Toxicology最新文献_第2页

Gender difference and BMDL exploration of developmental immunotoxicity induced by early-life low-dose exposure to 4-nonylphenol in Wistar rats

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-15 DOI: 10.1016/j.tox.2025.154085

Jiuming Yan , Xiaoya Wang , Jinghua Xie , Liang Wang , Qijie Wei , Zhenchao Jia , Jinyao Chen

Background

Nonylphenol (NP) is a widespread environmental endocrine disruptor with potential developmental immunotoxicity. The present study aimed to investigate the gender-specific developmental immunotoxic effects of early-life exposure to low doses of 4-nonylphenol (4-NP) on Wistar rats and the corresponding thresholds.

Methods

Pregnant rats (F0 generation) were exposed to low doses of 4-NP from gestational day 6 (GD6) to postnatal day 90 (PND90), and F1 offspring continued to be exposed until the maturation of the immune system on PND42. We assessed immune organ development, immune responses, lymphocyte subset composition, cytokine secretion, and the Th17/Treg cell balance as endpoints for developmental immunotoxicity. Benchmark Dose analysis was conducted to explore the thresholds.

Results

Early-life exposure to 4-NP led to significant gender-specific differences in the immune response. Female pups exhibited greater sensitivity to 4-NP, with reduced thymus and spleen weights, suppressed humoral immune function, decreased natural killer (NK) cell activity, and an imbalance in the Th17/Treg cell ratio. Male pups showed inhibition of NK cell activity but no significant changes in humoral immune function. Levels of phosphorylated STAT3, STAT5, and JAK3 proteins increased in the spleens of exposed pups of both gender. The lowest benchmark dose lower limit (BMDL) value of developmental immunotoxicity was lower in female rats (based on the thymus weight) than in male rats (based on the NK cell activity).

Conclusion

Early-life exposure to 4-NP has been shown to induce gender-specific developmental immunotoxicity in rats, with female pups exhibiting greater sensitivity. And developmental immunotoxicity may serve as a more sensitive indicator for the risk assessment of 4-NP. Th17/Treg balance may be interrupted through JNK/STAT pathway by 4-NP exposure, which needs to be further investigated.

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引用次数: 0

A network toxicology and molecular docking-based approach revealed shared hepatotoxic mechanisms and targets between the herbicide 2,4-D and its metabolite 2,4-DCP

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-13 DOI: 10.1016/j.tox.2025.154086

Rafael Xavier Martins , Cleyton Gomes , Matheus Carvalho , Juliana Alves da Costa Ribeiro Souza , Terezinha Souza , Davi Farias

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and its major environmental metabolite 2,4-dichlorophenol (2,4-DCP) are pollutants associated with hepatotoxicity, whose molecular mechanisms remain poorly understood. This study investigated the molecular pathways and targets involved in 2,4-D and 2,4-DCP-induced hepatotoxicity using protein-protein interaction (PPI) network analyses and molecular docking. Target genes were identified using PharmMapper and SwissTargetPrediction, and cross-referenced with hepatotoxicity-related genes from GeneCards and OMIM databases. The PPI network, constructed via STRING and visualized in Cytoscape, revealed 12 critical hub nodes, including HSP90AA1, RXRA, EGFR, SRC, CREBBP, PIK3R1, ESR1, AKT1, RAF1, IGF1R, MDM2, and MAPK14. Gene Ontology (GO) analysis indicated processes such as apoptosis, oxidative stress, mitochondrial dysfunction, and lipid metabolism impairment, while Reactome pathway analysis highlighted disruptions in PI3K/AKT and nuclear receptors signaling. Molecular docking confirmed significant interactions of 2,4-D and 2,4-DCP with key proteins, including SRC, AKT, RXRA, MDM2, and HSP90AA1. These results suggest that 2,4-D and 2,4-DCP share similar toxic mechanisms, providing new insights into their hepatotoxicity pathways for the first time.

