Obesity is a growing epidemic and a common problem among reproductive-age men that can both cause and exacerbate male-factor infertility by means of endocrine abnormalities, associated comorbidities, ...and direct effects on the fidelity and throughput of spermatogenesis. Robust epidemiologic, clinical, genetic, epigenetic, and nonhuman animal data support these findings. Recent works in the burgeoning field of epigenetics has demonstrated that paternal obesity can affect offspring metabolic and reproductive phenotypes by means of epigenetic reprogramming of spermatogonial stem cells. Understanding the impact of this reprogramming is critical to a comprehensive view of the impact of obesity on subsequent generations. Furthermore, and perhaps more importantly, conveying the impact of these lifestyle changes on future progeny can serve as a powerful tool for obese men to modify their behavior. Reproductive urologists and endocrinologists must learn to assimilate these new findings to better counsel men about the importance of paternal preconception health, a topic recently being championed by the Centers for Disease Control and Prevention.
Human testis development in prenatal life involves complex changes in germline and somatic cell identity. To better understand, we profiled and analyzed ∼32,500 single-cell transcriptomes of ...testicular cells from embryonic, fetal, and infant stages. Our data show that at 6–7 weeks postfertilization, as the testicular cords are established, the Sertoli and interstitial cells originate from a common heterogeneous progenitor pool, which then resolves into fetal Sertoli cells (expressing tube-forming genes) or interstitial cells (including Leydig-lineage cells expressing steroidogenesis genes). Almost 10 weeks later, beginning at 14–16 weeks postfertilization, the male primordial germ cells exit mitosis, downregulate pluripotent transcription factors, and transition into cells that strongly resemble the state 0 spermatogonia originally defined in the infant and adult testes. Therefore, we called these fetal spermatogonia “state f0.” Overall, we reveal multiple insights into the coordinated and temporal development of the embryonic, fetal, and postnatal male germline together with the somatic niche.
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•A transcriptional single-cell atlas of the fetal and postnatal human testes•Somatic niche cell types derive from a common progenitor ∼7 weeks after fertilization•PGCs transition directly into fetal state 0-like cells (state f0) starting at week 14•Fetal somatic niche cell specification precedes the PGC-to-state f0 transition
Guo et al. provide a transcriptional cell atlas of the fetal and postnatal human testes. Remarkably, starting from ∼14 weeks postfertilization, fetal primordial germ cells transition to a cell state highly similar to postnatal spermatogonial stem cells. Furthermore, somatic niche specification precedes this transition, which is consistent with guiding fetal germline development.
To describe detection of severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV-2) in seminal fluid of patients recovering from coronavirus disease 2019 (COVID-19) and to describe the expression ...profile of angiotensin-converting enzyme 2 (ACE2) and Transmembrane Serine Protease 2 (TMPRSS2) within the testicle.
Observational, cross-sectional study.
Tertiary referral center.
Thirty-four adult Chinese males diagnosed with COVID-19 through confirmatory quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) from pharyngeal swab samples.
None.
Identification of SARS-CoV-2 on qRT-PCR of single ejaculated semen samples. Semen quality was not assessed. Expression patterns of ACE2 and TMPRSS2 in the human testis are explored through previously published single-cell transcriptome datasets.
Six patients (19%) demonstrated scrotal discomfort suggestive of viral orchitis around the time of COVID-19 confirmation. Severe acute respiratory syndrome-CoV-2 was not detected in semen after a median of 31 days (interquartile range, 29-36 days) from COVID-19 diagnosis. Single-cell transcriptome analysis demonstrates sparse expression of ACE2 and TMPRSS2, with almost no overlapping gene expression.
Severe acute respiratory syndrome-CoV-2 was not detected in the semen of patients recovering from COVID-19 1 month after COVID-19 diagnosis. Angiotensin-converting enzyme 2-mediated viral entry of SARS-CoV-2 into target host cells is unlikely to occur within the human testicle based on ACE2 and TMPRSS2 expression. The long-term effects of SARS-CoV-2 on male reproductive function remain unknown.
The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To ...characterize this understudied process, we profiled and analyzed single-cell transcriptomes of ∼10,000 testicular cells from four boys spanning puberty and compared them to those of infants and adults. During puberty, undifferentiated spermatogonia sequentially expand and differentiate prior to the initiation of gametogenesis. Notably, we identify a common pre-pubertal progenitor for Leydig and myoid cells and delineate candidate factors controlling pubertal differentiation. Furthermore, pre-pubertal Sertoli cells exhibit two distinct transcriptional states differing in metabolic profiles before converging to an alternative single mature population during puberty. Roles for testosterone in Sertoli cell maturation, antimicrobial peptide secretion, and spermatogonial differentiation are further highlighted through single-cell analysis of testosterone-suppressed transfemale testes. Taken together, our transcriptional atlas of the developing human testis provides multiple insights into developmental changes and key factors accompanying male puberty.
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•A transcriptional single-cell atlas of the developing testes during human puberty•Distinctive phases of germ cell differentiation occur during puberty•Identification of a common progenitor for Leydig and myoid cells prior to puberty•Partial reversal of Sertoli and germ cell maturation upon testosterone suppression
Guo et al. provide a transcriptional cell atlas of the developing human testis during puberty, revealing dramatic developmental changes in both germ and somatic niche cell lineages. Furthermore, germ cells and Sertoli cells from testosterone-suppressed transfemale testes display partial developmental reversal, revealing critical roles for testosterone in maintaining testis maturation.
