Journal of Applied Toxicology最新文献

{"title":"Biodistribution and preclinical safety profile of legubicin: A novel conjugate of doxorubicin and a legumain-cleavable peptide linker","authors":"Yan Wang,&nbsp;Liping Wei,&nbsp;Yuan Liu,&nbsp;Cheng Liu,&nbsp;Minbo Hou,&nbsp;Lu Zhou,&nbsp;Le Wang,&nbsp;Hua Li,&nbsp;Yunliang Qiu,&nbsp; JingMa","doi":"10.1002/jat.4622","DOIUrl":"10.1002/jat.4622","url":null,"abstract":"<p>Legubicin is a novel conjugate of doxorubicin and a legumain-cleavable peptide linker. It has been developed to ameliorate the side effects of doxorubicin. Biodistribution in tumor-bearing mice, acute tolerance, and potential systemic toxic effects in Sprague–Dawley rats and beagle dogs of legubicin were assessed. Legubicin exists mainly as a protein complex in plasma after entering the circulation. Compared with conventional doxorubicin at an equal molar dose in mice, we found higher exposure to doxorubicin in tumor (approximately 1.7-fold increase) while lower exposure in normal tissues (an ~3.26-, 3.46-, and 1.29-fold reduction in heart, kidney, and plasma, respectively) in tumor-bearing mice after intravenous injection of legubicin. The acute maximum tolerance dose (MTD) of legubicin was &gt;16 mg/kg doxorubicin equivalent in female rats, 11 mg/kg doxorubicin equivalent in male rats (LD50 of conventional doxorubicin is 10.51 mg/kg), and &gt;8 mg/kg doxorubicin equivalent in dogs (MTD of conventional doxorubicin is 1.5 mg/kg). Four-week repeat-dose toxicity studies of intravenous legubicin were conducted in rats (5, 10, and 25 mg/kg/dose once weekly) and dogs (3/1.5, 10/5, and 20/10 mg/kg/dose once weekly); the dose levels were reduced from the second dose due to intolerable legubicin-associated toxicity at 20 mg/kg. Major organs of toxicity included the gastrointestinal tract, lymphoid and hematopoietic organs, kidney, skin, liver, reproductive organs, and peripheral nerves, which are all associated with doxorubicin. However, cardiotoxicity was only noted at MTD dose levels. Altogether, our results confirm an improved safety profile of legubicin over conventional doxorubicin and support its clinical benefit for treating cancer.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1426-1445"},"PeriodicalIF":2.7,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087182","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":"mtDNA amplifies beryllium sulfate-induced inflammatory responses via the cGAS-STING pathway in 16HBE cells","authors":"Xiaodong Liu,&nbsp;Tianyi Jiang,&nbsp;Huiyun Jin,&nbsp;Chenxi Yan,&nbsp;Yuqi Tong,&nbsp;Jiaquan Ding,&nbsp;Yaqi Li,&nbsp;Lian Huang,&nbsp;Zhaohui Zhang","doi":"10.1002/jat.4631","DOIUrl":"10.1002/jat.4631","url":null,"abstract":"<p>Beryllium sulfate (BeSO₄) can cause inflammation through the mechanism, which has not been elucidated. Mitochondrial DNA (mtDNA) is a key contributor of inflammation. With mitochondrial damage, released mtDNA can bind to specific receptors (e.g., cGAS) and then activate related pathway to promote inflammatory responses. To investigate the mechanism of mtDNA in BeSO₄-induced inflammatory response in 16HBE cells, we established the BeSO₄-induced 16HBE cell inflammation model and the ethidium bromide (EB)-induced ρ⁰16HBE cell model to detect the mtDNA content, oxidative stress-related markers, mitochondrial membrane potential, the expression of the cGAS-STING pathway, and inflammation-related factors. Our results showed that BeSO₄ caused oxidative stress, decline of mitochondrial membrane potential, and the release of mtDNA into the cytoplasm of 16HBE cells. In addition, BeSO₄ induced inflammation in 16HBE cells by activating the cGAS-STING pathway. Furthermore, mtDNA deletion inhibited the expression of cGAS-STING pathway, IL-10, TNF-α, and IFN-β. This study revealed a novel mechanism of BeSO₄-induced inflammation in 16HBE cells, which contributes to the understanding of the molecular mechanism of beryllium and its compounds-induced toxicity.