International Journal of Toxicology最新文献

{"title":"Differential Activation of Peroxisome Proliferator-Activated Receptor Alpha by Per- and Polyfluoroalkyl Substances.","authors":"Mary Helen Kanitz, Cynthia Striley","doi":"10.1177/10915818251393212","DOIUrl":"10.1177/10915818251393212","url":null,"abstract":"<p><p>Per- and polyfluoroalkylated substances (PFAS) are persistent anthropogenic chemicals widely distributed in the environment that are known to have toxic effects in animals and humans following exposure. Some PFAS have been shown to activate peroxisome proliferator-activated receptor α (PPARα), a transcription factor involved in lipid metabolism, leading to dyslipidemia or liver toxicity. PFAS comprise a wide range of compounds, and variations in their structural characteristics could reveal important details regarding the level of PPARα activation. In this work, using a Chemically Activated LUciferase eXpression (CALUX) assay, we experimentally tested the PPARα activation efficiency of several PFAS compounds of varying chain lengths and functional groups. Activation and potency were compared across and within PFAS class based on chemical differences. When compounds with the same number of carbons or perfluorinated carbons were compared across class, the rank from high to low activator class remained the same. Perfluorocarboxylated ether was found to be the strongest class, while polyfluorotelomer was the weakest, suggesting the importance of structural features in PPARa activation. Perfluorocarboxylates were consistently better PPARα activators than perfluorosulfonates. Comparing within these 2 classes, the number of perfluorinated carbon atoms better predicted activation than the number of carbon atoms. In the perfluorocarboxylated ether, perfluorocarboxylate, and perfluorosulfonate classes, a direct correlation existed between potency and the percentage of PPARα activation (R² = 0.702), a novel observation. These findings provide new insights regarding distinct chemical characteristics of PFAS compounds which may be predictive of PPARα activation level.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"258-264"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145495381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibitory Effects and Characteristics of Byakangelicol on the Activity of Multiple Cytochrome P450 Isoforms.","authors":"Ting Lin, Xiao He, Pingfa Lin, Ying Chang","doi":"10.1177/10915818251382082","DOIUrl":"10.1177/10915818251382082","url":null,"abstract":"<p><p>Byakangelicol, a furanocoumarin derived from <i>Angelica dahurica</i>, possesses anti-inflammatory and antitumor activities. Since cytochrome P450 2A6 (CYP2A6) is the major enzyme responsible for coumarin metabolism, it is important to evaluate the effect of byakangelicol on CYP enzyme activity. The purpose was to explore the effects of byakangelicol on CYPs and to provide a reference for its drug development and clinical application. The present study investigated the impact of byakangelicol on CYPs in human liver microsomes (HLMs). Byakangelicol demonstrated the capacity to suppress the activities of CYP1A2, 2A6, and 3A4 in HLMs, with IC₅₀ values of 19.42, 10.11, and 12.80 μM, respectively. Byakangelicol exhibited competitive inhibition of CYP1A2 and 2A6 with <i>K</i>_<i>i</i> values of 9.86 μM and 5.23 μM, whereas the inhibitory effect on CYP3A4 was noncompetitive with a <i>K</i>_<i>i</i> value of 6.55 μM. In addition, the inhibitory effect of byakangelicol on CYP3A4 was found to be time-dependent (<i>K</i>_<i>inact</i> = 0.041 min^-1 and <i>K</i>_<i>I</i> = 6.67 μM). This study revealed the inhibitory properties of byakangelicol on CYP1A2, 2A6, and 3A4 activity in HLMs. It suggests the potential for drug-drug interactions when byakangelicol is co-administered with drugs metabolized by these CYPs. These findings offer a foundation for investigating the interaction of byakangelicol with other drugs, which may assist in clinical prescription and drug development.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"279-286"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges and Opportunities of Cosmeceutical Regulations: A Global Perspective.","authors":"Munish Thakur, Rajni Bala","doi":"10.1177/10915818251399664","DOIUrl":"10.1177/10915818251399664","url":null,"abstract":"<p><p>The international cosmeceutical sector has experienced unprecedented expansion, compelling regulatory bodies to enhance and update systems to tackle consumer protection, product effectiveness, and ethical issues. This review critically evaluates and contrasts regulatory settings in key markets, such as the European Union, United States, Canada, Japan, China, India, and Brazil. The examination is concentrated on key features including product definitions, pre-market approval procedures, and ingredient regulation, labeling