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Perfluorooctanoic acid increases serum cholesterol in a PPARα-dependent manner in female mice.
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-03-01 DOI: 10.1007/s00204-025-03984-7
G Nielsen, D D Gondim, M C Cave, W J Heiger-Bernays, T F Webster, J J Schlezinger
{"title":"Perfluorooctanoic acid increases serum cholesterol in a PPARα-dependent manner in female mice.","authors":"G Nielsen, D D Gondim, M C Cave, W J Heiger-Bernays, T F Webster, J J Schlezinger","doi":"10.1007/s00204-025-03984-7","DOIUrl":"https://doi.org/10.1007/s00204-025-03984-7","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are a large group of persistent chemicals that are pervasive in the environment leading to widespread exposure for humans. Perfluorooctanoic acid (PFOA), one of the most commonly measured PFAS in people, disrupts liver and serum lipid homeostasis as shown in animal toxicity and human epidemiological studies. We tested the hypothesis that the effects of PFOA exposure in mice expressing mouse PPARα (mPPARα) are driven largely through PPARα-dependent mechanisms while non-PPARα dependent mechanisms will be more apparent in mice expressing human PPARα (hPPARα). Female and male mPPARα, hPPARα, and PPARα null mice were exposed to PFOA (0.5, 1.4 or 6.2 mg PFOA/L) via drinking water for 14 weeks. Concurrently, mice consumed an American diet containing human diet-relevant amounts of fat and cholesterol. Here, we focused on the effects in female mice, given the dearth of data reported on PFAS-induced effects in females. Increasing the duration of PFOA exposure reduced weight gain in all genotypes of female mice while end-of-study body fat was lower in PFOA exposed hPPARα and PPARα null mice. Serum cholesterol, but not triacylglyceride, concentrations were increased by PFOA exposure in a PPARα-dependent manner. Hepatic triacylglycerides were higher in vehicle-exposed mPPARα and PPARα null mice than hPPARα mice, and PFOA significantly reduced concentrations in mPPARα and PPARα null mice only. In contrast, PFOA increased hepatic cholesterol content in a PPARα-dependent manner. Changes in liver and serum cholesterol may be explained by a strong, PPARα-dependent downregulation of Cyp7a1 expression. PFOA significantly increased PPARα target gene expression in mPPARα mice. Other nuclear receptors were examined: CAR target gene expression was only induced by PFOA in hPPARα and PPARα null mice. PXR target gene expression was induced by PFOA in all genotypes. Results were similar in male mice with two exceptions: (1) vehicle-exposed male mice of all genotypes were equally susceptible to diet-induced hepatic steatosis; (2) male mice drank less water, resulting in lower serum PFOA levels, which may explain the less significant changes in lipid endpoints. Overall, our results show that PFOA modifies triacylglyceride and cholesterol homeostasis independently and that PPARα plays an important role in PFOA-induced increases in liver and serum cholesterol.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Metabolic activation and cytotoxicity of ibudilast mediated by CYP3A4.
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-02-28 DOI: 10.1007/s00204-025-03995-4
Lingwen Dong, Xialing Hao, Minglu Liu, Yanjie Zhai, Xu Wang, Xiaobao Tian, Weiwei Li, Ying Peng, Jiang Zheng
{"title":"Metabolic activation and cytotoxicity of ibudilast mediated by CYP3A4.","authors":"Lingwen Dong, Xialing Hao, Minglu Liu, Yanjie Zhai, Xu Wang, Xiaobao Tian, Weiwei Li, Ying Peng, Jiang Zheng","doi":"10.1007/s00204-025-03995-4","DOIUrl":"https://doi.org/10.1007/s00204-025-03995-4","url":null,"abstract":"<p><p>Ibudilast (IBD) is a relatively nonselective inhibitor of phosphodiesterase, commonly used for treating asthma, progressive multiple sclerosis and other neuropathological pain conditions. Although IBD was considered safe and harmless to human health, its clinical use might be associated with reported increases of serum AST and ALT as well as liver weight. However, the mechanisms behind such liver injury are still unknown. The purpose of