Toxicology最新文献

{"title":"Role of neuroglia cell-derived microvesicles in cobalt chloride-induced mitochondrial autophagy in neurons","authors":"Husheng Li ,&nbsp;Fuli Zheng ,&nbsp;Wenya Shao ,&nbsp;Guangxia Yu ,&nbsp;Hong Hu ,&nbsp;Zhenkun Guo ,&nbsp;Siying Wu ,&nbsp;Ying Tang ,&nbsp;Huangyuan Li","doi":"10.1016/j.tox.2025.154214","DOIUrl":"10.1016/j.tox.2025.154214","url":null,"abstract":"<div><div>The extensive use of cobalt resources has significantly increased the risk of cobalt contamination globally, with cobalt chloride posing a serious environmental and health concern. Although previous studies have shown that extracellular vesicles play a key role in intercellular communication, the mechanisms by which extracellular vesicles derived from neuroglia cells affect neuronal cells remain poorly understood. This study aimed to investigate whether microvesicles produced by neuroglia cells could mitigate cobalt chloride-induced neuronal damage and to explore the underlying mechanisms. Our results revealed that cobalt chloride induces cytotoxicity in HT22 and MN9D neuronal cells. A 24-hour cobalt chloride treatment triggered mitochondrial autophagy in both cell types and disrupted their mitochondrial dynamics. Further analysis showed that microvesicles secreted by GL261 neuroglia cells were taken up by both types of neuronal cells. Notably, the uptake of GL261-derived microvesicles by MN9D cells inhibited autophagy and restored mitochondrial membrane potential and reactive oxygen species levels. In conclusion, our findings highlight the critical role of neuroglia cell-derived microvesicles in cobalt chloride-induced neuronal toxicity and offer potential new targets and strategies for the prevention and treatment of cobalt chloride toxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154214"},"PeriodicalIF":4.8,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259010","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":"Next generation risk assessment and new approach methodologies for safe and sustainable by design chemicals and materials: Perspectives and challenges for occupational health","authors":"Veruscka Leso ,&nbsp;Bernd Nowack ,&nbsp;Achilleas Karakoltzidis ,&nbsp;Fotini Nikiforou ,&nbsp;Spyros Karakitsios ,&nbsp;Denis Sarigiannis ,&nbsp;Ivo Iavicoli","doi":"10.1016/j.tox.2025.154211","DOIUrl":"10.1016/j.tox.2025.154211","url":null,"abstract":"<div><div>Europe is facing increasingly challenging threats to health and well-being, including chemical pollution, climate change, and biodiversity loss. To counter such threats, the European Union has developed a series of policy strategies, including the Chemicals Strategy for Sustainability and the Zero Pollution Action Plan that pointed out the need for safe-and-sustainable-by-design (SSbD) chemicals/materials. The SSbD and the “zero pollution” ambition will inevitably lead to a transformation of the conditions of exposure to chemicals both in general living environments and workplaces with the consequent need to adequately anticipate and manage the chemical risk, starting from the assessment of the hazard and risk characterization. Among those, next generation risk assessment (NGRA) is defined as a human-relevant, exposure-led, hypothesis driven risk assessment approach, designed to prevent harm. To date, application of NGRA has been restricted to assessing the use of cosmetics, and it has not been implemented in occupational risk assessment. Occupational safety assessment represents an area that would benefit from increasing application of NGRA to safety decision making. Additionally, the application of new approach methodologies (NAMs) can support the generation of data useful to implement the operationalization of the SSbD framework, favorably impacting the adoption of suitable management strategies. In turn, the historical occupational preventive and protective approach to the health and safety of workers may provide support to adequately implement NGRA in the occupational context. Therefore, this work aims to provide an overview on the principal available NAMs and their possible implications for occupational chemical risk assessment and management.