Frontiers in toxicology最新文献

{"title":"Environmental exposure pathways of microplastics and their toxic effects on ecosystems and the nervous system.","authors":"Kuo Lu, Yixiang Que, Longfei Wang, Yanfan Wang, Jinyan Qiu, Yangyang Jia, Cong Ding, Dazhong Wang, Weyland Cheng, Yaodong Zhang","doi":"10.3389/ftox.2025.1649282","DOIUrl":"10.3389/ftox.2025.1649282","url":null,"abstract":"<p><p>Microplastics are a troubling consequence of modern civilization, permeating ecosystems worldwide and posing a risk to both the environment and human health. As studies have revealed their extensive distribution throughout bodies of water, soil, and the atmosphere, the ecological crisis and health issues linked to microplastics have become a significant concern within the global scientific community. These tiny particles can enter the human body through various routes, including ingestion, inhalation, and even skin contact, and they have been shown to cross critical barriers such as the placental and blood-brain barriers. Their accumulation in the food chain disrupts the delicate balance of ecosystems and may impair cognitive function and behavioral patterns in living organisms. Alarmingly, there is increasing evidence suggesting that microscopic particles may contribute to the increasing rates of neurodegenerative diseases. This paper reviews the pathways through which microplastics are ingested, their effects on biological functions, and the potential mechanisms that contribute to their neurotoxicity. We emphasize the urgent need for further research to elucidate the toxicological impacts of microplastics and devise effective strategies for mitigating their effects on both ecosystems and human health.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1649282"},"PeriodicalIF":4.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12491214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234216","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":"Error-corrected next-generation sequencing mutagenicity assays in human HepaRG cells as human-relevant genetic toxicology new approach methodology.","authors":"A Rasim Barutcu, Nimisha Bhattarai, Raymond Samuel, Jamie Scaglione, Leslie Recio","doi":"10.3389/ftox.2025.1657189","DOIUrl":"10.3389/ftox.2025.1657189","url":null,"abstract":"<p><p>Human metabolically competent HepaRG™ (HepaRG) cells have been developed as a human-relevant New Approach Methodology (NAM) in genetic toxicology, providing a non-animal alternative to rodent-based mutagenicity testing following a positive Ames test. Error-corrected next-generation sequencing (ecNGS) offers improved sensitivity, specificity, and mechanistic insight in genotoxicity and mutagenicity assessment.</p><p><strong>Methods: </strong>We applied duplex sequencing, an ecNGS approach, to quantify chemically induced point mutations in metabolically competent HepaRG cells. Cells were exposed to a diverse panel of genotoxic agents, including ethyl methanesulfonate (EMS), N-ethyl-N-nitrosourea (ENU), benzo[a]pyrene (BAP), cisplatin, cyclophosphamide, and etoposide. Mutation frequency, substitution patterns, and mutational signatures were analyzed, and results were compared with complementary cytogenetic endpoints.</p><p><strong>Results: </strong>Duplex sequencing detected dose-responsive increases in mutation frequency for ENU and EMS, with distinct substitution patterns consistent with alkylating mechanisms. BAP and cisplatin induced modest increases in mutation frequency and C>A-enriched spectra, while cyclophosphamide yielded minimal mutagenicity under the tested conditions. Etoposide triggered strong cytogenetic responses without increasing point mutations, consistent with its clastogenic mode of action. COSMIC mutational signature analysis revealed modest enrichment of SBS4 (BAP), SBS11 (EMS), and SBS31/32 (cisplatin), supporting the mechanistic relevance of the model.</p><p><strong>Discussion: </strong>These findings demonstrate the reproducibility and specificity of ecNGS for detecting low-frequency point mutations and characterizing mutational mechanisms. When combined with complementary cytogenetic assays, duplex sequencing enables a more complete and human-relevant evaluation of genotoxic potential. This study supports the integration of ecNGS into next-generation genotoxicity testing strategies as a NAM for regulatory decision-making.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1657189"},"PeriodicalIF":4.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202219","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":"Daflon and Centrum mitigate vancomycin-induced nephrotoxicity in rats by ameliorating oxidative stress, DNA damage, apoptosis, and inflammation.","authors":"Hanem F El-Gendy, Soaad Salamah, Eman Elhusseiny, Hazim O Khalifa, Hossny A El-Banna, Taha A Attia, Shaimaa Selim, Saber El Hanbally","doi":"10.3389/ftox.2025.1673083","DOIUrl":"10.3389/ftox.2025.1673083","url":null,"abstract":"<p><strong>Background: </strong>Vancomycin (VM) is widely used for treating life-threatening infections caused by Gram-positive bacteria resistant to other antibiotics. However, its nephrotoxic effects limit clinical use.