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Whole-genome sequencing studies of parent–offspring trios have provided valuable insights into the potential impact of de novo mutations (DNMs) on human health and disease. However, the molecular mechanisms that drive DNMs are unclear. Studies with multi-child families can provide important insight into the causes of inter-family variability in DNM rates but they are highly limited. We characterized 2479 de novo single nucleotide variants (SNVs) in 13 multi-child families of Mexican-American ethnicity. We observed a strong paternal age effect on validated de novo SNVs with extensive inter-family variability in the yearly rate of increase. Children of older fathers showed more C > T transitions at CpG sites than children from younger fathers. Validated SNVs were examined against one cancer (COSMIC) and two non-cancer (human germline and CRISPR-Cas 9 knockout of human DNA repair genes) mutational signature databases. These analyses suggest that inaccurate DNA mismatch repair during repair initiation and excision processes, along with DNA damage and replication errors, are major sources of human germline de novo SNVs. Our findings provide important information for understanding the potential sources of human germline de novo SNVs and the critical role of DNA mismatch repair in their genesis. Mutational signature analyses of de novo mutations in multi-child human families suggest that inaccurate DNA mismatch repair, DNA damage, and replication errors are major sources of age-related increases in germline mutations. [ABSTRACT FROM AUTHOR]

The study published in MedComm explores how disruptions in paternal gut microbiota can impact offspring health, leading to weight issues, developmental disorders, and increased early mortality. Researchers identified a "Gut-germline axis" dysregulation and placental dysfunction as key factors influencing adverse pregnancy outcomes. The findings suggest that restoring the father's gut microbiome could potentially reverse these effects, highlighting the importance of paternal gut microbiota in offspring health. Further research is needed to confirm these results and understand the implications of the "Gut-germline axis" in mammals. [Extracted from the article]

In this review, we introduce the concept of cell competition, which occurs between heterogeneous neighboring cell populations. Cells with higher relative fitness become "winners" that outcompete cells of lower relative fitness ("losers"). We discuss the idea of super-competitors, mutant cells that expand at the expense of wild-type cells. Work on adult stem cells (ASCs) has revealed principles of neutral competition, wherein ASCs can be stochastically lost and replaced, and of biased competition, in which a winning ASC with a competitive advantage replaces its neighbors. Germline stem cells (GSCs) are ASCs that are uniquely endowed with the ability to produce gametes and, therefore, impact the next generation. Mechanisms of GSC competition have been elucidated by studies in Drosophila gonads, tunicates, and the mammalian testis. Competition between ASCs is thought to underlie various forms of cancer, including spermatocytic tumors in the human testis. Paternal age effect (PAE) disorders are caused by de novo mutations in human GSCs that increase their competitive ability and make them more likely to be inherited, leading to skeletal and craniofacial abnormalities in offspring. Given its widespread effects on human health, it is important to study GSC competition to elucidate how cells can become winners or losers. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the impact of paternal age > 40 years on clinical pregnancy and perinatal outcomes among patients undergoing in vitro fertilization treatment. Methods: We selected 75 male patients (aged > 40 years) based on predefined inclusion and exclusion criteria. Propensity score matching was performed in a 1:3 ratio, resulting in a control group (aged = 40 years) of 225 individuals. Various statistical tests, including the Mann-Whitney U test, Chi-square test, Fisher's exact test, and binary logistic regression, were used to analyze the association between paternal age and clinical outcomes. Results: We found no statistically significant differences in semen routine parameters, clinical pregnancy outcomes, and perinatal outcomes between paternal aged > 40 and = 40 years. However, in the subgroup analysis, the live birth rate significantly decreased in those aged = 45 compared to those aged 41-42 and 43-44 years (31.25% vs. 69.23% and 65%, respectively; all p < 0.05). Additionally, the clinical pregnancy rate was significantly lower among those aged = 45 than among those aged 41-42 (43.75% vs. 74.36%; p=0.035). Conclusion: Paternal age = 45 years was associated with lower live birth and clinical pregnancy rates. [ABSTRACT FROM AUTHOR]

Background Limited research has explored the impact of mosquito repellents exposure during early life on ADHD symptoms. This study aimed to explore the associations of exposure to mosquito repellents from pregnancy to 3 years old and the prevalence of ADHD-like behaviours among children aged 3–9 years, and further identify the sensitive exposure period. Methods A cross-sectional study was conducted, including 12 275 children in Hefei City, China. Exposure was self-reported via primary caregivers. ADHD-like behaviours were measured by the Swanson, Nolan and Pelham, version IV scale (SNAP-IV), and Conners' Parent Rating Scale (CPRS). Cross-over analysis, binary logistic regression and linear regression were employed. Results After adjusting for confounding variables, early-life exposure to mosquito repellents was associated with a higher risk of ADHD-like behaviours (OR = 1.81, 95% CI = 1.49–2.19). By comparing the strength of the association for each subgroup, we found exposure during 1–3 years old was a sensitive period (OR = 1.89, 95% CI = 1.25–2.87) by the cross-over analysis. Furthermore, we found a dose–response relationship in which the likelihood of ADHD-like behaviours increased with children's early-life mosquito repellents exposure dose. Conclusions Early-life exposure to mosquito repellents is linked with an elevated risk of ADHD-like behaviours in children, with a sensitive period identified during 1–3 years old. [ABSTRACT FROM AUTHOR]

Advancing male age is often hypothesized to reduce both male fertility and offspring quality due to reproductive senescence. However, the effects of advancing male age on reproductive output and offspring quality are not always deleterious. For example, older fathers might buffer the effects of reproductive senescence by terminally investing in reproduction. Similarly, males that survive to reproduce at an old age might carry alleles that confer high viability (viability selection), which are then inherited by offspring, or might have high reproductive potential (selective disappearance). Differentiating these mechanisms requires an integrated experimental study of paternal survival and reproductive performance, as well as offspring quality, which is currently lacking. Using a cross-sectional study in Drosophila melanogaster , we test the effects of paternal age at conception (PAC) on paternal survival and reproductive success, and on the lifespans of sons. We discover that mating at an old age is linked with decreased future male survival, suggesting that mating-induced mortality is possibly due to old fathers being frail. We find no evidence for terminal investment and show that reproductive senescence in fathers does not onset until their late-adult life. Additionally, we find that as a father's lifespan increases, his probability of siring offspring increases for older PAC treatments only. Lastly, we show that sons born to older fathers live longer than those born to younger fathers due to viability selection. Collectively, our results suggest that advancing paternal age is not necessarily associated with deleterious effects for offspring and may even lead to older fathers producing longer-lived offspring. [ABSTRACT FROM AUTHOR]

The sperm epigenome is thought to affect the developmental programming of the resulting embryo, influencing health and disease in later life. Age‐related methylation changes in the sperm of old fathers may mediate the increased risks for reproductive and offspring medical problems. The impact of paternal age on sperm methylation has been extensively studied in humans and, to a lesser extent, in rodents and cattle. Here, we performed a comparative analysis of paternal age effects on protein‐coding genes in the human and marmoset sperm methylomes. The marmoset has gained growing importance as a non‐human primate model of aging and age‐related diseases. Using reduced representation bisulfite sequencing, we identified age‐related differentially methylated transcription start site (ageTSS) regions in 204 marmoset and 27 human genes. The direction of methylation changes was the opposite, increasing with age in marmosets and decreasing in humans. None of the identified ageTSS was differentially methylated in both species. Although the average methylation levels of all TSS regions were highly correlated between marmosets and humans, with the majority of TSS being hypomethylated in sperm, more than 300 protein‐coding genes were endowed with species‐specifically (hypo)methylated TSS. Several genes of the glycosphingolipid (GSL) biosynthesis pathway, which plays a role in embryonic stem cell differentiation and regulation of development, were hypomethylated (<5%) in human and fully methylated (>95%) in marmoset sperm. The expression levels and patterns of defined sets of GSL genes differed considerably between human and marmoset pre‐implantation embryo stages and blastocyst tissues, respectively. [ABSTRACT FROM AUTHOR]

