALLY. WE FOUND INHERITED RESILIENCE TO 3 MONTHS OF CCH IN MALES IS MATERNALLY MEDIATED (P = .006). STATISTICALLY, WE OBSERVED A STRONG TREND FOR THE PATERNAL GERMLINE TO CONTRIBUTE AS WELL (P = .052). WE ALSO FOUND THAT, IN CONTRAST TO WHAT IS WIDELY OBSERVED IN MALES, FEMALES DISPLAY INTACT RECOGNITION MEMORY (P = .001) AFTER 3 MONTHS OF CCH, REVEALING A HERETOFORE UNIDENTIFIED SEXUAL DIMORPHISM WITH RESPECT TO COGNITIVE IMPACT DURING DISEASE PROGRESSION. OVERALL, RESULTS OF OUR STUDY STRONGLY IMPLICATE EPIGENETIC CHANGES IN MATERNAL GERM CELLS, INDUCED BY OUR REPETITIVE SYSTEMIC HYPOXIC STIMULUS, CONTRIBUTING TO A MODIFIED DIFFERENTIATION PROGRAM CAPABLE OF ESTABLISHING A DEMENTIA-RESILIENT PHENOTYPE IN ADULT MALE FIRST-GENERATION PROGENY. (PSYCINFO DATABASE RECORD (C) 2023 APA, ALL RIGHTS RESERVED). 2023 8 4941 36 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 3300 38 HIGH-FAT DIET REPROGRAMS THE EPIGENOME OF RAT SPERMATOZOA AND TRANSGENERATIONALLY AFFECTS METABOLISM OF THE OFFSPRING. OBJECTIVES: CHRONIC AND HIGH CONSUMPTION OF FAT CONSTITUTES AN ENVIRONMENTAL STRESS THAT LEADS TO METABOLIC DISEASES. WE HYPOTHESIZED THAT HIGH-FAT DIET (HFD) TRANSGENERATIONALLY REMODELS THE EPIGENOME OF SPERMATOZOA AND METABOLISM OF THE OFFSPRING. METHODS: F0-MALE RATS FED EITHER HFD OR CHOW DIET FOR 12 WEEKS WERE MATED WITH CHOW-FED DAMS TO GENERATE F1 AND F2 OFFSPRING. MOTILE SPERMATOZOA WERE ISOLATED FROM F0 AND F1 BREEDERS TO DETERMINE DNA METHYLATION AND SMALL NON-CODING RNA (SNCRNA) EXPRESSION PATTERN BY DEEP SEQUENCING. RESULTS: NEWBORN OFFSPRING OF HFD-FED FATHERS HAD REDUCED BODY WEIGHT AND PANCREATIC BETA-CELL MASS. ADULT FEMALE, BUT NOT MALE, OFFSPRING OF HFD-FED FATHERS WERE GLUCOSE INTOLERANT AND RESISTANT TO HFD-INDUCED WEIGHT GAIN. THIS PHENOTYPE WAS PERPETUATED IN THE F2 PROGENY, INDICATING TRANSGENERATIONAL EPIGENETIC INHERITANCE. THE EPIGENOME OF SPERMATOZOA FROM HFD-FED F0 AND THEIR F1 MALE OFFSPRING SHOWED COMMON DNA METHYLATION AND SMALL NON-CODING RNA EXPRESSION SIGNATURES. ALTERED EXPRESSION OF SPERM MIRNA LET-7C WAS PASSED DOWN TO METABOLIC TISSUES OF THE OFFSPRING, INDUCING A TRANSCRIPTOMIC SHIFT OF THE LET-7C PREDICTED TARGETS. CONCLUSION: OUR RESULTS PROVIDE INSIGHT INTO MECHANISMS BY WHICH HFD TRANSGENERATIONALLY REPROGRAMS THE EPIGENOME OF SPERM CELLS, THEREBY AFFECTING METABOLIC TISSUES OF OFFSPRING THROUGHOUT TWO GENERATIONS. 