Toxicology最新文献_第3页

Differential life cycle toxic effects and molecular mechanisms of Di(2-ethylhexyl) phthalate (DEHP) exposure on the female reproductive system 邻苯二甲酸二（2-乙基己基）酯（DEHP）暴露对女性生殖系统的不同生命周期毒性效应和分子机制。

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-31 DOI: 10.1016/j.tox.2025.154275

Kangshuai Zhang , Yuxuan Lin , Xiance Sun , Cong Zhang , Haoyuan Deng , Xiaofeng Yao , Ningning Wang , Guang Yang

{"title":"Differential life cycle toxic effects and molecular mechanisms of Di(2-ethylhexyl) phthalate (DEHP) exposure on the female reproductive system","authors":"Kangshuai Zhang , Yuxuan Lin , Xiance Sun , Cong Zhang , Haoyuan Deng , Xiaofeng Yao , Ningning Wang , Guang Yang","doi":"10.1016/j.tox.2025.154275","DOIUrl":"10.1016/j.tox.2025.154275","url":null,"abstract":"<div><div>Di(2-ethylhexyl) phthalate (DEHP), the most prevalent plasticizer worldwide, can enter the human body via various exposure pathways, including ingestion, inhalation, skin contact, and medical applications. It has been observed to exhibit characteristic patterns of accumulation in the female reproductive system. Research has demonstrated that DEHP poses a threat to reproductive health in females across various life stages. Exposure during childhood has been demonstrated to induce central precocious puberty (CPP). Exposure during reproductive age has been shown to be closely associated with reduced fertility, reproductive system tumors, polycystic ovary syndrome (PCOS), and increased risk of endometriosis. Furthermore, exposure during the perinatal period has been demonstrated to increase the risk of embryo implantation failure, placental dysfunction, and abnormal ovarian development in offspring. The toxic effects of DEHP exhibit transgenerational transmission characteristics, with its metabolic products' endocrine-disrupting activity and oxidative stress-inducing capacity being the core toxic factors. This study integrates toxicological evidence linking DEHP exposure to female reproductive damage, providing important references for environmental health risk assessment and the prevention and control of female reproductive diseases.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154275"},"PeriodicalIF":4.6,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970198","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}

引用次数: 0

PFBS disrupts lipid metabolism and mitochondrial function in human trophoblast cells PFBS破坏人滋养层细胞的脂质代谢和线粒体功能。

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-28 DOI: 10.1016/j.tox.2025.154269

Julia Happel , Namya Mellouk , Christine Crute , Liping Feng

{"title":"PFBS disrupts lipid metabolism and mitochondrial function in human trophoblast cells","authors":"Julia Happel , Namya Mellouk , Christine Crute , Liping Feng","doi":"10.1016/j.tox.2025.154269","DOIUrl":"10.1016/j.tox.2025.154269","url":null,"abstract":"<div><div>Perfluorobutanesulfonic acid (PFBS) is an emerging short-chain per- and polyfluoroalkyl substance (PFAS), a group of persistent environmental contaminants associated with adverse reproductive outcomes. The placenta plays a critical role in the pathogenesis of pregnancy complications, and disrupted placentation is implicated in the mechanistic pathways linking PFBS exposure to these disorders. In particular, placental mitochondria function refines during pregnancy to optimize the dynamic growth of the fetus and placenta. Disruptions in mitochondrial function may therefore mediate the adverse effects of environmental exposure on pregnancy outcomes. This study investigated the effects of PFBS on the metabolism and mitochondrial function of human syncytiotrophoblast (STB), the primary nutrient-transporting cells of the placenta. Using a human trophoblast stem cell model, we differentiated cells into STBs and exposed them to an environmentally relevant dose of PFBS (100 µM) for 24 h. Transcriptomic (RNA-seq) analysis identified 22 downregulated genes and 10 upregulated genes (FDR < 0.05). Integrated transcriptomic and metabolomic analyses revealed that PFBS significantly disrupted lipid metabolism, notably downregulating <em>PPARG</em>, a key regulator of placental lipid homeostasis, and carnitine shuttle genes <em>CPT1A</em> and <em>SLC25A20</em>, which are essential for mitochondrial fatty acid import. Further functional assessments found increased mitochondrial DNA copy number, yet decreased ATP production, indicating mitochondrial dysfunction. However, PFBS exposure did not induce oxidative stress nor alter mitochondrial morphology. These findings demonstrate that PFBS induces metabolic toxicity in human STBs, primarily by disrupting lipid metabolism and mitochondrial energy production. This mechanism may underlie the observed associations between PFBS exposure, placental dysfunction, and adverse pregnancy outcomes.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154269"},"PeriodicalIF":4.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970180","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}

