Toxicology最新文献_第3页

Toxic effects and mechanism of silver nanoparticles with different particle sizes and surface coatings in lung epithelial cells 不同粒径和表面包覆银纳米颗粒对肺上皮细胞的毒性作用及其机制。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-06 DOI: 10.1016/j.tox.2026.154398

Zige Jiang , Yue Chen , Xiaoyu Guo , Ke Li , Liqun Chen

With nanotechnology's advancement and popularity, nanosafety assessment has attracted public attention, nanosafety assessment has attracted public attention. Silver nanoparticles (AgNPs) have been extensively applied in people’s work and life, but there is still limited knowledge of their potential toxicity to humans. Although many studies have shown that AgNPs causes physiological changes in the lung, the effects and molecular mechanisms of AgNPs on the lung are not fully understood at low-dose exposures and assessed with different physicochemical properties. To comprehensively compare the potential effects and molecular mechanisms of AgNPs with different particle sizes and surface modifications on A549 cells, three PVP-coated AgNPs with particle sizes of 20, 40, and 75 nm and Lipoic Acid (LA), mPEG, and BPEI-coated AgNPs with a particle size of 40 nm, which are referred to as PVP₂₀, PVP₄₀, PVP₇₅, LA₄₀, mPEG₄₀ and BPEI₄₀ were selected in this study. The methods used in this study included characterization of AgNP using transmission electron microscopy (TEM) and zeta potential, the study of cytotoxicity, oxidative stress, and subsequent damage to cell membrane integrity, apoptosis, and RNA-seq. Our findings indicated that AgNPs with different particle sizes and modifications had different toxicological effects, and the smaller size of AgNPs exerts the stronger cytotoxicity. In addition, transcriptome sequencing and qRT-PCR analyses confirmed that the mechanisms of action of these AgNPs varied, but PVP₂₀, PVP₄₀, PVP₇₅, LA₄₀, and BPEI₄₀ AgNPs could all affect A549 cells via IL-17 signaling pathway. Our research findings demonstrate the deleterious effects of different nanosilvers on lung epithelial cells and reveal related possible pathways of influence.

随着纳米技术的进步和普及，纳米安全评价引起了人们的广泛关注。纳米银在人们的工作和生活中得到了广泛的应用，但对其潜在毒性的认识仍然有限。尽管许多研究表明AgNPs会引起肺部的生理变化，但在低剂量暴露下，AgNPs对肺部的影响和分子机制尚未完全了解，并以不同的物理化学性质进行评估。为了综合比较不同粒径和表面修饰的AgNPs对A549细胞的潜在作用和分子机制，本研究选择了3种粒径分别为20、40和75nm的pvp包被AgNPs，以及硫辛酸（LA）、mPEG和bpei包被粒径为40nm的AgNPs，分别为PVP20、PVP40、PVP75、LA40、mPEG40和BPEI40。本研究中使用的方法包括使用透射电子显微镜（TEM）和zeta电位表征AgNP，研究细胞毒性，氧化应激以及随后对细胞膜完整性的损伤，凋亡和RNA-seq。结果表明，不同粒径和修饰的AgNPs具有不同的毒理学效应，粒径越小的AgNPs具有越强的细胞毒性。此外，转录组测序和qRT-PCR分析证实了这些AgNPs的作用机制不同，但PVP20、PVP40、PVP75、LA40和BPEI40 AgNPs都可以通过IL-17信号通路影响A549细胞。我们的研究结果证明了不同纳米银对肺上皮细胞的有害作用，并揭示了相关的可能影响途径。

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引用次数: 0

Development and analysis of the adverse outcome pathway network for neurotoxicity 神经毒性不良反应通路网络的发展与分析。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-05 DOI: 10.1016/j.tox.2026.154397

Xinyue Hui , Xingying Li , Sisi Liu , Guang-Guo Ying , Chang-Er Chen

Adverse Outcome Pathways (AOPs) and their networks offer a structured framework for understanding toxicological mechanisms and supporting non-animal testing strategies. This study developed a neurotoxicity-focused AOP network (NT-AOPn) based on AOP-Wiki data and analyzed its topological properties using graph theory. We identified key events with high connectivity and centrality—such as oxidative stress and decreased thyroxine—and determined the two most prevalent adverse outcomes: Impairment of Learning and Memory (ILM) and Decreased Cognitive Function (CFD). Further analysis of their subnetworks revealed system-level perturbations spanning metabolic, neurological, and reproductive systems, and uncovered two novel AOP pathways linking molecular initiating events to adverse outcomes. Additionally, chemical stressors including heavy metals and pesticides were associated with these pathways. Our findings enhance the mechanistic understanding of neurotoxicity and provide a foundation for in vitro assays and computational modeling in risk assessment.

