Lower urinary tract dysfunction (LUTD) substantially affects quality of life and is increasingly associated with metabolic syndrome (MetS). An intricate relationship exists between MetS components, such as obesity, diabetes, dyslipidaemia and hypertension, and bladder dysfunction. Insights from preclinical models show that MetS-driven autonomic dysfunction, increased intra-abdominal pressure, chronic bladder ischaemia, low-grade inflammation, dysregulated nutrient-sensing pathways and an altered oestrogen-to-testosterone ratio contribute to lower urinary tract symptoms. Diabetic models, such as streptozotocin-induced rodents and polygenic TallyHo mice, show biphasic diabetic LUTD progression, from detrusor hyperactivity to underactivity, driven by hyperglycaemia and neural degeneration. Obesity models, such as leptin-deficient ob/ob mice, undergo prostate and urethral changes exacerbating lower urinary tract symptoms, whereas dyslipidaemia models, such as Apoe-/- mice, show ischaemia-induced bladder remodelling. Hypertension and early-life stress further worsen LUTD through angiotensin-mediated pathways and visceral adiposity, respectively. Preclinical models provide important insights in this context but face limitations, including non-physiological bladder filling rates and interspecies differences, necessitating advanced approaches such as multi-omics and patient-derived urinoids. These tools could facilitate personalized therapies by elucidating disease mechanisms and enabling longitudinal monitoring but ethical challenges associated with clinical translation persist.

Testosterone replacement therapy (TRT) is increasingly utilized and associated with erythrocytosis, leading some individuals to undergo therapeutic phlebotomy or present for blood donation. This emerging intersection between clinical management and blood donation raises important questions regarding donor eligibility, donor safety, recipient exposure, and regulatory oversight. This review examines evidence on testosterone-associated erythrocytosis in the context of blood donation. We review the pathophysiologic mechanisms underlying testosterone-induced erythrocytosis, summarize the current regulatory framework governing therapeutic phlebotomy and donor eligibility, and critically evaluate studies examining donor characteristics, testosterone in blood components, and potential mitigation strategies. The existing donor eligibility regulations do not contain TRT-specific provisions, but blood centers can manage these individuals by first assessing the intent to donate (altruistic or reduction of red cell mass) followed by applying standard donor eligibility criteria, therapeutic phlebotomy policies, and medical director review where appropriate. Available evidence suggests that individuals receiving TRT are increasingly encountered in blood centers and may participate in repeated donations. Laboratory studies demonstrate measurable testosterone concentrations in blood products collected from TRT donors, although the clinical significance of these findings for transfusion recipients remains uncertain. Recent studies also demonstrate that testosterone concentrations in plasma components may be substantially reduced using pathogen reduction technology. However, these observations remain limited to component-level analyses and have not been linked to recipient outcomes. Current evidence is largely descriptive and laboratory-based, highlighting substantial gaps in understanding rather than providing definitive guidance for practice. Additional research is needed to clarify donor risk profiles, determine clinical relevance of hormone exposure in transfusion recipients, and define evidence-based approaches to management of TRT-associated donors within the blood supply.

Anxiety disorder risk is influenced by both adverse environmental factors and genetic background. We previously described high-avoidance animal (HAA) and low-avoidance animal (LAA) strains of male Hatano rats that may provide robust models for assessing interactions between genetic background and environment driving anxiety disorder pathogenesis. We examined the potential of environmental enrichment (EE), a non-pharmacological approach, to suppress trait anxiety disorders by comparing anxiety-related behaviors and physiological metrics between HAA and LAA lines exposed to EE or standard housing. At 4 weeks of age, 10-12 male rats from each strain were assigned to EE or standard conditions. EE for 4-5 weeks significantly (p = 0.0002 by Tukey-Kramer's test) reduced anxiety-related behaviors in LAAs in the elevated plus maze test, but had no similar anxiolytic effect in HAAs. In contrast, EE for 11 weeks significantly (p = 0.0072 by Tukey-Kramer's test) reduced passive avoidance memory retention in HAAs, but not in LAAs. Real-time quantitative PCR revealed upregulated expression of Bdnf exons 1, 3, and 4 in the hippocampus of LAAs following EE, while the same treatment increased the expression of Bdnf exon 3 in the hippocampus of HAAs. Alternatively, EE did not alter mRNA expression levels of the BDNF receptor TrkB and the glucocorticoid receptor in hippocampus, or influence plasma corticosterone, prolactin, and testosterone concentrations. These findings have potential clinical implications for anxiety disorders, suggesting that effects of EE may vary depending on an individual's genetic background and underlying biological characteristics.

Sertoli cells play a pivotal role in spermatogenesis by providing structural support and delivering essential nutrients and signaling molecules to developing germ cells. A key function of these cells is the regulation of androgen-binding protein (ABP), which maintains the high intratesticular testosterone levels necessary for proper spermatogenic progression. Despite the critical nature of ABP, the mechanisms underlying its degradation within Sertoli cells remain poorly understood. This study investigates the role of the valosin-containing protein (p97/VCP) in the autophagic degradation of ABP, with a particular focus on molecular pathways that may contribute to male infertility and testicular dysfunction. Sertoli 15P-1 cells were treated with testosterone, chloroquine, and rapamycin, and subjected to single and double immunofluorescence staining, Western blotting, and siRNA-mediated knockdown experiments to explore the interaction between p97/VCP and ABP. Western blot analysis demonstrated that p62 expression was highest in the chloroquine + testosterone (CQ + T) group compared to control siRNA (Csi), although not statistically significant (p > 0.05). LC3 expression peaked in the chloroquine (CQ) group (p > 0.05). As expected, the lowest expression of p97/VCP was detected in the VCPsi group following siRNA transfection. Immunofluorescence analyses revealed significant differences in protein colocalization patterns across all treatment groups, except for p62 in rapamycin-treated samples. These findings provide the first evidence in the literature of a direct relationship between p97/VCP and ABP within Sertoli cells, underscoring the relevance of autophagic pathways in the regulation of male reproductive hormones. The data suggest a novel regulatory mechanism by which p97/VCP may influence spermatogenesis and male fertility through ABP degradation. Furthermore, this work lays a foundational framework for future investigations in other ABP-expressing tissues such as the brain, liver, and placenta, potentially linking p97/VCP expression to ABP-associated endocrine and pathophysiological disorders beyond the testis.