引用次数: 0

Irf4 participates in benzene-induced hematopoietic senescence through mitochondrial ROS-dependent BCAA catabolism Irf4通过线粒体ros依赖性BCAA分解代谢参与苯诱导的造血衰老

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-28 DOI: 10.1016/j.tox.2025.154271

Ziyan Liu , Jingyu Wang , Wei Zhang , Huiwen Kang , Danyang Huang , Ziyan Wang , Guangyu Jiang , Ai Gao

{"title":"Irf4 participates in benzene-induced hematopoietic senescence through mitochondrial ROS-dependent BCAA catabolism","authors":"Ziyan Liu , Jingyu Wang , Wei Zhang , Huiwen Kang , Danyang Huang , Ziyan Wang , Guangyu Jiang , Ai Gao","doi":"10.1016/j.tox.2025.154271","DOIUrl":"10.1016/j.tox.2025.154271","url":null,"abstract":"<div><div>The continuous accumulation of senescent hematopoietic stem progenitors (HSPCs) contributes to hematopoietic damage. Benzene is a confirmed human carcinogen, and its damage to HSPCs is a key event in benzene poisoning. However, whether the environmental dose of benzene is involved in HSPC damage by inducing cellular senescence has not been reported. Here, male C57BL/6 J mice were exposed to benzene vapour for 12 weeks (0, 10, 50 ppm), and mouse hematopoietic progenitor cell line FDC-P1 was exposed to benzene metabolite 1,4-BQ for 24 h (0, 5, 10 μM). In vivo and in vitro models combined with single-cell RNA sequencing have shown that benzene and its metabolites caused senescence in whole bone marrow and hematopoietic progenitor cells. Proteomics showed that benzene exposure significantly up-regulated interferon regulatory factor 4 (Irf4) in the bone marrow. Irf4 inhibition alleviated cellular senescence and hematopoietic damage, suggesting that Irf4 is a key molecule in benzene-induced hematopoietic cell senescence. Mechanistically, benzene caused a decrease in branched-chain amino acids (BCAAs) in whole bone marrow, hematopoietic progenitor cells, and plasma, and an increase in the BCAA catabolic enzyme Bcat1, mitochondrial ROS, and Bckdh activity. Irf4 inhibition down-regulated Bcat1, alleviated mitochondrial oxidative stress-dependent Bckdh abnormality, and up-regulated BCAAs. BCAA supplementation effectively alleviated benzene-induced cellular senescence and hematopoietic damage. In conclusion, the study identified that Irf4 triggered benzene-induced hematopoietic progenitor cell senescence and hematopoietic damage by mitochondrial injury-induced excessive BCAA catabolism. This study provides new ideas on the molecular mechanism of benzene-induced hematopoietic damage from the perspective of metabolism and senescence.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154271"},"PeriodicalIF":4.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922940","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}

引用次数: 0

EAAT2 dysfunction mediates acrylamide-induced excitotoxicity and neuronal damage in a SH-SY5Y/U251 co-culture model 在SH-SY5Y/U251共培养模型中，EAAT2功能障碍介导丙烯酰胺诱导的兴奋毒性和神经元损伤

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-28 DOI: 10.1016/j.tox.2025.154273

Wanting Wang , Siyu Wu , Linyuan Zhang , Yulu Li , Luyao Tong , Airu Duan , Shujun Lv , Xiao Chen , Bin Li