不良结果通路（AOPs）及其网络为理解毒理学机制和支持非动物试验策略提供了一个结构化的框架。本文基于AOP- wiki数据构建了一个以神经毒性为中心的AOP网络（NT-AOPn），并利用图论分析了其拓扑性质。我们确定了具有高连通性和中心性的关键事件，如氧化应激和甲状腺素下降，并确定了两种最普遍的不良后果：学习和记忆障碍（ILM）和认知功能下降（CFD）。对其子网络的进一步分析揭示了跨越代谢、神经和生殖系统的系统级扰动，并发现了两种新的AOP途径，将分子启动事件与不良结果联系起来。此外，包括重金属和杀虫剂在内的化学应激源也与这些途径有关。我们的发现增强了对神经毒性的机制理解，并为风险评估中的体外分析和计算建模提供了基础。

引用次数: 0

Bisphenol AP promotes pulmonary fibrosis by regulating macrophage function in a bleomycin-induced mouse model 在博莱霉素诱导的小鼠模型中，双酚AP通过调节巨噬细胞功能促进肺纤维化。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-02 DOI: 10.1016/j.tox.2026.154396

Ze Chen , Zhenying Lin , Meng Ni , Baihe Li , Qianqian Zhang , Zelin Cao , Wei Li , Yanan Tang , Dongting Yao , Chunyu Cheng , Yi Hu , Xiaorui Liu , Jiuru Zhao , Zhiwei Liu

Bisphenols are extensively used in industrial and consumer products and may pose potential risks to human health. Previous studies have shown that bisphenol A (BPA) induces chronic inflammation and lung toxicity. Bisphenol AP (BPAP), a structural analogue of BPA, has also been associated with adverse health outcomes, including metabolic disorders and mood disturbances. However, its role in pulmonary diseases remains poorly characterized. In this study, a bleomycin (BLM)-induced pulmonary fibrosis (PF) model in C57BL/6 mice was employed to investigate the effects of BPAP on pulmonary pathology. Although BPAP exposure alone did not induce PF-related pathological changes, pretreatment with BPAP (0.4 mg/kg/day) initiated 14 days before BLM administration significantly aggravated BLM-induced histopathological alterations, inflammation, and collagen deposition. This exacerbation of fibrosis was accompanied by a marked upregulation of the M2 macrophage marker arginase-1. Further in vitro assays showed that 24-hour BPAP exposure inhibited macrophage proliferation, increased oxidative stress, and enhanced both phagocytic and chemotactic activities in the RAW 264.7 mouse macrophage cell line. Mechanistic analyses revealed that BPAP modulated several key molecules involved in cell cycle regulation, phagocytosis, and chemotaxis, specifically Ttk, Fcgr1, and Ccl5. These findings indicate that BPAP exacerbates BLM-induced PF by dysregulating macrophage function. This study provides new insights into the pulmonary toxicity of BPAP and underscores the potential health risks associated with its exposure.

双酚广泛用于工业和消费品，可能对人类健康构成潜在风险。先前的研究表明，双酚A （BPA）会引起慢性炎症和肺毒性。双酚AP （BPAP）是双酚a的结构类似物，也与不良健康结果有关，包括代谢紊乱和情绪障碍。然而，其在肺部疾病中的作用仍不清楚。本研究采用博来霉素（BLM）诱导的C57BL/6小鼠肺纤维化（PF）模型，探讨BPAP对肺病理的影响。虽然单独暴露BPAP不会引起pf相关的病理改变，但在BLM给药前14天开始使用BPAP （0.4mg/kg/天）预处理可显著加重BLM诱导的组织病理学改变、炎症和胶原沉积。这种纤维化的加剧伴随着M2巨噬细胞标记物精氨酸酶-1的显著上调。进一步的体外实验表明，24小时暴露于BPAP可抑制巨噬细胞增殖，增加氧化应激，增强RAW 264.7小鼠巨噬细胞的吞噬和趋化活性。机制分析显示，BPAP调节了参与细胞周期调节、吞噬和趋化的几个关键分子，特别是Ttk、Fcgr1和Ccl5。这些发现表明BPAP通过失调巨噬细胞功能加剧了blm诱导的PF。这项研究为BPAP的肺毒性提供了新的见解，并强调了与其暴露相关的潜在健康风险。