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1403-1415"},"PeriodicalIF":2.7,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081370","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":"Ecotoxicological effects of polystyrene nanoplastics on common carp: Insights into blood parameters, DNA damage, and gene expression","authors":"Ümit Acar,&nbsp;Burak Evren İnanan,&nbsp;Fahriye Zemheri-Navruz","doi":"10.1002/jat.4645","DOIUrl":"10.1002/jat.4645","url":null,"abstract":"<p>Plastics are ubiquitous in modern society due to their cost-effectiveness, lightweight nature, and versatility. However, their extensive use and inadequate recycling have led to a significant environmental challenge, with plastic waste accumulating rapidly and causing ecological and health problems, especially in aquatic environments. Nanoplastics, particles ranging from 1 to 100 nm, have emerged as a particularly concerning subset due to their ability to easily penetrate biological barriers and accumulate in tissues. In this study, we investigated the toxicity of carboxylate-modified polystyrene nanoplastics (PS-NPs) on common carp (<i>Cyprinus carpio</i>), a species often used in ecotoxicology research due to its ability to accumulate pollutants. The PS-NPs were characterized, and their effects on DNA damage gene expression related to oxidative stress and immunity were examined. PS-NPs with a diameter of 20–30 nm were found to possess a spherical shape and negatively charged surfaces. Exposure to PS-NPs led to significant DNA damage in the blood and brain cells of common carp, with higher concentrations resulting in more severe damage. Additionally, PS-NP exposure influenced the expression of genes related to antioxidative defense and stress response in the liver. Specifically, genes encoding superoxide dismutase (SOD), catalase (CAT), and heat shock protein 70 (Hsp70) showed upregulation, while glutathione peroxidase (GPx) and glutathione S-transferase (GST) exhibited downregulation at higher PS-NP concentrations. Furthermore, the immune-related genes interleukin-1ß (IL-1ß), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) displayed dose-dependent downregulation in the liver tissue. These findings suggest that exposure to PS-NPs induces oxidative stress, disrupts immune responses, and causes DNA damage in common carp. The results highlight the need for further research on the environmental impacts of PS-NPs and underscore the importance of proper waste management and recycling practices to mitigate plastic pollution.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1416-1425"},"PeriodicalIF":2.7,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081402","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 effect of flavonoids on multidrug and toxin extrusion protein 1 function: Implications for food/herb–drug interaction and drug-induced kidney injury","authors":"Xiaoyan Duan,&nbsp;Wanting Bai,&nbsp;Jiahuan Hu,&nbsp;Jinjin Wu,&nbsp;Huixin Tan,&nbsp;Fenghe Wang,&nbsp;Xuli Lang,&nbsp;Baolian Wang,&nbsp;Jinping Hu","doi":"10.1002/jat.4628","DOIUrl":"10.1002/jat.4628","url":null,"abstract":"<p>Multidrug and toxin extrusion protein 1 (MATE1), an efflux transporter mainly expressed in renal proximal tubules, mediates the renal secretion of organic cationic drugs. The inhibition of MATE1 will impair the excretion of drugs into the tubular lumen, leading to the accumulation of nephrotoxic drugs in the kidney and consequently potentiating nephrotoxicity. Screening and identifying potent MATE1 inhibitors can predict or minimize the risk of drug-induced kidney injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb–drug interactions. Our objective was to investigate the inhibitory effects of flavonoids on MATE1 in vitro and in vivo and to assess the effects of flavonoids on cisplatin-induced kidney injury. Thirteen flavonoids exhibited significant transport activity inhibition (&gt;50%) on MATE1 in MATE1-MDCK cells. Among them, the six strongest flavonoid inhibitors, including irisflorentin, silymarin, isosilybin, sinensetin, tangeretin, and nobiletin, markedly increased cisplatin cytotoxicity in these cells. In cisplatin-induced in vivo renal injury models, irisflorentin, isosilybin, and sinensetin also increased serum creatinine and blood urea nitrogen levels to different degrees, especially irisflorentin, which exhibited the most potent nephrotoxicity with cisplatin. The pharmacophore model indicated that the hydrogen bond acceptors at the 3, 5, and 7 positions may play a critical role in the inhibitory effect of flavonoids on MATE1. Our findings provide helpful information for predicting the potential risks of flavonoid-containing food/herb–drug interactions and avoiding the exacerbation of drug-induced kidney injury via MATE1 mediation.