Toxicology最新文献

{"title":"Effects of Methoxychlor on Broiler Gut Microbiota and Liver and its Residue Accumulation Risk to Human Health.","authors":"Yutong Tang, Ying Liu, Yongpeng Jin, Wanjun Zhang, Gaoyi Liu, Yiqiang Chen","doi":"10.1016/j.tox.2025.154105","DOIUrl":"https://doi.org/10.1016/j.tox.2025.154105","url":null,"abstract":"<p><p>Methoxychlor as a persistent organic pollutant poses significant risks to human health and the environment. Most toxicological studies focus on high-dose exposures, which do not reflect typical chronic and low-dose human exposure, necessitating the examination of the cumulative effects of chronic exposure to persistent organic pollutants. Our study exposed broilers to different concentrations of p,p'-methoxychlor (0.01-5 mg/kg) in feed, reflecting the doses commonly used in agricultural practices. The results show that even at low doses, methoxychlor causes liver damage, metabolic disturbances, disrupts the intestinal microbiota, and leads to significant accumulation of residues, particularly in the liver. When methoxychlor contamination in the feed exceeds 0.01 mg/kg, residue levels in the broiler liver surpass the EU-established limit, and the residue levels in the broiler muscle surpass this limit when contamination exceeds 0.2 mg/kg. In addition, methoxychlor disrupts the gut microbiota, causing significant shifts in microbial composition, including a decrease in beneficial bacteria and an increase in potentially harmful taxa. The gut dysbiosis, bioaccumulation potential of methoxychlor and changes in liver metabolic indicators may be associated with the liver pathology observed in this study, warranting further investigation. The harmful consequences significantly impact broiler production, leading to food safety concerns and risks to human health. At similar exposure levels, humans may face health risks comparable to those observed in broilers. This study provides important evidence for establishing strict regulations on methoxychlor residues in food products and assessing the potential risks of low-dose and long-term exposure to methoxychlor.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154105"},"PeriodicalIF":4.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531818","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":"Molecular mechanism of programmed cell death in drug-induced neuronal damage: A special focus on ketamine-induced neurotoxicity","authors":"Peipei Wang ,&nbsp;Tong Niu ,&nbsp;Degao Huang,&nbsp;Yuanlong Li,&nbsp;Zihan Jiang,&nbsp;Xia Wang,&nbsp;Linchuan Liao","doi":"10.1016/j.tox.2025.154102","DOIUrl":"10.1016/j.tox.2025.154102","url":null,"abstract":"<div><div>In recent years, the abuse of ketamine as a recreational drug has been growing, and has become one of the most widely abused drugs. Continuous using ketamine poses a risk of drug addiction and complications such as attention deficit disorder, memory loss and cognitive decline. Ketamine-induced neurotoxicity is thought to play a key role in the development of these neurological complications. In this paper, we focus on the molecular mechanisms of ketamine-induced neurotoxicity. According to our analyses, drugs in causing neurotoxicity are closely associated with programmed cell death (PCD) such as apoptosis, autophagy, necroptosis, pyroptosis, and Ferroptosis. Therefore, this review will collate the existing mechanisms of programmed death in ketamine-induced neurotoxicity as well as explore the possible mechanisms by outlining the mechanisms of programmed death in other drug-induced neurotoxicity, which may be helpful in identifying potential therapeutic targets for neurotoxicity induced by ketamine abuse.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"513 ","pages":"Article 154102"},"PeriodicalIF":4.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511627","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":"Synergistic effects of lead and copper co-exposure on promoting oxidative stress and apoptosis in the neuronal cells","authors":"Di Wu ,&nbsp;Desheng Wang ,&nbsp;Shuang-Shuang Tan ,&nbsp;Yu-Qi Li ,&nbsp;Su-Li Hong ,&nbsp;Tao Wang ,&nbsp;Gang Zheng","doi":"10.1016/j.tox.2025.154103","DOIUrl":"10.1016/j.tox.2025.154103","url":null,"abstract":"<div><div>Exposure to lead (Pb) or copper (Cu) is common and has been associated with increased risk of neurodegenerative disease. However, combined neurotoxic effects of co-exposure to these elements remain unclear. This study aimed to determine the toxic effects of Pb and Cu co-exposure on HT22 cells. In this study, Pb and Cu co-exposure exhibited enhanced toxicity, including increased reactive oxygen species (ROS) and Malondialdehyde (MDA) levels, Superoxide Dismutase 1 (SOD1) activity, lower cell viability and higher apoptotic rates, compared to single-element exposure. Pb