Frontiers in toxicology最新文献

{"title":"Preventing regrettable substitutions: a proposal for a tiered testing approach for BPA alternatives under the PARC initiative.","authors":"Kiara Aiello-Holden, Kristina Bartmann, Franca Maria Buratti, Nicolas J Cabaton, Lucia Coppola, Emanuela Corsini, Antonio De la Vieja, Hubert Dirven, Maria Dusinska, Naouale El Yamani, Nina Franko, Johanna M Gostner, Nathalie Grova, Louise Gütter, Patricia Iglesias-Hernández, Martina Iulini, Anja Kodila, Yvonne Kohl, Gabriele Lori, Henriqueta Louro, Francesca Marcon, Sakina Mhaouty-Kodja, Archibold Mposhi, Lydie Naulé, Simonetta Palleschi, Barbara Rossi, Elise Rundén-Pran, Francesca Salani, Nicoletta Santori, Maria João Silva, Marija Sollner Dolenc, Emanuela Testai, Mónica Torres-Ruiz, Jonathan Turner, Catherine Viguié, Daniel Zalko, Sabrina Tait","doi":"10.3389/ftox.2026.1815869","DOIUrl":"10.3389/ftox.2026.1815869","url":null,"abstract":"<p><p>Bisphenol A (BPA) alternatives are increasingly used in the manufacture of industrial and consumer products, following regulatory restrictions on BPA. However, insufficient safety data on these substitutes raise concern as regards potential regrettable substitutions. Under the EU Partnership for the Assessment of Risks from Chemicals (PARC), Work Package 5 (WP5) addresses this challenge by applying a human-relevant tiered hazard assessment strategy grounded on OECD test guidelines as first tier and expanding the battery to include NAMs (New Approach Methodologies). Eight BPA alternatives were prioritized for studies addressing key toxicological endpoints, namely, endocrine disruption (ED), developmental neurotoxicity (DNT), immunotoxicity, genotoxicity and carcinogenicity and metabolic fate examination (detoxification vs. potential bioactivation), to enable early identification of biological activity and support cross-endpoint prioritization. This manuscript describes the structure and implementation of the testing framework. This integrated testing strategy proposes a structured approach to identify substances of potential concern, guide targeted higher-tier studies, and support regulatory prioritization. PARC WP5 framework is testing whether coordinated NAM-based methods may contribute to next-generation risk assessment and help prevent regrettable substitutions among BPA alternatives for rapid regulatory adoption. Detailed experimental results will be reported separately upon completion of the project.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1815869"},"PeriodicalIF":5.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13391043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148564022","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":"The role of mycotoxins in lipid metabolism and homeostasis: a systematic review.","authors":"Bernadett Csókay, Eszter Ruff, Zsuzsanna Szőke, Levente Sára, Balázs Komoróczy, Apolka Szentirmay, Márkó Unicsovics, Katalin Sára-Popovics, Dóra Holéci, Balázs Hamar","doi":"10.3389/ftox.2026.1870680","DOIUrl":"10.3389/ftox.2026.1870680","url":null,"abstract":"<p><strong>Background: </strong>Mycotoxins are widespread food contaminants that pose a significant global health concern. While their hepatotoxic, nephrotoxic, and carcinogenic effects are well established and characterized, their effects on adipose tissue biology and systemic lipid regulation remain incompletely understood. Given adipose tissue's central role in lipid homeostasis, endocrine regulation, and as a storage reservoir for adipophilic compounds, understanding these effects is critical.</p><p><strong>Methods: </strong>This systematic review was conducted in accordance with the PRISMA 2020 guidelines, and prospectively registered to PROSPERO (CRD42022287044). A comprehensive literature search was conducted in CENTRAL, Embase, and MEDLINE (PubMed) through 16 January 2026. Experimental <i>in vivo</i> and <i>in vitro</i> studies examining the effects of mycotoxins on adipose tissue, lipid metabolism, or mycotoxin distribution in fat tissue were included. Risk of bias in animal studies was assessed using the SYRCLE Risk of Bias Tool. A descriptive qualitative synthesis was performed.</p><p><strong>Results: </strong>Twenty-one experimental studies met the inclusion criteria. Across animal models, mycotoxin exposure consistently disrupted lipid homeostasis, leading to elevated serum triglyceride, cholesterol, LDL, and VLDL levels, alongside reduced HDL concentrations. These effects were mediated through toxin-specific mechanisms, including inhibition of <i>ppar</i>α signaling by aflatoxins and ochratoxin, suppression of <i>pparγ</i> by deoxynivalenol, and activation of <i>pparγ</i> by zearalenone. Mycotoxins also impaired adipokine secretion, with reduced leptin and adiponectin levels, and were associated with insulin resistance and altered glucose metabolism. Importantly, although mycotoxins are primarily metabolized in the liver, multiple studies demonstrated substantial accumulation and prolonged retention in adipose tissue, suggesting a secondary toxicokinetic reservoir.