2016 10 3119 42 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 11 4932 32 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 12 4937 34 PATERNAL MORPHINE EXPOSURE IN RATS REDUCES SOCIAL PLAY IN ADOLESCENT MALE PROGENY WITHOUT AFFECTING DRUG-TAKING BEHAVIOR IN JUVENILE MALES OR FEMALE OFFSPRING. THE ONGOING OPIOID ADDICTION CRISIS NECESSITATES THE IDENTIFICATION OF NOVEL RISK FACTORS TO IMPROVE PREVENTION AND TREATMENT OF OPIOID USE DISORDER. PARENTAL OPIOID EXPOSURE HAS RECENTLY EMERGED AS A POTENTIAL REGULATOR OF OFFSPRING VULNERABILITY TO OPIOID MISUSE, IN ADDITION TO HERITABLE GENETIC LIABILITY. AN UNDERSTUDIED ASPECT OF THIS "MISSING HERITABILITY" IS THE DEVELOPMENTAL PRESENTATION OF THESE CROSS-GENERATIONAL PHENOTYPES. THIS IS AN ESPECIALLY RELEVANT QUESTION IN THE CONTEXT OF INHERITED ADDICTION-RELATED PHENOTYPES, GIVEN THE PROMINENT ROLE OF DEVELOPMENTAL PROCESSES IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS. PATERNAL MORPHINE SELF-ADMINISTRATION WAS PREVIOUSLY SHOWN TO ALTER THE SENSITIVITY TO THE REINFORCING AND ANTINOCICEPTIVE PROPERTIES OF OPIOIDS IN THE NEXT GENERATION. HERE, PHENOTYPING WAS EXPANDED TO INCLUDE THE ADOLESCENT PERIOD, WITH A FOCUS ON ENDOPHENOTYPES RELATED TO OPIOID USE DISORDERS AND PAIN. PATERNAL MORPHINE EXPOSURE DID NOT ALTER HEROIN OR COCAINE SELF-ADMINISTRATION IN MALE AND FEMALE JUVENILE PROGENY. FURTHER, BASELINE SENSORY REFLEXES RELATED TO PAIN WERE UNALTERED IN MORPHINE-SIRED ADOLESCENT RATS OF EITHER SEX. HOWEVER, MORPHINE-SIRED ADOLESCENT MALES EXHIBITED A REDUCTION IN SOCIAL PLAY BEHAVIOR. OUR FINDINGS SUGGEST THAT, IN MORPHINE-SIRED MALE OFFSPRING, PATERNAL OPIOID EXPOSURE DOES NOT AFFECT OPIOID INTAKE DURING ADOLESCENCE, SUGGESTING THAT THIS PHENOTYPE DOES NOT EMERGE UNTIL LATER IN LIFE. ALTERED SOCIAL BEHAVIORS IN MALE MORPHINE-SIRED ADOLESCENTS INDICATE THAT THE CHANGES IN DRUG-TAKING BEHAVIOR IN ADULTS SIRED BY MORPHINE-EXPOSED SIRES MAY BE DUE TO MORE COMPLEX FACTORS NOT YET FULLY ASSESSED. 2023 13 6559 32 TRANSGENERATIONAL INFLUENCE OF PARENTAL MORPHINE EXPOSURE ON PAIN PERCEPTION, ANXIETY-LIKE BEHAVIOR AND PASSIVE AVOIDANCE MEMORY AMONG MALE AND FEMALE OFFSPRING OF WISTAR RATS. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN THE FORMATION AND MAINTENANCE OF MEMORY WITHIN THE BRAIN. MOREOVER, THE EFFECT OF PARENTAL DRUG-EXPOSURE BEFORE GESTATION ON BEHAVIORAL STATE OF OFFSPRING HAS BEEN LITTLE STUDIED. THE MAIN OBJECTIVE OF THE CURRENT STUDY IS TO EVALUATE THE EFFECT OF PARENTAL MORPHINE EXPOSURE ON AVOIDANCE MEMORY, MORPHINE PREFERENCE AND ANXIETY-LIKE BEHAVIOR OF OFFSPRING. THE TOTAL OF 32 MALES AND 32 FEMALES WERE USED FOR MATING. THE ANIMALS WERE TREATED WITH MORPHINE. THE OFFSPRING ACCORDING TO THEIR PARENTAL MORPHINE TREATMENT WAS DIVIDED INTO FOUR GROUPS (N=16) INCLUDING PATERNALLY TREATED, MATERNALLY TREATED, BOTH OF PARENTS TREATED AND NAIVE ANIMALS. THE PAIN PERCEPTION, ANXIETY-LIKE BEHAVIOR, AND AVOIDANCE MEMORY WERE EVALUATED IN THE OFFSPRING. IN THE CURRENT STUDY, THE TOTAL OF 256 OFFSPRING WAS