Toxicology最新文献_第8页

Hydramethylnon-induced autophagy and apoptosis in human bronchial epithelial cells by homeostatic changes 盐酸非诱导支气管上皮细胞自噬和凋亡的稳态变化。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-11-13 DOI: 10.1016/j.tox.2025.154338

Yeon-Ho Kang , Sou Hyun Kim , Hye-Jin Jeong , Ah-Yoon Song , Hye-In Park , Eun-Hye Kim , Young-Suk Jung , Yong Joo Park

Household chemicals are commonly used products worldwide; however, their effects on human respiratory health are poorly understood. In this study, we aimed to investigate the effects of hydramethylnon (HDM), an insecticide frequently found in household products, on human bronchial epithelial cells (BEAS-2B) using in vitro experiments. The cells were exposed to varying concentrations of HDM (range, 1–4 µg/mL) for 24 h, followed by the evaluation of cell viability, apoptotic markers, metabolite levels, and antioxidant levels. The results showed that HDM exposure significantly increased oxidative stress by elevating the levels of reactive oxygen species, leading to the autophagosome accumulation and impaired autophagic flux (manifested by increased LC3B and p62 levels) and apoptosis (detected by increased cleaved caspase-3 and Bax/Bcl-2 levels and cytochrome c release). Flow cytometry confirmed that dose-dependent apoptotic cell death was further enhanced by chloroquine, an autophagy inhibitor. HDM exposure also resulted in a dose-dependent decrease in the messenger RNA levels of antioxidant enzymes, including catalase and glutathione peroxidase, and notable disruptions in sulfur-containing metabolites, including decreased levels of S-adenosylmethionine, S-adenosylhomocysteine, taurine, and glutathione. These metabolic perturbations were significantly aggravated by autophagy inhibition, suggesting autophagy-lysosome pathway plays a protective role against HDM-induced oxidative damage. These results suggest that HDM exposure poses substantial risks to human respiratory health through the oxidative stress-mediated disruption of antioxidant defense systems and metabolic pathways, ultimately impaired autophagic flux and mitochondria-mediated apoptosis in bronchial epithelial cells. This study highlights the need for improved safety guidelines and risk assessments of human inhalation exposure to household insecticides, particularly HDM.

家用化学品是世界范围内常用的产品；然而，它们对人类呼吸系统健康的影响却知之甚少。在本研究中，我们旨在通过体外实验研究家用产品中常见的杀虫剂hydramethylnon （HDM）对人支气管上皮细胞（BEAS-2B）的影响。将细胞暴露于不同浓度的HDM（范围，1-4µg/mL）中24小时，然后评估细胞活力、凋亡标志物、代谢物水平和抗氧化水平。结果表明，HDM暴露通过提高活性氧水平显著增加氧化应激，导致自噬体积累和自噬通量受损（表现为LC3B和p62水平升高）和细胞凋亡（检测为cleaved caspase-3和Bax/Bcl-2水平升高和细胞色素c释放）。流式细胞术证实，剂量依赖性凋亡细胞死亡在自噬抑制剂氯喹的作用下进一步增强。HDM暴露还导致抗氧化酶（包括过氧化氢酶和谷胱甘肽过氧化物酶）的信使RNA水平呈剂量依赖性下降，含硫代谢物（包括s -腺苷甲硫氨酸、s -腺苷同型半胱氨酸、牛磺酸和谷胱甘肽）的水平明显下降。自噬抑制显著加重了这些代谢扰动，提示自噬-溶酶体途径对hdm诱导的氧化损伤起保护作用。这些结果表明，HDM暴露通过氧化应激介导的抗氧化防御系统和代谢途径的破坏，最终损害支气管上皮细胞的自噬通量和线粒体介导的凋亡，对人类呼吸健康构成重大风险。这项研究强调需要改进人体吸入暴露于家用杀虫剂，特别是HDM的安全准则和风险评估。

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引用次数: 0

Ophthalmotoxicology of polyhalogenated compounds 多卤化化合物的眼毒理学。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-11-13 DOI: 10.1016/j.tox.2025.154337

Maxime Louzon , Christophe Chiquet , Mohamed Kamel , Lotfi Aleya , Hugo Blanc , Adrien Blanc

