Toxicology最新文献

{"title":"NOX4/Keap1/Nrf2/ROS signaling drives ferroptosis in trimethyltin chloride-induced cardiac developmental malformations","authors":"Jin Chen ,&nbsp;Hanwen Hu ,&nbsp;Jing Fu ,&nbsp;Yaolin He ,&nbsp;Hui Zhou ,&nbsp;Jingwei Lei ,&nbsp;Ming Huang ,&nbsp;Jianqi Wang ,&nbsp;Anfei Liu ,&nbsp;Zhenzhong Liu","doi":"10.1016/j.tox.2026.154394","DOIUrl":"10.1016/j.tox.2026.154394","url":null,"abstract":"<div><div>Trimethyltin chloride (TMT), a pervasive environmental organic tin pollutant, has been implicated in cardiac injury, though its underlying mechanisms remain unclear. TMT exposure triggers excessive reactive oxygen species (ROS) generation, a key inducer of ferroptosis—a regulated form of cell death driven by iron-dependent lipid peroxidation. NADPH oxidase 4 (NOX4), highly expressed during cardiac development, plays a critical role in myocardial ROS production, while the Keap1/Nrf2 pathway regulates cellular ROS homeostasis. We hypothesized that TMT induces cardiac developmental defects by activating NOX4/Keap1/ROS-mediated ferroptosis. TMT exposure induced cardiac malformations, pericardial edema, and reduced heart rate in zebrafish embryos. Further studies revealed that TMT upregulated nox4 expression in embryonic hearts. Notably, pharmacological inhibition or genetic knockdown of nox4 markedly attenuated TMT-induced cardiac defects. Moreover, nox4 suppression antagonized TMT-triggered dysregulation of the Keap1/Nrf2 axis, ROS overaccumulation, mitochondrial damage, and ferroptosis-related abnormalities—including Fe²⁺ accumulation, elevated lipid peroxidation, and downregulated glutathione peroxidase 4 (GPX4) expression. Crucially, inhibition or knockdown of keap1 similarly mitigated TMT-induced ROS bursts, mitochondrial injury, and ferroptosis progression. Intervention with ferroptosis-specific inhibitors (Liproxstatin-1 and Myricetin) confirmed that ferroptosis directly contributes to TMT-induced cardiac developmental defects. This study demonstrates that TMT induces cardiac malformations by activating ferroptosis via the nox4/Keap1/Nrf2/ROS signaling axis. These findings reveal a novel mechanism underlying TMT cardiotoxicity, provide theoretical insights for assessing TMT exposure as a risk factor for congenital heart disease, and identify potential molecular targets for therapeutic intervention.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154394"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900904","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":"A scalable human liver-on-a-chip platform for predictive safety assessment","authors":"Gauri Kulkarni ,&nbsp;Lizao Chen ,&nbsp;Jing Sang ,&nbsp;Ji Hye Seo ,&nbsp;Romain Grall ,&nbsp;Yunfang Wang ,&nbsp;Paige Gilbride ,&nbsp;Yu-Chieh Yuan ,&nbsp;Matthew Albaum-Getzen ,&nbsp;Jenna McCormack ,&nbsp;Jingzhe Ma ,&nbsp;Alyssa Fanelli ,&nbsp;Lingjun Meng ,&nbsp;Beibei Xu ,&nbsp;XuHai Huang ,&nbsp;Thomas Marshall ,&nbsp;Hardeep Singh ,&nbsp;Xiaohua Qian ,&nbsp;Zhiyong Xie ,&nbsp;Hui Bai ,&nbsp;Haiqing Bai","doi":"10.1016/j.tox.2025.154378","DOIUrl":"10.1016/j.tox.2025.154378","url":null,"abstract":"<div><div>Non-animal methods, including advanced <em>in-vitro</em> approaches such as liver-on-a-chip models, hold promise for hepatotoxicity testing but remain limited in pharmaceutical and regulatory adoption due to high costs, poor scalability, low reproducibility, and insufficient validation. To address these challenges, we introduce a drug-induced liver injury (DILI) model based on the commercially available and highly adaptable OC-Plex microfluidic platform. Primary human hepatocytes (PHHs) maintained long-term viability and metabolic competence, confirmed by albumin and urea production as well as cytochrome P450 gene expression. The system reliably detected acetaminophen (APAP) - induced hepatotoxicity across six mechanistic