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154211"},"PeriodicalIF":4.8,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259009","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":"Effects of CdTe quantum dot exposure on the calcium signaling pathway in rat dorsal root ganglion cells ND7/23","authors":"Changcun Bai ,&nbsp;Meng Tang","doi":"10.1016/j.tox.2025.154212","DOIUrl":"10.1016/j.tox.2025.154212","url":null,"abstract":"<div><div>Previous study has shown that CdTe QDs exposure reduced ND7/23 cells activity and induced cell apoptosis in a time-dependent manner. The mitochondrial pathway was involved in CdTe QDs-induced ND7/23 cell apoptosis. The toxic effects at the subcellular level of ND7/23 cells after CdTe QDs exposure was still unclear. Whether the two classical mechanisms, endoplasmic reticulum stress and calcium ion imbalance, were involved in the subcellular structural and functional dysfunction of ND7/23 cells induced by CdTe QDs, and whether the Ca^2 + -calpain2 pathway played a significant role in the CdTe QDs-induced ND7/23 cell apoptosis remained to be validated. Therefore, this research focused on the study of CdTe QDs exposure-induced endoplasmic reticulum stress, organelle damage, and calcium homeostasis imbalance in ND7/23 cells. The apoptosis signaling pathway mediated by calpain2 and endoplasmic reticulum stress were also investigated. The results showed that exposure to 10 μM CdTe QDs for 0–24 h resulted in an increase in intracellular and mitochondrial Ca²⁺ concentration, accompanied by swelling of the endoplasmic reticulum and mitochondria and loss of mitochondrial cristae. CdTe QDs exposure also led to an increase in the expression of endoplasmic reticulum stress-related Bip protein. CdTe QDs exposure also initiated the up-regulation of calpain2 and cleaved-caspase7 protein expression, as well as cleavage of caspase12 and PARP proteins in ND7/23 cells. Addition of the calcium chelator BAPTA-AM and the calpeptin 2 inhibitor calpeptin significantly inhibited CdTe QDs-induced apoptosis and reversed the expression of these proteins. This study confirmed that exposure to CdTe QDs triggered endoplasmic reticulum stress in ND7/23 cells, along with the activation of the calpain2-caspase12 signaling pathway, resulting in mitochondria-independent apoptosis.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154212"},"PeriodicalIF":4.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212758","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 synthetic cannabinoids ADB-FUBINACA and AMB-FUBINACA enhance in vitro neurodifferentiation of NG108-15 cells, along with PGC-1α dysregulation and mitochondrial dysfunction","authors":"Rui Filipe Malheiro ,&nbsp;João Figueiredo ,&nbsp;Helena Carmo ,&nbsp;Félix Carvalho ,&nbsp;João Pedro Silva","doi":"10.1016/j.tox.2025.154213","DOIUrl":"10.1016/j.tox.2025.154213","url":null,"abstract":"<div><div>There is growing concern regarding the use of Synthetic Cannabinoids (SCs) by young adults (including pregnant and breastfeeding women, and women of childbearing age), due to their potential to cause neurodevelopmental disorders. Here, we first-hand assessed the <em>in vitro</em> impact of two indazole-derived SCs, ADB-FUBINACA and AMB-FUBINACA, on the neurodifferentiation of NG108–15 cells, especially focusing on their modulation of mitochondrial function during such process. Both SCs tested enhanced neurite outgrowth in NG108–15 cells at biologically-relevant concentrations (&lt; 1 μM), a process that was blocked by SR141716A and hemopressin (antagonists of cell membrane and intracelular CB1 receptors, respectively). Moreover, this effect was accompanied by a CB1 receptor-independent reduction in mitochondrial membrane potential. Interestingly, ADB-FUBINACA, but not AMB-FUBINACA, decreased intracellular ATP levels through CB1 activation. Notably, voltage-dependent anion channel (VDAC) expression, an indirect marker of mitochondrial mass, remained unchanged during exposure to both SCs. ADB-FUBINACA increased the expression of the key energy regulator PGC-1α in the cytosol (1pM-1µM), while decreasing it in the mitochondrial fraction (1 nM and 1 µM), without affecting its nuclear translocation, supporting its role in mitochondrial turnover. Other mitogenesis markers, like NFR-1 and TFAM, remain unchanged. Additionaly, the Parkin-PINK1 mitophagy pathway was not activated at the concentrations tested. Our findings demonstrate that ADB-FUBINACA and AMB-FUBINACA enhance neuronal differentiation of NG108–15 cells via CB1 receptor activation, while concomitantly promoting mitochondrial dysfunction. Although further research is required to fully elucidate the mechanisms underlying these observations, our data already suggests that these SCs may impact proper neurodevelopment.