Toxicological Sciences最新文献

{"title":"The OASIS Consortium: Integrating Multi-Omics Technologies to Transform Chemical Safety Assessment.","authors":"David Rouquié, Andreas Bender, Jaime Cheah, Chrissy Crute, Deidre Dalmas, Jessica Ewald, Aaron Fullerton, Joshua A Harrill, Sabah Kadri, Nicole Kleinstreuer, Nynke Kramer, Jessica LaRocca, Constance A Mitchell, Srijit Seal, Shantanu Singh, Anne E Carpenter","doi":"10.1093/toxsci/kfaf128","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf128","url":null,"abstract":"<p><p>Next Generation Risk Assessment (NGRA) aims to improve safety testing of pharmaceuticals, agrochemicals, and industrial chemicals. NGRA employs New Approach Methodologies (NAMs), such as novel in vitro assays coupled with exposure modeling, to minimize the use of animal models which can fail to predict specific biological effects in humans. The strategy of the 'Omics for Assessing Signatures for Integrated Safety (OASIS) Consortium combines multi-omics technologies (including transcriptomics, proteomics, and Cell Painting (high-content imaging)) and multiple cell model systems (ranging from simple cell cultures to complex organotypic models). By integrating these approaches with internal exposure estimates, the consortium aims to improve the translation between in vitro and in vivo test systems, ultimately enhancing the relevance of safety assessment to human biology. OASIS's integrated approach aims to better translate the biological effects across different chemical and biological spaces, starting with the liver as a use case. By using compounds with well-characterized in vivo and in vitro nonclinical safety and toxicology data related to adverse organ specific effects in rats and humans, OASIS aims to create novel integrated methods that improve safety assessment while reducing animal use. Ideally, these efforts will contribute to regulatory science across sectors and support the adoption of more predictive, efficient, and cost-effective toxicological models.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092413","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":"Zebrafish Cell Lines and High-Throughput Transcriptomics: Advancing In vitro and Bioinformatics Methods for Supporting Environmental Risk Assessment.","authors":"Peter G Schumann, Joseph Bundy, Derik E Haggard, Logan Everett, Joshua A Harrill, Felix Harris, David Ryoo, Jacob Collins, Claudia Rivetti, Bruno Campos, Geoff Hodges, Carlie A LaLone","doi":"10.1093/toxsci/kfaf127","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf127","url":null,"abstract":"<p><p>Historic animal-based toxicity testing methods cannot keep pace with the need for prioritizing new and existing chemicals for comprehensive risk assessment. New approach methodologies such as high-throughput in vitro transcriptomics screening have emerged to address this challenge. However, most in vitro methods were developed using mammalian cell lines, including human, and may not adequately represent environmental species, potentially limiting the utility of this methodology for supporting environmental risk assessment. The objective of this study was to evaluate whether zebrafish cell lines can generate biologically meaningful chemical effects data in a high-throughput transcriptomics pipeline that is protective of toxicologically relevant aquatic apical endpoints. Forty-two test chemicals were screened in two commercially available zebrafish cell lines (ZFL liver and ZEM2S embryonic fibroblast) using the TempO-Seq zS1500+ platform. Transcriptomic points of departure (tPODs) were derived using two methods: Gene-level analysis (tPODgenes) with BMDExpress software and biological pathway altering concentrations (BPACs/tPODsignatures) from signature-based dose-response analysis. When converted to predicted external water concentrations using quantitative in vitro-in vivo extrapolation models, tPODs were generally protective of aquatic in vivo endpoints from the ECOTOX Knowledgebase. Differential gene expression and biological pathway analysis revealed potential cell-type specific effects for several chemicals, highlighting the value of using multiple cell types for capturing tissue-specific responses. Lastly, the biological pathway information was used to extrapolate the chemical effects data across species through an integration of protein-protein interaction network analysis and the Sequence Alignment to Predict Across Species Susceptibility tool, which has significant implications for improving the ecological relevance of these methods.