1   260 92 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2  4941 26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  1488 29 DNA DAMAGE RECOGNITION IN THE RAT ZYGOTE FOLLOWING CHRONIC PATERNAL CYCLOPHOSPHAMIDE EXPOSURE. THE DETRIMENTAL EFFECTS OF PRECONCEPTIONAL PATERNAL EXPOSURE TO THE ALKYLATING ANTICANCER AGENT, CYCLOPHOSPHAMIDE, INCLUDE ABERRANT EPIGENETIC PROGRAMMING, DYSREGULATED ZYGOTIC GENE ACTIVATION, AND ABNORMALITIES IN THE OFFSPRING THAT ARE TRANSMITTED TO THE NEXT GENERATION. THE ADVERSE DEVELOPMENTAL CONSEQUENCES OF GENOMIC INSTABILITIES TRANSMITTED VIA THE SPERMATOZOON EMPHASIZE THE NEED TO ELUCIDATE THE MECHANISMS BY WHICH THE EARLY EMBRYO RECOGNIZES DNA DAMAGE IN THE PATERNAL GENOME. LITTLE INFORMATION EXISTS ON DNA DAMAGE DETECTION IN THE ZYGOTE. WE ASSESSED THE IMPACT OF PATERNAL CYCLOPHOSPHAMIDE EXPOSURE ON PHOSPHORYLATED H2AX (GAMMAH2AX) AND POLY(ADP-RIBOSE) POLYMERASE-1(PARP-1), BIOMARKERS OF DNA DAMAGE, TO DETERMINE THE CAPACITY IN THE RAT ZYGOTE TO RECOGNIZE GENOMIC DAMAGE AND INITIATE A RESPONSE TO DNA LESIONS. AN AMPLIFIED BIPHASIC GAMMAH2AX RESPONSE WAS TRIGGERED IN THE PATERNAL PRONUCLEUS IN ZYGOTES SIRED BY DRUG-TREATED MALES; THE MATERNAL GENOME WAS NOT AFFECTED. PARP-1 IMMUNOREACTIVITY WAS SUBSTANTIALLY ELEVATED IN BOTH PARENTAL GENOMES, COINCIDENT WITH THE SECOND PHASE OF GAMMAH2AX INDUCTION IN EMBRYOS SIRED BY CYCLOPHOSPHAMIDE-EXPOSED SPERMATOZOA. THUS, PATERNAL EXPOSURE TO A DNA DAMAGING AGENT RAPIDLY ACTIVATES SIGNALS IMPLEMENTAL FOR DNA DAMAGE RECOGNITION IN THE ZYGOTE. INEFFICIENT REPAIR OF DNA LESIONS MAY LEAD TO PERSISTENT ALTERATIONS OF THE HISTONE CODE AND CHROMATIN INTEGRITY, RESULTING IN ABERRANT EMBRYOGENESIS. WE PROPOSE THAT THE RESPONSE OF THE EARLY EMBRYO TO DISTURBANCES IN SPERMATOZOAL GENOMIC INTEGRITY PLAYS A VITAL ROLE IN DETERMINING ITS OUTCOME.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4  6867 25 [PARENTAL AGEING AND ASSISTED REPRODUCTION TECHNOLOGIES: ANALYSIS OF RISK OF CHRONIC DISEASES IN THE PROGENY]. CONCEPTION OF A CHILD AT ADVANCED PARENTAL AGE (> 35 YEARS) HAS BEEN STEADILY INCREASING IN RECENT DECADES, ESPECIALLY IN DEVELOPED COUNTRIES. SOCIO-ECONOMIC FACTORS, EFFECTIVE CONTRACEPTIVES, AND THE AVAILABILITY OF ASSISTED REPRODUCTION TECHNOLOGIES (ART) HAVE A DIRECT IMPACT ON POSTPONING THE DECISION TO HAVE A BABY. ART ENABLES REPRODUCTIVE SUCCESS FOR PEOPLE DIAGNOSED AS INFERTILE OR WITH REDUCED POSSIBILITIES OF BECOMING PREGNANT DUE TO CONCOMITANT PATHOLOGIES. EPIDEMIOLOGICAL STUDIES INDICATE THAT BOTH ADVANCED PARENTAL AGE AND ART ARE ASSOCIATED WITH PATHOLOGIES OF PREGNANCY, SUCH AS GESTATIONAL DIABETES, RISK OF PRE-ECLAMPSIA, MISCARRIAGE, PLACENTAL ABRUPTION, PRETERM LABOR, STILLBIRTH, NEURODEVELOPMENTAL DISORDERS AND CHRONIC DISEASE OF THE OFFSPRING. IN OUR WORK, WE WILL FOCUS ON THE AVAILABLE INFORMATION ON METABOLIC CHANGES THAT INCREASE THE RISK OF DEVELOPING CARDIOVASCULAR DISEASES IN THE OFFSPRING OF PARENTS AT AN ADVANCED AGE AND CONCEIVED THROUGH ART. FINALLY, WE WILL ADDRESS THE