Polyhalogenated compounds (PHCs), including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and per- and polyfluoroalkyl substances (PFAS), are persistent organic pollutants that bioaccumulate in tissues and are increasingly recognized as threats to human health. While their neurotoxic and endocrine-disrupting effects are often described, their potential impact on the ocular system remains underexplored. However, recent evidence suggests that chronic PHC exposure may contribute to a spectrum of ocular pathologies, such as retinal degeneration, cataracts and retinoblastoma. To clarify these emerging risks, this review synthesizes findings at the intersection of toxicology, ophthalmology, and environmental health, highlighting mechanistic insights into how PHCs impair ocular function. Epidemiological studies linking environmental contaminant exposure to visual deficits are discussed alongside experimental data from animal models and in vitro systems, with a particular focus on oxidative stress, mitochondrial dysfunction, endocrine disruption, and altered retinoid signaling as plausible pathways mediating PHC-induced visual toxicity. Given the widespread nature of PHC exposure and the increasing global burden of visual impairment, further research and regulatory oversight are urgently needed to bridge the gap between environmental toxicology and ocular health, ultimately aiming to better understand and mitigate the visual risks posed by these persistent pollutants.

多卤化合物（PHCs），包括多氯联苯（PCBs）、多溴联苯醚（PBDEs）、多氯二苯并二恶英（pcdd）、多氯二苯并呋喃（pcdf）以及全氟和多氟烷基物质（PFAS），是持久性有机污染物，可在组织中生物积累，并日益被认为是对人类健康的威胁。虽然它们的神经毒性和内分泌干扰作用是公认的，但它们对眼部系统的潜在影响仍未得到充分探讨。然而，最近的证据表明，慢性PHC暴露可能导致一系列眼部病变，如视网膜变性、白内障和视网膜母细胞瘤。为了阐明这些新出现的风险，本综述综合了毒理学、眼科学和环境卫生交叉领域的研究结果，强调了PHCs损害眼功能的新机制。将环境污染物暴露与视觉缺陷联系起来的流行病学研究与动物模型和体外系统的实验数据一起进行了讨论，特别关注氧化应激、线粒体功能障碍、内分泌干扰和类视黄醇信号改变作为介导phc诱导的视觉毒性的可能途径。鉴于PHC暴露的广泛性质和日益增加的全球视力损害负担，迫切需要进一步的研究和监管监督，以弥合环境毒理学和眼健康之间的差距，最终旨在更好地了解和减轻这些持久性污染物造成的视力风险。

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引用次数: 0

An in vitro-in silico workflow for predicting renal clearance of environmental chemicals and drugs 预测肾脏对环境化学物质和药物清除的体外硅工作流。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-11-11 DOI: 10.1016/j.tox.2025.154336

Courtney Sakolish , Hsing-Chieh Lin , Haley L. Moyer , Lucie C. Ford , Charles H. Christen , Barbara A. Wetmore , Michael J. DeVito , Philip Hewitt , Stephen S. Ferguson , Farah Raad , Ivan Rusyn , Weihsueh A. Chiu

Accurate prediction of human renal clearance is essential for evaluating drug pharmacokinetics and environmental chemical risks, yet current methods often neglect rate-determining active transporter-mediated mechanisms. This study aimed to expand and validate a unified in vitro-in silico workflow for predicting renal clearance of both pharmaceuticals and per- and polyfluoroalkyl substances (PFAS) with varied elimination half-life ranges. We hypothesized that robust predictions of human renal clearance across diverse chemical classes can be achieved by combining human proximal tubule cell-based permeability/uptake assays with computational models of renal physiology. Human RPTEC/TERT1 cells and their OAT1-overexpressing variant were cultured in 96-well plates and Transwells to measure uptake, directional transport, and intracellular accumulation of 36 chemicals (28 PFAS, 7 drugs, 1 cosmetic ingredient). Time-course concentration data were used for either two-compartment (96-well) or three-compartment (Transwell) kinetic models. Permeability parameters were integrated into a physiologically-based kidney model for in vitro-to-in vivo extrapolation (IVIVE). A follow-up validation study with PFAS used independent experiments to derive similar predictions. Transwell-based three-compartment modeling yielded the most accurate absolute renal clearance predictions for rapidly eliminated drugs. For slowly cleared PFAS, simpler 96-well two-compartment modeling provided high correlation with observed human clearance, accurately distinguishing low-, medium- and high-clearance compounds; model predictions were consistently human health-protective. The PFAS validation study confirmed reproducibility of the approach. The proposed workflow is a conservative, scalable, mechanistically-informed and empirically-benchmarked approach for predicting renal clearance in humans. Transwell assays best support drug clearance estimation, whereas high-throughput 96-well formats enable reliable relative clearance ranking for PFAS, supporting both pharmaceutical development and environmental chemical risk assessment.