requirements, post-market surveillance, and integrating ethical and environmental considerations. The outcome shows significant advances in regulatory harmonization, especially in the area of ingredient safety and adverse event reporting; however, there are still considerable challenges. Pioneering among these are the lack of a standard definition for \"cosmeceuticals,\" highly variable ingredient limitations, and uneven application practice across jurisdictions. The speedy growth of e-commerce and cross-border sales additionally complicates regulatory control, adding to the possibility of non-compliant or counterfeited products reaching consumers. The review also identifies a shortage of empirical evidence to document the actual impact of recent regulatory reforms in the real world, as well as on innovation and market access. The present study recommends the promotion of international harmonization of standards, enhancement of post-market surveillance, convergence of ethical and sustainability dimensions, and targeted support for small- and medium-sized enterprises. Henceforth, while important progress has been achieved, the future of the industry rests on creating nimble, science-informed, and internationally harmonized regulatory systems that can keep pace with changing technologies and consumers' and public health priorities, ensuring both consumer safety and industry innovation.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"303-313"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the Neurotoxicity of Bisphenol A Using Network Toxicology, Molecular Docking, and Molecular Dynamics Simulation.","authors":"Wanyu Huang, Xuanyu Lin, Shuang Li, Wenzong Zhu","doi":"10.1177/10915818251396291","DOIUrl":"10.1177/10915818251396291","url":null,"abstract":"<p><p>Bisphenol A (BPA) is a prevalent environmental endocrine disruptor with potential impacts to the neurological system in humans. This study used an integrated method combining network toxicology, molecular docking, and molecular dynamics simulations to explore the molecular mechanisms underlying BPA-induced neurotoxicity. We identified 255 potential neurotoxicity-related targets through the integration and comprehensive analysis of multiple data sources, including the Comparative Toxicogenomics Database (CTD), ChEMBL, STITCH, GeneCards, and the Online Mendelian Inheritance in Man (OMIM) database. Analysis of the protein-protein interaction (PPI) network unveiled 52 core targets, among which TNF, TP53, INS, ESR1, and PTGS2 emerged as pivotal hubs in the toxicity network. Functional enrichment analysis indicated that the core targets of BPA's influence on neurotoxicity are predominantly enriched in vital signaling cascades, including inflammatory responses, pathways of neurodegeneration, MAPK signaling pathway, serotonergic synapse pathway, and pathways in cancer. Molecular docking results demonstrated that BPA exhibited stable binding interactions with core targets. Furthermore, molecular dynamics simulations provided insights into the interactions between BPA and key targets (ESR1, TNF, and TP53), supporting the potential conformational stability of these complexes. Collectively, these computational findings contribute to understanding the potential molecular mechanisms of BPA-induced neurotoxicity and are informative for generating hypotheses related to its pathogenesis.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"265-278"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145633776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editor's Note.","authors":"","doi":"10.1177/10915818261431887","DOIUrl":"10.1177/10915818261431887","url":null,"abstract":"","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"231"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two-Year Inhalation Studies in Mice and Rats With HFO-1234ze(E), a Near Zero Global Warming Potential Propellant for Use in Pressurized Metered Dose Inhalers.","authors":"Paul Giffen, Matthew Jacobsen, James Cartwright, Rhiannon Hall, Natalie Waterhouse, Paul Carter, Jim Saul, Lindsay Wright, Per Aberg, Stefan Platz","doi":"10.1177/10915818251384607","DOIUrl":"10.1177/10915818251384607","url":null,"abstract":"<p><p>HFO-1234ze(E) is being developed as a next-generation propellant (excipient), with near zero global warming potential, for use in pressurized metered dose inhalers. In accordance with regulatory guidance, an assessment of the carcinogenic potential of HFO-1234ze(E) was required to gain regulatory approval as a new excipient. HFO-1234ze(E) was therefore evaluated in two-year carcinogenicity studies in mice and rats by the inhalation route of administration. Study assessments included in-life observations, organ weights, histopathology, and hematology. Group mean (sex combined) inhaled doses were 2132, 6218, and 21,193 mg/kg/day in mice and 379, 120,8 and 3918 mg/kg/day in rats; in both studies, control animals were exposed to air alone under the same conditions as HFO-1234ze(E)-exposed animals. HFO-1234ze(E) was well tolerated at all doses. There were no HFO-1234ze(E)-related in-life effects and no neoplastic or non-neoplastic findings or effects on hematology in either study. In summary, HFO-1234ze(E) was not carcinogenic in mice or rats. These data support the use of HFO-1234ze(E) as a medical propellant.