SOURCES OF THE OBSERVED DISTURBANCES AT THE GAMETE AND EMBRYO LEVEL, RELATED TO OXYGEN STRESS, EPIGENETIC MODIFICATIONS AND DNA DAMAGE, CONSIDERING POSSIBLE RESCUE ACTIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  3586 28 IMPACT OF THE POLYCARBONATE STRIPPERS USED IN ASSISTED REPRODUCTION TECHNIQUES ON EMBRYONIC DEVELOPMENT. STUDY QUESTION: DO DAILY MANIPULATIONS OF PREIMPLANTATION EMBRYOS WITH POLYCARBONATE (PC)-MADE BISPHENOL A (BPA)-RELEASING STRIPPERS INFLUENCE EMBRYO DEVELOPMENT? SUMMARY ANSWER: COMPARED TO GLASS STRIPPERS, PC STRIPPERS ENHANCE THE BLASTOCYST DEVELOPMENT RATE BUT THIS DOES NOT SEEM TO BE BPA-RELATED. WHAT IS KNOWN ALREADY: PC STRIPPERS HAVE BEEN SHOWN TO RELEASE TINY AMOUNTS (AROUND 0.5 NG/ML BPA) OF BPA IN ROUTINE HUMAN IVF PROCEDURES. A CHRONIC EXPOSURE TO BPA EITHER IN VIVO OR IN VITRO DURING THE PREIMPLANTATION PERIOD CAN IMPACT POST-IMPLANTATION AND POST-NATAL DEVELOPMENT. BPA CAN ACT RAPIDLY BY BINDING TO MEMBRANE RECEPTORS AND INDUCING RAPID NON-GENOMIC EFFECTS. STUDY DESIGN, SIZE, DURATION: THIS EXPERIMENTAL STUDY USING MOUSE EMBRYOS HAD A BALANCED DESIGN AND BLINDED EVALUATIONS OF THE ENDPOINTS. PARTICIPANTS/MATERIALS, SETTING, METHODS: IN VIVO FERTILIZED ZYGOTES WERE OBTAINED FROM OUTBRED SWISS CD1 MICE CROSSINGS AFTER AN OVARIAN STIMULATION. THE ZYGOTES WERE ALLOCATED TO THREE DAILY HANDLING CONDITIONS (HCS) AND CULTURED UNTIL DAY 4 IN A SINGLE HUMAN COMMERCIAL MEDIUM. EACH DAY, THE EMBRYOS WERE HANDLED FOR 20 S EITHER IN A PC STRIPPER (HC1) OR IN A GLASS STRIPPER (HC2). IN HC3, THE EMBRYOS WERE PRE-EXPOSED TO 0.5 NG/ML BPA BEFORE BEING HANDLED FOR 20 S IN A GLASS STRIPPER. HANDLING OPERATIONS WERE REPEATED ON DAYS 1, 2 AND 3. EMBRYO DEVELOPMENT WAS ASSESSED BLINDLY ON DAY 4. EXPANDED BLASTOCYSTS WERE SELECTED FOR A TRANSCRIPTOMIC ANALYSIS USING AGILENT SUREPRINT G3 MOUSE GE V2 MICROARRAYS AND THE RETROTRANSPOSON LINE1-ORF2 EXPRESSION WAS ANALYSED USING QRT-PCR, AS A PROXY FOR A GLOBAL EVALUATION OF THE EPIGENETIC STATUS. MAIN RESULTS AND THE ROLE OF CHANCE: COMPARED TO THE EMBRYOS MANIPULATED IN HC2 (N = 243), THOSE IN HC1 (N = 228) DEVELOPED SIGNIFICANTLY MORE OFTEN TO THE BLASTOCYST STAGE (55 VS 46%; P < 0.05). IT APPEARS THE EFFECT OF THESE PC STRIPPERS WAS NOT BPA-RELATED BECAUSE EMBRYOS PRE-EXPOSED TO BPA (HC3, N = 230) SHOWED NO DIFFERENCE IN THE BLASTOCYST RATE WHEN COMPARED TO HC2 (43 VS 46%). WHEN ANALYSING SAME-STAGE BLASTOCYSTS, WE NOTICED NO DIFFERENCE IN THE EMBRYO GENE EXPRESSION BETWEEN THE THREE HC GROUPS. LARGE SCALE DATA: HTTPS://WWW.NCBI.NLM.NIH.GOV/GEO/QUERY/ACC.CGI?ACC=GSE148868. LIMITATIONS, REASONS FOR CAUTION: OUR RESULTS USING A MOUSE MODEL DESIGNED TO MIMIC HUMAN CONDITIONS (OUTBRED STRAIN, HUMAN COMMERCIAL IVF DISHES AND A UNIQUE COMMERCIAL HUMAN EMBRYONIC CULTURE MEDIA) ARE REASSURING SINCE NO GENE WAS FOUND TO BE DIFFERENTIALLY EXPRESSED, INCLUDING LINE-1 GENES, AS A PROXY FOR A GLOBAL EVALUATION OF THE EPIGENETIC STATUS. HOWEVER, NO GLOBAL EPIGENETIC ANALYSIS OF THE GENOME HAS BEEN PERFORMED. FURTHERMORE, WE