Frontiers in toxicology最新文献

{"title":"Determining a NOAEL for the consortium linking academic and regulatory insights on BPA toxicity (CLARITY-BPA) core study.","authors":"Melissa Badding, Noor Aly, Kevin Sondenheimer","doi":"10.3389/ftox.2025.1639737","DOIUrl":"10.3389/ftox.2025.1639737","url":null,"abstract":"<p><p>The CLARITY-BPA Core Study is the most comprehensive animal study of oral bisphenol A (BPA) exposure to date. Rats were exposed daily, <i>in utero</i> until postnatal day 21 or for the animals' lifetime. While the study authors concluded that several observations at the highest dose may be BPA treatment-related, a No-Observed-Adverse-Effect Level (NOAEL) has not been proposed in the published reports. Therefore, select endpoints deemed by the study authors to be potentially BPA treatment-related were further evaluated to determine a NOAEL. These include findings in the female reproductive tract and male pituitary gland at the highest dose level (25,000 μg/kg-bw/day). The data were examined for dose-response, relevance, and consistency of findings across study arms and timepoints, histopathological progression, and concordance with the estradiol positive control. Based on our evaluation, some of the female reproductive tract findings are possibly BPA treatment-related. However, there is a lack of consistency between study arms and/or timepoints, no significant dose-response, and a lack of progression to tumors for proliferative findings. Finally, the findings from the Core Study agree with previous high-quality guideline studies which determined that BPA did not pose adverse effects at doses below 25,000 μg/kg-bw/day in rodents. Altogether, some findings from the Core Study may be BPA treatment-related but they should not be considered adverse. Therefore, we hypothesize that the NOAEL from the Core Study is reasonably considered to be 25,000 μg/kg-bw/day.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1639737"},"PeriodicalIF":4.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of a novel questionnaire for assessing occupational exposure to organophosphate pesticides in Chilean agricultural workers.","authors":"Liliana Zúñiga-Venegas, Natalia Landeros, Floria Pancetti, Sandra Cortés, Boris Lucero, Ana M Brito, Ian S Acuña-Rodríguez, María Teresa Muñoz-Quezada","doi":"10.3389/ftox.2025.1588408","DOIUrl":"10.3389/ftox.2025.1588408","url":null,"abstract":"<p><strong>Background: </strong>Unintentional pesticide poisoning is a global health concern, disproportionately affecting agricultural workers in developing countries due to inadequate regulations and limited access to protective equipment. While questionnaires offer a cost-effective alternative for assessing organophosphate (OP) pesticide exposure compared to urinary (e.g., Dialkyl Phosphates, DAPs) or blood biomarkers (e.g., acetylcholinesterase, AChE, and butyrylcholinesterase, BChE), these tools require validation against gold-standard methods. This study validated a questionnaire assessing occupational OP exposure among Chilean agricultural workers in the Maule region, contrasting its performance against DAP levels and AChE and BChE inhibition.</p><p><strong>Methods: </strong>A longitudinal study was conducted with 51 agricultural workers. Urinary DAPs, measured via liquid chromatography-tandem mass spectrometry, AChE, and BChE activities, determined by Ellman's method, were measured before (T0) and during (T1) the spray season. The questionnaire was administered at T1. Sensitivity, specificity, predictive values, and Receiver Operating Characteristic (ROC) curve analyses were performed to assess the accuracy.</p><p><strong>Results: </strong>Urinary DAP levels and AChE inhibition increased in T1 (from 6.54 ± 4.66 to 12.39 ± 9.88 μg/g creatinine, <i>p</i> = 0.004, and from 2.26E-3±6.53E-4 to 1.44E-3±2.73E-4 mmol/min^-1*mgProt^-1, <i>p</i> < 0.001, respectively), with AChE inhibition (30.99%) exceeding Chilean regulatory threshold. The questionnaire score correlated with AChE inhibition (<i>p</i> = 0.0063) but not with BChE inhibition or DAP levels. Sensitivity was 64%, and specificity improved from 56% to 71% when using a 20% AChE inhibition threshold instead of a 30%.</p><p><strong>Conclusion: </strong>Agricultural workers in the Maule region are exposed to OP pesticides. The questionnaire shows potential as a screening tool for occupational exposure. These findings highlight the need to reassess the Chilean regulatory limits and refine the tool to enhance risk assessment and intervention planning.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1588408"},"PeriodicalIF":4.6,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12399619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of heated herbal products' tobacco harm reduction potential: pre-clinical and clinical studies.","authors":"Alvaro-Flavio Marinas-Lacasta, Ian M Fearon, Matthew Stevenson, Tasnim Abusalem, Fiona Chapman, Edgar Trelles Sticken, Roman Wieczorek, Sarah Jean Pour, Ole Dethloff, Ourania Komini, Mike Brown, Liam Simms, Thomas Nahde","doi":"10.3389/ftox.2025.1589480","DOIUrl":"10.3389/ftox.2025.1589480","url":null,"abstract":"<p><p>Data from pre-clinical and clinical studies form part of an integrated assessment of the tobacco harm reduction (THR) potential of novel products that may act as cigarette alternatives for adult smokers. We report data from pre-clinical (emissions chemistry and <i>in vitro</i> toxicology) and clinical (nicotine pharmacokinetics and subjective effects) studies conducted with the iSENZIA™ heated herbal system (HHS; PULZE™ 2.0 device with iSENZIA™ sticks), which utilizes electronic heating of a tea-based substrate to generate an inhalable nicotine-containing aerosol. The aerosols from the iSENZIA™ HHS contained significantly lower levels, by up to 99.8%, of the nine World Health Organization Study Group on Tobacco Product Regulation (WHO TobReg) analytes compared with 1R6F reference cigarette smoke and elicited significantly lower <i>in vitro</i> cytotoxicity, genotoxicity, and mutagenicity responses. The clinical study demonstrated that the iSENZIA™ HHS delivers satisfactory levels of nicotine to users and has lower abuse liability than cigarettes. Overall, our data suggest that iSENZIA™ has the potential to offer substantially reduced toxicant exposure, as well as a reduction in toxicity, compared to cigarettes, while delivering satisfactory levels of nicotine. These findings support the THR potential of the iSENZIA™ HHS as a reduced-risk, acceptable alternative product for adult smokers.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1589480"},"PeriodicalIF":4.6,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering exposome-related diseases through the pathologic metallome: a novel approach for clinical populations.","authors":"Riccardo Leinardi, François Huaux","doi":"10.3389/ftox.2025.1625874","DOIUrl":"10.3389/ftox.2025.1625874","url":null,"abstract":"<p><p>Environmental exposure to complex metal mixtures plays a critical role in the onset and progression of diverse chronic diseases, in ways that the traditional toxicological framework fails to capture. A paradigm shift is underway, moving toward a more integrated understanding of combined metal effects through the interdisciplinary study of the metallome, the distribution of metal ions and metalloids within a biological system. In this perspective, we highlight the clinical importance of metallome to identify specific subpopulations in which disease onset or progression is primarily driven by environmental metal exposure rather than genetic predisposition. To achieve this goal, robust and sensitive analytical methods are required to overcome the limitations of conventional approaches and enable the detection of the full spectrum of metal species, including metals sequestered within mineral particles present in body fluids and tissues. We propose methodological innovations in sample preparation and analysis that expand the current scope of metallome-associated research. Together, these advances support a comprehensive framework for assessing metal mixture effects in environmental health, bridging toxicology with clinical practice and enabling more targeted, exposure-informed public health interventions.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1625874"},"PeriodicalIF":4.6,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fetal bovine serum: how to leave it behind in the pursuit of more reliable science.","authors":"Tilo Weber, Atena Malakpour-Permlid, Aline Chary, Vito D'Alessandro, Leah Haut, Sebastian Seufert, Esther Veronika Wenzel, James Hickman, Karen Bieback, Joachim Wiest, Wilhelm Gerhard Dirks, Sandra Coecke, Stina Oredsson","doi":"10.3389/ftox.2025.1612903","DOIUrl":"10.3389/ftox.2025.1612903","url":null,"abstract":"<p><p>Cell cultures form the backbone for scientific research and development, but also for clinical diagnostics and biotechnology. Supplying cells <i>in vitro</i> with growth factors, hormones, and other nutrients is achieved most often by supplementing culture media with fetal bovine serum (FBS). Despite its nearly ubiquitous use, there are major reproducibility, safety, and animal welfare issues arguing the need to replace FBS. Fortunately, numerous FBS replacements have been validated and are publicly or commercially available, making it possible to leave FBS behind. Successful serum-free, animal-component-free, and chemically defined media applications are highlighted in this review for the cultivation of stem cells and organoids, the development of organ-on-a-chip systems, the bioprinting of tissues, and the production of cultivated meat, antibodies, and vaccines, including the conduct of cytotoxicity tests and the cryopreservation of cells. Moreover, the use of fully animal-free models and methodologies is further discussed to promote their broader acceptance and adoption within the global scientific research and development community. In this regard, this review discusses novel avenues to address the scientific and practical hurdles that might limit a full transition from FBS to fully defined cell culture media and offers a brief perspective on potential future directions.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1612903"},"PeriodicalIF":4.6,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12371577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidemiological investigation of venomous snakebites in Yunnan Province.","authors":"Qinfen Gao, Yajun Teng, Chao Xiao, Rui Zeng, Bin Han, Hong Gao, Jianhai Wang, Xiaoyan Li, Canju Yang, Jianneng Dai, Chunxi Li, Qunyan Huang, Zengzheng Li, Wei Zhang","doi":"10.3389/ftox.2025.1609487","DOIUrl":"10.3389/ftox.2025.1609487","url":null,"abstract":"<p><strong>Background: </strong>Snakebite envenoming constitutes a substantial public health concern worldwide. Yunnan Province, The lack of comprehensive epidemiological data on snakebite in Yunnan affects research, diagnostic, and treatment advancements. This research evaluates patient demographics, seasonal patterns, snake species associated with the disease, and treatment approaches to guide preventative and therapeutic initiatives in the province.