Chemical signalling and endocrine state are known to covary with social environment, but the speed of their response to social transitions under natural conditions remains unclear. We examined how major urinary proteins (MUPs) and faecal steroid hormone metabolites respond to shifts between solitary housing and a complex social setting in two house mouse subspecies, Mus musculus musculus and M. m. domesticus. Using repeated sampling in semi-natural enclosures, we measured MUP, testosterone, and corticosterone metabolite concentrations across three contexts: before social exposure, during the social phase, and after return to isolation. Reproductive output was quantified within a 44-day window around each sampling event. Entry into the enclosures triggered a strong, coordinated response: urinary MUP concentrations increased in both sexes and subspecies, paralleled by rises in testosterone and corticosterone metabolites during early social exposure. In males, this pattern reversed quite quickly after removal, with MUPs and both hormone metabolites declining within 24 h of renewed isolation. Under stable social conditions, urinary MUP concentrations increased with current reproductive output, whereas testosterone and corticosterone metabolites showed no such association. MUP concentrations were also unrelated to either hormone, suggesting that socially responsive MUP investment is not directly coupled to steroid levels. Despite baseline differences between subspecies and the expected male bias in MUP production, the main context-dependent patterns were consistent across taxa. Our results demonstrate pronounced social plasticity in chemical signalling and endocrine state, and indicate that MUP concentrations more closely reflect reproductive outcomes than steroid metabolite concentrations.

Psychological stress is a risk factor for male infertility, and adolescence is a critical period of vulnerability to stress. However, the effects of psychological stress on spermatogenesis in adolescent males remain unclear. To investigate this, we used a restraint stress model in adolescent Kunming mice, where animals were restrained for 2 and 4 h per day from postnatal day 28 to 56. Restraint stress resulted in a decreased sperm concentration and serum testosterone levels, together with increased sperm abnormalities, synaptonemal complex protein3 (SYCP3)-positive germ cells in the epididymis, and serum corticosterone levels in adult mice. Additionally, restraint stress altered seminiferous tubule histoarchitecture and the distribution of spermatogenic stages. Restraint-stressed mice exhibited increased proportions of zygotene- and pachytene-stage spermatocytes and a reduced proportion of diplotene-stage spermatocytes. Further analysis showed altered γH2AX and ataxia-telangiectasia and rad3-related (ATR) localization patterns together with increased frequencies of chromosomal synapsis abnormalities and abnormal chiasma formation, which were accompanied by increased spermatocyte apoptosis. The mRNA expression levels of key meiotic genes, including SPO11 initiator of meiotic double stranded breaks (SPO11), DNA meiotic recombinase 1 (DMC1), synaptonemal complex protein1 (SYCP1) and SYCP3, were reduced in stressed mice. In addition, restraint stress increased germ cell apoptosis and reduced litter size in adulthood. In conclusion, adolescent exposure to psychological stressors such as restraint stress is associated with impaired spermatogenesis and reduced reproductive capacity in adult male mice.

The COVID-19 pandemic has caused widespread morbidity and mortality worldwide, with emerging evidence documenting transient reproductive impairment in adult males following SARS-CoV-2 infection. However, prepubertal males appear especially vulnerable to infection-related testicular injury, yet the underlying mechanisms and long-term consequences remain poorly understood. We investigated the impact of systemic exposure to synthetic SARS-CoV-2 guanine-uracil (GU)-rich single-stranded RNA (ssRNA), a viral pathogen-associated molecular pattern (PAMP), on testicular integrity and reproductive outcomes in a juvenile mouse model. 4-week-old C57BL/6J males received systemic administration of GU-rich ssRNA, and we comprehensively assessed testicular architecture, molecular signatures, and offspring outcomes extending into adulthood. Exposure induced robust systemic and local inflammation that disrupted blood-testis barrier (BTB) integrity, disorganized seminiferous tubule architecture, and coordinately suppressed transcripts essential for spermatogonial maintenance (Kit, Csf1), germ cell survival (Bcl2, Bcl6), and meiotic progression (Spo11, Mlh1, Atm, Msh5). Paradoxically, despite significant upregulation of steroidogenic enzymes (Star, Hsd3b2, Cyp17a1, Hsd17b3), serum testosterone levels were markedly reduced, coinciding with profound downregulation of genes critical for ganglioside biosynthesis (B3galt4, St3gal5, St8sia1, B4galnt1), which are essential for maintaining lipid-raft-dependent junctional integrity and hormone transport. Paternal CoV2 GU-rich ssRNA exposure did not alter litter size or offspring sex distribution but was associated with reduced early postnatal offspring body weight, impaired glucose handling, and selective changes in metabolic tissue weights. Our findings reveal a critical developmental vulnerability window and provide mechanistic insights that support the need to monitor testicular function following systemic inflammation triggered by viral PAMPs in prepubertal males.