1 4941 161 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 2 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 3 6426 40 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 4 4051 41 MALE OBESITY: EPIGENETIC ORIGIN AND EFFECTS IN SPERM AND OFFSPRING. PURPOSE OF REVIEW: THE PREVALENCE OF OBESITY HAS INCREASED SUBSTANTIALLY IN THE CURRENT GENERATIONS OF WESTERN COUNTRIES, AND THE BURDEN OF OBESITY-RELATED COMPLICATIONS HAS BEEN GROWING STEADILY. IN MEN, OBESITY IS NOT ONLY A MAJOR RISK FACTOR FOR SERIOUS CHRONIC DISEASES, CONCERN IS GROWING THAT THE REPRODUCTIVE CAPACITY, AND MORE PARTICULARLY, THEIR OFFSPRING'S HEALTH MAY BE AFFECTED. OBESITY-RELATED IMPAIRED SPERMATOGENESIS IS ASSOCIATED WITH A DECREASE IN MICROSCOPIC AND MOLECULAR SPERM CHARACTERISTICS AND PREGNANCY SUCCESS. WE HYPOTHESIZE THAT EPIGENETICS IS AN IMPORTANT MEDIATOR EXPLAINING INTERACTIONS BETWEEN AN OBESOGENIC ENVIRONMENT AND SPERM/OFFSPRING OUTCOMES. RECENT FINDINGS: RECENT STUDIES HAVE EXPLORED INTER- AND TRANSGENERATIONAL EPIGENETIC EFFECTS IN SPERM CELLS AND IN OFFSPRING. FATHER-TO-CHILD EFFECTS HAVE BEEN REPORTED IN RELATION TO PRECONCEPTIONAL NUTRITIONAL AND LIFE-STYLE RELATED FACTORS. SUMMARY: HERE, WE SUMMARIZE THE CURRENT UNDERSTANDING ABOUT OBESITY AND MOLECULAR OR EPIGENETIC UNDERLYING MECHANISMS IN SPERM. WE IDENTIFY THE OBESOGENIC ENVIRONMENT OF THE FATHER BEFORE CONCEPTION AS A POTENTIAL ORIGIN OF HEALTH OR DISEASE IN THE OFFSPRING AND INCLUDE IT AS PART OF A NEW CONCEPT, THE PATERNAL ORIGINS OF HEALTH AND DISEASE (POHAD). 2017 5 5578 40 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 6 4496 40 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 7 1153 37 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 8 4011 38 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 9 3119 36 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 10 5773 49 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 11 6234 32 THE LONG-TERM EFFECTS OF PRENATAL DEVELOPMENT ON GROWTH AND METABOLISM. PEOPLE WHO WERE SMALL AT BIRTH AND HAD POOR INFANT GROWTH HAVE AN INCREASED RISK OF ADULT CARDIOVASCULAR DISEASE, OSTEOPOROSIS, AND TYPE 2 DIABETES, PARTICULARLY IF THEIR RESTRICTED EARLY GROWTH WAS FOLLOWED BY INCREASED CHILDHOOD WEIGHT GAIN. THESE RELATIONS EXTEND ACROSS THE NORMAL RANGE OF BIRTH SIZE IN A GRADED MANNER, SO REDUCED SIZE IS NOT A PREREQUISITE. IN ADDITION, LARGER BIRTH SIZE IS ASSOCIATED WITH RISKS OF OBESITY AND TYPE 2 DIABETES. THE ASSOCIATIONS APPEAR TO REFLECT DEVELOPMENTAL PLASTIC RESPONSES MADE BY THE FETUS AND INFANT BASED ON CUES ABOUT THE ENVIRONMENT, INFLUENCED BY MATERNAL CHARACTERISTICS INCLUDING