readouts—albumin, viability, cytokeratin-18 (CK18), urea, CYP3A4 activity, and mitochondrial function. As an initial proof-of-concept, we tested 17 compounds, including both drugs and cosmetic ingredients. Among 13 compounds with known toxicity liabilities in humans, our model shows a high predictive performance (85.7 % sensitivity, 100 % specificity, and 92.3 % accuracy). Together, these findings demonstrate the feasibility of a cost-effective, scalable, and human-relevant liver-on-a-chip system for predictive hepatotoxicity testing. With future development and validation, this model holds great potential to replace animal testing in chemical safety assessment.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154378"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805556","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":"Nickel refining fumes activate glutamine metabolism via the HIF‐1α/Notch pathway to drive epithelial-mesenchymal transition in Beas‐2B cells","authors":"Qian-Qian Sun ,&nbsp;Han-Nong Yu ,&nbsp;Rui-Ze Wu ,&nbsp;Bo Zhang ,&nbsp;Wen-Xue Yao ,&nbsp;Wei-Yang Liu ,&nbsp;Jia Han ,&nbsp;Li-Yan Ju ,&nbsp;Yu-Lin Pan ,&nbsp;Yong-Hui Wu","doi":"10.1016/j.tox.2025.154390","DOIUrl":"10.1016/j.tox.2025.154390","url":null,"abstract":"<div><div>Occupational exposure to nickel refining fumes (NiRF) represents a critical risk factor for respiratory diseases; however, the molecular mechanisms governing NiRF-induced epithelial-mesenchymal transition (EMT) in bronchial epithelial cells remain incompletely elucidated. In vitro experiments using the human bronchial epithelial cell line Beas-2B as a model demonstrated that NiRF exposure robustly activated the hypoxia-inducible factor-1α (HIF-1α)/Notch signaling pathway, while concomitantly triggering glutamine metabolic reprogramming. This reprogramming phenotype was characterized by the upregulated expression of the glutamine transporter SLC1A5 and enhanced expression of glutaminase 1 (GLS1). Functional validation assays revealed that small interfering RNA (siRNA)-mediated silencing of HIF-1α (siHIF-1α) or Notch1 (siNotch1) significantly downregulated GLS1 expression, and reversed NiRF-induced glutamine metabolic activation. Furthermore, pharmacological inhibition of glutamine metabolism via treatment with a GLS1 inhibitor effectively abrogated the EMT process in Beas-2B cells, as evidenced by the upregulated expression of the epithelial marker E-cadherin and the downregulated expression of the mesenchymal markers N-cadherin and vimentin. In vivo experiments further confirmed that NiRF promoted EMT in lung tissue cells in a dose-dependent manner, accompanied by activation of the HIF-1α/Notch signaling pathway and enhanced glutamine metabolism (as reflected by the upregulated expression of both SLC1A5 and GLS1). Collectively, these findings verify that glutamine metabolic activation, mediated by the HIF-1α/Notch pathway, constitutes the core mechanism underlying NiRF-driven EMT in Beas-2B cells. This study provides novel theoretical insights and potential therapeutic targets for elucidating the pathogenesis of occupational NiRF-associated respiratory injury and developing targeted intervention strategies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154390"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888943","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":"Cx43 phosphorylation at Ser368 facilitates PASMC dedifferentiation in nicotine-induced pulmonary arterial remodeling","authors":"Yi Xu ,&nbsp;Xiaomin Hou ,&nbsp;Su Guo ,&nbsp;Jin Zhou ,&nbsp;Xuelu Jiang ,&nbsp;Zhifa Zheng ,&nbsp;Liangyuan Zhao ,&nbsp;Xiaoxia Ren ,&nbsp;Lingbo Yang ,&nbsp;Yiwei Shi ,&nbsp;Xiaojiang Qin","doi":"10.1016/j.tox.2025.154389","DOIUrl":"10.1016/j.tox.2025.154389","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary arterial hypertension is a severe disease characterized by pulmonary vascular remodeling, which is closely associated with the phenotypic switching of pulmonary artery smooth muscle cells (PASMCs). Connexin 43 (Cx43) phosphorylation is a key regulator of intercellular communication. However, the specific mechanism underlying nicotine-induced dedifferentiation of PASMCs remains unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate the molecular mechanism by which Cx43 phosphorylation promotes nicotine-induced phenotypic switching of PASMCs, thereby driving pulmonary vascular remodeling.