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154213"},"PeriodicalIF":4.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144243040","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":"In vitro test battery for testing molecular initiating events in chemical-induced cholestasis","authors":"Amy Maerten ,&nbsp;Annika Drees ,&nbsp;Jian Jiang ,&nbsp;Julen Sanz-Serrano ,&nbsp;Lindsey Devisscher ,&nbsp;Mathieu Vinken","doi":"10.1016/j.tox.2025.154210","DOIUrl":"10.1016/j.tox.2025.154210","url":null,"abstract":"<div><div>Cholestatic liver injury is a complex adversity leading to the toxic accumulation of.noxious bile salts in the liver and systemic circulation. Cholestasis can be instigated by a plethora of chemicals originating from several applicability domains. Current efforts fail to predict the cholestatic potential of chemicals due to, at least in part, gaps in the mechanistic understanding of this type of adversity. A recently introduced adverse outcome pathway (AOP) network on cholestatic liver injury generated using artificial intelligence pulls up transporter changes, bile canalicular changes and hepatocellular changes as molecular initiating events (MIEs). The present study used this AOP network as the mechanistic basis for the development of an <em>in vitro</em> test battery to predict MIEs of cholestatic hepatotoxicity, including assays to monitor transporter changes at the sinusoidal uptake, canalicular efflux and basolateral efflux pole as well as bile canalicular changes. For this purpose, human HepaRG cells were exposed to known cholestatic chemicals covering various MIEs, non-cholestatic hepatotoxic chemicals and non-hepatotoxic chemicals. Subsequent application of the MIE test battery shows great potential for identifying cholestatic chemicals, while correctly predicting all negative control chemicals. In conclusion, the established <em>in vitro</em> test battery shows potential for early prediction of cholestatic chemicals.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154210"},"PeriodicalIF":4.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212759","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":"Understanding α-amanitin hepatotoxicity: Mechanisms from cellular models","authors":"Haowei Wang ,&nbsp;Xiaoxing Zhang ,&nbsp;Xiaodong Li ,&nbsp;Xinyu Zhang,&nbsp;Teng Sun,&nbsp;Yuqian Wang,&nbsp;Xinyu Zheng,&nbsp;Xinminxiu Zhao,&nbsp;Jianxing Liu,&nbsp;Shangwen Wang,&nbsp;Xiaofeng Zeng","doi":"10.1016/j.tox.2025.154208","DOIUrl":"10.1016/j.tox.2025.154208","url":null,"abstract":"<div><div>α-Amanitin (α-AMA), a principal lethal compound in mushroom intoxication, induces hepatotoxicity through multifaceted and complex mechanisms. This review synthesizes current knowledge of α-AMA-induced hepatotoxicity, particularly emphasizing recent advances derived from cellular model studies. Evidence indicates that α-AMA damages hepatocytes through multiple pathways, including RNA polymerase II inhibition, oxidative stress induction, apoptosis and autophagy activation, inflammatory response elicitation, and immunotoxicity. Recent studies have also revealed the involvement of endoplasmic reticulum stress and the N-glycosylation pathway in α-AMA-mediated hepatotoxicity. Although several detoxification agents are available for α-AMA poisoning, their therapeutic efficacy remains suboptimal. A comprehensive elucidation of the cellular mechanisms underlying α-AMA-induced hepatotoxicity is essential for developing more effective therapeutic strategies. Future research should prioritize the exploration of these mechanisms and leverage high-throughput screening and gene-editing technologies to identify novel therapeutic targets and advance the development of more efficacious detoxification agents.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154208"},"PeriodicalIF":4.