1 5578 122 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 2 6745 37 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 3 1153 38 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 2137 45 EPIGENETIC INHERITANCE AND EVOLUTION: A PATERNAL PERSPECTIVE ON DIETARY INFLUENCES. THE EARLIEST INDICATIONS FOR PATERNALLY INDUCED TRANSGENERATIONAL EFFECTS FROM THE ENVIRONMENT TO FUTURE GENERATIONS WERE BASED ON A SMALL NUMBER OF LONG-TERM EPIDEMIOLOGICAL STUDIES AND SOME EMPIRICAL OBSERVATIONS. ONLY RECENTLY HAVE EXPERIMENTAL ANIMAL MODELS AND A FEW ANALYSES ON HUMAN DATA EXPLORED THE TRANSGENERATIONAL NATURE OF PHENOTYPIC CHANGES OBSERVED IN OFFSPRING. CHANGES INCLUDE MULTIPLE METABOLIC DISORDERS, CANCER AND OTHER CHRONIC DISEASES. THESE PHENOTYPES CANNOT ALWAYS BE EXPLAINED BY MENDELIAN INHERITANCE, DNA MUTATIONS OR GENETIC DAMAGE. HENCE, A NEW COMPELLING THEORY ON EPIGENETIC INHERITANCE IS GAINING INTEREST, PROVIDING NEW CONCEPTS THAT EXTEND DARWIN'S EVOLUTIONARY THEORY. EPIGENETIC ALTERATIONS OR "EPIMUTATIONS" ARE BEING CONSIDERED TO EXPLAIN TRANSGENERATIONAL INHERITANCE OF PARENTALLY ACQUIRED TRAITS. THE RESPONSIBLE MECHANISMS FOR THESE EPIMUTATIONS INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND RNA-MEDIATED EFFECTS. THIS REVIEW EXPLORES THE LITERATURE ON A NUMBER OF TIME-DEPENDENT ENVIRONMENTALLY INDUCED EPIGENETIC ALTERATIONS, SPECIFICALLY THOSE FROM DIETARY EXPOSURES. WE SUGGEST A ROLE FOR THE MALE GERM LINE AS ONE OF NATURE'S TOOLS TO CAPTURE MESSAGES FROM OUR CONTINUOUSLY CHANGING ENVIRONMENT AND TO TRANSFER THIS INFORMATION TO SUBSEQUENT GENERATIONS. FURTHER, WE OPEN THE DISCUSSION THAT THE PATERNALLY INHERITED EPIGENETIC INFORMATION MAY CONTRIBUTE TO EVOLUTIONARY ADAPTATION. 2015 5 4941 40 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 4051 36 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 7 1922 31 ENVIRONMENTAL EPIGENETIC INTERACTION OF GAMETES AND EARLY EMBRYOSDAGGER. IN RECENT YEARS, THE DEVELOPMENTAL ORIGINS OF DISEASES HAVE BEEN INCREASINGLY RECOGNIZED AND ACCEPTED. AS SUCH, IT HAS BEEN SUGGESTED THAT MOST ADULTHOOD CHRONIC DISEASES SUCH AS DIABETES, OBESITY, CARDIOVASCULAR DISEASE, AND EVEN TUMORS MAY DEVELOP AT A VERY EARLY STAGE. IN ADDITION TO INTRAUTERINE ENVIRONMENTAL EXPOSURE, GERM CELLS CARRY AN IMPORTANT INHERITANCE ROLE AS THE PRIMARY LINK BETWEEN THE TWO GENERATIONS. ADVERSE EXTERNAL INFLUENCES DURING DIFFERENTIATION AND DEVELOPMENT CAN CAUSE DAMAGE TO GERM CELLS, WHICH MAY THEN INCREASE THE RISK OF CHRONIC DISEASE DEVELOPMENT LATER IN LIFE. HERE, WE FURTHER ELUCIDATE AND CLARIFY THE CONCEPT OF GAMETE AND EMBRYO ORIGINS OF ADULT DISEASES BY FOCUSING ON THE ENVIRONMENTAL INSULTS ON GERM CELLS, FROM DIFFERENTIATION TO MATURATION AND FERTILIZATION. 