Journal of Applied Toxicology最新文献

{"title":"A Repeated 28-Day Oral Dose Toxicity Study of Two Water Treatment Chemicals (Monoethanolamine and Monopropylamine) in Rats.","authors":"Jalal Hassan, Hadi Tabarraei, A Wallace Hayes, Hasti Khalili, Erfan Soroush, Niloofar Jafari, Shamsi Sadat Mosavi, Seyedeh Mandana Mojtahedzadeh, Mojtaba Ghadimi, Maryam Diansaei, Sina Montajab, Kiana Ghatei, Reyhaneh Kheiri, Asal Basiryanmahabadi, Kannan Subbaram, Parham Ziabakhsh, Melika Sohrabi, Anahita Massih, Donya Saberfard, Sanaz Naghdi, Phelipe Magalhães Duarte, Rasha Gharieb, Nafiseh Alinejad, Reihaneh Golchoobian, Sina Salajegheh Tazerji","doi":"10.1002/jat.4832","DOIUrl":"https://doi.org/10.1002/jat.4832","url":null,"abstract":"<p><p>With clean water becoming increasingly scarce, safe and effective treatment methods are essential. Chemical disinfectants like Monoethanolamine (MEA) and Monopropylamine (MPA) are widely used due to their cost-effectiveness, but their health risks remain unclear. To investigate the sub-chronic oral toxicity of two commercially used antiscalants to assess their potential health risks and to develop a safer and more sustainable water treatment methods, we conducted a 28-day study on 70 rats to assess their sub-chronic oral toxicity. Blood analysis revealed significant increases in WBC, MCV, MCH, PLT, and PCT levels, along with a notable rise in ALP (p < 0.05). Histopathological examination showed severe liver, heart, and lung damage, including necrosis, inflammatory cell accumulation, and tissue degeneration. These findings suggest that MEA and MPA pose serious health risks, raising concerns about their widespread use in water treatment. Given their potential impact on human health and the environment, it is crucial to reassess their safety and explore alternative disinfectants. Ensuring the long-term safety of water treatment methods is vital for public health and environmental sustainability, making further research and regulatory evaluation necessary.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317023","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":"A Novel Regulatory Network of Noncoding RNAs in the Cadmium-Induced Malignant Transformation of Human Bronchial Epithelial Cells.","authors":"Yueqing Shao, Pengya Zhao, Linlin Wang, Yanfang Yang, Lihua Huang","doi":"10.1002/jat.4838","DOIUrl":"https://doi.org/10.1002/jat.4838","url":null,"abstract":"<p><p>Long-term exposure to cadmium (Cd) is closely linked to an increased risk of lung cancer, yet the underlying mechanisms driving this malignant transformation remain elusive. Noncoding RNAs may hold the key to understanding the complex pathways involved in cadmium-induced carcinogenesis. This study reveals a novel regulatory network involving circ_000877, lnc237177, and miR-3192-5p, which targets cyclin-D1(CCND1) and matrix metalloproteinase 2 (MMP-2), thereby promoting the Cd-induced malignant transformation of human bronchial epithelial (16HBE) cells. Utilizing an established 16HBE malignant transformation model induced by Cd exposure, RNA sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) analyses indicated that both circ_000877 and lnc237177 were significantly upregulated. Functional assays further confirmed the roles of these molecules in facilitating malignant transformation. Mechanistically, circ_000877 and lnc237177 collaboratively targeted miR-3192-5p, thereby modulating both mRNA and protein expression levels of cyclin-D1 and MMP-2. Collectively, this study offers novel perspectives into the mechanism through which circRNA and lncRNA jointly regulate miRNA in a crosstalk network during Cd-induced malignant transformation, thereby enhancing our understanding of cadmium's toxicological impact.