Search Results (430)

Triple-negative breast cancer (TNBC) is an aggressive malignancy that disproportionately affects young women. The integration of immune checkpoint inhibitors (ICIs) has significantly improved outcomes in both early-stage and metastatic TNBC, shifting attention toward long-term survivorship issues, particularly endocrine function and fertility. However, the reproductive safety profile of ICIs remains insufficiently characterized. This narrative review synthesizes current preclinical and clinical evidence on ICI-associated reproductive toxicity, focusing on both direct immune-mediated gonadal injury and indirect disruption of the hypothalamic–pituitary–gonadal axis. Experimental models consistently demonstrate immune cell infiltration of ovarian and testicular tissue, cytokine-driven inflammatory cascades, follicular atresia, impaired spermatogenesis, and altered steroidogenesis following PD-1/PD-L1 and CTLA-4 blockade. Emerging clinical data report cases of immune-related orchitis, azoospermia, testosterone deficiency, diminished ovarian reserve, and premature ovarian insufficiency. Secondary hypogonadism due to immune-mediated hypophysitis represents an additional and frequently underdiagnosed mechanism. We further discuss the oncofertility challenges faced by young patients with TNBC treated with chemoimmunotherapy, emphasizing the uncertainty of fertility risk stratification and the importance of early fertility counseling and individualized fertility preservation strategies. To illustrate the potential clinical impact, we present the case of a 34-year-old nulliparous woman who developed premature ovarian insufficiency two years after neoadjuvant chemoimmunotherapy including atezolizumab, despite ovarian suppression. In conclusion, while ICIs have transformed the therapeutic landscape of TNBC, their potential long-term impact on reproductive and endocrine health represents a clinically significant concern. A precautionary, multidisciplinary oncofertility approach and prospective clinical registries are essential to define the true incidence and mechanisms of ICI-associated reproductive toxicity. Full article

Background/Objectives: Hodgkin lymphoma (HL) primarily affects individuals of reproductive age, making gonadal dysfunction after chemotherapy a critical survivorship concern. While fertility preservation options including gamete and gonadal tissue cryopreservation are available before treatment, evidence-based counseling requires regimen-specific risk estimates accounting for patient age and sex. Therefore, a meta-analysis was performed to assess presumed infertility in HL patients, stratified by chemotherapy regimen, age, and sex. Methods: This systematic review and meta-analysis, conducted within the FertiTOX project, included studies published between 2000 and February 2024. Eligible studies reported gonadal function outcomes ≥ 1 year after chemotherapy, excluding patients who received pelvic radiotherapy or stem cell transplantation, or had recurrent disease. Presumed infertility was defined by surrogate markers, including amenorrhea, premature ovarian failure, or abnormal hormonal levels in women, and azoospermia, oligozoospermia, or abnormal hormonal levels in men. Results: Of 2376 screened studies, 50 were included (meta-analysis: 43 studies; 5564 female and 1631 male patients). Overall presumed infertility prevalence was 21% in women (95% CI: 0.14–0.29) and 45% in men (95% CI: 0.29–0.62). The highest prevalence occurred after BEACOPP (women 38%; men 81%), while ABVD was associated with the lowest (6% each in women and men). Childhood/adolescent HL treatment resulted in lower prevalence in women (8%) but remained high in men (67%). Conclusions: Fertility risk depends on regimen, age, and sex, requiring tailored counseling. For female children/adolescents and all patients receiving ABVD, post-treatment fertility evaluation and treatment may suffice. However, pre-treatment fertility preservation is strongly recommended for male adolescents and patients receiving other regimens. Full article

The wnt gene family encodes a group of highly conserved secreted glycoproteins that play essential roles in vertebrate development, including tissue patterning, cell differentiation, and gonadal regulation. However, the genomic organization, evolutionary dynamics, and functional roles of Wnt signaling components in flatfish remain poorly understood. In this study, we performed a comprehensive genome-wide identification, evolutionary characterization, expression profiling, and functional analysis of wnt genes in Cynoglossus semilaevis, a flatfish species exhibiting ZW/ZZ sex determination and temperature-induced sex reversal. A total of 20 wnt genes were identified and classified into 13 subfamilies, displaying conserved structural organization and phylogenetic relationships consistent with other teleosts. Chromosomal mapping revealed lineage-specific WNT clusters, including a unique wnt3–wnt7b–wnt5b–wnt16 block, as well as syntenic associations with reproduction-related genes (e.g., adipor2, sema3a, nape-pld, erc2, lamb2), suggesting coordinated genomic regulation. Tissue transcriptome analysis demonstrated strong sex- and tissue-biased expression patterns, with wnt5a predominantly expressed in ovaries and wnt5b specifically upregulated in pseudo-male testes. Functional assays revealed that knockdown of wnt5a or wnt5b induced testis-specific genes (sox9b, tesk1) and suppressed ovarian markers (foxl2, cyp19a1a), indicating antagonistic regulatory roles in gonadal fate determination. Promoter analysis identified yy1a as a selective repressor of wnt5b, but not wnt5a, providing a mechanistic basis for paralog divergence. Furthermore, pull-down combined with LC–MS/MS analysis showed that WNT5b interacts with proteins enriched in ribosome biogenesis and ubiquitin-mediated proteolysis, suggesting a role in translational regulation and protein turnover during spermatogenesis. Together, these findings establish WNT5 signaling—particularly wnt5b—as a key driver of testicular development in C. semilaevis and provide new insights into the molecular mechanisms underlying sex differentiation and sex reversal in flatfish. Full article