2022 8 5167 31 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 9 4717 33 NON-GENOMIC TRANSGENERATIONAL INHERITANCE OF DISEASE RISK. THAT THERE IS A HERITABLE OR FAMILIAL COMPONENT OF SUSCEPTIBILITY TO CHRONIC NON-COMMUNICABLE DISEASES SUCH AS TYPE 2 DIABETES, OBESITY AND CARDIOVASCULAR DISEASE IS WELL ESTABLISHED, BUT THERE IS INCREASING EVIDENCE THAT SOME ELEMENTS OF SUCH HERITABILITY ARE TRANSMITTED NON-GENOMICALLY AND THAT THE PROCESSES WHEREBY ENVIRONMENTAL INFLUENCES ACT DURING EARLY DEVELOPMENT TO SHAPE DISEASE RISK IN LATER LIFE CAN HAVE EFFECTS BEYOND A SINGLE GENERATION. SUCH HERITABILITY MAY OPERATE THROUGH EPIGENETIC MECHANISMS INVOLVING REGULATION OF EITHER IMPRINTED OR NON-IMPRINTED GENES BUT ALSO THROUGH BROADER MECHANISMS RELATED TO PARENTAL PHYSIOLOGY OR BEHAVIOUR. WE REVIEW EVIDENCE AND POTENTIAL MECHANISMS FOR NON-GENOMIC TRANSGENERATIONAL INHERITANCE OF 'LIFESTYLE' DISEASE AND PROPOSE THAT THE 'DEVELOPMENTAL ORIGINS OF DISEASE' PHENOMENON IS A MALADAPTIVE CONSEQUENCE OF AN ANCESTRAL MECHANISM OF DEVELOPMENTAL PLASTICITY THAT MAY HAVE HAD ADAPTIVE VALUE IN THE EVOLUTION OF GENERALIST SPECIES SUCH AS HOMO SAPIENS. 2007 10 1921 49 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 11 4863 34 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 12 3784 28 INTERGENERATIONAL EFFECTS OF ALCOHOL: A REVIEW OF PATERNAL PRECONCEPTION ETHANOL EXPOSURE STUDIES AND EPIGENETIC MECHANISMS IN THE MALE GERMLINE. WHILE ALCOHOL USE DISORDER (AUD) IS A HIGHLY HERITABLE PSYCHIATRIC DISEASE, EFFORTS TO ELUCIDATE THAT HERITABILITY BY EXAMINING GENETIC VARIATION (E.G., SINGLE NUCLEOTIDE POLYMORPHISMS) HAVE BEEN INSUFFICIENT TO FULLY ACCOUNT FOR FAMILIAL AUD RISK. PERHAPS NOT COINCIDENTLY, THERE HAS BEEN A BURGEONING INTEREST IN NOVEL NONGENOMIC MECHANISMS OF INHERITANCE (I.E., EPIGENETICS) THAT ARE SHAPED IN THE MALE OR FEMALE GERM CELLS BY SIGNIFICANT LIFETIME EXPERIENCES SUCH AS EXPOSURE TO CHRONIC STRESS, MALNUTRITION, OR DRUGS OF ABUSE. WHILE MANY EPIDEMIOLOGICAL AND PRECLINICAL STUDIES HAVE LONG POINTED TO A ROLE FOR THE PARENTAL PRECONCEPTION ENVIRONMENT IN OFFSPRING BEHAVIOR, OVER THE LAST DECADE MANY STUDIES HAVE IMPLICATED A CAUSAL RELATIONSHIP BETWEEN THE ENVIRONMENTALLY SENSITIVE SPERM EPIGENOME AND INTERGENERATIONAL PHENOTYPES. THIS CRITICAL REVIEW WILL DETAIL THE HERITABLE EFFECTS OF ALCOHOL AND THE POTENTIAL ROLE FOR EPIGENETICS. 