Toxicology and applied pharmacology最新文献

{"title":"In vitro NIH3T3 mouse embryonic fibroblast cell model does not predict AAV2 or AAVdj-mediated cell transformation","authors":"Luping Qiu,&nbsp;Steven W. Kumpf,&nbsp;Elias M. Oziolor,&nbsp;Mark Sheehan,&nbsp;James E. Finley,&nbsp;David M. Rubitski,&nbsp;Jessie Qian,&nbsp;Mark M. Gosink ,&nbsp;Anna K. Kopec,&nbsp;Thomas A. Lanz,&nbsp;Andrew D. Burdick","doi":"10.1016/j.taap.2025.117229","DOIUrl":"10.1016/j.taap.2025.117229","url":null,"abstract":"<div><div>One of the potential risk factors of recombinant adeno-associated virus (rAAV)-based gene therapy is insertional mutagenesis, which has been associated with the development of hepatocellular carcinoma (HCC) in rAAV-treated neonatal mice. The objective of this study was to investigate if well-established <em>in vitro</em> cell transformation assays (CTA) in mouse cell lines can detect AAV2 or AAVdj-mediated cell transformation. Since AAV integration at the <em>Rian</em> locus in neonatal mice has been implicated in AAV-mediated HCC, an rAAV vector specifically targeting the mouse <em>Rian</em> locus and an additional rAAV vector previously shown to cause HCC in neonatal mice were both tested for the induction of cell transformation in NIH3T3 cells. To increase the frequency of AAV DNA integration at the <em>Rian</em> locus in the genome of NIH3T3 cells, double-strand breaks in <em>Rian</em> locus of NIH3T3 cells were created by CRISPR-Cas9 to increase the homologous crossover between viral DNA and the cell genome. When transduced cells were assayed in CTA, the transformation frequency observed in AAV-transduced NIH3T3 cells was not significantly different from that of untreated vehicle cells. The finding that rAAV is unable to transform the NIH3T3 <em>in vitro</em> indicates that either the transformation rate is less than the spontaneous rate of NIH3T3 cellular transformation, or <em>in vitro</em> CTA are not predictive of rAAV-induced HCC in mice.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117229"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984881","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":"Cadmium alters the cellular metabolome of human ovarian granulosa cells","authors":"Jun Zhang ,&nbsp;Guofeng Xu ,&nbsp;Shuang Liu ,&nbsp;Meng Yang","doi":"10.1016/j.taap.2024.117187","DOIUrl":"10.1016/j.taap.2024.117187","url":null,"abstract":"<div><div>Cadmium (Cd) is a toxic heavy metal that has been extensively implicated in disordered folliculogenesis, but the mechanisms underlying the ovarian toxicity of Cd remain to be explored fully. Granulosa cells are key players in ovarian follicular development and are the primary cells affected by Cd exposure-induced damage and dysfunction. In this study, we investigated how various levels of exposure of Cd (3 and 10 μM) to human granulosa cells (KGN cells) impacted the metabolism of the KGN cells utilizing a non-targeted metabolomics methodology. In vitro cell experiments revealed that Cd exposure dose-dependently diminished the viability of KGN cells. Metabolomics analysis revealed the presence of 296 (182 elevated and 114 reduced) and 397 (244 elevated and 153 reduced) differentially expressed metabolites after exposure to 3 and 10 μM, respectively. Cd exposure was found to significantly enrich nucleotide metabolism, sphingolipid metabolism, and ABC transporters in both groups. Although amino acid metabolic pathways exhibited significant enrichment across all groups, only glutathione, cysteine, and methionine metabolism were notably enriched in KGN cells exposed to 3 μM Cd, while glutathione and tryptophan metabolism were significantly enriched in the 10 μM Cd exposure cohort. The outcomes of this study provide mechanistic clues for elucidating Cd’s cytotoxic impact on granulosa cells, and deepen our understanding of the ovarian toxicity of Cd.