</p><p><strong>Objective: </strong>This study aimed to evaluate the protective effects of Daflon (DF) and Centrum (CE) against VM-induced nephrotoxicity in male rats.</p><p><strong>Methods: </strong>Fifty healthy male Wistar rats were randomly divided into five groups. Group 1 (negative control) received saline intraperitoneally (IP) for 7 days followed by oral distilled water for 7 days. Group 2 (positive control) received VM (400 mg/kg BW, IP) for 7 days. Group 3 received VM for 7 days followed by DF (100 mg/kg BW, oral) for 7 days. Group 4 received VM for 7 days followed by CE (15 mg/kg BW, oral) for 7 days. Group 5 received VM for 7 days followed by combined DF and CE treatment for 7 days. Blood and kidney samples were collected for hematological, biochemical, molecular, comet assay, and histopathological evaluations.</p><p><strong>Results: </strong>VM administration significantly elevated serum creatinine, urea, and uric acid levels (p < 0.01), increased renal malondialdehyde (MDA), and reduced catalase (CAT) and superoxide dismutase (SOD) activities (p < 0.05). It also induced marked histological changes and increased DNA fragmentation. DF and CE, particularly in combination (Group 5), significantly reduced renal injury, DNA fragmentation, and histopathological alterations. The protective effect followed the order: G5 > G4 > G3 > G2. Furthermore, VM upregulated <i>PARP1, RIP1, KIM1, TNF-α, and IL-1β</i> expression, which were markedly downregulated by DF and CE.</p><p><strong>Conclusion: </strong>DF and CE attenuated VM-induced nephrotoxicity through antioxidant, anti-inflammatory, and DNA-protective mechanisms. Their combination provided superior renal protection by reducing oxidative stress, inflammation, and apoptosis, while enhancing antioxidant defenses and DNA repair capacity.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1673083"},"PeriodicalIF":4.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202238","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":"Mercury exposure leading to functional vitamin B12 deficiency and subacute combined degeneration: a case report and literature review.","authors":"Isidora Semnic, Valentino Rački, Olivia Perković, Vladimira Vuletić","doi":"10.3389/ftox.2025.1580275","DOIUrl":"10.3389/ftox.2025.1580275","url":null,"abstract":"<p><strong>Introduction: </strong>The association between neurological symptomatology and heavy metal exposure has been reported in the literature. A few cases of extrapyramidal symptomatology and subacute combined degeneration have been described as manifestations of mercury intoxication. We highlight a case of a patient presenting with Parkinsonian features (tremor, rigidity, and bradykinesia), pyramidal deficits, dysarthria, paresthesia, mild cognitive decline, and emotional lability, with proven elevated mercury levels in blood and hair and elevated arsenic in urine.</p><p><strong>Case: </strong>A 60-year-old man, with history of mercury exposure while working at the Centre for Waste Management and Environmental Protection presented to a neurologist after 10 months of persistent tremors, muscle spasms, paresthesia, and irritability, followed by the onset of bradykinesia, slurred speech, rigidity, insomnia, and subtle cognitive decline. Laboratory investigations revealed functional vitamin B12 and vitamin D deficiencies, while toxicological quantitative analysis showed elevated blood mercury levels (15.2 μg/L) and hair root levels (3 μg/g). MRI of the brain was normal, whereas MRI of the posterior cervical spine detected signs of myelopathy. Florodeoxyglucose (FDG) Positron Emission Tomography (PET) of the brain revealed bilateral temporal and parietal glucose hypometabolism, most pronounced in the left inferior parietal and left superior temporal regions. Single-Photon Emission Computed Tomography (SPECT) imaging of dopaminergic neurons in the striatum was negative, and the patient was unresponsive to levodopa. Multivitamin therapy (vitamins B, E, and D) with selenium, in combination with symptomatic therapy (benzodiazepines, muscle relaxants, and antidepressants) provided minimal relief, leading to the introduction of N-acetyl cysteine, which resulted in moderate improvement of symptoms. Physical and speech therapy were of great importance in this case.</p><p><strong>Discussion: </strong>This case is unique because it represents the development of therapy-resistant extrapyramidal symptoms over 3 years of mercury exposure, likely leading to subacute combined degeneration due to functional vitamin B12 deficiency. Epidemiological data describe methylmercury poisoning, known as Minamata disease, which presents with -somatosensory deficits, ataxia, parkinsonism, dysarthria, and visual and hearing impairments.