DIET, BODY COMPOSITION, STRESS, AND EXERCISE LEVELS. THESE RESPONSES INVOLVE EPIGENETIC PROCESSES THAT MODIFY THE OFFSPRING'S PHENOTYPE. VULNERABILITY TO ILL HEALTH RESULTS IF THE ENVIRONMENT IN INFANCY, CHILDHOOD, AND LATER LIFE IS MISMATCHED TO THE PHENOTYPE INDUCED IN DEVELOPMENT, INFORMED BY THE DEVELOPMENTAL CUES. THIS MISMATCH MAY ARISE THROUGH UNBALANCED DIET OR BODY COMPOSITION OF THE MOTHER OR A CHANGE IN LIFESTYLE FACTORS BETWEEN GENERATIONS. THESE INSIGHTS OFFER NEW POSSIBILITIES FOR THE EARLY DIAGNOSIS AND PREVENTION OF CHRONIC DISEASE. 2011 12 6745 45 WHO'S YOUR DADDY?: PATERNAL INHERITANCE OF METABOLIC DISEASE RISK. PURPOSE OF REVIEW: ALTHOUGH THE IMPORTANCE OF OPTIMIZING MOTHERS' HEALTH PRIOR TO CONCEPTION AND DURING PREGNANCY IS NOW WELL ACCEPTED, RECENT DATA ALSO IMPLICATE HEALTH AND NUTRITIONAL STATUS OF FATHERS AS CONTRIBUTORS TO CHRONIC DISEASE RISK IN THEIR PROGENY. THIS BRIEF REVIEW WILL HIGHLIGHT RECENT EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES LINKING PATERNAL OVERNUTRITION, UNDERNUTRITION, AND OTHER FORMS OF STRESS, TO METABOLIC DISEASE IN THE OFFSPRING. RECENT FINDINGS: THE PAST 2 YEARS HAVE BROUGHT TREMENDOUS INSIGHTS INTO THE MECHANISMS BY WHICH PATERNAL EXPOSURES CAN CONTRIBUTE TO DISEASE SUSCEPTIBILITY IN THE NEXT GENERATION. RECENT DATA, BOTH FROM HUMANS AND EXPERIMENTAL MODELS, DEMONSTRATE THAT PATERNAL OBESITY AND UNDERNUTRITION RESULT IN EPIGENETIC REPROGRAMMING OF MALE GERM CELLS, NOTABLY ALTERED DNA METHYLATION, HISTONE RETENTION, AND EXPRESSION OF SMALL NONCODING RNAS AND TRANSFER RNA FRAGMENTS. NOVEL MECHANISMS HAVE ALSO BEEN IDENTIFIED, SUCH AS EPIDIDYMAL TRANSPORT VESICLES, SEMINAL FLUID HORMONES AND METABOLITES, AND A UNIQUE SEMINAL FLUID MICROBIOME. SUMMARY: PATERNAL NUTRITIONAL AND OTHER PERTURBATIONS ARE LINKED TO RISK OF METABOLIC DISEASE AND OBESITY IN OFFSPRING. GERM CELL-DEPENDENT MECHANISMS HAVE RECENTLY BEEN LINKED TO THESE INTERGENERATIONAL EFFECTS. NONGENETIC, PATERNAL INHERITANCE OF CHRONIC DISEASE HAS IMPORTANT IMPLICATIONS FOR PUBLIC HEALTH, AND MAY PROVIDE NOVEL OPPORTUNITIES FOR MULTIGENERATIONAL DISEASE PREVENTION. 2017 13 2183 43 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 14 5167 38 PRECONCEPTION PATERNAL MENTAL DISORDERS AND CHILD HEALTH: MECHANISMS AND INTERVENTIONS. MENTAL ILLNESS IS A SIGNIFICANT GLOBAL HEALTH ISSUE WITH A STEADY PREVALENCE. HIGH HERITABILITY IS SUSPECTED, BUT GENOME-WIDE ASSOCIATION STUDIES ONLY IDENTIFIED A SMALL NUMBER OF RISK GENES ASSOCIATED WITH MENTAL DISORDERS. THIS 'MISSING INHERITANCE' CAN BE PARTIALLY EXPLAINED BY EPIGENETIC HEREDITY. EVIDENCE FROM NUMEROUS ANIMAL MODELS AND HUMAN STUDIES