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092432","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":"Context-dependent contribution of peptidyl arginine deiminase 4 (PAD4) to neutrophil extracellular trap formation and liver injury in acute and chronic hepatotoxicant challenge.","authors":"Gina E Capece, Amish K Patel, Daniel Hu, Tayana Roychowdhury, Bianca Hazel, Jessica Kothapalli, Noah A Mac, Frederik Denorme, Robert A Campbell, Lauren G Poole","doi":"10.1093/toxsci/kfaf123","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf123","url":null,"abstract":"<p><p>Neutrophils play a complex role in the pathogenesis of chronic liver disease and have been linked to both liver damage and injury resolution. Recent reports propose that neutrophils drive liver injury and fibrosis through the formation of neutrophil extracellular traps (NETs). This study tests the hypothesis that the enzyme peptidyl arginine deiminase-4 (PAD4) drives NET formation and liver fibrosis in experimental chronic liver injury. Wild-type (PAD4+/+) and PAD4-deficient (PAD4-/-) mice were chronically challenged twice weekly with carbon tetrachloride (CCl4, 1 ml/kg, i.p) or vehicle (corn oil) for 6 weeks, and samples were collected 24 hours after the final challenge. In separate studies, mice were challenged once, and samples were collected 24-48 hours later. Circulating NET biomarkers (e.g., myeloperoxidase (MPO)-DNA complexes) were elevated in chronic CCl4-challenged wild-type mice compared to vehicle, though surprisingly, intrahepatic NETs were rarely observed. In contrast to our hypothesis, PAD4 deficiency did not eliminate circulating NET markers in chronic challenge. Furthermore, PAD4 deficiency did not impact liver fibrosis assessed by picrosirius red labeling or the myofibroblast marker α-smooth muscle actin, but caused a modest, sex-specific decrease in hepatic collagen type I immunolabeling. Interestingly, plasma NET biomarkers and intrahepatic NETs were both increased following acute CCl4 challenge in a PAD4-dependent manner. Furthermore, PAD4 deficiency reduced coagulation activity after 24 h and decreased hepatocellular necrosis 48 h after challenge. Our studies ultimately suggest that PAD4 affects liver injury uniquely depending on the stage of disease, and that mechanisms of NET formation may occur independent of PAD4 in chronic liver injury.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030559","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":"Testing the effects of two different zebrafish exposure paradigms on transcriptomic-based chemical risk assessment using the flame retardant Triphenyl Phosphate.","authors":"Michael G Morash, Morgan W Kirzinger, John C Achenbach, Ananda B Venkatachalam, Joseph P M Hui, Susanne Penny, Kevin Stemmler, Joëlle Pinsonnault Cooper, Deborah E Ratzlaff, Cindy L A Woodland, Lee D Ellis","doi":"10.1093/toxsci/kfaf124","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf124","url":null,"abstract":"<p><p>In the zebrafish larval toxicity model, phenotypic changes induced by chemical exposure can potentially be explained and predicted by the analysis of gene expression changes at sub-phenotypic concentrations. The increase in knowledge of gene pathway-specific effects arising from the zebrafish transcriptomic model has the potential to enhance the role of the larval zebrafish as a component of Integrated Approaches to Testing and Assessment (IATA). In this paper, we compared the transcriptomic responses of triphenyl phosphate between two standard exposure paradigms, the Zebrafish Embryo Toxicity (ZET) and General and Behavioural Toxicity (GBT) assays. The ZET assay represents a developmental model with chemical exposure from 6-120 hours post fertilization (hpf), which covers organogenesis, while the GBT represents a juvenile model with exposure from 72-120 hpf, which occurs post-organogenesis. This comparison demonstrates both similarities and differences between the two assays. While both models identified similar xenobiotic metabolism pathways, the difference in exposure window length and the time of transcriptomic sampling between the two methods also yielded unique sets of affected pathways, demonstrating their complimentary nature. Both data sets support previously described effects of triphenyl phosphate on aquatic and mammalian systems. This work validates and strengthens the use of both exposure paradigms and continues to demonstrate that zebrafish larvae are a valuable tool in the context of IATA towards reduced reliance on the use of higher vertebrate derived data for chemical risk assessment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030674","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":"The case for Equilibrative Nucleoside Transporters in current regulatory guidance.","authors":"Lucy Martinez-Guerrero, Xinyi Tang, Sean Ekins, Stephen H Wright, Nathan J Cherrington","doi":"10.1093/toxsci/kfaf122","DOIUrl":"10.1093/toxsci/kfaf122","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970497","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":"Dermal absorption and metabolism of [14C]-C12 alkyl benzoate in Finsolv TN in human skin in vitro.","authors":"Jay Dawick, Lauren Kavanagh, Clive Roper, Kirsty Paris, Frank Toner, Richard Cubberley, Matthew Dent, Ruth Pendlington","doi":"10.1093/toxsci/kfaf082","DOIUrl":"10.1093/toxsci/kfaf082","url":null,"abstract":"<p><p>C12 