Reproductive toxicology最新文献

{"title":"Effects of PD-1 inhibitors on ovarian function-based on two-sample mendelian randomization and visualization experimental validation","authors":"Jiaxin Zheng ,&nbsp;Na Zhu ,&nbsp;Chang Liu ,&nbsp;Xiang Li ,&nbsp;Keming Zhang ,&nbsp;Zhuo Yang ,&nbsp;Danbo Wang ,&nbsp;Bo Liu","doi":"10.1016/j.reprotox.2025.109057","DOIUrl":"10.1016/j.reprotox.2025.109057","url":null,"abstract":"<div><div>Although immune checkpoint inhibitors (ICIs) have transformed cancer treatment by improving survival, their ovarian safety remains uncertain. This study combined Mendelian randomization (MR) and experimental validation to assess the impact of PD-1 inhibitors on ovarian function. MR analysis used summary statistics from large European-ancestry genome-wide association studies (GWAS), applying the inverse-variance weighted (IVW) method, supported by sensitivity analyses. For in vitro experiments, mouse follicles were cultured with 10 µg/ml PD-1 inhibitor ch15mt (clinically relevant concentration), 200 nM doxorubicin (DOX), or PBS control. Follicular morphology was evaluated via diameter measurements; endocrine function by estradiol (E2) quantification using ELISA. Real-time cytoplasmic Ca²⁺ dynamics were monitored using FRET-based Cyto-Ca2 + probes for high-resolution stress assessment. MR results showed no significant association between genetically predicted PD-1 levels and risks of premature ovarian insufficiency, infertility, or alterations in ovarian hormones including AMH and E2. Sensitivity analyses confirmed MR robustness. In vitro, PD-1 inhibition did not affect follicular size or E2 secretion. Notably, DOX induced rapid Ca²⁺ elevation, while PD-1 inhibitor treatment had no detectable effect on Ca²⁺ fluctuations. This first integrative MR and experimental study demonstrates that PD-1 inhibitors at clinically relevant concentrations lack acute ovarian toxicity. While further work is needed to assess long-term effects, these findings demonstrate that standard anti-PD-1 immunotherapy regimens do not compromise follicular viability or endocrine function, strongly supporting their safety in fertility-sparing oncology protocols.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109057"},"PeriodicalIF":2.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulatory role of epigallocatechin-3-gallate (EGCG) on male and female reproductive disorders","authors":"Nayanika Roy ,&nbsp;Sarika Borle ,&nbsp;Dipty Singh","doi":"10.1016/j.reprotox.2025.109049","DOIUrl":"10.1016/j.reprotox.2025.109049","url":null,"abstract":"<div><div>Epigallocatechin-3-gallate (EGCG), a key bioactive compound in green tea, has gained prominence in recent years due to its numerous health-promoting benefits. Owing to its potent antioxidant, anti-inflammatory, and hormone-modulating properties, EGCG represents a promising therapeutic candidate for the management of andrological, gynecological, and pregnancy-associated disorders. In males, oxidative stress is a major factor in sperm dysfunction, leading to poor motility, abnormal morphology, and DNA fragmentation. EGCG enhances sperm quality by reducing oxidative damage, improving testosterone levels, mitigating testicular inflammation and protecting against environmental toxins that contribute to male infertility. In females, EGCG supports ovarian function, improves oocyte quality, and helps regulate hormonal imbalances by modulating estrogen synthesis, reducing inflammatory markers, and preventing abnormal cell proliferation in various gynaecological disorders. Additionally, its anti-cancer properties suggest a protective effect against prostate, ovarian, cervical, and endometrial cancers. During pregnancy, oxidative stress and inflammation can contribute to complications such as preeclampsia, gestational diabetes, and fetal alcohol syndrome. EGCG’s ability to enhance vascular health, improve placental function, and regulate immune responses suggests its potential in promoting a healthy pregnancy and fetal development. Though evidences support the merits of EGCG in reproductive health scenario, further research is needed to establish optimal dosages and long-term safety. This narrative review examines the therapeutic potential of EGCG in male and female reproductive disorders, as well as pregnancy, highlighting its antioxidant, anti-inflammatory, anti-cancer, anti-apoptosis and hormone-regulating properties. Additionally, it incorporates recent findings demonstrating the integration of EGCG into reproductive healthcare offering a promising natural therapeutic approach to improve fertility and pregnancy outcomes.