this work was to investigate metabolic activation of IBD and to define correlation between bioactivation and hepatotoxicity of IBD. Two oxidative metabolites, IBD-derived glutathione (GSH) conjugates (M1, M2), N-acetyl-L-cysteine (NAC) conjugates (M3, M4), and cysteine (Cys) conjugates (M5, M6) were detected in mouse liver microsomes fortified with IBD (100 μM) and trapping agents GSH, NAC, or Cys, respectively, and two GSH conjugates (M1 and M2), one NAC conjugate (M4) and one Cys conjugate (M5) were detected. Similar observation was obtained in human liver microsomal incubations. The formation of M1-M6 was NADPH-dependent. Moreover, biliary GSH conjugates and urinary NAC conjugates derived from IBD were detected in mice given IBD intragastrically at 100 mg/kg. The metabolism study suggested the formation of an epoxide intermediate. In addition, the epoxide intermediate was found to react with cysteine residues of hepatic protein in a dose-dependent manner. Further studies indicate that CYP3A4 dominated the metabolic activation of IBD. Exposure of primary hepatocytes to IBD resulted in decreased cell survival. Pretreatment of mice hepatocytes with ketoconazole attenuated the susceptibility to the cytotoxicity of IBD (25-400 μM). The reactive epoxide intermediate might correlate the hepatotoxicity induced by IBD. This work revealed the reactive epoxide intermediate might correlate the hepatotoxicity induced by IBD, and would provide new insights into the mechanisms behind the adverse reactions taking place in clinical use of IBD, especially for the reported liver injury.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Exposure to polystyrene nanoplastics causes anxiety and depressive-like behavior and down-regulates EAAT2 expression in mice.
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-02-28 DOI: 10.1007/s00204-025-04002-6
Ziyang Su, Rui Kong, Chengqing Huang, Kun Wang, Chenhao Liu, Xiaozhen Gu, Hui-Li Wang
{"title":"Exposure to polystyrene nanoplastics causes anxiety and depressive-like behavior and down-regulates EAAT2 expression in mice.","authors":"Ziyang Su, Rui Kong, Chengqing Huang, Kun Wang, Chenhao Liu, Xiaozhen Gu, Hui-Li Wang","doi":"10.1007/s00204-025-04002-6","DOIUrl":"https://doi.org/10.1007/s00204-025-04002-6","url":null,"abstract":"<p><p>Microplastics exposure can induce brain dysfunction like cognitive impairment, Parkinson's disease, and autism spectrum disorders. In this study, we aimed to investigate the effects of Polystyrene nanoplastics (NPS) on anxiety and depression in mice. First, Polystyrene nanoplastics (NPS) (10 mg/kg) were administered orally daily for two months starting at PND 21. Subsequently, behavioral tests about anxiety and depression were conducted, including the open field test, the elevated plus maze, the forced swimming test, and the tail suspension test. The results showed that NPS induced anxiety and depression-like behaviors in mice. The mPFC played a pivotal role in the etiology of anxiety and depression, in which nanoplastics led to impaired synaptic transmission and reduced neuronal activity in vivo in mPFC. Furthermore, the astrocyte marker GFAP was abnormally increased as observed in mPFC. The abnormal activation of astrocytes results in impaired glutamate recycling through decreasing the expression of the glutamate transporter protein EAAT2 after NPS exposure. In order to ascertain the function of EAAT2, the EAAT2 activator (LDN-212320) was employed to stimulate the expression of EAAT2. Following the activation of EAAT2, synaptic transmission, and anxiety and depressive behavior were rescued in the mice. Polystyrene nanoplastics induce anxiety and depressive-like behavior in mice possibly inhibiting astrocyte EAAT2 expression. Specific activation EAAT2 of astrocytes rescue anxiety and depressive behavior in nanoplastics exposed mice.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
T-2 toxin-induced splenic injury by disrupting the gut microbiota-spleen axis via promoting IL-6/JAK/STAT1 signaling-mediated inflammation and apoptosis and its mitigation by elemental nano-selenium.
