Toxicological Sciences最新文献

{"title":"Integrating exposomics and multi-omics with dysbiosis biomarkers for clinical and environmental connections implicated in neuropathology. Cause and cure cluses.","authors":"Hajar Heidari, Marah Vincent, David A Lawrence","doi":"10.1093/toxsci/kfag034","DOIUrl":"10.1093/toxsci/kfag034","url":null,"abstract":"<p><p>Multi-omic investigations into environmental effects on health and disease are aided by inclusion of microbial microbiomes with assessment of mirobes producing metabolites that differentially modulate host organ functions. The gut microbiome is key because many environmental toxicants enter the body orally and may disrupt gut microbes that help digest food, as well as the microbiome-gut-brain axis, which produces regulatory metabolites with systemic effects. Environmental stressors may differentially alter brain development and function, even among identical twins, in that over time, there may be divergence due to epigenetic effects from the environment, including microbes within the microbiome. The diversity of microbiomes is presented as playing a key role in the influence of organs on each other, health, and the development of disorders. The gut microbes and their metabolites may cause mitochondria to produce less ATP and more reactive oxygen species (ROS). The metabolites produced by microbes during the digestion of foods can nourish or harm a person's cellular and molecular functions and vary depending on each person's exposome. The detrimental effects of environmental stressors are discussed, focusing on how altered levels of neuropeptides, neurotransmitters, and the inflammatory/anti-inflammatory balance affect health and disorders. During ATP production, dysfunctional mitochondria may produce more ROS, which can lead to inflammation and oxidative stress, causing cell damage and disrupting products needed for neuronal development, connections, and functions. The balance between inflammatory/anti-inflammatory biomarkers and metabolites and between oxidants/antioxidants is discussed in relation to some clinical connections; for example, the proportions of CD4 and CD8 T cells in HIV patients and the ROS-to-glutathione ratio in inflammatory bowel disease and septic patients. These imbalances are reviewed regarding brain development and functions leading to anxiety, depression, and dementia. The integration of multi-omics, dysbiosis, and mitochondrial dysfunction with a person's clinical evaluation is discussed to inform the formulation of prevention measures and therapeutic interventions regarding environmental effects on the microbiome-gut-brain axis and physical and mental health.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147487431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeated bronchoalveolar lavage variability and impact in a 2-week nonclinical toxicology study.","authors":"Emily Hackshaw, James Nelson, Molly H Boyle","doi":"10.1093/toxsci/kfag044","DOIUrl":"10.1093/toxsci/kfag044","url":null,"abstract":"<p><p>Nonclinical inhalation studies often rely on systemic biomarkers of exposure and pharmacology for serial evaluations, since local pulmonary effects are generally limited to assessment by terminal procedures. In addition, invasive procedures raise concern with health impact for subsequent inhalation doses and artifacts in tissue histology that could confound interpretation of toxicity. To test a non-terminal lung monitoring technique for use in non-human primate repeat-dose inhalation toxicology studies, bronchoalveolar lavage was performed during the pretest phase (twice), following 7 d of treatment with saline or albuterol, and the day after the final dose. Evaluations included clinical observations and histopathology, as well as differential cell counts and quantification of protein, lactate dehydrogenase, and urea in bronchoalveolar lavage fluid. Animals sufficiently recovered from the procedure were dosed by conscious facemask inhalation several hours later, without incident, and had slightly lower lavage total cell counts. Bronchoalveolar lavage the day before necropsy was associated with mixed cell infiltrates or inflammation in 2 of 8 animals. Total white cell counts in lavage fluid were higher but more variable when collected as a terminal rather than survival procedure, although intra-animal variability between pretest occasions was notable as well. Urea concentration showed greater variability than total protein and lactate dehydrogenase, although values were near the method's limit of detection. In summary, this study showed that bronchoalveolar lavage can be performed as a serial evaluation in nonclinical studies, without benefit from multiple baseline occasions and with some effect on lung histopathology.