Key Points: Question: How do individuals with a diagnosis of schizophrenia recruited in a large volunteer-based research resource (UK Biobank) differ from those in the Psychiatric Genomics Consortium (PGC) or those recruited from clinical settings? Findings: In this cross-sectional study including more than 517 000 individuals, liability to schizophrenia in the UK Biobank had a high genetic correlation with the PGC. Compared with 4 clinically ascertained schizophrenia samples, UK Biobank participants with schizophrenia had significantly lower schizophrenia genetic liability as indexed by polygenic risk score, lower rates of copy number variants, and fewer phenotypic features of poor outcome. Meaning: In this study, individuals with schizophrenia in the UK Biobank had features of less severe illness, which indicates that registries such as the UK Biobank can help to capture the full range of heterogeneity in schizophrenia research. This cross-sectional study compares genetic liability to psychiatric disorders in individuals with schizophrenia in the UK Biobank with individuals in the Psychiatric Genomics Consortium and compares genetic liability and phenotypic features with participants recruited from clinical settings. Importance: Large-scale biobanks provide important opportunities for mental health research, but selection biases raise questions regarding the comparability of individuals with those in clinical research settings. Objective: To compare the genetic liability to psychiatric disorders in individuals with schizophrenia in the UK Biobank with individuals in the Psychiatric Genomics Consortium (PGC) and to compare genetic liability and phenotypic features with participants recruited from clinical settings. Design, Setting, and Participants: This cross-sectional study included participants from the population-based UK Biobank and schizophrenia samples recruited from clinical settings (CLOZUK, CardiffCOGS, Cardiff F-Series, and Cardiff Affected Sib-Pairs). Data were collected between January 1993 and July 2021. Data analysis was conducted between July 2021 and June 2023. Main Outcomes and Measures: A genome-wide association study of UK Biobank schizophrenia case-control status was conducted, and the results were compared with those from the PGC via genetic correlations. To test for differences with the clinical samples, polygenic risk scores (PRS) were calculated for schizophrenia, bipolar disorder, depression, and intelligence using PRS-CS. PRS and phenotypic comparisons were conducted using pairwise logistic regressions. The proportions of individuals with copy number variants associated with schizophrenia were compared using Firth logistic regression. Results: The sample of 517 375 participants included 1438 UK Biobank participants with schizophrenia (550 [38.2%] female; mean [SD] age, 54.7 [8.3] years), 499 475 UK Biobank controls (271 884 [54.4%] female; mean [SD] age, 56.5 [8.1] years), and 4 schizophrenia research samples (4758 [28.9%] female; mean [SD] age, 38.2 [21.0] years). Liability to schizophrenia in UK Biobank was highly correlated with the latest genome-wide association study from the PGC (genetic correlation, 0.98; SE, 0.18) and showed the expected patterns of correlations with other psychiatric disorders. The schizophrenia PRS explained 6.8% of the variance in liability for schizophrenia case status in UK Biobank. UK Biobank participants with schizophrenia had significantly lower schizophrenia PRS than 3 of the clinically ascertained samples and significantly lower rates of schizophrenia-associated copy number variants than the CLOZUK sample. UK Biobank participants with schizophrenia had higher educational attainment and employment rates than the clinically ascertained schizophrenia samples, lower rates of smoking, and a later age of onset of psychosis. Conclusions and Relevance: Individuals with schizophrenia in the UK Biobank, and likely other volunteer-based biobanks, represent those less severely affected. Their inclusion in wider studies should enhance the representation of the full spectrum of illness severity. [ABSTRACT FROM AUTHOR]

Background: Autism and different neurodevelopmental conditions frequently co-occur, as do their symptoms at sub-diagnostic threshold levels. Overlapping traits and shared genetic liability are potential explanations. Methods: In the population-based Norwegian Mother, Father, and Child Cohort study (MoBa), we leverage item-level data to explore the phenotypic factor structure and genetic architecture underlying neurodevelopmental traits at age 3 years (N = 41,708–58,630) using maternal reports on 76 items assessing children's motor and language development, social functioning, communication, attention, activity regulation, and flexibility of behaviors and interests. Results: We identified 11 latent factors at the phenotypic level. These factors showed associations with diagnoses of autism and other neurodevelopmental conditions. Most shared genetic liabilities with autism, ADHD, and/or schizophrenia. Item-level GWAS revealed trait-specific genetic correlations with autism (items rg range = − 0.27–0.78), ADHD (items rg range = − 0.40–1), and schizophrenia (items rg range = − 0.24–0.34). We find little evidence of common genetic liability across all neurodevelopmental traits but more so for several genetic factors across more specific areas of neurodevelopment, particularly social and communication traits. Some of these factors, such as one capturing prosocial behavior, overlap with factors found in the phenotypic analyses. Other areas, such as motor development, seemed to have more heterogenous etiology, with specific traits showing a less consistent pattern of genetic correlations with each other. Conclusions: These exploratory findings emphasize the etiological complexity of neurodevelopmental traits at this early age. In particular, diverse associations with neurodevelopmental conditions and genetic heterogeneity could inform follow-up work to identify shared and differentiating factors in the early manifestations of neurodevelopmental traits and their relation to autism and other neurodevelopmental conditions. This in turn could have implications for clinical screening tools and programs. [ABSTRACT FROM AUTHOR]

Background: Obesity is a metabolic syndrome where allelic and environmental variations together determine the susceptibility of an individual to the disease. Caloric restriction (CR) is a nutritional dietary strategy recognized to be beneficial as a weight loss regime in obese individuals. Preconceptional parental CR is proven to have detrimental effects on the health and development of their offspring. As yet studies on maternal CR effect on their offspring are well established but paternal CR studies are not progressing. In current study, the impact of different paternal CR regimes in diet-induced obese male Wistar rats (WNIN), on their offspring concerning metabolic syndrome are addressed. Methods: High-fat diet-induced obese male Wistar rats were subjected to caloric restriction of 50% (HFCR-I) and 40% (HFCR-II) and then they were mated with normal females. The male parent's reproductive function was assessed by sperm parameters and their DNMT's mRNA expression levels were also examined. The offspring's metabolic function was assessed by physiological, biochemical and molecular parameters. Results: The HFCR-I male parents have shown reduced body weights, compromised male fertility and reduced DNA methylation activity. Further, the HFCR-I offspring showed attenuation of the AMPK/SIRT1 pathway, which is associated with the progression of proinflammatory status and oxidative stress. In line, the HFCR-I offspring also developed altered glucose and lipid homeostasis by exhibiting impaired glucose tolerance & insulin sensitivity, dyslipidemia and steatosis. However, these effects were largely mitigated in HFCR-II offspring. Regarding the obesogenic effects, female offspring exhibited greater susceptibility than male offspring, suggesting that females are more prone to the influences of the paternal diet. Conclusion: The findings highlight that HFCR-I resulted in paternal undernutrition, impacting the health of offspring, whereas HFCR-II largely restored the effects of a high-fat diet on their offspring. As a result, moderate caloric restriction has emerged as an effective weight loss strategy with minimal implications on future generations. This underscores the shared responsibility of fathers in contributing to sperm-specific epigenetic imprints that influence the health of adult offspring. [ABSTRACT FROM AUTHOR]

In brief: In light of the increasing age of first-time fathers, this article summarizes the current scientific knowledge base on reproductive aging in the male, including sperm quality and health impacts for the offspring. The emerging role of NAD decline in reproductive aging is highlighted. Abstract: Over the past decades, the age of first-time fathers has been steadily increasing due to socio-economic pressures. While general mechanisms of aging are subject to intensive research, male reproductive aging has remained an understudied area, and the effects of increased age on the male reproductive system are still only poorly understood, despite new insights into the potential dire consequences of advanced paternal age for the health of their progeny. There is also growing evidence that reproductive aging is linked to overall health in men, but this review mainly focuses on pathophysiological consequences of old age in men, such as low sperm count and diminished sperm genetic integrity, with an emphasis on mechanisms underlying reproductive aging. The steady decline of NAD levels observed in aging men represents one of the emerging concepts in that regard. Because it offers some mechanistic rationale explaining the effects of old age on the male reproductive system, some of the NAD-dependent functions in male reproduction are briefly outlined in this review. The overview also provides many questions that remain open about the basic science of male reproductive aging. [ABSTRACT FROM AUTHOR]

Objective: Microcephaly (MC) is a clinical finding mostly reflecting deficiency of brain growth. The aim of this retrospective cohort study was to assess risk factors and follow-up features of children with MC. Methods: Children’s personal health records (n=7580) followed between 2002 and 2020 in the Unit of a Well Child Clinic were assessed retrospectively. The case group comprised children with MC. MC was defined as head circumference (HC) standard deviation score (SDS) value ≤-2 SDS. Age and sex-matched children with normal HC were selected as the control group. Results: Children with MC (n=49) had more disadvantaged sociodemographic characteristics, such as young maternal and paternal age and low maternal and paternal education. Breastfeeding was more common among controls (n=98). Resolution of MC was observed in 26 (53.1%) children with MC, whether it was mild (HC SDS between -2 and -2.9) or severe (HC SDS ≤3). Children with persistent MC had poorer developmental milestones than controls and cases with resolution. Sociodemographic features or developmental milestones in mild and severe MC did not differ. Conclusion: These results suggest that the use of a definition of MC of ≤-2 SDS would be appropriate in order not to miss cases on follow-up. Greater sociodemographic equality may prevent some cases of MC. Further studies are needed evaluating socioeconomic factors on MC. [ABSTRACT FROM AUTHOR]