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"247-257"},"PeriodicalIF":1.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13156415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145389735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced Glycation End Products Induce Cuproptosis and Then Promote the Activation and Migration of Cardiac Fibroblasts.","authors":"Jian Xiao, Zan-Hua Shi, Xin-Hua Ma, Dao-Miao Xu, Guang-Feng Ming","doi":"10.1177/10915818261443964","DOIUrl":"https://doi.org/10.1177/10915818261443964","url":null,"abstract":"<p><p>Excessive advanced glycation end products (AGEs) can lead to cardiovascular diseases such as myocardial fibrosis (MF). Although studies have found that AGEs induce cuproptosis, and cuproptosis promotes fibrosis, it has not been confirmed whether AGEs promote MF through cuproptosis. AGEs increased intracellular copper levels, promoted the expression of solute carrier family 31 member 1 (SLC31A1), and downregulated the expression of ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS), lipoylated (Lip)-dihydrolipoamide S-succinyltransferase (DLST), and Lip-dihydrolipoamide S-acetyltransferase (DLAT) in cardiac fibroblasts (CFs). All of these key cuproptosis regulatory gene expression abnormalities indicate that cuproptosis is induced. AGEs also decreased adenosine triphosphate content and inhibited the activities of mitochondrial complexes I and III, but these regulatory effects were significantly weakened after SLC31A1 downregulation. Meanwhile, AGEs significantly promoted the expression of alpha smooth muscle actin, collagen I, collagen III, and transforming growth factor-β1, while SLC31A1 siRNA or copper chelator ammonium tetrathiomolybdate (TTM) blocked these promoting effects. Similarly, CuCl₂ also induced fibrosis gene expression, while SLC31A1 overexpression (SLC31A1-O) further enhanced these effects, but TTM reduced CF activation induced by CuCl₂ plus SLC31A1-O. In addition, AGEs significantly promoted cell migration and enhanced the expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9, while SLC31A1 siRNA or TTM weakened these effects. SLC31A1-O plus copper treatment also had similar effects to AGEs, and these effects could also be blocked by TTM. Therefore, AGEs enhance copper transport by promoting SLC31A1 expression, which leads to intracellular copper overload and then induces cuproptosis, and finally promotes CF activation and migration.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"10915818261443964"},"PeriodicalIF":1.0,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Industry Perspective on Key Considerations for the ICH S13 Guidance: Nonclinical Safety Evaluations of Oligonucleotide-Based Therapeutics.","authors":"Jennifer D Sisler, Patrik Andersson, Alan Brown, Carole Harbison, Onyi Irrechukwu, Helen Lightfoot, Michaël Maes, Sucheta Mukherjee, Joel D Parry, Justin Schumacher, Anna Westlind Johnsson, Yi Yang, Tod A Harper","doi":"10.1177/10915818261417235","DOIUrl":"10.1177/10915818261417235","url":null,"abstract":"<p><p>Oligonucleotide therapeutics (ONTs) are a growing class of nucleic acid-based therapies with the potential to treat a variety of diseases through several different mechanisms of action (MoA). The most prevalent MoA entails the inhibition of therapeutically relevant levels of protein expression via mRNA degradation, exemplified by numerous approved ONTs. ONTs have unique physicochemical properties, pharmacokinetic characteristics, and MoAs that are distinct from other drug classes. The result can be a disconnect between the administered dose, plasma drug concentrations, pharmacodynamics, and toxicity. Thus, ONT development poses unique scientific and regulatory challenges that are not fully addressed by current International Council for Harmonisation (ICH) guidelines. The complexity of ONT development has recently been recognized with the acceptance of the new ICH topic proposal \"ICH S13-Nonclinical Safety Evaluation of Oligonucleotide-based Therapeutics.