2019 13 3569 45 IMPACT OF INTRA-UTERINE LIFE ON FUTURE HEALTH. SINCE THE EMERGENCE OF THE CONCEPT OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD), SUGGESTED BY BARKER IN THE 1980S, NUMEROUS EPIDEMIOLOGICAL STUDIES IN HUMANS HAVE CONFIRMED THE RELATIONSHIP BETWEEN MATERNAL OBESITY DURING PREGNANCY AND THE RISK OF OFFSPRING DEVELOPING VARIOUS CHRONIC ADULT ILLNESSES. THESE EFFECTS OF INTRAUTERINE LIFE ARE INDEPENDENT OF INHERITANCE OF DISEASE SUSCEPTIBILITY GENES AND/OR SOCIO-ECONOMIC FACTORS. REGARDING POTENTIAL MECHANISMS, RECENT DATA FROM ANIMAL MODELS SUGGESTS A ROLE OF INSULIN RESISTANCE EARLY IN DEVELOPMENT. ANOTHER POTENTIAL MECHANISM, IN THE CASE OF MATERNAL OBESITY, IS INCREASED PLACENTAL NUTRIENT TRANSFER. THE DOHAD CONCEPT ALSO INCLUDES FETAL EXPOSURE TO ENVIRONMENTAL ENDOCRINE DISRUPTORS (EEDS). A DANISH GROUP FOR THE FIRST TIME RECENTLY ANALYZED EED PASSAGE ACROSS THE PLACENTA IN HUMANS THROUGHOUT PREGNANCY. THIS STUDY SHOWED DIFFERENT LEVELS OF BIOACCUMULATION DEPENDING ON THE FETAL ORGAN, WITH GREATER VULNERABILITY IN MALE THAN FEMALE FETUSES. RECENT CLINICAL STUDIES SUGGESTED AN ASSOCIATION BETWEEN FETAL EXPOSURE TO PARTICULAR EEDS AND PRECOCIOUS PUBERTY, INCREASED INCIDENCE OF CRYPTORCHIDISM AND IMPAIRED SPERM QUALITY IN ADULTHOOD. THESE MODIFICATIONS OF THE IN-UTERO ENVIRONMENT ALSO APPEAR TO BE RESPONSIBLE FOR EPIGENETIC CHANGES THAT ARE TRANSMITTABLE OVER SEVERAL GENERATIONS. A RECENT EXAMPLE OF THIS IS THE DEMONSTRATION OF THE TRANSMISSION OF POLYCYSTIC OVARY SYNDROME (PCOS) IN MICE. IN SUMMARY, AN INCREASING NUMBER OF EXAMPLES OF THE IMPACT OF INTRAUTERINE LIFE ON THE HEALTH OF OFFSPRING HAVE APPEARED IN RECENT YEARS, ILLUSTRATING THE IMPORTANT ROLE THAT ENDOCRINOLOGISTS CAN PLAY IN PREVENTING PARTICULAR PATHOLOGIES IN FUTURE GENERATIONS. 2022 14 1802 31 EFFECT OF PATERNAL DIET ON SPERMATOGENESIS AND OFFSPRING HEALTH: FOCUS ON EPIGENETICS AND INTERVENTIONS WITH FOOD BIOACTIVE COMPOUNDS. INFERTILITY IS A GROWING PUBLIC HEALTH PROBLEM. CONSUMPTION OF ANTIOXIDANT BIOACTIVE FOOD COMPOUNDS (BFCS) THAT INCLUDE MICRONUTRIENTS AND NON-NUTRIENTS HAS BEEN HIGHLIGHTED AS A POTENTIAL STRATEGY TO PROTECT AGAINST OXIDATIVE AND INFLAMMATORY DAMAGE IN THE MALE REPRODUCTIVE SYSTEM INDUCED BY OBESITY, ALCOHOL, AND TOXICANTS AND, THUS, IMPROVE SPERMATOGENESIS AND THE FERTILITY PARAMETERS. PATERNAL CONSUMPTION OF SUCH DIETARY COMPOUNDS COULD NOT ONLY BENEFIT THE FATHERS BUT THEIR OFFSPRING AS WELL. STUDIES IN THE NEW FIELD OF PATERNAL ORIGINS OF HEALTH AND DISEASE SHOW THAT PATERNAL MALNUTRITION CAN ALTER SPERM EPIGENOME, AND THIS CAN ALTER FETAL DEVELOPMENT AND PROGRAM AN INCREASED RISK OF METABOLIC DISEASES AND BREAST CANCER IN ADULTHOOD. BFCS, SUCH