There is some evidence that offspring of patients with schizophrenia have higher somatic morbidity, which is thought to be partially due to genetic links between somatic disorders and schizophrenia. This study explored differences in somatic diseases and conditions of adoptees with high genetic risk (HR) or low genetic risk (LR) for schizophrenia spectrum disorders. The study is part of the Finnish Adoptive Family Study of Schizophrenia. The adoptive research design used made it possible to examine how the somatic health of adoptees raised in similar adoptive families, is affected by their genetic susceptibility to schizophrenia. The study sample consisted of 373 adoptees, of whom 190 had HR and 183 had LR for schizophrenia spectrum disorders. Data on somatic morbidity were gathered from the hospital records and from the national registers of the Care Register of Health Care and the Social Insurance Institution. The only statistically significant difference found was in genitourinary diseases, the likelihood being twofold higher in HR adoptees compared to LR adoptees (16.8% vs. 8.2%; adj. OR = 2.13, 95% CI 1.06–4.25, p =.033). Adoptees who were female and aged over 40 had a higher prevalence of genitourinary illnesses than non-adoptees. The significant prevalence of genitourinary diseases in adoptees at risk for schizophrenia spectrum disorders suggests that some specific somatic diseases and schizophrenia may have a shared hereditary etiology. More research is required for specific somatic diseases in study populations that can differentiate between the effects of genetic and environmental factors. [ABSTRACT FROM AUTHOR]

While there is long‐standing interest in the role of inter‐ and transgenerational plasticity via the maternal line, it rarely has been studied via the paternal line. Thus, consequences of the paternal environment for parental fitness and for performance of offspring in the environments experienced by either fathers or mothers are not known. We studied the intergenerational plasticity (IGP) of the plant species Paeonia ostii (Paeoniaceae) and tested the hypothesis that exposure of fathers to environmental stress (i) reduces parental fitness and performance of offspring grown under non‐stressful conditions, but (ii) mitigates the negative effects of environmental stress on fitness of parents and performance of offspring.Crosses were made in a greenhouse within six families of P. ostii between parents grown under drought and in a mesic environment, and the offspring of each cross were grown under both dry and mesic conditions. Production and germination of seeds and morphological and physiological traits of offspring were measured as indicators of parental fitness and offspring performance, respectively.Paternal drought decreased seed number per fruit, except when maternal plants also were grown in drought conditions. Offspring drought decreased seedling performance. However, when fathers experienced drought this negative effect on the offspring was partly mitigated, in particular when mothers also had experienced drought. In contrast, offspring grown in mesic conditions had improved seedling performance, especially when either parent (or both) also were grown in mesic conditions. Such statistical differences remained when seed mass was included as a covariate.Overall, paternal pollen of P. ostii mediated IGP to drought almost as well as it did for maternal ovules. IGP was adaptive if environments remained constantly dry across generations but maladaptive if environments changed. Hence, under future climate changes, paternal IGP might be both a blessing and a curse, with the blessing occurring when the focal habitat becomes drier and pollen comes from already‐dry places, while the curse may dominate in predictably moist habitats surrounded by drier habitats. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

The global fall in male fertility is a complicated process driven by a variety of factors, including environmental exposure, lifestyle, obesity, stress, and aging. The availability of assisted reproductive technology (ART) has allowed older couples to conceive, increasing the average paternal age at first childbirth. Advanced paternal age (APA), most often considered male age ≥40, has been described to impact several aspects of male reproductive physiology. In this prospective cohort study including 200 normozoospermic patients, 105 of whom were ≤35 years (non-APA), and 95 of whom were ≥42 years (APA), we assessed the impact of paternal age on different endpoints representative of sperm quality and cryopreservation tolerance. Non-APA patients had superior fresh semen quality; DNA fragmentation was notably increased in APA as compared to non-APA individuals (21.7% vs. 15.4%). Cryopreservation further increased the DNA fragmentation index in APA (26.7%) but not in non-APA patients. Additionally, APA was associated with increased mtDNAcn in both fresh and frozen/thawed sperm, which is indicative of poorer mitochondrial quality. Cryopreservation negatively impacted acrosome integrity in both age groups, as indicated by reduced incidences of unreacted acrosome in relation to fresh counterparts in non-APA (from 71.5% to 57.7%) and APA patients (from 75% to 63%). Finally, cryopreservation significantly reduced the phosphorylation status of proteins containing tyrosine residues in sperm from young males. Therefore, the present findings shed light on the effects of paternal age and cryopreservation on sperm quality and serve as valuable new parameters to improve our understanding of the mechanisms underlying sperm developmental competence that are under threat in current ART practice. [ABSTRACT FROM AUTHOR]

The Ras family of small GTPases coordinates tissue development by modulating cell proliferation, cell-cell adhesion, and cellular morphology. Perturbations of any of these key steps alter nervous system development and are associated with neurological disorders. While the underlying causes are not known, genetic mutations in Ras and Rap GTPase signaling pathways have been identified in numerous neurodevelopmental disorders, including autism spectrum, neurofibromatosis, intellectual disability, epilepsy, and schizophrenia. Despite diverse clinical presentations, intersections between these two signaling pathways may provide a better understanding of how deviations in neurodevelopment give rise to neurological disorders. In this review, we focus on presynaptic and postsynaptic functions of Ras and Rap GTPases. We highlight various roles of these small GTPases during synapse formation and plasticity. Based on genomic analyses, we discuss how disease-related mutations in Ras and Rap signaling proteins may underlie human disorders. Finally, we discuss how recent observations have identified molecular interactions between these pathways and how these findingsmay provide insights into themechanisms that underlie neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Background: Patients with schizophrenia are at a higher risk of developing cancer. However, the causal relationship between schizophrenia and different tumor types remains unclear. Methods: Using a two-sample, two-way Mendelian randomization method, we used publicly available genome-wide association analysis (GWAS) aggregate data to study the causal relationship between schizophrenia and different cancer risk factors. These tumors included lung adenocarcinoma, lung squamous cell carcinoma, small-cell lung cancer, gastric cancer, alcohol-related hepatocellular cancer, tumors involving the lungs, breast, thyroid gland, pancreas, prostate, ovaries and cervix, endometrium, colon and colorectum, and bladder. We used the inverse variance weighting (IVW) method to determine the causal relationship between schizophrenia and different tumor risk factors. In addition, we conducted a sensitivity test to evaluate the effectiveness of the causality. Results: After adjusting for heterogeneity, evidence of a causal relationship between schizophrenia and lung cancer risk was observed (odds ratio [OR] =1.001, 95% confidence interval [CI], 1.000-1.001; P=0.0155). In the sensitivity analysis, the causal effect of schizophrenia on the risk of lung cancer was consistent in both direction and degree. However, no evidence of causality or reverse causality between schizophrenia and other tumors was found. Conclusion: This study elucidated a causal relationship between the genetic predictors of schizophrenia and the risk of lung cancer, thereby providing a basis for the prevention, pathogenesis, and treatment of schizophrenia in patients with lung cancer. [ABSTRACT FROM AUTHOR]

Background: Knowledge of the association between parental personality disorders and mental disorders in children is limited. To examine the association between parental personality disorders and the risk of mental disorders in offspring. Methods: We linked Danish health registers to create a cohort of children born from January 1, 1995, to December 31, 2016. Children were followed until their 18th birthday, diagnosis set, emigration, death, or December 31, 2016. Parental personality disorders according to the International Classification of Diseases (ICD) Eighth or 10th Revision. Poisson regression analyses were used to estimate the incidence risk ratio (IRR) and cumulative incidence of ICD 10th mental disorders in offspring (age 0–17). Results: The study cohort included 1,406,965 children. For girls, maternal or paternal personality disorder (MPD/PPD) was associated with mental disorders: MPD girls (IRR, 2.74; 95% CI, 2.59–2.89) and PPD girls (IRR, 2.10; 95% CI, 1.94–2.27). Likewise, the risk was increased for both MPD boys (IRR, 2.44; 95% CI, 2.33–2.56) and PPD boys (IRR, 2.04; 95% CI, 1.91–2.18). For girls and boys combined, exposure to two parents with a personality disorder was associated with the highest risk (IRR, 3.69; 95% CI, 3.15–4.33). At age 18, the cumulative incidence of any mental disorder in children of one or two parents with a personality disorder was 34.1% (95% CI, 33.0–35.1), which was twice the cumulative incidence of mental disorders in nonexposed children (15.2% [95% CI, 15.1–15.3]). Conclusion: Children of parents with a personality disorder were at a 2 to 3.5 times higher risk of mental disorders compared with nonexposed offspring. Possible mechanisms of transmission of mental disorders from parent to child involve genetic, environmental, and gene–environment pathways. More research into these mechanisms and research into preventive interventions is warranted. [ABSTRACT FROM AUTHOR]

This study examines the hypothesis that temperamental (dis)similarity is associated with twin relationship quality. In a longitudinal study that followed 322 monozygotic twins (who share close to 100% of their genes) and 1199 dizygotic twins (who on average, share 50% of their segregating genes) throughout childhood, mothers (N = 1547) and fathers (N = 536) reported on their twins' relationships on at least one of four measurement points when the twins were between 3 and 8–9 years of age. Mothers also reported on the twins' temperament. Negative associations were found between reports by both parents on the twins' closeness and their temperament difference throughout childhood, while positive associations were found between twins' conflict and their temperament difference in late childhood. Latent growth modeling indicated that the association between temperament differences and the twins' mother-reported closeness was evident beyond the effect of zygosity. A different pattern was found for twin conflict: the more the twins differed in their temperament (specifically negative emotionality) with age, the more the conflict between them increased. Our findings support the hypothesis that personality similarities can contribute to positive relationships from early childhood, and vice versa, beyond the effect of genetic similarity. [ABSTRACT FROM AUTHOR]

