Bisphenol TMC (BPTMC), a novel bisphenol A substitute, is widely used as a plastic additive and frequently co-occurs with microplastics (MPs) in various environmental media. Their coexistence may alter biological effects, adding complexity to environmental risk assessment. This study investigated the reproductive and transgenerational toxicity of BPTMC and polylactic acid (PLA) MPs on zebrafish, both individually and in combination, focusing on sex-specific endocrine-disrupting mechanisms. Both BPTMC and PLA impaired gonadal function and germ cell development. BPTMC exhibited sex-specific endocrine disruption, significantly increasing 17β-estradiol in males while decreasing it in females, alongside a more pronounced reduction in testosterone in males. Parental exposure also induced transgenerational developmental toxicity in F1 offspring, including increased mortality and malformations, reduced heart rate, and decreased body length. These effects were linked to the dysregulation of key hypothalamic-pituitary-gonadal axis genes (gnrh3, fshβ, cyp19a1a, esr2a, esr2b). Molecular docking further confirmed that BPTMC activates Esr2a and Esr2b, contributing to reproductive dysfunction. Notably, co-exposure to PLA mitigated BPTMC toxicity, likely by adsorbing BPTMC, reducing its aqueous concentration by 35 % and lowering its bioavailability. This study offers new insights into the biological interactions between plastic additives and MPs, enhancing our understanding of the combined ecological risks posed by emerging contaminants.

Obesity and metabolic syndrome are major contributors to male infertility. These conditions disrupt the hypothalamic-pituitary-gonadal (HPG) axis and compromise testicular steroidogenesis and spermatogenesis through mechanisms that include altered aromatase activity, insulin resistance, chronic inflammation, and oxidative stress. Irisin, an exercise-induced myokine, has emerged as a metabolic signal with potential effects on male reproductive function. This review summarizes irisin biology, proposed mechanisms of action, and putative functions of irisin in male reproduction, with emphasis on obesity-associated fertility impairment. Studies in high-fat diet-induced obese rodent models indicate that exogenous irisin can improve metabolic homeostasis, restore testosterone production, increase expression of key steroidogenic enzymes, and mitigate obesity-associated reductions in spermatogenesis and sperm quality. These effects are commonly attributed to anti-inflammatory, antioxidant, and cytoprotective actions, as well as modulation of cellular energy metabolism through AMP-activated protein kinase and mitogen-activated protein kinase signalling. Irisin has also been reported to influence central neuroendocrine pathways involved in gonadotropin regulation and to improve sexual behaviour in rodent models of metabolic- and antidepressant-induced sexual dysfunction. However, the physiological relevance of irisin in men's reproductive physiology remains incompletely defined. Clinical evidence is largely associative, and data on irisin receptor expression and downstream signalling in the male reproductive tract are limited. Key gaps also include the regulation of irisin secretion and potential tissue-specific actions across stages of male reproductive development. Translational studies are needed to clarify irisin's actions within the HPG axis and gonads, and to evaluate its potential to mitigate obesity-related male reproductive dysfunction.

Sexual dysfunction (SD) is common in patients with obstructive sleep apnoea (OSA). Although continuous positive airway pressure (CPAP) therapy improves SD, it does not consistently modify testosterone or estradiol levels, suggesting involvement of other hormonal pathways. We analysed sex hormone levels in 70 patients with OSA before and after two weeks of CPAP withdrawal. No statistically significant treatment effects were observed for testosterone, androstenedione, gestagens, dehydroepiandrosterone sulfate, luteinizing hormone or follicle-stimulating hormone, whereas dehydroepiandrosterone (DHEA) increased after CPAP withdrawal. As DHEA secretion is adrenocorticotropic hormone-responsive, this increase may point to stress-related mechanisms, rather than direct sex steroid-mediated pathways, as potential contributors to OSA-related SD.

Abuse of Anabolic-Androgenic Steroids (AAS) by professional and recreational athletes for endurance performance and physique is increasing globally, consequently resulting in secondary pathophysiological effects. The present investigation aims to determine the effect of one of the AAS, stanozolol (ST), on uterine physiology and histology. A total of 15 female mice were assigned to three experimental groups (n = 5). ST was dosed subcutaneously (low-dose, 0.5 mg/kg bwt; high-dose, 5.0 mg/kg bwt or 1% alcohol-baseline control) for 30 days, and treatment was withdrawn on the 31st day. In this study, we evaluated histomorphometry of the uterus, immunoexpression of the estrogen receptor α (ERα), the androgen receptor (AR), and the prolactin receptor (PRLR), after ST treatment. In addition, we measured serum levels of testosterone (T), estradiol (E2), and prolactin (PRL). Morphometric evaluation of uterus demonstrated aberrant endometrial luminal epithelial proliferation, marked by irregular branching with papillary formations. Prolonged administration of ST resulted in disruption of uterine organization, reflecting its deleterious impact on uterine histoarchitecture. In the high-dose treated group, divergent ERα immunoexpression-characterized by endometrial downregulation and myometrial upregulation-correlated with increased myometrial thickness and subsequent hyperplasia. ST, being a derivative of Dihydrotestosterone (DHT), an anabolic steroid, may exert its androgenic-to-enhanced anabolic efficacy through non-genomic actions in the myometrium, while inducing distinct pathologic changes in the endometrium, suggesting a compartment-specific effect in the murine uterus. Prolonged treatment of ST augmented stromal immunoexpression of AR in the endometrium, suggesting AR-dependent mechanisms in this compartment. Substantial hyperexpression of prolactin receptor (PRLR) in both endometrium and myometrium suggests a potential stimulatory effect of ST on PRLR. High-dose ST administration significantly elevated circulating T and PRL levels while suppressing E2 concentrations, indicating interference with the hypothalamic-pituitary-gonadal (HPG) axis, reflecting an altered hormonal milieu. It is inferred that prolonged treatment of ST resulted in aberrant endometrial proliferation, histoarchitectural anomalies, compartment-specific differential immunoexpression of hormone receptors in the endometrium and myometrium, and altered serum hormonal milieu.