AS ASCORBIC ACID, ALPHA-TOCOPHEROL, POLYUNSATURATED FATTY ACIDS, TRACE ELEMENTS, CARNITINES, N-ACETYLCYSTEINE, AND COENZYME Q10, HAVE BEEN SHOWN TO IMPROVE MALE GAMETOGENESIS, MODULATE EPIGENETICS OF GERM CELLS, AND THE EPIGENETIC SIGNATURE OF THE OFFSPRING, RESTORING OFFSPRING METABOLIC HEALTH INDUCED BY STRESSORS DURING EARLY LIFE. THIS INDICATES THAT, FROM A FATHER'S PERSPECTIVE, PRECONCEPTION IS A VALUABLE WINDOW OF OPPORTUNITY TO START POTENTIAL NUTRITIONAL INTERVENTIONS WITH THESE BFCS TO MAXIMIZE SPERM EPIGENETIC INTEGRITY AND PROMOTE ADEQUATE FETAL GROWTH AND DEVELOPMENT, THUS PREVENTING CHRONIC DISEASE IN ADULTHOOD. 2022 15 4011 34 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 16 260 29 ADVANCES IN RESEARCH INTO GAMETE AND EMBRYO-FETAL ORIGINS OF ADULT DISEASES. THE FETAL AND INFANT ORIGINS OF ADULT DISEASE HYPOTHESIS PROPOSED THAT THE ROOTS OF ADULT CHRONIC DISEASE LIE IN THE EFFECTS OF ADVERSE ENVIRONMENTS IN FETAL LIFE AND EARLY INFANCY. IN ADDITION TO THE FETAL PERIOD, FERTILIZATION AND EARLY EMBRYONIC STAGES, THE CRITICAL TIME WINDOWS OF EPIGENETIC REPROGRAMMING, RAPID CELL DIFFERENTIATION AND ORGANOGENESIS, ARE THE MOST SENSITIVE STAGES TO ENVIRONMENTAL DISTURBANCES. COMPARED WITH EMBRYO AND FETAL DEVELOPMENT, GAMETOGENESIS AND MATURATION TAKE DECADES AND ARE MORE VULNERABLE TO POTENTIAL DAMAGE FOR A LONGER EXPOSURE PERIOD. THEREFORE, WE SHOULD SHIFT THE FOCUS OF ADULT DISEASE OCCURRENCE AND PATHOGENESIS FURTHER BACK TO GAMETOGENESIS AND EMBRYONIC DEVELOPMENT EVENTS, WHICH MAY RESULT IN INTERGENERATIONAL, EVEN TRANSGENERATIONAL, EPIGENETIC RE-PROGRAMMING WITH TRANSMISSION OF ADVERSE TRAITS AND CHARACTERISTICS TO OFFSPRING. HERE, WE FOCUS ON THE RESEARCH PROGRESS RELATING TO DISEASES THAT ORIGINATED FROM EVENTS IN THE GAMETES AND EARLY EMBRYOS AND THE POTENTIAL EPIGENETIC MECHANISMS INVOLVED. 2019 17 4084 34 MATERNAL NUTRITION DURING PREGNANCY AND HEALTH OF THE OFFSPRING. THE ABILITY OF MOTHER TO PROVIDE NUTRIENTS AND OXYGEN FOR HER BABY IS A CRITICAL FACTOR FOR FETAL HEALTH AND ITS SURVIVAL. FAILURE IN SUPPLYING THE ADEQUATE AMOUNT OF NUTRIENTS TO MEET FETAL DEMAND CAN LEAD TO FETAL MALNUTRITION. THE FETUS RESPONDS AND ADAPTS TO UNDERNUTRITION BUT BY DOING SO IT PERMANENTLY ALTERS THE STRUCTURE AND FUNCTION OF THE BODY. MATERNAL OVERNUTRITION ALSO HAS LONG-LASTING AND DETRIMENTAL EFFECTS ON THE HEALTH OF THE OFFSPRING. THERE IS GROWING EVIDENCE THAT MATERNAL NUTRITION CAN INDUCE EPIGENETIC MODIFICATIONS OF THE FETAL GENOME. ONLY RELATIVELY RECENTLY HAS EVIDENCE FROM EPIDEMIOLOGICAL AND ANIMAL STUDIES EMERGED SUGGESTING THAT FETAL RESPONSES TO THE INTRAUTERINE ENVIRONMENT MAY UNDERLIE THE PREVALENCE OF MANY CHRONIC DISEASES OF ADULTHOOD INCLUDING TYPE 2 (NON-INSULIN-DEPENDENT) DIABETES. IT IS NOW OF CRUCIAL IMPORTANCE TO GAIN THE UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THE RELATIONSHIP BETWEEN FETAL ALTERATIONS TO THE INTRA-UTERINE ENVIRONMENT AND THEIR LONG-TERM EFFECTS ON THE HEALTH OF AN INDIVIDUAL. 