</p><p><strong>Conclusion: </strong>Mycotoxins exert significant, toxin-specific effects on lipid metabolism and adipose tissue function and may contribute to cardiometabolic dysfunction. Adipose tissue appears to play a key role in mycotoxin bioaccumulation, with potential implications for chronic exposure and delayed systemic toxicity.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1870680"},"PeriodicalIF":5.1,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148610695","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":"Aip mutation leads to significant alterations in gene expression, altered sensitivity to Ahr ligands, and early lethality in zebrafish.","authors":"Dante M Perone, Jane K La Du, Sibel I Karchner, Neelakanteswar Aluru, Spencer R Stinson, Lisa Truong, Mark E Hahn, Robyn L Tanguay","doi":"10.3389/ftox.2026.1875384","DOIUrl":"10.3389/ftox.2026.1875384","url":null,"abstract":"<p><p>Humans and other organisms are regularly exposed to chemical compounds that elicit toxicity through the aryl hydrocarbon receptor (AHR) signaling pathway. AHR agonists include polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and some natural products, pharmaceuticals, and endogenous compounds. Interindividual differences in sensitivity to AHR agonists exists. Several populations of Atlantic killifish (<i>Fundulus heteroclitus</i>) have independently evolved resistance to high levels of pollution. Genome-wide association studies suggested that variation in the AHR interacting protein (AIP) was associated with resistance to AHR ligands. AIP binds to AHR in the cytosol where it plays a role in stability and nuclear localization; however, its exact function is poorly understood. Two CRISPR-Cas9 generated <i>aip</i> mutant zebrafish (<i>Danio rerio</i>) lines were utilized. Homozygous mutants (<i>aip</i> ^<i>-/-</i> ) from either line died at 7-10-days post-fertilization (dpf), while no such effect is observed in <i>ahr</i> mutant lines. Larvae were exposed to four toxic AHR ligands from diverse chemical classes. <i>aip</i> ^<i>-/-</i> larvae exposed to PCB126, 5-nitroacenaphthene, and benzo(k) fluoranthene showed reduced sensitivity compared to both heterozygous (<i>aip</i> ^<i>+/-</i> ) and wildtype (<i>aip</i> ^<i>+/+</i> ) larvae. However, changes in sensitivity were ligand-dependent. In contrast, <i>aip</i> ^<i>-/-</i> larvae demonstrated increased sensitivity to leflunomide. mRNA sequencing was performed at five dpf on unexposed larvae of all genotypes from both mutant lines. Approximately 1,000 differentially expressed genes and alternative splicing products were observed in <i>aip</i> ^<i>-/-</i> larvae. Gene sets and transcription factor binding motifs involved in cellular stress, apoptosis, innate immune response, proteolysis, replication, and metabolism were enriched. Single-cell deconvolution of the bulk RNA-seq results was performed using MuSiC, which estimated transcriptomic contributions from 28 different cell types, with significant shifts in transcriptional abundance estimated for cell types from structural tissues of mesodermal origin, neural tissues, immune cells, and metabolic organs. Our findings highlight the context-dependent nature of Aip in Ahr modulation and the critical roles that Aip plays in regulating cellular homeostasis.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1875384"},"PeriodicalIF":5.1,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521517","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":"A systems-level integration of liver-kidney transcriptomics and genome-scale metabolic models reveals organ-specific injury mechanisms.","authors":"Venkat R Pannala, Archana Hari, Scott S Auerbach, Anders Wallqvist","doi":"10.3389/ftox.2026.1866643","DOIUrl":"10.3389/ftox.2026.1866643","url":null,"abstract":"<p><p>The liver and kidneys are the primary organs that clear chemicals from the body, yet they often exhibit different pathological responses to the same systemic exposure. While high-throughput transcriptomics (HTT) can map broad molecular perturbations, identifying the differential mechanisms that govern organ-specific injury remains a challenge. To address this knowledge gap, we investigated the dose-dependent effects of three peroxisome proliferator-activated receptor alpha agonists-coumarin, fenofibrate, and perfluorooctanoic acid (PFOA)-on liver and kidney metabolism to understand the organ-specific mechanisms of toxicity. We used HTT data from 5-day <i>in vivo</i> rat exposure studies and performed a comparative analysis on the paired liver and kidney data, using gene co-expression and pathway enrichment analyses together with genome-scale models, to investigate their differential sensitivity to chemical exposure. Our results revealed that all three chemicals caused larger gene perturbations