Toxicological Sciences最新文献

{"title":"Mast cells are key mediators in the pulmonary inflammatory response to formaldehyde exposure.","authors":"Matthew Gibb, Angela N Reinert, Troy Schedin, Daniel T Merrick, Jared M Brown, Alison K Bauer","doi":"10.1093/toxsci/kfaf025","DOIUrl":"10.1093/toxsci/kfaf025","url":null,"abstract":"<p><p>Formaldehyde (FA) is a common chemical linked to respiratory problems such as airway hyperresponsiveness and pulmonary inflammation. Due to its toxicological effects and ease of mass production, FA is also recognized as a significant chemical threat by the U.S. Department of Homeland Security. This study investigates the role of mast cells in the pulmonary inflammatory response to acute high-dose FA exposure. Using wild-type (C57BL/6J) and mast cell-deficient (KitW-sh) mouse models, we assessed the impact of oropharyngeal aspiration of FA on lung pathology. Our findings reveal that C57BL/6J mice experienced significant increases in cellular infiltration, altered immune cell populations, and changes in lipid mediator profiles. In contrast, KitW-sh mice exhibited significantly reduced inflammatory responses. Notably, the presence of mast cells was associated with enhanced dendritic cell migration and differential production of bioactive lipid mediators, such as specialized pro-resolving mediators and pro-inflammatory leukotrienes in C57BL/6J mice. These results highlight the crucial role of mast cells in the immune response to FA and suggest they could be therapeutic targets for treating FA-induced lung inflammation.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"180-190"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484016","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":"Mixed lineage kinase domain-like protein deficiency exacerbates early injury in a mouse model of acetaminophen hepatotoxicity.","authors":"Giselle Sanchez-Guerrero, David S Umbaugh, Sawyer H Smith, Jephte Y Akakpo, Hartmut Jaeschke, Anup Ramachandran","doi":"10.1093/toxsci/kfaf022","DOIUrl":"10.1093/toxsci/kfaf022","url":null,"abstract":"<p><p>An overdose of acetaminophen (APAP) is the leading cause of drug-induced hepatotoxicity and acute liver failure in the United States. It is established that the predominant mode of hepatocyte cell death after an APAP overdose is through necrosis, and it is now recognized that this occurs through regulated pathways involving RIP kinases. These kinases, along with the pseudo-kinase MLKL, are central players in classical necroptotic cell death. Despite the skepticism regarding the role of necroptosis in APAP-induced liver injury, recent research demonstrating necroptosis-independent roles for MLKL led us to re-examine the role of this pseudo-kinase in APAP pathophysiology. Treatment of Mlkl-/- mice with a moderate (300 mg/kg) overdose of APAP resulted in an exacerbation of liver injury at 6- and 12-h post-APAP as evidenced by elevated plasma alanine aminotransferase activities, and extensive necrosis accompanied by diminished glutathione levels. Interestingly, these differences between Mlkl-/- and wild-type mice were negated at the 24-h mark, previously scrutinized by others. At 6 and 12 h post-APAP, Mlkl-/- mice exhibited augmented translocation of AIF and Endonuclease G without affecting JNK activation, suggesting enhanced mitochondrial permeability transition in the absence of MLKL. Lack of MLKL also impacted autophagy, the unfolded protein response and endoplasmic reticulum stress, with decreased levels of p62 and LC3B and increased expression of CHOP and GRP78 at 6 h post-APAP. In essence, our findings illuminate a noncanonical role for MLKL in the early phases of APAP-induced liver injury, warranting further exploration of its influence on APAP pathophysiology.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"220-232"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of new approach methods for the assessment of data-poor chemicals.","authors":"Katie Paul Friedman, Russell S Thomas, John F Wambaugh, Joshua A Harrill, Richard S Judson, Timothy J Shafer, Antony J Williams, Jia-Ying Joey Lee, Lit-Hsin Loo, Matthew Gagné, Alexandra S Long, Tara S Barton-Maclaren, Maurice Whelan, Mounir Bouhifd, Mike Rasenberg, Ulla Simanainen, Tomasz Sobanski","doi":"10.1093/toxsci/kfaf019","DOIUrl":"10.1093/toxsci/kfaf019","url":null,"abstract":"<p><p>The use of new approach methods (NAMs), including high-throughput, in vitro bioactivity data, in setting a point-of-departure (POD) will accelerate the pace of human health hazard assessments. Combining hazard and exposure predictions into a bioactivity:exposure ratio (BER) for use in risk-based prioritization and utilizing NAM-based bioactivity flags to indicate potential hazards of interest for further prediction or mechanism-based screening together comprise a prospective approach for management of substances with limited traditional toxicity testing data. In this work, we demonstrate a NAM-based assessment case study conducted via the Accelerating the Pace of Chemical