准确预测人体肾脏清除率对于评估药物药代动力学和环境化学风险至关重要，但目前的方法往往忽略了决定速率的主动转运蛋白介导机制。本研究旨在扩展和验证一个统一的体外硅工作流程，用于预测药物和具有不同消除半衰期范围的全氟烷基和多氟烷基物质（PFAS）的肾脏清除。我们假设，通过将基于人体近端小管细胞的通透性/摄取测定与肾脏生理学计算模型相结合，可以实现对不同化学类别的人体肾脏清除率的可靠预测。在96孔板和Transwells中培养人RPTEC/TERT1细胞及其oat1过表达变体，测量22种化学物质（14种PFAS， 7种药物，1种化妆品成分）的摄取、定向运输和细胞内积累。时间过程浓度数据用于两室（96井）或三室（Transwell）动力学模型。渗透性参数被整合到基于生理的肾脏模型中，用于体外到体内外推（IVIVE）。一项针对PFAS的后续验证研究使用独立实验得出了类似的预测。基于transwell的三室模型对快速消除的药物产生了最准确的绝对肾脏清除率预测。对于缓慢清除的PFAS，更简单的96孔双室模型与观察到的人体清除率高度相关，可以准确区分低、中、高清除率的化合物；模型预测始终对人类健康有益。PFAS验证研究证实了该方法的可重复性。所提出的工作流程是一种保守的、可扩展的、机械的、经验基准的预测人类肾脏清除率的方法。Transwell分析最能支持药物清除率评估，而高通量96孔格式则可以对PFAS进行可靠的相对清除率排序，从而支持药物开发和环境化学风险评估。

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引用次数: 0

Toxic effects of gadolinium on spermatogenesis are associated with inflammation, oxidative stress, apoptosis and autophagy 钆对精子发生的毒性作用与炎症、氧化应激、细胞凋亡和自噬有关。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-11-09 DOI: 10.1016/j.tox.2025.154335

Sara Falvo , Giulia Grillo , Massimo Venditti , Gabriella Chieffi Baccari , Maria Maddalena Di Fiore , Tiziana Cappello , Maria Maisano , Giuseppe Petito , Rosalba Senese , Concetta De Stefano , Giuseppe Zaffino , Alessandra Santillo

The widespread use of gadolinium (Gd) in industrial and medical applications has raised concerns about its environmental persistence, particularly in water and soil. Once ingested, Gd may exert toxic effects on various organs, but its impact on male reproductive health remains largely unexplored. This study investigated the effects of orally administered GdCl₃ or Gd₂O₃ on spermatogenesis and sperm quality in adult rats. To this purpose, male rats were allowed to drink GdCl₃ or Gd₂O₃ (10–20–40 mg/Kg bw) for 4 weeks. Gd exposure triggered a strong inflammatory response, evidenced by NF-κB activation and increased TNFα and IL-6 levels in serum and testis. This was accompanied by oxidative stress, as indicated by elevated TBARS levels, as well as apoptosis and autophagy processes activation. Notably, Gd-treated animals exhibited a downregulation of spermatogenesis-related proteins (PCNA, p-H3, SYCP3, PRM2). Histological analysis revealed morphological and morphometric alterations in the seminiferous tubules, along with compromised sperm quality. To explore the cellular mechanisms, in vitro experiments were carried out using mouse GC-1 spermatogonial cells treated with GdCl₃ or Gd₂O₃ for 24 h. Gd exposure resulted in cytotoxicity and reduced cell proliferation, with decreased levels of p-ERK1/2 and PCNA. Gd exposure also disrupted oxidative homeostasis and induced autophagy and apoptosis, likely through the inhibition of the AKT signaling pathway. This study provides the first evidence that oral Gd exposure adversely affects spermatogenesis through inflammation, oxidative stress, and impairment of key cellular pathways, highlighting Gd as a potential environmental threat to male reproductive health.