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-02-27 DOI: 10.1007/s00204-025-04005-3
Meng Liu, Xue-Wu Li, Hua Sun, Yi-Qin Yan, Zhi-Yuan Xia, Alainaa Refaie, Ni-Ya Zhang, Shuai Wang, Chen Tan, Lv-Hui Sun
{"title":"T-2 toxin-induced splenic injury by disrupting the gut microbiota-spleen axis via promoting IL-6/JAK/STAT1 signaling-mediated inflammation and apoptosis and its mitigation by elemental nano-selenium.","authors":"Meng Liu, Xue-Wu Li, Hua Sun, Yi-Qin Yan, Zhi-Yuan Xia, Alainaa Refaie, Ni-Ya Zhang, Shuai Wang, Chen Tan, Lv-Hui Sun","doi":"10.1007/s00204-025-04005-3","DOIUrl":"https://doi.org/10.1007/s00204-025-04005-3","url":null,"abstract":"<p><p>T-2 toxin is one of the most toxic A trichothecene mycotoxins prevalent in the environment and food chain, which brings severe health hazards to both animals and humans and it can significantly damage immune function. In this study, we comprehensively explained the impact of T-2 toxin on the spleen through gut microbiota-spleen axis by integrating the transcriptome and microbiome. Our results revealed that dietary T-2 toxin ≥ 1.0 mg/kg exposure significantly inhibited the growth performance and caused spleen injury in broilers chicks, accompanied by oxidative stress and histopathological damage. Cecal microbiome analysis suggested that T-2 toxin exposure caused gut microbial dysbiosis, especially leading to the decrease of some beneficial bacteria genera that enhanced gut barrier and reduced inflammation, including Blautia, Coprococcus, Lachnospira and Anaerostipes belonging to Lachnospiraceae family. Transcriptome analysis suggested that T-2 toxin exposure directly caused splenic inflammation and immune-related signaling, such as cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, NOD-like receptor signaling pathway and JAK-STAT signaling pathway. Furthermore, by integrating the transcriptome and microbiome analysis, we found that spleen damage induced by T-2 toxin was associated with the abnormal activation of IL-6/JAK/STAT1 signaling pathway-mediated inflammation and apoptosis, which was further verified by western bolt analysis. Notably, dietary selenium supplementation could protect chicks from T-2 toxin-induced adverse effects on growth performance and spleen injury by inhibiting the expression of the IL-6/JAK/STAT1 signaling-related genes. In summary, our findings provided new insights into the immunotoxicity mechanisms of T-2 toxin in the chickens' spleen and highlighted the potential of selenium to alleviate T-2 toxin-induced immunotoxicity.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Canine coronavirus infection is intensified by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-02-22 DOI: 10.1007/s00204-025-03981-w
Luca Del Sorbo, Claudia Cerracchio, Francesco Serra, Silvia Canzanella, Rosa Giugliano, Sara Lambiase, Nicolás Pizarro Aránguiz, Mauro Esposito, Maria Grazia Amoroso, Giovanna Fusco, Filomena Fiorito
{"title":"Canine coronavirus infection is intensified by 2,3,7,8-tetrachlorodibenzo-p-dioxin.","authors":"Luca Del Sorbo, Claudia Cerracchio, Francesco Serra, Silvia Canzanella, Rosa Giugliano, Sara Lambiase, Nicolás Pizarro Aránguiz, Mauro Esposito, Maria Grazia Amoroso, Giovanna Fusco, Filomena Fiorito","doi":"10.1007/s00204-025-03981-w","DOIUrl":"https://doi.org/10.1007/s00204-025-03981-w","url":null,"abstract":"<p><p>In humans as well as in animals, the toxic contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) stimulates immunosuppression and increases responsiveness to infectious diseases. The relationship between environmental contaminants and different infectious diseases, including COVID-19, has been described. Nevertheless, reports about the potential impact of TCDD on coronaviruses (CoVs) are limited. In this study, the impact of TCDD (0-100 pg/mL) was assessed during infection in vitro with canine coronavirus (CCoV-II), the alphaCoV causing moderate enteric disease in dogs, although genetic alterations may surprisingly generate new dangerous strains. For instance, outbreaks of lethal infections in dogs were related to highly virulent CCoV strains, and cases of pneumonia and malaise in humans were associated with new canine-feline recombinant strains of CCoV, underlining the cross-species spread capability of CoVs. Herein, during CCoV infection, TCDD induced a substantial growth in virus yield and in the expression of viral nucleocapsid protein in infected groups. Infected cells exhibited alterations in cell morphology, extensively enhanced by TCDD. Moreover, in infection, TCDD modulated the protein levels of aryl hydrocarbon receptor (AHR), a signaling responsive to both environmental contaminant and CoVs infections. Overall, our findings showed that TCDD, playing a role in AHR signaling, may worsen CCoV infection.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
PFC/PFAS concentrations in human milk and infant exposure through lactation: a comprehensive review of the scientific literature.