Background: A significant association between women's reproductive traits and the risk of schizophrenia (SCZ) has been discovered, but the causalities remain unclear. We designed a two-sample univariate Mendelian randomization (MR) study using female-specific SNPs collected from a large-scale genome-wide association study as a genetic tool to explore the causal effect of female reproductive traits on the risk of SCZ, and conducted a multivariate MR study to re-validate the above findings. Methods: From extensive genome-wide association studies (GWAS) of people with European ancestry (n = 176,881 to 418,758 individuals), summary-level data on five female reproductive variables were extracted. Summary-level information on SCZ was taken from a GWAS meta-analysis involving 320,404 people with European ancestry. The inverse variance weighting estimations for both univariable MR (UVMR) and multivariable MR (MVMR) were presented as the primary results. MR-Egger, weighted median, simple mode, and weighted mode regression methods for UVMR, and MVMR-Egger, MVMR-Lasso, and MVMR-median methods for MVMR were used for sensitivity analyses. Results: The UVMR produced compelling proof for a connection between genetically predicted later age at first sexual intercourse (AFS) (OR, 0.632; 95% CI, 0.512–0.777; P < 0.01) and decreased SCZ risk. Pleiotropy analysis of the AFS-SCZ association confirmed the robustness of the MR results (P > 0.05). Consistent, substantial causal effects of AFS (OR, 0.592; 95%CI, 0.407–0.862; P < 0.01) on the risk of SCZ were demonstrated after adjusting for body mass index, years of schooling, and smoking initiation using MVMR. Conclusions: Our findings provide convincing evidence that early AFS is a risk factor for SCZ. SCZ risk may be decreased by raising awareness of reproductive healthcare for women. [ABSTRACT FROM AUTHOR]

There is strong evidence that obesity is a risk factor for poor semen quality. However, the effects of multigenerational paternal obesity on the susceptibility to cadmium (a reproductive toxicant)-induced spermatogenesis disorders in offspring remain unknown. Here, we show that, in mice, spermatogenesis and retinoic acid levels become progressively lower as the number of generations exposed to a high-fat diet increase. Furthermore, exposing several generations of mice to a high fat diet results in a decrease in the expression of Wt1, a transcription factor upstream of the enzymes that synthesize retinoic acid. These effects can be rescued by injecting adeno-associated virus 9-Wt1 into the mouse testes of the offspring. Additionally, multigenerational paternal high-fat diet progressively increases METTL3 and Wt1 N6-methyladenosine levels in the testes of offspring mice. Mechanistically, treating the fathers with STM2457, a METTL3 inhibitor, restores obesity-reduced sperm count, and decreases Wt1 N6-methyladenosine level in the mouse testes of the offspring. A case-controlled study shows that human donors who are overweight or obese exhibit elevated N6-methyladenosine levels in sperm and decreased sperm concentration. Collectively, these results indicate that multigenerational paternal obesity enhances the susceptibility of the offspring to spermatogenesis disorders by increasing METTL3-mediated Wt1 N6-methyladenosine modification. The mechanisms through which multigenerational paternal obesity affects spermatogenesis in offspring remain poorly understood. Here, the authors show that it affects Wt1 m6A modifications, decreasing the fertility of offspring. [ABSTRACT FROM AUTHOR]

The COVID–19 pandemic has created unprecedented challenges for health care systems globally. This study aimed to explore the presence of mental illness in a Spanish cohort of COVID-19-infected population and to evaluate the association between the presence of specific mental health conditions and the risk of death and hospitalization. This is a retrospective cohort study including all individuals with confirmed infection by SARS-CoV-2 from the PRECOVID (Prediction in COVID–19) Study (Aragon, Spain). Mental health illness was defined as the presence of schizophrenia and other psychotic disorders, anxiety, cognitive disorders, depression and mood disorders, substance abuse, and personality and eating disorders. Multivariable logistic regression models were used to examine the likelihood of 30-day all-cause mortality and COVID–19 related hospitalization based on baseline demographic and clinical variables, including the presence of specific mental conditions, by gender. We included 144,957 individuals with confirmed COVID–19 from the PRECOVID Study (Aragon, Spain). The most frequent diagnosis in this cohort was anxiety. However, some differences were observed by sex: substance abuse, personality disorders and schizophrenia were more frequently diagnosed in men, while eating disorders, depression and mood, anxiety and cognitive disorders were more common among women. The presence of mental illness, specifically schizophrenia spectrum and cognitive disorders in men, and depression and mood disorders, substance abuse, anxiety and cognitive and personality disorders in women, increased the risk of mortality or hospitalization after COVID–19, in addition to other well-known risk factors such as age, morbidity and treatment burden. Identifying vulnerable patient profiles at risk of serious outcomes after COVID–19 based on their mental health status will be crucial to improve their access to the healthcare system and the establishment of public health prevention measures for future outbreaks. [ABSTRACT FROM AUTHOR]

Background: The process of gamete formation and early embryonic development involves rapid DNA replication, chromosome segregation and cell division. These processes may be affected by mutations in the BRCA1/2 genes. The aim of this study was to evaluate BRCA mutation inheritance and its effect on early embryonic development according to the parental origin of the mutation. The study question was approached by analyzing in vitro fertilization cycles (IVF) that included pre-implantation testing (PGT-M) for a BRCA gene mutation. Methods: This retrospective cohort study compared cycles of pre-implantation genetic testing for mutations (PGT-M) between male and female patients diagnosed with BRCA 1/2 mutations (cases), to a control group of two other mutations with dominant inheritance (myotonic dystrophy (MD) and polycystic kidney disease (PKD)). Results were compared according to mutation type and through a generalized linear model analysis. Results: The cohort included 88 PGT-M cycles (47 BRCA and 41 non-BRCA) among 50 patients. Maternal and paternal ages at oocyte retrieval were comparable between groups. When tested per cycle, FSH dose, maximum estradiol level, oocytes retrieved, number of zygotes, and number of embryos available for biopsy and affected embryos, were not significantly different among mutation types. All together 444 embryos were biopsied: the rate of affected embryos was comparable between groups. Among BRCA patients, the proportion of affected embryos was similar between maternal and paternal mutation origin (p = 0.24). In a generalized linear model analysis, the relative oocyte yield in maternal BRCA patients was significantly lower (0.7, as related to the non BRCA group)(p < 0.001). Zygote formation and blastulation were not affected by the BRCA gene among paternal cases (P = 0.176 and P = 0.293 respectively), nor by paternal versus maternal BRCA carriage (P = 0.904 and P = 0.149, respectively). Conclusions: BRCA PGT-M cycles performed similarly compared to non-BRCA cycles. Inheritance rate and cycle parameters were not affected by the parental origin of the mutation. [ABSTRACT FROM AUTHOR]

Background: Preclinical animal studies and clinical studies indicate that both maternal as well as paternal genetic alterations/gene defects might affect the phenotype of the next-generation without transmissions of the affected gene. Currently, the question of whether the same genetic defect present in the mother or father leads to a similar phenotype in the offspring remains insufficiently elucidated. Methods: In this head-to-head study, we crossbred female and male mice with heterozygous endothelial eNOS knockout (eNOS+/−) with male and female wildtype (wt) mice, respectively. Subsequently, we compared the phenotype of the resulting wt offspring with that of wt offspring born to parents with no eNOS deficiency. Results: Wt female offspring of mothers with heterozygous eNOS showed elevated liver fat accumulation, while wt male offspring of fathers with heterozygous eNOS exhibited increased fasting insulin, heightened insulin levels after a glucose load, and elevated liver glycogen content. By quantitative mass-spectrometry it was shown that concentrations of six serum metabolites (lysoPhosphatidylcholine acyl C20:3, phosphatidylcholine diacyl C36:2, phosphatidylcholine diacyl C38:1, phosphatidylcholine acyl-alkyl C34:1, phosphatidylcholine acyl-alkyl C36:3, and phosphatidylcholine acyl-alkyl C42:5 (PC ae C42:5) as well as four liver carbon metabolites (fructose 6-phosphate, fructose 1,6-bisphosphate, glucose 6-phosphate and fumarate) were different between wt offspring with eNOS+/− mothers and wt offspring with eNOS+/− fathers. Importantly, fumarate was inversely correlated with the liver fat accumulation in female offspring with eNOS+/− mothers and increased liver glycogen in offspring of both sexes with eNOS+/− fathers. The qRT-PCR results revealed that the gene expression patterns were different between wt offspring with eNOS+/− mothers and those offspring with eNOS+/− fathers. Different gene expression patterns were correlated with different observed phenotypic changes in male/female offspring born to mothers or fathers with a heterozygous eNOS genotype. Conclusion: The identical parental genetic alteration (heterozygous eNOS deficiency), without being passed on to the offspring, results in distinct metabolic, liver phenotype, and gene expression pattern variations depending on whether the genetic alteration originated from the father or the mother. [ABSTRACT FROM AUTHOR]