in the liver compared to the kidney, in agreement with their well-known hepatotoxicity. Fenofibrate and PFOA triggered a profound upregulation in pathways related to fatty acid metabolism but suppressed several pathways related to amino acid metabolism in both organs. All three chemicals showed a strong upregulated antioxidant response in the liver, indicating an adaptive response to chemical stress, with fenofibrate and PFOA entering uncontrolled endoplasmic reticulum stress, which was also observed for PFOA in the kidney. Our comparative analysis revealed a striking divergence in cellular repair mechanisms in response to stress across both tissues: while the liver strongly upregulated apoptotic and cell-cycle repair pathways, signaling active hepatotoxicity, the kidney consistently downregulated these same vital processes in response to all three chemicals, indicating differential mechanisms that may lead to organ toxicity.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1866643"},"PeriodicalIF":5.1,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148521459","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":"Comparative cytotoxicity and genotoxicity of commercial glyphosate-based herbicide formulations and co-formulants in human leukocyte and hepatocyte cell lines.","authors":"Moustafa Sherif, Abderrahim Nemmar, Bassam R Ali, Khadija Makame, Károly Nagy, Balázs Ádám","doi":"10.3389/ftox.2026.1770738","DOIUrl":"10.3389/ftox.2026.1770738","url":null,"abstract":"<p><strong>Background: </strong>Risk assessments usually test active ingredients but not full commercial formulations. We compared cytotoxic and genotoxic effects of three glyphosate-based herbicides (Roundup Mega, Glyfos, Fozat-480) and two co-formulants (ROKAmin SR22, EMPIGEN BB) in human HL60 (leukocyte) and HepG2 (hepatocyte) cells.</p><p><strong>Methods: </strong>Cells were exposed for 1 h to increasing concentrations (0.1-10,000 μM depending on formulation). Cytotoxicity was measured by propidium iodide staining; genotoxicity was assessed by the alkaline comet assay (tail DNA %, tail length, tail moment, Olive tail moment). Positive (100 μM H₂O₂) and negative controls were included. Data are means of three independent experiments.</p><p><strong>Results: </strong>Cytotoxicity occurred at lower concentrations in HL60 than HepG2. Roundup Mega and Glyfos produced the strongest genotoxic responses; Roundup Mega increased tail length in HL60 from 0.1 μM, while Glyfos produced consistent genotoxicity in HepG2 from 100 μM. Co-formulants alone showed limited genotoxicity, though ROKAmin SR22 induced DNA% in tail at higher concentrations. Genotoxic effects often occurred at sub-cytotoxic concentrations.</p><p><strong>Conclusion: </strong>Commercial GBH formulations can be more genotoxic than the active ingredient alone; formulation composition influences potency and target-cell sensitivity. These results support formulation-specific testing to improve human health risk assessment.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1770738"},"PeriodicalIF":5.1,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13375184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474574","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 and clinical analysis of <i>Gelsemium</i> poisoning in Guangxi, Southern China: a decade of surveillance data.","authors":"Yanxu Zhong, Mengmeng Shi, Wei Mao, Huitian Deng, Xiaofeng Huang, Yuyan Jiang","doi":"10.3389/ftox.2026.1821880","DOIUrl":"10.3389/ftox.2026.1821880","url":null,"abstract":"<p><strong>Background: </strong><i>Gelsemium elegans</i> Benth, commonly known as \"duan chang cao\", is a highly toxic plant belonging to the family <i>Gelsemiaceae</i>. It is distributed in southern China with its potent toxicity poses a persistent threat to public health.</p><p><strong>Objective: </strong>This study aims to comprehensively characterize the epidemiology and clinical features of <i>Gelsemium</i> poisoning in Guangxi, Southern China, based on surveillance data, in order to provide an evidence-based foundation for timely and effective prevention and control measures.</p><p><strong>Methods: </strong>A secondary analysis was conducted on 10 years of <i>Gelsemium</i> poisoning surveillance data (2015-2024) from Guangxi. Descriptive statistics were applied to summarize epidemiological patterns and clinical manifestations.</p><p><strong>Result: </strong>From 2015 to 2024, <i>Gelsemium</i> poisoning in Guangxi showed a high but fluctuating mortality rate, peaking at 100% in 2015. The highest mortality risk (19.0%) occurred in individuals aged 20-59 years. Cases clustered geographically in Chongzuo, Yulin, Guigang, Qinzhou, and Laibin, with incidence peaking in autumn. Alcohol infusion was the leading cause of fatal poisoning (29.5%), mainly in household and rural banquet settings. Consumption of the rhizome resulted in the highest death rate (21.1%). Dizziness and blurred vision were common clinical symptoms. Significant differences in incidence, hospitalization, and mortality rates were observed based on location, season, cooking method, source part, and misidentification (<i>P</i> < 0.05).