{"title":"EAAT2 dysfunction mediates acrylamide-induced excitotoxicity and neuronal damage in a SH-SY5Y/U251 co-culture model","authors":"Wanting Wang , Siyu Wu , Linyuan Zhang , Yulu Li , Luyao Tong , Airu Duan , Shujun Lv , Xiao Chen , Bin Li","doi":"10.1016/j.tox.2025.154273","DOIUrl":"10.1016/j.tox.2025.154273","url":null,"abstract":"<div><div>Acrylamide (ACR) is a pervasive environmental and workplace contaminant with established neurotoxic effects but unclear pathogenic mechanisms. In this study, we screened for potential ACR binding targets associated with neurotoxicity and identified the astrocytic glutamate transporter EAAT2. Molecular docking and dynamics simulations revealed that ACR interacts stably with the glutamate-binding pocket of EAAT2, potentially impairing transport function. After exposing SH-SY5Y human neuroblastoma cells to ACR (0–500 μg/mL) for 1, 3, or 5 days, a significant decrease in EAAT2 expression was indeed observed. Concurrently, it induced significant time- and dose-dependent reductions in viable cell numbers, increases in Tau phosphorylation (AT8, pS396, pS262), and the accumulation of insoluble Tau oligomers, as well as the downregulation of neurotrophic signaling factors BDNF and TrkB. Moreover, in transwell co-cultures of mature SY5Y cells and U251 astrocytes, ACR administration (111 μg/mL, 72 h) resulted in reactive transformation of astrocytes, extracellular glutamate accumulation and enhanced neuronal calcium influx via extrasynaptic NMDA receptors. This resulted in downstream neurotoxic responses including BDNF/TrkB suppression, caspase-3 activation, Tau hyperphosphorylation and secondary neuronal injury. Astrocytic overexpression of <em>SLC1A2</em> (EAAT2) significantly reversed all of these pathogenic responses. Taken together, these findings suggest that ACR induces neuronal excitotoxicity by interfering with astrocytic EAAT2-mediated regulation of extracellular glutamate, leading to extrasynaptic NMDAR overactivation, intracellular calcium overload, and Tau-related neurodegeneration. The EAAT2 is a potential therapeutic target for mitigating ACR-induced neurotoxicity and associated sequelae such as cognitive impairment.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154273"},"PeriodicalIF":4.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916486","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}

引用次数: 0

Developmental toxicity of microplastics in human stem cells using adverse outcome pathway based integrated approaches to testing and assessment approach 微塑料在人类干细胞中的发育毒性，基于不良结果通路的综合方法测试和评估方法。

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-26 DOI: 10.1016/j.tox.2025.154268

Jaeseong Jeong , Keon Kang , Hyunwoo Kim , Chaein Chong , Jeongeun Im , Jin-Sung Park , Minhaeng Cho , Jinhee Choi

{"title":"Developmental toxicity of microplastics in human stem cells using adverse outcome pathway based integrated approaches to testing and assessment approach","authors":"Jaeseong Jeong , Keon Kang , Hyunwoo Kim , Chaein Chong , Jeongeun Im , Jin-Sung Park , Minhaeng Cho , Jinhee Choi","doi":"10.1016/j.tox.2025.154268","DOIUrl":"10.1016/j.tox.2025.154268","url":null,"abstract":"<div><div>Micro/nanoplastics (MNPs), detected in human tissues including the placenta, raise significant concerns regarding their potential impact on early human development. However, the mechanisms underlying their developmental toxicity remain poorly understood. To address this, we applied an Integrated Approaches to Testing and Assessment (IATA) framework to evaluate the developmental toxicity of polystyrene (PS) MNPs by combining adverse outcome pathway (AOP) development, experimental testing within an Integrated Testing Strategy (ITS), and literature-based data integration. As part of the ITS, experimental evaluations were conducted using human embryonic stem cells (ESCs) to assess PS MNP uptake, effects on germ layer differentiation, and size-dependent cytotoxicity. To further refine the assessment, an IATA approach was applied by integrating independent findings from the literature, strengthening the weight of evidence for AOP-based hazard evaluation. The alignment between ESC-based results and broader toxicological data enhances the predictive capacity of developmental toxicity assessments and supports the regulatory application of non-animal testing strategies. These findings contribute to the advancement of mechanism-based, human-relevant toxicity evaluation and provide a structured framework for assessing the developmental risks associated with emerging contaminants like MNPs.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154268"},"PeriodicalIF":4.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970154","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}