DID NOT EVALUATE POST-IMPLANTATION EVENTS, ALTHOUGH BPA EXPOSURE DURING PERI-CONCEPTION COULD AFFECT FOETO-PLACENTAL AND POST-NATAL DEVELOPMENT. WIDER IMPLICATIONS OF THE FINDINGS: BASED ON THE PRECAUTIONARY PRINCIPLE, SEVERAL EUROPEAN COUNTRIES BANNED THE USE OF BPA IN BABY BOTTLES AND FOOD PACKAGING SEVERAL YEARS BEFORE EUROPEAN AGENCIES TOOK AN OFFICIAL POSITION. THE QUESTION OF APPLYING THIS PRINCIPLE TO PLASTICS IN CLOSED CONTACT WITH HUMAN EMBRYOS IS RAISED. FURTHER STUDIES ARE NEEDED FOR A DECISION TO BE MADE. STUDY FUNDING/COMPETING INTEREST(S): THIS STUDY WAS SUPPORTED BY A GRANT FROM THE AGENCE DE BIOMEDECINE (AOR 2016). THE AUTHORS DECLARE NO COMPETING INTEREST.	2021	

6  6672 35 USE OF A MOUSE IN VITRO FERTILIZATION MODEL TO UNDERSTAND THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS. THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS HOLDS THAT ALTERATIONS TO HOMEOSTASIS DURING CRITICAL PERIODS OF DEVELOPMENT CAN PREDISPOSE INDIVIDUALS TO ADULT-ONSET CHRONIC DISEASES SUCH AS DIABETES AND METABOLIC SYNDROME. IT REMAINS CONTROVERSIAL WHETHER PREIMPLANTATION EMBRYO MANIPULATION, CLINICALLY USED TO TREAT PATIENTS WITH INFERTILITY, DISTURBS HOMEOSTASIS AND AFFECTS LONG-TERM GROWTH AND METABOLISM. TO ADDRESS THIS CONTROVERSY, WE HAVE ASSESSED THE EFFECTS OF IN VITRO FERTILIZATION (IVF) ON POSTNATAL PHYSIOLOGY IN MICE. WE DEMONSTRATE THAT IVF AND EMBRYO CULTURE, EVEN UNDER CONDITIONS CONSIDERED OPTIMAL FOR MOUSE EMBRYO CULTURE, ALTER POSTNATAL GROWTH TRAJECTORY, FAT ACCUMULATION, AND GLUCOSE METABOLISM IN ADULT MICE. UNBIASED METABOLIC PROFILING IN SERUM AND MICROARRAY ANALYSIS OF PANCREATIC ISLETS AND INSULIN SENSITIVE TISSUES (LIVER, SKELETAL MUSCLE, AND ADIPOSE TISSUE) REVEALED BROAD CHANGES IN METABOLIC HOMEOSTASIS, CHARACTERIZED BY SYSTEMIC OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION. ADOPTING A CANDIDATE APPROACH, WE IDENTIFY THIOREDOXIN-INTERACTING PROTEIN (TXNIP), A KEY MOLECULE INVOLVED IN INTEGRATING CELLULAR NUTRITIONAL AND OXIDATIVE STATES WITH METABOLIC RESPONSE, AS A MARKER FOR PREIMPLANTATION STRESS AND DEMONSTRATE TISSUE-SPECIFIC EPIGENETIC AND TRANSCRIPTIONAL TXNIP MISREGULATION IN SELECTED ADULT TISSUES. IMPORTANTLY, DYSREGULATION OF TXNIP EXPRESSION IS ASSOCIATED WITH ENRICHMENT FOR H4 ACETYLATION AT THE TXNIP PROMOTER THAT PERSISTS FROM THE BLASTOCYST STAGE THROUGH ADULTHOOD IN ADIPOSE TISSUE. OUR DATA SUPPORT THE VULNERABILITY OF PREIMPLANTATION EMBRYOS TO ENVIRONMENTAL DISTURBANCE AND DEMONSTRATE THAT CONCEPTION BY IVF CAN REPROGRAM METABOLIC HOMEOSTASIS THROUGH METABOLIC, TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS WITH LASTING EFFECTS FOR ADULT GROWTH AND FITNESS. THIS STUDY HAS WIDE CLINICAL RELEVANCE AND UNDERSCORES THE IMPORTANCE OF CONTINUED FOLLOW-UP OF IVF-CONCEIVED OFFSPRING.