Toxicological Sciences最新文献

{"title":"Navigating Complexity in Modern Toxicology: The Role of Omics in Short-Term In Vivo Studies.","authors":"Constance A Mitchell, Leah Wehmas, David Rouquie, Florian Caiment, Richard A Currie, Christine E Crute","doi":"10.1093/toxsci/kfaf120","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf120","url":null,"abstract":"<p><p>Toxicology is shifting toward predictive, mechanism-based approaches that support quicker, more human-relevant risk assessments and reduce reliance on animal testing. Central to this shift are short-term in vivo studies enriched with omics endpoints which provide early molecular indicators of toxicity. These data enable the derivation of molecular points of departures (mPODs) and other biologically anchored metrics that can inform potency ranking, hazard identification, and risk assessment. This commentary summarizes insights from the 2025 Society of Toxicology (SOT) session of the same name and highlights the importance of aligning technical advances with regulatory needs. Next Generation Risk Assessment (NGRA) is a safety evaluation approach that incorporates emerging tools such as in vitro methods, computational models, and omics data to inform decision-making for human health or the environment, while aiming to reduce dependence on traditional animal testing. NGRA frameworks, while potentially generic in principle, must be tailored to the specific regulatory requirements and exposure contexts of different product sectors, including pharmaceuticals, industrial chemicals, agrochemicals, and cosmetics. Short-term mechanistic animal studies serve as a bridge between traditional long-term animal testing and new approach methodologies (NAMs). From a technical standpoint, the generation, analysis, and interpretation of omics data have matured considerably, bringing regulatory acceptance within reach. Remaining challenges include standardizing bioinformatics pipelines, building confidence through validation against apical endpoints, and expanding training. Addressing these gaps through collaborative science and flexible regulatory frameworks will be key to realizing the full potential of omics-enabled hazard profiles to support NGRA.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970519","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":"Statistical analysis of multi-endpoint phenotypic screening increases sensitivity of planarian neurotoxicity testing.","authors":"Danielle Ireland, Laura J Word, Eva-Maria S Collins","doi":"10.1093/toxsci/kfaf117","DOIUrl":"10.1093/toxsci/kfaf117","url":null,"abstract":"<p><p>There is an urgent need for high-throughput screening (HTS) models to replace, refine, and/or reduce (\"3Rs\") vertebrate toxicity testing. Replacing in vivo animal studies is challenging for neurotoxicity and developmental neurotoxicity (DNT) where the functional relevancy of adverse outcomes needs to be assessed on the whole organism. We previously screened the NTP 87-compound library (NTP87), consisting of known and suspected developmental neurotoxicants, and showed that planarian HTS can identify known (developmental-) neurotoxicants. Because analysis methods can impact screening results and our original analysis used lowest observed effect level (LOEL) only, we hypothesized that use of state-of-the-art statistical analysis would increase sensitivity of planarian HTS to identify neurotoxicity and DNT. Using the original NTP87 planarian data, we quantified eight additional behavioral endpoints for a total of 26 readouts on days 7 and 12 of exposure days, evaluated at 5 log-scale concentrations (10 nM-100 µM). Benchmark concentration (BMC) modeling replaced LOEL analysis. We also calculated a concentration-independent multi-readout summary measure using weighted Aggregate Entropy (wAggE), providing insight into systems-level toxicity. Lastly, we compared the planarian BMC data to in vitro and developing zebrafish data from independent screens of the NTP87 library that were analyzed using the same BMC pipeline. Planarian and developing zebrafish screens showed similar sensitivity. Regenerating planarian hits helped correctly identify known neurotoxicants of the NTP87 library. Hierarchical clustering showed that organismal, neuron outgrowth, and neuron firing models were the main contributors to the NTP87 DNT battery's information content, emphasizing their relevance for DNT testing.