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引用次数: 0

In vivo high-throughput toxicity screening of brominated flame retardants using a Caenorhabditis elegans transcription factor RNAi platform 利用秀丽隐杆线虫转录因子RNAi平台对溴化阻燃剂进行体内高通量毒性筛选。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-02 DOI: 10.1016/j.tox.2026.154395

Siyeol Ahn , Elizabeth Dufourcq Sekatcheff , Jinhee Choi

Brominated flame retardants (BFRs) such as tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCDD), and decabromodiphenyl ethane (DBDPE) are extensively used in a variety of consumer products, including electronics, textiles, and furniture. However, their environmental persistence and potential for neurodevelopmental toxicity have raised increasing concern. Legacy compounds such as TBBPA and HBCDD are undergoing regulation or being phased out, while alternatives like DBDPE remain poorly characterized, leaving uncertainties regarding their suitability as replacements. In order to rapidly fill knowledge gaps on these data poor substances and avoid regrettable substitutions, we established a high-throughput, mechanism-based in vivo toxicity screening platform. A RNAi approach on Caenorhabditis elegans Transcription Factors (TF) was used to assess biological pathways that were triggered by BFR exposure, leading to neurotoxicity (assessed via locomotion behavior). Using a 384-TF RNAi library, we identified 44 TFs modulating TBBPA-induced neurotoxicity. Pathway analyses (Reactome and CTD) highlighted retinoic acid receptor signaling as a key event, which mapped to four neurodevelopmental AOPs (AOP 520, 523, 532, and 533). Gene expression analysis of sex-1 and unc-55 confirmed retinoic acid signaling pathway activation. Application of the same framework to HBCDD and DBDPE revealed partially conserved behavioral and molecular responses, supporting the cross-chemical applicability of the TBBPA-derived AOP network. These findings demonstrate the utility of C. elegans-based TF RNAi screening as a fit-for-purpose New Approach Methodology (NAM) for mechanistic toxicology. By linking molecular initiating events to adverse outcomes, this strategy enables early hazard identification and read across strategy via AOP-informed, animal-free chemical risk assessment within next-generation risk assessment (NGRA) frameworks.

溴化阻燃剂（BFRs），如四溴双酚A （TBBPA）、六溴环十二烷（HBCDD）和十溴二苯乙烷（DBDPE）广泛用于各种消费品，包括电子产品、纺织品和家具。然而，它们的环境持久性和潜在的神经发育毒性引起了越来越多的关注。TBBPA和HBCDD等传统化合物正在接受监管或逐步淘汰，而DBDPE等替代品的特性仍然很差，因此它们作为替代品的适用性存在不确定性。为了快速填补这些数据贫乏物质的知识空白，避免遗憾的替代，我们建立了一个高通量、基于机制的体内毒性筛选平台。采用RNAi方法对秀丽隐杆线虫转录因子（TF）进行研究，以评估暴露于BFR引发的生物通路，从而导致神经毒性（通过运动行为评估）。使用384-TF RNAi文库，我们鉴定了44个tf调节tbbpa诱导的神经毒性。途径分析（Reactome和CTD）强调视黄酸受体信号是一个关键事件，它映射到四个神经发育AOPs （AOP 520、523、532和533）。性别-1和unc-55基因表达分析证实维甲酸信号通路激活。将相同的框架应用于HBCDD和DBDPE，揭示了部分保守的行为和分子反应，支持了tbbpa衍生的AOP网络的跨化学适用性。这些发现证明了基于秀丽隐杆线虫的TF RNAi筛选作为一种适合于机制毒理学的新方法方法（NAM）的实用性。通过将分子启动事件与不良后果联系起来，该策略可以通过下一代风险评估（NGRA）框架内的aop信息、无动物化学风险评估，实现早期危险识别和跨策略读取。

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引用次数: 0

NOX4/Keap1/Nrf2/ROS signaling drives ferroptosis in trimethyltin chloride-induced cardiac developmental malformations NOX4/Keap1/Nrf2/ROS信号驱动三甲基氯化锡诱导的心脏发育畸形中的铁凋亡

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2026-01-02 DOI: 10.1016/j.tox.2026.154394

Jin Chen , Hanwen Hu , Jing Fu , Yaolin He , Hui Zhou , Jingwei Lei , Ming Huang , Jianqi Wang , Anfei Liu , Zhenzhong Liu