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317022","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":"Advances in Research on Neurotoxicity and Mechanisms of Manganese, Iron, and Copper Exposure, Alone or in Combination.","authors":"Ya-Qi Mo, Jian-Yuan Zhong, Meng-Jun Teng, Jian-Chao Peng, Hai Huang, Michael Aschner, Yue-Ming Jiang","doi":"10.1002/jat.4833","DOIUrl":"https://doi.org/10.1002/jat.4833","url":null,"abstract":"<p><p>Manganese (Mn), iron (Fe), and copper (Cu) are all essential trace elements for the human body; however, exposure to excessive amounts of these metals, either alone or in combination, can lead to neurotoxicity. Mn, Fe, and Cu can impair the nervous system through oxidative stress, apoptosis, and mitochondrial dysfunction. Mn disrupts dopamine neurogenesis through overexpression of α-synuclein (α-syn). Fe increases oxidative damage to lipids, proteins, and DNA through the Fenton reaction, leading to ferroptosis. Cu elevates nitrite oxide levels and inhibits the antioxidant system. Compared to exposure to individual metals, combined exposure to Mn and Fe results in less toxicity, suggesting an antagonistic effect. Combined exposure to Mn and Cu may exacerbate hepatocyte injury and mitochondrial dysfunction, leading to severe brain dysfunction. In Alzheimer's disease (AD), Fe and Cu contribute to the accelerated formation and accumulation of β-amyloid (Aβ) plaques, promote Fenton chemistry, and lead to the generation of reactive oxygen species (ROS) and localized neuroinflammation. However, the mechanistic basis of neurotoxicity arising from combined exposure to Mn, Fe, and Cu remains poorly understood, underscoring the need for further research to elucidate their synergistic effects and to inform prevention and therapeutic strategies for related neurodegenerative disorders.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317024","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":"The Role of miR-124-3p/UHRF1 in NaAsO₂-Induced Apoptosis of LX-2 Cells via DNMT1/SOCS1.","authors":"Mengyao Zhang, Mingxiao Ma, Yimi Wang, Shugang Li","doi":"10.1002/jat.4828","DOIUrl":"https://doi.org/10.1002/jat.4828","url":null,"abstract":"<p><p>The exact molecular mechanism underlying arsenic-induced liver injury remains elusive. In this study, we investigated the role of NaAsO₂ in promoting apoptosis in LX-2 cells via miR-124-3p/UHRF1 regulation of the DNMT1/SOCS1 axis. LX-2 cells were treated with different concentrations of NaAsO₂, miR-124-3p mimic, UHRF1 inhibitor NSC232003, and UHRF1 agonist. Cell viability, apoptosis, and the expression of related proteins and mRNA were assessed using CCK-8, immunofluorescence, flow cytometry, Western blot, and RT-qPCR. Compared with the control group, NaAsO₂ significantly reduced cell activity, increased the levels of pro-apoptotic proteins BAX and Caspase3, and decreased the expression of anti-apoptotic protein BCL2. Flow cytometry analysis confirmed a significant increase in the apoptosis rate. Following NaAsO₂ exposure, miR-124-3p expression was downregulated, while the mRNA and protein levels of UHRF1 and DNMT1 were upregulated, accompanied by reduced SOCS1 expression. Notably, co-treatment with either the miR-124-3p mimic or the UHRF1 inhibitor NSC232003 and NaAsO₂ significantly attenuated apoptosis, downregulated UHRF1 and DNMT1 expression, and restored SOCS1 levels compared with NaAsO₂ treatment alone. In summary, NaAsO₂ induces apoptosis in LX-2 cells by modulating the DNMT1/SOCS1 pathway through miR-124-3p/UHRF1 signaling. This study investigated the mechanism by which NaAsO₂ induces apoptosis in LX-2 cells through the regulation of miR-124-3p/UHRF1 and DNMT1/SOCS1. The experiments revealed that NaAsO₂ decreased cell viability, upregulated pro-apoptotic proteins BAX and Caspase3, downregulated anti-apoptotic protein BCL2, and increased the apoptosis rate. NaAsO₂ reduced the expression of miR-124-3p, increased the expression of UHRF1 and DNMT1, and inhibited SOCS1. The results indicated that miR-124-3p/UHRF1 regulation of DNMT1/SOCS1 played a role in NaAsO₂-induced apoptosis of LX-2 cells.