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  4863 28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8  3119 20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9   622 32 BIOETHICS IN HUMAN EMBRYOLOGY: THE DOUBLE-EDGED SWORD OF EMBRYO RESEARCH. THERE HAS BEEN A SIGNIFICANT INCREASE IN THE USE OF ASSISTED REPRODUCTIVE THERAPIES (ARTS) OVER THE PAST SEVERAL DECADES, ALLOWING MANY COUPLES WITH INFERTILITY TO CONCEIVE. DESPITE THE ACHIEVEMENTS IN THIS FIELD, A MOUNTING BODY OF EVIDENCE CONCERNING THE EPIGENETIC RISKS ASSOCIATED WITH ART INTERVENTIONS SUCH AS OVARIAN HORMONAL STIMULATION, INTRACYTOPLASMIC SPERM INJECTION (ICSI), AND IN VITRO CULTURE (IVC) OF OOCYTES AND EMBRYOS HAS ALSO EMERGED. INDUCED DEVELOPMENT OF MULTIPLE FOLLICLES, THE IVC MEDIA ITSELF, AND EXTENDED CULTURE MAY ALTER THE EPIGENOME OF BOTH GAMETES AND EMBRYOS, RESULTING IN YET TO BE FULLY UNDERSTOOD DEVELOPMENTAL, POSTNATAL, AND ADULT LIFE HEALTH CONSEQUENCES. INVESTIGATORS HAVE ATTEMPTED TO DECIPHER THE MOLECULAR MECHANISMS MEDIATING ART-INDUCED EPIGENETIC CHANGES USING EITHER HUMAN SAMPLES OR ANIMAL MODELS WITH SOME SUCCESS. AS RESEARCH IN THIS FIELD CONTINUES TO EXPAND, THE ETHICAL RESPONSIBILITIES OF EMBRYOLOGISTS AND RESEARCHERS HAVE BECOME CRITICALLY IMPORTANT. HERE, WE BRIEFLY DISCUSS THE ETHICAL ASPECTS OF ART RESEARCH, CONCENTRATING ON THE CONSTRAINTS ARISING FROM THE PERCEIVED 'UNNATURALNESS' OF MANY OF THESE PROCEDURES. SECONDLY, WE FOCUS ON THE BIOETHICS AND MORALITY OF HUMAN EMBRYO RESEARCH IN GENERAL AND HOW ETHICALLY ACCEPTABLE MODEL SYSTEMS MAY BE USED TO MIMIC EARLY HUMAN EMBRYOGENESIS. LASTLY, WE REVIEW THE 14-DAY CULTURE LIMIT OF HUMAN EMBRYOS AND THE NOTION THAT THIS RULE COULD BE CONSIDERED OF TAKEN INTO ACCOUNT USING NEW TECHNOLOGIES AND CUES FROM ANIMAL MODELS. THE 'BLACK BOX' OF EARLY POST-IMPLANTATION EMBRYOGENESIS MIGHT BE REVEALED USING EMBRYO MODELS. AS LONG AS THIS DISTINCT MORAL LINE HAS BEEN DRAWN AND CLOSELY FOLLOWED, WE SHOULD NOT FEAR SCIENTIFIC GROWTH IN EMBRYO RESEARCH. ALTHOUGH IN VITRO FERTILIZATION (IVF) IS ETHICALLY ACCEPTABLE, RESEARCH WITH HUMAN EMBRYOS TO IMPROVE ITS SUCCESS RAISES SERIOUS ETHICAL CONCERNS THAT ARE IN NEED OF CONSTANT REVISITING.GLOSSARY INDEX: MORAL STATUS: THE ASCRIPTION OF OBLIGATIONS AND RIGHTS TO EMBRYOS ON THE BASIS OF SENTIENCE; SENTIENCE: THE CAPACITY OF THE DEVELOPING EMBRYO TO EXPERIENCE FEELINGS AND SENSATIONS, SUCH AS THE AWARENESS OF PAIN; ECTOGENESIS: THE GROWTH OF THE EMBRYO IN AN ARTIFICIAL ENVIRONMENT OUTSIDE THE MOTHER'S BODY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10  3595 23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  4066 20 MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION AS AN INDICATOR OF OFFSPRING METABOLIC SYNDROME RISK IN LATER LIFE THROUGH EPIGENETIC IMPRINTING: A SYSTEMATIC REVIEW. AIMS: THIS REVIEW EXAMINED WHETHER MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION EFFECTS AN OFFSPRING'S LIKELIHOOD OF DEVELOPING CHRONIC METABOLIC RELATED CONDITIONS DUE TO EPIGENETIC IMPRINTING. METHODS: A LITERATURE SEARCH WAS CONDUCTED IN MULTIPLE SCIENCE DATABASES AND LIMITED TO STUDIES PUBLISHED AFTER 2012, IN ENGLISH LANGUAGE AND PEER REVIEWED. THE DATA FROM SELECTED ARTICLES WERE