The accumulation of heavy metals in fish tissues is widely recognized as an indicator of aquatic environmental pollution, and the analysis of their content provides a basis for assessing ecological risk and the safety of aquatic food. The European eel (Anguilla anguilla) is a species frequently used as a bioindicator in environmental studies due to its wide geographic distribution, long life cycle, and high capacity for bioaccumulation of heavy metals in various tissues. The aim of this study was to assess the variation in the accumulation of heavy metals, i.e., mercury (Hg), lead (Pb), arsenic (As), and cadmium (Cd), in the tissues (muscle, liver, gonads, and gills) of European eels caught in two locations in Polish inland waters. The obtained results showed significant differences both in the concentration levels of individual elements and in their co-occurrence in the examined tissues. The statistical methods used, including correlation analysis, heat maps, and principal component analysis (PCA), allowed for a comprehensive assessment of the relationships between metals and the identification of factors differentiating the studied populations. The obtained results clearly indicate that fish residing in similar environments for long periods exhibit significant differences in heavy metal content in various fish tissues. Fish obtained from environments with potentially higher levels of heavy metal inputs, such as the Oder River EMU compared with the Vistula River EMU, showed higher levels of heavy metal accumulation in tissues. This study also found that the concentration of heavy metals tested did not exceed the safe standards for human fish consumption. Full article

Obesity treatments increasingly target multiple pathways beyond appetite suppression. We evaluated KBN2202, a salicylate-derived small molecule, in a high-fat diet (60% kcal from fat) mouse model using female and male C57BL/6J mice treated for 8 weeks with oral KBN2202 (20 mg/kg/day) or a matched-volume vehicle (1% DMSO/PBS). Body weight was recorded weekly, and food intake was measured daily; serum hormones and cytokines, adipose tissue histology, and open-field behavior were assessed at the end of the study. Under our experimental conditions, HFD increased body weight and gonadal white adipose tissue (gWAT)/brown adipose tissue (BAT) mass in females, whereas males showed only modest HFD-associated weight gain and did not develop a clear obesity phenotype. KBN2202 significantly reduced peri-ovarian gWAT mass and adipocyte size without altering overall body weight. In females, circulating glucagon-like peptide-1 (GLP-1) increased, uncoupling protein 1 (UCP1) in gWAT showed a non-significant upward trend, and serum TNF-α was selectively decreased, while MCP-1 and IL-1β were unchanged. Locomotor activity was unaltered, and anxiety-like behavior was reduced. Male mice did not show comparable adipose effects. These findings indicate depot-specific, peripheral modulation of adipose remodeling, hormonal balance, and inflammatory tone by KBN2202, supporting its further investigation as an adipose-targeted metabolic modulator complementary to incretin-based therapies. Full article

Sex determination and differentiation in teleosts are governed by complex genetic regulatory networks that include evolutionarily conserved mechanisms. In this study, we investigated Boleophthalmus pectinirostris, a Gobiidae species lacking heterogametic sex chromosomes, using comparative gonadal transcriptome analysis to identify sex differentially expressed genes (DEGs). RNA sequencing of ovarian and testicular tissues identified 17,214 DEGs, including 14,302 upregulated in males and 2912 upregulated in females. These DEGs were primarily associated with male (e.g., dmrt1, amh, amhr2) or female (e.g., bmp15, gdf9, rspo1) sex determination and differentiation, steroidogenesis (e.g., hsd17b1, hsd3b1, cyp17a1), and meiosis (e.g., cyp26b1, aldh1a2, piwil2). Functional enrichment analysis revealed that male upregulated DEGs were involved in spermatogenesis pathways such as calcium signaling, while female upregulated DEGs were associated with oogenesis pathways including oocyte meiosis and progesterone-mediated oocyte maturation. Conserved regulators, notably dmrt1 and amh, were predicted to act as key hubs in protein–protein interaction networks, being primarily associated with reproductive processes and sex differentiation in B. pectinirostris. The amh gene produces two alternatively spliced isoforms that differ by a partial deletion in the second exon, both expressed in ovaries and testes. Collectively, this study provides the first comprehensive molecular framework of sex determination and differentiation in Gobiidae species, offering critical insights into the regulatory mechanisms of B. pectinirostris reproductive development. Full article

