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The ubiquitin proteasome system regulates meiotic recombination in yeast through its association with the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I. In mammals, the proteasome activator subunit PA200 targets acetylated histones for degradation during somatic DNA double strand break repair and during histone replacement during spermiogenesis. We investigated the role of the testis-specific proteasomal subunit α4s (PSMA8) during spermatogenesis, and found that PSMA8 was localized to and dependent on the central region of the synaptonemal complex. Accordingly, synapsis-deficient mice show delocalization of PSMA8. Moreover, though Psma8-deficient mice are proficient in meiotic homologous recombination, there are alterations in the proteostasis of several key meiotic players that, in addition to the known substrate acetylated histones, have been shown by a proteomic approach to interact with PSMA8, such as SYCP3, SYCP1, CDK1 and TRIP13. These alterations lead to an accumulation of spermatocytes in metaphase I and II which either enter massively into apoptosis or give rise to a low number of aberrant round spermatids that apoptose before histone replacement takes place.

It is estimated that infertility affects 8–12% of couples globally, with a male factor being a primary or contributing cause in approximately 50% of couples. Causes of male subfertility vary highly, but can be related to congenital, acquired, or idiopathic factors that impair spermatogenesis. Many health conditions can affect male fertility, which underscores the need for a thorough evaluation of patients to identify treatable or reversible lifestyle factors or medical conditions. Although semen analysis remains the cornerstone for evaluating male infertility, advanced diagnostic tests to investigate sperm quality and function have been developed to improve diagnosis and management. The use of assisted reproductive techniques has also substantially improved the ability of couples with infertility to have biological children. This Seminar aims to provide a comprehensive overview of the assessment and management of men with infertility, along with current controversies and future endeavours.

Extracellular vesicles (EVs) are a unique mode of intercellular communication capable of incredible specificity in transmitting signals involved in cellular function, including germ cell maturation. Spermatogenesis occurs in the testes, behind a protective barrier to ensure safeguarding of germline DNA from environmental insults. Following DNA compaction, further sperm maturation occurs in the epididymis. Here, we report reproductive tract EVs transmit information regarding stress in the paternal environment to sperm, potentially altering fetal development. Using intracytoplasmic sperm injection, we found that sperm incubated with EVs collected from stress-treated epididymal epithelial cells produced offspring with altered neurodevelopment and adult stress reactivity. Proteomic and transcriptomic assessment of these EVs showed dramatic changes in protein and miRNA content long after stress treatment had ended, supporting a lasting programmatic change in response to chronic stress. Thus, EVs as a normal process in sperm maturation, can also perform roles in intergenerational transmission of paternal environmental experience. Evidence for sperm small noncoding RNA-mediated intergenerational transmission implies communication from responsive somatic cells to sperm. Here, authors show that epididymal cells alter extracellular vesicle cargo after stress exposure, to impact offspring neurodevelopment and stress reactivity.

Male infertility affects half of infertile couples and, currently, a relevant percentage of cases of male infertility is considered as idiopathic. Although the male contribution to human fertilization has traditionally been restricted to sperm DNA, current evidence suggest that a relevant number of sperm transcripts and proteins are involved in acrosome reactions, sperm‒oocyte fusion and, once released into the oocyte, embryo growth and development. The aim of this review is to provide updated and comprehensive insight into the molecular biology of spermatogenesis, including evidence on spermatogenetic failure and underlining the role of the sperm-carried molecular factors involved in oocyte fertilization and embryo growth. This represents the first step in the identification of new possible diagnostic and, possibly, therapeutic markers in the field of apparently idiopathic male infertility.

Transposable elements (TEs) contribute to the large amount of repetitive sequences in mammalian genomes and have been linked to species-specific genome innovations by rewiring regulatory circuitries. However, organisms need to restrict TE activity to ensure genome integrity, especially in germline cells to protect the transmission of genetic information to the next generation. This review features our current understandings of mammalian PIWI-interacting RNAs (piRNAs) and their role in TE regulation in spermatogenesis. Here we discuss functional implication and explore additional molecular mechanisms that inhibit transposon activity and altogether illustrate the paradoxical arms race between genome evolution and stability. Transposable elements can be activated during germ cell maturation, potentially leading to genome instability and rewiring of the genetic circuitry. In this review, the authors discuss how the piRNA machinery suppresses these elements to ensure accurate spermatogenesis.

Spermatogenesis is a complex process that can be disrupted by genetic and epigenetic changes, potentially leading to male infertility. Recent research has rapidly increased the number of coding mutations causally linked to impaired spermatogenesis in humans and mice. However, the role of noncoding mutations remains largely unexplored. To evaluate the effects of noncoding mutations on spermatogenesis, we first identified an evolutionarily conserved topologically associated domain boundary near two genes with important roles in mammalian testis function: Dmrtb1 and Lrp8. We then used CRISPR-Cas9 to generate a mouse line where 26 kb of the boundary was removed including a strong and evolutionarily conserved CTCF binding site. ChIP-seq and Hi-C experiments confirmed the removal of the CTCF site and a resulting mild increase in the DNA–DNA interactions across the domain boundary. Mutant mice displayed significant changes in testis gene expression, a higher frequency of histological abnormalities, a drop of 47–52% in efficiency of meiosis, a 15–18% reduction in efficiency of spermatogenesis, and, consistently, a 12–28% decrease in daily sperm production compared to littermate controls. Despite these quantitative changes in testis function, mutant mice show no significant changes in fertility. This suggests that noncoding deletions affecting testis gene regulation may have smaller effects on fertility compared to coding mutations of the same genes. Our results demonstrate that disruption of a topologically associated domain boundary can have a negative impact on sperm production and highlight the importance of considering noncoding mutations in the analysis of patients with male infertility.