钆在工业和医疗应用中的广泛使用引起了人们对其环境持久性的关注，特别是在水和土壤中的持久性。一旦摄入，Gd可能对各种器官产生毒性作用，但其对男性生殖健康的影响在很大程度上仍未被探索。本研究调查了口服GdCl₃或Gd₂O₃对成年大鼠精子发生和精子质量的影响。为此，雄性大鼠连续4周饮用GdCl3或Gd2O3 （10-20-40mg/Kg bw）。Gd暴露引发了强烈的炎症反应，其证据是NF-κB活化，血清和睾丸中TNFα和IL-6水平升高。这伴随着氧化应激，如TBARS水平升高所示，以及细胞凋亡和自噬过程激活。值得注意的是，gd处理的动物表现出精子发生相关蛋白（PCNA, p-H3, SYCP3, PRM2）的下调。组织学分析显示精子小管形态和计量学改变，精子质量受损。为了探究其细胞机制，用GdCl₃或Gd₂O₃处理小鼠GC-1精原细胞24h进行了体外实验。Gd暴露导致细胞毒性和细胞增殖减少，p-ERK1/2和PCNA水平降低。Gd暴露也可能通过抑制AKT信号通路破坏氧化稳态，诱导自噬和凋亡。本研究首次提供证据表明，口服Gd暴露会通过炎症、氧化应激和关键细胞通路的损伤对精子发生产生不利影响，强调Gd是男性生殖健康的潜在环境威胁。

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引用次数: 0

Antiparasitic agent emodepside exerts cytotoxicity in human corneal stromal cells by blocking the interaction between mini-chromosome maintenance 6 protein (MCM6) and chromatin licensing and DNA replication factor 1 (CDT1) 抗寄生虫药emodepside通过阻断微染色体维持6蛋白（MCM6）与染色质许可和DNA复制因子1 （CDT1）之间的相互作用，对人角膜基质细胞产生细胞毒性。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-11-05 DOI: 10.1016/j.tox.2025.154334

Han Gao , Hanyu Gao , Hao Yin

Emodepside, a novel antiparasitic agent, exhibits remarkable efficacy against nematodes. Recent research from a phase 2b clinical trial has demonstrated that the most frequent adverse event in the emodepside treatment group is blurred vision, but the mechanism of blurred vision remains largely unexplored. To provide references for secure medication and prospective therapeutic interventions of emodepside, we conducted an investigation into the cytotoxic effects of emodepside on the corneal stroma and its underlying mechanisms using an in vitro model of human corneal stromal (HCS) cells. The loading of the mini-chromosome maintenance 6 protein (MCM6) onto chromatin at replication origins by chromatin licensing and DNA replication factor 1 (CDT1) constitutes a crucial step in licensing DNA for replication. This study demonstrates that emodepside directly binds to the CDT1-binding domain (CBD) of MCM6, competitively blocking the MCM6-CDT1 interaction as confirmed by modified enzyme-linked immunosorbent assay and drug affinity responsive target stability assays. Molecular docking reveals that emodepside binds to CBD through hydrogen bonds with Lys754, Ile760, and Lys770. In HCS cells, this blockade results in the inhibition of DNA replication licensing and a decrease in DNA synthesis, as evidenced by the ethynyl-deoxyuridine incorporation assay, leading to cell cycle arrest at the G₀/G₁ phase. Moreover, emodepside-induced cell cycle arrest in HCS cells leads to dose-dependent apoptosis and proliferation inhibition with the IC₅₀ value being 32.3 μM. In conclusion, this study not only provides new insights into the mechanism of emodepside-induced vision blur but also offers a valuable molecular tool for the research of MCM6-CDT1 interaction.