SUPPORTS THE POSSIBILITY THAT PRECONCEPTION PATERNAL MENTAL HEALTH INFLUENCES THEIR OFFSPRING'S MENTAL HEALTH VIA NONGENETIC MEANS. HERE, WE REVIEW TWO POTENTIAL PATHWAYS, INCLUDING SPERM EPIGENETICS AND SEMINAL PLASMA COMPONENTS. THE CURRENT REVIEW HIGHLIGHTS THE ROLE OF SPERM EPIGENETICS AND EXPLORES EPIGENETIC MESSAGE ORIGINATION AND SUSCEPTIBILITY TO CHRONIC STRESS. MEANWHILE, POSSIBLE SPATIOTEMPORAL WINDOWS AND EVENTS THAT INDUCE SEXUALLY DIMORPHIC MODES AND EFFECTS OF PATERNAL STRESS TRANSMISSION ARE INFERRED IN THIS REVIEW. ADDITIONALLY, WE DISCUSS EMERGING INTERVENTIONS THAT COULD POTENTIALLY BLOCK THE INTERGENERATIONAL TRANSMISSION OF PATERNAL PSYCHIATRIC DISORDERS AND REDUCE THE INCIDENCE OF MENTAL ILLNESS. UNDERSTANDING THE UNDERLYING MECHANISMS BY WHICH PRECONCEPTION PATERNAL STRESS IMPACTS OFFSPRING HEALTH IS CRITICAL FOR IDENTIFYING STRATEGIES SUPPORTING HEALTHY DEVELOPMENT AND SUCCESSFULLY CONTROLLING THE PREVALENCE OF MENTAL ILLNESS. 2023 15 1376 32 DEVELOPMENTAL PROGRAMMING OF BODY COMPOSITION: UPDATE ON EVIDENCE AND MECHANISMS. PURPOSE OF REVIEW: A GROWING BODY OF EPIDEMIOLOGICAL AND EXPERIMENTAL DATA INDICATE THAT NUTRITIONAL OR ENVIRONMENTAL STRESSORS DURING EARLY DEVELOPMENT CAN INDUCE LONG-TERM ADAPTATIONS THAT INCREASE RISK OF OBESITY, DIABETES, CARDIOVASCULAR DISEASE, AND OTHER CHRONIC CONDITIONS-A PHENOMENON TERMED "DEVELOPMENTAL PROGRAMMING." A COMMON PHENOTYPE IN HUMANS AND ANIMAL MODELS IS ALTERED BODY COMPOSITION, WITH REDUCED MUSCLE AND BONE MASS, AND INCREASED FAT MASS. IN THIS REVIEW, WE SUMMARIZE THE RECENT LITERATURE LINKING PRENATAL FACTORS TO FUTURE BODY COMPOSITION AND EXPLORE CONTRIBUTING MECHANISMS. RECENT FINDINGS: MANY PRENATAL EXPOSURES, INCLUDING INTRAUTERINE GROWTH RESTRICTION, EXTREMES OF BIRTH WEIGHT, MATERNAL OBESITY, AND MATERNAL DIABETES, ARE ASSOCIATED WITH INCREASED FAT MASS, REDUCED MUSCLE MASS, AND DECREASED BONE DENSITY, WITH EFFECTS REPORTED THROUGHOUT INFANCY AND CHILDHOOD, AND PERSISTING INTO MIDDLE AGE. MECHANISMS AND MEDIATORS INCLUDE MATERNAL DIET, BREASTMILK COMPOSITION, METABOLITES, APPETITE REGULATION, GENETIC AND EPIGENETIC INFLUENCES, STEM CELL COMMITMENT AND FUNCTION, AND MITOCHONDRIAL METABOLISM. DIFFERENCES IN BODY COMPOSITION ARE A COMMON PHENOTYPE FOLLOWING DISRUPTIONS TO THE PRENATAL ENVIRONMENT, AND MAY CONTRIBUTE TO DEVELOPMENTAL PROGRAMMING OF OBESITY AND DIABETES RISK. 2019 16 6088 42 THE EFFECTS OF ASSISTED REPRODUCTION TECHNOLOGIES ON METABOLIC HEALTH AND DISEASEDAGGER. THE INCREASING PREVALENCE OF METABOLIC DISEASES PLACES A SUBSTANTIAL BURDEN ON HUMAN HEALTH THROUGHOUT THE WORLD. IT IS BELIEVED THAT PREDISPOSITION TO METABOLIC