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970471","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":"Development of a Physiologically Based Pharmacokinetic Model of N,N-Dimethyltryptamine, Harmine, and Their Interactions from Ayahuasca in Rats and Humans.","authors":"Naphat Wittayakarn, Yu-Mei Tan, Pattanachai Choomalaiwong, Samantha Chen, Daniel Hoer, Nilubon Thaoboonruang, Manupat Lohitnavy","doi":"10.1093/toxsci/kfaf118","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf118","url":null,"abstract":"<p><p>Ayahuasca is a traditional Amazonian brew composed of Psychotria viridis, containing N,N-dimethyltryptamine (DMT), and Banisteriopsis caapi, which includes harmala alkaloids such as harmine. Ayahuasca can produce potent psychoactive effects primarily due to DMT, whose metabolism is inhibited by harmine via monoamine oxidase-A (MAO-A) enzymes. This inhibition increases DMT's systemic bioavailability, thereby allowing more DMT to reach the brain and intensify its psychedelic effects. Beyond its traditional psychoactive uses, ayahuasca has shown potential therapeutic benefits for mental health conditions such as depression, anxiety, and substance use disorders. To support better design of dosing regimens in both preclinical and clinical settings, we developed linked physiologically based pharmacokinetic (PBPK) models for DMT and harmine in rats and humans. The models account for multiple routes of administration (intraperitoneal, oral, intravenous, and buccal) and integrate harmine's inhibition of DMT metabolism in liver and lungs. Key absorption and metabolism parameters were optimized using published time-concentration data. The models reasonably predicted plasma concentrations of DMT and harmine across various dosing conditions. Simulation results offer insights into how the route of administration and co-administration with harmine influence exposure. The model also enables exploration of the dose metric driving the therapeutic effects, suggesting that plasma concentration above a threshold may be more relevant than peak levels. Overall, this PBPK model offers a mechanistic framework for guiding preclinical and clinical studies, supporting safer and more effective therapeutic use of ayahuasca and potentially other psychedelic compounds.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970461","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":"Advanced Cardiac Organoid Model for Studying Doxorubicin-Induced Cardiotoxicity.","authors":"Xian Wu, Savanna Williams, Jacques Robidoux, Srinivas Sriramula, Abdel-Rahman Abdel","doi":"10.1093/toxsci/kfaf115","DOIUrl":"10.1093/toxsci/kfaf115","url":null,"abstract":"<p><p>Cardiac organoids provide an in vitro platform for studying heart disease mechanisms and drug responses. However, a major limitation is the immaturity of cardiomyocytes, restricting their ability to mimic adult cardiac physiology. Additionally, the inadequacy of commonly used extracellular matrices (ECM), which fail to replicate the biochemical and mechanical properties of natural heart tissue, poses significant challenges. Consequently, structural integrity in cardiac organoids is impaired. Moreover, scalability remains an obstacle, as conventional ECM substitutes hinder mass production of organoids for high-throughput toxicology screening. To overcome these challenges, we developed an advanced model promoting fibroblast-driven ECM self-secretion, enabling physiologically relevant tissue architecture and function. Using the ECM-free, mature cardiomyocyte-integrated organoid model, we investigated the cardiotoxicity of doxorubicin, a widely used chemotherapeutic agent known to impair cardiac function. Cardiomyocytes derived from induced pluripotent stem cells were characterized for maturity by immunostaining for cTNT and MYL2 alongside gene expression analysis. Organoids treated with doxorubicin showed reduced size and increased collagen deposition. These structural changes correlated with functional impairments, including decreased beating rate and disrupted synchronous beating. In 2D culture, exposure to doxorubicin induced fibroblast activation, promoted early molecular signatures of endothelial-to-mesenchymal transition in endothelial cells, and triggered cytotoxic effects in cardiomyocytes. This study highlights the importance of ECM remodeling in advancing cardiac organoid models and demonstrates its potential for more accurate cardiotoxicity assessment. Addressing these limitations enhances the physiological relevance of cardiac organoid systems for drug safety assessment and cardiac disease modeling.