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109049"},"PeriodicalIF":2.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential disease-related risk of saccharin in ovarian cancer: An integrative multi-evidence analysis","authors":"Yang Song ,&nbsp;Hao Yang ,&nbsp;Yanchun Wang ,&nbsp;Chenchen Lin ,&nbsp;Xuemei Wang","doi":"10.1016/j.reprotox.2025.109044","DOIUrl":"10.1016/j.reprotox.2025.109044","url":null,"abstract":"<div><div>Saccharin is a widely used artificial sweetener with controversial safety concerns, particularly regarding reproductive health. Using a network-toxicology framework, we integrated compound- and disease-target databases and intersected them with differentially expressed genes and WGCNA co-expression modules from GEO datasets, yielding 49 candidate targets. Protein–protein interaction analysis and functional prioritization identified five hubs: TNF, MMP2, ERBB2, BCL2L1, and NFE2L2. GO/KEGG enrichment indicated over-representation of biological processes related to inflammatory response, apoptosis, and oxidative stress, alongside multiple cancer-associated pathways. Molecular docking against representative target structures indicated favorable binding of saccharin across hubs, with binding energies ≤ −5.0 kcal/mol. Mendelian randomization then tested the causal effects of gene expression on ovarian cancer risk and suggested a protective signal for TNF (odds ratio [OR] 0.99886, P = 0.0448) and increased risk for BCL2L1 (OR 1.00128, P = 0.0188). In two independent GEO datasets (GSE26712 and GSE14407), TNF and BCL2L1 were identified as differentially expressed genes between tumor and normal tissues. Molecular dynamics simulations further supported binding stability, with backbone RMSD stabilizing at 0.16–0.19 nm. These findings offer mechanistic insights into saccharin-induced ovarian toxicity and support further evaluation of artificial sweeteners' reproductive risks.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109044"},"PeriodicalIF":2.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking T-type calcium channels disrupts spermatogenesis in vivo and adversely affects spermatocytes in vitro by impairing mitochondrial function and autophagic flux","authors":"Xiuling Zhao ,&nbsp;Lei Wang ,&nbsp;Shiqin Huang ,&nbsp;Lin Liu ,&nbsp;Xiaorong Wang ,&nbsp;Liping Pu ,&nbsp;Hao Chen ,&nbsp;Junyu Nie","doi":"10.1016/j.reprotox.2025.109048","DOIUrl":"10.1016/j.reprotox.2025.109048","url":null,"abstract":"<div><div>T-type calcium channels are pivotal in spermatogenesis. To evaluate the molecular mechanisms by which T-type calcium channels regulate spermatogenesis, we constructed animal and cellular models using T-type calcium channel inhibitor flunarizine (FNZ). Intraperitoneal administration of FNZ (30 mg/kg) significantly impaired sperm motility, inhibited testicular germ cell proliferation, and disrupted sperm mitochondrial function in male mice. FNZ, at concentrations of 7.5 μM, 15 μM, and 30 μM, significantly inhibited mouse spermatocyte (GC-2) cells proliferation. The detrimental effects of FNZ were mediated through the disruption of calcium homeostasis, mitochondrial dysfunction, and the induction of apoptosis. Moreover, FNZ exposure resulted in the accumulation of autophagosomes and an upregulation of P62 protein, which is implicated in autophagic degradation. Notably, the autophagy activator Rapamycin (Rapa) was found to mitigate FNZ-induced cellular damage in GC-2 cells by enhancing autophagy process. Conversely, chloroquine (CQ), an autophagy inhibitor that disrupts lysosomal degradation, corroborated the role of FNZ in autophagy modulation. Our results indicate that FNZ induces mitochondrial damage, impairs sperm motility and spermatocyte proliferation, and is accompanied by obstacles to autophagic flux.