Toxicological Sciences最新文献

Functional genomic analysis of non-canonical DNA regulatory elements of the aryl hydrocarbon receptor. 芳烃受体非规范DNA调控元件的功能基因组分析。

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-23 DOI: 10.1093/toxsci/kfaf146

Shayan Shahriar, Tajhal D Patel, Manjula Nakka, Sandra L Grimm, Cristian Coarfa, Daniel A Gorelick

{"title":"Functional genomic analysis of non-canonical DNA regulatory elements of the aryl hydrocarbon receptor.","authors":"Shayan Shahriar, Tajhal D Patel, Manjula Nakka, Sandra L Grimm, Cristian Coarfa, Daniel A Gorelick","doi":"10.1093/toxsci/kfaf146","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf146","url":null,"abstract":"The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental toxicants like halogenated and polycyclic aromatic hydrocarbons, which then binds to DNA and regulates gene expression. AHR is implicated in numerous physiological processes, including liver and immune function, cell cycle control, oncogenesis, and metabolism. Traditionally, AHR binds a consensus DNA sequence (GCGTG), the xenobiotic response element (XRE), recruits coregulators, and modulates gene expression. Yet, recent evidence suggests AHR can also regulate gene expression via a non-consensus sequence (GGGA), termed the non-consensus XRE (NC-XRE). The prevalence and functional significance of NC-XRE motifs in the genome have remained unclear. While ChIP and reporter studies hinted at AHR-NC-XRE interactions, direct evidence for transcriptional regulation in a native context was lacking. In this study, we analyzed AHR binding to NC-XRE sequences genome-wide in mouse liver, integrating ChIP-seq and RNA-seq data to identify candidate AHR target genes containing NC-XRE motifs in their regulatory regions. We found NC-XRE motifs in 82% of AHR-bound DNA, significantly enriched compared to random regions, and present in promoters and enhancers of AHR targets. Functional genomics on the Serpine1 gene revealed that deleting NC-XRE motifs reduced TCDD-induced Serpine1 upregulation, demonstrating direct regulation. These findings provide the first direct evidence for AHR-mediated regulation via NC-XRE in a natural genomic context, advancing our understanding of AHR-bound DNA and its impact on gene expression and physiological relevance.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145347504","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}

引用次数: 0

A cell-based Sonic hedgehog signaling transduction system to identify additive and synergistic chemical interactions. 一个基于细胞的Sonic hedgehog信号转导系统，用于识别添加剂和协同化学相互作用。

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-15 DOI: 10.1093/toxsci/kfaf143

Tyler G Beames, Joshua L Everson, Dhara A Desai, Kayla Y Perez, Elizabeth Wu, Johann K Eberhart, Robert J Lipinski

{"title":"A cell-based Sonic hedgehog signaling transduction system to identify additive and synergistic chemical interactions.","authors":"Tyler G Beames, Joshua L Everson, Dhara A Desai, Kayla Y Perez, Elizabeth Wu, Johann K Eberhart, Robert J Lipinski","doi":"10.1093/toxsci/kfaf143","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf143","url":null,"abstract":"Chemical co-exposures are important contributors to adverse biological responses yet remain poorly understood, especially in the context of prenatal development. Sonic hedgehog (Shh) signaling is an essential developmental pathway that is sensitive to small molecule disruption and directly linked to common and etiologically complex human birth defects. Numerous mechanistically diverse small molecule Shh pathway antagonists have been identified, but their interactions in pathway disruption have received minimal attention. We established a tractable co-culture model in which autonomous SHH ligand production initiates this complex inter- and intracellular signal transduction cascade and culminates in activation of a GLI-responsive luminescent reporter. Compounds reported to target SHH ligand processing (RU-SKI 43, AY 9944, U18666A), SMO-mediated signal transduction (cyclopamine, vismodegib, piperonyl butoxide, cannabidiol), and GLI transcription factors (GANT 61, arsenic trioxide) reduced Shh pathway-driven reporter activity with AC50 values in the low micromolar range or below. We then evaluated chemical interactions among Shh pathway inhibitors using isobolographic analysis. Co-exposure assays revealed additive interactions from combined SMO and GLI inhibition, while disruption of SMO and cholesterol dynamics synergistically decreased Shh pathway activity. Unexpectedly, piperonyl butoxide synergized with other SMO inhibitors, and further characterization of piperonyl butoxide's impacts on Shh signaling supported an additional mechanism of inhibition independent of SMO. In zebrafish embryos, combined exposure to piperonyl butoxide and cyclopamine also produced a synergistic increase in craniofacial dysmorphogenesis. These findings demonstrate the importance of tractable models that recapitulate complex signal transduction pathways to empirically test for additive and synergistic chemical interactions in risk assessment.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145303620","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}