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引用次数: 0

Hippocampal MEF2C phosphorylation mediates synaptic plasticity in lead-induced learning and memory impairments

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-11 DOI: 10.1016/j.tox.2025.154082

Shuo Yang , Yanhui Zhu , Jinmei Xiao , Lingyu Yan , Xuebing Zhuang , Qi Li , Yue Li , Jie Xie , Guihua Du , Fankun Zhou , Guangqin Fan , Chang Feng

Lead (Pb), an ancient metallic environmental pollutant, has received widespread attention and has been strictly controlled, but current findings have found the hazards of Pb to be much higher than previously estimated. Pb exposure can lead to memory impairment. However, the underlying molecular mechanisms have not been fully elucidated. Dynamic changes in dendritic spines form the structural basis of memory, and MEF2C, a key regulator of dendritic plasticity, plays an important role in hippocampus-dependent learning and memory. This study focused on the role of ERK-induced MEF2C phosphorylation in Pb-induced learning and memory impairments. A rat model of Pb exposure from the embryo to adolescence and the model of Pb exposure in PC12 cells were established. The results showed that Pb exposure reduced the phosphorylation level of MEF2C in the rat hippocampus by affecting the expression of ERK5. In addition, it reduced the expression of MEF2C at the translation stage, which affected its transcriptional ability and led to abnormal expression of the downstream factor ARC, causing alterations in neuronal dendritic plasticity and affecting its memory ability. Further experiments showed that regulating the phosphorylation level of MEF2C could affect neurite growth in PC12 cells exposed to Pb. Our findings demonstrate that Pb exposure may contribute to memory impairment by affecting MEF2C and its phosphorylation levels, resulting in altered dendritic plasticity.

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引用次数: 0

Mitochondrial activity and steroid secretion in mouse ovarian granulosa cells are suppressed by a PFAS mixture

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-09 DOI: 10.1016/j.tox.2025.154083

Aleksandra Tatarczuch , Justyna Gogola-Mruk , Katarzyna Kotarska , Zbigniew Polański , Anna Ptak

The accumulation of a number of per- and polyfluoroalkyl substances (PFASs) in ovarian follicular fluid (FF) has been documented, raising serious questions about their impact on female fertility. Here, we tested the hypothesis that a mixture of PFASs acts in a paracrine manner on granulosa cells (GCs) as a metabolism-disrupting chemical. We selected perfluorooctane sulfonate (PFOS; 22.4 ng/mL), perfluorooctanoic acid (PFOA; 14.5 ng/mL), perfluorohexane sulfonate (PFHxS; 21.3 ng/mL), perfluorodecanoic acid (PFDA; 0.9 ng/mL), perfluoroheptane sulphonate (PFHpA; 0.6 ng/mL), perfluoroundecanoic acid (PFUnDA; 0.4 ng/mL), and perfluorononanoic acid (PFNA; 2 ng/mL), which were the most commonly detected PFASs in FF of women undergoing assisted reproductive technology treatment. Exposure of mouse GCs to the PFAS mixture decreased the amount of active mitochondria and the mitochondrial membrane potential, which correlated with a reduction in ATP production and inhibition of oxidative phosphorylation (OXPHOS). At the same time, expression of the mitochondrial membrane-associated steroidogenic enzyme 3-beta-hydroxysteroid dehydrogenase (3βHSD) and production of the major steroids progesterone and estradiol were decreased. In addition, expression and activity of superoxide dismutase 1 (SOD1), an enzyme that neutralizes reactive oxygen species (ROS), were decreased while ROS levels and lipid peroxidation were increased without cell death, indicating that the PFAS mixture had subtoxic effects. Our results show that PFAS mixtures, at concentrations similar to those found in human FF led to GC dysfunction by impairing mitochondrial function and steroid secretions and therefore may have implications for reproductive health.