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109048"},"PeriodicalIF":2.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effect of ginsenoside Rg3 on DBP-induced spermatogenesis injury via the Src/PI3K signaling pathway","authors":"Huan Li ,&nbsp;Hongyan Wang ,&nbsp;Xiaolei Xu,&nbsp;Li Qu,&nbsp;Xiuling Sun,&nbsp;Jing Zhang","doi":"10.1016/j.reprotox.2025.109047","DOIUrl":"10.1016/j.reprotox.2025.109047","url":null,"abstract":"<div><div>This study aimed to investigate the protective mechanism of Ginsenoside Rg3 (Rg3) against Di-n-butyl phthalate (DBP) induced spermatogenic damage, focusing on the Src/PI3K/Akt pathway. In vivo experiments demonstrated that Rg3 restored DBP-induced dysregulation of gap junction (GJ) protein connexin 43 (Cx43), improved testicular structure, enhanced sperm parameters (count and motility), and upregulated phosphorylation of Src, PI3K, and Akt (p-Src, p-PI3K, p-Akt) in mice. In vitro studies, using the metabolite of DBP, monobutyl phthalate (MBP), and pathway inhibitors (PP2 for Src and LY294002 for PI3K), further confirmed these effects. Rg3 increased antioxidant enzyme activity, reduced oxidative stress marker MDA, and enhanced the expression of p-Src, p-PI3K, p-Akt, and Cx43 in MBP-treated TM4 Sertoli cells. Inhibitor experiments confirmed that the Src/PI3K pathway mediates Rg3’s protective action. These findings suggest that Rg3 alleviates DBP/MBP-induced male reproductive dysfunction by enhancing antioxidant capacity and reactivating the Src/PI3K/Akt signaling pathway, which helps restore blood-testis barrier (BTB) integrity through Cx43 stabilization. Thus, Rg3 may serve as a potential therapeutic agent for environmental toxicant-related male infertility.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109047"},"PeriodicalIF":2.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of imidacloprid exposure on the mouse ovary in vivo","authors":"Vasiliki E. Mourikes,&nbsp;Colin Lee,&nbsp;Jadesola I. Oladosu,&nbsp;Ashley Deviney,&nbsp;Winter Stubblefield,&nbsp;Mary J. Laws,&nbsp;Megan Mahoney,&nbsp;Jodi A. Flaws","doi":"10.1016/j.reprotox.2025.109045","DOIUrl":"10.1016/j.reprotox.2025.109045","url":null,"abstract":"<div><div>Imidacloprid (IMI) is an insect-selective synthetic nicotine derivative used in commercial agricultural systems, home gardening, and veterinary pharmaceuticals. People are exposed to IMI through consumption of contaminated food and water and through contact with companion animals. However, the effects of IMI on the female reproductive system are not well understood. Thus, we tested the hypothesis that IMI reaches the ovaries and adversely affects the female reproductive system. Adult female mice were orally exposed to vehicle control (dimethyl sulfoxide) or IMI for 30 days. Estrous cyclicity was monitored for the last 14 days of the dosing period and mice were euthanized in diestrus. Sera were collected for gonadotropin and sex steroid hormone quantification. Ovaries were collected for IMI and IMI metabolite quantification, and to assess follicle numbers and gene expression. IMI and metabolites were significantly higher in exposed mice compared to controls. Further, IMI decreased the number of healthy ovarian follicles and increased the ovarian expression of the enzymes <em>Cyp2e1</em> and <em>Cyp19a1</em> compared to control. IMI also increased circulating luteinizing hormone levels (LH), but did not affect circulating follicle-stimulating hormone levels or sex steroid hormone levels compared to control. IMI did not affect body weight, ovarian weight, or estrous cyclicity compared to control. Collectively, these data indicate that IMI reaches the ovaries and affects some female reproductive outcomes such as ovarian follicle numbers, LH levels, and ovarian expression of enzymes.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109045"},"PeriodicalIF":2.