DISEASE STARTS EARLY IN LIFE, A PERIOD OF GREAT SUSCEPTIBILITY TO EPIGENETIC REPROGRAMMING DUE TO ENVIRONMENTAL INSULTS. ASSISTED REPRODUCTIVE TECHNOLOGIES (ART), I.E., TREATMENTS FOR INFERTILITY, MAY AFFECT EMBRYO DEVELOPMENT, RESULTING IN MULTIPLE ADVERSE HEALTH OUTCOMES IN POSTNATAL LIFE. THE MOST FREQUENTLY OBSERVED ALTERATION IN ART PREGNANCIES IS IMPAIRED PLACENTAL NUTRIENT TRANSFER. MOREOVER, CONSEQUENT INTRAUTERINE GROWTH RESTRICTION AND LOW BIRTH WEIGHT FOLLOWED BY CATCH-UP GROWTH CAN ALL PREDICT FUTURE OBESITY, INSULIN RESISTANCE, AND CHRONIC METABOLIC DISEASES. IN THIS REVIEW, WE HAVE FOCUSED ON EVIDENCE OF ADVERSE METABOLIC ALTERATIONS ASSOCIATED WITH ART, WHICH CAN CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC ADULT-ONSET DISEASES, SUCH AS METABOLIC SYNDROME, TYPE 2 DIABETES, AND CARDIOVASCULAR DISEASE. DUE TO HIGH PHENOTYPIC PLASTICITY, ART PREGNANCIES CAN PRODUCE BOTH OFFSPRING WITH ADVERSE HEALTH OUTCOMES, AS WELL AS HEALTHY INDIVIDUALS. WE FURTHER DISCUSS THE SEX-SPECIFIC AND AGE-DEPENDENT METABOLIC ALTERATIONS REFLECTED IN ART OFFSPRING, AND HOW THE DEGREE OF INTERFERENCE OF A GIVEN ART PROCEDURE (FROM MILD TO MORE SEVERE MANIPULATION OF THE EGG) AFFECTS THE OCCURRENCE AND DEGREE OF OFFSPRING ALTERATIONS. OVER THE LAST FEW YEARS, STUDIES HAVE REPORTED SIGNS OF CARDIOMETABOLIC ALTERATIONS IN ART OFFSPRING THAT ARE DETECTABLE AT A YOUNG AGE BUT THAT DO NOT APPEAR TO CONSTITUTE A HIGH RISK OF DISEASE AND MORBIDITY PER SE. THESE ABNORMAL PHENOTYPES COULD BE EARLY INDICATORS OF THE DEVELOPMENT OF CHRONIC DISEASES, INCLUDING METABOLIC SYNDROME, IN ADULTHOOD. THE EARLY DETECTION OF METABOLIC ALTERATIONS COULD CONTRIBUTE TO PREVENTING THE ONSET OF DISEASE IN ADULTHOOD. SUCH EARLY INTERVENTIONS MAY COUNTERACT THE RISK FACTORS AND IMPROVE THE LONG-TERM HEALTH OF THE INDIVIDUAL. 2021 17 6554 27 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 18 2274 29 EPIGENETIC REGULATION AND FETAL PROGRAMMING. FETAL PROGRAMMING ENCOMPASSES THE ROLE OF DEVELOPMENTAL PLASTICITY IN RESPONSE TO ENVIRONMENTAL AND NUTRITIONAL SIGNALS DURING EARLY LIFE AND ITS POTENTIAL ADVERSE CONSEQUENCES (RISK OF CARDIOVASCULAR, METABOLIC AND BEHAVIOURAL DISEASES) IN LATER LIFE. THE FIRST STUDIES IN THIS FIELD HIGHLIGHTED AN ASSOCIATION BETWEEN POOR FETAL GROWTH AND CHRONIC ADULT DISEASES. HOWEVER, ENVIRONMENTAL SIGNALS DURING EARLY LIFE MAY LEAD TO ADVERSE LONG-TERM EFFECTS INDEPENDENTLY OF OBVIOUS EFFECTS ON FETAL GROWTH. ADVERSE LONG-TERM EFFECTS REFLECT A MISMATCH BETWEEN EARLY (FETAL AND NEONATAL) ENVIRONMENTAL CONDITIONS AND THE CONDITIONS THAT THE INDIVIDUAL WILL CONFRONT LATER IN LIFE. THE MECHANISMS