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837740","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":"Circular RNA hsa_circ_0099188 Regulates Inducible Nitric Oxide Synthase and Chemokine Transcription in Macrophages by Targeting the hsa-miR-381-3p/PPP3CA and hsa-miR-381-3p/KLF4 Pathways in Response to 4,4'-Methylene Diphenyl Diisocyanate-Glutathione Conjugate exposure.","authors":"Chen-Chung Lin, Brandon F Law, Justin M Hettick","doi":"10.1093/toxsci/kfaf114","DOIUrl":"10.1093/toxsci/kfaf114","url":null,"abstract":"<p><p>Workplace exposure to 4,4'-methylene diphenyl diisocyanate (MDI), the most used monomeric diisocyanate, can lead to the development of occupational asthma (OA). However, the molecular mechanisms by which MDI induces OA remain poorly understood. Previous studies have shown that exposure to MDI or MDI-glutathione (GSH) conjugate reduces the levels of endogenous human (hsa)/murine (mmu)-microRNA(miR)-206/381-3p, triggering the activation of calcineurin/nuclear factor of activated T cells (NFAT)/inducible nitric oxide synthase (NOS2) regulatory axis and Krüppel-Like Factor 4 (KLF4)/chemokine pathways in macrophages. Circular RNAs (circRNAs) play important roles on miR and miR-mediated functions in the cells. CircRNA hsa_circ_0008726 is induced by MDI-glutathione (GSH) to downregulate endogenous hsa-miR-206-3p in macrophages; however, the MDI-GSH mediated circRNA response to downregulate hsa-miR-381-3p is currently unknown. The expression of previously identified candidate circRNAs that bind hsa-miR-381-3p were analyzed in differentiated/enhanced THP-1 macrophages treated with MDI-GSH conjugates using RT-qPCR. MDI-GSH exposure induces endogenous hsa_circ_0099188 and its host gene thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE); however, other candidate circRNAs were neither detected nor altered. RNA immunoprecipitation (RIP) experiments confirmed the binding of hsa-miR-381-3p to hsa_circ_0099188. Further experiments demonstrate that modulating hsa_circ_0099188 expression through siRNAs or overexpression plasmids alter the levels of endogenous hsa-miR-381-3p, PPP3CA, and KLF4, as well as NOS2 and M2 macrophage-associated markers and chemokine transcripts. These findings suggest that MDI/MDI-GSH exposure leads to the downregulation of hsa-miR-381-3p by inducing the expression of hsa_circ_0099188/TRHDE, thereby enhancing the regulatory effects of hsa-miR-381-3p in macrophages.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837742","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":"Mediation Analysis of the Molecular Phenotypes in a Severe MASH-like Liver Injury Mouse Model.","authors":"Zhuolin Song, Volodymyr P Tryndyak, Rose A Willett, Igor P Pogribny, Ivan Rusyn, Fred A Wright","doi":"10.1093/toxsci/kfaf116","DOIUrl":"10.1093/toxsci/kfaf116","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease, is a leading cause of cirrhosis and lacks effective therapies. Understanding the molecular mediators of disease progression remains a critical gap. This study aimed to investigate the roles of molecular phenotypes as mediators of MASH disease features in a diet-induced mouse model. Data used for these analyses was from a previous study where male and female CC042 mice were fed either a control or high-fat, high-sucrose (HF/HS) diet for 20, 40, or 60 weeks. Associations and mediated relationships between molecular and metabolic phenotypes, and histopathologic markers of liver injury, inflammation, and lipid accumulation were assessed using regression modeling and causal mediation analyses. We observed strong associations between the HF/HS diet and duration of treatment and liver pathology, with limited effect of sex. Mediation analysis revealed that liver lipid phenotypes, particularly monounsaturated and polyunsaturated fatty acids, consistently mediated the effects of diet on liver disease scores. TNF-α and Cxcl10, despite being treatment-induced, showed modest evidence of mediation on MASH or specific liver disease outcomes. Serum insulin showed modest mediation of inflammation and osmium staining, while serum glucose and triglycerides were not significant mediators. These findings highlight evidence that liver lipid metabolism may act as primary mediators of MASH progression in this mouse model. The study underscores the value of mediation analysis for improved characterization of metabolic pathways in disease pathogenesis and supports the use of serum lipids as accessible biomarkers for clinical risk stratification and therapeutic targeting in MASH.