</div></div><div><h3>Methods</h3><div>Using <em>Tagln-Cre; Cx43</em>^{<em>+ /+</em>} and <em>Tagln-Cre; Cx43</em>^{<em>flox/+</em>} deletion mice exposed to nicotine, a series of <em>in vivo</em> and <em>in vitro</em> experiments were conducted to investigate the mechanism by which nicotine promotes pulmonary arterial remodeling via protein kinase C-mediated phosphorylation of Cx43 and subsequent dedifferentiation of PASMCs. The involvement of this kinase pathway was further validated with its specific inhibitor, chelerythrine chloride.</div></div><div><h3>Results</h3><div>Nicotine increased PASMC dedifferentiation by promoting Cx43 phosphorylation at Ser368 (Cx43-pS368). In <em>Tagln-Cre; Cx43</em> ^{<em>flox/+</em>} mice, these pathological changes were reduced. In vitro, chelerythrine chloride was utilized to inhibit nicotine-induced Cx43-pS368. This suppression of Cx43-pS368 effectively attenuated nicotine-induced PASMC dedifferentiation, thereby ameliorating pulmonary arterial remodeling.</div></div><div><h3>Conclusion</h3><div>Nicotine can induce PASMC phenotypic transformation by modulating Cx43-pS368, thereby promoting pulmonary artery remodeling. Targeting this pathway could provide a therapeutic strategy for nicotine-related pulmonary vascular diseases.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154389"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889886","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":"Mechanistic insights into TDCPP-induced DNA damage in GT1-7 cells","authors":"Bingli Lei ,&nbsp;Jiaying Li ,&nbsp;Yingxin Yang ,&nbsp;Xiaoyu Lu ,&nbsp;Tingying Liu ,&nbsp;Na Li ,&nbsp;Yang Li ,&nbsp;Xinyang Li ,&nbsp;Chenglian Feng","doi":"10.1016/j.tox.2025.154391","DOIUrl":"10.1016/j.tox.2025.154391","url":null,"abstract":"<div><div>As a typical organophosphate ester compound, tris(1,3-dichloro-2-propyl) phosphate (TDCPP) exhibits both estrogenic activity and genotoxicity. However, the involvement of estrogen signaling pathways in TDCPP-induced genotoxicity remains unclear. This study evaluated the effects of TDCPP (0.001–200 μM) on DNA damage and repair-related endpoints in GT1–7 mouse hypothalamic cells, and examined the roles of estrogen nuclear receptors (ERα/β) and G protein-coupled estrogen membrane receptor 1 (GPER1), as well as their downstream ERK1/2 and AKT signaling pathways, in TDCPP-induced DNA damage. Our results showed that TDCPP exposure elevated intracellular levels of reactive oxygen species (ROS) and malondialdehyde (MDA), induced DNA damage and G2/M cell cycle arrest, and increased mitochondrial damage and micronucleus formation. In addition, TDCPP significantly increased the protein expression of ATM and γ-H2AX, key markers of DNA double-strand breaks (DSBs), and upregulated the mRNA expression of most DSB repair-related genes, while downregulated mRNA expression of most DNA single-strand break (SSB) repair-related genes. TDCPP also upregulated both protein and gene expression of GPER1 and enhanced ERK1/2 phosphorylation. Pretreatment with the GPER1 inhibitor G15 or the ERK1/2 inhibitor U0126 significantly suppressed TDCPP-induced upregulation of ATM and γ-H2AX protein expression, reversed changes in mRNA levels of DSB/SSB repair-related genes, and reduced TDCPP-induced DNA damage in GT1–7 cells. These findings indicate that TDCPP activates the GPER1-ERK1/2 signaling pathway, which plays a critical role in mediating its DNA-damaging effects.