UNDERLYING THIS RISK REMAIN UNCLEAR. HOWEVER, EXPERIMENTAL DATA IN RODENTS AND RECENT OBSERVATIONS IN HUMANS SUGGEST THAT EPIGENETIC CHANGES IN REGULATORY GENES AND GROWTH-RELATED GENES PLAY A SIGNIFICANT ROLE IN FETAL PROGRAMMING. IMPROVEMENTS IN OUR UNDERSTANDING OF THE BIOCHEMICAL AND MOLECULAR MECHANISMS AT PLAY IN FETAL PROGRAMMING WOULD MAKE IT POSSIBLE TO IDENTIFY BIOMARKERS FOR DETECTING INFANTS AT HIGH RISK OF ADULT-ONSET DISEASES. SUCH IMPROVEMENTS SHOULD ALSO LEAD TO THE DEVELOPMENT OF PREVENTIVE AND THERAPEUTIC STRATEGIES. 2008 19 2806 47 FETAL PROGRAMMING AND THE RISK OF NONCOMMUNICABLE DISEASE. THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) HYPOTHESIS PROPOSES THAT ENVIRONMENTAL CONDITIONS DURING FETAL AND EARLY POST-NATAL DEVELOPMENT INFLUENCE LIFELONG HEALTH AND CAPACITY THROUGH PERMANENT EFFECTS ON GROWTH, STRUCTURE AND METABOLISM. THIS HAS BEEN CALLED 'PROGRAMMING'. THE HYPOTHESIS IS SUPPORTED BY EPIDEMIOLOGICAL EVIDENCE IN HUMANS LINKING NEWBORN SIZE, AND INFANT GROWTH AND NUTRITION, TO ADULT HEALTH OUTCOMES, AND BY EXPERIMENTS IN ANIMALS SHOWING THAT MATERNAL UNDER- AND OVER-NUTRITION AND OTHER INTERVENTIONS (E.G., GLUCOCORTICOID EXPOSURE) DURING PREGNANCY LEAD TO ABNORMAL METABOLISM AND BODY COMPOSITION IN THE ADULT OFFSPRING. EARLY LIFE PROGRAMMING IS NOW THOUGHT TO BE IMPORTANT IN THE ETIOLOGY OF OBESITY, TYPE 2 DIABETES, AND CARDIOVASCULAR DISEASE, OPENING UP THE POSSIBILITY THAT THESE COMMON DISEASES COULD BE PREVENTED BY ACHIEVING OPTIMAL FETAL AND INFANT DEVELOPMENT. THIS IS LIKELY TO HAVE ADDITIONAL BENEFITS FOR INFANT SURVIVAL AND HUMAN CAPITAL (E.G., IMPROVED COGNITIVE PERFORMANCE AND PHYSICAL WORK CAPACITY). FETAL NUTRITION IS INFLUENCED BY THE MOTHER'S DIET AND BODY SIZE AND COMPOSITION, BUT HARD EVIDENCE THAT THE NUTRITION OF THE HUMAN MOTHER PROGRAMMES CHRONIC DISEASE RISK IN HER OFFSPRING IS CURRENTLY LIMITED. RECENT FINDINGS FROM FOLLOW-UP OF CHILDREN BORN AFTER RANDOMISED NUTRITIONAL INTERVENTIONS IN PREGNANCY ARE MIXED, BUT SHOW SOME EVIDENCE OF BENEFICIAL EFFECTS ON VASCULAR FUNCTION, LIPID CONCENTRATIONS, GLUCOSE TOLERANCE AND INSULIN RESISTANCE. WORK IN EXPERIMENTAL ANIMALS SUGGESTS THAT EPIGENETIC PHENOMENA, WHEREBY GENE EXPRESSION IS MODIFIED BY DNA METHYLATION, AND WHICH ARE SENSITIVE TO THE NUTRITIONAL ENVIRONMENT IN EARLY LIFE, MAY BE ONE MECHANISM UNDERLYING PROGRAMMING. 2013 20 1921 53 ENVIRONMENTAL EPIGENETIC INHERITANCE THROUGH GAMETES AND IMPLICATIONS FOR HUMAN REPRODUCTION. BACKGROUND: TRADITIONAL STUDIES FOCUSED ON DNA AS THE HERITABLE INFORMATION CARRIER THAT PASSES THE PHENOTYPE FROM PARENTS TO OFFSPRING. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT INFORMATION, THAT IS INDEPENDENT OF THE DNA SEQUENCE, TERMED EPIGENETIC INFORMATION, CAN BE INHERITED BETWEEN GENERATIONS. RECENTLY, IN OUR LAB, WE FOUND THAT PREDIABETES IN FATHERS INCREASES THE SUSCEPTIBILITY TO DIABETES IN OFFSPRING THROUGH GAMETIC CYTOSINE METHYLATION CHANGES. PATERNAL PREDIABETES CHANGED OVERALL METHYLATION PATTERNS IN SPERM, AND A LARGE PORTION OF DIFFERENTIALLY METHYLATED LOCI CAN BE TRANSMITTED TO PANCREATIC ISLETS OF OFFSPRING UP TO THE SECOND GENERATION. IN THIS REVIEW, WE SURVEY THE EXTENSIVE EXAMPLES OF ENVIRONMENTALLY INDUCED EPIGENETIC INHERITANCE IN VARIOUS SPECIES, RANGING FROM CAENORHABDITIS ELEGANS TO HUMANS. WE FOCUS MAINLY ON ELUCIDATING THE MOLECULAR BASIS OF ENVIRONMENTAL EPIGENETIC INHERITANCE THROUGH GAMETES, WHICH IS AN EMERGING THEME AND HAS IMPORTANT IMPLICATIONS FOR EXPLAINING THE PREVALENCE OF OBESITY, TYPE 2 DIABETES AND OTHER CHRONIC NON-GENETIC DISEASES, WHICH IS ALSO IMPORTANT FOR UNDERSTANDING THE INFLUENCE OF ENVIRONMENTAL EXPOSURES ON REPRODUCTIVE AND OVERALL HEALTH IN OFFSPRING. METHODS: FOR THIS REVIEW, WE INCLUDED RELEVANT DATA AND INFORMATION OBTAINED THROUGH A PUBMED DATABASE SEARCH FOR ALL ENGLISH LANGUAGE ARTICLES PUBLISHED UP TO AUGUST 2014 WHICH INCLUDED THE TERM 'ENVIRONMENTAL EPIGENETIC INHERITANCE' AND 'TRANSGENERATIONAL EPIGENETIC INHERITANCE'. WE FOCUSED ON RESEARCH PAPERS USING ANIMAL MODELS INCLUDING DROSOPHILA, C. ELEGANS, MOUSE AND RAT. HUMAN DATA WERE ALSO INCLUDED. RESULTS: EVIDENCE FROM ANIMAL MODELS SUGGESTS THAT ENVIRONMENTAL EPIGENETIC INHERITANCE THROUGH GAMETES EXISTS IN VARIOUS SPECIES. EXTENSIVE MOLECULAR EVIDENCE SUGGESTS THAT EPIGENETIC INFORMATION CARRIERS INCLUDING DNA METHYLATION, NON-CODING RNAS AND CHROMATIN PROTEINS IN GAMETES PLAY IMPORTANT ROLES IN THE TRANSMISSION OF PHENOTYPES FROM PARENTS TO OFFSPRING. CONCLUSIONS: GIVEN THE LARGE NUMBER OF EXPERIMENTAL EVIDENCE FROM VARIOUS ORGANISMS, IT IS CLEAR THAT PARENTAL ENVIRONMENTAL ALTERATIONS CAN AFFECT THE PHENOTYPES OF OFFSPRING THROUGH GAMETIC EPIGENETIC ALTERATIONS. THIS MORE RECENT THINKING BASED ON NEW DATA MAY HAVE IMPLICATIONS IN EXPLAINING THE PREVALENCE OF OBESITY, TYPE 2 DIABETES AND OTHER CHRONIC NON-GENETIC DISEASES. THIS ALSO IMPLIES THAT, IN THE NEAR FUTURE, EPIGENETIC FACTORS WHICH ARE HERITABLE SHOULD BE REGARDED IMPORTANT IN DETERMINING THE RISK OF CERTAIN DISEASES. MOREOVER, IDENTIFICATION OF EPIGENETIC MARKERS IN GAMETES (POLAR BODY OR SPERM) MAY HOLD GREAT PROMISE FOR PREDICTING SUSCEPTIBILITY TO AND PREVENTING CERTAIN NON-GENETIC DISEASES IN OFFSPRING, AS WELL AS PROVIDING INDICATIONS ON PARENTAL ENVIRONMENTAL EXPOSURES. 2015