alkyl benzoate is present in the commercial emollient cosmetic ingredient C12-15 alkyl benzoate (Finsolv TN). Finsolv TN is a mixture of linear and branched esters of benzoic acid and aliphatic alcohols where linear C12 alkyl benzoate is a representative homolog with the shortest alkyl C-chain and lowest molecular weight. A preliminary non-GLP in vitro skin penetration study which monitored dermal bioavailability of all C12-15 alkyl benzoate constituents using GC-MS was carried out which demonstrated C12 alkyl benzoate could be considered a worst-case representative constituent to determine dermal absorption of the overall substance. Subsequently, [14C]-C12 alkyl benzoate was mixed into Finsolv TN, and applied, neat (10 µl/cm2), to dermatomed human skin mounted in a flow-through diffusion cell system. Receptor fluid was collected up to 24 h postdose and the skin was decontaminated at 8 h postdose. The absorbed dose, dermal delivery, potentially absorbable dose and dermally absorbed value of [14C]-C12 alkyl benzoate were 0.41%, 0.97%, 2.20%, and 2.97%, respectively. Metabolism during absorption was assessed in skin from the same donors, with no C12 alkyl benzoate detected in the receptor fluid, although the primary metabolite, [14C]-benzoic acid (>93%), was detected. A phenyl acetate esterase assay confirmed the presence of esterase activity in the donor skins used. Therefore, this study confirmed that dermal exposure of C12-15 alkyl benzoate (Finsolv TN) results in an absorbed dose of 2.97% completely metabolized to benzoic acid and aliphatic alcohol(s) in human skin. These findings indicate that a more in-depth investigation and assessment of toxicokinetic behavior (specifically for occupational exposures via the skin) provide opportunities to develop exposure-led strategies to avoid unnecessary animal testing allowing registrants to fulfill obligations to adhere to the \"last resort\" principle under REACH.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"37-47"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275956","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":"Adapting existing toxicokinetic models to relate perfluoroalkyl and polyfluoroalkyl intake to biomarkers in humans.","authors":"Kara J Dean, Régis Pouillot, Jane M Van Doren, Sofia M Santillana Farakos","doi":"10.1093/toxsci/kfaf087","DOIUrl":"10.1093/toxsci/kfaf087","url":null,"abstract":"<p><p>Exposures to per- and polyfluoroalkyl substances (PFAS) are associated with various adverse health outcomes, and a wide range of PFAS compounds have been detected in human serum, the environment, and food. Toxicokinetic models, however, have been developed for only a subset of the compounds of interest. To facilitate reverse dosimetry and risk assessment for the less studied PFAS compounds in food, we developed and evaluated an approach to adapt existing toxicokinetic models for nonhuman primates to predict human serum levels. The approach was validated with perfluorooctanoic acid and perfluorooctanesulfonic acid data and applied to perfluorohexanesulfonate. Results indicate that the approach yields similar dosimetry estimates to those of other models, particularly those used for regulatory purposes, suggesting the methodology can be leveraged to inform decision-making in data-sparse spaces. Applying and adapting the framework will improve our ability to connect dietary PFAS exposures to endpoints of concern for a wide range of PFAS compounds.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"139-147"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144508423","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":"Chemical-induced heart defects using a transgenic zebrafish model.","authors":"Shujie Liu, Toru Kawanishi, Atsuko Shimada, Yuko Nukada, Masaaki Miyazawa, Hiroyuki Takeda, Junichi Tasaki","doi":"10.1093/toxsci/kfaf083","DOIUrl":"10.1093/toxsci/kfaf083","url":null,"abstract":"<p><p>Congenital heart defects (CHDs) are common birth defects attributed to genetic and environmental factors, such as pharmaceuticals and chemicals. Identifying modifiable environmental factors and understanding their impact on heart development is crucial for mitigating chemical-induced CHDs. Given the increasing number of chemical agents, efficient high-throughput systems are essential to evaluate their teratogenic potential during cardiovascular development, which is a major concern for chemical safety. In this study, we developed 3 transgenic zebrafish reporter lines, myl7:EGFP, kdrl:mRFP, and gata1:mKate2, which enable real-time visualization of myocardial and endocardial development and cardiac function based on blood flow. These transgenic embryos were used to investigate the teratogenic effects of chemicals well known to induce heart defects in mammals, including humans. Our real-time imaging revealed that the teratogens induced significant malformations in cardiac morphogenesis, including abnormal heart tube