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caffeic acid phenethyl ester disrupts germ layer specification in Xenopus embryos","authors":"Gang-Ho Yoon,&nbsp;Myeoung Su Kim,&nbsp;Sun-Cheol Choi","doi":"10.1016/j.reprotox.2025.109046","DOIUrl":"10.1016/j.reprotox.2025.109046","url":null,"abstract":"<div><div><em>Xenopus</em> embryo serves as an ideal model for teratogenesis assays to observe the effects of any compounds on the cellular processes crucial for early development and adult tissue homeostasis. In our screening of a chemical library with frog embryo, caffeic acid phenethyl ester (CAPE) was found to upregulate the FGF/MAPK pathway, disrupting germ layer formation in early development. Exposure to CAPE interfered with the formation of anterior-posterior body axis and of ectodermal derivatives such as eyes, dorsal fin and pigment cells. These inhibitory effects were achieved by promoting paraxial mesodermal specification and neural differentiation concomitant with a repression of epidermal and neural crest cell fates. This compound also induced the caudalization of anterior neural fate, thereby recapitulating the activity of the FGF/MAPK signals in the anterior-posterior patterning of neural tissue. Consistently, phosphorylation of extracellular signal-regulated kinase (ERK) was elevated in CAPE-treated cells, which was mediated by the FGFR1 and FGFR4 pathway. Together, these results suggest that CAPE functions as an activator of the FGF/MAPK signaling pathway, generating severe teratogenic effects on germ layer specification in vertebrate early development.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109046"},"PeriodicalIF":2.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Positioning nutrigenomics and nutrigenetics within the framework of male infertility exploration","authors":"Emmanuel Osei Nkansah,&nbsp;Binbin Xu,&nbsp;Yunzhu Lan,&nbsp;Mohammad Ishraq Zafar","doi":"10.1016/j.reprotox.2025.109043","DOIUrl":"10.1016/j.reprotox.2025.109043","url":null,"abstract":"<div><div>Male infertility, a complex result of genetic, environmental, and lifestyle factors, has gained significant focus in contemporary medical research. The intricate interplay between genetics, nutrition, and male fertility is crucial for understanding the complex mechanisms that underlie male reproductive health. The twenty-first century has seen a paradigm shift in medicine, where holistic personalized medical care is posited to be ideal and effective. In this regard, this narrative review explored how the convergence of dietary habits and genetic predispositions influence male fertility in the context of predictive, preventive, and personalized medicine. This review explored the evolving landscape of genetic insights into male infertility, creating awareness of their possible engagement as genetic predictors for idiopathic male infertility. It also dissects the roles of nutrigenomics and nutrigenetics in shaping preventive male reproductive medicine strategies through distinguishing the influence of dietary components on genetic expression and further elucidating how epigenetic alterations, influenced by dietary components, impact male fertility, potentially imparting transgenerational effects. Furthermore, this review offers potential personalized reproductive remedies in the form of functional and super foods, gut microbiome enhancers, redox homeostasis and proposes personalized nutrition as an intervention with high prospects in the context of improving male fertility.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109043"},"PeriodicalIF":2.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of urinary phthalate metabolites and polycystic ovary syndrome in women undergoing in vitro fertilization","authors":"Wenjie Zhou ,&nbsp;Shuifang Lei ,&nbsp;Hong Lv ,&nbsp;Yangqian Jiang ,&nbsp;Tianyu Sun ,&nbsp;Yanjie Zhang ,&nbsp;Hongxia Ma ,&nbsp;Jie Wu ,&nbsp;Yuan Lin","doi":"10.1016/j.reprotox.2025.109041","DOIUrl":"10.1016/j.reprotox.2025.109041","url":null,"abstract":"<div><h3>Background/objectives</h3><div>Phthalates are a group of ubiquitous environmental endocrine disruptors that can be detected in human body and exert adverse effects on reproductive health. We aimed to explore the correlation of phthalate exposure with polycystic ovary syndrome (PCOS).