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837743","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":"Why rat oral cavity tumors should not be the basis of quantitative cancer risk assessment for oral exposure to hexavalent chromium.","authors":"D Proctor, X Jiang, H Reichert, C Thompson","doi":"10.1093/toxsci/kfaf112","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf112","url":null,"abstract":"<p><p>Several regulatory agencies have developed threshold-based drinking water guidelines for hexavalent chromium [Cr(VI)] protective of nonneoplastic and neoplastic lesions in rodents using small intestine tumor data in mice. However, in 2024 the U.S. Environmental Protection Agency Integrated Risk Information System (IRIS) set an oral cancer slope factor based on oral cavity tumors in rats following chronic exposure up to 180 ppm Cr(VI) in drinking water. Herein, we review previously published in vivo mechanistic data in rat oral cavity tissue indicating the absence of mutation responses in oral cavity tissue of transgenic Big Blue® rats, and absence of transcriptomic responses in F344 rats indicative of toxicological or homeostatic changes in the oral cavity following exposures up to 180 ppm Cr(VI). In addition, we extended an IRIS meta-analysis of gastrointestinal cancers by including oral cavity cancers, using the same epidemiological studies and approach as IRIS. We observed a significantly decreased meta-relative risk (meta-RR: 0.81, 95%CI: 0.69-0.95 and 0.74, 95%CI: 0.068-0.81 using random and fixed effect models). Given the lack of evidence for genotoxicity or even homeostatic responses to Cr(VI) in the rat oral cavity and the absence of oral cancer risk in humans, oral toxicity criteria for Cr(VI) should not be based on oral cavity tumors in rats. Many agencies have instead developed threshold-based toxicity criteria using nonneoplastic intestinal lesions observed in mice due to strong evidence for a cytotoxicity/regenerative proliferation mode of action for intestinal tumors which were observed at lower drinking water concentrations than rat oral tumors.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837745","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":"Are New Approach Methodologies (NAMs) the Holy Grail of Toxicology?","authors":"Hartmut Jaeschke, Anup Ramachandran","doi":"10.1093/toxsci/kfaf113","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf113","url":null,"abstract":"<p><p>New Approach Methodologies (NAMs), including organoids, microphysiological systems and computer modeling, are gaining increased popularity for toxicological testing and even mechanistic research. With the use of human cells, the primary objectives of NAMs are to develop more human-relevant test systems and to reduce, and ultimately eliminate, animal experiments. There are many advantages of using NAMs for biological research. For example, NAMs can be used to test the dose- and time-dependent toxicity of numerous chemicals and mixtures in a cost-effective way and reduce animal use. Although these are worthwhile goals when considering the big picture, the problems are in the details. First, in vivo insight is needed to build and refine NAMs, including computer modeling. Second, primary human cells are difficult to obtain reliably and in sufficient quantities; substitutes such as immortalized cell lines or induced pluripotent stem cells (iPSCs) have the advantage of being more robust and available in unlimited numbers, but their basal and stress-induced gene expression profiles are quite different compared to primary cells. Third, critical aspects such as metabolic competency, presence of various cell types in an organ, spatial aspects, oxygen gradients, role of inflammatory cells are very difficult to replicate in vitro. Therefore, in vivo experiments are necessary to verify results obtained with NAMs. Importantly, the results of both NAMs and the in vivo animal experiments need to be translatable to human disease processes. The advantages and limitations of NAMs are being discussed using the challenges of investigating mechanisms of drug hepatotoxicity as an example.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144837741","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":"ToxPoint: Mucus matters: pollution alters mucus pathophysiology.","authors":"Kaitlyn R Rouillard, Ilona Jaspers, David B Hill","doi":"10.1093/toxsci/kfae082","DOIUrl":"10.1093/toxsci/kfae082","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"228-229"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142112254","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":"ToxPoint: Waste incineration management of plastic materials-an issue of increasing global public health importance.","authors":"Keith Rogers, Ilona Jaspers","doi":"10.1093/toxsci/kfae111","DOIUrl":"10.1093/toxsci/kfae111","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"230-232"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376086","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}