</p><p><strong>Conclusion: </strong>Toxicological screening for heavy metals in blood and urine should be considered in patients presenting with unexplained, levodopa-resistant extrapyramidal symptoms, behavioral and sleep disturbances, cognitive decline, and other non-specific neurological signs.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1580275"},"PeriodicalIF":4.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139776","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":"Antibody-based alternatives to animal testing for toxin detection and antitoxin evaluation.","authors":"Seo-Hyuk Chang, Jieun Jang, Wonjun Yang, Nam-Kyung Lee, Seoyeon Choi, Hyo-Il Jung, Wantae Kim, Boksik Cha, Sung-Jin Yoon, Ji-Yoon Noh, Jangwook Lee","doi":"10.3389/ftox.2025.1636246","DOIUrl":"10.3389/ftox.2025.1636246","url":null,"abstract":"<p><p>Animal experiments have long played a central role in biomedical research and toxicology, yet their limitations in translational accuracy and ethical concerns have intensified the demand for reliable alternatives. Antibody-based technologies are versatile tools used to develop non-animal testing methods capable of detecting toxins and evaluating antitoxins. Enzyme-linked immunosorbent assay and lateral flow assays, among other techniques, have demonstrated high specificity, sensitivity, and reproducibility and are useful in diagnostics, therapeutic development, and as platforms to replace traditional animal assays. Recent developments in <i>in vitro</i> systems, including organoids and microphysiological systems, as well as the integration of AI-based <i>in silico</i> models, offer promising directions. Standardization and regulatory acceptance remain key challenges. A coordinated approach can facilitate the development of antibody-based systems to fulfill the goal of the 3Rs.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1636246"},"PeriodicalIF":4.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139764","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":"Occupational exposure and its mechanistic link to allergic asthma and lung function decline; a data-driven approach coupled to mining of adverse outcome pathway signatures.","authors":"Rob Stierum, Manosij Ghosh, Marjolein Meijerink, Xavier Pinho, Joost Westerhout, Vivi Schlünssen, Anjoeka Pronk, Jolanda van Bilsen","doi":"10.3389/ftox.2025.1589380","DOIUrl":"10.3389/ftox.2025.1589380","url":null,"abstract":"<p><p>Within occupational epidemiology, the establishment of associations between chemical exposures and health outcome, in particular of individual chemicals present in the exposome, is difficult. Epidemiological studies are valuable but may be prone to confounders, or lack detailed exposure characterisation. Rodent studies may suffer from interspecies differences in comparison to humans. Here, we explore if a data driven approach can leverage human relevant mechanistic information to inform presumed associations between chemical exposures and two common respiratory disorders: lung function decline (LFD) and allergic asthma (AA). Using public toxicogenomics datasets, we identified Gene Ontology Bioprocesses (GO BPs) enriched in human respiratory cells, exposed <i>in vitro</i> to either diesel ultrafine particles (UFP) or respiratory sensitisers. In addition, for LFD and AA, GO BPs were curated from Molecular Initiating Events (MIEs) and Key Events (KEs) extracted from the Adverse Outcome Pathway (AOP) Wiki, and DisGeNET, a gene-disease database. Considering the commonality in GO BPs, a clear overlap was observed between GO BPs derived from UFP and LFD (a.o. \"negative -\"/\"positive\" regulation of cell activation,\" \"positive regulation of ion transport,\" \"stem cell proliferation\"). 20 GO BPs were overlapping between sensitisers in combination with AA (e.g., \"responses to xenobiotic stimulus,\" \"response to oxidative stress\" and \"regulation of response to cytokine stimulus\"). For AA, sensitiser concentrations used in in vitro were generally higher compared to equivalent concentrations expected <i>in vivo</i> (from PBK modelling). Yet, the overlapping GO BPs discovered for these endpoints were plausible and aided in providing mechanistic insights. Currently, limitations exist in the approach to infer causality (e.g., data availability, coverage of AOPs, <i>in vitro</i> to <i>in vivo</i> dosimetry issues), however it can inform on the identification of chemicals within the occupational exposome and putative mechanistic linkage with occupational diseases. Finally, the annotated MIEs and KEs for LFD and AA may serve as valuable resource for further AOP developments.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1589380"},"PeriodicalIF":4.