Risk Assessment initiative, a consortium of international research and regulatory scientists. The primary objective was to develop a reusable and adaptable approach for addressing chemicals with limited traditional toxicity data using a NAM-based POD, BER, and bioactivity-based flags for indication of putative endocrine, developmental, neurological, and immunosuppressive effects via data generation and interpretation for 200 substances. Multiple data streams, including in silico and in vitro NAMs, were used. High-throughput transcriptomics and phenotypic profiling data, as well as targeted biochemical and cell-based assays, were combined with generic high-throughput toxicokinetic models parameterized with chemical-specific data to estimate dose for comparison to exposure predictions. This case study further enables regulatory scientists from different international purviews to utilize efficient approaches for prospective chemical management, addressing hazard and risk-based data needs, while reducing the need for animal studies. This work demonstrates the feasibility of using a battery of toxicodynamic and toxicokinetic NAMs to provide a NAM-based POD for screening-level assessment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"74-105"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450271","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":"Developmental immunotoxicity study of tris(chloropropyl) phosphate in Hsd:Sprague Dawley SD rats exposed through dosed feed.","authors":"Victor J Johnson, Kristen Ryan, Michael I Luster, Arun Pandiri, Kristen Hobbie, Michelle Cora, Keith R Shockley, Gary R Burleson, Guanhua Xie, Dori R Germolec","doi":"10.1093/toxsci/kfaf006","DOIUrl":"10.1093/toxsci/kfaf006","url":null,"abstract":"<p><p>Tris(chloropropyl) phosphate (TCPP) is a member of organophosphate flame retardants used commonly as a replacement for polybrominated diphenyl ethers in consumer and commercial products. Flame retardants have been shown to modulate immune function in vivo and in vitro and there is evidence that at least some related compounds such as organophosphate pesticides can cause developmental immunotoxicity. Developmental immunotoxicology studies were conducted by administering 0, 2500, 5000, or 10,000 ppm TCPP in feed to pregnant Hsd:Sprague Dawley SD rats from gestation day 6 through weaning on postnatal day 28. Feed exposure to TCPP was continued in the F1 offspring until terminal euthanasia at ∼16 to 21 weeks of age when assessments for developmental immunotoxicity were conducted. Innate, humoral, and cell-mediated immune function were assessed in the F1 adults. The antibody-forming cells (AFCs) response to sheep red blood cells was reduced in male and female F1 rats in the 10,000 ppm treatment group but coincided with reduced bodyweights. The AFC response was also significantly reduced in male rats exposed to 5000 ppm where only moderate effects on bodyweights occurred. TCPP exposure affected baseline T-cell proliferation without stimulation; however, the relevance of this change for immunotoxicity risk is unknown. TCPP exposure did not affect cytotoxic T-lymphocyte activity. Only minor and inconsistent treatment-related effects on hematology, innate NK cell function, and immune cell population distributions in the spleen were observed. Taken together, these data indicate that TCPP has the potential to impact humoral immune responses following developmental exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"166-179"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256821","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":"Investigation of urinary miRNA profile changes in amphotericin B-induced nephrotoxicity in C57BL/6 mouse, Sprague-Dawley rats and Beagle dogs.","authors":"Adeyemi O Adedeji, Michael R Tackett, Genesis Tejada, James E McDuffie","doi":"10.1093/toxsci/kfaf029","DOIUrl":"10.1093/toxsci/kfaf029","url":null,"abstract":"<p><p>MicroRNA (miRNAs) have been associated with drug-induced kidney injury (DIKI). However, there are few reports on the utility of miRNAs, when monitoring for nephrotoxicity across multiple species. The purpose of this study was to assess the value of urinary miRNA profile changes as renal safety biomarkers, when monitoring for kidney injury in investigative toxicology studies. To this end, we evaluated urine miRNA expression levels in response to amphotericin B (AmpB)-induced nephrotoxicity in mice, rats, and dogs. The results showed that 35 miRNAs were significantly differentially expressed across the 3 species in response to the induced renal injuries. Dogs showed the highest number of miRNAs with significant changes. miR-205-5p and miR-31-5p were the most consistently altered miRNA biomarkers across all 3 species. In rodents, these 2 miRNAs were the most sensitive markers and showed comparable or better sensitivities than the previously published urine protein biomarkers with the same nephrotoxicant. In dogs, none of the upregulated miRNAs were as sensitive as urine clusterin protein as observed in a previously published study with AmpB. Taken together, these miRNAs could complement the more established urinary protein biomarkers in monitoring DIKI in mice, rats, and dogs. To our knowledge, this is the first report that demonstrates the comparative utility of urinary miRNAs for the early detection of DIKI across 3 nonclinical animal models.