and Cu co-exposure also resulted in significantly increased cellular labile Cu level by altering the protein levels of Cu transporters, including Copper Transporter-1 (CTR1), ATPase Copper Transporting-α(ATP7A) and ATPase Copper Transporting-β (ATP7B). Treating with antioxidants or Cu chelator to the co-exposed cells blocked the reduction cell viability and elevation of apoptotic rates. This study suggests that Pb and Cu co-exposure can result in a synergistic toxicity in neuronal cells by inducing oxidative stress and apoptosis. The cellular Cu accumulation may play an important role in inducing these synergistic effects, and both antioxidation and Cu chelation may be promising control measures to alleviate the neurotoxicity of Pb and Cu co-exposure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"513 ","pages":"Article 154103"},"PeriodicalIF":4.8,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511163","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":"Copper oxide nanoparticles disrupt lysosomal function and promote foam cell formation in RAW264.7 macrophages","authors":"Yilin Luo ,&nbsp;Kun Zhang ,&nbsp;Lejiao Mao ,&nbsp;Meiling Tan ,&nbsp;Xiaomei Dong ,&nbsp;Na Li ,&nbsp;Yuexing Zhou ,&nbsp;Chengzhi Chen ,&nbsp;Zhen Zou ,&nbsp;Jun Zhang","doi":"10.1016/j.tox.2025.154101","DOIUrl":"10.1016/j.tox.2025.154101","url":null,"abstract":"<div><div>Macrophage-derived foam cells are crucial in the development of atherosclerosis, a multifaceted and progressive disorder characterized by lipid and fibrous accumulation in major arteries. Copper oxide nanoparticles (CuONPs) have found widespread applications but their potential role in atherosclerosis remains understudied. In this study, we investigated the impact of CuONPs on foam cell formation in RAW264.7 macrophages. Our results showed that CuONPs, at concentrations as low as 10 μg/ml, significantly exacerbated foam cell formation induced by oxidized low-density lipoprotein (ox-LDL). Exposure to CuONPs stimulated LDL release and elevated the expression of NLRP3 inflammasome components, including NLRP3, Caspase-1, and IL-1β. Transmission electron microscopy (TEM) revealed accumulation of CuONPs within macrophage lysosomes, leading to disrupted lysosomal function. CuONPs-treated cells exhibited autophagosome accumulation due to impaired lysosomal degradation, as confirmed by Western blot analysis showing abnormal expression of LAMP-1 and LAMP-2 proteins. Flow cytometry analysis further demonstrated decreased lysosomal acidity in CuONPs-exposed cells. Our findings reveal a novel mechanism whereby CuONPs activate the inflammasome, disrupt lysosomal function, and hinder cholesterol efflux, thereby exacerbating the formation of macrophage-derived foam cells. These results highlight the potential risks of CuONPs exposure and provide important insights into the role of environmental particulate matter in the development of atherosclerosis.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"513 ","pages":"Article 154101"},"PeriodicalIF":4.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477038","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":"6PPD induces apoptosis and autophagy in SH-SY5Y cells via ROS-mediated PI3K/AKT/mTOR pathway: In vitro and in silico approaches","authors":"Ziwei Wang,&nbsp;Shutao Wang,&nbsp;Yingying Liu,&nbsp;Xingyu Wang,&nbsp;Wanlun Li,&nbsp;Hong Qi,&nbsp;Hou You","doi":"10.1016/j.tox.2025.154091","DOIUrl":"10.1016/j.tox.2025.154091","url":null,"abstract":"<div><div>N-(1,3-dimethylbutyl)-N’-phenyl-p-phenylenediamine (6PPD), an extensively employed antioxidant in rubber materials, is considered as an emerging contaminant. 6PPD was proven to have potential neurotoxicity, which poses risks to human health. However, the research on its neurotoxicity is still limited. This work explored the neurotoxicity of 6PPD to SH-SY5Y cells and in-depth mechanisms with a combination of <em>in vitro</em> and <em>in silico</em> approaches. Our results indicated that 6PPD could reduce cell viability and cause oxidative damage by increasing reactive oxygen species (ROS) accumulation and altering the levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA). 6PPD induced neuronal apoptosis of mitochondrial pathway and autophagy dysfunction, as characterized by the increased expressions of Cleaved caspase-3, Bax/Bcl-2, Beclin-1, LC3-II/I, and P62. 6PPD downregulated the expression of PI3K, p-AKT, and p-mTOR, while the PI3K inhibitor suppressed PI3K/AKT/mTOR pathway and promoted both apoptosis and autophagy, indicating that PI3K/AKT/mTOR pathway was involved in 6PPD-induced apoptosis and autophagy. The inhibition of this pathway was attributed to ROS accumulation in SH-SY5Y cells. Molecular docking analysis further revealed that 6PPD exhibits strong binding affinity to PI3K, AKT, and mTOR protein molecules, which could effectively interfere with downstream signaling pathways. These findings enrich the understanding of 6PPD-induced neurotoxicity and contribute to the evaluation of ecological risks associated with 6PPD.