EXTRACTED AND A QUALITATIVE APPROACH WAS EMPLOYED DUE TO HETEROGENEITY OF RESULTS. RESULTS: NEWBORNS FROM OBESE FATHERS SHOWED ALTERED METHYLATION OVERALL AND SIGNIFICANT HYPOMETHYLATION AT THE INSULIN-LIKE GROWTH FACTOR 2 (IGF2) GENE. HIGH MATERNAL PRE-PREGNANCY BODY MASS INDEX (BMI) WAS ASSOCIATED WITH ALTERED OFFSPRING DNA METHYLATION LEVELS AND GESTATIONAL DIABETES MELLITUS INDUCED SIGNIFICANTLY INCREASED METHYLATION LEVELS IN OFFSPRING. GESTATIONAL WEIGHT GAIN WAS NOT ASSOCIATED WITH DIFFERENTIALLY METHYLATED CORD BLOOD. BIRTH WEIGHT WAS HIGHER IN OFFSPRING EXPOSED TO FAMINE IN EARLY GESTATION. OFFSPRING BORN POST MATERNAL BARIATRIC SURGERY SHOWED A LOWER PERCENTAGE OF BODY FAT AND IMPROVED FASTING INSULIN LEVELS COMPARED TO SIBLINGS BORN PRE-MATERNAL BARIATRIC SURGERY. CONCLUSIONS: THE AVAILABLE EVIDENCE SUGGESTS THAT POOR MATERNAL AND PATERNAL PERICONCEPTIONAL NUTRITION CAN INCREASE THE RISK OF METABOLIC SYNDROME IN OFFSPRING, THROUGH EPIGENETIC IMPRINTING. POTENTIAL PARENTS SHOULD BE ADVISED THAT MAINTAINING A HEALTHY DIET AND BMI IS LIKELY TO REDUCE THE RISK OF METABOLIC SYNDROME IN OFFSPRING.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  4065 23 MATERNAL AND GESTATIONAL INFLUENCES ON CHILDHOOD BLOOD PRESSURE. EXPOSURES THAT CONTRIBUTE TO A SUB-OPTIMAL INTRAUTERINE ENVIRONMENT CAN HAVE AN EFFECT ON THE DEVELOPING FETUS. IMPAIRED FETAL GROWTH THAT RESULTS IN LOW BIRTH WEIGHT IS AN ESTABLISHED RISK FACTOR FOR CARDIO-METABOLIC DISORDERS LATER IN LIFE. RECENT EPIDEMIOLOGIC AND PROSPECTIVE COHORT STUDIES THAT INCLUDE THE MATERNAL AND GESTATIONAL PERIOD HAVE IDENTIFIED MATERNAL AND GESTATIONAL CONDITIONS THAT CONFER INCREASED RISK FOR SUBSEQUENT CARDIO-METABOLIC DISORDERS IN THE ABSENCE OF LOW BIRTH WEIGHT. MATERNAL PRE-CONCEPTION HEALTH STATUS, INCLUDING CHRONIC OBESITY AND TYPE 2 DIABETES, INCREASE RISK FOR CHILDHOOD OBESITY AND OBESITY-RELATED HIGHER BLOOD PRESSURE (BP) IN CHILD OFFSPRING. MATERNAL GESTATIONAL EXPOSURES, INCLUDING GESTATIONAL DIABETES, GESTATIONAL HYPERTENSION, AND PREECLAMPSIA, ARE ASSOCIATED WITH HIGHER BP IN OFFSPRING. OTHER MATERNAL EXPOSURES SUCH AS CIGARETTE SMOKE AND AIR POLLUTION ALSO INCREASE RISK FOR HIGHER BP IN CHILD OFFSPRING. RECENT, BUT LIMITED, DATA INDICATE THAT ASSISTED REPRODUCTIVE TECHNOLOGIES CAN BE ASSOCIATED WITH HYPERTENSION IN CHILDHOOD, DESPITE OTHERWISE NORMAL GESTATION AND HEALTHY NEWBORN. GESTATIONAL EXPOSURES ASSOCIATED WITH HIGHER BP IN CHILDHOOD CAN BE RELATED TO FAMILIAL LIFESTYLE FACTORS, GENETICS, OR EPIGENETIC MODIFICATION OF FETAL DEOXYRIBONUCLEIC ACID (DNA). THESE FACTORS, OR COMBINATION OF FACTORS, AS WELL AS OTHER ADVERSE INTRAUTERINE CONDITIONS, COULD INDUCE FETAL PROGRAMING LEADING TO HEALTH CONSEQUENCES IN LATER LIFE. CURRENT AND DEVELOPING RESEARCH WILL PROVIDE ADDITIONAL INSIGHTS ON GESTATIONAL EXPOSURES AND FETAL ADJUSTMENTS THAT INCREASE RISK FOR HIGHER BP LEVELS IN CHILDHOOD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  3578 19 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14  1930 