Toxicology Mechanisms and Methods最新文献

{"title":"Transcriptomic profiling reveals crizotinib-induced hepatotoxicity through ROS-mediated activation of the JNK/NLRP3 pathway.","authors":"Min Li, Zhouli Yue, Menglin Wang, Yan Wang, Peng Xiao, Wei Yuan, Jiduo Shen, Yucheng Li","doi":"10.1080/15376516.2025.2536058","DOIUrl":"10.1080/15376516.2025.2536058","url":null,"abstract":"<p><p>Crizotinib, a first-generation tyrosine kinase inhibitor, demonstrates excellent clinical efficacy in treating non-small cell lung cancer (NSCLC). However, its clinical application is often limited by severe hepatotoxicity, the underlying mechanisms of which remain poorly understood. This study aimed to investigate the molecular mechanisms of crizotinib-induced hepatotoxicity in mice using transcriptomic analysis. Male ICR mice were orally administered crizotinib at doses of 100, 200, and 300 mg/kg for 7 consecutive days. Hepatotoxicity was assessed by measuring serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, along with histopathological evaluation <i>via</i> hematoxylin and eosin (H&E) staining. Transcriptomic and bioinformatics analyses of liver tissues were conducted to identify potential toxicological pathways. Oxidative stress markers were quantified using biochemical assay kits. Hepatic macrophage activation was examined by F4/80 immunostaining, and protein expression levels were analyzed by western blotting. Crizotinib administration resulted in dose-dependent liver injury, as indicated by elevated serum ALT and AST levels, body weight loss, and histological abnormalities. Transcriptomic profiling revealed significant enrichment of oxidative stress-related pathways, with protein-protein interaction (PPI) analysis identifying Jun as a key hub gene. Crizotinib significantly increased hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) levels, while reducing reduced glutathione (GSH) levels and the GSH/GSSG ratio. Additionally, crizotinib significantly upregulated Bax and downregulated Bcl-2 expression, promoted macrophage infiltration, and increased the expression of JNK and NLRP3 proteins. These findings suggest that crizotinib-induced hepatotoxicity may be mediated by ROS-induced activation of the JNK/NLRP3 signaling pathway, which subsequently promotes hepatic inflammation and apoptosis.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-10"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675665","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":"Comparison of carcinogenic potential of alternative tobacco products. A systematic review.","authors":"Paulina Natalia Kopa-Stojak, Rafał Pawliczak","doi":"10.1080/15376516.2025.2536664","DOIUrl":"https://doi.org/10.1080/15376516.2025.2536664","url":null,"abstract":"<p><strong>Objective: </strong>This study attempts to summarize current knowledge about the carcinogenic potential of alternative tobacco products: electronic cigarettes (ECs), heat-not-burn (HnB) cigarettes and snus/nicotine pouches (NPs). We focus on determining the effect of such products on epigenetic alteration, especially for genes and pathways which are fundamental for cancer development.</p><p><strong>Methods: </strong>The literature was searched in PubMed, Embase and Scopus databases using the combination of terms: 'ENDS', 'electronic cigarette', 'e-cigarette', 'heat-not-burn cigarette', 'heated tobacco product', 'snus', 'nicotine pouch', 'cancer', 'epigenetic changes', 'DNA damage', 'carcinogenesis' in July 2025.</p><p><strong>Results: </strong>Analyzed studies confirmed the effect of both ECs and HnB products on DNA damage induction, DNA repair capacity reduction, miRNAs expression, global DNA methylation status and histone modifications. In addition, snus/NPs use leads to induction of DNA damage and changes of the expression of genes associated with oxidative and cellular stress, DNA damage, cell growth and proliferation.</p><p><strong>Conclusions: </strong>Cell-based and animal-based models confirmed some carcinogenic potential of ECs, HnB cigarettes and snus/NPs, as well as effects of ECs and HnB on epigenetic changes, which may predispose to cancer development. However, there is only a limited number of studies on such effect for snus/NPs and most of them describe their effect on the induction of DNA damage, cell growth and proliferation, which may increase probability of malignant cells transformation. Therefore, to fully explain the carcinogenic potential of such products, a comprehensive clinical studies for healthy exclusive ECs, HnB products and snus/NPs users and patients with tobacco-specific cancers should be carried out in the future.