引用次数: 0

The endothelial growth factor Angiopoietin-2 is an accurate prognostic biomarker in patients with acetaminophen-induced acute liver failure. 内皮生长因子血管生成素-2是对乙酰氨基酚诱导的急性肝衰竭患者的准确预后生物标志物。

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-15 DOI: 10.1093/toxsci/kfaf130

David S Umbaugh, Nga T Nguyen, Steven C Curry, Jody A Rule, William M Lee, Anup Ramachandran, Hartmut Jaeschke

{"title":"The endothelial growth factor Angiopoietin-2 is an accurate prognostic biomarker in patients with acetaminophen-induced acute liver failure.","authors":"David S Umbaugh, Nga T Nguyen, Steven C Curry, Jody A Rule, William M Lee, Anup Ramachandran, Hartmut Jaeschke","doi":"10.1093/toxsci/kfaf130","DOIUrl":"10.1093/toxsci/kfaf130","url":null,"abstract":"Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF) in the United States, with many patients rapidly progressing to hyperacute liver failure. While hepatocytes are the main target of APAP toxicity, endothelial cells (ECs) are also affected. However, the efficacy of an endothelial-specific biomarker to predict patient outcomes remains unknown. This study aimed to evaluate angiopoietin-2 (ANGPT2) as a prognostic biomarker for poor outcomes in APAP-induced ALF. Using human and mouse single-cell RNA sequencing data, we found that ANGPT2 expression was significantly elevated in ECs following APAP exposure. We measured circulating ANGPT2 levels in two independent APAP-ALF cohorts: a cohort from Phoenix (n = 43) and the ALF Study Group (n = 80). In the Phoenix cohort, ANGPT2 levels were significantly higher in non-survivors with an area under the receiver-operating-characteristic-curve (AUROC) of 0.938. In the ALF Study Group cohort, we stratified patients based on time of symptom onset, finding that ANGPT2 had improved prognostic value in early-presenting patients, with day 1 and 3 AUC values of 0.825 and 0.918, respectively. Lastly, we combined the patient cohorts (n = 110), finding that ANGPT2 alone or in combination with Model for End-Stage Liver Disease (MELD) score outperformed MELD alone based on AUC (ANGPT2: 0.87, MELD: 0.83, ANGPT2+MELD: 0.90). Conclusions: ANGPT2 is a promising prognostic biomarker for APAP-induced ALF, reflecting endothelial stress and offering superior predictive value compared to MELD alone, especially in early-presenting patients. Its capacity for predicting poor outcomes underscores its value in improving patient prognosis and therapeutic intervention strategies in APAP overdose cases.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145303658","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}

引用次数: 0

Cell Painting in HepaRG Cells: An Interlaboratory Reproducibility Study. HepaRG细胞的细胞绘画：一项实验室间可重复性研究。

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-13 DOI: 10.1093/toxsci/kfaf139

Eric Sherer, Wei Chen, Dillon Aberasturi, Ksheera Sagar, Yang Li, Zachary Sutake, Jiaqi Xu, Felix R Harris, Joshua A Harrill, Jessica LaRocca