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Withdrawal interval estimations of oxytetracycline and chlortetracycline in swine using physiologically based pharmacokinetic models: a global trade perspective.","authors":"Kun Mi, Hiroko Enomoto, Ronald E Baynes, Zhoumeng Lin","doi":"10.1093/toxsci/kfag042","DOIUrl":"10.1093/toxsci/kfag042","url":null,"abstract":"<p><p>Violative drug residues in animal-derived food are a global food safety concern. Physiologically based pharmacokinetic (PBPK) modeling is a valuable tool for predicting drug residues in edible tissues and determining withdrawal intervals (WDIs). This study aimed to develop a PBPK model for oxytetracycline (OTC) and chlortetracycline (CTC) in swine to determine WDIs based on different regulatory requirements of different countries. The models were calibrated and evaluated with the pharmacokinetic data after oral administration via feed and drinking water collected from the Food Animal Residue Avoidance Databank (FARAD). The models can accurately capture the observed kinetics in plasma and edible tissues (liver, muscle, kidney, and fat), and most of the model predictions were within a 3-fold factor of observed data (87.9% for OTC and 88.9% for CTC). WDIs of OTC and CTC were determined using the population PBPK models based on maximum residue limits (MRLs) from 13 countries or regions under the label dosage regimens. The models were converted to a web-based PBPK dashboard. The models are a useful tool for predicting tissue residues and estimating WDIs based on different MRLs across countries, thereby supporting food safety assessment and international trade of meat products derived from swine treated with OTC and CTC.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An adverse outcome pathway-aligned ex vivo mouse testicular organ culture platform for mechanistic integration of multi-level endpoints with recovery assessment.","authors":"Hideaki Nakagiri, Kyoichi Kodama, Shimpei Terasaka, Makoto Kashima, Naohiro Ikeda, Yuko Nukada, Kenkichi Fujii, Yoshikazu Nagao","doi":"10.1093/toxsci/kfag037","DOIUrl":"10.1093/toxsci/kfag037","url":null,"abstract":"<p><p>Mechanistic understanding is important for improving the safety assessment of male reproductive toxicity; however, current evaluations still rely primarily on in vivo studies. Therefore, the development of new approach methodologies (NAMs) requires test systems capable of capturing key events organized within adverse outcome pathways (AOPs). The PDMS ceiling (PC) method is a testicular organ culture technique previously used to detect testicular toxicity. However, its applicability as an AOP-aligned platform for multi-level mechanistic assessment, including recovery evaluation, has not been fully examined. Here, we evaluated the utility of the PC-based organ culture system for AOP-aligned assessment of testicular toxicity. Methoxyacetic acid (MAA), a testicular toxicant with established AOPs, was used as a reference compound. Molecular, cellular, and histological endpoints were assessed under identical conditions, and a membrane-supported PC (msPC) configuration was introduced to enable controlled recovery assessment. Testes from Acro3-EGFP transgenic mice, in which EGFP expression driven by the acrosin promoter accumulates in developing acrosomes, were cultured and exposed to MAA. GFP fluorescence indicating spermatogenic progression decreased in a concentration-dependent manner. Histological and immunohistochemical analyses demonstrated selective loss of pachytene spermatocytes with apoptosis, whereas transcriptomic profiling suggested disruption of cell cycle- and meiosis-related pathways consistent with established AOP-defined key events. Recovery of GFP fluorescence and tissue morphology occurred earlier in the msPC system than in the conventional PC method. These findings support the PC-based organ culture system as an AOP-aligned platform within NAMs for evaluating testicular toxicity and recovery.