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117187"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786863","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":"Knockdown of regulator of Calcineurin 2 promotes transcription factor EB-mediated lipophagy to prevent non-alcoholic fatty liver disease","authors":"Lei Shan,&nbsp;Pengzhan Guo,&nbsp;Mumeike Wen,&nbsp;Yue Sun,&nbsp;Fei Gao,&nbsp;Kai Zhang,&nbsp;Ning Zhang,&nbsp;Baoshan Yang","doi":"10.1016/j.taap.2024.117210","DOIUrl":"10.1016/j.taap.2024.117210","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. The present work aimed to explore the function of regulator of Calcineurin 2 (RCAN2) in NAFLD and its related mechanisms. Mice were fed with high-fat diet (HFD) to construct NAFLD model. Adeno-associated virus injection was performed to interference with RCAN2 in mice. RCAN2 knockdown meliorated HFD-induced NAFLD and impaired glucose metabolism. Abnormal lipid metabolism and inflammation in HFD-fed mice were relieved when RCAN2 was downregulated. Besides, hepatocyte Huh-7 cells, treated with free fatty acids (oleic acid and palmitic acid), were used as NAFLD models in vitro. We found that knockdown of RCAN2 inhibited the accumulation of lipid droplets and inflammation induced by free fatty acids. RCAN2 interference increased the activity of calcineurin (CaN), which enhanced the nuclear translocation of Transcription factor EB (TFEB). Autophagosome and lysosome biogenesis was augmented, and autophagy-dependent lipid degradation (lipophagy) was promoted. Collectively, we demonstrate that RCAN2 insufficiency protects against NAFLD by promoting TFEB-mediated lipophagy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117210"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877926","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":"Thiostrepton suppresses colorectal cancer progression through reactive oxygen species related endoplasmic reticulum stress","authors":"Zhexuan Li ,&nbsp;Juan Nie ,&nbsp;Runyu Zhou ,&nbsp;Hui Huang ,&nbsp;Xuemei Li ,&nbsp;Li Wang ,&nbsp;Lin Lv ,&nbsp;Sichong Ren ,&nbsp;Ming Zhao","doi":"10.1016/j.taap.2024.117221","DOIUrl":"10.1016/j.taap.2024.117221","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Due to the poor therapeutic efficacy of CRC treatments and poor prognosis of the disease, effective treatment strategies are urgently needed. As long-term proteotoxic stress is a major cause of cell death, agents that induce proteotoxic stress offer a promising strategy for cancer intervention. Thiostrepton is a natural antibiotic derived from the <em>Streptomyces</em> genus. In the present study, we found that thiostrepton triggered apoptosis, reduced the migration of CRC cells, and inhibited xenograft tumour growth <em>in vivo</em>. Mechanistically, thiostrepton reduced proteasome activity; induced the aggregation of ubiquitinated proteins; caused endoplasmic reticulum (ER) stress, which was characterized by increased protein levels of GRP78, ATF4, P-eIF2α, and CHOP and cytosolic calcium release; and ultimately resulted in cell death. Thiostrepton-related changes in cell survival and cell migration, as well as mechanistical processes, were almost completely reversed by treatment with the antioxidant <em>N</em>-acetylcysteine (NAC), suggesting that the mechanism is dependent on reactive oxygen species (ROS). These results demonstrated that thiostrepton induced apoptosis and inhibited migration through ROS-induced ER stress and proteotoxic stress in colorectal cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117221"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902857","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":"Cardiac inotropy and cardiac calcium sensitization of PanLN800(-Forte), a cationic heptamethine indocyanine fluorescent contrast agent for intraoperative pan lymph node imaging","authors":"Robin A. Faber ,&nbsp;Victor M. Baart ,&nbsp;Mark W. Bordo ,&nbsp;Taryn L. March ,&nbsp;Adrianus R.P.M. Valentijn ,&nbsp;Stefan Harmsen ,&nbsp;Martin Pool ,&nbsp;Jacobus Burggraaf ,&nbsp;John V. Frangioni ,&nbsp;Alexander L. Vahrmeijer","doi":"10.1016/j.taap.2024.117222","DOIUrl":"10.1016/j.taap.2024.117222","url":null,"abstract":"<div><h3>Introduction</h3><div>Accurate staging of malignancies often requires comprehensive evaluation of lymph nodes. However, finding these lymph nodes during oncological surgery is a daunting and time-consuming task, which increases the risk of missed lymph nodes and complications. Near-infrared (NIR) fluorescence imaging with the experimental fluorescent contrast agent PanLN800(-Forte) could provide real-time identification of lymph nodes and may solve this longstanding problem. In the current study we performed the preclinical toxicology evaluation of PanLN800(-Forte) towards its clinical translation for intraoperative pan lymph node imaging in thoracic surgery.