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-02-22 DOI: 10.1007/s00204-025-03980-x
Neus González, Jose L Domingo
{"title":"PFC/PFAS concentrations in human milk and infant exposure through lactation: a comprehensive review of the scientific literature.","authors":"Neus González, Jose L Domingo","doi":"10.1007/s00204-025-03980-x","DOIUrl":"https://doi.org/10.1007/s00204-025-03980-x","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS), previously known as perfluorinated compounds (PFC), are a group of synthetic chemicals widely used over the past decades. Their extensive application, combined with their environmental persistence, has contributed to their ubiquitous presence in the environment and the associated toxicological risks. Regarding humans, blood serum testing remains the primary method for biomonitoring PFAS exposure, while breast milk has also been used due to the transfer of these substances from mothers to infants during lactation. This paper aims to review the scientific literature (using PubMed and Scopus databases) on PFAS concentrations in the breast milk of non-occupationally exposed women. Where available, the estimated daily intake of these compounds by breastfeeding infants is also examined. The reviewed studies are categorized by continent and country/region, revealing a significant lack of data for many countries, including both developed and developing nations. The findings indicate substantial variability in PFAS concentrations, influenced by factors such as geographic location, sampling year, and the specific PFAS analyzed. Among the identified compounds, perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are most commonly detected, along with perfluorohexanesulfonic acid (PFHxS) and perfluorononanoic acid (PFNA), being the only PFAS with regulated maximum levels in certain foodstuffs. Most studies were conducted before the implementation of the current (updated) tolerable weekly intake (TWI) values for these substances. Consequently, the majority reported a low health risk for breastfeeding infants, even in high-intake scenarios. Nevertheless, biomonitoring studies are urgently needed in countries with limited or no data, and new investigations should assess whether current estimated intakes exceed the updated TWI. Special focus should be given to rural and industrial areas where exposure levels remain poorly understood.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Development of human growth hormone-treated chimeric mice with humanized livers for an evaluation model of drug-induced fatty liver disease.
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-02-21 DOI: 10.1007/s00204-025-03986-5
Sho Morioka, Seigo Sanoh, Yuji Ishida, Suzue Furukawa, Yuko Ogawa, Yaichiro Kotake, Chise Tateno
{"title":"Development of human growth hormone-treated chimeric mice with humanized livers for an evaluation model of drug-induced fatty liver disease.","authors":"Sho Morioka, Seigo Sanoh, Yuji Ishida, Suzue Furukawa, Yuko Ogawa, Yaichiro Kotake, Chise Tateno","doi":"10.1007/s00204-025-03986-5","DOIUrl":"https://doi.org/10.1007/s00204-025-03986-5","url":null,"abstract":"<p><p>Chimeric mice with humanized livers were used to evaluate drug-induced liver injury (DILI). However, lipid accumulation is observed in the human hepatocytes of chimeric mice because of human growth hormone deficiency (GHD), which is an obstacle in the evaluation of drug-induced fatty liver disease (DIFLD), a common type of DILI. Previously, we showed that lipid droplets were reduced by the administration of human growth hormone (h-GH) to chimeric mice. Although h-GH administration reduces the lipid droplets, an optimal h-GH treatment method for assessing DIFLD has not yet been developed. This study investigated the appropriate h-GH dosage required to reduce lipid droplets and reproduce physiological conditions in humans. Moreover, the LXR agonist TO901317 was administered to h-GH-treated chimeric mice to evaluate the new h-GH treatment's effectiveness for DIFLD assessment. The results in blood h-GH levels, oil-red O liver sections, and gene expression levels in the liver suggested that 0.25 mg/kg/day would be an appropriate h-GH dosage to reduce lipid droplets and reproduce human physiological condition. At this dose, TO901317-induced lipid accumulation and lipid synthesis-related gene expression in humanized livers in a dose-dependent manner, suggesting that this new mouse model could be useful for evaluating human DIFLD. In summary, the administration of h-GH at an appropriate dosage regulated lipid homeostasis in the humanized livers of chimeric mice and h-GH-administered chimeric mice may represent a highly sensitive evaluation model for human DIFLD. The study also suggests a correlation between GH levels and lipid metabolism, potentially related to conditions like GHD and aging.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Octamethylcyclotetrasiloxane (D4) lacks endocrine disruptive potential via estrogen pathways