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"53-64"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558059","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":"Epidermal growth factor receptor in placental health and disease: pathways, dysfunction, and chemical disruption.","authors":"Anita A Waye, Jacob Moeller, Almudena Veiga-Lopez","doi":"10.1093/toxsci/kfaf024","DOIUrl":"10.1093/toxsci/kfaf024","url":null,"abstract":"<p><p>Formation of the placenta during gestation is required to support fetal growth and development. Derived from the placenta, trophoblast cells express nuclear and membrane-bound receptors. Among these receptors is the epidermal growth factor receptor (EGFR) which plays a key role in placental development. Activation of EGFR-mediated signaling in trophoblast cells regulates critical processes, such as proliferation, differentiation, invasion, and fusion during pregnancy, making it essential for normal placental formation. Dysfunction of EGFR in placental trophoblast cells has been associated with adverse pregnancy outcomes, including intrauterine growth restriction, preeclampsia, and preterm birth. Ubiquitous environmental chemicals, like polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorine pesticides, and bisphenols, have been reported to modulate EGFR signaling pathways, potentially contributing to placental dysfunction. This review explores the pivotal role of EGFR signaling in placental development and function, with a focus on how environmental chemicals interfere with EGFR-mediated pathways and placental cell functions as well as their implications for pregnancy outcomes. Findings presented herein underscore the need for further research into the effects of exposure to environmental chemicals on modulating EGFR signaling pathways in the context of placental health.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"11-27"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477039","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":"Cadmium exposure and osteoporosis: epidemiological evidence and mechanisms.","authors":"Cai Tang, Xingmin Lv, Lingling Zou, Yi Rong, Lu Zhang, Maoting Xu, Sheng Li, Guiquan Chen","doi":"10.1093/toxsci/kfaf031","DOIUrl":"10.1093/toxsci/kfaf031","url":null,"abstract":"<p><p>Cadmium (Cd) is a toxic heavy metal with a long biological half-life, exerting adverse effects on most tissues and organs in the human body. Inhalation, ingestion, and skin contact are the main ways of exposure to Cd. Bone is one of the target organs of Cd. The aging of the population has been considered as the reason for the high incidence rate of osteoporosis, but recent studies have emphasized that the risk of osteoporosis is related to Cd exposure. With the widespread use of Cd-containing materials in industrial and agricultural activities, the risk of Cd exposure is worrying. This review covers the epidemiological, in vivo, and in vitro studies on Cd exposure and osteoporosis. Epidemiological evidence has emphasized a positive association between Cd exposure and the occurrence rates of osteoporosis and fractures. Experimental studies have demonstrated that Cd induces osteoporosis through both direct and indirect pathways. The indirect pathway encompasses inducing renal dysfunction to impair calcium and phosphorus metabolism, whereas the direct pathway consists of directly influencing bone cells. This review aims to emphasize that Cd exposure may be an overlooked risk factor for osteoporosis and to elucidate the direct and indirect molecular mechanisms by which Cd induces osteoporosis. Understanding the pathogenesis of Cd-induced osteoporosis is crucial for the development of preventive and therapeutic strategies.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"1-10"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701423","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":"DNA adducts form in mouse lung and liver after oral naphthalene exposure.","authors":"Morgan C Domanico, Nicole M Collette, Esther Ubick, Xinxin Ding, Bruce A Buchholz, Laura S Van Winkle","doi":"10.1093/toxsci/kfaf017","DOIUrl":"10.1093/toxsci/kfaf017","url":null,"abstract":"<p><p>Naphthalene is a ubiquitous combustion product and environmental contaminant with known human exposure. Chronic exposure to naphthalene vapor leads to respiratory tumor formation in rodents. Naphthalene forms DNA adducts (precursors to genotoxicity) in tissue explants but it is unclear if this occurs in vivo. Wild-type C57BL/6 mice were orally exposed to 50 mg/kg 14C-naphthalene. Naphthalene-DNA adducts were detected by accelerator mass spectrometry at 2- to 72-h post-exposure in both lung and liver, with decreasing abundance over time. Adducts persisted even at 72-h after exposure, which indicates possible evasion of DNA repair and potential to contribute to mutagenesis.