</p><p><strong>Conclusion: </strong>Enhancing surveillance, food safety regulations, and targeted health education plays a key role in preventing <i>Gelsemium</i> poisoning. Establishing strong monitoring and quick intervention systems may further reduce its impact.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1821880"},"PeriodicalIF":5.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457914","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":"Biomarker selection and reporting architecture in human proximal tubular <i>in vitro</i> models of cisplatin-induced nephrotoxicity: a systematic review.","authors":"María Gabriella Rodríguez-Marcano, Ornella Pierucci, Jesús Romero Lugo","doi":"10.3389/ftox.2026.1862941","DOIUrl":"10.3389/ftox.2026.1862941","url":null,"abstract":"<p><p>Cisplatin-induced acute kidney injury remains a major dose-limiting complication in oncology. Human proximal tubule <i>in vitro</i> models are widely used to investigate nephrotoxic mechanisms; however, biomarker selection and reporting patterns vary considerably across studies. This PRISMA-guided systematic review aimed to characterize the frequency, biological categorization, and co-reporting patterns of biomarkers used in human proximal tubule <i>in vitro</i> models of cisplatin-induced injury. A systematic search of PubMed, Scopus, and Web of Science identified experimental <i>in vitro</i> studies published between 2014 and 2024 that reported quantifiable biomarkers following cisplatin exposure. Biomarkers were classified into predefined structural injury, regulated cell death, and mechanistic categories. Descriptive frequency analyses were performed, and co-occurrence relationships among the 12 most frequently reported biomarkers were evaluated using a binary presence-absence matrix. Fifty-eight studies met inclusion criteria. Kidney injury molecule-1 was the most frequently reported structural biomarker. Mechanistic endpoints, particularly oxidative stress and intracellular signaling markers, predominated over structural injury markers. Co-reporting analysis revealed recurrent pathway-oriented groupings, suggesting hypothesis-driven panel selection rather than standardized implementation across studies. These findings highlight the need for improved harmonization and structured biomarker strategies to enhance reproducibility, predictive robustness, and translational alignment in vitro nephrotoxicity research.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1862941"},"PeriodicalIF":5.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457978","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":"Phenotypic and functional characterization of THP-1-derived macrophages: impact of serum and serum-free differentiation conditions on surface marker expression and immune function.","authors":"Nour Attar, Naila Rajabli, Aline Chary, Charlotte B A Stoffels, Tommaso Serchi, Pamina Weber","doi":"10.3389/ftox.2026.1843205","DOIUrl":"10.3389/ftox.2026.1843205","url":null,"abstract":"<p><strong>Introduction: </strong>Macrophages are essential components of the innate immune system, involved in inflammation and host defense. However, primary human macrophages are limited by availability, donor variability, and ethical constraints. The THP-1 human monocytic leukemia cell line is a practical alternative due to its high expansion capacity, ease of culture, and ability to acquire a macrophage-like phenotype using stimulation agent such as phorbol 12-myristate 13-acetate (PMA). To date, most laboratories generate macrophage-like cells by differentiating THP-1 cells, yet protocols vary widely between laboratories. Currently, the impact of differentiation conditions on both surface marker expression and the functional profile of macrophages remain poorly understood. Factors such as serum supplementation, PMA concentration, exposure duration, resting time, and seeding density can significantly influence macrophage behaviour.</p><p><strong>Methods: </strong>In this study, we characterized the phenotype and functionality of THP-1-derived macrophages under different differentiation conditions, with or without serum supplementation. Phenotype was assessed by flow cytometry, and functionality was evaluated through responses to the reference multi-walled carbon nanotube NM-401 following exposure using the VITROCELL® PowderX system for accurate aerosolization. Phagocytic activity was quantified using fluorescence measurements and further characterized through confocal microscopy. Inflammatory responses were assessed by measuring cytokine secretion following lipopolysaccharide (LPS) stimulation.