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226727","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":"Comparative study of CYP450 gene regulation in human pluripotent stem cell-derived liver 2D cell and 3D organoid models","authors":"Eunhye Kang,&nbsp;Ji-Woo Kim,&nbsp;Seongyea Jo,&nbsp;Ji Hyeon Ryu,&nbsp;Haneul Noh,&nbsp;Han-Jin Park,&nbsp;Hyemin Kim","doi":"10.1016/j.tox.2025.154209","DOIUrl":"10.1016/j.tox.2025.154209","url":null,"abstract":"<div><div>Human pluripotent stem cell (hPSC)-derived hepatic models, including 2D hepatocyte-like cells (2D HLCs) and hepatic organoids (HOs), are valuable <em>in vitro</em> models for evaluating the safety and efficacy of drugs. However, 2D HLCs show limited expression and activity of drug-metabolizing enzymes, particularly cytochrome P450 (CYP450), which are involved in detoxification, a major liver function. HOs have more mature properties than 2D HLCs, particularly enhanced CYP450 gene expression. However, the transcriptional regulatory mechanisms that correlate with CYP450 expression in HOs remain unclear. Epigenetic mechanisms, including DNA methylation and histone modification, are essential for controlling gene expression during stem cell differentiation. Here, we identified epigenetic states around transcriptional regulatory regions and compared them with those in primary human hepatocytes. We found that significantly higher CYP450 gene expression in hPSC-derived HOs than in 2D HLCs was strongly associated with decreased DNA methylation and increased enrichment of histone H3 lysine 27 acetylation in their transcriptional regulatory regions. Furthermore, because of the higher expression of nuclear receptor genes, especially constitutive androstane receptor and pregnane X receptor, HOs showed higher NR-mediated induction of CYP3A4, UGT1A1, and MDR1 than 2D HLCs. Therefore, these results suggest that mature epigenetic regulation may have an impact on drug metabolism and toxicity outcomes in hPSC-derived hepatic models and, hence, be used as an indicator of model maturation.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154209"},"PeriodicalIF":4.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212923","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":"Integrated transcriptomic and metabolomic analysis reveals the induction of anoikis in renal proximal tubular epithelial cells by 2,6-Dichloro-1,4-benzoquinone","authors":"Ting Xu ,&nbsp;Limei Gu ,&nbsp;Yawen Chen ,&nbsp;Sheng Wei ,&nbsp;Huan Wang ,&nbsp;Xueping Guo ,&nbsp;Jiacheng Wang ,&nbsp;Daqiang Yin","doi":"10.1016/j.tox.2025.154207","DOIUrl":"10.1016/j.tox.2025.154207","url":null,"abstract":"<div><div>2,6-dichloro-1,4-benzoquinone (DCBQ) is the most frequently detected and highly toxic halobenzoquinones, a class of aromatic disinfection byproducts (DBPs), yet its renal toxicity and underlying mechanisms largely remain unknown. In this research, we utilized a dual-omics strategy to explore the toxicological impact of DCBQ on human renal proximal tubular epithelial (RPTEC/TERT1) cells. After the cytotoxicity of DCBQ was uncovered by CCK-8 and cell cycle tests, the significantly changed biological events associated with cell adhesion, extracellular matrix (ECM) remodeling, and organelle lumen homeostasis were highlighted as mechanistic cues primarily by integrated transcriptomic and metabolomics analysis. Our subsequent experiments confirmed that DCBQ significantly disrupted mitochondrial membrane potential and led to anoikis, a unique type of programmed cell death distinguished by cell separation from the ECM. Notably, DCBQ exposure significantly suppressed the PI3K/AKT and Ras/ERK signaling pathways, which may have contributed to reduced cell viability, G1 phase cell cycle arrest and induction of anoikis. These results offered new perspectives on the nephrotoxic mechanisms of DCBQ, highlighting its potential to impair cell-ECM interaction and even induce future cancer progression. Our study also proved the benefits of dual-omics application and integrated data analysis for understanding the comprehensive health risks of those poorly-studied emerging contaminants.