33 ENVIRONMENTAL EXPOSURES AROUND CONCEPTION: DEVELOPMENTAL PATHWAYS LEADING TO LIFETIME DISEASE RISK. ENVIRONMENT AROUND CONCEPTION CAN INFLUENCE THE DEVELOPMENTAL PROGRAMME WITH LASTING EFFECTS ON GESTATIONAL AND POSTNATAL PHENOTYPE AND WITH CONSEQUENCES FOR ADULT HEALTH AND DISEASE RISK. PERI-CONCEPTION EXPOSURE COMPRISES A CRUCIAL PART OF THE 'DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE' (DOHAD) CONCEPT. IN THIS REVIEW, WE CONSIDER THE EFFECTS OF MATERNAL UNDERNUTRITION EXPERIENCED DURING THE PERI-CONCEPTION PERIOD IN SELECT HUMAN MODELS AND IN A MOUSE EXPERIMENTAL MODEL OF PROTEIN RESTRICTION. HUMAN DATASETS INDICATE THAT MACRONUTRIENT DEPRIVATION AROUND CONCEPTION AFFECT THE EPIGENOME, WITH ENDURING EFFECTS ON CARDIOMETABOLIC AND NEUROLOGICAL HEALTH. THE MOUSE MODEL, COMPRISING MATERNAL LOW PROTEIN DIET EXCLUSIVELY DURING THE PERI-CONCEPTION PERIOD, HAS REVEALED A STEPWISE PROGRESSION IN ALTERED DEVELOPMENTAL PROGRAMMING FOLLOWING INDUCTION THROUGH MATERNAL METABOLITE DEFICIENCY. THIS PROGRESSION INCLUDES DIFFERENTIAL EFFECTS IN EXTRA-EMBRYONIC AND EMBRYONIC CELL LINEAGES AND TISSUES, LEADING TO MALADAPTATION IN THE GROWTH TRAJECTORY AND INCREASED CHRONIC DISEASE COMORBIDITIES. THE TIMELINE EMBRACES AN ARRAY OF MECHANISMS ACROSS NUTRIENT SENSING AND SIGNALLING, CELLULAR, METABOLIC, EPIGENETIC AND PHYSIOLOGICAL PROCESSES WITH A COORDINATING ROLE FOR MTORC1 SIGNALLING PROPOSED. EARLY EMBRYOS APPEAR ACTIVE PARTICIPANTS IN ENVIRONMENTAL SENSING TO OPTIMISE THE DEVELOPMENTAL PROGRAMME FOR SURVIVAL BUT WITH THE TRADE-OFF OF LATER DISEASE. SIMILAR ADVERSE HEALTH OUTCOMES MAY DERIVE FROM OTHER PERI-CONCEPTION ENVIRONMENTAL EXPERIENCES, INCLUDING MATERNAL OVERNUTRITION, MICRONUTRIENT AVAILABILITY, POLLUTANT EXPOSURE AND ASSISTED REPRODUCTIVE TREATMENTS (ART) AND SUPPORT THE NEED FOR PRECONCEPTION HEALTH BEFORE PREGNANCY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  4932 20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17  6173 26 THE HEALTH OUTCOMES OF HUMAN OFFSPRING CONCEIVED BY ASSISTED REPRODUCTIVE TECHNOLOGIES (ART). CONCERNS HAVE BEEN RAISED ABOUT THE HEALTH AND DEVELOPMENT OF CHILDREN CONCEIVED BY ASSISTED REPRODUCTIVE TECHNOLOGIES (ART) SINCE 1978. CONTROVERSIALLY, ART HAS BEEN LINKED WITH ADVERSE OBSTETRIC AND PERINATAL OUTCOMES, AN INCREASED RISK OF BIRTH DEFECTS, CANCERS, AND GROWTH AND DEVELOPMENT DISORDERS. EMERGING EVIDENCE SUGGESTS THAT ART TREATMENT MAY ALSO PREDISPOSE INDIVIDUALS TO AN INCREASED RISK OF CHRONIC AGEING RELATED DISEASES SUCH AS OBESITY, TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE. THIS REVIEW WILL SUMMARIZE THE AVAILABLE EVIDENCE ON THE SHORT-TERM AND LONG-TERM HEALTH OUTCOMES OF ART SINGLETONS, AS MULTIPLE PREGNANCIES AFTER MULTIPLE EMBRYOS TRANSFER, ARE ASSOCIATED WITH LOW BIRTH WEIGHT AND PRETERM DELIVERY, WHICH CAN SEPARATELY INCREASE RISK OF ADVERSE POSTNATAL OUTCOMES, AND IMPACT LONG-TERM HEALTH. WE WILL ALSO EXAMINE THE POTENTIAL FACTORS THAT MAY CONTRIBUTE TO THESE HEALTH RISKS, AND DISCUSS