Toxicology最新文献

{"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}

{"title":"Microplastic exposure induces preeclampsia-like symptoms via HIF-1α/TFRC-mediated ferroptosis in placental trophoblast cells","authors":"Haoyi Jia ,&nbsp;Siyu Liu ,&nbsp;Wenhao Wang ,&nbsp;Pengyuan He ,&nbsp;Fujun Zhao ,&nbsp;Xianming Xu","doi":"10.1016/j.tox.2025.154197","DOIUrl":"10.1016/j.tox.2025.154197","url":null,"abstract":"<div><div>Microplastic (MP) pollution is an emerging environmental concern with potential health risks, yet its impact on pregnancy remains largely unexplored. This study investigated the effects of polystyrene microplastic (PS-MP) exposure on placental function and its role in preeclampsia (PE) pathogenesis. Pregnant rats were exposed to PS-MP, which induced PE-like symptoms including elevated blood pressure, increased proteinuria, and altered expression of angiogenic factors. Transcriptomic and molecular analyses revealed PS-MP triggered ferroptosis in placental trophoblast cells by activating the HIF-1α/TFRC axis, resulting in iron overload and oxidative stress. PS-MP exposure impaired trophoblast migration, invasion, and angiogenesis; these effects were ameliorated by ferroptosis inhibition. These findings identified PS-MP-induced ferroptosis as a critical mechanism underlying placental dysfunction, highlighting PS-MP as a potential environmental risk factor for PE. Understanding the impact of MP on pregnancy provides crucial insights into their reproductive toxicity and underscores the need for further research on mitigating their effects.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154197"},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134837","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":"Predicting in vitro assays related to liver function using probabilistic machine learning","authors":"Flavio M. Morelli ,&nbsp;Marian Raschke ,&nbsp;Natalia Jungmann ,&nbsp;Michaela Bairlein ,&nbsp;Marina García de Lomana","doi":"10.1016/j.tox.2025.154195","DOIUrl":"10.1016/j.tox.2025.154195","url":null,"abstract":"<div><div>While machine learning has gained traction in toxicological assessments, the limited data availability requires the quantification of uncertainty of <em>in silico</em> predictions for reliable decision-making. This study addresses the challenge of predicting the outcome of <em>in vitro</em> assays associated with liver function by systematically comparing various probabilistic methods. Our research fills a critical gap by integrating multiple data modalities – chemical descriptors, gene expression, and morphological profiles – into a probabilistic framework aimed at predicting <em>in vitro</em> assays and quantifying uncertainty. We present a comprehensive evaluation of the performance of these data modalities and describe how this framework and the <em>in vitro</em> assay predictions can be integrated to estimate the probability of drug-induced liver injury (DILI) occurrence. Additionally, we contribute new experimental data for reactive oxygen species generation and hepatocyte toxicity assays, providing valuable resources for future research. Our findings underscore the importance of incorporating uncertainty quantification in toxicity predictions, potentially leading to a safer drug development process and reduced reliance on animal testing.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154195"},"PeriodicalIF":4.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120926","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":"Chronic low-level exposure to Pb, Hg, and Cd mixture triggers brain premature aging in rat","authors":"Jie Xie ,&nbsp;Lu Ouyang ,&nbsp;Jiajun Li ,&nbsp;Shuo Yang ,&nbsp;Qi Li ,&nbsp;Yue Li ,&nbsp;Lingyu Yan ,&nbsp;Yihong Fu ,&nbsp;Qijun Li ,&nbsp;Yuting Xia ,&nbsp;Xinling Chen ,&nbsp;Ziyang Fu ,&nbsp;Weipeng Sun ,&nbsp;Guihua Du ,&nbsp;Fankun Zhou ,&nbsp;Chang Feng ,&nbsp;Guangqin Fan","doi":"10.1016/j.tox.2025.154196","DOIUrl":"10.1016/j.tox.2025.154196","url":null,"abstract":"<div><div>Lead (Pb), mercury (Hg), and cadmium (Cd), prevalent neurotoxic heavy metals in the environment, are commonly detected at low concentrations in the blood of the general population. Our previous studies demonstrated that Pb, Hg, and Cd mixture induced neurodevelopmental toxicity even at very low levels. However, the long-term effects of low-level Pb, Hg, Cd exposure on brain aging remain unclear. In this study, female rats were exposed to a mixture of 10 mg/L Pb(CH₃COO)₂, 0.05 mg/L HgCl₂, and 3.5 mg/L CdCl₂ via drinking water from mating until offspring weaning. Offspring continued to exposed to heavy metal mixture (3.5 mg/L Pb(CH₃COO)₂, 0.015 mg/L HgCl₂, and 0.5 mg/L CdCl₂) for 32 weeks. At 52 weeks of age, brain aging was comprehensively evaluated through behavioral testing, histopathological examination, and telomere assessment. The results revealed that prolonged low-level exposure to the Pb, Hg, and Cd mixture compromised telomeric function by shortening telomere length, inhibiting telomerase activity, and induced neuronal loss in the hippocampal CA1 and CA3 regions. Additionally, Golgi staining revealed disrupted dendritic spines in the hippocampus and altered spine-related signaling pathways (Snk-SPAR pathway). Furthermore, behavioral testing showed that exposure to this mixture impaired spatial memory and social cognition. In conclusion, prolonged exposure to low levels of Pb, Hg, and Cd accelerated brain aging by causing hippocampal telomere dysfunction, neuronal loss, dendritic degeneration, and cognitive decline in rats. These findings offer novel insights into the potential neurotoxic effects of chronic exposure to low-level of Pb, Hg, and Cd mixtures on neurological health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154196"},"PeriodicalIF":4.8,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111954","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}