引用次数: 0

Prepubertal exposure to gadolinium-based contrast agents impairs sperm quality and elevates oxidative stress in adult rats 在成年大鼠中，青春期前暴露于钆造影剂会损害精子质量并升高氧化应激

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-26 DOI: 10.1016/j.tox.2025.154270

Catarina Conrado de Britto , Amanda Seraphim de Oliveira , Leticia Mingorance Crepaldi , Ronni Rômulo Novaes e Brito , Sandra Maria Miraglia , Samara Urban de Oliva

{"title":"Prepubertal exposure to gadolinium-based contrast agents impairs sperm quality and elevates oxidative stress in adult rats","authors":"Catarina Conrado de Britto , Amanda Seraphim de Oliveira , Leticia Mingorance Crepaldi , Ronni Rômulo Novaes e Brito , Sandra Maria Miraglia , Samara Urban de Oliva","doi":"10.1016/j.tox.2025.154270","DOIUrl":"10.1016/j.tox.2025.154270","url":null,"abstract":"<div><div>Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging. Gadolinium (Gd) retention has been reported in various tissues of both patients and experimental animals, even in those with normal renal and hepatic function and an intact blood-brain barrier. Gadoteric Acid (Dotarem®) is approved for use in children of all ages, including neonates. In these groups, the blood-tissue barriers in the male reproductive tract are still developing, which may lead to more pronounced Gd retention than in adults. The aim of this study was to evaluate the effects of a single prepubertal exposure (15 days postnatal, pnd) to gadoteric acid (Gadoterate meglumine - Dotarem®) on sperm quality and quantity in adult rats. Male rats were treated with a single dose of gadoteric acid at a clinical-equivalent dose (0.6 mMol/kg) or at one-tenth that dose (0.06 mMol/kg), at 15pnd (prepubertal phase). The rats were euthanized at 110pnd (adult phase). Gd-treated animals exhibited reduced testicular and epididymal weights, decrease daily sperm production, and increased epididymal sperm transit time. Sperm motility, viability, morphology, mitochondrial function, acrosomal and DNA integrity, and chromatin compaction were also negatively affected. Furthermore, increased oxidative stress markers and lipid peroxidation were observed in sperm and testicular tissue. A single prepubertal exposure to Gd, before the establishment of testicular and epididymal barriers, may lead to long-term alterations in sperm quantitative and qualitative parameters and induce oxidative stress in sperm and male reproductive tissues in adulthood.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154270"},"PeriodicalIF":4.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922941","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}

引用次数: 0

FOXO3 mediated gene expression modulates doxorubicin sensitivity in human cardiomyocytes FOXO3介导的基因表达调节人心肌细胞对阿霉素的敏感性

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-23 DOI: 10.1016/j.tox.2025.154267

J.G. Faber, M. van Herwijnen, D. Hauser, S. Daemen, F. Caiment, T. van den Beucken

{"title":"FOXO3 mediated gene expression modulates doxorubicin sensitivity in human cardiomyocytes","authors":"J.G. Faber, M. van Herwijnen, D. Hauser, S. Daemen, F. Caiment, T. van den Beucken","doi":"10.1016/j.tox.2025.154267","DOIUrl":"10.1016/j.tox.2025.154267","url":null,"abstract":"<div><div>Anthracyclines such as doxorubicin (DOX) are widely used and effective chemotherapeutic agents, but their clinical use is limited by dose-dependent cardiotoxicity, known as anthracycline-induced cardiotoxicity (AIC). Previously, we identified FOXO3 as a key transcription factor involved in cardiomyocyte stress response pathways. However, its precise role in modulating DOX sensitivity remains incompletely understood. This study aims to investigate the role of FOXO3 in cardiomyocyte transcriptional regulation and its impact on DOX-induced stress responses. By analyzing transcriptomic alterations in FOXO3-deficient cells, we seek to deepen the knowledge on FOXO3 and its potential role in cardioprotection. We generated a novel RNA sequencing dataset from immortalized human cardiomyocytes (hCMs) treated with DOX to compare global gene expression changes between FOXO3-depleted and control cells. Functional pathway analysis was conducted to identify dysregulated biological processes. FOXO3 nuclear translocation following DOX exposure was assessed through immunofluorescence, and key transcriptional changes were validated using RT-qPCR. We observed that DOX treatment induces FOXO3 nuclear translocation in hCMs and that FOXO3 depletion alters the transcriptional landscape of cardiomyocytes under basal conditions as well as after DOX exposure. Deregulated expression of genes related to DNA repair, oxidative stress response and apoptotic signaling, may explain the increased DOX sensitivity of FOXO3 depleted hCMs.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154267"},"PeriodicalIF":4.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144904361","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}