{"title":"Cell Painting in HepaRG Cells: An Interlaboratory Reproducibility Study.","authors":"Eric Sherer, Wei Chen, Dillon Aberasturi, Ksheera Sagar, Yang Li, Zachary Sutake, Jiaqi Xu, Felix R Harris, Joshua A Harrill, Jessica LaRocca","doi":"10.1093/toxsci/kfaf139","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf139","url":null,"abstract":"Traditional toxicological safety assessment relies heavily on the use of animals, and animal-free new approach methodologies (NAMs) are therefore critical for increasing the efficiency and human relevance of chemical hazard screening. Cell Painting, a high-content imaging assay that quantifies phenotypic changes at the cellular level, is an approach that has been widely used in pharmacologic discovery purposes. In the present study, Cell Painting methodologies were adapted to the human liver cell line, HepaRG, given that the liver is a common target organ in standard repeat dose toxicological studies. The HepaRG cell line was selected for its expression of phase I and II enzymes and ability to metabolize xenobiotic chemicals, which are critical features for an in vitro toxicological assay to assess chemicals that could be extensively metabolized in vivo. An interlaboratory reproducibility assessment was conducted to optimize culture conditions, image acquisition, computational workflows for image segmentation and feature extraction, and derivation of phenotype altering concentrations (PACs). Two laboratories, the US EPA Center for Computational Toxicology and Exposure (Site 1), and Corteva Agriscience (Site 2), tested a set of 20 phenotypic reference chemicals in the HepaRG Cell Painting assay for derivation of PACs. The results from Site 1 and Site 2 were highly concordant both in terms PAC estimates and the profiles of phenotypic effects observed for the test chemicals. These results support the reproducibility and robustness of the Cell Painting assay in the metabolically competent HepaRG cell line, thereby providing a NAM with the potential to predict in vivo toxicity.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281140","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}

引用次数: 0

Toxicological Profile of Chemical Interference of Thyroid Hormone Metabolism via Deiodinase Enzymes In a Rodent Model. 在啮齿动物模型中通过脱碘酶对甲状腺激素代谢的化学干扰的毒理学概况。

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-13 DOI: 10.1093/toxsci/kfaf141

R Thomas, J Ford, C Kuehn, C Wood, Mg Hawks, S Degitz, Me Gilbert

{"title":"Toxicological Profile of Chemical Interference of Thyroid Hormone Metabolism via Deiodinase Enzymes In a Rodent Model.","authors":"R Thomas, J Ford, C Kuehn, C Wood, Mg Hawks, S Degitz, Me Gilbert","doi":"10.1093/toxsci/kfaf141","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf141","url":null,"abstract":"Thyroid hormones (TH) are highly iodinated molecules that regulate many aspects of mammalian physiology and are essential for normal growth and development. Deiodinases (Dio) are a family of metabolizing enzymes controlling systemic and local availability of the major TH secreted from the thyroid gland. Despite their critical role in TH regulation, the toxicological characterization of the effects of chemical interference of Dios in mammalian models has remained relatively underexplored. Here we investigated the effects of exposure to iopanoic acid (IOP), a potent in vitro inhibitor of Dio enzymes. Adult rats administered IOP (0, 1, 5, 10 and 50 mg/kg/day, oral gavage) for 14 days exhibited an increase in serum thyroxine (T4) and reverse T3 (rT3), consistent with an inhibition of deiodinase 1 (Dio1). To verify these serum TH effects were induced by IOP action on deiodination pathways, we examined Dio activity ex-vivo in liver from exposed animals. TH metabolites quantified by liquid chromatography mass spectrometry (LC-MS/MS) were used as the readout of Dio activity. Dose-dependent reductions in Dio1 and Dio3 activity were confirmed in hepatic microsomes prepared from IOP-exposed animals. The findings provide a signature pattern for serum TH change to assist translation of in vitro assays for this mode of action of environmental contaminants and interpretation of regulatory reports of serum TH profiles. By elucidating the mechanistic underpinning of chemical-induced perturbations of this critical TH metabolic pathway, the findings may inform risk-based decision making and serve to help to refine regulatory strategies for TH system disrupting compounds.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281207","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}

引用次数: 0

Contribution of particle-induced lysosome membrane permeabilization to NLRP3 inflammasome activation and mitochondrial ROS production. 颗粒诱导的溶酶体膜渗透对NLRP3炎性体激活和线粒体ROS产生的贡献。

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-10 DOI: 10.1093/toxsci/kfaf140