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12450882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132921","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":"Exploring plasticisers-osteoporosis links and mechanisms: a cohort and network toxicology study.","authors":"Xingyao Yang, Xin Wang, Shifu Bao, Zhengjiang Li, Shuxing Xing, Zhangzhen Du","doi":"10.3389/ftox.2025.1617663","DOIUrl":"10.3389/ftox.2025.1617663","url":null,"abstract":"<p><strong>Background: </strong>Plasticisers, widely present in daily life, have been linked to osteoporosis (OP), though the precise mechanisms remain unclear.</p><p><strong>Methods: </strong>This study examined the association between mono (2-ethylhexyl) phthalate (MEHP) and OP using multivariate logistic regression based on NHANES data. Network toxicology identified key targets and pathways involved in MEHP-induced OP. Molecular docking and dynamics simulations validated the stability of MEHP-target interactions. The effects of MEHP on osteogenic differentiation were further assessed in mouse bone marrow stromal cells (BMSCs).</p><p><strong>Results: </strong>All logistic regression models confirmed a significant positive correlation between MEHP levels and OP. Network toxicology analysis identified CTSD, SOAT1, and VCP as key targets and the apoptosis pathway as a key mechanism in MEHP-induced OP. Molecular simulations demonstrated stable MEHP binding to these targets. Cellular experiments revealed that MEHP significantly inhibited BMSC osteogenesis by downregulating CTSD and VCP, while SOAT1 showed a weaker correlation.</p><p><strong>Conclusion: </strong>MEHP exposure is positively associated with OP risk, with CTSD, VCP, and the apoptosis pathway potentially playing key roles in impairing BMSC osteogenesis.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1617663"},"PeriodicalIF":4.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12440899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088345","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 impact of perfumes and cosmetic products on human health: a narrative review.","authors":"Sharifa Alblooshi","doi":"10.3389/ftox.2025.1646075","DOIUrl":"10.3389/ftox.2025.1646075","url":null,"abstract":"<p><strong>Background: </strong>The use of perfumes and cosmetic products is widespread, serving personal hygiene, aesthetic, and olfactory functions. However, concerns have been raised regarding the potential health impacts associated with long-term exposure to various ingredients used in these products.</p><p><strong>Objectives: </strong>This narrative review aims to synthesize evidence on the health risks associated with perfumes and cosmetics, focusing on specific health concerns, including fertility, respiratory health, cancer risk, allergies, skin disorders, endocrine disruption, and neurological effects. It also discusses the presence of heavy metals in cosmetics, regulatory challenges, and the need for transparency in ingredient disclosure.</p><p><strong>Methods: </strong>A comprehensive review of the literature that was published between 2005 and 2024 was conducted, examining findings from interdisciplinary studies relevant to the health impacts of cosmetic and fragrance products. The review highlights health concerns linked to specific chemical components, including synthetic chemicals such as phthalates, parabens, and volatile organic compounds (VOCs).</p><p><strong>Results: </strong>The findings indicate that many synthetic chemicals in perfumes and cosmetics are associated with adverse health outcomes. These include allergies, respiratory issues, endocrine disruption, reproductive problems, and potentially cancer. Heavy metals in cosmetics also pose significant health risks. Despite regulatory guidelines, the cumulative and long-term effects of combined exposure to multiple cosmetic ingredients remain poorly understood and inadequately addressed.</p><p><strong>Conclusion: </strong>There is a pressing need for stricter regulatory oversight and improved transparency in ingredient disclosure to safeguard consumer health. Further research is required to clarify the long-term health risks associated with the daily use of cosmetic products and to develop safer alternatives.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1646075"},"PeriodicalIF":4.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12425936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145066555","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":"Stroke risk following bee and wasp stings: a systematic review of ischemic and hemorrhagic events.","authors":"Jorge Vasconez-Gonzalez, Juan S Izquierdo-Condoy, Karen Delgado-Moreira, María de Lourdes Noboa-Lasso, Esteban Gamez-Rivera, Camila Salazar-Santoliva, María Belén Lopez-Molina, Esteban Ortiz-Prado","doi":"10.3389/ftox.2025.1632308","DOIUrl":"10.3389/ftox.2025.1632308","url":null,"abstract":"<p><strong>Background: </strong>Each year, approximately 100 million cases of bee and wasp stings are re-ported globally, with the majority resulting in mild reactions. However, in rarer instances, these stings can lead to severe and potentially fatal outcomes, including ischemic or hemorrhagic cerebral events. This article aims to synthesize and analyze the current evidence on the association between bee and wasp stings and the occurrence of ischemic and hemorrhagic strokes.