</p><p><strong>Results and discussion: </strong>Our findings demonstrate that differentiation conditions influence the phenotype and functional responses of THP-1-derived macrophages and highlight the importance of optimizing differentiation protocols to achieve consistent and reproducible outcomes, supporting the development of standardized, animal-free in vitro toxicity testing.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1843205"},"PeriodicalIF":5.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13368413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450943","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":"Developmental toxicity and physicochemical characterization of cisplatin-loaded ginger oil nanoemulsion in casper zebrafish.","authors":"A N K V Sravani, John Thomas","doi":"10.3389/ftox.2026.1862521","DOIUrl":"10.3389/ftox.2026.1862521","url":null,"abstract":"<p><strong>Introduction: </strong>This study used Casper zebrafish embryos and larvae as a model to examine the creation and safety evaluation of a cisplatin-loaded ginger essential oil nanoemulsion (Cisp-GE-NE).</p><p><strong>Methods: </strong>The Cisp-GE-NE was made using an oil-in-water ultrasonic dispersion technique with Tween 80, and it was characterised using FTIR analysis, DLS, zeta potential, and UV-visible spectroscopy. A sustained release of cisplatin was noted at pH values of 3.5, 5.5, and 7.4.</p><p><strong>Results: </strong>With LC50 values of 5.3 μg/mL, 14.4 μg/mL, and 3.7 μg/mL, zebrafish embryos exposed to different concentrations of Cisp-GE-NE showed decreased epiboly progression, morphological abnormalities, and significant mortality. Spinal curvature, pericardial oedema, smaller eyes, reduced swim bladder inflation, and decreased body length were among the most notable larval defects. Neurodevelopmental toxicity was indicated by behavioural studies that revealed different swimming patterns in light and dark environments.</p><p><strong>Discussion and conclusion: </strong>The results draw attention to the possible toxicity of nanoemulsion systems based on ginger oil and stress the significance of conducting a safety assessment before their use in clinical or environmental settings.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1862521"},"PeriodicalIF":5.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13368485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148457987","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":"Modular <i>in vitro</i> evaluation of buparlisib-polymeric nanomedicines in 2D and 3D models of glioblastoma.","authors":"Jarmila Havelkova, Yuriy Petrenko, Anna Stehlikova, Dana Marekova, Katerina Peskova, Michal Pechar, Martin Studenovsky, Tomáš Etrych, Robert Pola, Pavla Jendelova","doi":"10.3389/ftox.2026.1783704","DOIUrl":"10.3389/ftox.2026.1783704","url":null,"abstract":"<p><strong>Introduction: </strong>In this study, we developed a modular in vitro platform that integrates advanced polymer-drug conjugation chemistry with stepwise cytotoxicity screening in both 2D (monolayer) and 3D (spheroids) glioblastoma (GBM) models. Buparlisib was selected as the model therapeutic agent due to its well-characterised mechanism of action, high blood-brain barrier permeability, and relevance to PI3K-targeted therapy.</p><p><strong>Methods: </strong>Two mechanistically distinct conjugation strategies were explored using N-(2-hydroxypropyl)methacrylamide-based copolymers (pHPMA). The first strategy was based on a redox-sensitive disulphide linkage designed for intracellular glutathione-triggered release, whereas the second used an azide-bearing derivative compatible with strain-promoted azide-alkyne cycloaddition. Drug release was assessed by high-performance liquid chromatography. Biological activity was systematically evaluated in U87MG, U118MG, and T98G cells under 2D conditions using a resazurin-based metabolic activity assay. Subsequently, the more promising disulphide-based formulations were assessed in 3D spheroids by metabolic activity measurements and live-cell monitoring of spheroid growth dynamics.</p><p><strong>Results: </strong>Free buparlisib showed the strongest inhibitory effect, while its modification and polymer conjugation reduced the apparent activity. Nevertheless, the disulphide-based derivative and polymer conjugate retained concentration-dependent activity, whereas the azide-based polymer conjugate showed minimal effects. Moreover, treatment responses differed between cell lines and between 2D and 3D models.</p><p><strong>Discussion: </strong>Overall, linker chemistry, cell-line-specific behaviour, and model dimensionality strongly influenced the biological performance of the polymeric buparlisib formulations. The redox-sensitive polymer conjugate therefore represents the more promising strategy for further development.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"8 ","pages":"1783704"},"PeriodicalIF":5.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450976","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}