The study's primary aim was to examine the relationship between paternal age and perinatal outcomes. This study used data from two hospital birth registries to examine the association between paternal age and adverse perinatal outcomes. The sample included all live singleton births between 2010 and 2022. The primary exposure was paternal age, and the following perinatal outcomes were considered: mode of conception, mode of delivery, pregnancy complications, and neonatal outcomes. A total of 15,232 pregnant women were considered. Maternal and paternal ages were 31.9 ± 5.3 and 36.5 ± 6.5 years, respectively. Independent of maternal, paternal age was associated with lower odds of spontaneous conceptions (OR 0.930, 95 % CI 0.968/0.993; p=0.003) and higher odds of intracytoplasmatic sperm injection (OR 1.054, 95 % CI 1.045/1.062; p=0.0001), respectively. In contrast to maternal age, paternal age decreased the odds of any (OR 0.922, 95 % CI 0.985/0.999; p=0.032) and urgent/emergent (OR 0.984, 95 % CI 0.975/0.993; p=0.0001) cesarean delivery. Paternal age did not affect the gestation length, placental or neonatal weight, blood loss during delivery, and neonatal 5th-minute Apgar score. Paternal age is associated with perinatal outcomes. These findings suggest that advanced paternal age may have implications for reproductive counseling and prenatal care. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical and genetic characteristics of a patient with long QT syndrome type 14 (long QT syndrome‐14, LQT14, OMIM # 616247) caused by a de novo CALM1 mutation. Methods: The clinical data of the patient were collected, next‐generation sequencing technology was used to determine the exome gene sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing. Results: A 5‐year and 9‐month‐old girl was admitted to the hospital due to a syncopal episode. During the attack, the main symptoms were loss of consciousness, cyanosis of the face and lips, and weakness of limbs. The child had multiple seizures in the past, all of which occurred after emotional excitement and activity. She was diagnosed with epilepsy for more than 3 years, but the effect of antiepileptic treatment was not satisfactory. The electrocardiogram was normal in the past. A month ago, convulsions occurred again after exercise, and the electrocardiogram showed QTc 496 ms. The treadmill test showed a significant prolongation of QTc after exercise, and the genetic results suggested a new heterozygous variant of CALM1, c.395A>G; p. (Asp132Gly). Consequently, she was diagnosed with LQT14 and treated with propranolol. During a follow‐up of 15 months, there were no seizures or syncope. Conclusions: This patient had multiple episodes of convulsions or syncope after emotional stimulation or activity, with intermittent prolongation of the QTc on routine ECG, marked prolongation of the QTc after exercise, and T‐wave alternans, which differed from the LQT14 phenotype caused by the previous CALM1 mutation. [ABSTRACT FROM AUTHOR]

The fraternal birth order effect (FBOE) is the phenomenon whereby the probability that a man has a same-sex sexual orientation in adulthood increases with each biological older brother. Several studies have found evidence that the FBOE is limited to right-handed men, and left-handed men do not show an FBOE. Recent debates about the appropriate methods for quantifying the FBOE center on distinguishing the FBOE from other effects, such as the female fecundity effect (FFE), whereby mothers more prone to bearing gay sons are also more fecund. The FBOE and FFE are confounded in that a real FFE will result in data consistent with the FBOE under some analyses. Here, we applied some recent proposed analytic methods for the FBOE to the property of handedness. A straightforward application of Khovanova's technique to the binary trait of handedness yielded support for a fraternal birth order effect consistent with the maternal immune hypothesis, in that the ratios of handedness differed between men with one older brother only, and men with one younger brother only, while no such effect was seen in women. This effect was not seen, however, when the confounding effects of parental age were controlled for. Models including factors to simultaneously test multiple posited effects find significant female fecundity effects, as well as paternal age and birth order effects on handedness in men, but no FBOE. The effects seen in women were different, with no fecundity or parental age effects, but birth order and sex of older siblings had effects. We conclude, based on this evidence, that many of the factors thought to contribute to sexual orientation in men may also have an influence on handedness, and further note that parental age is a potential confound which may be overlooked by some analyses of the FBOE. [ABSTRACT FROM AUTHOR]

The article offers information on the familial aggregation and comorbidity of disorders such as alcohol use disorder (AUD), drug use disorders, attention deficit hyperactivity disorder (ADHD), major depression, and anxiety disorders. Topics include the transmission of risk for these disorders from parents with AUD to their offspring, differences in risk between sons and daughters, and the impact of affected mothers and fathers on offspring risk.

Background: Previous observational studies have reported inconsistent findings regarding the incidence of cancer in patients with schizophrenia compared to the general population. The causal relationship between schizophrenia and cancer remains unclear and requires further investigation. Objective: To investigate the causal relationship between schizophrenia and cancer. Methods: In this study, a two-sample Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies to determine the causal relationship. The effect estimates were calculated using the random-effects inverse-variance-weighted method. Results: We determined a causal relationship between genetic predisposition to schizophrenia and cancer, with schizophrenia increasing lung cancer (odds ratio (OR) = 1.0007; 95% confidence interval (CI), 1.0001-1.0013; p = 0.0192), thyroid cancer (OR = 1.5482; CI, 1.1112-2.1569; p =0.0098), colorectal cancer (OR = 1.0009; CI, 1.0001-1.0018; p = 0.0344), ovarian cancer (OR = 1.0770; CI, 1.0352- 1.1203; p = 0.0002), breast cancer (OR = 1.0011; CI, 1.0001- 1.0022; p =0.0352) and reduced the risk of malignant neoplasm of the stomach (OR = 0.8502; CI, 0.7230-0.9998; p = 0.0496). Conclusions: This study conducted a two-sample MR analysis and discovered a positive causal relationship between schizophrenia and breast, ovarian, thyroid, lung, and colorectal cancers. On the other hand, an inverse causal relationship was found between schizophrenia and malignant neoplasm of the stomach. [ABSTRACT FROM AUTHOR]

Schizophrenia (SZ) is a complex disorder with a highly polygenic inheritance. It can be conceived as the extreme expression of a continuum of traits that are present in the general population often broadly referred to as schizotypy. However, it is still poorly understood how these traits overlap genetically with the disorder. We investigated whether polygenic risk for SZ is associated with these disorder-related phenotypes (schizotypy, psychotic-like experiences, and subclinical psychopathology) in a sample of 253 non-clinically identified participants. Polygenic risk scores (PRSs) were constructed based on the latest SZ genome-wide association study using the PRS-CS method. Their association with self-report and interview measures of SZ-related traits was tested. No association with either schizotypy or psychotic-like experiences was found. However, we identified a significant association with the Motor Change subscale of the Comprehensive Assessment of At-Risk Mental States (CAARMS) interview. Our results indicate that the genetic overlap of SZ with schizotypy and psychotic-like experiences is less robust than previously hypothesized. The relationship between high PRS for SZ and motor abnormalities could reflect neurodevelopmental processes associated with psychosis proneness and SZ. [ABSTRACT FROM AUTHOR]

Background: Early life stress (ELS) and parental psychopathology, such as schizophrenia (SZ), have been associated with altered neurobiological and behavioral outcomes later in life. Previous studies have investigated the effects of ELS and parental SZ on various aspects of behavior, however, we have studied the combined effects of these stressors and how they interact, as individuals in reallife situations may experience multiple stressors simultaneously. Objective: The aim of this study was to investigate the impact of ELS and schizophrenia on locomotor activity, anxiety-like behavior, exploratory tendencies, and spatial memory in Sprague Dawley (SD) rats. Methods: Male and female SD pups were randomly assigned to eight groups: control, ELS, schizophrenia, and ELS + schizophrenia. ELS was induced by prenatal stress (maternal stress) and maternal separation (MS) during the first 2 weeks of life, while SZ was induced by subcutaneous administration of ketamine. Behavioral tests included an open field test (OFT) for motor abilities and a Morris water maze (MWM) for cognitive abilities. ANOVA and post hoc Tukey tests were utilized to analyze the data. Results: Our results show that ELS and parental psychopathology had enduring effects on SZ symptoms, particularly psychomotor retardation (p < 0.05). The OFT revealed increased anxiety-like behavior in the ELS group (p = 0.023) and the parental psychopathology group (p = 0.017) compared to controls. The combined ELS and parental psychopathology group exhibited the highest anxiety-like behavior (p = 0.006). The MWM analysis indicated impaired spatial memory in the ELS group (p = 0.012) and the combined ELS and parental psychopathology group (p = 0.003) compared to controls. Significantly, the exposure to ELS resulted in a decrease in the population of glial fibrillary acidic protein-positive (GFAP+) astrocytes. However, this effect was reversed by positive parental mental health. Conclusion: Our findings highlight the interactive effects of ELS and parental psychopathology on anxiety-like behavior and spatial memory in rats. ELS was linked to increased anxiety-like behavior, while SZ was associated with anhedonialike behavior. Positive parenting augments neuroplasticity, synaptic function, and overall cognitive capacities. [ABSTRACT FROM AUTHOR]