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-02-20 DOI: 10.1007/s00204-024-03896-y
Christopher J. Borgert, Lyle D. Burgoon
{"title":"Octamethylcyclotetrasiloxane (D4) lacks endocrine disruptive potential via estrogen pathways","authors":"Christopher J. Borgert,&nbsp;Lyle D. Burgoon","doi":"10.1007/s00204-024-03896-y","DOIUrl":"10.1007/s00204-024-03896-y","url":null,"abstract":"<div><p>Octamethylcyclotetrasiloxane (D4) is a volatile, highly lipophilic monomer used to produce silicone polymers found in many consumer products and used widely in industrial applications and processes. Many reviews of the toxicology of D4 conclude that its adverse effects on endocrine-sensitive endpoints occur by a MoA dependent on systemic toxicity rather than one mediated via endocrine activity, but others identify D4 as an estrogenic endocrine disruptive chemical (EDC) based on results of screening-level assays indicating that D4 interacts with ERα and at high doses, affects estrogen-sensitive endpoints in rodents. To resolve these divergent interpretations, we tested two specific hypotheses related to the interaction of D4 with estrogen receptor–alpha subtype (ERα) at the biochemical and molecular levels of biological organization and a third specific hypothesis related to estrogenic and anti-estrogenic pathways at the physiological level. At the physiological level, we used an established WoE methodology to evaluate all data relevant to estrogen agonist and antagonist activity of D4 by examining its effects on ERα-relevant endpoints in rodent toxicology studies. At the biochemical level, we calculated whether D4 could produce a functionally significant change in the ERα occupancy by 17β-estradiol (E2) using equations well-established in pharmacology. For these calculations, we used data on the potency and kinetics of D4 from studies in rats as well as published potency and affinity data on endogenous estrogens and their circulating concentrations in humans. At the molecular level, we used established molecular docking techniques to evaluate the potential for D4 and related chemicals to fit within and to activate or block the binding pocket of ERα. Our analyses indicate that the estrogenic effect of D4 is molecularly, biochemically, and physiologically implausible, which corroborates previous evaluations of D4 that concluded it is not an estrogenic endocrine disruptor. The claim that D4 exhibits estrogenic endocrine disruptive properties based on a presumed link between the results of screening-level assays (RUA and ERTA) and adverse effects is not supported by the data and relies on deficient evaluative and interpretative methods. Instead, a plausible mechanistic explanation for the various adverse effects of D4 observed in rodent studies, including its effects in reproduction studies, is that these are secondary to high-dose-dependent, physico-chemical effects that perturb cell membrane function and produce rodent-specific sensory irritation<b>.</b></p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1431 - 1443"},"PeriodicalIF":4.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03896-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Targeting MLKL ameliorates T-2 toxin-induced cartilage damage by inhibiting chondrocyte death and matrix degradation in mice
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-02-18 DOI: 10.1007/s00204-025-03966-9
Meng Zhang, Xiaoru Zhao, Yue Liu, Yinan Liu, Yawen Shi, Ying Zhang, Jinghong Chen