Jacob Albright, Andrij Holian

{"title":"Contribution of particle-induced lysosome membrane permeabilization to NLRP3 inflammasome activation and mitochondrial ROS production.","authors":"Jacob Albright, Andrij Holian","doi":"10.1093/toxsci/kfaf140","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf140","url":null,"abstract":"Nickel oxide nanoparticles (NiONPs) can trigger reactive oxygen species (ROS) production and NLRP3 inflammasome activation in macrophages as key steps in promoting lung inflammation. However, the impact of NiONP-induced lysosome membrane permeabilization (LMP) on mitochondrial ROS (mtROS) production and NLRP3 inflammasome activation is unknown. Murine ex vivo alveolar macrophages (mexAM) were exposed to NiONPs or crystalline silica (cSiO2) as a positive control particle. Imipramine was used to inhibit LMP before measuring mtROS and NLRP3 inflammasome activation and MitoTEMPO was used to block mtROS before measuring LMP and NLRP3 inflammasome activation. The ability of phagocytosed NiONPs to leach Ni2+ and stimulate ROS production was also assessed. Exposure to either particle resulted in LMP, mtROS production, and NLRP3 inflammasome activation with cSiO2 causing greater effects than NiONPs. LMP was rate-limiting in cSiO2-induced NLRP3 inflammasome activation and mtROS production, which further activated the inflammasome. Similar to cSiO2, NiONP-induced LMP was rate limiting in NLRP3 inflammasome activation. In contrast to cSiO2, NiONP-induced mtROS was detected whether or not LMP was inhibited. Furthermore, NiONP-derived Ni2+ ions were present in the cytosol whether or not LMP occurred, and Ni2+ release was proportional to measured mtROS production and hydroxyl radical formation. The inability of MitoTEMPO to block the effects of Ni2+ ions on mtROS production suggested an alternative unclear mechanism was involved. This study demonstrates that LMP serves as a pivotal upstream trigger of NLRP3 inflammasome activation and potentially ROS production in response to cSiO2 and NiONPs-underscoring the crucial role of lysosomes in particle-induced inflammation.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275992","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}

引用次数: 0

Effects of Urban PM2.5 on Primary Sinonasal Epithelial Cells in Individuals with Chronic Rhinosinusitis. 城市PM2.5对慢性鼻窦炎患者原发性鼻窦上皮细胞的影响

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-10 DOI: 10.1093/toxsci/kfaf142

Juliana Theorell, Jenny Drnevich, Vishal Verma, Sudheer Salana, Victoria S Lee, Robert M Sargis, Almudena Veiga-Lopez

{"title":"Effects of Urban PM2.5 on Primary Sinonasal Epithelial Cells in Individuals with Chronic Rhinosinusitis.","authors":"Juliana Theorell, Jenny Drnevich, Vishal Verma, Sudheer Salana, Victoria S Lee, Robert M Sargis, Almudena Veiga-Lopez","doi":"10.1093/toxsci/kfaf142","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf142","url":null,"abstract":"Fine particulate matter (PM2.5), airborne particles with an aerodynamic diameter of ≤ 2.5 µm, a major air pollutant, has been implicated in sinonasal inflammatory diseases such as chronic rhinosinusitis (CRS) even at levels below national air quality standards. PM2.5 is thought to exacerbate CRS by compromising the epithelial barrier, impairing mucociliary clearance, and promoting inflammation. However, evidence linking PM2.5 exposure to sinonasal epithelial remodeling remains limited. This study investigated the effects of environmentally relevant doses of urban PM2.5 organic extract (PM2.5 OE) on primary sinonasal epithelial cell cultures derived from individuals with and without CRS. We hypothesized that PM2.5 OE exposure would induce transcriptional changes indicative of mucociliary remodeling, reduce transepithelial resistance, and increase inflammatory cytokine production. Primary nasal epithelial cells from healthy (N = 8) and CRS subjects (N = 10) were differentiated in an air-liquid interface, followed by acute (24-h) and subacute (5-day) exposure to an environmentally relevant dose of PM2.5 OE (9 μg/mL; 1.34 µg/cm2) or the vehicle control. PM2.5 OE exposure did not significantly alter these outcomes, regardless of disease status. Instead, variation was primarily driven by biological sex and CRS, with male CRS samples exhibiting downregulation of cilia assembly pathways. Cytokine production from unexposed cultures demonstrated sex-specific differences, with female-derived cultures displaying a more pro-inflammatory profile, highlighting intrinsic immune variability. These findings underscore the importance of biological sex and disease status when evaluating environmental exposures suggesting that longer exposures may be necessary to fully capture PM2.5 OE-induced effects. This work highlights the need to investigate the crosstalk between environmental exposures and individual-specific factors influencing CRS disease progression.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275971","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}