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144284441","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":"Protective Effects of Squid Gonad Phospholipids Against Hepatotoxicity Induced by Multi-Glycoside From Tripterygium wilfordii (GTW): Inhibition of Inflammatory Response and Boost of GTW Metabolism in Zebrafish.","authors":"Ning Li, Jibin Liu, Te Zheng, Dan Li, Lei Zhang, Shanshan Zhang, Qing Xia, Rostyslav Stoika, Kechun Liu, Yun Zhang","doi":"10.1002/jat.4830","DOIUrl":"https://doi.org/10.1002/jat.4830","url":null,"abstract":"<p><p>Multi-glycoside from Tripterygium wilfordii Hook.f. (GTW) has shown clinical efficacy in suppressing immunological dysfunction, but is associated with severe hepatotoxicity. Phospholipids derived from marine organisms, particularly enriched in long-chain polyunsaturated fatty acids, possess various beneficial bioactivities and significant medicinal value. However, the antagonistic action of phospholipids against GTW-induced hepatotoxicity remains unclear. In this study, we explored the protective effect of squid gonads-derived phospholipids (SPLs) against GTW-induced hepatotoxicity using a zebrafish model. We evaluated the changes in a range of parameters following SPLs co-treatment, including liver morphology, histology, transaminase activities, microRNA-122 (miR-122) transcript level, and expressions of genes related to liver injury. The results indicated that SPLs significantly attenuated GTW-induced malformations and changes in the liver and yolk sac areas of zebrafish. The abnormal elevation of transaminase activities and dramatic downregulation of miR-122 induced by GTW were remarkably reversed by SPLs. Histological and ultrastructural examinations showed SPLs alleviated GTW-induced abnormalities in the liver tissue, including loose cell-to-cell contact, vacuolar structures, focal necrosis, and mitochondrial ultrastructural abnormalities. Moreover, SPLs significantly reversed the abnormal expressions of genes related to inflammation within the Myd88/NF-κB signaling pathway, and those involved in drug/xenobiotic metabolism. Molecular docking simulations revealed that these key inflammatory and drug metabolic regulators exhibited stable docking affinities with seven major components of SPLs. These findings suggest that SPLs may exert protective effects against GTW-induced hepatotoxicity, potentially through the inhibition of inflammatory responses and the restoration of GTW metabolism. Therefore, SPLs may serve as a promising therapeutic candidate for mitigating GTW-induced hepatotoxicity.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144284440","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":"Black Carbon, Oxidative Potential, and Zebrafish Toxicity: A Toxicological Study of PM_2.5 in Tennessee.","authors":"Voke Tonia Aminone, TuNha Pham, Courtney Roper","doi":"10.1002/jat.4831","DOIUrl":"https://doi.org/10.1002/jat.4831","url":null,"abstract":"<p><p>Fine particulate matter (PM_2.5) is a threat to human health and varies by location. PM_2.5 can cause oxidative stress, leading to serious health outcomes, especially during development. Additionally, black carbon (BC), a PM_2.5 component, is associated with developmental issues. This study analyzes the oxidative potential (OP) of PM_2.5 and utilizes zebrafish to analyze the developmental impacts of PM_2.5collected in 2 months from four locations in Tennessee. BC analysis was conducted on collected filters, while OP analysis was performed using the dithiothreitol (DTT) assay on extracted PM_2.5. The extracted PM_2.5 (pooled based on months and locations) and controls (vehicle, field blank) were used for developmental exposures in zebrafish (n = 33/treatment group). PM_2.5 and BC trended positively, and BC contribution in PM_2.5 ranged from 6% to 36%. There were no significant differences between sampling locations across months for PM_2.5 or BC. However, OP differed across locations and months, with significant differences between months at three out of our four locations. Zebrafish morphology was not altered following exposure to PM_2.5, but significant differences in the swim distances were observed between treatments and control groups as well as between PM_2.5-treated groups from different locations and months. The findings from this research provide insight into the oxidative and developmental effects of exposure to PM_2.5 and its components to ultimately support air pollution risk assessments incorporating mechanistic effects and subclinical biomarkers.