High-dose testosterone is an emerging treatment option for selected patients with castration-resistant prostate cancer (CRPC), but its efficacy is limited by frequent primary and acquired resistance. Preclinical studies suggest that high-dose testosterone induces tumor metabolic reprogramming that promotes resistance, however clinical validation is lacking. In the prospective ACROBAT trial, we performed longitudinal plasma metabolomic profiling and high-dimensional immune cell phenotyping of 10 patients with CRPC treated with high-dose oral testosterone undecanoate. Testosterone exposure increased circulating metabolites within the arginine-ornithine-polyamine axis, including guanidoacetic acid, creatine, homoarginine, and N1-acetylspermidine. Notably, non-responders exhibited elevated levels of circulating polyamines, including putrescine. Although we observed no significant changes in circulating immune cell subset frequencies, integrative analyses revealed positive associations between polyamine-related metabolites and immunosuppressive myeloid populations, including monocytic myeloid-derived suppressor cells. Collectively, these data provide clinical evidence that high-dose testosterone therapy increases polyamine synthesis from arginine, which is associated with therapy resistance and abundance of immunosuppressive myeloid cells. Implications: High-dose testosterone treatment of patients with castration-resistant prostate cancer enrolled on the ACROBAT trial increased circulating polyamines, which were associated with non-response to treatment and greater abundance of circulating immunosuppressive myeloid cells.

Torsion-induced ischemia causes lipid peroxidation in tissue, increases membrane permeability, and induces irreversible necroptosis in cells. The aim was to investigate the effects of thymoquinone (THQ) on receptor-interacting serine-threonine kinases (RIP1 and RIP3) after testicular torsion-induced ischemia/reperfusion (I/R). Control, ischemia/reperfusion (I/R), thymoquinone (THQ) 10 mg/kg and ischemia/reperfusion + thymoquinone (I/R+THQ). At the end of the experiment, spermiogram, histological and immunohistochemical, gene expression and biochemical analyses were performed on testicular tissue by collecting blood samples. Motility, testicular tissue seminiferous tubule epithelium thickness, tubule diameter and JTBS decreased in the I/R group compared to the Control and THQ groups.Both gene expression and immunoreactivity intensities of RIP1 and RIP3 increased in I/R. Furthermore, glial cell-derived neurotrophic factor (GDNF) and androgen-binding protein (ABP) decreased, steroidogenic acute regulatory protein (StAR), blood testosterone, and luteinizing hormone (LH) increased, and follicle-stimulating hormone (FSH) remained unchanged. THQ had a regulatory effect on all parameters. In addition to histopathological findings in testicular tissue, changes in RIP1, RIP3, GDNF, and StAR expression after I/R caused damage to both spermatogenic and non-spermatogenic tissue cell lines. Furthermore, changes in hormone levels indicate tissue dysfunction. The results reveal novel findings suggesting that THQ, applied after I/R, may be an effective compound for improving the structural and functional integrity of tissue; however, these findings need to be confirmed using various techniques with different application times and doses.

Polycystic ovary syndrome (PCOS) is a common and complex endocrine and metabolic disorder whose etiology has not yet been fully elucidated. Emerging research has revealed an association between PCOS pathogenesis and post-translational modifications of proteins. However, the effect of neddylation on PCOS pathogenesis has not been investigated. In this study, key proteins of the neddylation pathway (Nedd8, neddylation-activating enzyme (NAE), and Cullin-1/2/3) were significantly upregulated in the granulosa cells of patients with PCOS; this was accompanied by enhanced apoptosis (increased Bax and Caspase-3, decreased Bcl-2) and elevated expression of the androgen synthesis-related proteins, namely: androgen receptor (AR) and Cytochrome P450 Family 17 Subfamily A Member 1(CYP17A1). In the in vitro DHT-induced PCOS KGN cell model, key neddylation pathway proteins (Nedd8, NAE, and Cullin-1) were upregulated. Overexpression of Nedd8 and inhibition of neddylation by MLN4924 promoted apoptosis. However, inhibition of neddylation by MLN4924 reversed AR/CYP17A1 protein expression. In a rat model of PCOS, MLN4924 treatment significantly suppressed the expression of Nedd8, NAE, and Cullin-1/2/3 in the ovarian tissue, restored estrous cycles, alleviated ovarian morphological abnormalities (characterized by increased corpora lutea and reduced cystic follicles), and decreased serum testosterone and LH levels. MLN4924 significantly promoted ovarian granulosa cell apoptosis, but reduced the expression of androgen synthesis-related proteins. Together, these findings indicate the unrecognized role of neddylation in PCOS, while highlighting that MLN4924 represents a potential therapeutic approach for PCOS treatment.