</div></div><div><h3>Capsule</h3><div>TDCPP induced DNA damage in GT1–7 cells by activating GPER1-ERK1/2 signaling pathway.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154391"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893085","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":"Macrophage-epithelial cells crosstalk and the role of CCL2-CCR2 axis in single-walled carbon nanotubes-induced lung inflammation and fibrosis","authors":"Yalu Shen ,&nbsp;Zhen Shi ,&nbsp;Jiayang Zou ,&nbsp;Yunfei Zhou ,&nbsp;Qingqing Yang ,&nbsp;Wenrui Zhao ,&nbsp;Yu Gan ,&nbsp;Xinxin Hu ,&nbsp;Tong Shen ,&nbsp;Xiang Zhang","doi":"10.1016/j.tox.2025.154388","DOIUrl":"10.1016/j.tox.2025.154388","url":null,"abstract":"<div><div>Environmental and occupational exposure to carbon nanotube (CNT) raises concerns over their safety and adverse health impacts, especially lung inflammation and fibrosis. Immune cells and epithelial cells within alveoli interact with each other to maintain lung homeostasis. To date, the contribution of lung macrophage-epithelial cells crosstalk to single-walled CNT (SWCNT)-caused lung injury and underlying mechanisms have not been systematically investigated. Here, we established a mice model of lung exposure to SWCNT and found that SWCNT induced M1-typed lung macrophages polarization during inflammation stage and abnormal epithelium regeneration during fibrosis stage, characterized by impaired alveolar epithelial type Ⅱ (AT2) cells to alveolar epithelial type Ⅰ (AT1) cells transition. Mechanistically, conditioned medium experiments combined with chemokines CCL2 siRNA intervene revealed that damaged lung epithelial cells-derived CCL2 by SWCNT activated CCR2 in macrophages, subsequently polarizing to M1 state. <em>In vivo</em> experiments further demonstrated CCL2-CCR2 axis regulated SWCNT-polarized M1 lung macrophages and pro-inflammatory cytokines secretion, which are involved in the impairment of AT2-AT1 cells transition. Importantly, inhibition of CCL2-CCR2 axis effectively restored SWCNT-induced lung inflammation and fibrosis. In conclusion, our findings elucidate the crosstalk of lung macrophages and epithelial cells, which further regulates the progression of SWCNT-induced lung injury, and target CCL2-CCR2 axis is expected to be potential therapeutic strategy for the prevention and treatment of lung injury induced by nanoparticles.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154388"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145858130","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":"The regulatory roles of BMAL1 in TDCIPP-induced autophagy and apoptosis in HT22 cells","authors":"Yu Liu ,&nbsp;Ruoxuan Liang ,&nbsp;Benhong Xu","doi":"10.1016/j.tox.2026.154405","DOIUrl":"10.1016/j.tox.2026.154405","url":null,"abstract":"<div><div>Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), a common organophosphate flame retardant, is extensively used in various consumer products and has emerged as an environmental pollutant. Recent studies have documented the neurotoxic effects of TDCIPP, highlighting its ability to promote neuronal apoptosis and induce autophagy. Nonetheless, the underlying regulatory mechanisms remain poorly understood. The present study observed an upregulation of Brain and Muscle ARNT-Like 1 (BMAL1) in TDCIPP-treated mouse HT22 cells, indicating that BMAL1 may play a critical role in TDCIPP-induced neuronal autophagy and apoptosis. Furthermore, the impact of BMAL1 knockdown on TDCIPP-induced autophagy and apoptosis in HT22 cells was explored using Western blot (WB) and flow cytometry (FACS) analysis. The results demonstrated that TDCIPP exposure modulated the expression levels of BMAL1 and autophagy-related proteins and increased the phosphorylation of mTOR. The suppression of BMAL1 expression resulted in decreased AMPK expression, thereby blocking cell autophagy. Collectively, the results highlight the role of BMAL1 in the cell death mechanism induced by TDCIPP through the AMPK signaling pathway in HT22 cells. Therefore, the present study provides a new perspective and evidence on the mechanism of TDCIPP-induced neurotoxicity in HT22 cells.