UNDERLYING MECHANISMS, INCLUDING EPIGENETIC CHANGES THAT MAY OCCUR DURING THE PREIMPLANTATION PERIOD AND REPROGRAM DEVELOPMENT IN UTERO, AND ADULT HEALTH, LATER IN LIFE. LASTLY, THIS REVIEW WILL CONSIDER THE FUTURE DIRECTIONS WITH THE VIEW TO OPTIMIZE THE LONG-TERM HEALTH OF ART CHILDREN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18   483 28 ART AND HEALTH: CLINICAL OUTCOMES AND INSIGHTS ON MOLECULAR MECHANISMS FROM RODENT STUDIES. SINCE THE BIRTH OF THE FIRST IVF-CONCEIVED CHILD IN 1978, THE USE OF ASSISTED REPRODUCTIVE TECHNOLOGIES (ART) HAS GROWN DRAMATICALLY, CONTRIBUTING TO THE SUCCESSFUL BIRTH OF 5 MILLION INDIVIDUALS WORLDWIDE. HOWEVER, THERE ARE SEVERAL REPORTED ASSOCIATIONS OF ART WITH PREGNANCY COMPLICATIONS, SUCH AS LOW BIRTHWEIGHT (LBW), PRETERM BIRTH, BIRTH DEFECTS, EPIGENETIC DISORDERS, CANCER AND POOR METABOLIC HEALTH. WHETHER THIS IS ATTRIBUTED TO ART PROCEDURES OR TO THE SUBSET OF THE POPULATION SEEKING ART REMAINS A CONTROVERSY, BUT THE MOST RELEVANT QUESTION TODAY CONCERNS THE POTENTIAL LONG-TERM IMPLICATIONS OF ASSISTED CONCEPTION. RECENT EVIDENCE HAS EMERGED SUGGESTING THAT ART-CONCEIVED CHILDREN HAVE DISTINCT METABOLIC PROFILES THAT MAY PREDISPOSE TO CARDIOVASCULAR PATHOLOGIES IN ADULTHOOD. BECAUSE THE ELDEST IVF INDIVIDUALS ARE STILL TOO YOUNG TO EXHIBIT COMPONENTS OF CHRONIC MIDDLE-AGED SYNDROMES, THE USE OF ANIMAL MODELS HAS BECOME PARTICULARLY USEFUL IN DESCRIBING THE EFFECTS OF UNUSUAL OR STRESSFUL PREIMPLANTATION EXPERIENCES ON ADULT FITNESS. ELUCIDATING THE MOLECULAR MECHANISMS BY WHICH EMBRYOS INTEGRATE ENVIRONMENTAL SIGNALS INTO DEVELOPMENT AND METABOLIC GENE EXPRESSION PROGRAMS WILL BE ESSENTIAL FOR OPTIMIZING ART PROCEDURES SUCH AS IN VITRO CULTURE CONDITIONS, EMBRYO SELECTION AND TRANSFER. IN THE FUTURE, ADDITIONAL ANIMAL STUDIES TO IDENTIFY MECHANISMS UNDERLYING UNFAVORABLE ART OUTCOMES, AS WELL AS MORE EPIDEMIOLOGICAL REVIEWS TO MONITOR THE LONG-TERM HEALTH OF ART CHILDREN ARE REQUIRED, GIVEN THAT ART PROCEDURES HAVE BECOME ROUTINE MEDICAL PRACTICE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  3304 28 HIGH-GLUCOSE CONCENTRATIONS CHANGE DNA METHYLATION LEVELS IN HUMAN IVM OOCYTES. STUDY QUESTION: WHAT ARE THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON DNA METHYLATION OF HUMAN OOCYTES? SUMMARY ANSWER: HIGH-GLUCOSE CONCENTRATIONS ALTERED DNA METHYLATION LEVELS OF PEG3 AND ADIPONECTIN IN HUMAN IN VITRO MATURATION OOCYTES. WHAT IS KNOWN ALREADY: MATERNAL DIABETES HAS A DETRIMENTAL INFLUENCE ON OOCYTE QUALITY INCLUDING EPIGENETIC MODIFICATIONS, AS SHOWN IN NON-HUMAN MAMMALIAN SPECIES. STUDY DESIGN, SIZE, DURATION: IMMATURE METAPHASE I (MI) STAGE OOCYTES OF GOOD QUALITY WERE RETRIEVED FROM PATIENTS WHO HAD NORMAL OVARIAN POTENTIAL AND WHO UNDERWENT ICSI IN THE REPRODUCTIVE MEDICINE CENTER OF PEOPLE'S HOSPITAL OF ZHENGZHOU UNIVERSITY. MI OOCYTES WERE CULTURED IN MEDIUM WITH DIFFERENT GLUCOSE CONCENTRATIONS (CONTROL, 10 MM AND 15 MM) IN VITRO AND 48 H LATER, OOCYTES WITH FIRST POLAR BODY EXTRUSION WERE COLLECTED TO CHECK