Trimethyltin chloride (TMT), a pervasive environmental organic tin pollutant, has been implicated in cardiac injury, though its underlying mechanisms remain unclear. TMT exposure triggers excessive reactive oxygen species (ROS) generation, a key inducer of ferroptosis—a regulated form of cell death driven by iron-dependent lipid peroxidation. NADPH oxidase 4 (NOX4), highly expressed during cardiac development, plays a critical role in myocardial ROS production, while the Keap1/Nrf2 pathway regulates cellular ROS homeostasis. We hypothesized that TMT induces cardiac developmental defects by activating NOX4/Keap1/ROS-mediated ferroptosis. TMT exposure induced cardiac malformations, pericardial edema, and reduced heart rate in zebrafish embryos. Further studies revealed that TMT upregulated nox4 expression in embryonic hearts. Notably, pharmacological inhibition or genetic knockdown of nox4 markedly attenuated TMT-induced cardiac defects. Moreover, nox4 suppression antagonized TMT-triggered dysregulation of the Keap1/Nrf2 axis, ROS overaccumulation, mitochondrial damage, and ferroptosis-related abnormalities—including Fe²⁺ accumulation, elevated lipid peroxidation, and downregulated glutathione peroxidase 4 (GPX4) expression. Crucially, inhibition or knockdown of keap1 similarly mitigated TMT-induced ROS bursts, mitochondrial injury, and ferroptosis progression. Intervention with ferroptosis-specific inhibitors (Liproxstatin-1 and Myricetin) confirmed that ferroptosis directly contributes to TMT-induced cardiac developmental defects. This study demonstrates that TMT induces cardiac malformations by activating ferroptosis via the nox4/Keap1/Nrf2/ROS signaling axis. These findings reveal a novel mechanism underlying TMT cardiotoxicity, provide theoretical insights for assessing TMT exposure as a risk factor for congenital heart disease, and identify potential molecular targets for therapeutic intervention.

三甲基氯化锡（TMT）是一种普遍存在的环境有机锡污染物，与心脏损伤有关，但其潜在机制尚不清楚。TMT暴露会引发过量活性氧（ROS）的产生，这是铁中毒的关键诱导剂，铁中毒是一种由铁依赖性脂质过氧化作用驱动的细胞死亡的调节形式。NADPH氧化酶4 （NOX4）在心脏发育过程中高表达，在心肌ROS产生中起关键作用，而Keap1/Nrf2通路调节细胞ROS稳态。我们假设TMT通过激活NOX4/Keap1/ ros介导的铁下垂诱导心脏发育缺陷。TMT暴露诱导斑马鱼胚胎心脏畸形、心包水肿和心率降低。进一步的研究表明，TMT上调了胚胎心脏中nox4的表达。值得注意的是，药物抑制或基因敲除nox4可显著减轻tmt诱导的心脏缺陷。此外，nox4抑制可拮抗tmt引发的Keap1/Nrf2轴失调、ROS过度积累、线粒体损伤和铁中毒相关异常，包括Fe 2 +积累、脂质过氧化升高和谷胱甘肽过氧化物酶4 （GPX4）表达下调。关键是，抑制或敲低keap1同样减轻了tmt诱导的ROS爆发、线粒体损伤和铁下垂进展。使用铁下垂特异性抑制剂（利普司他汀-1和杨梅素）进行干预证实，铁下垂直接导致tmt诱导的心脏发育缺陷。本研究表明，TMT通过nox4/Keap1/Nrf2/ROS信号轴激活铁下垂诱导心脏畸形。这些发现揭示了TMT心脏毒性的新机制，为评估TMT暴露作为先天性心脏病危险因素提供了理论见解，并确定了治疗干预的潜在分子靶点。

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引用次数: 0

Bisphenol TMC exhibits greater estrogenic activity than Bisphenol A and three other structural analogues exemplified by higher estrogen receptor α-mediated gene expression and breast cancer cell proliferation 双酚TMC比双酚A和其他三种结构类似物具有更高的雌激素受体α介导的基因表达和乳腺癌细胞增殖。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-12-31 DOI: 10.1016/j.tox.2025.154393

Friedrich L. Joos , Rianne E. van Diest , Martin Smieško , Marie-Christin Jäger , Manuel Kley , Alex Odermatt , Jamal Bouitbir