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-15"},"PeriodicalIF":2.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754378","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":"A comparative analysis of <i>in vitro</i> cytotoxicity across various glove types using four different methods.","authors":"Renata Calil Lemos, Ludmila Rosa Bergsten Torralba, Mirian Noemi Pinto Vidal, Ronald Santos Silva, Taline Ramos Conde, Helena Pereira da Silva Zamith","doi":"10.1080/15376516.2025.2537317","DOIUrl":"10.1080/15376516.2025.2537317","url":null,"abstract":"<p><p>The coronavirus disease 2019 (COVID-19) pandemic has led to increased use of protective materials among healthcare workers and the general population, resulting in a rise in health issues such as allergies. Glove types, such as latex, nitrile, and vinyl, are notable sources of cutaneous reactions; however, most of their cytotoxic effects are considered negligible. Given the significant exposure of healthcare professionals to gloves and the absence of mandatory toxicological testing to ensure the quality of these medical products under Brazilian legislation, this study aimed to evaluate the <i>in vitro</i> cytotoxicity of three glove-types: natural rubber latex (NRL) surgical, nitrile, and vinyl medical examination gloves, using mouse fibroblast L-929 cell cultures. Four methods were employed based on guidelines from the United States Pharmacopeia (USP), Brazilian Pharmacopeia (BP), the Organization for Economic Cooperation and Development (OECD) and the International Organization Standardization (ISO). All latex gloves tested would be considered unsafe for use, exhibiting at least moderate cytotoxicity in the agar diffusion, direct contact and elution test methods. In contrast, 75% of nitrile gloves and 67% of vinyl gloves were considered safe, showing mild cytotoxicity in the agar diffusion method, which proved to be the most effective for differentiating cytotoxicity among glove materials. Both nitrile and vinyl gloves showed significantly lower cytotoxicity than latex gloves in the promising Neutral Red Uptake (NRU) method. These findings support the recommendation for mandatory inclusion of the agar diffusion and elution test methods as regulatory quality control assays for evaluating glove cytotoxicity.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-13"},"PeriodicalIF":2.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675663","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":"Progression and prospects of machine learning techniques in nanotoxicology: riding the AI-driven wave.","authors":"Siyuan Chen, Tianshu Wu","doi":"10.1080/15376516.2025.2536659","DOIUrl":"https://doi.org/10.1080/15376516.2025.2536659","url":null,"abstract":"<p><p>The widespread application of nanoparticles (NPs) has led to an increasing number of NPs being distributed in the ecological environment. This has raised concerns about human health and promoted the development of nanotoxicology. Traditional toxicity assessments, limited by high costs and time consumption, make machine learning (ML) an attractive alternative. ML models, particularly deep learning (DL) networks, can predict NP toxicity by analyzing extensive datasets, providing a more efficient and ethical method compared to animal testing. This review systematically summarizes the applications and challenges of ML in nanotoxicology. It discusses the importance of NPs properties in toxicity prediction and the difficulties in modeling the dynamic interactions with biological systems. The potential of integrating ML with other computational approaches to improve toxicity assessment is also considered. Despite progress, ML faces challenges such as limited training data, issues with model interpretability, and the complexity of nanomaterial-biological interactions. Overcoming these challenges requires enhanced data collection, interdisciplinary collaboration, and more directed ML models. Looking forward, the integration of ML with nanotoxicology is poised to revolutionize toxicity assessments, facilitating the development of safer nanotechnology applications.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-20"},"PeriodicalIF":2.