THE DNA METHYLATION LEVELS. PARTICIPANTS/MATERIALS, SETTING, METHODS: MI OOCYTES UNDERWENT IN VITRO MATURATION (IVM) AT 37 DEGREES C WITH 5% MIXED GAS FOR 48 H. THEN THE MATURE OOCYTES WERE TREATED WITH BISULFITE BUFFER. TARGET SEQUENCES WERE AMPLIFIED USING NESTED OR HALF-NESTED PCR AND THE DNA METHYLATION STATUS WAS TESTED USING COMBINED BISULFITE RESTRICTION ANALYSIS (COBRA) AND BISULFITE SEQUENCING (BS). MAIN RESULTS AND THE ROLE OF CHANCE: HIGH-GLUCOSE CONCENTRATIONS SIGNIFICANTLY DECREASED THE FIRST POLAR BODY EXTRUSION RATE. COMPARED TO CONTROLS, THE DNA METHYLATION LEVELS OF PEG3 IN HUMAN IVM OOCYTES WERE SIGNIFICANTLY HIGHER IN 10 MM (P < 0.001) AND 15 MM (P < 0.001) CONCENTRATIONS OF GLUCOSE. BUT THE DNA METHYLATION LEVEL OF H19 WAS NOT AFFECTED BY HIGH-GLUCOSE CONCENTRATIONS IN HUMAN IVM OOCYTES. WE ALSO FOUND THAT THERE WAS A DECREASE IN DNA METHYLATION LEVELS IN THE PROMOTER OF ADIPONECTIN IN HUMAN IVM OOCYTES BETWEEN CONTROLS AND OOCYTES EXPOSED TO 10 MM GLUCOSE (P = 0.028). LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: IT IS NOT CLEAR WHETHER THE ALTERATIONS ARE BENEFICIAL OR NOT FOR THE EMBRYO DEVELOPMENT AND OFFSPRING HEALTH. THE EFFECTS OF HIGH-GLUCOSE CONCENTRATIONS ON THE WHOLE PROCESS OF OOCYTE MATURATION ARE STILL NOT ELUCIDATED. ANOTHER ISSUE IS THAT THE NUMBER OF OOCYTES USED IN THIS STUDY WAS LIMITED. WIDER IMPLICATIONS OF THE FINDINGS: THIS IS THE FIRST TIME THAT THE EFFECTS OF HIGH-GLUCOSE CONCENTRATION ON DNA METHYLATION OF HUMAN OOCYTES HAVE BEEN ELUCIDATED. OUR RESULT INDICATES THAT IN HUMANS, THE HIGH RISK OF CHRONIC DISEASES IN OFFSPRING FROM DIABETIC MOTHERS MAY ORIGINATE FROM ABNORMAL DNA MODIFICATIONS IN OOCYTES. STUDY FUNDING/COMPETING INTEREST(S): THIS WORK WAS SUPPORTED BY THE FUND OF NATIONAL NATURAL SCIENCE FOUNDATION OF CHINA (81401198) AND DOCTOR FOUNDATION OF QINGDAO AGRICULTURAL UNIVERSITY (1116008).THE AUTHORS DECLARE THAT THERE ARE NO POTENTIAL CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20  5584 20 ROLE OF OBESITY IN FEMALE REPRODUCTION. CONTEMPORARY SCIENTISTS NEED NO "P VALUE" AND "RELATIVE RISK" STATISTICS TO BE EXQUISITELY AWARE OF THE INCREASING PREVALENCE OF OBESITY AND COMPLICATIONS POSED BY OBESITY. IT IS NOW WELL RECOGNIZED THAT OBESITY IS STRONGLY ASSOCIATED WITH TYPE 2 DIABETES, HYPERTENSION, VASCULAR DISEASE, TUMORS AND REPRODUCTIVE DISORDERS. OBESE WOMEN SHOW LOWER LEVELS OF GONADOTROPIN HORMONES, REDUCED FECUNDITY, HIGHER MISCARRIAGE RATES AND POORER OUTCOMES OF IN VITRO FERTILIZATION, REVEALING THAT OBESITY AFFECTS FEMALE REPRODUCTION. IN ADDITION, ADIPOSE TISSUE CONTAINS SPECIAL IMMUNE CELLS AND OBESITY-INDUCED INFLAMMATION IS A CHRONIC, LOW-GRADE INFLAMMATORY RESPONSE. HEREIN, WE MAINLY REVIEW DETRIMENTAL INFLUENCES OF OBESITY IN THE COMPLETE PROCESS OF FEMALE REPRODUCTION, INCLUDING HYPOTHALAMIC-PITUITARY-OVARIAN AXIS, OOCYTE MATURATION, EMBRYO AND FETAL DEVELOPMENT. IN THE LATTER PART, WE VIEW OBESITY-INDUCED INFLAMMATION AND DISCUSS RELATED EPIGENETIC IMPACT ON FEMALE REPRODUCTION.	2023