The high incidence of anthropogenic impacts in the Mediterranean basin raises concerns on the health and quality of commercial fish species. This study aims to evaluate the health status of the European hake, Merluccius merluccius, from three areas of the Catalan coast (NW Mediterranean Sea) with different anthropogenic impacts (i.e., chemical pollution, litter, …) and assess if hake could serve as a sentinel species. We measured biomarkers of chemical exposure including B-esterases, antioxidant enzymes (GST, GR, GPx, CAT), biotransformation markers (EROD), lipid peroxidation, and macro-parasite assemblages. Hake showed, generally, a good health status across all areas with homogeneous patterns for most parameters. Tissue-specific differences included elevated gonadal cholinesterases and higher brain and hepatic carboxylesterase activities in the south, and increased hepatic EROD but lower lipid peroxidation in the central Barcelona area. Parasite assemblages were dominated by Digenea, Cestoda, and Nematoda, with higher cestode prevalence in both central and south zones. In summary, despite a greater prevalence of environmental pollution in the central region, there was a homogeneous pattern in hake health indicators throughout the three studied fishing zones. These results establish a baseline for hake health in Mediterranean waters and suggest that the species’ high mobility and wide depth range may limit its utility to detect local-scale pollution impacts, though it may serve as a regional-scale bioindicator. Full article

Marbled flounder (Pseudopleuronectes yokohamae) exhibits a distinct female growth advantage and an XX/XY sex determination system. To exploit these traits, we investigated 17α-methyltestosterone (MT)-induced transcriptomic changes in gonadal tissue with the goal of generating pseudomale XX broodstock for all-female fry production. Full-sibling diploid juveniles (60 days post-hatching, dph) were fed diets containing 0 (control), 0.5, or 2 mg/kg MT for 120 days, followed by a 60-day recovery period on a commercial diet prior to sampling. Testicular transcriptomes were profiled via high-throughput sequencing, and key differentially expressed genes were validated using qPCR. Both MT treatments resulted in 100% masculinization. Testicular transcriptome analysis revealed 972 differentially expressed genes (DEGs) (180 up, 792 down) in the 0.5 mg/kg MT-treated males (MT05M) compared to the control males, and 1245 DEGs (842 up, 403 down) in the 2 mg/kg MT group (MT20M). Gene Ontology terms were enriched for extracellular space and signaling receptor regulator activity. KEGG pathway analysis indicated significant enrichment in neuroactive ligand–receptor interaction, ovarian steroidogenesis, and TGF-β signaling. qPCR confirmed significant downregulation (p < 0.05) of sox17, bmp4, and smad6, while dmrt1 was downregulated only in the MT20M group. These findings demonstrate that MT effectively masculinizes P. yokohamae by modulating key sex-related genes and signaling pathways, providing a transcriptomic foundation and potential mechanistic insights for optimizing pseudomale induction to enable all-female aquaculture production. Full article

Background/Objectives: Endocrine autoimmune diseases, including autoimmune thyroid, pituitary, parathyroid, adrenal, and gonadal diseases, result from complex interactions between genetic susceptibility and environmental triggers. Advances in genomics and epigenomics have provided novel insights into the molecular pathways leading to immune dysregulation and endocrine tissue destruction. This review summarizes recent progress in understanding the genetic and epigenetic bases, emphasizing shared and disease-specific mechanisms that contribute to autoimmunity and endocrine dysfunction. Methods: A comprehensive literature search was performed in PubMed, Scopus, and Web of Science up to August 2025, focusing on genome-wide association studies (GWAS), next-generation sequencing, and epigenetic profiling (DNA methylation, histone modification, and non-coding RNA regulation). Results: More than 60 susceptibility loci have been identified across endocrine autoimmune diseases (EADs), including key genes in immune tolerance (HLA, CTLA4, PTPN22) and endocrine-specific pathways. Epigenetic studies reveal that altered DNA methylation and histone acetylation patterns in immune and endocrine cells modulate gene expression without changing the DNA sequence, linking environmental exposures to disease onset. Dysregulated microRNAs further influence immune signaling and cytokine networks. Conclusions: Genetic and epigenetic discoveries highlight the multifactorial nature of EADs and reveal potential biomarkers for early detection and targets for precision immunotherapy. Future research integrating multi-omics and longitudinal analyses will be crucial to unravel causal mechanisms and develop personalized preventive strategies. Full article