This review surveys the causes and consequences of DNA damage in the male germ line from spermatogonial stem cells to fully differentiated spermatozoa. Within the stem cell population, DNA integrity is well maintained as a result of excellent DNA surveillance and repair; however, a progressive increase in background mutation rates does occur with paternal age possibly as a result of aberrant DNA repair as well as replication error. Once a germ cell has committed to spermatogenesis, it responds to genetic damage via a range of DNA repair pathways or, if this process fails, by the induction of apoptosis. When fully‐differentiated spermatozoa are stressed, they also activate a truncated intrinsic apoptotic pathway which results in the activation of nucleases in the mitochondria and cytoplasm; however, the physical architecture of these cells prevents these enzymes from translocating to the nucleus to induce DNA fragmentation. Conversely, hydrogen peroxide released from the sperm midpiece during apoptosis is able to penetrate the nucleus and induce DNA damage. The base excision repair pathway responds to such damage by cleaving oxidized bases from the DNA, leaving abasic sites that are alkali‐labile and readily detected with the comet assay. As levels of oxidative stress increase and these cells enter the perimortem, topoisomerase integrated into the sperm chromatin becomes activated by SUMOylation. Such activation may initially facilitate DNA repair by reannealing double strand breaks but ultimately prepares the DNA for destruction by nucleases released from the male reproductive tract. The abasic sites and oxidized base lesions found in live spermatozoa are mutagenic and may increase the mutational load carried by the offspring, particularly in the context of assisted conception. A variety of strategies are described for managing patients expressing high levels of DNA damage in their spermatozoa, to reduce the risks such lesions might pose to offspring health. [ABSTRACT FROM AUTHOR]

Intergenerational transmission is a crucial aspect of human development. Although prior studies have demonstrated the continuity of psychopathology and maladaptive upbringing environments between parents and offspring, the underlying neurobiological mechanisms remain unclear. We have begun a novel neuroimaging research project, the Transmit Radiant Individuality to Offspring (TRIO) study, which focuses on biological parent-offspring trios. The participants of the TRIO study were Japanese parent-offspring trios consisting of offspring aged 10-40 and their biological mother and father. Structural and functional brain images of all participants were acquired using magnetic resonance imaging (MRI). Saliva samples were collected for DNA analysis. We obtained psychosocial information, such as intelligence, mental health problems, personality traits, and experiences during the developmental period from each parent and offspring in the same manner as much as possible. By April 2023, we completed data acquisition from 174 trios consisting of fathers, mothers, and offspring. The target sample size was 310 trios. However, we plan to conduct genetic and epigenetic analyses, and the sample size is expected to be expanded further while developing this project into a multi-site collaborative study in the future. The TRIO study can challenge the elucidation of the mechanism of intergenerational transmission effects on human development by collecting diverse information from parents and offspring at the molecular, neural, and behavioral levels. Our study provides interdisciplinary insights into how individuals' lives are involved in the construction of the lives of their descendants in the subsequent generation. [ABSTRACT FROM AUTHOR]

Due to the increased incidence of obesity, it is of great importance to identify all the possible consequences in those who suffer from it and their descendants. This study aimed to investigate how paternal obesity, resulting from an 18-week high-fat diet (HFD), affects the metabolic and reproductive health of offspring. In the fathers (F0 generation), the HFD led to significant weight gain, primarily due to increased visceral fat. It also resulted in impaired glucose control and reduced insulin sensitivity. Furthermore, F0 males from the HFD group had reduced sperm concentration and lower sperm viability but were still able to sire litters. F1 offspring were monitored during 18 weeks; F1 offspring from obese fathers displayed increased body weight during the experimental window, especially in males, without significant metabolic disturbances. Additionally, F1 males showed reduced sperm viability, indicating potential reproductive implications. On the other hand, F1 females showed normal estrous cycle patterns but had a reduced number of primordial follicles, suggesting a decrease in their follicular reserve and reproductive potential. This study highlights that metabolic and reproductive issues may be passed down to future generations through the paternal line. [ABSTRACT FROM AUTHOR]

The etiology and pathogenesis of schizophrenia remain poorly understood, though it has been established that the contribution of heredity to the development of the disease is 80–85%. Over the past decade, significant progress has been made in the search for specific genetic variants associated with the development of schizophrenia. In this review, we discuss the results of recent large-scale studies seeking genetic associations with schizophrenia: genome-wide association studies (GWAS) and searches for rare variants (mutations or copy number variations, CNV), including studies using whole-exome sequencing. We synthesize data on currently known genes which are significantly associated with the development of schizophrenia and discuss their biological functions to identify the main molecular pathways involved in the pathophysiology of schizophrenia. [ABSTRACT FROM AUTHOR]

Advanced age has been reported to negatively affect sperm parameters and spermatozoa DNA integrity. A decline in sperm criteria was also associated with altered epigenetic marks such as DNA methylation with a potential downstream impact on in vitro fertilization success and clinical outcomes. The aim of the present retrospective study was to clarify the association between advanced paternal age (APA) and sperm parameters, DNA integrity and DNA methylation profile. A total of 671 patients consulting for infertility underwent sperm analysis, sperm DNA integrity assessment and methylation level measurement. The principal finding was that individuals over 40 years of age exhibit a significant increase in DNA fragmentation levels compared to the younger group (15% versus 9%, respectively, p = 0.04). However, there was no significant difference in DNA decondensation and sperm parameters in association with APA. In addition, a drop in the global methylation level was also found in men over 40 years (6% in the young group versus 2% in the old group, p = 0.03). As a conclusion, men over 40 years are at higher risk of elevated sperm DNA fragmentation and lower methylation level. Based on these observations, it is recommended that the assessment of sperm DNA fragmentation should be taken into consideration particularly after the age of 40. Our findings support the idea that paternal age is a crucial factor that should not be neglected during fertility evaluation and treatment since it is associated with epigenetics changes in sperm. Although the underlying mechanism remains to be clarified, we believe that environmental and professional exposure factors are likely involved in the process. [ABSTRACT FROM AUTHOR]

In brief: Whether sperm DNA fragmentation (SDF) affects embryo development and clinical outcomes is still controversial, which limits the utility of SDF testing in assisted reproductive technology management. This study demonstrates that high SDF is associated with the incidence of segmental chromosomal aneuploidy and increased paternal whole chromosomal aneuploidies. We aimed to investigate the correlation of sperm DNA fragmentation (SDF) with the incidence and paternal origin of whole and segmental chromosomal aneuploidies of embryos at the blastocyst stage. A retrospective cohort study was conducted with a total of 174 couples (women aged 35 years or younger) who underwent 238 cycles (including 748 blastocysts) of preimplantation genetic testing for monogenic diseases (PGT-M). All subjects were divided into two groups based on the sperm DNA fragmentation index (DFI) level: low DFI (<27%) and high DFI (=27%). The rates of euploidy, whole chromosomal aneuploidy, segmental chromosomal aneuploidy, mosaicism, parental origin of aneuploidy, fertilization, cleavage, and blastocyst formation were compared between low- and high-DFI groups. We found no significant differences in fertilization, cleavage, or blastocyst formation between the two groups. Compared to that in the low-DFI group, segmental chromosomal aneuploidy rate was significantly higher in the high-DFI group (11.57% vs 5.83%, P = 0.021; OR: 2.32, 95% CI: 1.10-4.89, P = 0.028). The whole chromosomal embryonic aneuploidy of paternal origin was significantly higher in cycles with high DFI than in cycles with low DFI (46.43% vs 23.33%, P = 0.018; OR: 4.32, 95% CI: 1.06-17.66, P = 0.041). However, the segmental chromosomal aneuploidy of paternal origin was not significantly different between the two groups (71.43% vs 78.05%, P = 0.615; OR: 1.01, 95% CI: 0.16-6.40, P = 0.995). In conclusion, our results suggested that high SDF was associated with the incidence of segmental chromosomal aneuploidy and increased paternal whole chromosomal aneuploidies in embryos. [ABSTRACT FROM AUTHOR]

Carbonyl stress is a condition featuring increased rich reactive carbonyl compounds, which facilitate the formation of advanced glycation end products including pentosidine. We previously reported the relationship between enhanced carbonyl stress and disrupted white matter integrity in schizophrenia, although which microstructural component is disrupted remained unclear. In this study, 32 patients with schizophrenia (SCZ) and 45 age- and gender-matched healthy volunteers (HC) were recruited. We obtained blood samples for carbonyl stress markers (plasma pentosidine and serum pyridoxal) and multi-modal magnetic resonance imaging measures of white matter microstructures including apparent axonal density (intra-cellular volume fraction (ICVF)) and orientation (orientation dispersion index (ODI)), and inflammation (free water (FW)). In SCZ, the plasma pentosidine level was significantly increased. Group comparison revealed that mean white matter values were decreased for ICVF, and increased for FW. We found a significant negative correlation between the plasma pentosidine level and mean ICVF values in SCZ, and a significant negative correlation between the serum pyridoxal level and mean ODI value in HC, regardless of age. Our results suggest an association between enhanced carbonyl stress and axonal abnormality in SCZ. [ABSTRACT FROM AUTHOR]