</p><p><strong>Methods: </strong>This retrospective analysis reviewed clinical records of venomous snakebite cases admitted to hospitals in 16 cities within Yunnan Province from January 2022 to November 2024. Collected data covered diverse aspects, including patient demographics (age, sex), circumstances of the bite (location, size, and time), species identification, observed clinical symptoms, treatments administered (e.g., antivenin and alternative therapies), and hospital stay duration. Subsequently, the effect of different therapeutic measures on these patients' hospital stays was analyzed.</p><p><strong>Results: </strong>A total of 2,112 venomous snakebite cases were recorded, with incidence rates rising annually: 406/46.73 million in 2022, 825/46.73 million in 2023, and 886/46.73 million in 2024. <i>Ovophis</i> (52.08%) and <i>Trimeresurus</i> (28.74%) species were predominant. These findings align with the annual distribution of anti-venom serum administered to affected individuals. Most incidents occurred during June to September, primarily in mountainous and forested areas or paddy fields, comprising approximately 52.40% of the total cases. Nearly all bites (99.05%) were localized to the limbs, presenting with swelling and pain as the dominant clinical features. Statistical analysis revealed that factors such as incision and debridement, additional anti-venom serum, fibrinogen supplementation, plasma administration, Ji Desheng Snake Medicine, and magnesium sulfate compresses were significantly associated with extended hospital stays (<i>P</i> < 0.05).</p><p><strong>Conclusion: </strong>Snake bites in Yunnan Province mainly affect young and middle-aged agricultural workers in rural and mountainous areas. The predominant venomous snakes in the area are hemotoxic. The findings emphasize the necessity of early intervention with antivenom and adjunctive therapies, including fibrinogen and plasma administration. Delays in getting medical help or improper treatment can lead to longer hospital stays.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1609487"},"PeriodicalIF":4.6,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12364869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refinement of a workflow for human relevance assessment of adverse outcome pathways and associated new approach methodologies.","authors":"Annick D van den Brand, Julia J Meerman, Christina H J Veltman, Mirjam Luijten","doi":"10.3389/ftox.2025.1616817","DOIUrl":"10.3389/ftox.2025.1616817","url":null,"abstract":"<p><p>In chemical risk assessment the human relevance of adverse health effects observed in experimental animal studies and the underlying toxicological mechanisms, i.e., adverse outcome pathways is often assumed, unless evidence suggests otherwise. Yet, detailed systematic guidance as to how human relevance of perturbed AOPs should be assessed and which data or information should be considered is lacking. Building on previous work we present a refined workflow for human relevance assessment of AOPs and associated new approach methodologies The updated workflow structurally defines the required information for assessing the human relevance of the AOP by means of biological and empirical considerations. Furthermore, the modified workflow better guides assessment of the relevance of NAMs. This is of importance for the use of NAM data in human health risk assessment. In addition, we suggest an approach for weight of evidence assessment by integrating the different lines of evidence. The refined workflow is now accompanied by developed guidance and templates as well as an expanded toolbox, i.e., a list of information sources, to further facilitate application of the workflow. Finally, remaining issues and challenges are discussed. This work is a next step towards to the ultimate goal of a harmonized, structured and transparent approach for human relevance assessment of AOPs and associated NAMs.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1616817"},"PeriodicalIF":4.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12392633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: Successful management of severe suicidal lamotrigine overdose-induced status epilepticus with sustained low-efficiency dialysis.","authors":"Naoki Kawahara, Hiroki Matsui, Koji Morishita","doi":"10.3389/ftox.2025.1622752","DOIUrl":"10.3389/ftox.2025.1622752","url":null,"abstract":"<p><strong>Introduction: </strong>Lamotrigine, a common antiepileptic, typically has a favorable safety profile. However, an overdose can lead to severe central nervous system complications, including refractory status epilepticus. The optimal management of severe overdose with refractory status epilepticus remains uncertain, and the role of extracorporeal removal methods, such as blood purification, has not been fully established.