Emodepside是一种新型的抗寄生虫剂，对线虫具有显著的防治效果。最近一项2b期临床试验的研究表明，emodepside治疗组最常见的不良事件是视力模糊，但视力模糊的机制在很大程度上仍未被探索。为了为emodepside的安全用药和前瞻性治疗干预提供参考，我们利用人角膜基质（HCS）细胞体外模型研究emodepside对角膜基质的细胞毒性作用及其潜在机制。通过染色质许可和DNA复制因子1 （CDT1）将迷你染色体维持蛋白（MCM6）装载到复制起点的染色质上，是DNA复制许可的关键步骤。本研究表明，emodepside直接与MCM6的cdt1结合域（CBD）结合，竞争性地阻断MCM6- cdt1相互作用，经改良酶联免疫吸附试验和药物亲和反应靶稳定性试验证实。分子对接发现emodepside通过与Lys754、Ile760和Lys770的氢键与CBD结合。在HCS细胞中，这种阻断导致DNA复制许可的抑制和DNA合成的减少，正如乙基脱氧尿苷掺入试验所证明的那样，导致细胞周期阻滞在G0/G1期。此外，emodepide诱导的HCS细胞周期阻滞导致剂量依赖性的凋亡和增殖抑制，IC50值为32.3μM。综上所述，本研究不仅为emodepide诱导的视力模糊机制提供了新的见解，也为MCM6-CDT1相互作用的研究提供了有价值的分子工具。

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引用次数: 0

Real-life organochlorine mixture-induced lipid dysregulation and oxidative stress in Leydig TM3 cells: Mechanistic insights into male reprotoxicity 现实生活中有机氯混合物诱导的间质TM3细胞脂质失调和氧化应激：男性生殖毒性的机制见解。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-11-04 DOI: 10.1016/j.tox.2025.154332

Ishita Virmani, Eliška Sychrová, Eliška Řehůřková, Darshak Gadara, Zdeněk Spáčil, Jiří Novák, Iva Sovadinová

Persistent environmental pollutants such as organochlorines (OCs) remain a global concern due to their widespread distribution, bioaccumulative nature, and endocrine-disrupting potential. While associations with male reproductive toxicity are well documented, the underlying mechanisms, particularly those involving lipid metabolism in testicular cells, are not fully understood. This study investigates the mechanistic basis of male reprotoxicity induced by a real-life OC mixture (OC-MIX), modeled after the contaminant profile of ringed seal blubber and comprising 20 environmentally relevant OCs, including pesticides (e.g., dichlorodiphenyltrichloroethane) and industrial compounds (e.g., polychlorinated biphenyls). We applied a mechanistic in vitro test battery that combines receptor-specific reporter gene assays with functional profiling in immature murine Leydig TM3 cells exposed to OC-MIX concentrations ranging from 0.04 to 50 µg/mL. OC-MIX exhibited strong antiandrogenic and dioxin-like activities. Functional assays revealed reduced testosterone and progesterone levels, increased oxidative stress, and impaired mitochondrial function. These effects were driven by broad lipid dysregulation, including enhanced fatty acid degradation and acylcarnitine depletion, which was evident even at the lowest tested concentration (2.5 µg/mL). These lipid alterations were not primarily mediated via androgen receptor antagonism or aryl hydrocarbon receptor agonism. Instead, the lipidomic signature closely resembled that of the lipotoxic drug amiodarone, rather than a non-cytotoxic fatty acid mixture. Our findings underscore the central role of lipid metabolism in testicular function and demonstrate that OC-MIX exerts reproductive toxicity via complex, non-classical endocrine mechanisms. This study highlights the value of integrating lipidomics with mechanistic in vitro models to assess the reproductive toxicity of environmental chemical mixtures.

持久性环境污染物，如有机氯（OCs），由于其广泛分布、生物蓄积性和内分泌干扰潜力，仍然是全球关注的问题。虽然与男性生殖毒性的关联已被充分记录，但其潜在机制，特别是涉及睾丸细胞脂质代谢的机制，尚未完全了解。本研究调查了现实生活中的有机化合物混合物（OC- mix）诱导雄性生殖毒性的机制基础，该混合物以环海豹脂肪的污染物概况为模型，由20种与环境相关的有机化合物组成，包括杀虫剂（如二氯二苯三氯乙烷）和工业化合物（如多氯联苯）。我们对暴露于0.04至50µg/mL OC-MIX浓度范围内的未成熟小鼠Leydig TM3细胞进行了一种结合受体特异性报告基因测定和功能分析的机制体外试验电池。OC-MIX具有较强的抗雄激素和二恶英样活性。功能分析显示睾酮和孕酮水平降低，氧化应激增加，线粒体功能受损。这些影响是由广泛的脂质失调驱动的，包括脂肪酸降解增强，酰基肉碱耗损，即使在最低测试浓度（2.5µg/mL）下也很明显。这些脂质改变主要不是通过雄激素受体拮抗或芳烃受体激动介导的。相反，脂质组学特征与脂毒药物胺碘酮非常相似，而不是非细胞毒性脂肪酸混合物。我们的研究结果强调了脂质代谢在睾丸功能中的核心作用，并证明OC-MIX通过复杂的非经典内分泌机制发挥生殖毒性。这项研究强调了将脂质组学与体外机制模型结合起来评估环境化学混合物的生殖毒性的价值。