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STUDY QUESTION Is the presence of DNA in the blastocoel fluid (BF) of expanded blastocysts, assessed by whole genome amplification (WGA), associated with the clinical outcome at the first transfer? SUMMARY ANSWER At the first transfer, blastocysts with negative BF-WGA have more chance to implant and to develop to term than those with positive BF-WGA results, both in preimplantation genetic testing for aneuploidies (PGT-A) cycles (where only euploid blastocysts resulting from the chromosomal analysis of trophectoderm (TE) biopsies were transferred) and in IVF/ICSI conventional cycles. WHAT IS KNOWN ALREADY Retrospective studies conducted in patients undergoing PGT-A have shown that the incidence of negative BF-WGA was significantly higher in TE-euploid blastocysts than in TE-aneuploid blastocysts. In addition, after the transfer of TE-euploid blastocysts, the ongoing clinical pregnancy rate was significantly higher in the group with negative BF-WGA compared with those with positive BF-WGA. STUDY DESIGN, SIZE, DURATION A prospective cohort study including 102 consecutive PGT-A patients (Group 1) and 88 consecutive conventional IVF/ICSI patients (Group 2), was conducted between January 2019 and December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS In both groups, BFs were collected from expanded blastocysts of high grade and processed for WGA. DNA amplification was evaluated by agarose gel electrophoresis for the presence (positive BF-WGA) or absence (negative BF-WGA) of a band. Directly after the BF retrieval, blastocysts from Group 1 underwent TE biopsy and vitrification. In Group 2, blastocysts were vitrified immediately after BF collection. In Group 1, only euploid blastocysts were considered for transfer according to the results of TE biopsies. In both groups, the selection of the blastocyst to be transferred was based on BF-WGA results giving priority, if available, to those with negative amplification. The primary outcome investigated was the live birth rate (LBR) at the first transfer. The main variable under investigation was the negative BF-WGA and results were corrected for confounders (maternal and paternal age, number of retrieved oocytes, male factor) by multiple logistic regression analysis. MAIN RESULTS AND THE ROLE OF CHANCE In Group 1, 60 patients transferred negative BF-WGA blastocysts and 42 positive BF-WGA blastocysts, and the LBR at the first transfer was 53.3% and 26.2%, respectively (P  =   0.0081). After testing for selected confounders in a multiple logistic analysis, the transfer of blastocysts with negative BF-WGA resulted in an odds ratio of (OR) 3.52 (95% CI: 1.48–8.88, P  =   0.0057) compared to transfer of positive BF-WGA blastocysts. In Group 2, at the first transfer 30 deliveries resulted from blastocysts with negative BF-WGA (48.4%) and three from the transfer of positive BF-WGA blastocysts in 26 patients (11.5%; P  =   0.0014). Multiple logistic analysis indicated that the transfer of blastocysts with negative BF-WGA resulted in an OR 6.89 (95% CI: 1.98–32.95, P  =   0.0056) compared to transfer of positive BF-WGA blastocysts. The LBR per transfer and the cumulative LBR per patient showed the same trend. LIMITATIONS, REASONS FOR CAUTION The study was performed in a single center. WIDER IMPLICATIONS OF THE FINDINGS The data from this study highlight the heterogeneity of blastocysts of similar morphology, even in those classified as euploid by TE analysis. Failure to detect DNA in BFs after WGA is associated with a significantly higher LBR at the first embryo transfer as well as per transfer and per patient. The processing of the BF by WGA is an easy and cost-effective tool that could become a valuable option to offer patients the highest chances of term pregnancy in the shortest time possible. STUDY FUNDING/COMPETING INTEREST(S) The study received no funding from external sources. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Neonatal mice emit ultrasonic vocalizations (USVs) when separated from their mothers. Since the USVs attract their mothers' attention and trigger maternal retrieval, they are considered to serve as social signals for communication. We have modeled paternal aging effects on the vocal communication of offspring in mice. However, little is known about the neural basis underlying neonatal USV production. To identify responsible brain regions driving the vocal behavior, we comprehensively mapped the neuronal activity associated with USV production in the entire brain of mice at postnatal day 6 (P6). Using an expression of immediate‐early gene c‐Fos as a neuronal activity marker, correlations between the numbers of USVs and c‐Fos positive neurons were analyzed. We identified 23 candidate brain regions associated with USV production in the mice at P6. Our study would be a first step toward comprehensively understanding the neuronal mechanisms that regulate and develop vocal behaviors in neonatal mice. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is sperm telomere length (STL) associated with sperm nuclear DNA damage and mitochondrial DNA abnormalities? SUMMARY ANSWER Sperm telomere length is related to sperm nuclear DNA integrity and mitochondrial DNA abnormalities in healthy young college students. WHAT IS KNOWN ALREADY Many studies have revealed the correlations between sperm genetic alterations in both the nucleus and mitochondria and sperm functionality, however, the possible associations between the telomere, an important component of chromosome, and conventional indicators of mitochondrial DNA and nuclear DNA changes have not been investigated. STUDY DESIGN, SIZE, DURATION A prospective cohort study, Male Reproductive Health in Chongqing College Students (MARHCS), was conducted from June 2013 to June 2015. We pooled data collected from the follow-up study in 2014 and a total of 444 participants were included. PARTICIPANTS/MATERIALS, SETTING, METHODS STL was measured by quantitative (Q)-PCR. Sperm nuclear DNA integrity was determined using sperm chromatin structure assay (SCSA) and comet assay. Mitochondrial DNA damage was assessed by mitochondrial DNA copy number (mtDNAcn) evaluated with Q-PCR, and mtDNA integrity was determined with long PCR. MAIN RESULTS AND THE ROLE OF CHANCE The univariable-linear regression analysis revealed that STL was significantly positively correlated with markers of sperm nuclear DNA damage including the DNA fragmentation index (DFI) and comet parameters (the percentage of DNA in the tail, tail length, comet length, and tail moment). Additionally, STL was also significantly positively correlated with mtDNAcn and significantly negatively correlated with mtDNA integrity. After adjustment for potential confounders, these relationships remained appreciable. Moreover, we investigated potential effects of biometric factors, including age, parental age at conception, and BMI on STL and found that STL was increased with paternal age at conception. LIMITATIONS, REASONS FOR CAUTION A mechanistic explanation of the correlation between STL, sperm nuclear DNA integrity, and mtDNA abnormalities cannot be provided with a cross-sectional study design, so well-designed longitudinal studies are still necessary. In addition, a single semen samples were provided and were not all obtained at the same time point, which may increase the intraindividual bias in this study. WIDER IMPLICATIONS OF THE FINDINGS The findings extend the literature including assessment of mitochondrial dysfunction, sperm nuclear DNA damage, and telomere length and provide new insights into the relevance of STL in male reproduction. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Natural Science Foundation of China (No. 82073590), the National Natural Science Foundation of China (No. 81903363), the National Natural Science Foundation of China (No. 82130097), and the National Key R&D Program of China (2022YFC2702900). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

