Background The current study aimed to determine the impact of SARS-CoV-2 infection on male fertility. Methods This is a single-center, hospital-based observational study that included autopsied testicular and epididymal specimens of deceased COVID-19 male patients ( n =6) and recruited recovering COVID-19 inpatients ( n =23) with an equal number of age-matched controls, respectively. We performed histopathological examinations on testicular and epididymal specimens, and also performed TUNEL assay and immunohistochemistry. Whereas, we investigated the semen specimen for sperm parameters and immune factors. Findings Autopsied testicular and epididymal specimens of COVID-19 showed the presence of interstitial edema, congestion, red blood cell exudation in testes, and epididymides. Thinning of seminiferous tubules was observed. The number of apoptotic cells within seminiferous tubules was significantly higher in COVID-19 compared to control cases. It also showed an increased concentration of CD3+ and CD68+ in the interstitial cells of testicular tissue and the presence of IgG within seminiferous tubules. Semen from COVID-19 inpatients showed that 39.1% ( n =9) of them have oligozoospermia, and 60.9% ( n =14) showed a significant increase in leucocytes in semen. Decreased sperm concentration, and increased seminal levels of IL-6, TNF-α, and MCP-1 compared to control males were observed. Interpretation Impairment of spermatogenesis was observed in COVID-19 patients, which could be partially explained as a result of an elevated immune response in testis. Additionally, autoimmune orchitis occurred in some COVID-19 patients. Further research on the reversibility of impairment and developing treatment are warranted. Funding This study was supported by Ministry of Science and Technology of China Plan, Hubei Science and Technology Plan, National Key Research and Development Program of China, HUST COVID-19 Rapid Response Call, China and National Natural Science Foundation of China; these funding bodies are public institutions, and they had no role in study conception, design, interpretation of results, and manuscript preparation.

Despite investigative interest, the artificial derivation of pluripotent stem cells remains inefficient and incomplete reprogramming hinders its potential as a reliable tool in regenerative medicine. By contrast, fusion of terminally differentiated gametes at fertilization activates efficient epigenetic reprogramming to ensure totipotency of early embryos. Understanding the epigenetic mechanisms required for the transition from the fertilized egg to the embryo can improve efforts to reprogram differentiated cells to pluripotent/totipotent cells for therapeutic use. We review recent discoveries that are providing insight into the molecular mechanisms required for epigenetic reprogramming to totipotency in vivo.

DNA methylation, repressive histone marks, and PIWI-interacting RNA (piRNA) are essential for the control of retrotransposon silencing in the mammalian germline. However, it remains unknown how these repressive epigenetic pathways crosstalk to ensure retrotransposon silencing in the male germline. Here, we show that UHRF1 is responsible for retrotransposon silencing and cooperates with repressive epigenetic pathways in male germ cells. Conditional loss of UHRF1 in postnatal germ cells causes DNA hypomethylation, upregulation of retrotransposons, the activation of a DNA damage response, and switches in the global chromatin status, leading to complete male sterility. Furthermore, we show that UHRF1 interacts with PRMT5, an arginine methyltransferase, to regulate the repressive histone arginine modifications (H4R3me2s and H3R2me2s), and cooperates with the PIWI pathway during spermatogenesis. Collectively, UHRF1 regulates retrotransposon silencing in male germ cells and provides a molecular link between DNA methylation, histone modification, and the PIWI pathway in the germline.

Available online xxx Keywords: Coronavirus SARS-CoV-2 ACE2 EZH2 H3.3 a b s t r a c tThe outbreak of corona virus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is spreading globally and quickly, leading to emerging health issues. SARS-CoV-2 enters into and infects host cells through its spike glycoprotein recognizing the cell receptor Angiotensin-converting enzyme II (ACE2).Here, we noticed that ACE2 was further enhanced by SARS-CoV-2 infection. Human germ cells and early embryos express high level of ACE2. Notably, RNA-seq result showed that reduction of H3K27me3, but not H3K4/9/36me3, led to upregulation of Ace2 expression in mouse germ cell line GC-2. In agreement with this result, we found in human embryonic stem cells that ACE2 expression was significantly increased in absence of EZH2, the major enzyme catalyzing H3K27me3. ChIP-seq analysis further confirmed decrease of H3K27me3 signal and increase of H3K27ac signal at ACE2 promoter upon EZH2 knockout. Therefore, we propose that EZH2-mediated H3K27me3 at ACE2 promoter region inhibits ACE2 expression in mammalian cells. This regulatory pattern may also exist in other human cells and tissues. Our discovery provides clues for pathogenesis and targeted drug therapy towards ACE2 expression for prevention and adjuvant therapy of COVID-19.