</div></div><div><h3>Methods</h3><div>We included 420 females who underwent assisted reproductive technology (ART) treatments between 2015 and 2018 in Jiangsu, China, comprising 94 PCOS cases and 326 controls. Seventeen phthalate metabolites and three metabolites of phthalate substitutes were measured in the urine before the ART treatment. Multiple logistic and linear regression models were performed to assess the relationships of phthalate exposure with PCOS and sex hormone levels, including luteinizing hormone (LH), estradiol (E₂), follicle-stimulating hormone (FSH), and mediation analysis was conducted to assess the mediating effect of sex hormones. Potential covariates in the regression models include age, area of residence, household income, education, body mass index (BMI), tobacco use and alcohol intake.</div></div><div><h3>Results</h3><div>We found that the concentration of di (2-ethylhexyl) phthalate (ΣDEHP) (aOR = 1.40, 95 % CI: 1.02–1.92, <em>P</em> = 0.039) was associated with higher odds of PCOS. Additionally, increased levels of ΣDEHP (β = 0.08, 95 % CI: 0.01–0.15, <em>P</em> = 0.021) and its metabolites were correlated with elevated LH concentrations. In the mediation analysis, elevated LH mediated 34.56 % of the association between ΣDEHP and PCOS, respectively.</div></div><div><h3>Conclusion</h3><div>Exposure to environmental levels of DEHP was associated with increased odds of PCOS, partially mediated by elevated LH levels.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109041"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluvastatin mitigates the testicular toxicity of Azathioprine via regulating mTOR pathway and restoring autophagy/apoptosis balance","authors":"Samar Sakr ,&nbsp;Nahla M. Ibrahim ,&nbsp;Basma A. Ibrahim ,&nbsp;Ansam M. Z. El Desoky ,&nbsp;Bassant T. Abd Elbaki ,&nbsp;Mamdouh Eldesoqui ,&nbsp;Zeinab A. Mohammed","doi":"10.1016/j.reprotox.2025.109042","DOIUrl":"10.1016/j.reprotox.2025.109042","url":null,"abstract":"<div><div>Azathioprine (AZA) is a widely employed immunosuppressive and chemotherapeutic medication that may exhibit detrimental effects on testes. Fluvastatin is a lipid-lowering agent with promising reproductive properties. This work aimed to assess the testicular toxicity of AZA and the probable protective role of fluvastatin. Forty adult male albino rats were assigned to four equal groups: Control, Fluvastatin (6 mg/kg), AZA (15 mg/kg), and AZA and fluvastatin. After 4 weeks, sera were obtained for testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) investigations. Semen samples were collected to test sperm parameters. Testes were harvested for biochemical investigations, gene transcription, and histological and immunohistochemical examinations. In the AZA group, results exposed a considerable decline in sperm parameters, sex hormones, and testicular weight. Oxidative stress was evident by the diminished catalase (CAT) and superoxide dismutase (SOD) activity, and malondialdehyde (MDA) levels elevation. Inflammation was reflected by increased NOD-Like Receptor family Pyrin domain-containing 3 inflammasome (NLRP3), Interleukin-6 (IL-6), and Interleukin-1 Beta (IL-1β), besides decreased Interleukin-10 (IL-10). Gene transcription indicated that AZA disrupts the mammalian target of the rapamycin (mTOR) cascade and the autophagic and apoptotic-related genes in testes, thus impairing the blood-testis barrier (BTB) and spermatogenesis. Testes displayed disorganized germinal epithelium and deformed seminiferous tubules. A positive p53 immunoreaction and a lost vimentin spoke-like pattern were also demonstrated. Fluvastatin exhibited antioxidant and anti-inflammatory defense, regulated the mTOR pathway, restored the lost autophagy/apoptosis balance, and improved the architectural and immunohistochemical alterations. Therefore, fluvastatin can be considered a candidate for future usage to combat AZA-induced testicular toxicity.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109042"},"PeriodicalIF":2.8,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}