2006 18 4995 36 PERINATAL ENVIRONMENT AND ITS INFLUENCES ON METABOLIC PROGRAMMING OF OFFSPRING. THE INTRAUTERINE ENVIRONMENT SUPPORTS THE DEVELOPMENT AND HEALTH OF OFFSPRING. PERTURBATIONS TO THIS ENVIRONMENT CAN HAVE DETRIMENTAL EFFECTS ON THE FETUS THAT HAVE PERSISTENT PATHOLOGICAL CONSEQUENCES THROUGH ADOLESCENCE AND ADULTHOOD. THE DEVELOPMENTAL ORIGINS OF THE HEALTH AND DISEASE CONCEPT, ALSO KNOWN AS THE "BARKER HYPOTHESIS", HAS BEEN PUT FORTH TO DESCRIBE THE INCREASED INCIDENCE OF CHRONIC DISEASE SUCH AS CARDIOVASCULAR DISEASE AND DIABETES IN HUMANS AND ANIMALS EXPOSED TO A LESS THAN IDEAL INTRAUTERINE ENVIRONMENT. MATERNAL INFECTION, POOR OR EXCESS NUTRITION, AND STRESSFUL EVENTS CAN NEGATIVELY INFLUENCE THE DEVELOPMENT OF DIFFERENT CELL TYPES, TISSUES AND ORGAN SYSTEMS ULTIMATELY PREDISPOSING THE ORGANISM TO PATHOLOGICAL CONDITIONS. ALTHOUGH THERE ARE A VARIETY OF CONDITIONS ASSOCIATED TO EXPOSURE TO ALTERED INTRAUTERINE ENVIRONMENTS, THE FOCUS OF THIS REVIEW WILL BE ON THE CONSEQUENCES OF STRESS AND HIGH FAT DIET DURING THE PRE- AND PERINATAL PERIODS AND ASSOCIATED OUTCOMES RELATED TO OBESITY AND OTHER METABOLIC CONDITIONS. WE FURTHER DISCUSS POSSIBLE NEUROENDOCRINE AND EPIGENETIC MECHANISMS RESPONSIBLE FOR THE METABOLIC PROGRAMMING OF OFFSPRING. THE PAPER REPRESENTS AN INVITED REVIEW BY A SYMPOSIUM, AWARD WINNER OR KEYNOTE SPEAKER AT THE SOCIETY FOR THE STUDY OF INGESTIVE BEHAVIOR [SSIB] ANNUAL MEETING IN PORTLAND, JULY 2009. 2010 19 4083 37 MATERNAL NUTRITION AND FETAL DEVELOPMENT. NUTRITION IS THE MAJOR INTRAUTERINE ENVIRONMENTAL FACTOR THAT ALTERS EXPRESSION OF THE FETAL GENOME AND MAY HAVE LIFELONG CONSEQUENCES. THIS PHENOMENON, TERMED "FETAL PROGRAMMING," HAS LED TO THE RECENT THEORY OF "FETAL ORIGINS OF ADULT DISEASE." NAMELY, ALTERATIONS IN FETAL NUTRITION AND ENDOCRINE STATUS MAY RESULT IN DEVELOPMENTAL ADAPTATIONS THAT PERMANENTLY CHANGE THE STRUCTURE, PHYSIOLOGY, AND METABOLISM OF THE OFFSPRING, THEREBY PREDISPOSING INDIVIDUALS TO METABOLIC, ENDOCRINE, AND CARDIOVASCULAR DISEASES IN ADULT LIFE. ANIMAL STUDIES SHOW THAT BOTH MATERNAL UNDERNUTRITION AND OVERNUTRITION REDUCE PLACENTAL-FETAL BLOOD FLOWS AND STUNT FETAL GROWTH. IMPAIRED PLACENTAL SYNTHESES OF NITRIC OXIDE (A MAJOR