To investigate the effect of epigenetic modifications on sex determination and differentiation in northern pike (Esox lucius), we employed Whole-Genome Bisulfite Sequencing (WGBS) to analyze the DNA methylation patterns in gonadal tissues of females, males, and neomales. First, we obtained high-quality sequencing data, including a total of 410.16 Gb of raw reads and 361.48 Gb of clean reads, with an 86% unique mapping rate, and a bisulfite conversion efficiency of 99.6%. Subsequently, comparative analysis revealed that 66,581 differentially methylated CG regions (i.e., DNA regions with a high frequency of CG dinucleotides), 1215 differentially methylated CHG regions (i.e., DNA regions where CG is followed by another nucleotide), and 3185 differentially methylated CHH regions (i.e., regions where cytosine is methylated in a CHH sequence, with ‘H’ representing A, T, or C) were identified among the three groups. Furthermore, we identified four key differentially methylated candidate genes (Rspo1, hsd11b2, CYP27A1 and smad3) associated with sex determination and differentiation processes in E. lucius. Finally, by integrating GO and KEGG enrichment analyses, we explored the role of epigenetic modification regulatory networks in the sex determination and differentiation of E. lucius and identified multiple metabolic pathways related to sex determination and differentiation processes (Notch signaling pathway, Wnt signaling pathway and Ovarian steroidogenesis). This study thereby lays a foundation for subsequent functional verification. Full article

Background an Objectives: The Mediterranean sea urchins Paracentrotus lividus and Arbacia lixula co-occur on shallow rocky reefs but display contrasting ecological and physiological traits. We compared their gonadal metabolomes to identify species-specific metabolic strategies. Methods: High-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy to intact gonadal tissues, combining multivariate chemometric modelling with targeted integration, boxplot-based univariate analysis and pathway analysis. Results:A. lixula showed an osmolyte- and redox-oriented phenotype with elevated betaine, taurine, sarcosine, trimethylamine (TMA), trimethylamine N-oxide (TMAO), carnitine, creatine, malonate, methylmalonate, uridine and xanthine. In contrast, P. lividus exhibited an amino-acid-enriched anabolic profile dominated by lysine, glycine and glutamine, together with higher levels of formaldehyde, methanol and 3-carboxypropyl-trimethylammonium. Pathway analysis indicated that A. lixula metabolites mapped onto glycine/serine–threonine metabolism and the folate-linked one-carbon pool, whereas P. lividus metabolites were enriched in glyoxylate/dicarboxylate, nitrogen and amino-acid pathways. These contrasting osmolyte–C₁ versus nitrogen–amino-acid strategies are compatible with species-specific host–microbiota metabolic interactions inferred from published microbiome data. Conclusions: Overall, our results support a framework in which A. lixula adopts a resilience-oriented osmolyte strategy and P. lividus an efficiency-oriented anabolic strategy, highlighting HR-MAS NMR metabolomics as a powerful approach to investigate adaptive biochemical diversity in marine invertebrates. Full article

Alpha-lipoic acid (ALA) is well-known for its antioxidant and anti-inflammatory functions in various disease models. Here, we tested whether pre-exposure to ALA can protect the testes from cellular damage caused by scrotal heat shock (HS) in mice. Methods: Thirty-six Swiss albino mice were divided into control (CTRL, n = 6), HS (n = 10), and two ALA dose (HS + ALA 200 mg/kg, n = 10; and HS + ALA 400 mg/kg, n = 10) groups. ALA supplementation was administered orally for 30 days. Subsequently, the animals, except the controls, were subjected to an HS water bath at 43 °C for 20 min. Two days later, they were euthanized, and biometric data from gonads and accessory sexual glands, testicular samples for histomorphometric and immunohistochemical analyses, and sperm from the epididymis cauda were obtained for evaluation. Results: Animals submitted to HS had a lower body weight, decreased relative mass of testes and prostate, reduced seminiferous epithelium height and tubular diameter, and increased degeneration in seminiferous tubules. Additionally, sperm analysis showed a reduced linear progressive velocity (VSL) and straightness (STR), increased midpiece defects, and fewer sperm with functional membranes. Immunohistochemical evaluation revealed a reduced superoxide dismutase (SOD1) staining intensity in the testes. Preventive exposure to ALA at 200 mg/kg did not normalize the relative testicular mass, but it reduced the number of giant cells, decreased midpiece defects, normalized the number of sperm with functional membranes, and partially preserved SOD1 expression. Although animals treated with ALA 400 mg/kg showed an improvement in relative testicular mass, this dose was less efficient in other parameters. Conclusions: This study showed that while 30 days of oral ingestion of ALA before the induction of acute degenerative injury did not fully protect male mouse gonads at the tissue level, some parameters related to testicular function and sperm quality showed a partial improvement. Full article