引用次数: 0

Development of a multiplexed, high content imaging-based assay for assessing chemical effects on proliferation and apoptosis in human neural progenitor cells 开发一种基于多路复用、高含量成像的检测方法，用于评估人类神经祖细胞增殖和凋亡的化学作用

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-23 DOI: 10.1016/j.tox.2025.154266

Gabrielle Byrd , Theresa M. Freudenrich , Seline Choo , Kathleen Wallace , Kelly Carstens , Megan Culbreth , Timothy J. Shafer , Joshua A. Harrill

{"title":"Development of a multiplexed, high content imaging-based assay for assessing chemical effects on proliferation and apoptosis in human neural progenitor cells","authors":"Gabrielle Byrd , Theresa M. Freudenrich , Seline Choo , Kathleen Wallace , Kelly Carstens , Megan Culbreth , Timothy J. Shafer , Joshua A. Harrill","doi":"10.1016/j.tox.2025.154266","DOIUrl":"10.1016/j.tox.2025.154266","url":null,"abstract":"<div><div>Collaborative research between the US EPA, European research institutes, and the OECD has resulted in a developmental neurotoxicity <em>in vitro</em> testing battery (DNT-IVB) that assesses multiple biological processes that are critical for neurodevelopment. The DNT-IVB was developed to address the large number of chemicals that have not been tested in time- and resource-intensive <em>in vivo</em> DNT guideline studies. In keeping with recommendations that the DNT-IVB should evolve with the science, this work has taken two 96-well DNT-IVB assays that independently measure human neural progenitor cell proliferation or apoptosis and combined them into a multiplexed, 384-well assay that simultaneously measures proliferation, apoptosis, and cell viability. The 384-well assay and accompanying data analysis pipeline were developed and optimized, then a total of 315 chemicals were screened. Robust Z-prime and strictly standardized mean difference values indicated that the 384-well assay was excellent for both proliferation and apoptosis endpoints, improving upon the 96-well assays. Out of the 315 chemicals, 158 had been assessed in the original 96-well assays. The multiplexed assay produced highly comparable results to the original 96-well assays in terms of activity, potency, sensitivity and specificity, and identified more chemicals as selective for the proliferation endpoint. Multiplexed assay activity calls generally matched 96-well assay activity calls. With comparable performance to the 96-well assays but with significantly improved throughput, the multiplexed, 384-well assay is proposed as an updated alternative to the existing 96-well proliferation and apoptosis assays that are included in the DNT-IVB.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154266"},"PeriodicalIF":4.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916485","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}

引用次数: 0

Cadmium-induced gut dysbiosis precedes the onset of hippocampus-dependent learning and memory deficits in mice 镉诱导的肠道失调先于小鼠海马依赖性学习和记忆缺陷的发生

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-22 DOI: 10.1016/j.tox.2025.154265