引用次数: 0

The Differential Toxicity of Three Different Oxidized Nickel Compound Nanoparticles and the Effects of Particle Surface Ligands in Mouse Alveolar Macrophages. 三种不同氧化镍复合纳米颗粒对小鼠肺泡巨噬细胞的毒性差异及颗粒表面配体的影响。

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-08 DOI: 10.1093/toxsci/kfaf133

Rebekah L Kendall, Raymond F Hamilton, Jacob M Albright, Yu Zhao, Yingjie Hang, Chaoyun Tang, Dale Porter, Nianqiang Wu, Andrij Holian

{"title":"The Differential Toxicity of Three Different Oxidized Nickel Compound Nanoparticles and the Effects of Particle Surface Ligands in Mouse Alveolar Macrophages.","authors":"Rebekah L Kendall, Raymond F Hamilton, Jacob M Albright, Yu Zhao, Yingjie Hang, Chaoyun Tang, Dale Porter, Nianqiang Wu, Andrij Holian","doi":"10.1093/toxsci/kfaf133","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf133","url":null,"abstract":"Nickel-compound engineered nanomaterials (Ni-X NP) have diverse applications, yet their continued use raises concerns for potential health impacts on exposure. This study investigated three structurally distinct Ni-X-NP -pure NiO (NCZ), NiO@Ni(OH)2 (SIG), and Ni@NiO@Ni(OH)2 (AA)-to determine how core composition and surface functionalization contribute to bioactivity. Each Ni-X NP was modified with surface moieties (-OH, -COOH, and -CH3) to assess efficacy of surface modifications reducing bioactivity. Ni-X NP were thoroughly characterized for structure, surface chemistry, and Ni2+ ion release in simulated lysosomal fluid. Red blood cells (RBC) were used to evaluate hemolytic capabilities of the nanoparticles and primary murine alveolar macrophages (AM) and cultured murine ex vivo alveolar macrophages (mexAM) were used to assess uptake, cytotoxicity, IL-1β release, and lysosomal membrane permeability (LMP). Results showed that NiO@Ni(OH)2 nanoparticles induced the greatest hemolysis in RBC, elicited the greatest IL-1β response in AM and mexAM, and produced the most LMP in mexAM. The Ni@NiO@Ni(OH)2 nanoparticle released the most Ni2+ and caused profound reductions in AM cell viability but failed to cause RBC hemolysis or LMP. Pure NiO nanoparticles exhibited minimal bioactivity and low Ni2+ release. Surface modification with (-COOH) or (-CH3) effectively reduced bioactivity in LMP-mediated inflammation but had minimal effect on Ni2+-driven toxicity. This study reveals that Ni-X NP bioactivity depends on both core composition and surface chemistry, and that surface functionalization reduces inflammation only when lysosomal damage is the primary driver. These findings underscore the need for careful design and evaluation of engineered nanomaterials.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252726","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}

引用次数: 0

De-risking seizure liability: integrating adverse outcome pathways (AOPs), new approach methodologies (NAMs), and in silico approaches while highlighting knowledge gaps. 降低癫痫发作风险：整合不良结果途径（AOPs），新方法方法（NAMs）和计算机方法，同时突出知识差距。

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-01 DOI: 10.1093/toxsci/kfaf109

Mamta Behl, Agnes Karmaus, Mohan Rao, Thomas Lane, Joshua Harris, Clifford Sachs, Alexandre Borrel, Oluwakemi Oyetade, Aswani Unnikrishnan, Jonathan Hamm, Helena T Hogberg