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154207"},"PeriodicalIF":4.8,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144209612","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":"Metabolomic and redox alterations in liver cells exposed to biomass burning pollution mixture differ by fatty acids-induced NAFLD","authors":"Michal Pardo ,&nbsp;Dror M. Bittner ,&nbsp;Efrat Sharon ,&nbsp;Chunlin Li ,&nbsp;Marina Kurkina ,&nbsp;Yinon Rudich ,&nbsp;Lauren M. Petrick","doi":"10.1016/j.tox.2025.154199","DOIUrl":"10.1016/j.tox.2025.154199","url":null,"abstract":"<div><div>Biomass burning (BB), a significant source of atmospheric pollutants, produces wood tar (WT) particulates, composing a considerable portion of carbonaceous aerosols that pose health risks. Among these health risks is nonalcoholic fatty liver disease (NAFLD), a widely spread condition worldwide. This study uses untargeted metabolomics and functional assays to investigate how pre-existing metabolic conditions, modeled as NAFLD, influence liver cell responses to BB exposure. Human HepG2 cells were pre-incubated with either lauric acid (LA), a saturated fatty acid (FA), or oleic acid (OA), an unsaturated FA, to simulate NAFLD condition before exposure to water-soluble WT (WS-WT), a BB derived mixture. Our findings reveal that OA pre-incubation alters metabolite profiles more significantly than LA pre-incubation alone and that significantly different metabolomic alterations were observed by pretreatment following exposure to WS-WT. Further, OA pre-incubation provides more protective effects against WS-WT exposure than LA. Metabolomic analysis showed that OA-preincubated cells exhibited higher levels of long-chain FA metabolites that are crucial for mitochondrial β-oxidation, suggesting enhanced lipid metabolism and mitochondrial function. In contrast, LA pre-incubation increased mitochondrial dysfunction and susceptibility to WS-WT cytotoxicity, as evidenced by reduced oxygen consumption rate (OCR) levels. Additionally, exposure to WS-WT decreased GSH/GSSG ratio, indicating redox imbalance, particularly in LA-treated cells. This study demonstrates that pre-existing metabolic conditions may influence cellular responses to environmental toxins. They emphasize the need for complementing traditional toxicological assays with omics to identify systemic responses to complex exposure mixtures, and further research into the metabolic pathways and the development of targeted interventions for pollution-associated NAFLD.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154199"},"PeriodicalIF":4.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187996","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":"Perfluoroalkyl substance pollutants disrupt microglia function and trigger transcriptional and epigenomic changes","authors":"Yating Cheng ,&nbsp;Jian-Rong Li ,&nbsp;Hangjin Yu ,&nbsp;Shuang Li ,&nbsp;Boranai Tychhon ,&nbsp;Chao Cheng ,&nbsp;Yi-Lan Weng","doi":"10.1016/j.tox.2025.154198","DOIUrl":"10.1016/j.tox.2025.154198","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFAS), commonly referred to as “forever chemicals”, are widely utilized in various industries and consumer products worldwide. Their exposure has been associated with numerous diseases and malignancies, including neurodevelopmental and neurodegenerative disorders. However, the molecular mechanisms underlying PFAS-induced adverse effects on the central nervous system (CNS) remain poorly understood. In this study, we investigated the transcriptomic and epigenetic changes in microglia exposed to perfluorooctane sulfonate (PFOS), a prevalent PFAS compound. Our findings demonstrate that 24-hour PFOS exposure (25 and 50 µM) disrupts the microglial transcriptome and compromises their homeostatic state, marked by increased inflammation and impaired actin cytoskeleton remodeling. Comparative analysis with <em>in vivo</em> transcriptional states revealed that PFOS-exposed microglia exhibit gene expression profiles resembling those of aged microglia. Additionally, profiling of active chromatin regions uncovered significant alterations in the H3K27ac landscape in PFOS-exposed microglia. Notably, these epigenetic disruptions persisted even after PFOS withdrawal, with a subset of H3K27ac-enriched regions remaining altered, suggesting the presence of lasting epigenetic scars. Furthermore, transcription factor analysis implicated the AP-1 and TEAD families as potential upstream regulators connecting the altered chromatin landscape to transcriptomic changes. Collectively, these findings provide mechanistic insights into how PFOS exposure disrupts microglial function and highlight its potential role in exacerbating neurodegenerative processes.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"517 ","pages":"Article 154198"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151916","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}