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引用次数: 0

Micro and nanoplastics in human carcinogenesis: Insights from in vitro studies 微塑料和纳米塑料在人类癌变中的作用：来自体外研究的见解。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-11-01 DOI: 10.1016/j.tox.2025.154331

Geovanna Carla Amaro Silva, Matheus Naia Fioretto, Micheli Canuto Lima, Wellerson Rodrigo Scarano, Flávia Karina Delella

Many types of cancer affecting humans have been investigated for centuries, underscoring their significance as a major global health challenge shaped by genetic, epigenetic, and environmental factors. In contrast, plastic production has only recently gained attention in healthcare, largely due to its degradation and the resulting formation of micronanoplastics (MNPs), which pose potential risks to both the environment and human health. In both contexts, experimental models are crucial for elucidating the mechanisms linking MNPs exposure to cancer, with in vitro studies serving as a key investigative approach. This narrative review compiles in vitro evidence on the effects of MNPs exposure across various tumor cell types. Current findings indicate that MNPs can bioaccumulate and disrupt organ-specific homeostasis, primarily through oxidative stress induction and interference with lipid peroxidation. Within tumor environments, the dose and physicochemical properties of MNPs play a decisive role in determining the severity of their effects. Overall, MNPs appear to activate signaling pathways that promote cell proliferation and tumor-specific invasiveness, thereby contributing to a tumor-promoting microenvironment. Based on available in vitro data, a possible correlation emerges between MNPs-induced carcinogenesis and the identification of potential biomarkers of plastic exposure and tumor progression. This review thus provides a critical foundation for future in vivo and clinical studies aimed at clarifying the role of MNPs in cancer development.

几个世纪以来，人们对影响人类的许多类型的癌症进行了研究，强调了它们作为由遗传、表观遗传和环境因素形成的主要全球健康挑战的重要性。相比之下，塑料生产直到最近才在医疗保健领域引起关注，这主要是由于塑料的降解和由此形成的微微塑料（MNPs）对环境和人类健康构成潜在风险。在这两种情况下，实验模型对于阐明MNPs暴露于癌症的机制至关重要，体外研究是一种关键的调查方法。这篇叙述性综述汇编了MNPs暴露在各种肿瘤细胞类型中的影响的体外证据。目前的研究结果表明，MNPs可以生物积累并破坏器官特异性稳态，主要通过氧化应激诱导和对脂质过氧化的干扰。在肿瘤环境中，MNPs的剂量和理化性质在决定其作用的严重程度方面起着决定性作用。总的来说，MNPs似乎激活了促进细胞增殖和肿瘤特异性侵袭的信号通路，从而有助于促进肿瘤的微环境。根据现有的体外数据，mnps诱导的致癌作用与塑料暴露和肿瘤进展的潜在生物标志物的鉴定之间可能存在相关性。因此，该综述为未来旨在阐明MNPs在癌症发展中的作用的体内和临床研究提供了重要基础。

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引用次数: 0

Long-term low-dose N, N-dimethylformamide exposure disturbs hepatic lipid and glucose homeostasis in mice 长期低剂量N， N-二甲基甲酰胺暴露会扰乱小鼠肝脏脂质和葡萄糖稳态。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-10-30 DOI: 10.1016/j.tox.2025.154329

