Yong‐Gang Duan

Background: Chronic epididymo‐orchitis contributes significantly to male infertility through immune cell infiltration and pro‐inflammatory cytokine elevation. High glucose intake promotes Th17 differentiation and autoimmunity, but its effects on autoimmune testicular inflammation remain unclear. Objectives: To determine whether chronic high glucose supplementation exacerbates experimental autoimmune epididymo‐orchitis (EAEO), impairs spermatogenesis, and drives CD4 ⁺ T‐cell dysregulation, particularly Th17 polarization, in the reproductive tract. Materials and Methods: EAEO was induced in male C57BL/6 mice with or without chronic 10% glucose supplementation in drinking water. Sperm parameters, ROS levels, apoptosis, and histopathology were evaluated. CD4 ⁺ T‐cell subsets (Th1, Th17, Treg, TNF‐α ⁺ effector memory) were quantified by flow cytometry in testis, epididymis, spleen, and testicular inguinal lymph nodes (iLN) at days 30, 60, and 90 post‐immunizations. Results: High glucose intake accelerated EAEO progression, markedly worsening sperm concentration and motility, elevating sperm ROS, increasing germ cell apoptosis, and causing severe histopathological damage. In the reproductive tract, glucose induced an upward trend of CD4 ⁺ T cells and late‐phase selective Th17 skewing (days 60–90), with significant IL‐17A ⁺ CD4 ⁺ Teff increases and accompanying TNF‐α ⁺ CD4 ⁺ CD44 ⁺ Teff upregulation, while IFN‐γ ⁺ Th1 responses remained modest. These pro‐inflammatory changes were strictly localized, with no significant Th17, Th1, Treg, or TNF‐α alterations in spleen or iLN. Discussion and Conclusion: Chronic high glucose exacerbates EAEO by intensifying oxidative stress, apoptosis, and tissue injury while promoting a late‐phase, tissue‐restricted Th17‐biased CD4 ⁺ T‐cell response in the testis and epididymis. These findings reveal a metabolic‐immune axis that may accelerate immune‐mediated male subfertility via localized Th17 mechanisms.

Background: Infection and inflammation of the genital tract are major potentially treatable factors contributing to male infertility. The profile of small non‐coding RNA (sncRNAs) in spermatozoa can be altered by environmental exposures and inflammatory conditions.Objectives: Experimental autoimmune epididymo‐orchitis (EAEO) is a well‐established model of autoimmune‐induced chronic testicular and epididymal inflammation. This model investigates the effect of chronic inflammation on sperm sncRNA profiles and offspring phenotypes.Materials and methods: Regarding the EAEO model, mice were immunized with testis homogenates thrice. Subsequently, flow cytometry and histological analyses were conducted on EAEO mice. Next‐generation sequencing was used to profile small RNA of spermatozoa from the caput, corpus, and cauda epididymis. We performed a comprehensive integrative analysis of sperm sncRNAs and chronic epididymitis and identified their molecular signatures. The metabolic functions of the first‐generation (F1) offspring were evaluated using a glucose tolerance test (GTT).Results: Body weight and metabolic function were significantly altered in F1 offspring from EAEO sperm donors. The analysis of cauda sperm sncRNA profiles revealed that the proportions of miRNAs and tsRNAs increased and decreased, respectively, after autoimmunization. Three differentially expressed miRNAs and seven differentially expressed tsRNAs were significantly correlated with F1 metabolic dysfunction. The expression patterns of miRNAs and tsRNAs in mice partially overlapped with those observed in the spermatozoa from human patients with chronic epididymitis.Discussion and conclusions: We revealed that autoimmune epididymo‐orchitis alters sncRNA profiles in mouse spermatozoa. Offspring from mice with autoimmune orchitis develop metabolic disorders. A comprehensive analysis of human and mouse inflammation data revealed an association between alterations in the miRNA and tsRNA profiles of epididymal spermatozoa and offspring phenotypes.

Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.

Background: General obesity classified by body mass index has been linked to a reduction in semen quality; however, evidence on the adverse effect of central obesity on semen quality remains limited.Objectives: To investigate the association between central obesity and semen quality.Materials and methods: We conducted a cross‐sectional study of 4513 sperm donation volunteers in Guangdong Provincial Human Sperm Bank during 2018–2021. Three central obesity indicators, including waist circumference, waist‐to‐hip ratio, and waist‐to‐height ratio, were measured using a multi‐frequency bioelectrical impedance analysis for each subject. Semen analysis was conducted according to the World Health Organization laboratory manual for the examination and processing of human semen 5th edition. Linear regression models and unconditional logistic regression models were used to quantify the association between central obesity and semen parameters.Results: With adjustment for age, race, education level, marital status, fertility status, occupation, year of semen collection, abstinence period, ambient temperature, and relative humidity, central obesity defined as waist circumference ≥90 cm, waist‐to‐hip ratio ≥0.9, or waist‐to‐height ratio ≥0.5 was significantly associated with a 0.27 (95% confidence interval: 0.15, 0.38) mL, 14.47 (3.60, 25.34) × 10⁶, 7.06 (0.46, 13.76) × 10⁶, and 6.80 (0.42, 13.18) × 10⁶ reduction in semen volume, total sperm number, total motile sperm number, and total progressive motile sperm number, respectively, and a 53% (10%, 112%) increase in odds of below the World Health Organization 2010 reference value for semen volume. These associations did not significantly vary across age. Similar results were observed for central obesity defined using each of the three indicators, except that subjects with a waist circumference ≥90 cm had a slightly higher total motility (estimated change: 1.30%; 95% confidence interval: 0.27%, 2.34%) and progressive motility (estimated change: 1.27%; 95% confidence interval: 0.23%, 2.31%).Discussion and conclusion: We found that central obesity was significantly associated with a reduction in semen volume, total sperm number, total motile sperm number, and total progressive motile sperm number. Future studies are warranted to confirm our results in other regions and populations.

Epididymitis is an epididymal inflammation that may lead to male infertility. Dendritic cells (DCs) and myeloid differentiation primary response gene 88 (Myd88) were associated with epididymitis in rodents. However, the functions of Myd88 on epididymal DCs remain unclear. This study investigated the role of Myd88 in DCs for epididymitis. The Myd88 signaling pathway, phenotypes of DC subsets, and cytokines were investigated in lipopolysaccharide (LPS)-induced epididymitis in mice. CRISPR-Cas9 was used to knockout Myd88 in bone-marrow-derived dendritic cells (BMDCs) and immortalized mouse epididymal (DC2) cell line. In the vivo experiments, levels of the proinflammatory cytokines IL-1α, IL-6, IL-17A, TNF-α, IL-1β, MCP-1, and GM-CSF, mRNA for MyD88 related genes, and the percentages of monocyte-derived DCs (Mo-DCs) were significantly elevated in mice with epididymitis. In the vitro experiments, LPS significantly promoted the apoptosis of BMDCs. In addition, the concentration of inflammatory cytokines in BMDCs and DC2s were increased in the LPS group, while decreasing after the knockout of Myd88. These findings indicate that Myd88 on DCs is involved in the inflammation of epididymitis in mice, which may be a potential target for better strategies regarding the treatment of immunological male infertility.