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"513 ","pages":"Article 154091"},"PeriodicalIF":4.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473076","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":"NNMT is involved in deoxynivalenol-induced hepatocyte toxicity via promoting ferroptosis","authors":"Weiling Huang ,&nbsp;Chenchen Song ,&nbsp;Yu Hua ,&nbsp;Aimei Liu","doi":"10.1016/j.tox.2025.154084","DOIUrl":"10.1016/j.tox.2025.154084","url":null,"abstract":"<div><div>Deoxynivalenol (DON) is a common contamination mycotoxin that which exerts significant hepatotoxicity, posing a serious threat to human and animal health. Ferroptosis has been linked to the development of hepatotoxicity induced by DON. However, the mechanism by which DON promotes ferroptosis in hepatocytes is not well understood. Although studies have shown that DON upregulates the expression of nicotinamide N-Methyltransferase (NNMT), its role in DON hepatotoxicity has not been elucidated. In this study, we found that DON inhibited SLC7A11/GPX4 and increased cytosolic free Fe^2 + and lipid ROS, thereby inducing ferroptosis of HepG2 cells. Overexpression of NNMT markedly downregulated the expression of SLC7A11, GPX4, GCLC, and NQO1, exacerbated the DON-induced increase in free Fe²⁺ and lipid ROS, thus promoting ferroptosis. Silencing or inhibition of NNMT produced opposite effects and abolished the DON-induced ferroptosis. Further application of SLC7A11 and GPX4 inhibitor treatments confirmed that following DON exposure, NNMT triggered ferroptosis by inhibiting SLC7A11 and GPX4, to reduce cell viability and inhibit cell growth. Taken together, this study found that DON-induced NNMT may enhance ferroptosis by inhibiting the SLC7A11/GPX4 proteins in HepG2 cells. These findings provide valuable insights for controlling DON hepatotoxicity and hepatocellular carcinoma.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"513 ","pages":"Article 154084"},"PeriodicalIF":4.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473081","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":"High content imaging of relative ATP levels for mitochondrial toxicity prediction in human induced pluripotent stem cell derived cardiomyocytes.","authors":"John Bassett, Bharathi Balasubramanian, Holly Clouse, Elena Trepakova","doi":"10.1016/j.tox.2025.154088","DOIUrl":"https://doi.org/10.1016/j.tox.2025.154088","url":null,"abstract":"<p><p>Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are increasingly being evaluated in assays aimed at better understanding potential cardiotoxic liability of newly developed therapeutic compounds. Disruption of mitochondria has been implicated in the mechanism of drug-induced cardiotoxicity of some compounds. Therefore, we have developed a high content imaging assay for the investigation of mitochondrial toxicity in hiPSC-CMs using ATP-Red, a fluorescent dye capable of detecting subcellular localization of relative ATP levels in living cells. We demonstrated time-dependent decreases in ATP-Red signal over 6h treatment with known mitochondrial toxicants antimycin (0.03, 0.1µM) or oligomycin (3, 10µM). Concentration-dependent decreases in ATP-Red signal with antimycin (0.001-0.3µM) and oligomycin (0.003-1µM) were rescued by restoring glycolysis through glucose supplementation. Decreased ATP levels were also identified in a selection of clinically available drugs with reported association with mitochondrial toxicity but absent in compounds with no known association with mitochondrial dysfunction. ATP measurements using the ATP-Red imaging assay were consistent with orthogonal measurements of whole cell ATP levels in lysed hiPSC-CMs following compound treatment. Similar findings were also obtained with measurement of mitochondrial membrane potential, except amiodarone which had no change despite decreased ATP levels. The developed high throughput imaging assay, assessing subcellular ATP dynamics, could provide mechanistic insights for tested compounds.