\" In preparation for the ICH S13 Step 2 public consultation period, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) DruSafe ONT Working Group convened to identify and discuss key considerations for ONT development, and to communicate areas where regulatory clarity and harmonization are most needed. Specifically, these include strategies to assess off-target toxicities, safety pharmacology, general toxicity studies, First-In-Human dose selection, genotoxicity studies, reproductive and developmental toxicity studies, carcinogenicity assessments, and the appropriate use of a surrogate molecule in development. The intended goals of this paper are to provide a means for communicating input towards the ICH process and to provide a resource for assisting with the public review of the draft ICH S13 Guidance.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"127-135"},"PeriodicalIF":1.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13053874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathology as a Core Discipline in the Biological Evaluation of Medical Devices.","authors":"Kathleen A Funk, JoAnn C L Schuh, Brad Bolon, Valerie Thomas, Jeffrey I Everitt, Abraham Nyska, Jaime Paulin","doi":"10.1177/10915818251388381","DOIUrl":"10.1177/10915818251388381","url":null,"abstract":"<p><p>The device development process encompasses an intersection of biological, physical, and engineering sciences principles culminating in translation of data from nonclinical animal studies to predict potential tissue responses in human patients. Evaluation of tissue reactions to the implanted device relies heavily on the core discipline of toxicologic pathology. Historically and currently, a disconnect between physical and biological scientists is highlighted by the frequent miscommunications due to differences in scientific language and divergent approaches to animal study design and/or data generation and interpretation. To facilitate communication among biologists, engineers, and materials scientists in the medical device community, this article provides fundamental principles and key resources necessary for rational pathology evaluation of tissue responses to implanted devices from the expert perspective of experienced toxicologic pathologists. The unique contributions of toxicologic pathologists to developing and marketing medical devices will be discussed, emphasizing the role of expert pathologists in balancing scientific issues with respect to evaluating biological responses and regulatory considerations. Additionally, discrepancies will be addressed that may arise if regulatory guidance is applied rigidly rather than adjusted as warranted by the context-specific evidence to best answer particular safety-related questions.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"157-170"},"PeriodicalIF":1.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ozone Preexposure Exacerbates Septic Lung Injury Through ADAR1 Modulation and Pyroptosis Activation.","authors":"Quanzhen Wang, Yajun Liu, Yuke Zhang, Lei Zhou, Tiangang Zhou, Fen Liu, Huanqin Chen, Zhiming Jiang","doi":"10.1177/10915818251391421","DOIUrl":"10.1177/10915818251391421","url":null,"abstract":"<p><p>Chronic ozone exposure in urban environments compromises lung function, predisposing individuals to severe sepsis outcomes from common infections. Pyroptosis, a type of programmed cell death, is implicated in sepsis and lung injury, and its regulation is crucial for understanding disease severity. We focused on pyroptosis due to its role in inflammation, tissue damage, and organ dysfunction in septic patients, as well as its link to ozone exposure through inflammasome activation. To elucidate the underlying molecular mechanisms, we integrated bioinformatics and experimental approaches. We analyzed public genomic data repositories to identify pyroptosis-related genes and those linked to sepsis and ozone-induced lung injury. Three pyroptosis-related genes (caspase-1, interleukin-1β, and gasdersmin D) were upregulated, while adenosine deaminase acting on RNA 1 (ADAR1) was downregulated. To validate these findings, mice were exposed to ozone followed by lipopolysaccharide-induced sepsis. After 12 hours, lung tissue damage, inflammation, and pyroptosis were assessed. Two-way ANOVA revealed significant LPS × ozone interactions, with one-way ANOVA showing dose-dependent ozone effects on inflammation and pyroptosis. Results confirmed the bioinformatics predictions, showing ADAR1 levels initially increased in septic mice but declined with ozone exposure. Concurrently, ozone exacerbated caspase-1-mediated pyroptosis in lung tissue. Our findings demonstrate that ozone preexposure worsens septic lung injury by modulating ADAR1 and pyroptosis. By elucidating the ADAR1-pyroptosis interplay, this study highlights a novel mechanism contributing to the pathogenesis of ozone-induced lung injury in sepsis, revealing ADAR1 as a key regulatory molecule.</p>","PeriodicalId":14432,"journal":{"name":"International Journal of Toxicology","volume":" ","pages":"198-211"},"PeriodicalIF":1.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145504077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}