Bisphenol A (BPA) and its structural analogues are widely used in plastics production, raising concern due to endocrine-disrupting properties. While many analogues share structural similarities with BPA, their endocrine-disrupting effects remain insufficiently characterized. Cyclo-di-bisphenol A diglycidyl ether (cyclo-di-BADGE), tetrabromobisphenol S (TBBPS), bisphenol SIP (BPSIP), and bisphenol TMC (BPTMC) are particularly understudied. We assessed the estrogenic activity of these four BPA analogues compared to BPA. Transactivation assays in HEK-293 cells expressing estrogen receptor alpha (ERα) revealed that BPTMC was a more potent ERα agonist than BPA, with an EC₅₀ of 87 ± 20 nM versus 400 ± 100 nM for BPA, while the other tested analogues showed no significant agonistic activity. In silico analysis attributed this higher affinity to greater hydrophobicity and a bulkier bridging group between its phenolic rings. None of the compounds inhibited 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activity. However, BPTMC selectively inhibited 17β-HSD2 (IC₅₀ = 4.8 ± 0.6 µM) but not BPA. Importantly, 24 h exposure of ERα-positive MCF-7 breast cancer cells to 1 µM BPTMC upregulated the expression of the ERα target genes GREB1, TFF1, and PGR, comparable to 10 nM E2, which was abolished by 100 nM of the ERα antagonist fulvestrant. Moreover, BPTMC stimulated MCF-7 cell proliferation at nanomolar concentrations over 72 h, and cell count analyses confirmed this effect. BPA also increased cell numbers, and both effects were reversed by fulvestrant. Collectively, we identified BPTMC as a potent ERα agonist capable of eliciting transcriptional and mitogenic responses at low concentrations, raising concerns about its endocrine-disrupting and breast cancer-promoting effects.

双酚A （BPA）及其结构类似物广泛用于塑料生产，由于其内分泌干扰特性引起了人们的关注。虽然许多类似物在结构上与双酚a相似，但它们对内分泌的干扰作用仍未充分表征。环二双酚A二缩水甘油酯醚（环二- badge）、四溴双酚S （TBBPS）、双酚SIP （BPSIP）和双酚TMC （BPTMC）的研究尤其不足。我们评估了这四种双酚a类似物与双酚a的雌激素活性。在表达雌激素受体α (ERα)的HEK-293细胞中进行的转激活实验表明，BPTMC是比BPA更有效的ERα激动剂，其EC50为87 ± 20nM，而BPA为400 ± 100nM，而其他被测试的类似物没有明显的激动活性。硅分析将这种高亲和力归因于更大的疏水性和其酚环之间更大的桥接基团。没有一种化合物抑制17β-羟基类固醇脱氢酶1型（17β-HSD1）的活性。然而，BPTMC选择性抑制17β-HSD2 (IC50 = 4.8 ± 0.6µM)，而对BPA没有抑制作用。重要的是，将ERα阳性MCF-7乳腺癌细胞暴露于1µM BPTMC中24小时，ERα靶基因GREB1、TFF1和PGR的表达上调，与10nM E2相当，而100nM的ERα拮抗剂氟维西汀可以消除E2的表达。此外，BPTMC在纳摩尔浓度下刺激MCF-7细胞增殖超过72小时，细胞计数分析证实了这一作用。BPA也增加了细胞数量，而这两种作用被氟维司汀逆转了。总的来说，我们确定BPTMC是一种有效的ERα激动剂，能够在低浓度下引发转录和有丝分裂反应，引起人们对其内分泌干扰和促进乳腺癌作用的关注。

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引用次数: 0

Maternal exposure to polypropylene nanoplastics disrupts sex- and region-specific lipid metabolism in the brains of C57BL/6N mouse offspring 母体接触聚丙烯纳米塑料会破坏C57BL/6N小鼠后代大脑中性别和区域特异性脂质代谢

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-12-31 DOI: 10.1016/j.tox.2025.154392

Jangjae Lee , Subin Park , Da Yong Lee , Sung-Hee Cho

Polypropylene nanoplastics (PPNPs), produced through the degradation of widely used plastic products, are increasingly recognized as emerging environmental contaminants with potential neurodevelopmental toxicity. However, the long-term biochemical consequences of prenatal PPNP exposure on brain development remain poorly understood. In this study, we performed a region- and sex-specific targeted lipidomic analysis to examine how maternal oral exposure to PPNPs during pregnancy and lactation alters brain lipid composition in offspring at postnatal day 21. Using liquid chromatography–tandem mass spectrometry (LC–MS/MS), we profiled lipid classes in the hippocampus (HP), cortex (CTX), cerebellum (CB), and dorsal raphe nucleus (DR) of both male and female mice. Our findings revealed distinct, region-specific lipid remodeling patterns in response to PPNP exposure. Females exhibited consistent reductions in neuroprotective lipids, including lysophosphatidylethanolamines (LPEs) and plasmalogens, most prominently in the hippocampus. Males, in contrast, displayed elevated triglyceride levels and region-specific alterations in phospholipid composition, such as reduced phosphatidylcholines in the hippocampus and dorsal raphe. These results indicate that maternal nanoplastic exposure, even without postnatal contact, can cause persistent, sex-specific disturbances in brain lipid metabolism. To our knowledge, this study provides the first targeted lipidomic characterization of offspring brains following maternal PPNP exposure and highlights the importance of brain region–specific lipid analysis for identifying localized disruptions in neurodevelopment caused by environmental pollutants.