VASODILATOR AND ANGIOGENESIS FACTOR) AND POLYAMINES (KEY REGULATORS OF DNA AND PROTEIN SYNTHESIS) MAY PROVIDE A UNIFIED EXPLANATION FOR INTRAUTERINE GROWTH RETARDATION IN RESPONSE TO THE 2 EXTREMES OF NUTRITIONAL PROBLEMS WITH THE SAME PREGNANCY OUTCOME. THERE IS GROWING EVIDENCE THAT MATERNAL NUTRITIONAL STATUS CAN ALTER THE EPIGENETIC STATE (STABLE ALTERATIONS OF GENE EXPRESSION THROUGH DNA METHYLATION AND HISTONE MODIFICATIONS) OF THE FETAL GENOME. THIS MAY PROVIDE A MOLECULAR MECHANISM FOR THE IMPACT OF MATERNAL NUTRITION ON BOTH FETAL PROGRAMMING AND GENOMIC IMPRINTING. PROMOTING OPTIMAL NUTRITION WILL NOT ONLY ENSURE OPTIMAL FETAL DEVELOPMENT, BUT WILL ALSO REDUCE THE RISK OF CHRONIC DISEASES IN ADULTS. 2004 20 4790 39 NUTRITIONAL ADVERSITY, SEX AND REPRODUCTION: 30 YEARS OF DOHAD AND WHAT HAVE WE LEARNED? IT IS WELL ESTABLISHED THAT EARLY LIFE ENVIRONMENTAL SIGNALS, INCLUDING NUTRITION, SET THE STAGE FOR LONG-TERM HEALTH AND DISEASE RISK - EFFECTS THAT SPAN MULTIPLE GENERATIONS. THIS RELATIONSHIP BEGINS EARLY, IN THE PERICONCEPTIONAL PERIOD AND EXTENDS INTO EMBRYONIC, FETAL AND EARLY INFANT PHASES OF LIFE. NOW KNOWN AS THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD), THIS CONCEPT DESCRIBES THE ADAPTATIONS THAT A DEVELOPING ORGANISM MAKES IN RESPONSE TO EARLY LIFE CUES, RESULTING IN ADJUSTMENTS IN HOMEOSTATIC SYSTEMS THAT MAY PROVE MALADAPTIVE IN POSTNATAL LIFE, LEADING TO AN INCREASED RISK OF CHRONIC DISEASE AND/OR THE INHERITANCE OF RISK FACTORS ACROSS GENERATIONS. REPRODUCTIVE MATURATION AND FUNCTION IS SIMILARLY INFLUENCED BY EARLY LIFE EVENTS. THIS SHOULD NOT BE SURPRISING, SINCE PRIMORDIAL GERM CELLS ARE ESTABLISHED EARLY IN LIFE AND THUS VULNERABLE TO EARLY LIFE ADVERSITY. A MULTITUDE OF 'MODIFYING' CUES INDUCING DEVELOPMENTAL ADAPTATIONS HAVE BEEN IDENTIFIED THAT RESULT IN CHANGES IN REPRODUCTIVE DEVELOPMENT AND IMPAIRMENTS IN REPRODUCTIVE FUNCTION. MANY TYPES OF NUTRITIONAL CHALLENGES INCLUDING CALORIC RESTRICTION, MACRONUTRIENT EXCESS AND MICRONUTRIENT INSUFFICIENCIES HAVE BEEN SHOWN TO INDUCE EARLY LIFE ADAPTATIONS THAT PRODUCE LONG-TERM REPRODUCTIVE DYSFUNCTION. MANY PATHWAYS HAVE BEEN SUGGESTED TO UNDERPIN THESE ASSOCIATIONS, INCLUDING EPIGENETIC REPROGRAMMING OF GERM CELLS. WHILE THE MECHANISMS STILL REMAIN TO BE FULLY INVESTIGATED, IT IS CLEAR THAT A LIFECOURSE APPROACH TO UNDERSTANDING LIFETIME REPRODUCTIVE FUNCTION IS NECESSARY. FURTHERMORE, INVESTIGATIONS OF THE IMPACTS OF EARLY LIFE ADVERSITY MUST BE EXTENDED TO INCLUDE THE PATERNAL ENVIRONMENT, ESPECIALLY IN EPIDEMIOLOGICAL AND CLINICAL STUDIES OF OFFSPRING REPRODUCTIVE FUNCTION. 2019