Associations between male infertility and cancer are gaining clinical attention. Relationships between infertility and cancer have traditionally been studied in women, but recent work has focused on ...the male component of reproduction. Infertile men are at an elevated risk to develop various malignancies later in life, primarily genitourinary malignancies such as testicular and prostate cancer. Rates of testicular and high-grade prostate cancer in infertile men appear to be at least double the risk in the general population. The link between infertility and malignancy highlights the importance of thorough evaluation and long-term follow up-beyond a simple semen analysis. A detailed urologic evaluation, possibly including scrotal ultrasound, may be beneficial to screen infertile men for testicular cancer. Publications have also demonstrated that male infertility can be a biomarker for cancer risk in first- and second-degree relatives. Testicular cancer risk in first-degree relatives of infertile men is 52% higher than the risk in relatives of fertile control men, and male infertility has been associated with a two- to threefold elevation in risk of childhood cancer in the siblings of infertile men. Links between infertility and malignancy are multifactorial, and exact mechanistic explanations are still not fully understood. Although more studies are needed to assess levels of risk and create screening recommendations in this population, understanding the relationship between male infertility and malignancy is crucial to provide comprehensive counseling for infertile men and their families.
Human adult spermatogonial stem cells (hSSCs) must balance self-renewal and differentiation. To understand how this is achieved, we profiled DNA methylation and open chromatin (ATAC-seq) in SSEA4+ ...hSSCs, analyzed bulk and single-cell RNA transcriptomes (RNA-seq) in SSEA4+ hSSCs and differentiating c-KIT+ spermatogonia, and performed validation studies via immunofluorescence. First, DNA hypomethylation at embryonic developmental genes supports their epigenetic “poising” in hSSCs for future/embryonic expression, while core pluripotency genes (OCT4 and NANOG) were transcriptionally and epigenetically repressed. Interestingly, open chromatin in hSSCs was strikingly enriched in binding sites for pioneer factors (NFYA/B, DMRT1, and hormone receptors). Remarkably, single-cell RNA-seq clustering analysis identified four cellular/developmental states during hSSC differentiation, involving major transitions in cell-cycle and transcriptional regulators, splicing and signaling factors, and glucose/mitochondria regulators. Overall, our results outline the dynamic chromatin/transcription landscape operating in hSSCs and identify crucial molecular pathways that accompany the transition from quiescence to proliferation and differentiation.
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•Open chromatin in hSSCs correlates with pioneer factors and hormone receptors•hSSC differentiation involves four sequential cellular/developmental states•Key transitions involve the cell cycle, transcription factors, signaling, and metabolism
Cairns and colleagues show that human spermatogonial stem cells (hSSCs) bear unique DNA methylation and open chromatin landscapes, which may enable proper development, niche responsiveness, and “poised” pluripotency. Interestingly, single-cell transcriptome and immunofluorescence analyses reveal four cellular states, spanning from quiescent hSSCs to proliferating, metabolically active, differentiating spermatogonia.
Human adult spermatogenesis balances spermatogonial stem cell (SSC) self-renewal and differentiation, alongside complex germ cell-niche interactions, to ensure long-term fertility and faithful genome ...propagation. Here, we performed single-cell RNA sequencing of ~6500 testicular cells from young adults. We found five niche/somatic cell types (Leydig, myoid, Sertoli, endothelial, macrophage), and observed germline-niche interactions and key human-mouse differences. Spermatogenesis, including meiosis, was reconstructed computationally, revealing sequential coding, non-coding, and repeat-element transcriptional signatures. Interestingly, we identified five discrete transcriptional/developmental spermatogonial states, including a novel early SSC state, termed State 0. Epigenetic features and nascent transcription analyses suggested developmental plasticity within spermatogonial States. To understand the origin of State 0, we profiled testicular cells from infants, and identified distinct similarities between adult State 0 and infant SSCs. Overall, our datasets describe key transcriptional and epigenetic signatures of the normal adult human testis, and provide new insights into germ cell developmental transitions and plasticity.
With cannabis consumption on the rise and use prominent among males of reproductive age it is essential to understand the potential impact of cannabis on male fertility. We reviewed the literature ...regarding the effects of cannabis on male fertility.
We performed a literature search using PubMed®/MEDLINE® to identify relevant studies of the effects of cannabis on male fertility. Relevant studies were identified and reviewed.
The strongest evidence of cannabis induced alterations in male fertility is in the category of semen parameters. Research supports a role for cannabis in reducing sperm count and concentration, inducing abnormalities in sperm morphology, reducing sperm motility and viability, and inhibiting capacitation and fertilizing capacity. Animal models demonstrate a role for cannabis in testicular atrophy, and reduced libido and sexual function but to our knowledge these results have not yet been replicated in human studies. Studies of hormonal changes suggest inconclusive effects on testosterone levels, lowered luteinizing hormone levels and unchanged follicle-stimulating hormone levels.
Current research suggests that cannabis may negatively impact male fertility. Further studies are needed to validate that robust findings in animal models will carry over into human experience. Clinicians should be aware of these potential effects when prescribing medical marijuana therapies to men of reproductive age, and they should consider the degree of cannabis use as a possible component of a complete male infertility workup.
Many couples initially deferred attempts at pregnancy or delayed fertility care due to concerns about coronavirus disease 2019 (COVID-19). One significant fear during the COVID-19 pandemic was the ...possibility of sexual transmission. Many couples have since resumed fertility care while accepting the various uncertainties associated with severe acute respiratory syndrome coronavirus 2, including the evolving knowledge related to male reproductive health. Significant research has been conducted exploring viral shedding, tropism, sexual transmission, the impact of male reproductive hormones, and possible implications to semen quality. However, to date, limited definitive evidence exists regarding many of these aspects, creating a challenging landscape for both patients and physicians to obtain and provide the best clinical care. This review provides a comprehensive assessment of the evolving literature concerning COVID-19 and male sexual and reproductive health, and guidance for patient counseling.
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