USED FOR THE EXPERIMENTS (4 TASKS X 4 GROUPS OF OFFSPRING X 8 FEMALE OFFSPRING X 8 MALE OFFSPRING). THE FINDING REVEALED THAT THE AVOIDANCE MEMORY AND VISCERAL PAIN WERE REDUCED SIGNIFICANTLY IN MALE AND FEMALE OFFSPRING WITH AT LEAST ONE MORPHINE-TREATED PARENT. MOREOVER, ANXIETY-LIKE BEHAVIOR WAS REDUCED SIGNIFICANTLY IN THE MALE OFFSPRING WITH AT LEAST ONE MORPHINE-TREATED PARENT. WHILE ANXIETY-LIKE BEHAVIOR WAS INCREASED SIGNIFICANTLY IN FEMALE OFFSPRING THAT WERE TREATED BY MORPHINE EITHER MATERNALLY OR BOTH OF PARENTS. THE DATA REVEALED THAT THE ENDOGENOUS OPIOID SYSTEM MAY BE ALTERED IN THE OFFSPRING OF MORPHINE-TREATED PARENT(S), AND EPIGENETIC ROLE COULD BE IMPORTANT. HOWEVER, ANALYSIS OF VARIANCE SIGNIFIED THE IMPORTANT ROLE OF MATERNAL INHERITANCE. 2019 14 4942 34 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 4011 29 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 16 1804 44 EFFECT OF RAT PARENTAL MORPHINE EXPOSURE ON PASSIVE AVOIDANCE MEMORY AND MORPHINE CONDITIONED PLACE PREFERENCE IN MALE OFFSPRING. DRUG ADDICTION IS A CHRONIC DISORDER RESULTED FROM COMPLEX INTERACTION OF GENETIC, ENVIRONMENTAL, AND DEVELOPMENTAL FACTORS. EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT AND MAINTENANCE OF ADDICTION AND ALSO MEMORY FORMATION IN THE BRAIN. WE HAVE EXAMINED PASSIVE AVOIDANCE MEMORY AND MORPHINE CONDITIONED PLACE PREFERENCE (CPP) IN THE OFFSPRING OF MALE AND/OR FEMALE RATS WITH A HISTORY OF ADULTHOOD MORPHINE CONSUMPTION. ADULT MALE AND FEMALE ANIMALS RECEIVED CHRONIC ORAL MORPHINE FOR 21DAYS AND THEN WERE MAINTAINED DRUG FREE FOR 10DAYS. AFTER THAT, THEY WERE LET TO MATE WITH EITHER AN ABSTINENT OR CONTROL RAT. MALE OFFSPRING'S MEMORY WAS EVALUATED BY STEP THROUGH TEST. BESIDES, REWARDING EFFECTS OF MORPHINE WERE CHECKED WITH CCP PARADIGM. OFFSPRING OF ABSTINENT ANIMALS SHOWED SIGNIFICANT MEMORY IMPAIRMENT COMPARED TO THE CONTROL GROUP WHICH WAS MORE PROMINENT IN THE OFFSPRING OF ABSTINENT FEMALES. CONDITIONING RESULTS SHOWED THAT ADMINISTRATION OF A HIGH DOSE OF MORPHINE (10MG/KG) THAT COULD SIGNIFICANTLY INDUCE CPP IN CONTROL RATS, WAS NOT ABLE TO INDUCE SIMILAR RESULTS IN THE OFFSPRING OF MORPHINE ABSTINENT PARENTS; AND CPP WAS MUCH MORE PROMINENT WHEN IT WAS INDUCED IN THE OFFSPRING OF MORPHINE EXPOSED FEMALES COMPARED TO THE PROGENY OF MORPHINE EXPOSED MALES. IT IS CONCLUDED THAT PARENTAL MORPHINE CONSUMPTION IN ADULTHOOD EVEN BEFORE MATING HAS DESTRUCTIVE EFFECTS ON MEMORY STATE OF THE MALE OFFSPRING AND ALSO LEADS TO TOLERANCE TO THE REWARDING EFFECTS OF MORPHINE. THESE EFFECTS ARE GREATER WHEN THE MORPHINE CONSUMER PARENT IS THE FEMALE ONE. 2018 17 4863 33 ORIGINS OF LIFETIME HEALTH AROUND THE TIME OF CONCEPTION: CAUSES AND