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of human microbiota (SIHUMIx) and zebrafish models reveals microbiome-mediated host responses to azoxystrobin.","authors":"Chloe Wray, Victor Castañeda-Monsalve, Beatrice Engelmann, Ulrike E Rolle-Kampczyk, Nicole Schweiger, Sebastian Gutsfeld, Debjyoti Ghosh, Siraz Kader, Charles R Tyler, Nico Jehmlich, Tamara Tal","doi":"10.1093/toxsci/kfag022","DOIUrl":"10.1093/toxsci/kfag022","url":null,"abstract":"<p><p>The gut microbiome is essential for neurodevelopment via bidirectional gut-brain axis signaling, yet environmental chemicals can potentially disrupt this communication by altering community structure and xenobiotic metabolism. In this study, we investigated whether the fungicide azoxystrobin, a known metabolic disruptor, modulates microbiome composition and function to influence neurobehavior. We utilized a simplified human gut microbiota model (SIHUMIx) and a vertebrate host model (larval zebrafish) to elucidate microbiome-mediated mechanisms of xenobiotic neurotoxicity. SIHUMIx was exposed to azoxystrobin for 7 days at 10% of the acceptable daily intake, followed by recovery. Integrated metaproteomic and metabolomic analyses revealed functional reprogramming of the microbiota, characterized by upregulation of vitamin and cofactor biosynthesis, nutrient acquisition, and detoxification pathways, and decreases in carbohydrate fermentation and amino acid turnover, consistent with reduced short-chain fatty acid levels. Microbiome-depleted and SIHUMIx-inoculated larvae were exposed to azoxystrobin at 4 days post fertilization, and neurobehavioral outcomes were assessed after 24 h using the Visual and Acoustic Motor Response assay. Azoxystrobin exposure disrupted non-associative habituation learning independent of microbiome status but induced dark-phase hyperactivity only in colonized larvae, indicating a microbiome-dependent phenotype. Targeted metabolomics revealed lower serotonin levels in microbiome-depleted larvae relative to colonized controls and that azoxystrobin exposure reduced serotonin in colonized larvae toward depleted levels. These results suggest that microbiota-dependent serotonergic signaling may modulate host responses to azoxystrobin. This integrated ex vivo-in vivo approach supports the concept that the microbiome is a key determinant of neurotoxic responses and underscores the importance of incorporating microbiome-mediated effects into chemical risk assessment frameworks.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147378484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progeny effects of rotenone exposure depend on parental toxicity.","authors":"Christina M Bergemann, Danielle F Mello, Rojin Chitrakar, Kinsey Fisher, Shefali R Bijwadia, Javier Huayta, Ian T Ryde, Rick Presman, Zhiqing Huang, Amy H Herring, Susan K Murphy, L Ryan Baugh, Joel N Meyer","doi":"10.1093/toxsci/kfag011","DOIUrl":"10.1093/toxsci/kfag011","url":null,"abstract":"<p><p>Parental exposure to toxicants can affect progeny health. However, laboratory studies often employ exposures that result in loading of pollutants to gametes or toxic effects to parents, which could indirectly affect germ cell or gamete health. Here, we took advantage of the biology of Caenorhabditis elegans to carry out a study in which we minimized the potential for maternal loading of toxicants, and used an exposure paradigm that either did (high concentration) or did not (low concentration) significantly impact the health of the P0 generation. We hypothesized that parental exposure to mitochondrial toxicants during germ cell and gamete development, at levels not causing P0 toxicity, would result in altered mitochondria and organismal health in offspring. In the P0 generation, a high rotenone concentration altered growth, mitochondrial respiration, gene expression, induction of the mitochondrial unfolded protein response, and susceptibility to dopaminergic neurodegeneration induced by a chemical rechallenge later in life. However, we observed minor or no effects in P0 at a low concentration. In high-exposure F1 offspring, we observed altered embryo size, larval developmental stage distribution, spare respiratory capacity, heat shock protein expression, and dopaminergic neurodegeneration after a secondary rotenone challenge. The only effects observed in the F1 offspring of the low exposure were a 1.7% decrease in egg size (size later in development was normal), and moderate evidence of a slightly increased sensitivity to heat shock protein expression and dopaminergic neurodegeneration caused by a secondary later-in-life rotenone exposure. We recommend that parental toxicity be carefully assessed to contextualize offspring outcomes.