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733438","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":"Enhanced anti-cancer efficacy of Sorafenib and Pioglitazone via VEGF inhibition in DMBA-induced breast cancer model.","authors":"Kinal Soni, Jigna Shah","doi":"10.1080/15376516.2025.2537889","DOIUrl":"10.1080/15376516.2025.2537889","url":null,"abstract":"<p><p>Breast cancer remains the most prevalent cancer among women and a significant cause of mortality, partly due to treatment resistance and adverse effects. Sorafenib, a tyrosine kinase inhibitor, and Pioglitazone, a PPAR-γ agonist, exhibit anti-cancer properties. This study explores improved anti-cancer effects of combination of Sorafenib and Pioglitazone for breast cancer treatment. Protein-ligand molecular docking was performed to identify interactions of both drugs with various proteins. Cytotoxic effects of Sorafenib and Pioglitazone, individually and in combination, were evaluated on MCF-7 cells using MTT assay. DMBA-induced breast cancer model in female Sprague-Dawley rats assessed tumor volume, survival rates, oxidative stress markers, cytokines, tumor markers, and histopathology. Rats were divided into six groups, including control, individual treatments, combination therapy, and a doxorubicin standard group. Sorafenib demonstrated dose-dependent cytotoxicity. Pioglitazone exhibited limited cytotoxic effects when used alone but showed significant cytotoxicity when combined with Sorafenib. Combination therapy resulted in reduced tumor volume, enhanced survival rates, and restored body weight in DMBA-induced treatment animals. It significantly lowered oxidative stress parameters and pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, as well as phosphorylated Akt levels. It inhibited tumor angiogenic markers VEGFR2 and VEGFR3 and promoted tumor suppressor p53 levels. Histopathological analysis confirms a reduction in tumor cell invasion and inflammation. The combination of Sorafenib and Pioglitazone exhibited enhanced anti-cancer effects by suppressing oxidative stress, inflammatory markers, pAkt, VEGF2, and VEGF3, as well as upregulating p53 levels, highlighting the promising potential of this combination for breast cancer treatment.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-20"},"PeriodicalIF":3.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691647","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":"5-Hydroxymethylfurfural causes reproductive toxicity in male mice by increasing oxidative stress and apoptosis through the Nrf2/HO-1 signaling pathway.","authors":"Yasemin Aydin, Iremnur Sarialioglu, Gulsah Armut, Ertan Calmaz, Banu Orta Yilmaz","doi":"10.1080/15376516.2025.2537319","DOIUrl":"10.1080/15376516.2025.2537319","url":null,"abstract":"<p><p>5-Hydroxymethylfurfural (HMF) is a furan derivative compound commonly found in heat-treated carbohydrate-rich foods. Although its toxicological properties are well-studied, its effects on the male reproductive system at cellular and molecular levels remain unclear. This study is one of the first to evaluate the toxicity of HMF on the male reproductive system by conducting comprehensive analyses in both <i>in vitro</i> and <i>in vivo</i> models. In the <i>in vitro</i> model, TM3 Leydig cells were divided into four groups: control, 0.1, 1, and 10 mM HMF for 24 h. The study evaluated cell cytotoxicity and proliferation, oxidative stress levels, and antioxidant enzyme activity. The mRNA expression levels of oxidative stress- and apoptosis-related genes (<i>Sod1, Gpx1, Nrf2, Ho1, Keap1, Bax, Bcl-2, Casp3, Trp53,</i> and <i>Parp1</i>) were analyzed by RT-qPCR. In the <i>in vivo</i> model, BALB/c mice were divided into three groups: control, 30 mg/kg, and 300 mg/kg HMF administered orally for 21 days, and testicular tissues were evaluated with similar biochemical and genetic analyses. HMF significantly increased cytotoxicity, suppressed proliferation, and caused a significant increase in ROS levels in TM3 cells (<i>p</i> < 0.05). Moreover, HMF increased lipid peroxidation, suppressed antioxidant enzyme activities, and altered the expression of oxidative stress- and apoptosis-related genes in both TM3 cells and testicular tissue (<i>p</i> < 0.05). These statistically significant findings demonstrate that HMF induces oxidative damage and impairs cellular defense and survival mechanisms. In summary, our results highlight the potential reproductive risks associated with dietary HMF exposure and support the need for reassessing its toxicological safety limits.