IF 4.8 3区医学

Toxicology Pub Date : 2025-05-28 DOI: 10.1016/j.tox.2025.154199

Michal Pardo, Dror M Bittner, Efrat Sharon, Chunlin Li, Marina Kurkina, Yinon Rudich, Lauren M Petrick

{"title":"Metabolomic and redox alterations in liver cells exposed to biomass burning pollution mixture differ by fatty acids-induced NAFLD.","authors":"Michal Pardo, Dror M Bittner, Efrat Sharon, Chunlin Li, Marina Kurkina, Yinon Rudich, Lauren M Petrick","doi":"10.1016/j.tox.2025.154199","DOIUrl":"https://doi.org/10.1016/j.tox.2025.154199","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"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}

引用次数: 0

Perfluoroalkyl substance pollutants disrupt microglia function and trigger transcriptional and epigenomic changes 全氟烷基物质污染物破坏小胶质细胞功能并引发转录和表观基因组变化。

IF 4.8 3区医学

Toxicology Pub Date : 2025-05-24 DOI: 10.1016/j.tox.2025.154198

Yating Cheng , Jian-Rong Li , Hangjin Yu , Shuang Li , Boranai Tychhon , Chao Cheng , Yi-Lan Weng

{"title":"Perfluoroalkyl substance pollutants disrupt microglia function and trigger transcriptional and epigenomic changes","authors":"Yating Cheng , Jian-Rong Li , Hangjin Yu , Shuang Li , Boranai Tychhon , Chao Cheng , 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}

引用次数: 0

Microplastic exposure induces preeclampsia-like symptoms via HIF-1α/TFRC-mediated ferroptosis in placental trophoblast cells 微塑料暴露通过HIF-1α/ tfrc介导的胎盘滋养细胞铁凋亡诱导子痫前期样症状

IF 4.8 3区医学

Toxicology Pub Date : 2025-05-23 DOI: 10.1016/j.tox.2025.154197

Haoyi Jia , Siyu Liu , Wenhao Wang , Pengyuan He , Fujun Zhao , Xianming Xu

{"title":"Microplastic exposure induces preeclampsia-like symptoms via HIF-1α/TFRC-mediated ferroptosis in placental trophoblast cells","authors":"Haoyi Jia , Siyu Liu , Wenhao Wang , Pengyuan He , Fujun Zhao , 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}

引用次数: 0

Predicting in vitro assays related to liver function using probabilistic machine learning 使用概率机器学习预测与肝功能相关的体外分析。

IF 4.8 3区医学

Toxicology Pub Date : 2025-05-19 DOI: 10.1016/j.tox.2025.154195

Flavio M. Morelli , Marian Raschke , Natalia Jungmann , Michaela Bairlein , Marina García de Lomana

{"title":"Predicting in vitro assays related to liver function using probabilistic machine learning","authors":"Flavio M. Morelli , Marian Raschke , Natalia Jungmann , Michaela Bairlein , 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}

引用次数: 0

Chronic low-level exposure to Pb, Hg, and Cd mixture triggers brain premature aging in rat 长期低水平暴露于铅、汞、镉混合物会引起大鼠脑早衰。

IF 4.8 3区医学

Toxicology Pub Date : 2025-05-18 DOI: 10.1016/j.tox.2025.154196

Jie Xie , Lu Ouyang , Jiajun Li , Shuo Yang , Qi Li , Yue Li , Lingyu Yan , Yihong Fu , Qijun Li , Yuting Xia , Xinling Chen , Ziyang Fu , Weipeng Sun , Guihua Du , Fankun Zhou , Chang Feng , Guangqin Fan

{"title":"Chronic low-level exposure to Pb, Hg, and Cd mixture triggers brain premature aging in rat","authors":"Jie Xie , Lu Ouyang , Jiajun Li , Shuo Yang , Qi Li , Yue Li , Lingyu Yan , Yihong Fu , Qijun Li , Yuting Xia , Xinling Chen , Ziyang Fu , Weipeng Sun , Guihua Du , Fankun Zhou , Chang Feng , 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(CH<sub>3</sub>COO)<sub>2</sub>, 0.05 mg/L HgCl<sub>2</sub>, and 3.5 mg/L CdCl<sub>2</sub> via drinking water from mating until offspring weaning. Offspring continued to exposed to heavy metal mixture (3.5 mg/L Pb(CH<sub>3</sub>COO)<sub>2</sub>, 0.015 mg/L HgCl<sub>2</sub>, and 0.5 mg/L CdCl<sub>2</sub>) 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}