ObjectiveEffects of the diet-induced gut microbiota dysbiosis reach far beyond the gut. We aim to uncover the direct evidence involving the gut–testis axis in the aetiology of impaired spermatogenesis.DesignAn excessive-energy diet-induced metabolic syndrome (MetS) sheep model was established. The testicular samples, host metabolomes and gut microbiome were analysed. Faecal microbiota transplantation (FMT) confirmed the linkage between gut microbiota and spermatogenesis.ResultsWe demonstrated that the number of arrested spermatogonia was markedly elevated by using 10× single-cell RNA-seq in the MetS model. Furthermore, through using metabolomics profiling and 16S rDNA-seq, we discovered that the absorption of vitamin A in the gut was abolished due to a notable reduction of bile acid levels, which was significantly associated with reduced abundance of Ruminococcaceae_NK4A214_group. Notably, the abnormal metabolic effects of vitamin A were transferable to the testicular cells through the circulating blood, which contributed to abnormal spermatogenesis, as confirmed by FMT.ConclusionThese findings define a starting point for linking the testicular function and regulation of gut microbiota via host metabolomes and will be of potential value for the treatment of male infertility in MetS.

METTL3 catalyzes the formation of N -methyl-adenosine (m A) which has important roles in regulating various biological processes. However, the in vivo function of Mettl3 remains largely unknown in mammals. Here we generated germ cell-specific Mettl3 knockout mice and demonstrated that Mettl3 was essential for male fertility and spermatogenesis. The ablation of Mettl3 in germ cells severely inhibited spermatogonial differentiation and blocked the initiation of meiosis. Transcriptome and m A profiling analysis revealed that genes functioning in spermatogenesis had altered profiles of expression and alternative splicing. Our findings provide novel insights into the function and regulatory mechanisms of Mettl3-mediated m A modification in spermatogenesis and reproduction in mammals.

ObjectiveHigh-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally influence spermatogenesis and sperm motility.DesignFaecal microbes derived from the HFD-fed or normal diet (ND)-fed male mice were transplanted to the mice maintained on ND. The gut microbes, sperm count and motility were analysed. Human faecal/semen/blood samples were collected to assess microbiota, sperm quality and endotoxin.ResultsTransplantation of the HFD gut microbes into the ND-maintained (HFD-FMT) mice resulted in a significant decrease in spermatogenesis and sperm motility, whereas similar transplantation with the microbes from the ND-fed mice failed to do so. Analysis of the microbiota showed a profound increase in genus Bacteroides and Prevotella, both of which likely contributed to the metabolic endotoxaemia in the HFD-FMT mice. Interestingly, the gut microbes from clinical subjects revealed a strong negative correlation between the abundance of Bacteroides-Prevotella and sperm motility, and a positive correlation between blood endotoxin and Bacteroides abundance. Transplantation with HFD microbes also led to intestinal infiltration of T cells and macrophages as well as a significant increase of pro-inflammatory cytokines in the epididymis, suggesting that epididymal inflammation have likely contributed to the impairment of sperm motility. RNA-sequencing revealed significant reduction in the expression of those genes involved in gamete meiosis and testicular mitochondrial functions in the HFD-FMT mice.ConclusionWe revealed an intimate linkage between HFD-induced microbiota dysbiosis and defect in spermatogenesis with elevated endotoxin, dysregulation of testicular gene expression and localised epididymal inflammation as the potential causes.Trial registration number NCT03634644.

Traditionally, testosterone and estrogen have been considered to be male and female sex hormones, respectively. However, estradiol, the predominant form of estrogen, also plays a critical role in male sexual function. Estradiol in men is essential for modulating libido, erectile function, and spermatogenesis. Estrogen receptors, as well as aromatase, the enzyme that converts testosterone to estrogen, are abundant in brain, penis, and testis, organs important for sexual function. In the brain, estradiol synthesis is increased in areas related to sexual arousal. In addition, in the penis, estrogen receptors are found throughout the corpus cavernosum with high concentration around neurovascular bundles. Low testosterone and elevated estrogen increase the incidence of erectile dysfunction independently of one another. In the testes, spermatogenesis is modulated at every level by estrogen, starting with the hypothalamus-pituitary-gonadal axis, followed by the Leydig, Sertoli, and germ cells, and finishing with the ductal epithelium, epididymis, and mature sperm. Regulation of testicular cells by estradiol shows both an inhibitory and a stimulatory influence, indicating an intricate symphony of dose-dependent and temporally sensitive modulation. Our goal in this review is to elucidate the overall contribution of estradiol to male sexual function by looking at the hormone＇s effects on erectile function, spermatogenesis, and libido.