聚丙烯纳米塑料（PPNPs）是由广泛使用的塑料制品降解产生的，越来越被认为是一种具有潜在神经发育毒性的新兴环境污染物。然而，产前PPNP暴露对大脑发育的长期生化后果仍然知之甚少。在这项研究中，我们进行了一项区域和性别特异性的靶向脂质组学分析，以研究母亲在怀孕和哺乳期间口服PPNPs如何改变出生后21天后代的脑脂质组成。使用液相色谱-串联质谱（LC-MS/MS），我们分析了雄性和雌性小鼠海马（HP）、皮质（CTX）、小脑（CB）和中缝背核（DR）中的脂类。我们的研究结果揭示了不同的，区域特异性脂质重塑模式响应PPNP暴露。雌性小鼠表现出神经保护脂质的持续减少，包括溶血磷脂酰乙醇胺（LPEs）和磷脂原，在海马中最为显著。相比之下，雄性表现出甘油三酯水平升高和磷脂组成的区域特异性改变，如海马和中脑背的磷脂酰胆碱减少。这些结果表明，母亲接触纳米塑料，即使没有产后接触，也会导致持续的、性别特异性的脑脂质代谢紊乱。据我们所知，这项研究首次提供了母体PPNP暴露后后代大脑的靶向脂质组学特征，并强调了大脑区域特异性脂质分析对于识别环境污染物引起的局部神经发育中断的重要性。

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引用次数: 0

Mechanistic insights into TDCPP-induced DNA damage in GT1-7 cells tdcpp诱导的GT1-7细胞DNA损伤机制研究

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-12-31 DOI: 10.1016/j.tox.2025.154391

Bingli Lei , Jiaying Li , Yingxin Yang , Xiaoyu Lu , Tingying Liu , Na Li , Yang Li , Xinyang Li , Chenglian Feng

As a typical organophosphate ester compound, tris(1,3-dichloro-2-propyl) phosphate (TDCPP) exhibits both estrogenic activity and genotoxicity. However, the involvement of estrogen signaling pathways in TDCPP-induced genotoxicity remains unclear. This study evaluated the effects of TDCPP (0.001–200 μM) on DNA damage and repair-related endpoints in GT1–7 mouse hypothalamic cells, and examined the roles of estrogen nuclear receptors (ERα/β) and G protein-coupled estrogen membrane receptor 1 (GPER1), as well as their downstream ERK1/2 and AKT signaling pathways, in TDCPP-induced DNA damage. Our results showed that TDCPP exposure elevated intracellular levels of reactive oxygen species (ROS) and malondialdehyde (MDA), induced DNA damage and G2/M cell cycle arrest, and increased mitochondrial damage and micronucleus formation. In addition, TDCPP significantly increased the protein expression of ATM and γ-H2AX, key markers of DNA double-strand breaks (DSBs), and upregulated the mRNA expression of most DSB repair-related genes, while downregulated mRNA expression of most DNA single-strand break (SSB) repair-related genes. TDCPP also upregulated both protein and gene expression of GPER1 and enhanced ERK1/2 phosphorylation. Pretreatment with the GPER1 inhibitor G15 or the ERK1/2 inhibitor U0126 significantly suppressed TDCPP-induced upregulation of ATM and γ-H2AX protein expression, reversed changes in mRNA levels of DSB/SSB repair-related genes, and reduced TDCPP-induced DNA damage in GT1–7 cells. These findings indicate that TDCPP activates the GPER1-ERK1/2 signaling pathway, which plays a critical role in mediating its DNA-damaging effects.

Capsule

TDCPP induced DNA damage in GT1–7 cells by activating GPER1-ERK1/2 signaling pathway.