引用次数: 0

Effects of two typical organophosphate flame retardants on DNA damage of GT1–7 cells and relevant molecular mechanism 两种典型有机磷阻燃剂对GT1-7细胞DNA损伤的影响及其分子机制

IF 4.8 3区医学

Toxicology Pub Date : 2025-05-17 DOI: 10.1016/j.tox.2025.154192

Bingli Lei , Xiaoyu Lu , Yingxin Yang , Jiaying Li , Yufang Zhong , Xiaolan Zhang , Jian Li

{"title":"Effects of two typical organophosphate flame retardants on DNA damage of GT1–7 cells and relevant molecular mechanism","authors":"Bingli Lei , Xiaoyu Lu , Yingxin Yang , Jiaying Li , Yufang Zhong , Xiaolan Zhang , Jian Li","doi":"10.1016/j.tox.2025.154192","DOIUrl":"10.1016/j.tox.2025.154192","url":null,"abstract":"<div><div>The tris (2-chloroethyl) phosphate (TCEP) and tri-n-butyl phosphate (TNBP) are two typical organophosphate esters (OPEs), which have estrogenic activity. However, fewer studies have been conducted on their genotoxicity and mechanisms. In this study, we evaluated the effects of TCEP and TNBP on cellular DNA damage in GT1–7 cells and examined the role of estrogen signaling in regulating DNA damage. The results showed that TCEP and TNBP significantly inhibited the cell viability and elevated intracellular reactive oxygen species (ROS) levels at higher exposure concentrations. TCEP and TNBP at test concentrations significantly increased comet tail length, comet tail DNA percentage (Tail DNA%), and Olive tail moment (OTM) values, indicating that TCEP and TNBP induced cellular DNA damage. In addition, TCEP and TNBP significantly upregulated the mRNA levels of target genes related to DNA damage-repair pathways, and elevated the expression of ataxia-telangiectasia mutated (ATM) and γ-H<sub>2</sub>AX proteins associated with DNA double-strand breaks. Furthermore, TCEP and TNBP significantly up-regulated the expression of membrane bound G-protein coupled estrogen receptor 1 (GPER) protein and increased the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) at 10 µM. While the pretreatment of GPER1 inhibitor G15 and ERK1/2 inhibitor U0126 significantly inhibited the up-regulation of mRNA expression of the target genes associated with the DNA damage-repair pathways and decreased the DNA damage induced by TCEP and TNBP. These findings indicate that TCEP and TNBP activate GPER1/ERK1/2 signaling pathway which plays an important role in regulating DNA damage. The study will provide a novel insight into the genotoxicity mechanism of OPEs.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154192"},"PeriodicalIF":4.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099726","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

Deoxynivalenol and male reproductive toxicity: Unraveling the hidden risks 脱氧雪腐镰刀菌醇与男性生殖毒性：揭示潜在风险。

IF 4.8 3区医学

Toxicology Pub Date : 2025-05-16 DOI: 10.1016/j.tox.2025.154191

Ana Laura Paulino Leite Gomes , Glaura Scantamburlo Alves Fernandes , Ana Paula Frederico Rodrigues Loureiro Bracarense

{"title":"Deoxynivalenol and male reproductive toxicity: Unraveling the hidden risks","authors":"Ana Laura Paulino Leite Gomes , Glaura Scantamburlo Alves Fernandes , Ana Paula Frederico Rodrigues Loureiro Bracarense","doi":"10.1016/j.tox.2025.154191","DOIUrl":"10.1016/j.tox.2025.154191","url":null,"abstract":"<div><div>Deoxynivalenol (DON) is a highly prevalent mycotoxin known for its deleterious effects on the gastrointestinal and immune systems. Recent studies have also demonstrated its potential to impair reproductive function. This review compiles current evidence on the impact of DON on male reproductive organs, with particular emphasis on its hormonal suppressive effects, disruption of the germinal epithelium, and compromise of the blood–testis barrier. This review also highlights the impact of DON on less-explored reproductive organs, such as the epididymis, prostate, and seminal vesicles. These effects are primarily mediated by increased oxidative stress, inflammation, and apoptosis. Collectively, these alterations result in reduced sperm quality and quantity, thereby impairing male fertility. In addition, we examine studies evaluating the consequences of parental DON exposure on offspring development, which reveal adverse effects across multiple developmental stages. The findings presented consolidate the classification of DON as a relevant toxicant to male reproductive health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154191"},"PeriodicalIF":4.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094935","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