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154088"},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459395","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":"Polystyrene microplastics trigger colonic inflammation in rats via the TLR4/NF-κB/COX-2 pathway and modulation of intestinal microbiota","authors":"Xuemin Feng ,&nbsp;Meng Zhang ,&nbsp;Tianyang Zhao ,&nbsp;Jianwei Cui ,&nbsp;Hui Ye ,&nbsp;Chunkui Zhou ,&nbsp;Lin Ye ,&nbsp;Liting Zhou","doi":"10.1016/j.tox.2025.154090","DOIUrl":"10.1016/j.tox.2025.154090","url":null,"abstract":"<div><div>Polystyrene microplastics (PS-MPs) are common microplastics that pose significant health hazards to humans. Due to multifunctionality in the gut system, MP-associated damage and mechanisms require further exploration. This study was undertaken with the objective of elucidating the impact of PS-MP exposure on colonic inflammation in rats, and to explore its potential mechanisms. Forty-eight specific-pathogen-free Wistar male rats were administered 0, 0.5, 5, and 50 mg/kg/d of PS-MPs for 90 days, after which intestinal flora distribution, inflammatory factor levels in the colon, and <em>TLR4/NF-κB/COX-2</em> gene levels were examined. To clarify whether PS-MPs directly infiltrate intestinal epithelial cells and induce cytotoxicity, human intestinal epithelial cells (HIECs) were exposed to a range of PS-MP concentrations (0 ∼ 100 μg/mL) for 48 h, and CCK-8 assays were conducted to assess the cell survival rates. In the colon tissue of rats exposed to PS-MP, goblet cells decreased, muscular layer arrangements were disordered, and disrupted and discontinuous crypt structures appeared in colon tissue, while high numbers of inflammatory cells infiltrated the colonic mucosa and submucosa. PS-MPs could accumulate in HIECs, and cell survival rates were decreased. In the colons of rats exposed to PS-MPs, the levels of Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were found to be elevated. Additionally, the mRNA and protein levels of TLR4/MyD88 in the colons of PS-MP-exposed rats exhibited a significant increase. Furthermore, the TLR4/NF-κB/COX-2 signaling pathway in rat colons was activated after MP exposure. When the TLR4/NF-κB/COX-2 signaling pathway was inhibited, the significant increases in IL-6 and TNF-α levels caused by PS-MPs were significantly reversed. PS-MP exposure also altered intestinal flora abundance in rats. Compared with the control group, the proportion of Firmicutes, Proteobacteria and Actinobacteria in PS-MPs exposed group was increased. In contrast, the proportion of Bacteroidetes and Verrucomicrobia decreased. Taken together, our results suggest that PS-MP could exert adverse effects on the gastrointestinal health of rats. Pro-inflammatory cytokine (IL-6, IL-1β and TNF-α) levels increased, and the TLR4/NF-κB/COX-2 signaling pathway was triggered. Thus, flora changes and increased intestinal inflammation may interact with each other.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"513 ","pages":"Article 154090"},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437727","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":"EFSA prohibits titanium dioxide in food- should pharmaceuticals be next?","authors":"Chandni Dand,&nbsp;Aanchal Bajaj,&nbsp;Sarika Wairkar","doi":"10.1016/j.tox.2025.154089","DOIUrl":"10.1016/j.tox.2025.154089","url":null,"abstract":"<div><div>Titanium dioxide (TiO₂) is a natural, inorganic compound widely used across various industries due to its multiple properties. Recently, the European Food Safety Authority (EFSA) raised safety concerns regarding the use of TiO₂ in foods, specifically its potential for genotoxicity, accumulation in the body, and associated health risks when used as a food additive. As a result, its use in food has been banned in the food industry in the European Union (EU) since 2022. Furthermore, the safety of TiO₂ is currently being evaluated as a pharmaceutical excipient, and its use is likely to be banned in EU by 2025. The food industry is significantly impacted by the ban, and a subsequent pharmaceutical ban can lead to issues such as the lack of a single replacement for its multiple applications, product redevelopment/revalidation and regulatory submissions. Other regulatory authorities from other countries conducted independent reviews and concluded that there is insufficient evidence to justify a ban on TiO₂ in foods, thereby allowing its continued use. Various substitutes, both natural and synthetic, are being explored, however none can fully replicate all the properties provided by TiO₂ alone. In this review, we discuss the safety concerns associated with TiO₂, which have led to its ban on food products, as well as the challenges that may arise if a similar ban is imposed on its use in pharmaceuticals.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"513 ","pages":"Article 154089"},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459387","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":"Emerging concerns associated with e-waste exposure.","authors":"Chukwuebuka ThankGod Eze, David O Carpenter","doi":"10.1016/j.tox.2025.154087","DOIUrl":"10.1016/j.tox.2025.154087","url":null,"abstract":"","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154087"},"PeriodicalIF":4.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442064","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}