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection and characterization of alterations in miRNA in urine of firefighters.","authors":"Patrick C Sachs, Julie S Bjerring, James Blando, Robert D Bruno","doi":"10.1093/toxsci/kfag010","DOIUrl":"10.1093/toxsci/kfag010","url":null,"abstract":"<p><p>Firefighters are exposed to high levels of toxic chemicals while fighting fires, and previous studies have established these men and women have a significantly elevated risk for various cancers. Improved risk management for firefighters requires the identification of biomarkers indicative of physiological response. Micro-RNAs (miRNAs) have emerged as promising noninvasive prognostic and diagnostic biomarkers for various diseases. Here, we isolated miRNA from the urine of a large dataset of firefighters, collected pre- and post-fire exposure, as well as from healthy non-firefighter controls. miRNA was analyzed by microarray using the Affymetrix GeneChip miRNA 4.0 array. Analysis revealed 23 human miRNAs were significantly up-regulated and 25 significantly down-regulated in firefighters compared with control samples (analysis 1). Gene targets of these miRNAs were analyzed using the Online Database for Annotation, Visualization, and Integrated Discovery (DAVID) and found to cluster in several pathways and disease associations with smoking, cancer, and inflammatory diseases. Furthermore, we performed a longitudinal analysis of samples from firefighters that provided a sample prior to a fire exposure and immediately after a fire (analysis 2). This analysis found 20 miRNAs that were significantly up-regulated post-fire exposure. Of these, 5 were also up-regulated in firefighters vs control samples (hsa-miR-1268b, hsa-miR-4433b-3p, hsa-miR-4253, hsa-miR-6824-5p, and hsa-miR-3188). Again, analysis of gene targets of these miRNAs found association of mostly the same pathways and disease processes found in analysis 1. These findings are consistent with epidemiological evidence for increased risks associated with firefighting and offer a proof of concept and framework for the use of miRNA in urine as biomarkers for health risk assessment associated with firefighting.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal preclinical assessment of glucocorticoid-induced disruption of bone remodeling in Sprague-Dawley rats.","authors":"Anik Tuladhar, Caitlyn Carter, Erin Vaughan, Martin J Voorbach, Pankaj Kumar, Anastasia Marinopoulos, Ayusha Acharya, DeAnne Stolarik, Elizabeth J Sande, Timothy Brayman, Karen E Parrish, Xin Huang, Sjoerd J Finnema, Romy Christmann, Terry R Van Vleet, Brian Enright, Magali Guffroy, Stacey Fossey","doi":"10.1093/toxsci/kfag026","DOIUrl":"10.1093/toxsci/kfag026","url":null,"abstract":"<p><p>Skeletal toxicity is a critical consideration during drug development arising from on-target mechanisms and off-target effects. Standard histopathology used in preclinical toxicity studies lacks sensitivity to detect subtle skeletal alterations. Early detection of bone changes is essential especially for compounds that may interfere with skeletal remodeling, growth, or maintenance. We characterized serum markers of bone formation and turnover (procollagen type I N-terminal propeptide and osteocalcin) and resorption (C-terminal telopeptide of type I collagen) across developmental age group (1 to 8 mo) in naïve Sprague-Dawley rats and evaluated marker responsiveness in a positive-control prednisolone model (2-mo-old rats dosed 14 or 28 d). Biomarkers were interpreted alongside histology, imaging by micro-computed tomography and dual-energy X-ray absorptiometry. Serum biomarkers of bone formation and resorption decreased with age, along with physiological growth plate thinning in naive rats. In prednisolone-treated rats, biomarkers decreased at 14 and 28 d of daily dosing; histology demonstrated reduced growth plate thickness, increased marrow adiposity, and imaging revealed alteration of trabecular microarchitecture and bone mineral density relative to controls. These data indicate that serum bone biomarkers are sensitive to both normal maturational change and pharmacologic suppression of remodeling, and these biomarker shifts correspond with skeletal toxicity, reflecting early structural deterioration induced by glucocorticoid exposure. We show that integrating serum biomarkers with histology and high-resolution imaging enhances early detection of skeletal toxicity in preclinical studies with compounds having known or expected bone effects based on their pharmacology and informs selection of serum sampling time frame and translational monitoring strategies using imaging.