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1388-1402"},"PeriodicalIF":2.7,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956542","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 marijuana, cannabinoids, and female reproductive system.","authors":"Leila Najafi, Zia Moasses, Soghra Bahmanpour","doi":"10.1002/jat.4630","DOIUrl":"https://doi.org/10.1002/jat.4630","url":null,"abstract":"<p><p>The marijuana is considered as widely used recreational illicit drug that has become popular among women of reproductive age. It is believed that the marijuana use may have negative impacts on the female fertility. However, the exact mechanisms of its reproductive toxicity remain unclear. The studies suggest that the exogenous cannabinoids may interfere with endocannabinoid system and disrupt hypothalamic-pituitary-ovary axis. Consequently, it impacts the female fertility by disruption of normal secretion of ovarian sex hormones and menstrual cycles. However, other studies have shown that medical marijuana is useful analgesic agent for pain management. But, given that the wide range of cannabinoids side effects are reported, it seems that caution should be taken in the recreational use of these substances. In summary, this article aimed to review the possible impacts of marijuana and its derivatives on the main female reproductive organs and embryonic growth and development.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956623","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":"Featured Cover","authors":"Xianli Meng,&nbsp;Shuhui Xie,&nbsp;Jing Liu,&nbsp;Bingxuan Lv,&nbsp;Xin Huang,&nbsp;Qiang Liu,&nbsp;Xia Wang,&nbsp;Anna Malashicheva,&nbsp;Ju Liu","doi":"10.1002/jat.4629","DOIUrl":"https://doi.org/10.1002/jat.4629","url":null,"abstract":"<p>The cover image is based on the Research Article <i>Low dose cadmium inhibits syndecan-4 expression in glycocalyx of glomerular endothelial cells</i> by Xianli Meng et al., https://doi.org/10.1002/jat.4592.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 6","pages":"i"},"PeriodicalIF":3.3,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4629","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140952981","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":"Twenty-eight days of repeated dose sub-acute toxicological evaluation of polyherbal Ayurvedic medicine BPGrit in Sprague–Dawley rats","authors":"Acharya Balkrishna,&nbsp;Sandeep Sinha,&nbsp;Kunal Bhattacharya,&nbsp;Anurag Varshney","doi":"10.1002/jat.4625","DOIUrl":"10.1002/jat.4625","url":null,"abstract":"<p>A pre-clinical toxicological evaluation of herbal medicines is necessary to identify any underlying health-associated side effects, if any. BPGrit is an Ayurveda-based medicine prescribed for treating hypertensive conditions. High-performance liquid chromatography-based analysis revealed the presence of gallic acid, ellagic acid, coumarin, cinnamic acid, guggulsterone E, and guggulsterone Z in BPGrit. For sub-acute toxicity analysis of BPGrit, male and female Sprague–Dawley rats were given repeated oral gavage at 100, 300, and 1000 mg/kg body weight/day dosages for 28 days, followed by a 14-day recovery phase. No incidences of mortality, morbidity, or abnormal clinical signs were observed in BPGrit-treated rats throughout the study period. Also, the body weight and food consumption habits of the experimental animals did not change during the study duration. Hematological, biochemical, and histopathological analysis did not indicate any abnormal changes occurring in the BPGrit-treated rats up to the highest tested dose of 1000 mg/kg body weight/day. Finally, the study established the “no-observed-adverse-effect level” for BPGrit at &gt;1000 mg/kg body weight/day in Sprague–Dawley rats.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1372-1387"},"PeriodicalIF":2.7,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915772","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":"Hepatotoxicity of titanium dioxide nanoparticles.","authors":"Jangrez Khan, Nicholas D Kim, Collette Bromhead, Penelope Truman, Marlena C Kruger, Beth L Mallard","doi":"10.1002/jat.4626","DOIUrl":"https://doi.org/10.1002/jat.4626","url":null,"abstract":"<p><p>The food additive E171 (titanium dioxide, TiO₂), is widely used in foods, pharmaceuticals and cosmetics. It is a fine white powder, with at least one third of its particles sized in the nanoparticulate (˂100 nm range, TiO₂ NPs). The use of E171 is controversial as its relevant risk assessment has never been satisfactorily accomplished. In vitro and in vivo studies have shown dose-dependent toxicity in various organs including the liver. TiO₂ NPs have been shown to induce inflammation, cell death and structural and functional changes within the liver. The toxicity of TiO₂ NPs in experimental models varies between organs and according to their physiochemical characteristics and parameters such as dosage and route of administration. Among these factors, ingestion is the most significant exposure route, and the liver is a key target organ. The aim of this review is to highlight the reported adverse effects of orally administered TiO₂ NPs on the liver and to discuss the controversial state of its toxicity.