CONSEQUENCES. PARENTAL ENVIRONMENTAL FACTORS, INCLUDING DIET, BODY COMPOSITION, METABOLISM, AND STRESS, AFFECT THE HEALTH AND CHRONIC DISEASE RISK OF PEOPLE THROUGHOUT THEIR LIVES, AS CAPTURED IN THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE CONCEPT. RESEARCH ACROSS THE EPIDEMIOLOGICAL, CLINICAL, AND BASIC SCIENCE FIELDS HAS IDENTIFIED THE PERIOD AROUND CONCEPTION AS BEING CRUCIAL FOR THE PROCESSES MEDIATING PARENTAL INFLUENCES ON THE HEALTH OF THE NEXT GENERATION. DURING THIS TIME, FROM THE MATURATION OF GAMETES THROUGH TO EARLY EMBRYONIC DEVELOPMENT, PARENTAL LIFESTYLE CAN ADVERSELY INFLUENCE LONG-TERM RISKS OF OFFSPRING CARDIOVASCULAR, METABOLIC, IMMUNE, AND NEUROLOGICAL MORBIDITIES, OFTEN TERMED DEVELOPMENTAL PROGRAMMING. WE REVIEW PERICONCEPTIONAL INDUCTION OF DISEASE RISK FROM FOUR BROAD EXPOSURES: MATERNAL OVERNUTRITION AND OBESITY; MATERNAL UNDERNUTRITION; RELATED PATERNAL FACTORS; AND THE USE OF ASSISTED REPRODUCTIVE TREATMENT. STUDIES IN BOTH HUMANS AND ANIMAL MODELS HAVE DEMONSTRATED THE UNDERLYING BIOLOGICAL MECHANISMS, INCLUDING EPIGENETIC, CELLULAR, PHYSIOLOGICAL, AND METABOLIC PROCESSES. WE ALSO PRESENT A META-ANALYSIS OF MOUSE PATERNAL AND MATERNAL PROTEIN UNDERNUTRITION THAT SUGGESTS DISTINCT PARENTAL PERICONCEPTIONAL CONTRIBUTIONS TO POSTNATAL OUTCOMES. WE PROPOSE THAT THE EVIDENCE FOR PERICONCEPTIONAL EFFECTS ON LIFETIME HEALTH IS NOW SO COMPELLING THAT IT CALLS FOR NEW GUIDANCE ON PARENTAL PREPARATION FOR PREGNANCY, BEGINNING BEFORE CONCEPTION, TO PROTECT THE HEALTH OF OFFSPRING. 2018 18 3595 28 IMPLICATIONS OF MATERNAL CONDITIONS AND PREGNANCY COURSE ON OFFSPRING'S MEDICAL PROBLEMS IN ADULT LIFE. IN THE LAST DECADE, NUMEROUS EPIDEMIOLOGICAL, CLINICAL AND EXPERIMENTAL DATA SHOW THAT PERICONCEPTIONAL, PERINATAL AND POSTNATAL ENVIRONMENT DETERMINES THE OFFSPRING'S RISK FOR LATER-LIFE CHRONIC DISEASE. FOR THIS PHENOMENON, THE TERM "FETAL" OR "PERINATAL PROGRAMMING" IS USED. IN EXPOSED OFFSPRING ALREADY IN CHILDHOOD AND EARLY ADULTHOOD, METABOLIC AND CARDIOVASCULAR CHANGES CAN BE OBSERVED, LEADING TO OBESITY, DIABETES AND HYPERTENSION. NOWADAYS, THE MODE OF CONCEPTION (E.G., IN VITRO FERTILIZATION), MATERNAL METABOLIC CONDITIONS (E.G., UNDERNUTRITION, OVERNUTRITION, DIABETES) AND COMPLICATIONS DURING PREGNANCY (E.G., PREECLAMPSIA, INTRAUTERINE GROWTH RESTRICTION) ARE SUSPECTED TO BE NEGATIVE PREDICTORS FOR OFFSPRING'S LONG-TERM HEALTH. MECHANISMS RESPONSIBLE FOR THESE EFFECTS STILL REMAIN MAINLY UNCLEAR, BUT INCLUDE EPIGENETIC, TRANSCRIPTIONAL, ENDOPLASMIC RETICULUM STRESS, AND REACTIVE OXYGEN SPECIES. THIS REVIEW PRESENTS A PIECE OF THE PUZZLE WITH REGARDS TO PERICONCEPTIONAL AND EARLY PERINATAL CONDITIONS DETERMINING LATER-LIFE RISK FOR CHRONIC ADULT DISEASE. 