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154405"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978151","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":"PM2.5 exposure exacerbates airway pyroptosis related inflammatory response in asthmatic mice by activating NLRP3 inflammasome","authors":"Hui Du ,&nbsp;Zhi Liu ,&nbsp;Lingli Ge ,&nbsp;Yuxi Lei ,&nbsp;Yuxin Wang ,&nbsp;Jian Lan ,&nbsp;Dongchi Zhao","doi":"10.1016/j.tox.2025.154376","DOIUrl":"10.1016/j.tox.2025.154376","url":null,"abstract":"<div><h3>Background</h3><div>Fine particulate matter (PM2.5)-induced airway epithelial damage plays a pivotal role in driving the development of airway inflammation. Although pyroptosis is recognized for its highly proinflammatory nature, its precise role in PM2.5-associated airway inflammation, particularly in asthmatic condition, remains to be fully elucidated.</div></div><div><h3>Methods</h3><div>In ovalbumin (OVA)-sensitized asthmatic mice, we assessed pulmonary histopathology, inflammatory cell counts and Th2 cytokine levels (IL-4, IL-5, and IL-13) in bronchoalveolar lavage fluid (BALF), airway hyperresponsiveness (AHR), and airway epithelial pyroptosis. To investigate the effects of PM2.5 on airway epithelial cells, BEAS-2B cells were exposed to PM2.5. Cell viability was evaluated using the CCK-8 assay, while pyroptosis-related protein levels and inflammatory cytokine release were analyzed by Western blot and ELISA, respectively. Additionally, transmission electron microscopy (TEM) was employed to examine PM2.5-induced ultrastructural changes in BEAS-2B cells. To further elucidate the underlying mechanism, we administered the NLRP3 inhibitor MCC950 and the Caspase-1 inhibitor Ac-YVAD-cmk to verify the involvement of NLRP3 inflammasome activation and pyroptosis in PM2.5-exposed asthmatic mice.</div></div><div><h3>Results</h3><div>PM2.5 exposure significantly aggravated airway inflammation in asthmatic mice, as demonstrated by elevated histopathological inflammatory scores in lung tissues and increased pro-inflammatory cytokine levels in BALF. Furthermore, PM2.5 upregulated the abundance of pyroptosis-related markers, namely NLRP3, Caspase-1, GSDMD, and IL-1β, in the lung tissues of asthmatic mice. In BEAS-2B cells, PM2.5 exposure led to a dose-dependent reduction in cell viability and promoted the activation of NLRP3 inflammasome, subsequently leading to Caspase-1-mediated GSDMD cleavage and IL-1β secretion. TEM further confirmed pyroptosis, revealing characteristic morphological alterations such as cytoplasmic vacuolation, mitochondrial swelling, and plasma membrane pore formation in BEAS-2B cells exposed to PM2.5. Critically, inhibition of NLRP3 (MCC950) or Caspase-1 (Ac-YVAD-cmk) markedly attenuated PM2.5-induced pyroptosis and ameliorated airway inflammation in asthmatic mice, underscoring the pivotal role of the NLRP3/Caspase-1/GSDMD axis in this pathogenic process.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that PM2.5 exposure induces airway epithelial pyroptosis through NLRP3 inflammasome activation, thereby exacerbating airway inflammation in asthmatic mice.