</div></div><div><h3>Methods</h3><div>A single extended dose toxicology study was conducted to determine the safety and potential toxicity of PanLN800(-Forte) after administration of a single intravenous dose to Wistar Han rats. The study included a control group and two treatment groups (5.0 mg/kg and 15.0 mg/kg PanLN800(-Forte)), each consisting of 10 male and 10 female rats. Experimental endpoints included moribundity/mortality, clinical signs, body weights, body weight gains, clinical pathology, toxicity, and gross necropsy observations.</div></div><div><h3>Results</h3><div>Unexpected acute mortality was observed after administration of 5.0 mg/kg PanLN800(-Forte) to rats. No clear cause of sudden death was found after gross necropsy and pathology observations. To understand the mechanism of toxicity of PanLN800(-Forte), several additional tests were performed. By elimination, acute cardiac toxicity appears to be the cause of acute mortality in rats, in which PanLN800(-Forte) was found to be a potent inotrope acting as a cardiac calcium sensitizer.</div></div><div><h3>Conclusion</h3><div>PanLN800(-Forte) is not a viable fluorescent contrast agent for lymph node imaging in surgery because of cardiac calcium sensitization but may be a novel treatment for heart failure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117222"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915645","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":"T-2 toxin triggers immunotoxic effects in goats by inducing ferroptosis and neutrophil extracellular traps","authors":"Jing Huang ,&nbsp;Kaifeng He ,&nbsp;Xin Guo ,&nbsp;Jiaxuan Wang ,&nbsp;Han Hu ,&nbsp;Xuhui Zhang ,&nbsp;Na Guo ,&nbsp;Yiwen Wang ,&nbsp;Wenlong Huang ,&nbsp;Rongsheng Huang ,&nbsp;Tingting Liu ,&nbsp;Xi Jiang ,&nbsp;Deizhi Zhang ,&nbsp;Qianyong Li ,&nbsp;Zhengkai Wei","doi":"10.1016/j.taap.2025.117232","DOIUrl":"10.1016/j.taap.2025.117232","url":null,"abstract":"<div><div>T-2 toxin, a prevalent mycotoxin, represents a notable global public health risk. Neutrophil extracellular traps (NETs) and ferroptosis are involved in a variety of pathophysiological processes and are implicated in goat immunity. However, the impact of T-2 toxin on NETs release, ferroptosis, and their interplay have not been previously documented. In this study, neutrophils were stimulated with T-2 toxin for 4 h. The structure and mechanism of NETs were analyzed using immunofluorescence and Pico Green staining. The expressions of glutathione peroxidase 4 (GPX4) and ferritin (FT) was quantified by qRT-PCR and western blotting. The levels of ROS and lipid ROS were assessed using DCFH-DA and C11 BODIPY 581/591 probes, and cellular mitochondria Fe²⁺ were detected by using Mito-FerroGreen probe. Inhibitors were utilized to explore the interaction between these two processes. The results confirmed that the T-2 toxin stimulated the NETs production, characterized by a structure co-modified by citrullinated histones (citH3), neutrophil elastase (NE) and DNA. Notably, significant inhibition of NETs production by T-2 toxin was observed with the NOX inhibitor DPI (<em>P</em> &lt; 0.001), the ERK inhibitor U0126 (P &lt; 0.001), the TLR2 inhibitor C29 (P &lt; 0.001), and the TLR4 inhibitor TLR4-IN-C34 (P &lt; 0.001). T-2 toxin triggered ferroptosis in neutrophils by suppressing GPX4 and FT expression, elevating ROS and lipid ROS, and augmenting the concentration of mitochondrial Fe²⁺. The ferroptosis inhibitor Fer-1 could rescue this induction; however, Fer-1 was unable to inhibit NETs which is induced by T-2 toxin. Conversely, T-2 toxin effectively triggered the downregulation of GPX4, which was counteracted by DPI, U0126, C29, and C34. This research elucidates the immunotoxic mechanisms of T-2 toxin in goat neutrophils and offers a novel perspective on preventing and treating T-2 toxin.