{"title":"Targeting MLKL ameliorates T-2 toxin-induced cartilage damage by inhibiting chondrocyte death and matrix degradation in mice","authors":"Meng Zhang,&nbsp;Xiaoru Zhao,&nbsp;Yue Liu,&nbsp;Yinan Liu,&nbsp;Yawen Shi,&nbsp;Ying Zhang,&nbsp;Jinghong Chen","doi":"10.1007/s00204-025-03966-9","DOIUrl":"10.1007/s00204-025-03966-9","url":null,"abstract":"<div><p>T-2 toxin is the most toxic mycotoxin found in contaminated food and animal feed that threatens health. Exposure to T-2 toxin causes cartilage damage and leads to joint disorders, but the mechanisms underlying T-2 toxin-induced cartilage damage remain unclear. The results showed that T-2 toxin-induced chondrocyte death in articular cartilage from rats fed T-2 toxin (200 ng/g b.w./day) caused a significant increase in phosphorylated receptor-interacting protein 3 (p-RIPK3) and phosphorylated mixed lineage kinase-like protein (p-MLKL). In vitro studies showed that T-2 toxin (48 ng/mL) reduced the viability of C-28/I2 chondrocytes, increased cell apoptosis, and significantly upregulated the expression of p-MLKL. The results suggest that chondrocyte necroptosis is involved in T-2 toxin-induced cartilage damage. Furthermore, necrostatin-1 (Nec-1), a necroptosis inhibitor, significantly attenuated T-2 toxin-induced cell death and the increase of p-MLKL. Further studies showed that <i>mlkl</i><sup>−/−</sup> mice suppressed T-2 toxin-induced chondrocyte death, and <i>mlkl</i><sup>−/−</sup> mice upregulated T-2 toxin-induced proteoglycan content and type II collagen reduction in mouse articular cartilage, and reduced increased matrix metalloproteinase-13 expression. Besides, the p-RIPK3 and p-MLKL were significantly increased in the articular cartilage of KBD patients. This study highlights the role of RIPK3/MLKL-mediated necroptosis in T-2 toxin-induced articular cartilage damage. Inhibition of MLKL alleviates T-2 toxin-induced cartilage damage by reducing chondrocyte death and matrix degradation in mice. These results suggest a potential therapeutic target for mitigating T-2 toxin-induced cartilage damage.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1505 - 1516"},"PeriodicalIF":4.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 role of NLRP3 inflammasome activation in proinflammatory and cytotoxic effects of metal nanoparticles
IF 4.8 2区 医学
Archives of Toxicology Pub Date : 2025-02-17 DOI: 10.1007/s00204-025-03972-x
Michael Aschner, Anatoly V. Skalny, Airton C. Martins, Yousef Tizabi, Irina P. Zaitseva, Abel Santamaria, Rongzhu Lu, Yordanka Y. Gluhcheva, Alexey A. Tinkov
{"title":"The role of NLRP3 inflammasome activation in proinflammatory and cytotoxic effects of metal nanoparticles","authors":"Michael Aschner,&nbsp;Anatoly V. Skalny,&nbsp;Airton C. Martins,&nbsp;Yousef Tizabi,&nbsp;Irina P. Zaitseva,&nbsp;Abel Santamaria,&nbsp;Rongzhu Lu,&nbsp;Yordanka Y. Gluhcheva,&nbsp;Alexey A. Tinkov","doi":"10.1007/s00204-025-03972-x","DOIUrl":"10.1007/s00204-025-03972-x","url":null,"abstract":"<div><p>Exposure to metal nanoparticles (NPs) is known to induce inflammatory responses in various tissues, thus limiting their therapeutic potential. NOD-like receptor protein 3 (NLRP3) inflammasome activation is an essential component of innate immunity playing a significant role in inflammation and development of inflammatory diseases. Therefore, the objective of the present review was to summarize data on the role of NLRP3 inflammasome in proinflammatory effects induced by metal NPs, and to discuss the underlying molecular mechanisms, including its dependence on the physical and chemical properties of metal NPs. Titanium, zinc, silver, aluminum, iron, cobalt, nickel, vanadium, and tungsten nanoparticles, as well as metal-based quantum dots have all been shown to induce NLRP3 inflammasome activation in vitro in macrophages and monocytes, dendritic cells, keratinocytes, hepatocytes, enterocytes, microglia, astrocytes, lung epithelial cells, endotheliocytes, as well as certain types of cancer cells. In vivo studies confirmed the role of NLRP3 pathway activation in development of colitis, pulmonary inflammation, liver damage, osteolysis, and neuroinflammation induced by various metal nanoparticles. Briefly, particle endocytosis with subsequent lysosomal damage, induction of ROS formation, K<sup>+</sup> efflux, increased intracellular Ca<sup>2+</sup> levels, and NF-κB pathway activation results in NLRP3 inflammasome complex assembly, caspase-1 activation, and cleavage of pro-IL-1β and pro-IL-18 to mature proinflammatory cytokines, while gasdermin D cleavage induces pyroptotic cell death. Moreover, small-sized and rod-shaped metal NPs exert a more profound stimulatory effect on NLRP3 inflammasome activation, but contrary findings have also been reported. Taken together, it is concluded that NLRP3 inflammasome may mediate both adverse proinflammatory effects of metal nanoparticles, as well as their beneficial effect when used as antitumor agents.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 4","pages":"1287 - 1314"},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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