Are young men attempting to achieve paternity through intracytoplasmic sperm injection candidates for general health screenings?
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Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure
Androgen exposure (AE) poses a profound health threat to women, yet its transgenerational impacts on male descendants remain unclear. Here, employing a large-scale mother-child cohort, we show that maternal hyperandrogenism predisposes sons to β-cell dysfunction. Male offspring mice with prenatal AE exhibited hyperglycemia and glucose intolerance across three generations, which were further exacerbated by aging and a high-fat diet. Mechanistically, compromised insulin secretion underlies this transgenerational susceptibility to diabetes. Integrated analyses of methylome and transcriptome revealed differential DNA methylation of β-cell functional genes in AE-F1 sperm, which was transmitted to AE-F2 islets and further retained in AE-F2 sperm, leading to reduced expression of genes related to insulin secretion, including Pdx1, Irs1, Ptprn2, and Cacna1c. The methylation signatures in AE-F1 sperm were corroborated in diabetic humans and the blood of sons with maternal hyperandrogenism. Moreover, caloric restriction and metformin treatments normalized hyperglycemia in AE-F1 males and blocked their inheritance to offspring by restoring the aberrant sperm DNA methylations. Our findings highlight the transgenerational inheritance of impaired glucose homeostasis in male offspring from maternal AE via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations’ metabolic health.
Comparing vasectomy techniques, recovery and complications: tips and tricks
Vasectomies are safe and effective, achieving up to 99.7% in sterilization, with complication rates around 1–2%. As vasectomy uptake rises, physicians should stay informed about counseling, isolation and occlusion techniques, post-op recovery, and associated risks and complications. Historically, pre-vasectomy counseling has been performed in-person, but recent literature has shown that telehealth is a viable alternative, and a physical exam may not be necessitated. With regard to vas isolation and occlusion, current international guidelines support a minimally invasive approach such as no-scalpel vasectomy with mucosal cautery and fascial interposition, as they are the most effective in achieving vasectomy success and have the lowest complication rates. After a vasectomy, patients should undergo a post-vasectomy semen analysis 8–16 weeks after the procedure to ensure severe non-motile oligozoospermia (≤100,000 non-motile sperm/mL) or azoospermia. While risks and complications from vas isolation and occlusion are rare, patients should be informed about the potential for hematomas, infections, postoperative pain, and vas recanalization. In the U.S, vasectomies have increased in utilization from previous years, likely in the setting of increased access to telehealth and restricted female reproductive access. This trend raises questions about future fertility options such as vasectomy reversals and highlights the need for informed decision-making.
What makes a man unmanly? The global concept of ‘unmanliness’
This paper presents the findings of a multi-national study that led to the development of a new analytical framework in masculinity research—the Global Concept of ‘Unmanliness’ (GCU). Drawing on three key theories—hegemonic masculinity, precarious manhood and masculinity threat, and emasculation—we conducted an innovative study across 15 countries (selected from an initial pool of 62) to examine cultural perceptions of ‘unmanliness.’ Participants provided open-ended responses to identify traits and behaviors considered unmanly within their cultural contexts. By analyzing common themes expressed by young men, we propose the Global Concept of ‘Unmanliness’ as a framework for understanding how societies define and enforce masculinity norms. Furthermore, comparing these findings with the Global Gender Gap Index (GGGI) revealed a key distinction in how ‘unmanliness’ is characterized across different levels of gender emancipation. In countries with high GGGI rankings (e.g., Norway, Ireland, Germany), ‘unmanliness’ is more often associated with physical traits and behaviors linked to femininity (e.g., clothing, makeup). Conversely, in countries with low GGGI rankings (e.g., Pakistan, Morocco, Nigeria), it is more commonly defined by acts such as violence against women. Our study highlights how cultural and structural gender dynamics shape the boundaries of masculinity and offers a new lens for cross-cultural research on gender norms.
Single-cell transcriptomic atlas of the human testis across the reproductive lifespan
Testicular aging is associated with declining reproductive health, but the molecular mechanisms are unclear. Here we generate a dataset of 214,369 single-cell transcriptomes from testicular cells of 35 individuals aged 21–69, offering a resource for studying testicular aging and physiology. Machine learning analysis reveals a stronger aging response in somatic cells compared to germ cells. Two waves of aging-related changes are identified: the first in peritubular cells of donors in their 30s, marked by increased basement membrane thickness, indicating a priming state for aging. In their 50s, testicular cells exhibit functional changes, including altered steroid metabolism in Leydig cells and immune responses in macrophages. Further analyses reveal the impact of body mass index on spermatogenic capacity as age progresses, particularly after age 45. Altogether, our findings illuminate molecular alterations during testis aging and their relationship with body mass index, providing a foundation for future research and offering potential diagnostic markers and therapeutic targets.
SETD1B-mediated broad H3K4me3 controls proper temporal patterns of gene expression critical for spermatid development
Epigenetic programming governs cell fate determination during development through intricately controlling sequential gene activation and repression. Although H3K4me3 is widely recognized as a hallmark of gene activation, its role in modulating transcription output and timing within a continuously developing system remains poorly understood. In this study, we provide a detailed characterization of the epigenomic landscapes in developing male germ cells. We identified thousands of spermatid-specific broad H3K4me3 domains regulated by the SETD1B-RFX2 axis, representing a previously underappreciated form of H3K4me3. These domains, overlapping with H3K27ac-marked enhancers and promoters, play critical roles in orchestrating robust transcription and accurate temporal control of gene expression. Mechanistically, these broad H3K4me3 compete effectively with regular H3K4me3 for transcriptional machinery, thereby ensuring robust levels and precise timing of master gene expression in mouse spermiogenesis. Disruption of this mechanism compromises the accuracy of transcription dosage and timing, ultimately impairing spermiogenesis. Additionally, we unveil remarkable changes in the distribution of heterochromatin marks, including H3K27me3 and H3K9me2, during the mitosis-to-meiosis transition and completion of meiotic recombination, which closely correlates with gene silencing. This work underscores the highly orchestrated epigenetic regulation in spermatogenesis, highlighting the previously unrecognized role of Setd1b in the formation of broad H3K4me3 domains and transcriptional control, and provides an invaluable resource for future studies toward the elucidation of spermatogenesis.
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