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117232"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012088","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":"Toxic effects of dibutyl phthalate on trophoblast through mitochondria mediated cellular dysfunction","authors":"Hyewon Jang ,&nbsp;Gwonhwa Song ,&nbsp;Whasun Lim ,&nbsp;Sunwoo Park","doi":"10.1016/j.taap.2024.117186","DOIUrl":"10.1016/j.taap.2024.117186","url":null,"abstract":"<div><div>Dibutyl phthalate is a chemical commonly used as a plasticizer in the production of daily necessaries, such as cosmetics and toys. Although several toxic effects of dibutyl phthalate have been confirmed, those related to pregnancy are unknown. Trophoblasts are critical for fetal and placental development, and trophoblast damage may cause preeclampsia. This study aimed to confirm the toxic effect of dibutyl phthalate on trophoblasts. We used the human trophoblast cell line HTR-8/SVneo and human choriocarcinoma JEG-3 cells as a placental trophoblast model to investigate the toxic effects of dibutyl phthalate. Both cell lines were treated with dibutyl phthalate (0–20 μg/mL) to verify the mechanisms regulating trophoblast function. Dibutyl phthalate treatment significantly reduced trophoblast viability, reduced invasion ability, and induced mitochondrial depolarization. Ultimately, dibutyl phthalate regulated the PI3K and MAPK signaling pathways and the expression of autophagy-related proteins ATG5, LC3B, and SQSTM1/p62. We concluded that dibutyl phthalate induced autophagy and effectively weakened trophoblast function. Additionally, we conducted experiments to assess the potential effects of monobutyl phthalate, a metabolite of dibutyl phthalate, on cellular mobility, penetration, and autophagy induction. Our results demonstrated that monobutyl phthalate impaired these functions and weakened the trophoblast barrier, after dibutyl phthalate metabolized. Thus, exposure to dibutyl phthalate and its metabolite monobutyl phthalate can damage trophoblast function, highlighting their potential as hazardous substances that impair trophoblast barrier integrity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117186"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795144","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":"Metabolomics based early warning model for acute kidney injury risk in patients exposed to diquat","authors":"Shengkai Zhu ,&nbsp;Xinyu Li ,&nbsp;Chengzhao Wu ,&nbsp;Xu Zhao ,&nbsp;Shuiying Xu ,&nbsp;Yujing Zhao ,&nbsp;Xiaobo Peng ,&nbsp;Xiaohe Xiao ,&nbsp;Ming Niu","doi":"10.1016/j.taap.2024.117207","DOIUrl":"10.1016/j.taap.2024.117207","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is one of the most important indications of severe clinical symptoms in patients with diquat poisoning and is closely related to poor prognosis. However, current studies have rarely focused on early warnings of diquat-related AKI, which is not conducive to the treatment of patients with early clinical diquat poisoning. In this study, untargeted plasma metabolomics was employed to reveal the differences between diquat-poisoned patients with and without AKI, as well as between patients and healthy volunteers. The results showed that 48 metabolites were significantly changed in the patients, among which 3-hydroxybutyrylcarnitine, SAICAR, dodecanoic acid, and tetrahydrofolyl-[Glu](2) could be used to effectively differentiate the above three groups. Based on the ratios of the first two metabolites and the ratios of the last two metabolites, a decision tree model for the early warning of diquat-induced AKI was established with an accuracy rate of 88.7 %. This model provides great support for accurate clinical diagnosis and intervention regarding the AKI risk of diquat-exposed patients.