formation, incomplete cardiac looping, and reduced heart chamber size. These teratogens also disrupted the expression of cardiac progenitor markers, suggesting impaired cardiac progenitor development. These defects were detected at the early stages (4-48 h post-fertilization), suggesting that the stages of progenitor development to heart looping were most susceptible to teratogen exposure, i.e. the critical period for teratogen-induced heart defects. Functional defects, such as impaired blood flow, were observed using real-time imaging of the gata1-reporter line. This study demonstrates the utilization of transgenic zebrafish embryo models for high-throughput teratogenicity testing, which also allows us to analyze the mechanisms underlying chemical-induced heart defects. Therefore, our zebrafish models would contribute to the identification and reduction of risks associated with CHDs.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"57-73"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275955","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":"Neurotoxicants driving glial aging: role of astrocytic aging in non-cell autonomous neurodegeneration.","authors":"Pablo Reina-Gonzalez, Muhammet Ay, Monica Langley, Elizabeth Plunk, Rachel Strazdins, Abdulla Abu-Salah, Aiesha Anchan, Ahmed Shah, Souvarish Sarkar","doi":"10.1093/toxsci/kfaf088","DOIUrl":"10.1093/toxsci/kfaf088","url":null,"abstract":"<p><p>Astrocytes, the most abundant glial cells in the central nervous system (CNS), play essential roles in maintaining neuronal homeostasis, synaptic regulation, and blood-brain barrier integrity. However, these cells can undergo senescence-a cellular state characterized by irreversible growth arrest and the secretion of proinflammatory factors-in response to aging and pathological stressors, contributing to synaptic dysfunction and neurodegenerative diseases. This review examines the molecular mechanisms driving astrocytic senescence, including oxidative stress, DNA damage, and inflammatory signaling pathways such as NF-κB and the senescence-associated secretory phenotype. A particular focus is placed on the diverse array of known chemical inducers of astrocyte senescence, such as pesticides and heavy metals, which provide critical insights into the processes governing cellular aging in the brain. By analyzing the effects of these inducers, we highlight their implications for neurodegenerative disease progression and brain aging. Understanding astrocytic senescence offers new insights into age-related neuropathology and presents promising avenues for targeted therapies in neurodegenerative disorders induced by environmental toxicants.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"20-28"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664061","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":"Comparative review of human health reference values of the United States.","authors":"George M Woodall, Sarah E Kobylewski-Saucier, Rachel M Shaffer, April M Luke, Laura M Carlson","doi":"10.1093/toxsci/kfaf092","DOIUrl":"10.1093/toxsci/kfaf092","url":null,"abstract":"<p><p>Human health reference values (HHRVs) developed by US governmental agencies and professional organizations are derived for specific purposes related to their organizational or statutory mandates, and for individual chemicals or substance groups (e.g. manganese compounds). Choosing an appropriate chemical-specific value should be based on the risk assessment need and the specific exposure context, along with a basic understanding of the various types and the intended purposes of each available HHRV. In this overview, HHRVs have been broadly organized into 3 main categories: values for the general public, occupational exposure limits, and emergency response values. The goal of this overview is to equip the reader with a greater understanding of HHRVs, how they are meant to be applied, and key aspects to consider in selecting the most appropriate value. These key aspects include target population (e.g. general public of all ages vs. working-age adults), duration and frequency of exposure, health effect severity, confidence in the data set, use of well-documented and contemporary derivation methods, transparency and documentation of the value derivation, and the thoroughness of the review process. Chemical- and exposure scenario-specific needs should determine which HHRV is most appropriate; however, a most appropriate HHRV may not be available for every chemical and situation. Therefore, we present both considerations and limitations to guide the selection of an alternate HHRV based on suitability for the assessment scenario from among the available chemical-specific values.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"1-19"},"PeriodicalIF":4.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12533516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718731","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}