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-17"},"PeriodicalIF":3.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675662","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":"Ontogenetic development of metabolic and detoxification genes in <i>Seriola rivoliana</i> larvae.","authors":"Danitzia A Guerrero-Tortolero, Rafael Campos-Ramos","doi":"10.1080/15376516.2025.2534373","DOIUrl":"https://doi.org/10.1080/15376516.2025.2534373","url":null,"abstract":"<p><p>The early larval stages in marine organisms have evolved to possess a genomic response ensuring survival and protection against environmental stressors, defined as the 'chemical defensome'. The larval fish defensome consists of genes transcribed and upregulated after hatching to form detoxification proteins, catalyzing enzymes, transporters, transcription factors, and antioxidant proteins. Therefore, we aimed to analyze the timing of transcription and upregulation of metabolic, protective and detoxification genes during the ontogenetic development in <i>Seriola rivoliana</i> larvae up to the onset of exogenous feeding. Larvae samples from each experimental replicate were taken after hatching (day zero), day one (24 h post-hatching), day two (48 h post-hatching), day three (72 h post-hatching), and day four (96 h post-hatching). We used RNA-seq followed by gene annotation to identify these genes and to evaluate differential gene expression. From day one after hatching, results showed the upregulation of cytochrome P450 and other genes that coded for enzymes capable of bio-transform xenobiotic compounds such as reductases, hydrolases, transferases and dehydrogenases. Additionally, a set of genes of the superfamily of ATP-binding cassette transporters became upregulated for cholesterol homeostasis and many others involved in detoxification and multidrug resistance of xenobiotics. We also analyzed genes involved in stress-responses (transcription factors) and genes that code for antioxidants proteins. However, none of them showed differential expression. Our study suggests an orchestrated and organized ontogenetic sequential upregulation of the defensome as a natural process to adapt to the environment, the regulation process of macronutrients, and a defensive metabolic response in case of encountering harmful xenobiotic compounds or toxins in food and water at the onset of exogenous feeding, which contributes to the understanding of the chemical defensome in early marine larval development.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-15"},"PeriodicalIF":3.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144650627","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":"<i>In vitro</i> effects of environmentally relevant concentrations of nonylphenol and selected pyrethroid metabolites on a mouse sertoli cell line (TM4).","authors":"Nthabiseng Kgabele Matjomane, Lisa Repsold, Sean Mark Patrick, Magdalena Catherina van Zijl, Michelle Helen Visagie, Natalie Hildegard Aneck-Hahn","doi":"10.1080/15376516.2025.2528100","DOIUrl":"10.1080/15376516.2025.2528100","url":null,"abstract":"<p><p>Advances in the chemical industry and increased environmental pollution have contributed to declining reproductive health. Many pollutants act as endocrine-disrupting chemicals (EDCs), with (anti-)estrogenic and (anti-)androgenic properties that disrupt hormonal balance and contribute to male reproductive dysfunction. Mouse Sertoli cells, which closely resemble human Sertoli cells, are targets for various environmental contaminants, making the cell line an ideal model for male reproductive toxicological studies. Sertoli cells (TM4) were exposed to environmentally relevant concentrations of EDCs, including cypermethrin, deltamethrin, rac-trans permethrinic acid, 3-phenoxybenzoic acid and <i>para</i>-nonylphenol (<i>p</i>-NP), for 24 h <i>in vitro.</i> Cytotoxicity was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, oxidative stress <i>via</i> an intracellular total reactive oxygen species (ROS) activity assay kit, and morphological changes <i>via</i> hematoxylin & eosin staining. The MTT assay revealed a moderate decrease (approximately 20% cell death) in cell viability. ROS levels were significantly higher in EDC-treated cells than in controls, with small effect sizes confirmed through Cohen's <i>d</i> analysis. Morphological changes, including membrane elongation, cytoplasmic vesicles, and reduced cell density, were most pronounced in <i>p-</i>NP-exposed cells. These findings suggest that exposure to pyrethroids and nonylphenol may induce toxicity in mouse Sertoli cells.