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Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of noncoding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date (SAMD12, STARD7, MARCHF6, YEATS2, TNRC6A, and RAPGEF2). FAME occurs worldwide; however, repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade‐off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors such as maternal or paternal inheritance, parental age, and repeat length alone have been suggested to influence repeat variation; however, further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress toward a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci, and development of cell and animal models. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is preimplantation genetic testing (PGT) associated with adverse perinatal outcome and early childhood health? SUMMARY ANSWER Children born after PGT had comparable perinatal outcomes to children born after IVF/ICSI and comparable findings regarding early childhood health. WHAT IS KNOWN ALREADY PGT is offered to couples affected by monogenic disorders (PGT-M) or inherited chromosomal aberrations (PGT-SR), limiting the risk of transferring the disorder to the offspring. PGT, an invasive technique, requires genetic analysis of one or up to ten cells from the embryo and is combined with IVF or ICSI. Several studies, most of them small, have shown comparable results after PGT and IVF/ICSI concerning perinatal outcome. Only a few studies with limited samples have been published on PGT and childhood health. STUDY DESIGN, SIZE, DURATION We performed a register-based study including all singletons born after PGT (n = 390) in Sweden during 1 January 1996–30 September 2019. Singletons born after PGT were compared with all singletons born after IVF/ICSI (n = 61 060) born during the same period of time and with a matched sample of singletons (n = 42 034) born after spontaneous conception selected from the Medical Birth Register. Perinatal outcomes, early childhood health, and maternal outcomes were compared between pregnancies after PGT and IVF/ICSI as well as between pregnancies after PGT and spontaneous conception. Primary outcomes were preterm birth (PTB) and low birthweight (LBW) whereas childhood morbidity was the secondary outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on women who went through PGT and gave birth were obtained from the local databases at the two PGT centres in Sweden, whereas data on IVF treatment for the IVF/ICSI group were obtained from the national IVF registers. These data were then cross-linked to national health registers; the Medical Birth Register, the Patient Register, and the Cause of Death Register. Logistic multivariable regression analysis and Cox proportional hazards models were performed with adjustment for relevant confounders. MAIN RESULTS AND THE ROLE OF CHANCE The mean follow-up time was 4.6 years for children born after PGT and 5.1 years for children born after spontaneous conception, whereas the mean follow-up time was 9.0 years for children born after IVF/ICSI. For perinatal outcomes, PTB occurred in 7.7% of children after PGT and in 7.3% of children after IVF/ICSI, whereas the rates were 4.9% and 5.2% for LBW (adjusted odds ratio (AOR) 1.22, 95% CI 0.82–1.81 and AOR 1.17, 95% CI 0.71–1.91, respectively). No differences were observed for birth defects. In comparison to spontaneous conception, children born after PGT had a higher risk for PTB (AOR 1.73, 95% CI 1.17–2.58). Regarding early childhood health, the absolute risk of asthma was 38/390 (9.7%) in children born after PGT and 6980/61 060 (11.4%) in children born after in IVF/ICSI, whereas the corresponding numbers were 34/390 (8.7%) and 7505/61 060 (12.3%) for allergic disorders. Following Cox proportional hazards models, no significant differences were found for these outcomes. Sepsis, hypothyroidism, attention deficit hyperactivity disorder, autism spectrum disorders, mental retardation, cerebral palsy, and epilepsy were diagnosed in a maximum of three PGT children. No PGT children died during the follow-up period. Regarding maternal outcomes, the rates of placenta praevia and caesarean delivery were significantly higher after PGT in comparison to spontaneous conception (AOR 6.46, 95% CI 3.38–12.37 and AOR 1.52, 95% CI 1.20–1.92, respectively), whereas no differences were seen comparing pregnancies after PGT and IVF/ICSI. LIMITATIONS, REASONS FOR CAUTION The rather small sample size of children born after PGT made it impossible to adjust for all relevant confounders including fertilization method and culture duration. Moreover, the follow-up time was short for most of the children especially in the PGT group, probably lowering the absolute number of diagnoses in early childhood. WIDER IMPLICATIONS OF THE FINDINGS The results are reassuring and indicate that the embryo biopsy itself has no adverse effect on the perinatal, early childhood, or maternal outcomes. Although the results are comparable to IVF/ICSI also regarding early childhood outcome, they should be taken with caution due to the low number of children with diagnoses and short follow-up time. Long-term follow-up studies on children born after PGT are scarce and should be conducted considering the invasiveness of the technique. STUDY FUNDING/COMPETING INTEREST(S) The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (LUA/ALF 70940), the Board of National Specialised Medical Care at Sahlgrenska University Hospital and Hjalmar Svensson Research Foundation. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Advanced paternal age has been repeatedly shown to modulate offspring quality via male‐ and/or female‐driven processes, and there are theoretical reasons to expect that some of these effects can be sex‐specific. For example, sex allocation theory predicts that, when mated with low‐condition males, mothers should invest more in their daughters compared to their sons. This is because male fitness is generally more condition‐dependent and more variable than female fitness, which makes it less risky to invest in female offspring. Here, we explore whether paternal age can affect the quality and quantity of offspring in a sex‐specific way using Drosophila melanogaster as a model organism. In order to understand the contribution of male‐driven processes on paternal age effects, we also measured the seminal vesicle size of young and older males and explored its relationship with reproductive success and offspring quality. Older males had lower competitive reproductive success, as expected, but there was no difference between the offspring sex ratio of young and older males. However, we found that paternal age caused an increase in offspring quality (i.e., offspring weight), and that this increase was more marked in daughters than sons. We discuss different male‐ and female‐driven processes that may explain such sex‐specific paternal age effects. [ABSTRACT FROM AUTHOR]

Objective: NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort. Methods: We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene‐based splicing assay, RT‐PCR analysis on the patients' RNA, and cell‐based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression. Results: Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3′ end of NIPA1 exon 3 near the exon–intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression. Interpretation: SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent‐onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Can long-read amplicon sequencing be beneficial for preclinical preimplantation genetic testing (PGT) workup in couples with a de novo pathogenic variant in one of the prospective parents? SUMMARY ANSWER Long-read amplicon sequencing represents a simple, rapid and cost-effective preclinical PGT workup strategy that provides couples with de novo pathogenic variants access to universal genome-wide haplotyping-based PGT programs. WHAT IS KNOWN ALREADY Universal PGT combines genome-wide haplotyping and copy number profiling to select embryos devoid of both familial pathogenic variants and aneuploidies. However, it cannot be directly applied in couples with a de novo pathogenic variant in one of the partners due to the absence of affected family members required for phasing the disease-associated haplotype. STUDY DESIGN, SIZE, DURATION This is a prospective study, which includes 32 families that were enrolled in the universal PGT program at the University Hospital of Leuven between 2018 and 2022. We implemented long-read amplicon sequencing during the preclinical PGT workup to deduce the parental origin of the disease-associated allele in the affected partner, which can then be traced in embryos during clinical universal PGT cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS To identify the parental origin of the disease-associated allele, genomic DNA from the carrier of the de novo pathogenic variant and his/her parent(s) was used for preclinical PGT workup. Primers flanking the de novo variant upstream and downstream were designed for each family. Following long-range PCR, amplicons that ranged 5–10 kb in size, were sequenced using Pacific Bioscience and/or Oxford Nanopore platforms. Next, targeted variant calling and haplotyping were performed to identify parental informative single-nucleotide variants (iSNVs) linked to the de novo mutation. Following the preclinical PGT workup, universal PGT via genome-wide haplotyping was performed for couples who proceeded with clinical PGT cycle. In parallel, 13 trophectoderm (TE) biopsies from three families that were analyzed by universal PGT, were also used for long-read amplicon sequencing to explore this approach for embryo direct mutation detection coupled with targeted long-read haplotyping. MAIN RESULTS AND THE ROLE OF CHANCE The parental origin of the mutant allele was identified in 24/32 affected individuals during the preclinical PGT workup stage, resulting in a 75% success rate. On average, 5.95 iSNVs (SD = 4.5) were detected per locus of interest, and the average distance of closest iSNV to the de novo variant was ∼1750 bp. In 75% of those cases (18/24), the de novo mutation occurred on the paternal allele. In the remaining eight families, the risk haplotype could not be established due to the absence of iSNVs linked to the mutation or inability to successfully target the region of interest. During the time of the study, 12/24 successfully analyzed couples entered the universal PGT program, and three disease-free children have been born. In parallel to universal PGT analysis, long-read amplicon sequencing of 13 TE biopsies was also performed, confirming the segregation of parental alleles in the embryo and the results of the universal PGT. LIMITATIONS, REASONS FOR CAUTION The main limitation of this approach is that it remains targeted with the need to design locus-specific primers. Because of the restricted size of target amplicons, the region of interest may also remain non-informative in the absence of iSNVs. WIDER IMPLICATIONS OF THE FINDINGS Targeted haplotyping via long-read amplicon sequencing, particularly using Oxford Nanopore Technologies, provides a valuable alternative for couples with de novo pathogenic variants that allows access to universal PGT. Moreover, the same approach can be used for direct mutation analysis in embryos, as a second line confirmation of the preclinical PGT result or as a potential alternative PGT procedure in couples, where additional family members are not available. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by KU Leuven funding (no. C1/018 to J.R.V.) and Fonds Wetenschappelijk Onderzoek (1241121N to O.T.). J.R.V. is co-inventor of a patent ZL910050-PCT/EP2011/060211-WO/2011/157846 'Methods for haplotyping single-cells' and ZL913096-PCT/EP2014/068315-WO/2015/028576 'Haplotyping and copy number typing using polymorphic variant allelic frequencies' licensed to Agilent Technologies. All other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Objective: This study was performed to (I) evaluate the potential effect of advanced paternal age on global DNA methylation in spermatozoa, and (II) to investigate the association between the outcome of intracytoplasmic sperm injection (ICSI), semen parameters, and advanced paternal age. Material and Methods: This study comprised 230 semen samples collected from males with a mean age of 38.2±8.5 years. Medical records were used to gather clinical information related to the female partner. The participants were divided into three groups depending on age: age <30 years; age 30-40 years; and age >40 years. The DNA was extracted from purified spermatozoa. Then the sperm global DNA methylation, sperm DNA fragmentation, and chromatin decondensation were evaluated by an ELISA, TUNEL, and Chromomycin A3 staining, respectively. Results: The sample counts were n=50 (21.8%), n=90 (39.1%) and n=90 (39.1%) for the <30, 30-40 and >40 year age-groups, respectively. A significant variation was found in the age of males included in this study (p<0.001). There was a significant reduction in sperm count, total motility, and non-progressive motility in the older group compared to the younger group (p<0.001). There was also a significant elevation in chromatin decondensation, DNA fragmentation, and global DNA methylation of spermatozoa in the older age group (p<0.001). Finally, there was a significant positive correlation between the percentage of non-motile sperm, sperm chromatin decondensation, DNA fragmentation, global DNA methylation status, and paternal age (p<0.001). Conclusion: These results suggest that advanced paternal age increased the DNA fragmentation, chromatin decondensation, and global DNA methylation level in human spermatozoa, which negatively affects the ICSI outcomes in couples undergoing ICSI cycles. [ABSTRACT FROM AUTHOR]