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117207"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855223","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":"Safety assessment on CBD-rich hemp extract in sub-chronic cross-sex study with rats","authors":"Jan Dehner ,&nbsp;Hana Holcova Polanska ,&nbsp;Katerina Petrlakova ,&nbsp;Sanja Cavar Zeljkovic ,&nbsp;Tibor Beres ,&nbsp;Michal Hendrych ,&nbsp;Jan Storch ,&nbsp;Petr Tarkowski ,&nbsp;Michal Masarik ,&nbsp;Petr Babula ,&nbsp;Jan Vacek","doi":"10.1016/j.taap.2024.117218","DOIUrl":"10.1016/j.taap.2024.117218","url":null,"abstract":"<div><div>Cannabidiol (CBD) is a phytocannabinoid from <em>Cannabis sativa</em> L., in which there is currently growing interest for medicinal use. Here, we focused on the safety and pharmacokinetics of a CBD-rich (77 %, <em>w</em>/<em>w</em>) full-spectrum hemp extract in male and female rats. A 90-day sub-chronic toxicity assay was conducted with doses of 0.5, 5, 10, and 35 mg CBD extract/kg/day administered orogastrically. No adverse effects or disruption in organ or body weight, behaviour, locomotion, food intake, or impact on morbidity/mortality were observed. Pathomorphological examination showed no gastrointestinal or liver changes. Blood cell analysis showed a significant (<em>p</em> &lt; 0.05) decrease in the number of leukocytes for both sexes, and a significant difference (<em>p</em> &lt; 0.01 or 0.05) between the control and treated animals for mean corpuscular haemoglobin concentration, mean corpuscular volume of erythrocytes, and percentage of neutrophils and monocytes. However, blood cell analysis revealed significant (<em>p</em> &lt; 0.05) sex-dependent differences, such as haematocrit and erythrocyte count. The levels of ions (Ca²⁺, Na⁺, K⁺ and Cl⁻), alkaline phosphatase activity, and creatinine level in treated animals were also observed for both sexes. Males exhibited decreased alanine transaminase activities, and females exhibited hyperalbuminemia (<em>p</em> &lt; 0.01). CBD was quantified in treated animals in a dose-dependent manner, with statistical significance varying from <em>p</em> &lt; 0.05 to 0.0001. The accumulation of CBD in the individual tissues increased in the order: brain &lt; serum &lt; liver &lt; heart &lt;&lt; kidney &lt;&lt;&lt; muscle and skin. The results indicated sex-dependent latent disruption of kidney and liver homeostasis, most likely reversible in nature.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117218"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142897828","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":"Cadmium biphasically impacts the adaptive immune system via regulating mitochondrial activation of hematopoietic stem cells in mice","authors":"Yifan Zhao ,&nbsp;Chuanxuan Wang ,&nbsp;Jun Du ,&nbsp;Wei Wang ,&nbsp;Jiaojiao Wu ,&nbsp;Ting Liu ,&nbsp;Peng Xue ,&nbsp;Yingzi Ju ,&nbsp;Xinyu Hong ,&nbsp;Jianheng Zheng ,&nbsp;Weidong Qu ,&nbsp;Yubin Zhang","doi":"10.1016/j.taap.2024.117216","DOIUrl":"10.1016/j.taap.2024.117216","url":null,"abstract":"<div><div>Cadmium (Cd) is a highly toxic metal in human body, and therefore understanding the immunotoxicity of Cd is significant for public health. The aim of this study was to investigate the role of hematopoietic stem cells (HSC) in regulating the immunotoxicity of Cd. After exposure to 10 ppm Cd via drinking water for up to 9 months, C57BL/6 mice had a suppressed adaptive immune system at day 135 but had an enhanced adaptive immune system at day 270 during Cd exposure. The biphasic impacts of Cd on the adaptive immune system were correlated to the mitochondrial (MT) activation of HSC. Mechanistically, a direct action of Cd activated the non-canonical Wnt signaling to increase MT activation in HSC in the bone marrow (BM) at day 90, thus resulting in an impaired adaptive immune system in mice at day 135 during Cd exposure; conversely, Cd reduced the production of thrombopoietin (TPO) by osteoblasts in the BM to suppress MT activation in HSC at day 180, which in turn caused an enhanced adaptive immune system in mice at day 270 during Cd exposure. Thus, Cd biphasically impacts the adaptive immune system via regulating MT activation of HSC, providing a novel angle for understanding the immunotoxicology of metals.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117216"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898156","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}