作为一种典型的有机磷酸酯化合物，三（1,3-二氯-2-丙基）磷酸（TDCPP）具有雌激素活性和遗传毒性。然而，雌激素信号通路在tdpp诱导的遗传毒性中的作用尚不清楚。本研究评估了TDCPP （0.001-200μM）对GT1-7小鼠下丘脑细胞DNA损伤和修复终点的影响，并探讨了雌激素核受体（ERα/β）和G蛋白偶联雌激素膜受体1 （GPER1）及其下游ERK1/2和AKT信号通路在TDCPP诱导的DNA损伤中的作用。我们的研究结果表明，TDCPP暴露会提高细胞内活性氧（ROS）和丙二醛（MDA）水平，诱导DNA损伤和G2/M细胞周期阻滞，并增加线粒体损伤和微核形成。此外，TDCPP显著提高了DNA双链断裂（DSB）关键标记物ATM和γ-H2AX的蛋白表达，上调了大多数DSB修复相关基因的mRNA表达，下调了大多数DNA单链断裂（SSB）修复相关基因的mRNA表达。TDCPP还上调GPER1蛋白和基因表达，增强ERK1/2磷酸化。GPER1抑制剂G15或ERK1/2抑制剂U0126预处理可显著抑制tdpp诱导的ATM和γ-H2AX蛋白表达上调，逆转DSB/SSB修复相关基因mRNA水平的变化，减轻tdpp诱导的GT1-7细胞DNA损伤。这些发现表明，TDCPP激活GPER1-ERK1/2信号通路，在介导其dna损伤作用中起关键作用。胶囊：TDCPP通过激活GPER1-ERK1/2信号通路诱导GT1-7细胞DNA损伤。

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引用次数: 0

Nickel refining fumes activate glutamine metabolism via the HIF‐1α/Notch pathway to drive epithelial-mesenchymal transition in Beas‐2B cells 镍精炼烟雾通过HIF-1α/Notch通路激活谷氨酰胺代谢，驱动Beas-2B细胞上皮-间质转化。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-12-30 DOI: 10.1016/j.tox.2025.154390

Qian-Qian Sun , Han-Nong Yu , Rui-Ze Wu , Bo Zhang , Wen-Xue Yao , Wei-Yang Liu , Jia Han , Li-Yan Ju , Yu-Lin Pan , Yong-Hui Wu

Occupational exposure to nickel refining fumes (NiRF) represents a critical risk factor for respiratory diseases; however, the molecular mechanisms governing NiRF-induced epithelial-mesenchymal transition (EMT) in bronchial epithelial cells remain incompletely elucidated. In vitro experiments using the human bronchial epithelial cell line Beas-2B as a model demonstrated that NiRF exposure robustly activated the hypoxia-inducible factor-1α (HIF-1α)/Notch signaling pathway, while concomitantly triggering glutamine metabolic reprogramming. This reprogramming phenotype was characterized by the upregulated expression of the glutamine transporter SLC1A5 and enhanced expression of glutaminase 1 (GLS1). Functional validation assays revealed that small interfering RNA (siRNA)-mediated silencing of HIF-1α (siHIF-1α) or Notch1 (siNotch1) significantly downregulated GLS1 expression, and reversed NiRF-induced glutamine metabolic activation. Furthermore, pharmacological inhibition of glutamine metabolism via treatment with a GLS1 inhibitor effectively abrogated the EMT process in Beas-2B cells, as evidenced by the upregulated expression of the epithelial marker E-cadherin and the downregulated expression of the mesenchymal markers N-cadherin and vimentin. In vivo experiments further confirmed that NiRF promoted EMT in lung tissue cells in a dose-dependent manner, accompanied by activation of the HIF-1α/Notch signaling pathway and enhanced glutamine metabolism (as reflected by the upregulated expression of both SLC1A5 and GLS1). Collectively, these findings verify that glutamine metabolic activation, mediated by the HIF-1α/Notch pathway, constitutes the core mechanism underlying NiRF-driven EMT in Beas-2B cells. This study provides novel theoretical insights and potential therapeutic targets for elucidating the pathogenesis of occupational NiRF-associated respiratory injury and developing targeted intervention strategies.

职业接触镍精炼烟雾（NiRF）是呼吸道疾病的一个关键危险因素；然而，调控nrf诱导支气管上皮细胞上皮-间质转化（EMT）的分子机制仍未完全阐明。以人支气管上皮细胞系Beas-2B为模型的体外实验表明，NiRF暴露可显著激活缺氧诱导因子-1α (HIF-1α)/Notch信号通路，同时引发谷氨酰胺代谢重编程。这种重编程表型的特征是谷氨酰胺转运体SLC1A5的表达上调和谷氨酰胺酶1 （GLS1）的表达增强。功能验证实验显示，小干扰RNA （siRNA）介导的HIF-1α (siHIF-1α)或Notch1 （siNotch1）的沉默可显著下调GLS1的表达，逆转nif诱导的谷氨酰胺代谢激活。此外，GLS1抑制剂对谷氨酰胺代谢的药理学抑制有效地消除了Beas-2B细胞中的EMT过程，上皮标志物E-cadherin的表达上调，间充质标志物N-cadherin和vimentin的表达下调。体内实验进一步证实，NiRF以剂量依赖的方式促进肺组织细胞的EMT，同时激活HIF-1α/Notch信号通路，增强谷氨酰胺代谢（SLC1A5和GLS1的表达上调）。总之，这些发现证实了由HIF-1α/Notch通路介导的谷氨酰胺代谢激活构成了nif驱动的Beas-2B细胞EMT的核心机制。本研究为阐明职业性nrf相关呼吸损伤的发病机制和制定有针对性的干预策略提供了新的理论见解和潜在的治疗靶点。