{"title":"De-risking seizure liability: integrating adverse outcome pathways (AOPs), new approach methodologies (NAMs), and in silico approaches while highlighting knowledge gaps.","authors":"Mamta Behl, Agnes Karmaus, Mohan Rao, Thomas Lane, Joshua Harris, Clifford Sachs, Alexandre Borrel, Oluwakemi Oyetade, Aswani Unnikrishnan, Jonathan Hamm, Helena T Hogberg","doi":"10.1093/toxsci/kfaf109","DOIUrl":"10.1093/toxsci/kfaf109","url":null,"abstract":"Animal studies are commonly used in drug development and in chemical and environmental toxicology to predict human toxicity, but their reliability, particularly in the central nervous system (CNS), is limited. For example, animal models often fail to predict drug-induced seizures, leading to unforeseen convulsions in clinical trials. Evaluating environmental compounds, such as pesticides, also poses challenges due to time and resource constraints, resulting in compounds remaining untested. To address these limitations, a government-industry collaboration identified 27 biological target families linked to seizure mechanisms by combining key events from adverse outcome pathways (AOPs) with drug discovery data. Over a hundred in vitro assay endpoints were identified, covering 26 of the target families, including neurotransmitter receptors, transporters, and voltage-gated calcium channels. A review of reference compounds identified 196 seizure-inducing and 34 seizure-negative chemicals, with 80% being tested in the in vitro assays. However, some target familes were more data-poor than others, highlighting significant data gaps. This proof-of-concept study demonstrates how mechanistic seizure liability can be assessed using an AOP framework and in vitro data. It underscores the need for expanded screening panels to include additional seizure-relevant targets. By integrating mechanistic insights into early drug development and environmental risk assessment, this approach enhances compound prioritization, complements animal studies, and optimizes resource use. Ultimately, this strategy refines CNS safety evaluation in drug development, improves public health protection to neurotoxicants, and bridges knowledge gaps.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"306-319"},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12469190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715193","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}

引用次数: 0

TGx-DDI (Toxicogenomic DNA Damage-Inducing) Biomarker Validation: Multi-Site Ring Trial Supporting Regulatory Use. TGx-DDI（毒物基因组DNA损伤诱导）生物标志物验证：支持监管使用的多位点环试验。

IF 4.1 3区医学

Toxicological Sciences Pub Date : 2025-10-01 DOI: 10.1093/toxsci/kfaf138

Xiaotong Wang, Christine E Crute, Ashley Allemang, Jiri Aubrecht, Florence Burleson, Yasmin Dietz-Baum, Lena Dorsheimer, Albert Fornace, Roland Froetschl, Ulrike Hemmann, Constance A Mitchell, Stefan Pfuhler, Andrew Williams, Lorreta Yun-Tien Lin, Syril Pettit, Carole Yauk, Henghong Li

{"title":"TGx-DDI (Toxicogenomic DNA Damage-Inducing) Biomarker Validation: Multi-Site Ring Trial Supporting Regulatory Use.","authors":"Xiaotong Wang, Christine E Crute, Ashley Allemang, Jiri Aubrecht, Florence Burleson, Yasmin Dietz-Baum, Lena Dorsheimer, Albert Fornace, Roland Froetschl, Ulrike Hemmann, Constance A Mitchell, Stefan Pfuhler, Andrew Williams, Lorreta Yun-Tien Lin, Syril Pettit, Carole Yauk, Henghong Li","doi":"10.1093/toxsci/kfaf138","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf138","url":null,"abstract":"Standard in vitro genotoxicity assays often suffer from low specificity, leading to irrelevant positive findings that require costly in vivo follow-up studies. The TGx-DDI (Toxicogenomic DNA Damage-Inducing) transcriptomic biomarker was developed to address this limitation by identifying DNA damage-inducing compounds through gene expression profiling in human TK6 lymphoblastoid cells. To qualify TGx-DDI as a reliable, reproducible biomarker for augmenting genotoxicity hazard assessment, a multi-site ring-trial was conducted across four laboratories using 14 blinded test compounds and standardized protocols. TK6 cells were exposed to three concentrations of each compound, followed by RNA extraction and digital nucleic acid counting using the NanoString nCounter® platform. A three-pronged bioinformatics approach-Nearest Shrunken Centroid Probability Analysis, Principal Component Analysis, and Hierarchical Clustering-was used to assign DDI or non-DDI classifications. TGx-DDI demonstrated 100% sensitivity, 86% specificity, and 91% accuracy in distinguishing DDI from non-DDI compounds under validated test conditions. High inter-laboratory concordance was observed (agreement coefficients ≥ 0.61), and transcriptomic data showed strong cross-site correlation (Pearson r > 0.84). The biomarker reproducibly classified test agents even when conducted across study sites. These results demonstrate that TGx-DDI is a robust and reproducible transcriptomic biomarker that enhances the specificity of genotoxicity testing by distinguishing biologically relevant DNA damage responses. Its integration into genotoxicity testing strategies can support regulatory decision-making, reduce unnecessary animal use, and improve the assessment of human health risks.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201410","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}

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