Nanoplastics disrupt hepatic lipid metabolism via the inhibition of PPARγ: a study based on digestive system exposure 纳米塑料通过抑制PPARγ破坏肝脏脂质代谢：一项基于消化系统暴露的研究。

IF 4.8 3区医学

Toxicology Pub Date : 2025-05-14 DOI: 10.1016/j.tox.2025.154194

Shenya Xu , Mei Li , Yudan Zheng , Menghuan Xu , Jieyu Zhou , Shizhi Wang , Shuwei Li , Meilin Wang

{"title":"Nanoplastics disrupt hepatic lipid metabolism via the inhibition of PPARγ: a study based on digestive system exposure","authors":"Shenya Xu , Mei Li , Yudan Zheng , Menghuan Xu , Jieyu Zhou , Shizhi Wang , Shuwei Li , Meilin Wang","doi":"10.1016/j.tox.2025.154194","DOIUrl":"10.1016/j.tox.2025.154194","url":null,"abstract":"<div><div>Nanoplastics (NPs) are emerging environmental contaminants capable of crossing biological barriers and accumulating in organs such as the liver, raising growing concerns about their potential contribution to nonalcoholic fatty liver disease (NAFLD). Notably, bottled water has been recognised as a major daily source of NP exposure. However, the associations between NP exposure and NAFLD onset, as well as the mechanistic basis, remain unclear. To investigate this, we analysed data from the National Health and Nutrition Examination Survey (NHANES) 2013–2016 cycles, using daily bottled water intake to estimate NP exposure and the hepatic steatosis index (HSI) as an indicator of liver fat accumulation. Animal and cellular experiments were conducted to evaluate NP-induced hepatic alterations. Additionally, transcriptomic analysis of liver tissues was performed, and integration with DisGeNET and the Comparative Toxicogenomics Database (CTD) enabled bioinformatic analyses and identification of key regulatory pathways. Epidemiological results revealed a significant positive correlation between bottled water consumption and HSI. Experimental findings demonstrated that NP exposure induced liver vacuolisation, oxidative damage, metabolic disruption, and inflammation in both in vivo and in vitro models. Transcriptomic and database integration revealed that NP exposure suppressed the PPAR signalling pathway, particularly by downregulating PPARγ expression, with excessive ROS generation likely contributing to this inhibition. These results were summarised in an adverse outcome pathway (AOP) framework, illustrating how NP exposure may impair PPARγ signalling and promote hepatic lipid accumulation. In conclusion, this study provides evidence that environmental NP exposure may be a contributing factor to NAFLD development and highlights the potential public health impact of the intake of NPs from bottled water.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154194"},"PeriodicalIF":4.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086852","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

Tobacco smoking exposure-mediated ELAVL1 regulates bladder cancer cell senescence via autophagy activation 烟草暴露介导的ELAVL1通过自噬激活调节膀胱癌细胞衰老。

IF 4.8 3区医学

Toxicology Pub Date : 2025-05-14 DOI: 10.1016/j.tox.2025.154193

Qiuyi Pu , Fang Gao , Yanping Xiao , Jiajin Wu , Chao Wang , Xiaoxiao Mo , Zhengdong Zhang , Rui Zheng , Dongmei Wu