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147356191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Removal of volatile organic compounds by chemical filters significantly inhibited the development of atopic dermatitis symptoms in mice: potential implications for air-conditioning systems in healthcare environments.","authors":"Chiharu Ohira, Kengo Tomita, Yukiko Ota, Keiichi Yano, Mona Amano, Mao Kaneki, Atsushi Yamada, Riku Usui, Yuzo Nagai, Masaki Nagane, Satoshi Takagi, Tomoki Fukuyama","doi":"10.1093/toxsci/kfag009","DOIUrl":"10.1093/toxsci/kfag009","url":null,"abstract":"<p><p>Volatile organic compounds (VOCs) are increasingly implicated in systemic diseases, but their contribution to skin disorders such as atopic dermatitis (AD) remains unclear. This study assessed VOC concentrations in medical environments, their effects on AD development, and the efficacy of VOC removal using chemical filters. Total VOC levels were monitored in 3 types of veterinary hospitals. AD-like lesions were induced in female NC/Nga mice by repeated dermal application of toluene diisocyanate or house dust mite ointment, with or without topical exposure to a VOC mixture (10 μg/ml). Clinical parameters, including dermatitis scores, transepidermal water loss, and skin thickness, were measured weekly, and immunological and histological analyses were performed. VOC monitoring revealed that 1 hospital exhibited concentrations exceeding 400 μg/m³. In the mouse model, direct VOC exposure significantly aggravated keratinocyte inflammation and worsened AD symptoms. Application of chemical filtering systems effectively reduced VOC levels in real clinical settings, and their use in the experimental model suppressed AD development. However, therapeutic application of VOC removal showed only limited effects on systemic immunological markers. These findings suggest that VOCs present in healthcare environments may contribute to the onset and progression of AD. Incorporating VOC-removing filters into air-conditioning systems could serve as a preventive strategy to improve the management of allergic skin diseases.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term electrical stimulation promotes partial functional and morphological maturation of human-induced pluripotent stem cell-derived cardiomyocytes enabling cardiotoxicity risk mitigation at early-stage drug discovery for cardiac contractility modulation.","authors":"Hayato Miyoshi, Kaoru Morimura, Reiko Hara, Ritsuko Hori, Eriko Watanabe, Nobuyuki Mochizuki, Ayako Kamei, Rika Yamazaki, Katsuyuki Kazusa","doi":"10.1093/toxsci/kfag018","DOIUrl":"10.1093/toxsci/kfag018","url":null,"abstract":"<p><p>In drug discovery, assessing cardiac contractile force is crucial because of its association with the development of cardiovascular events and heart failure. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a promising in vitro model for drug discovery, particularly for assessing proarrhythmic risk. However, the availability of robust in vitro models to evaluate cardiac contractility has been limited. Here, we demonstrate that subjecting hiPSC-CMs to electrical stimulation for 48 h using a multielectrode array system induces partial functional and morphological maturation, as evidenced by a positive force-frequency relationship, increased conduction velocity of depolarization signals and improved sarcomere orientation with distinct Z-bands compared to unstimulated controls. We confirmed that electrical stimulation enables the evaluation of the positive inotropic effects of drug compounds with diverse pharmacological actions. The functional maturation induced by the electrical stimulation was observed across different facilities. The method also effectively detected prolonged QT intervals. These findings demonstrate the utility of the electrical stimulation for 48 h for hiPSC-CMs using the multielectrode array assay system to assess drug-induced contractile function and detect prolonged QT intervals in a single experiment, thereby enhancing the early-stage assessment of cardiotoxicity in drug discovery.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13169201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146228808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}