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915617","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":"In vitro genotoxicological evaluation of protein-rich powder derived from Xanthobacter sp. SoF1","authors":"Katharina Klinzing,&nbsp;Ida Aabrandt Søndergaard,&nbsp;Teresa Chirom,&nbsp;James Whitwell,&nbsp;Laura Bisini,&nbsp;Cristina Marabottini,&nbsp;Fabrice Nesslany,&nbsp;Petri Tervasmäki,&nbsp;Juha-Pekka Pitkänen","doi":"10.1002/jat.4621","DOIUrl":"10.1002/jat.4621","url":null,"abstract":"<p>One way of limiting the environmental impact of food production and improving food security is to replace part of the animal- or plant-based protein in the human diet with protein sourced from microorganisms. The recently discovered bacterium <i>Xanthobacter</i> sp. <i>SoF1</i> (VTT-E-193585) grows autotrophically using carbon dioxide gas as the only carbon source, yielding protein-rich biomass that can be processed further into a powder and incorporated into various food products. Since the safety of this microbial protein powder for human consumption had not been previously assessed, its genotoxic potential was evaluated employing three internationally recognized and standardized studies: a bacterial reverse mutation test, an <i>in vitro</i> chromosomal aberration assay in human lymphocytes, and an <i>in vitro</i> micronucleus test in human lymphocytes. No biologically relevant evidence of genotoxicity or mutagenicity was found.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1347-1360"},"PeriodicalIF":2.7,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4621","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140903933","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":"Immediate dry decontamination using efficient absorbent materials is beneficial following skin exposure to low-volatile toxic chemicals","authors":"Lina Thors,&nbsp;Elisabeth Wigenstam,&nbsp;Johanna Qvarnström,&nbsp;Pär Wästerby,&nbsp;Linda Öberg,&nbsp;Anders Bucht","doi":"10.1002/jat.4627","DOIUrl":"10.1002/jat.4627","url":null,"abstract":"<p>In a chemical mass casualty incident requiring skin decontamination, dry removal using absorbent materials may be beneficial to enable immediate decontamination. The efficacy of absorbent materials has therefore been evaluated, alone or procedures including both dry and wet decontamination, following skin exposure to two low volatile toxic chemicals using an in vitro human skin penetration model. Additionally, removal using active carbon wipes was evaluated with or without the Dahlgren Decon solution. All dry decontamination procedures resulted in a significantly decreased skin penetration rate of the industrial chemical 2-butoxyethanol compared to the control without decontamination. Wet decontamination following dry absorption significantly improved the efficacy compared to dry removal alone. Dry decontamination post-exposure to the chemical warfare nerve agent VX showed no decontamination efficacy. However, dry and wet decontamination resulted in a decreased agent skin penetration rate during the last hour of the experiment. At −15°C, significantly reduced VX skin penetration rates were demonstrated for both dry decontamination alone and the dry and wet decontamination procedure. The Dahlgren Decon solution significantly reduced the amount of VX penetrating the skin, but the active carbon wipe alone did not impact the skin penetration rate. In conclusion, absorbent materials are beneficial for the removal of low-volatile chemicals from the skin, but the degree of efficacy varies between chemicals. Despite the variability, immediate dry decontamination using available absorbent materials prior to wet decontamination is recommended as a general procedure for skin decontamination. The procedure should also be prioritized in cold-weather conditions to prevent patient hypothermia.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 9","pages":"1361-1371"},"PeriodicalIF":2.7,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4627","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908753","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}