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"42-46"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374573","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":"ABBV-712-induced cardiac pathology in rats is related to off-target-driven acute vasodilation, tachycardia, and increased cardiac contractility.","authors":"Rebecca Kohnken, Stacey Fossey, Wayne R Buck, Jason Segreti, Jessica Treadway, Jonathon Green, Yevgeniya E Koshman, Mark Zafiratos, Scott Mittelstadt, Eric Blomme, Charles M Foley","doi":"10.1093/toxsci/kfaf021","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf021","url":null,"abstract":"<p><p>Following an observation of myocardial toxicity in rats with an experimental TYK2 inhibitor (ABBV-712), investigative studies were performed to identify the mechanism. Telemetry-instrumented rats were administered ABBV-712 with or without atenolol to investigate effects of co-dosing on hemodynamic parameters and cardiac pathology. In vitro studies included cytotoxicity assessment in human-induced pluripotent stem cell-derived cardiomyocytes and relaxation of isolated rat aorta. Off-target pharmacology was evaluated by binding and inhibition screening assays. Finally, TYK2 knockout mice were administered ABBV-712 to evaluate hemodynamics as compared with wild-type animals. ABBV-712 resulted in decreased mean arterial pressure and increased heart rate in rats that was prevented by pre-dosing atenolol. ABBV-712-induced myocardial necrosis was also prevented by atenolol, suggesting a mechanistic link between hemodynamic changes and cardiac pathology. The pathology was unrelated to direct cytotoxicity on cardiomyocytes as demonstrated in vitro and was shown to be a compound-related effect on vascular relaxation mediated by the endothelium. The toxicity was considered an off-target effect, as demonstrated by similar hemodynamic responses between TYK2 knockout and wild-type mice administered ABBV-712, as well as by the lack of hemodynamic alterations in the knockout mouse. Inhibition of identified off-targets was unlikely to be the cause of the hemodynamic changes. In conclusion. a novel TYK2 inhibitor was associated with decreased mean arterial pressure, increased heart rate, and secondary myocardial necrosis in rats. These effects were unrelated to TYK2 inhibition. This report is an example of a cross-functional mechanistic investigation into the pharmacologic cause of an identified cardiovascular toxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"205 1","pages":"233-244"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015609","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":"Comparisons of PK-Sim and R program for physiologically based pharmacokinetic model development for broiler chickens and laying hens: meloxicam as a case study.","authors":"Zhicheng Zhang, Lisa A Tell, Zhoumeng Lin","doi":"10.1093/toxsci/kfaf016","DOIUrl":"10.1093/toxsci/kfaf016","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic (PBPK) models play a critical role in evaluating drug residue concentrations and estimating withdrawal intervals (WDIs) for food-producing animals. These models are facilitated by various programming software (e.g. R program) and predefined PBPK platforms, such as Open Systems Pharmacology (OSP) suite integrated by PK-Sim and Mobi, which offers a user-friendly graphical interface. Both R and OSP are open-source software. However, there is a lack of comparative analyses of both platforms and their potential impact on PBPK models. This study aims to evaluate the influence of different platforms on PBPK workflow, parameters selection, and output results, which is exemplified via a case study for meloxicam in chickens in both platforms. Our findings indicate that while the choice of PBPK platforms affected the workflow and input parameters, the predictive performance of established models remained consistent across both platforms. Both platforms predicted meloxicam pharmacokinetics in plasma and tissues accurately across different exposure scenarios. The PBPK-estimated WDIs under various dosing regimens from both platforms were quite similar. Notable differences between OSP suite and R were primarily observed during sensitivity analysis and parameter identification processes, especially the time consumption. This study offers insight into software variances and their implications for translating PBPK modeling knowledge between users of 2 platforms. Also, it provides a PBPK model structure template implemented in both software platforms for food safety and risk assessment in poultry and a detailed tutorial on expanding the model structure in PK-Sim and Mobi.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"28-41"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400002","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}