The swimming crab (Portunus trituberculatus) is an economically important marine crab species in China. Understanding the structure and function of the male reproductive system in the swimming crab is crucial for increasing reproductive efficiency. Although studies on its reproductive biology have increased in recent years, the ultrastructure of the male copulatory system remains insufficiently explored. In this study, gonadal tissues [testes (T), anterior vas deferens (AVD), middle vas deferens (MVD), posterior vas deferens (PVD)] and copulatory organs [first gonopod (G1), second gonopod (G2), penis] of P. trituberculatus were sampled as experimental materials, and we systematically investigated the morphological and functional characteristics of male reproductive and copulatory organs in P. trituberculatus using anatomical, stereomicroscopic and scanning electron microscopic techniques. The results indicate that the male copulatory system comprises the G1, G2, and the penis. The G1 shows a tubular structure, with its endopodite bearing spines that anchor the female during copulation. The G2 is short, stout, solid and rod-shaped, with surface folds and blunt teeth, indicating its role in propelling the spermatophore within the G1. The penis is flexible and covered with elongated, rigid setae. Internally, the reproductive system displays a bilaterally symmetrical “H”-shaped architecture, consisting of the testes; anterior, middle, and posterior vas deferens; and the ejaculatory ducts. These segments have different structures and function in forming, storing, and transporting spermatophores. These findings provide important insights into the reproductive strategies and mating mechanisms of P. trituberculatus. Full article

We report the first identification of several large (1.4–2.2 MDa), highly stable protein–peptide complexes in various organs and tissues (body wall, gonads, respiratory trees, gut, and coelomic fluid) of the sea cucumber Paracaudina chilensis. Gel filtration and transmission electron microscopy methods were used to estimate the molecular weights and sizes of the complexes. According to light scattering assay data, these multiprotein complexes undergo significant dissociation only in the presence of 3.0 M MgCl₂ or 8.0 M urea containing 0.1 M EDTA and DTT. Analysis of the complexes using SDS-PAGE and MALDI mass spectrometry showed that all complexes contain numerous proteins (>10 kDa), whose number and composition vary among organs. Additionally, using MALDI mass spectrometry, it was shown that the whole-organism complexes contain 254 distinct peptides (<10 kDa). The peptide content in organ-specific complexes decreases in the following order: respiratory trees (104) > coelomic fluid (76) > body wall (64) > gut (58) > gonads (55). In contrast to individual proteins and peptides, multiprotein complexes have expanded possibilities, since they can interact with various molecules and cells. Thus, they can perform the functions of all peptides and proteins located on their surfaces. We propose that the unique protein and peptide composition of each complex facilitates the specific biological functions of its respective organ. Full article

Background/Objectives: Organic UV filters are chemical compounds that are commonly used in sunscreen products to absorb UV radiation from the Sun. To date, the filters have been detected in aquatic environments worldwide, as well as in aquatic organisms, including fish and coral. Hydroxy-4-methoxybenzophenone (BP-3) is a common organic UV filter and it is well documented to be among the filters that are detectable worldwide in water samples and aquatic organisms. Long-term exposure in vivo studies have demonstrated that high doses of BP-3 can cause endocrine-disrupting effects in aquatic organisms. Methods: Using gonadal cell culture and quantitative RT-PCR, our study aimed to ascertain the effect of environmentally relevant doses of BP-3 (detected in aquatic systems) on the gene expression of reproductive targets, estrogen and growth hormone receptors (ERs and GHRs), in Mozambique tilapia (Oreochromis mossambicus) after an acute 24 h treatment. Results/Conclusions: Our study is the first to use an in vitro design to investigate the mechanism of the action of BP-3 on gonadal tissue in fish. Our results show that BP-3 does not induce gene regulation directly on the gonads of tilapia at doses that are comparable to what is detectable in aquatic environments after 24 h. We do verify, as seen in other teleost species, homologous regulation of ERβ in male tilapia gonadal tissue. Full article