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266343","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":"Toxicity Assessment of a Derivative Designed by Using the Privileged Structure Dihydropyridine: LQFM310, a Nifedipine Analog.","authors":"Amanda C Silva, Michele R Machado, Gerlon A R Oliveira, Gessyca G Costa, Gisele A R Oliveira, Luciano M Lião, Eric S Gil, Ricardo Menegatti, Gloria N S Silva","doi":"10.1002/jat.4829","DOIUrl":"https://doi.org/10.1002/jat.4829","url":null,"abstract":"<p><p>The privileged structures, such as dihydropyridine, are present in bioactive compounds exhibiting biological activities by interacting with multiple pharmacological targets. The dihydropyridine-containing compounds are usually related to the calcium channel-blocking abilities in the treatment of cardiovascular diseases, such as nifedipine. Other pharmaceutical applications have been described for these compounds, being a starting point for the obtaining of new drug candidates. The privileged structures are usually related to nontoxic effects; however, other chemical groups of dihydropyridine-containing compounds may result in impairment of the safety profile, such as nifedipine, described as teratogenic and embryotoxic in vivo. Here, we designed LQFM310 through the molecular hybridization strategy by incorporating the dimethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate scaffold from nifedipine and butyl hydroxytoluene (BHT). As the phenolic hydroxyl from BHT is capable of conferring antioxidant activity, the electrochemical analysis was performed. In addition, the toxicological profile of LQFM310 was investigated by using the embryo-larval stage of zebrafish (Danio rerio) and compared to nifedipine. As a result, LQFM310 demonstrated the antioxidant potential and did not induce significant lethal or sublethal effects in the toxicological assay. However, nifedipine induced 100% mortality in embryos and larvae from 25 μM for 96 h post fertilization (hpf) and sublethal effects at 10 μM. Therefore, LQFM310 demonstrated a safer profile than nifedipine in the zebrafish-based toxicity model, identifying that the nitroaromatic scaffold may be responsible for the toxicity effect of nifedipine. Considering the presence of privileged structures as dihydropyridine, LQFM310 is a promising compound for investigation in pharmacology assays of several diseases.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258168","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":"Revealing the Impact of Mono(2-ethylhexyl) Phthalate (MEHP) on Prostate Cancer Based on Network Toxicology and Molecular Docking Approaches.","authors":"Chenyu Liang, Weicheng Tian, Hengxi Zeng, Ziyang Xia, Zijie Luo, Yue Zhuo, Minlian Pan, Kangbu Wu, Siyu Xiong, Xuejing Lin, Xinchun Li, Jiaxi Yu","doi":"10.1002/jat.4826","DOIUrl":"https://doi.org/10.1002/jat.4826","url":null,"abstract":"<p><p>Mono(2-ethylhexyl) phthalate (MEHP) is a ubiquitous environmental contaminant and endocrine-disrupting chemical (EDC), identified as a potential carcinogen. Emerging studies have begun to elucidate the impact of MEHP on prostate cancer (PCa), yet its pathogenic effects and the underlying molecular mechanisms remain unclear. This study seeks to explore the molecular basis through which MEHP affects the onset and progression of PCa. Using network toxicology and bioinformatics, we identified MEHP-related pathogenic genes in PCa. An innovative predictive model was developed by employing multiple machine learning ensemble algorithms, and its performance was validated using the area under the receiver operating characteristic (ROC) curve. Furthermore, at the single-cell resolution, the role of key MEHP-associated molecules, including several critical genes, in the oncogenic progression of PCa was identified. Through the construction of an environmental pollutant-key gene-PCa network, we investigated the interactions between environmental pollutants and the key genes VGF, ASPN, FOXS1, APLN, and AMH. Molecular docking studies demonstrated that the APLN, FOXS1, and ASPN genes exhibited favorable binding energies and high affinities for MEHP. The findings of this study provide a theoretical foundation for understanding the pathogenic role of MEHP in PCa and its potential molecular mechanisms. They also promote the application of network toxicology, molecular docking, machine learning, and single-cell analysis in the study of environmental pollutants.