</p><p><strong>Methodology: </strong>A systematic review was conducted in accordance with PRISMA guidelines. Searches were performed in PubMed, Scopus, and Scielo databases, including studies published in English and Spanish without time restrictions. Studies that met the inclusion criteria, specifically focusing on \"bee sting\" or \"wasp sting\" and \"stroke\" or \"cerebrovascular disease\" in humans, were included.</p><p><strong>Results: </strong>Out of the 83 articles initially identified, 28 met the inclusion criteria and were included in this systematic review, documenting a total of 29 cases of stroke associated with bee or wasp stings. The distribution of cases was nearly equal between bee and wasp stings. Ischemic stroke emerged as the most commonly reported type, with clinical manifestations primarily affecting the nervous system. Common symptoms included hemiparesis or hemiplegia, hypertension, dysarthria or aphasia, and loss of consciousness or syncope. This pattern underscores the significant neurological and systemic impact of envenomation, which, while rare, can lead to severe and potentially life-threatening complications.</p><p><strong>Conclusion: </strong>While cerebrovascular events like ischemic and hemorrhagic strokes following bee or wasp stings are rare, the risk is significant and can be life-changing. The impact of a stroke extends beyond immediate symptoms, affecting long-term quality of life. Therefore, it is crucial that healthcare facilities establish protocols to recognize and manage these rare but severe complications. Further research is needed to better understand and mitigate this risk.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1632308"},"PeriodicalIF":4.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12415000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031271","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":"Integral approach to organelle profiling in human iPSC-derived cardiomyocytes enhances <i>in vitro</i> cardiac safety classification of known cardiotoxic compounds.","authors":"Brigitta R Szabo, Jeroen Stein, Anna Savchenko, Thomas Hutschalik, Filip Van Nieuwerburgh, Tim Meese, Georgios Kosmidis, Paul G A Volders, Elena Matsa","doi":"10.3389/ftox.2025.1644119","DOIUrl":"10.3389/ftox.2025.1644119","url":null,"abstract":"<p><strong>Introduction: </strong>Efficient preclinical prediction of cardiovascular side effects poses a pivotal challenge for the pharmaceutical industry. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are becoming increasingly important in this field due to inaccessibility of human native cardiac tissue. Current preclinical hiPSC-CMs models focus on functional changes such as electrophysiological abnormalities, however other parameters, such as structural toxicity, remain less understood.</p><p><strong>Methods: </strong>This study utilized hiPSC-CMs from three independent donors, cultured in serum-free conditions, and treated with a library of 17 small molecules with stratified cardiac side effects. High-content imaging (HCI) targeting ten subcellular organelles, combined with multi-electrode array data, was employed to profile drug responses. Dimensionality reduction and clustering of the data were performed using principal component analysis (PCA) and sparse partial least squares discriminant analysis (sPLS-DA).</p><p><strong>Results: </strong>Both supervised and unsupervised clustering revealed patterns associated with known clinical side effects. In supervised clustering, morphological features outperformed electrophysiological data alone, and the combined data set achieved a 76% accuracy in recapitulating known clinical cardiotoxicity classifications. RNA-sequencing of all drugs <i>versus</i> vehicle conditions was used to support the mechanistic insights derived from morphological profiling, validating the former as a valuable cardiotoxicity tool.</p><p><strong>Conclusion: </strong>Results demonstrate that a combined approach of analyzing morphology and electrophysiology enhances <i>in-vitro</i> prediction and understanding of drug cardiotoxicity. Our integrative approach introduces a potential framework that is accessible, scalable and better aligned with clinical outcomes.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1644119"},"PeriodicalIF":4.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016775","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}