</p><p><strong>Case description: </strong>A 20-year-old female with bipolar disorder presented with altered consciousness and status epilepticus 7 h after ingestion of 4.9 g of lamotrigine. As a case of lamotrigine intoxication, initial management with gastric lavage, activated charcoal, benzodiazepines, and levetiracetam failed to control the seizures, and the patient required continuous midazolam and ventilation. Slow low-efficiency dialysis (SLED) was initiated 18 h after admission. Lamotrigine levels substantially decreased from 33.9 to 13.5 μg/mL within 5 h post-SLED, representing a 60.2% reduction. The patient showed marked neurological improvement, with seizure cessation, allowing for discontinuation of midazolam. She was extubated on day 4 and discharged on day 7 with full recovery.</p><p><strong>Discussion: </strong>This case highlights the successful use of SLED in severe lamotrigine overdose-induced refractory status epilepticus. The correlation among SLED use, reduced lamotrigine levels, and clinical improvement suggests that blood purification may be beneficial in severe toxicity, especially in patients with status epilepticus. This adds to the evidence supporting blood purification for accelerated drug removal and improved outcomes in select severe cases. Prompt recognition of this potentially life-threatening condition and consideration of intensive care, including blood purification, are vital for successful management.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1622752"},"PeriodicalIF":4.6,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12350258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144877057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research on the impact of graphene oxide in feed on growth and health parameters in calves.","authors":"Tereza Aulichova, Sylvie Skalickova, Kopec Tomas, Pompido Chilala, Pavel Horky","doi":"10.3389/ftox.2025.1560078","DOIUrl":"10.3389/ftox.2025.1560078","url":null,"abstract":"<p><p>Mycotoxins, as feed contaminants, pose serious health risks and cause significant economic losses on farms. The selection of an appropriate and effective adsorbent remains a key challenge for many researchers. Graphene oxide (GO) and its derivatives have garnered interest due to their exceptional physicochemical properties. However, the increasing use of GO necessitates a thorough investigation into its potential toxic impacts on animal and human health, as well as the environment. This study evaluates the effects of GO as a feed additive on calf health. Ten calves (100 ± 6 kg) participated in a 20-day experiment: five in the control group (C) and five in the experimental group (T). The control group (C) received feed without GO, while the experimental group (T) was fed a diet containing 30 g of GO/kg/day. Key parameters evaluated included growth performance, biochemical markers (ALT, AST, ALP), and mineral levels (Ca, P, Mg, K, Na, Cl, Fe, Cu, Zn). The average weight gain was 16.20 ± 0.32 kg in the control group and 15.40 ± 0.26 kg in the GO group, with no statistically significant difference (p > 0.05). Calves fed GO-enriched feed exhibited significant reductions in Fe (p = 0.041) and Zn (p = 0.0006) levels, while Mg increased significantly in the control group (p = 0.029). Liver parameters in group T showed significant increases in ALT (p = 0.022), AST (p = 0.027), and ALP (p = 0.015) after 20 days. Additionally, GPx activity was significantly decreased in the GO group (p = 0.011). These results suggest that GO at a dose of 30 g/kg/day in feed can negatively affect calf health.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1560078"},"PeriodicalIF":4.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cadmium decreases human gingival fibroblast viability and induces pro-inflammatory response associated with Akt and MAPK pathway activation.","authors":"Tipparat Parakaw, Sirada Srihirun, Nathawut Sibmooh, Nisarat Ruangsawasdi, Phisit Khemawoot, Pornpun Vivithanaporn","doi":"10.3389/ftox.2025.1583865","DOIUrl":"10.3389/ftox.2025.1583865","url":null,"abstract":"<p><p>Smoking and particulate matter 2.5 (PM2.5) expose millions to cadmium (Cd), a toxic heavy metal linked to pro-inflammatory responses, oxidative stress, and disease pathogenesis. In the oral cavity, chronic Cd exposure contributes to the progression of periodontal diseases and oral cancers. However, the direct effect of Cd on oral tissues and the underlying mechanisms remains unclear. This study explored the impact of environmentally relevant concentrations of Cd on human gingival fibroblasts (HGFs) by evaluating cell viability, pro-inflammatory cytokine secretion (IL-6 and IL-8), COX-2 expression, and the activation of key signaling pathways: Akt, ERK1/2, and JNK. Cd exposure significantly reduced HGF viability, elevated IL-6 and IL-8 secretion, and upregulated COX-2 expression. These effects were attenuated by inhibitors targeting Akt, ERK1/2, and JNK pathways. By integrating cytokine profiling, COX-2 expression, and inhibitor-based pathway analysis, our study provides mechanistic insights into how low-level Cd exposure triggers early inflammatory responses in gingival fibroblasts. Our findings reveal that Cd exerts pro-inflammatory and cytotoxic effects on HGFs, which may play a role as one of the factors in the pathogenesis of smoking-related oral diseases. Targeting Akt, ERK1/2, and JNK signaling pathways could offer therapeutic strategies to attenuate Cd-induced oral pro-inflammatory responses and tissue damage.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1583865"},"PeriodicalIF":4.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12325209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144796215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}