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258164","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":"Occupational Health Risk Assessment of Heavy Metal Exposure `Among Gas Station Workers in Erbil City.","authors":"Sara Abdulkhaliq Yasin, Zhian Rashid Salih","doi":"10.1002/jat.4827","DOIUrl":"https://doi.org/10.1002/jat.4827","url":null,"abstract":"<p><p>The level of heavy metals (HMs) such as chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), mercury (Hg), lead (Pb), and vanadium (V) was measured in dust during July and August of 2024, from 39 different gas stations within Erbil city. The test was conducted to assess the contamination levels and the possible cancer and noncancer risks. The metal concentrations in mg/kg ranged from highest to lowest as follows: (Zn) 4912.41, (Mn) 1501.80, (Fe) 1287.23, (Cu) 543.72, (Pb) 365.34, (Cr) 201.54, (Ni) 164.07, (V) 124.78, (As) 111.74, (Co) 48.30, (Se) 1.17, and (Hg) 1.14 (mg/kg). Among the metals, Hg had the lowest concentration of 1.14 mg/kg, while Zn had the highest level of 4912.41 mg/kg. Each metal's noncancer and cancer risks through inhalation, ingestion, and dermal routes were estimated using the hazard quotient (HQ), hazardous index (HI), and cancer risk (CR). The computed hazardous quotient and hazardous index indicated no risk of noncarcinogenic effects of all metals, with a value of 3.45E-02. However, the carcinogenic risk results suggest that all metals pose a risk exceeding the local population's safe range, with a value of 2.69 E-04.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258163","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":"Pharmacokinetics and Pharmacodynamics of Recombinant Human Interleukin 12 in Dog and Rabbit Models of Toxicity.","authors":"Benjamin D Green, Peter C Soema, Heleen Kraan, Laura Hammer, Edith Mathiowitz, Dominick L Auci","doi":"10.1002/jat.4824","DOIUrl":"https://doi.org/10.1002/jat.4824","url":null,"abstract":"<p><p>Interleukin 12 (IL-12) is a potent pro-inflammatory Th1 cytokine with transient antitumor effects when given systemically. Local administration has recently shown more promising results, particularly when lower doses are delivered directly to tumor microenvironments, promoting anti-tumor T-cell immunity. In addition, IL-12 holds promise as a mucosal adjuvant. Renewed attention has led to novel delivery strategies that will necessitate pivotal non-clinical toxicology studies. Because recombinant human IL-12 (rhIL-12) is not functional in rodents, non-human primates (NHPs) have traditionally been used for these studies. However, their high cost and ethical concerns incentivize the search for alternative models. To this end, we examined the pharmacodynamics and pharmacokinetics of microencapsulated rhIL-12 in beagle dogs, which displayed expected transient IFNγ increases and hematopoietic and systemic effects similar to those seen in humans. Although New Zealand White (NZW) rabbits were hypothesized to be responsive to rhIL-12, no evidence of activity was observed, despite significant exposure in a study using microencapsulated rhIL-12. These results support beagle dogs as a useful alternative to NHPs for rhIL-12 toxicology studies, while ruling out NZW rabbits as a suitable model. Moreover, sex-based pharmacokinetic differences were observed, which might explain enhanced efficacy with microencapsulated rhIL-12 in several animal models.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215944","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}