Shu-Jun Hong , Ming-Bao Zhang , Le-Yi Qi , Tian-Hao Zhao , Pin Wang , Tao Zeng

N, N-dimethylformamide (DMF) is a widely used industrial solvent with well-documented hepatotoxicity at high exposure levels. However, some epidemiological studies suggest that occupational exposure below the current occupational exposure limits (OELs) may still have adverse effects on workers. This study was designed to investigate the hepatotoxicity of subacute (28 days) and chronic (6 months) DMF exposure at OEL-relevant levels in mice. Mice exposed to 75 mg/kg bw DMF (a dose equivalent to the OEL of 20 mg/m³) for 28 days showed no signs of liver injury, while higher doses (150 and 300 mg/kg bw) led to increased serum aminotransferase activities, elevated liver weight/body weight ratio, and reduced hepatic lipid levels. However, 6 months of DMF exposure at 75 mg/kg bw caused a significant reduction in liver lipid content, activation of AMPK, and suppression of SREBP-1c, which were accompanied by elevated fasting blood glucose (FBG) levels, increased area under the curve (AUC) in glucose tolerance tests (GTTs), and enhanced lipolysis in white adipose tissue. Increased liver weight/body weight ratio, upregulation of AMPK and p-AMPK protein expression, white adipose tissue lipolysis, elevated FBG level, and increased AUC in GTTs were also observed in mice exposed to 37.5 mg/kg bw DMF. These results indicate that chronic DMF exposure at current OELs may disrupt hepatic metabolic homeostasis, highlighting the necessity to reestablish the OELs for DMF. Further validation of these results using an inhalation exposure model in both male and female mice, with dosimetry accurately bridging to human occupational exposure, is warranted.

N， N-二甲基甲酰胺（DMF）是一种广泛使用的工业溶剂，在高暴露水平下具有充分证明的肝毒性。然而，一些流行病学研究表明，低于现行职业暴露限值（OELs）的职业暴露仍可能对工人产生不利影响。本研究旨在研究与oel相关水平的DMF亚急性（28天）和慢性（6个月）暴露对小鼠的肝毒性。小鼠暴露于75mg/kg bw DMF（剂量相当于OEL 20mg/m3） 28天，无肝损伤迹象，而更高剂量（150和300mg/kg bw）导致血清转氨酶活性升高，肝脏重量/体重比升高，肝脏脂质水平降低。然而，暴露于75mg/kg bw的DMF 6个月后，肝脏脂质含量显著降低，AMPK活化，SREBP-1c抑制，同时伴有空腹血糖（FBG）水平升高，葡萄糖耐量试验（gts）曲线下面积（AUC）增加，白色脂肪组织的脂肪分解增强。37.5mg/kg bw DMF小鼠肝脏重量/体重比升高，AMPK和p-AMPK蛋白表达上调，白色脂肪组织脂解，FBG水平升高，gtt AUC升高。这些结果表明，在目前的OELs下，慢性DMF暴露可能会破坏肝脏代谢稳态，强调了重建DMF OELs的必要性。在雄性和雌性小鼠中使用吸入暴露模型进一步验证这些结果是有必要的，剂量学准确地连接到人类职业暴露。

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引用次数: 0

Polystyrene nanoplastics increase migration in normal lung cells while inducing differential cytotoxicity in lung cancer cells 聚苯乙烯纳米塑料增加正常肺细胞的迁移，同时诱导肺癌细胞的差异细胞毒性。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-10-30 DOI: 10.1016/j.tox.2025.154328

Yeongjae Kim , Seong Jun Park , Jung-Min Oh

Micro and nanoplastics, widely present in indoor and ambient air, are emerging inhalable contaminants that can accumulate in the respiratory tract. The potential health risks associated with their accumulation in the human body are increasingly recognized. Polystyrene nanoplastics (PS-NPs)-induced toxicity has been studied; however, the different responses between normal and cancerous lung cells remain poorly understood. In this study, we exposed normal (IMR90, BEAS-2B) and cancerous (A549, HCC1833, NCI-H727, NCI-H1755) human lung cell lines to various sizes of PS-NPs (50–1000 nm) and evaluated cellular uptake, viability, gene expression, and cell migration. Confocal imaging revealed an efficient internalization of PS-NPs across all cell types, indicating that differences in downstream responses are not caused by uptake efficiency. Cancer cells in the lungs showed increased sensitivity to PS-NPs-induced cytotoxicity, accompanied by significant downregulation of the antioxidant enzyme superoxide dismutase 1, implicating redox imbalance as a possible mechanism of toxicity. However, the cells in the normal lung exhibited no significant change in viability but displayed increased cell migration following exposure to PS-NPs. Collectively, our findings highlight the distinct and cell-type-specific effects of PS-NPs on lung cells, suggesting that inhaled nanoplastics may contribute to pulmonary dysfunction and malignancy through multiple mechanisms, including oxidative stress and altered cell migration.