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-10"},"PeriodicalIF":3.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561256","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":"Behavioral pharmacology and toxicology of dimethyl sulfoxide in <i>artemia</i> nauplii: vehicle or positive control?","authors":"Areeha Khalid, Matthew Pytynia, Sheila Cazares, Desiree K Batangan, Cassandra Repole, Andrew B Hawkey","doi":"10.1080/15376516.2025.2527160","DOIUrl":"10.1080/15376516.2025.2527160","url":null,"abstract":"<p><p>Dimethyl sulfoxide (DMSO) is a routinely used solvent in toxicology studies that are focused on toxicants with low natural solubility in water. However, prior research suggests that DMSO can alter neurological and behavioral outcomes under some circumstances, which could affect its suitability for neurotoxicology research. The current study evaluated the suitability of DMSO vehicles in an aquatic invertebrate model, <i>Artemia</i> nauplii. Subjects were exposed to solutions of 0.01-1% DMSO and assessed for mortality, motility, morphology, and recovery. In Experiment 1, 1-hr exposures significantly decreased swimming speed and increased rotation rates (0.01%, 1%) (slow, spiral swimming). In Experiment 2, 48-hr exposures suppressed swimming speed (0.1%, 1%), and path rotation (1%) (slower, non-spiral swimming), as well as body length (1%). In Experiment 3, following either 1-hr or 48-hr exposures to 1% DMSO, swimming speed and rotation rate persisted through 4-hr post-treatment, and recovered after a 24-hr washout period. Our results indicate that DMSO does affect motility and related behaviors in <i>Artemia</i> after 1- or 48-hr exposures, that these effects are reversible, and that progressive exposure to DMSO can alter the profile of effects. Consideration must be taken when determining what solvent to use when studying toxicants in aquatic species like <i>Artemia</i>.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"1-19"},"PeriodicalIF":3.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529681","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 effect of simvastatin induced neurotoxicity on mitochondrial function in human neuronal cells.","authors":"Lauren Millichap, Nadia Turton, Razan Alomosh, Robert A Heaton, Amy Bateman, Nasser Al-Shanti, Adam P Lightfoot, Elisabetta Damiani, Fabio Marcheggiani, Patrick Orlando, Sonia Silvestri, Luca Tiano, Iain P Hargreaves","doi":"10.1080/15376516.2025.2471807","DOIUrl":"10.1080/15376516.2025.2471807","url":null,"abstract":"<p><p>3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) inhibitors, commonly known as statins, are drugs frequently used in the treatment of hypercholesterolemia and hyperlipidemia. However, the current study has demonstrated that simvastatin induces neurotoxicity and is associated with cellular coenzyme Q₁₀ (CoQ₁₀) depletion. CoQ₁₀ has a significant role in the mitochondrial electron transport chain (ETC), in addition to being a fundamental lipid-soluble antioxidant. Depletion of CoQ₁₀ is frequently associated with impaired mitochondrial function and increased oxidative stress. The aim of this study was to investigate the potential mechanisms of simvastatin-induced neurotoxicity assessing mitochondrial function and evidence of oxidative stress in an <i>in vitro</i> SH-SY5Y human neuronal cell line. Fluorescence studies assessed <i>via</i> flow cytometry determined significant increases in intracellular and mitochondrial reactive oxygen species production following SH-SY5Y treatment with simvastatin compared to control cells. Additionally, spectrophotometric enzyme studies determined a significant (<i>p</i> < 0.0001) inhibition of ETC complex I and II-III activities which accompanied a significant decrease in neuronal CoQ₁₀ content (<i>p</i> < 0.005) and cell viability (<i>p</i> < 0.0001). The results of the present study have indicated evidence of mitochondrial dysfunction and increased oxidative stress, resulting in increased loss of neuronal viability following simvastatin treatment. Thus, these results demonstrate evidence of neurotoxicity associated with statin therapy.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":" ","pages":"592-603"},"PeriodicalIF":3.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543670","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}