Hao Wang , Joe Jongpyo Lim , Haiwei Gu , Zhengui Xia , Julia Yue Cui

{"title":"Cadmium-induced gut dysbiosis precedes the onset of hippocampus-dependent learning and memory deficits in mice","authors":"Hao Wang , Joe Jongpyo Lim , Haiwei Gu , Zhengui Xia , Julia Yue Cui","doi":"10.1016/j.tox.2025.154265","DOIUrl":"10.1016/j.tox.2025.154265","url":null,"abstract":"<div><div>Cadmium (Cd) is a heavy metal recognized as a neurotoxicant, but the detailed mechanisms contributing to its neurotoxicity remain to be fully elucidated. The gut-brain axis—a bidirectional communication pathway between the gut microbiome and the central nervous system—has been implicated in various neurological disorders. Since Cd targets the gut microbiome, it is important to investigate whether this axis contributes to Cd-induced neurotoxicity. In this study, adult male mice were exposed to environmentally relevant levels of Cd (3 mg/L) via drinking water for nine weeks. Cognitive function was assessed throughout the exposure period, and fecal samples were collected biweekly to track changes in the gut microbiome. We found that Cd exposure caused gut dysbiosis before the onset of cognitive deficits, with specific bacterial species correlating with impaired cognition. RNA sequencing revealed alterations in the expression of genes involved in cognition and neuroinflammation in the hippocampus. Additionally, Cd exposure reduced the expression of genes related to intestinal barrier integrity, increased levels of inflammatory cytokines, and altered the levels of neuroactive microbial metabolites. These findings suggest a critical role for the gut-brain axis in mediating Cd neurotoxicity and highlight the gut microbiome as a potential target for therapeutic strategies to prevent or mitigate Cd-induced cognitive decline.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154265"},"PeriodicalIF":4.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893252","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}

引用次数: 0

Integration of vitro models with machine learning and epidemiological data reveals PCB-induced glucose metabolism disruption linked to mitochondrial dysfunction 结合机器学习和流行病学数据的体外模型显示，多氯联苯诱导的葡萄糖代谢紊乱与线粒体功能障碍有关

IF 4.6 3区医学

Toxicology Pub Date : 2025-08-18 DOI: 10.1016/j.tox.2025.154264

Peiwen Li, Qianying Liu, Yu Wang, Jiazhen Zhang, Chen Gao, Yan Yan, Zhuoya Zhao, Tao Jing, Meian He

{"title":"Integration of vitro models with machine learning and epidemiological data reveals PCB-induced glucose metabolism disruption linked to mitochondrial dysfunction","authors":"Peiwen Li, Qianying Liu, Yu Wang, Jiazhen Zhang, Chen Gao, Yan Yan, Zhuoya Zhao, Tao Jing, Meian He","doi":"10.1016/j.tox.2025.154264","DOIUrl":"10.1016/j.tox.2025.154264","url":null,"abstract":"<div><div>Polychlorinated biphenyls (PCBs) have been reported to be associated with type 2 diabetes mellitus (T2DM); thus, the knowledge of their endocrine disruption mechanisms would be vital for assessing health risks. This study revealed the potential mechanism of abnormal glucose metabolism due to acute PCB-153 exposure in HepG2 cells through integrated transcriptome and DNA methylation analysis. Based on a joint analysis of two omics, the random forest machine learning model was established with 200 trees and cross-validated five times. Potential biomarkers identified by machine learning pointed to impaired mitochondrial function. Subsequent validation confirmed PCB-153-induced mitochondrial dysfunction, evidenced by reduced mitochondrial DNA copy number (mtDNAcn), adenosine triphosphate (ATP) production, mitochondrial membrane potential, and ATPase activity, alongside altered morphology and elevated reactive oxygen species (ROS). Critically, abnormal glucose metabolism was significantly attenuated and even recovered to control levels after enhancement of mitochondrial function, suggesting that PCB-153 promoted glucose metabolic defects in relation to mitochondrial dysfunction. The decline of mtDNAcn in the T2DM nested case-control population provided further evidence for long-term PCBs exposure inducing mitochondrial dysfunction. In addition, significant multiplicative and additive interactions were observed between mtDNAcn and PCB-138, PCB-153, lowly chlorinated PCBs, highly chlorinated PCBs, ΣNDL-PCBs on the 5-year FBG levels changes (<em>P</em><sub>interaction</sub>: 0.004–0.03; RERI: −0.44 to −0.31; AP: −0.39 to −0.21). Our findings highlighted the importance of maintaining normal mitochondrial function in glucose metabolism of non-dioxin-like PCBs exposure and provided new insights into T2DM pathogenesis caused by PCBs exposure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154264"},"PeriodicalIF":4.6,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144864839","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}

引用次数: 0