微塑料和纳米塑料广泛存在于室内和环境空气中，是新兴的可吸入污染物，可在呼吸道中积累。与它们在人体内积累有关的潜在健康风险日益得到认识。聚苯乙烯纳米塑料（PS-NPs）的毒性研究；然而，正常和癌变肺细胞之间的不同反应仍然知之甚少。在这项研究中，我们将正常（IMR90, BEAS-2B）和癌（A549, HCC1833, NCI-H727, NCI-H1755）人肺细胞系暴露于不同大小的PS-NPs （50-1000nm）中，并评估了细胞摄取，活力，基因表达和细胞迁移。共聚焦成像揭示了PS-NPs在所有细胞类型中的有效内化，表明下游反应的差异不是由摄取效率引起的。肺部癌细胞对ps - nps诱导的细胞毒性表现出更高的敏感性，并伴有抗氧化酶超氧化物 歧化酶 1的显著下调，暗示氧化还原失衡可能是毒性的机制。然而，暴露于PS-NPs后，正常肺细胞的活力没有明显变化，但细胞迁移增加。总之，我们的研究结果强调了PS-NPs对肺细胞的独特和细胞类型特异性作用，表明吸入纳米塑料可能通过多种机制导致肺功能障碍和恶性肿瘤，包括氧化应激和细胞迁移改变。

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引用次数: 0

The effects of direct addition of lead(ii) acetate to a human in vitro model of hematopoiesis recapitulates exposure to lead in utero 直接将醋酸铅（ii）添加到人类体外造血模型的影响概括了子宫内铅的暴露。

IF 4.6 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-10-30 DOI: 10.1016/j.tox.2025.154323

Joseph W. Zagorski , Kyleigh N. Cross , Austin Goodyke , Emily Siegwald , Marcos Cordoba Munoz , Norbert E. Kaminski

Metal and heavy metal exposure during pregnancy and early immune system development is a known environmental health concern in the United States and worldwide. Michigan’s aging infrastructure has led to disparities in heath equity regarding exposure to lead. Flint, Michigan drew national attention for dangerous lead levels in the community’s water sources. However, a 2016 report from the Michigan Department of Health and Human Services confirmed that no Michigan county has more lead-poisoned children than Kent County (Grand Rapids, MI), with a disproportionate number of lead-poisoned youth. Lead exposure during pregnancy has been associated with adverse obstetrical outcomes. Additionally, lead is a known immunotoxicant that easily crosses the placental barrier, and yet little is known about the effects of lead on the human developing immune system. Additionally, international regulatory agencies are moving to adopt new approach methodologies (NAM) for chemical safety assessments and regulatory decision-making. The purpose of the present study was to utilize a previously published NAM, which has been shown to develop cells from the myeloid and lymphoid immune lineages, to determine the effects of lead on human immune development, while confirming these findings with ex vivo human umbilical cord PBMCs exposed to lead in utero. Our results demonstrate that the in vitro approach recapitulates human exposure data and previously published rodent models.

在美国和世界范围内，怀孕和早期免疫系统发育期间的金属和重金属暴露是一个众所周知的环境健康问题。密歇根州老化的基础设施导致铅暴露方面的健康公平存在差异。密歇根州弗林特市因社区水源含铅量超标而引起全国关注。然而，密歇根州卫生与公共服务部2016年的一份报告证实，密歇根州肯特县（密歇根州大急流城）的铅中毒儿童人数最多，其中铅中毒青少年人数不成比例。妊娠期铅暴露与不良的产科结局有关。此外，铅是一种已知的免疫毒物，很容易穿过胎盘屏障，但对铅对人类发育中的免疫系统的影响知之甚少。此外，国际监管机构正在采取新的方法（NAM）进行化学品安全评估和监管决策。本研究的目的是利用先前发表的一项研究，确定铅对人类免疫发育的影响，同时用在子宫内暴露于铅的离体人脐带PBMCs证实这些发现，该研究已被证明可以从髓系和淋巴系免疫谱系中发育细胞。我们的结果表明，体外方法概括了人类暴露数据和先前发表的啮齿动物模型。

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引用次数: 0