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引用次数: 0

Cx43 phosphorylation at Ser368 facilitates PASMC dedifferentiation in nicotine-induced pulmonary arterial remodeling Cx43 Ser368位点磷酸化促进尼古丁诱导的肺动脉重构中PASMC去分化。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-12-30 DOI: 10.1016/j.tox.2025.154389

Yi Xu , Xiaomin Hou , Su Guo , Jin Zhou , Xuelu Jiang , Zhifa Zheng , Liangyuan Zhao , Xiaoxia Ren , Lingbo Yang , Yiwei Shi , Xiaojiang Qin

Background

Pulmonary arterial hypertension is a severe disease characterized by pulmonary vascular remodeling, which is closely associated with the phenotypic switching of pulmonary artery smooth muscle cells (PASMCs). Connexin 43 (Cx43) phosphorylation is a key regulator of intercellular communication. However, the specific mechanism underlying nicotine-induced dedifferentiation of PASMCs remains unclear.

Purpose

This study aimed to investigate the molecular mechanism by which Cx43 phosphorylation promotes nicotine-induced phenotypic switching of PASMCs, thereby driving pulmonary vascular remodeling.

Methods

Using Tagln-Cre; Cx43^+ /+ and Tagln-Cre; Cx43^flox/+ deletion mice exposed to nicotine, a series of in vivo and in vitro experiments were conducted to investigate the mechanism by which nicotine promotes pulmonary arterial remodeling via protein kinase C-mediated phosphorylation of Cx43 and subsequent dedifferentiation of PASMCs. The involvement of this kinase pathway was further validated with its specific inhibitor, chelerythrine chloride.

Results

Nicotine increased PASMC dedifferentiation by promoting Cx43 phosphorylation at Ser368 (Cx43-pS368). In Tagln-Cre; Cx43 ^flox/+ mice, these pathological changes were reduced. In vitro, chelerythrine chloride was utilized to inhibit nicotine-induced Cx43-pS368. This suppression of Cx43-pS368 effectively attenuated nicotine-induced PASMC dedifferentiation, thereby ameliorating pulmonary arterial remodeling.

Conclusion

Nicotine can induce PASMC phenotypic transformation by modulating Cx43-pS368, thereby promoting pulmonary artery remodeling. Targeting this pathway could provide a therapeutic strategy for nicotine-related pulmonary vascular diseases.

背景：肺动脉高压是一种以肺血管重构为特征的严重疾病，与肺动脉平滑肌细胞（PASMCs）的表型转换密切相关。连接蛋白43 （Cx43）磷酸化是细胞间通讯的关键调节因子。然而，尼古丁诱导PASMCs去分化的具体机制尚不清楚。目的：本研究旨在探讨Cx43磷酸化促进尼古丁诱导的PASMCs表型转换，从而驱动肺血管重构的分子机制。方法：taglen - cre；Cx43+/+和Tagln-Cre；通过对暴露于尼古丁的Cx43flox/+缺失小鼠进行一系列体内和体外实验，探讨尼古丁通过蛋白激酶c介导的Cx43磷酸化和随后的PASMCs去分化促进肺动脉重塑的机制。这种激酶途径的参与通过其特异性抑制剂氯化chelerythrine进一步验证。结果：尼古丁通过促进Cx43 Ser368位点的磷酸化（Cx43- ps368）增加PASMC去分化。在Tagln-Cre;Cx43flox/+小鼠，这些病理改变减轻。在体外，利用氯化chelerythrine抑制尼古丁诱导的Cx43-pS368。这种对Cx43-pS368的抑制有效地减弱了尼古丁诱导的PASMC去分化，从而改善了肺动脉重塑。结论：尼古丁可通过调节Cx43-pS368诱导PASMC表型转化，从而促进肺动脉重塑。靶向这一途径可能为尼古丁相关肺血管疾病提供一种治疗策略。

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引用次数: 0