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154376"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800687","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":"Interaction-profile cheminformatic read-across identifies the UV filter benzophenone-4 as a PPARγ agonist and potential obesogen","authors":"Junpyo Gong ,&nbsp;In Guk Park ,&nbsp;Seokyoung Hwang ,&nbsp;Jayhyun Cho,&nbsp;Min Ju Lee,&nbsp;Minkyu Kim,&nbsp;Junseo Kang,&nbsp;Seungchan An,&nbsp;Minsoo Noh","doi":"10.1016/j.tox.2025.154362","DOIUrl":"10.1016/j.tox.2025.154362","url":null,"abstract":"<div><div>Obesogens are chemicals, often encountered as environmental contaminants, that disrupt metabolic regulation and promote obesity. Here, we present a cheminformatics framework that integrates interaction-profile docking simulations with cluster-level enrichment analysis to enhance read-across and prioritize candidate environmental metabolic disruptors. Protein-ligand contact features from docking to obesity-related nuclear receptors were summarized at the pose level and combined into a 327-dimensional interaction-profile descriptor. Dimensionality-reduced descriptors from 6022 Tox21 compounds were clustered, and enrichment analysis against Tox21 assay results identified clusters associated with specific nuclear receptor activities. One cluster was selectively enriched for peroxisome proliferator-activated receptor γ (PPARγ) agonists. Although benzophenone-4 (BP-4, sulisobenzone), a sunscreen UV filter in this cluster, is labeled as inactive in Tox21, experimental validation confirmed selective PPARγ binding and recruitment of SRC-2 and PGC-1α coactivators. In human bone marrow-derived mesenchymal stem cells, BP-4 promoted adipogenic differentiation, lipid accumulation, and adiponectin production, establishing its potential as an environmental obesogen. This study demonstrates the power of combining interaction-profile read-across with functional assays to predict environmental metabolic disruptors and provides a mechanistic template for systematic chemical safety evaluation.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154362"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655654","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":"Food-borne polystyrene microplastic exposure exacerbates cognitive deficiency via enhanced neuronal synaptic damage and neuroinflammation in Alzheimer's disease","authors":"Chong Liu ,&nbsp;Yan Zhao ,&nbsp;Ji-ji Dao ,&nbsp;Yu-ke Ma ,&nbsp;Jie Liu ,&nbsp;Chen-meng Qiao ,&nbsp;Chun Cui ,&nbsp;Yan-qin Shen ,&nbsp;Shuang-xi Chen ,&nbsp;Li Yu ,&nbsp;Wei-jiang Zhao","doi":"10.1016/j.tox.2025.154371","DOIUrl":"10.1016/j.tox.2025.154371","url":null,"abstract":"<div><div>The impact of polystyrene microplastics (PS-MPs) on the nervous system has been documented, yet the potential role of PS-MPs exposure in exacerbating neuronal damage and neuroinflammation in Alzheimer's disease (AD) remains unclear. Our research demonstrated that oral exposure to PS-MPs caused hippocampal mitochondrial damage in APP/PS1 mice, reduced expression of hippocampal mitochondrial and synapse-associated proteins, inhibited ErbB4 signaling pathway, and damaged hippocampal neurons. Additionally, PS-MPs exposure induced overactivation of astrocytes and microglia with NLRP3 pathway activation, increased β-amyloid (Aβ) deposition, and ultimately worsened cognitive dysfunction in APP/PS1 mice. Subsequent in vitro findings showed that PS-MPs exacerbated hippocampal neuronal damage under Aβ pathology, suppressed ErbB4 signaling pathway, and disrupted mitochondrial and synaptic function. The compromised hippocampal neurons enhanced microglial NLRP3 pathway activation. These results suggest that exposure to PS-MPs induces hippocampal neuronal damage, impairs mitochondrial and synaptic function, and exacerbates neuroinflammation and cognitive deficits, ultimately contributing to AD progression. Collectively, these findings enhance our understanding of the mechanisms by which MPs expedite the progression and influence management of AD.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"520 ","pages":"Article 154371"},"PeriodicalIF":4.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757679","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}