2016 19 3578 24 IMPACT OF PARENTAL OVER- AND UNDERWEIGHT ON THE HEALTH OF OFFSPRING. PARENTAL EXCESS WEIGHT AND ESPECIALLY PREGESTATIONAL MATERNAL OBESITY AND EXCESSIVE WEIGHT GAIN DURING PREGNANCY HAVE BEEN RELATED TO AN INCREASED RISK OF METABOLIC (OBESITY, TYPE 2 DIABETES, CARDIOVASCULAR DISEASE, METABOLIC SYNDROME) AND NONMETABOLIC (CANCER, OSTEOPOROSIS, ASTHMA, NEUROLOGIC ALTERATIONS) DISEASES IN THE OFFSPRING, PROBABLY MEDIATED BY EPIGENETIC MECHANISMS OF FETAL PROGRAMMING. MATERNAL UNDERWEIGHT IS LESS COMMON IN DEVELOPED SOCIETIES, BUT THE DISCREPANCY BETWEEN A POOR NUTRITIONAL ENVIRONMENT IN UTERO AND A NORMAL OR EXCESSIVE POSTNATAL FOOD SUPPLY WITH RAPID GROWTH CATCH-UP APPEARS TO BE THE MAIN CANDIDATE MECHANISM OF THE DEVELOPMENT OF CHRONIC DISEASES DURING THE OFFSPRING'S ADULTHOOD. THE ROLE OF THE POSTNATAL ENVIRONMENT IN BOTH SCENARIOS (PARENTAL OVERWEIGHT OR UNDERWEIGHT) ALSO SEEMS TO INFLUENCE THE OFFSPRING'S HEALTH. LIFESTYLE INTERVENTIONS BEFORE AND DURING PREGNANCY IN BOTH PARENTS, BUT ESPECIALLY IN THE MOTHER, AS WELL AS IN CHILDREN AFTER BIRTH, ARE ADVISABLE TO COUNTERACT THE MANY UNDESIRABLE CHRONIC CONDITIONS DESCRIBED. 2019 20 5578 29 ROLE OF MIRNA IN THE TRANSMISSION OF METABOLIC DISEASES ASSOCIATED WITH PATERNAL DIET-INDUCED OBESITY. THE CONCEPT OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASES (DOHAD) RECOGNIZES THAT AN UNFAVORABLE MATERNAL ENVIRONMENT ALTERS THE DEVELOPMENTAL TRAJECTORY OF THE FETUS AND CAN LEAD TO LONG-TERM RISK OF DEVELOPING CHRONIC NONCOMMUNICABLE DISEASES. MORE RECENTLY, THE CONCEPT OF A PATERNAL TRANSMISSION [PATERNAL ORIGINS OF HEALTH AND DISEASES (POHAD)] HAS EMERGED STRESSING THE IMPACT OF PATERNAL OVERWEIGHT OR OBESITY ON OFFSPRING'S HEALTH AND DEVELOPMENT. WHILE VERY FEW EXAMPLES OF PATERNAL EPIGENETIC INHERITANCE OF METABOLIC DISORDERS HAVE BEEN EVIDENCED IN HUMAN, MANY EXPERIMENTAL MOUSE MODELS BASED ON HIGH-FAT DIET (HFD)-INDUCED PATERNAL OBESITY HAVE BEEN DEVELOPED TO BREAKDOWN MOLECULAR MECHANISMS INVOLVED IN THE PROCESS. BESIDES DNA METHYLATION AND CHROMATIN STRUCTURE, SPERM SHORT NONCODING RNAS HAVE BEEN CONSIDERED AS THE MAIN EPIGENETIC VECTOR OF INHERITANCE OF PATERNALLY ENVIRONMENTALLY INDUCED CHANGES. AMONG THEM, SPERM MIRNAS ARE ONE PARTICULAR SUBSPECIES SENSITIVE TO ENVIRONMENTAL CHANGES AND OBESITY CAN MODIFY THE SPERM MIRNA PROFILE. ONCE DELIVERED INTO THE ZYGOTE, THESE MOLECULES MIGHT INDUCE EPIGENETIC MODIFICATIONS IN THE EMBRYO, THEREBY LEADING TO CONSEQUENCES FOR FETUS DEVELOPMENT AND OFFSPRING PHYSICAL AND METABOLIC HEALTH LATER ON IN LIFE. FURTHERMORE, SOME DATA ALSO SUGGEST THAT METABOLIC PATHOLOGIES MAY BE INTERGENERATIONALLY OR TRANSGENERATIONALLY TRANSMITTED. 2019