{"title":"Tobacco smoking exposure-mediated ELAVL1 regulates bladder cancer cell senescence via autophagy activation","authors":"Qiuyi Pu , Fang Gao , Yanping Xiao , Jiajin Wu , Chao Wang , Xiaoxiao Mo , Zhengdong Zhang , Rui Zheng , Dongmei Wu","doi":"10.1016/j.tox.2025.154193","DOIUrl":"10.1016/j.tox.2025.154193","url":null,"abstract":"<div><div>Tobacco smoking is a well-established risk factor for bladder cancer, which shows connection to cell senescence in various diseases. However, the regulatory mechanisms linking tobacco smoking exposure to senescence regulation in bladder cancer remain incompletely characterized. In this investigation, we demonstrated that the smoking carcinogen 4-aminobiphenyl (4-ABP) inhibited cell senescence while enhancing proliferative, invasive, and migratory capacities of bladder cancer cells, as evidenced by SA-β-gal staining, western blot and cell malignant phenotype experiments. We further identified 275 cell senescence-related genes specific to bladder cancer based on CellAge database, the Nanjing bladder cancer dataset and public database. Through genome-wide association studies in 580 bladder cancer cases and 1101 controls, we pinpointed that rs12978895 G>A in <em>ELAVL1</em> was significantly correlated with decreased bladder cancer risk (odds ratio = 0.79, 95 % confidence interval = 0.68–0.92) and interacted with smoking (<em>P</em> = 0.043). In genetic regulation, both experimental and population study showed that the A allele of rs12978895 significantly reduced <em>ELAVL1</em> expression, while elevated <em>ELAVL1</em> levels were observed in tumor tissues. Notably, exposed to smoking carcinogen 4-ABP resulted in a markedly increased expression of <em>ELAVL1</em>, which inhibited senescence of bladder cancer cells. Mechanistically, 4-ABP upregulated <em>ELAVL1</em> suppressed cell senescence through autophagy activation, thus promoting bladder cancer progression. This study elucidated the genetic susceptibility and biological function of <em>ELAVL1</em> in tobacco smoking exposure cell models, shedding light on the etiology of bladder cancer.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154193"},"PeriodicalIF":4.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085814","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

1-nitropyrene triggers trophoblast dysfunction via EMPs-mediated ferroptosis through Glutathione peroxidase 4 1-硝基芘通过谷胱甘肽过氧化物酶4介导的emps介导的铁凋亡触发滋养细胞功能障碍。

IF 4.8 3区医学

Toxicology Pub Date : 2025-05-14 DOI: 10.1016/j.tox.2025.154190

Shuping Yu , Kai Wang , Yan Kang , Yaming Mu , Zhenya Fang , Meihua Zhang , Shuxian Li

{"title":"1-nitropyrene triggers trophoblast dysfunction via EMPs-mediated ferroptosis through Glutathione peroxidase 4","authors":"Shuping Yu , Kai Wang , Yan Kang , Yaming Mu , Zhenya Fang , Meihua Zhang , Shuxian Li","doi":"10.1016/j.tox.2025.154190","DOIUrl":"10.1016/j.tox.2025.154190","url":null,"abstract":"<div><div>1-Nitropyrene (1-NP), a prevalent environmental pollutant, poses significant risks to vascular and placental health. This study demonstrates that 1-NP induces vascular endothelial dysfunction by dose-dependently reducing human umbilical vein endothelial cell (HUVEC) viability, inhibiting proliferation, promoting apoptosis, and impairing tube formation. Notably, endothelial microparticles (EMPs) isolated from 1-NP-treated HUVECs (N-EMPs) exhibited distinct biological effects compared to control EMPs (C-EMPs). N-EMPs suppressed trophoblast viability, proliferation, invasion, and migration, correlating with N-cadherin downregulation and E-cadherin upregulation. Mechanistically, ferroptosis emerged as the primary driver of N-EMPs-induced trophoblast dysfunction, evidenced by reactive oxygen species (ROS) accumulation, glutathione depletion, elevated malondialdehyde and Fe²⁺ levels, and mitochondrial oxidative stress. Crucially, glutathione peroxidase 4 (GPX4) was identified as a central regulator, with its expression significantly downregulated by N-EMPs. Overexpression of GPX4 reversed ferroptosis markers (restoring GSH/SOD, reducing MDA/Fe²⁺) and rescued trophoblast viability, migration, and invasiveness. These findings establish a previously unrecognized pathogenic cascade wherein 1-NP triggers endothelial injury, releasing cytotoxic EMPs that propagate ferroptosis-dependent trophoblast dysfunction via GPX4 suppression. The central role of EMPs as mediators of environmental pollutant toxicity highlights their potential as biomarkers and therapeutic targets for mitigating placental developmental disorders caused by 1-NP exposure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"516 ","pages":"Article 154190"},"PeriodicalIF":4.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086850","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

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