{"title":"Mitochondrial activity and steroid secretion in mouse ovarian granulosa cells are suppressed by a PFAS mixture","authors":"Aleksandra Tatarczuch , Justyna Gogola-Mruk , Katarzyna Kotarska , Zbigniew Polański , Anna Ptak","doi":"10.1016/j.tox.2025.154083","DOIUrl":"10.1016/j.tox.2025.154083","url":null,"abstract":"<div><div>The accumulation of a number of per- and polyfluoroalkyl substances (PFASs) in ovarian follicular fluid (FF) has been documented, raising serious questions about their impact on female fertility. Here, we tested the hypothesis that a mixture of PFASs acts in a paracrine manner on granulosa cells (GCs) as a metabolism-disrupting chemical. We selected perfluorooctane sulfonate (PFOS; 22.4 ng/mL), perfluorooctanoic acid (PFOA; 14.5 ng/mL), perfluorohexane sulfonate (PFHxS; 21.3 ng/mL), perfluorodecanoic acid (PFDA; 0.9 ng/mL), perfluoroheptane sulphonate (PFHpA; 0.6 ng/mL), perfluoroundecanoic acid (PFUnDA; 0.4 ng/mL), and perfluorononanoic acid (PFNA; 2 ng/mL), which were the most commonly detected PFASs in FF of women undergoing assisted reproductive technology treatment. Exposure of mouse GCs to the PFAS mixture decreased the amount of active mitochondria and the mitochondrial membrane potential, which correlated with a reduction in ATP production and inhibition of oxidative phosphorylation (OXPHOS). At the same time, expression of the mitochondrial membrane-associated steroidogenic enzyme 3-beta-hydroxysteroid dehydrogenase (3βHSD) and production of the major steroids progesterone and estradiol were decreased. In addition, expression and activity of superoxide dismutase 1 (SOD1), an enzyme that neutralizes reactive oxygen species (ROS), were decreased while ROS levels and lipid peroxidation were increased without cell death, indicating that the PFAS mixture had subtoxic effects. Our results show that PFAS mixtures, at concentrations similar to those found in human FF led to GC dysfunction by impairing mitochondrial function and steroid secretions and therefore may have implications for reproductive health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"512 ","pages":"Article 154083"},"PeriodicalIF":4.8,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hepatic and extra-hepatic metabolism of propylene glycol ethers in the context of central nervous system toxicity

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-08 DOI: 10.1016/j.tox.2025.154081

Sophie Werner , David Pamies , Marie-Gabrielle Zurich , Laura Suter-Dick

Propylene glycol ethers (PGEs) are mixtures of an α-isomer and a β-isomer (β-PGE) that is oxidized via alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) to potentially neurotoxic alkoxy propionic acids (β-metabolites). While the liver is the primary organ for ADH- and ALDH-mediated metabolism, the contribution to the metabolism of β-PGEs by the blood-brain barrier (BBB) and the brain remains unknown. Here, we aimed to assess the neurotoxic potential of PGEs after systemic exposure by (1) comparing 3D HepaRG and human liver subcellular fraction (S9) for the in vitro determination of the kinetics of hepatic metabolism for β-PGEs, (2) evaluating the BBB-permeability of PGEs and β-metabolites, (3) determining the presence of ADH1 and ALDH2 and the extent of metabolization of β-PGEs in the BBB and brain. The results show that 3D HepaRG and S9 served as competent systems to estimate the enzymatic kinetic (clearance) for β-metabolite formation. We observed that PGEs and the β-metabolites could cross the BBB, based on their permeance across a cellular barrier consisting of the hCMEC/D3 cell line. Metabolic enzymes were not exclusive to the liver, as expression of ADH1 and ALDH2 was demonstrated using RT-qPCR, Western blot, and immunostainings in the BBB in vitro models and in BrainSpheres. Furthermore, LC-MS/MS quantification of the β-metabolites in all in vitro models revealed that 3D HepaRG had a similar metabolic capacity to primary human hepatocytes and that the amount of β-metabolite formed per protein in the BBB was approximately 10–30 % of that in the liver. We also demonstrated active metabolism in the BrainSpheres. In conclusion, the hepatic in vitro models provided data that will help to refine toxicokinetic models and predict internal exposures, thereby supporting the risk assessment of PGEs. In addition, the high permeance of the PGEs and the β-metabolites across the BBB increases the plausibility of neurotoxicity upon systemic exposure. This is further supported by the presence of active ADH1 and ALDH2 enzymes in the BBB in vitro systems and in BrainSpheres, suggesting metabolite formation in the central nervous system. Hence, we suggest that BBB-permeance and extra-hepatic metabolism of the β-PGEs may contribute to the neurotoxicity of PGEs.

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引用次数: 0

Benzyl butyl phthalate promotes ferroptosis in Sertoli cells via disrupting ceruloplasmin-mediated iron balance

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-05 DOI: 10.1016/j.tox.2025.154078

Yu Dong, Shuge Shu, Xiangyu Yu, Xinting Chen, Qiong Li, Xiaobing Shen, Yongquan Yu

Widespread environmental contamination with benzyl butyl phthalate (BBP) has raised concerns due to its high potential for bioaccumulation and male reproductive toxicity. However, the mechanisms underlying BBP-induced male reproductive damage remain unclear. As the adjacent Sertoli cell-formed blood-testis barrier (BTB) creates a privileged niche for spermatogenesis and may serve as the first target of reproductive toxicants, we mainly focused on the detrimental effect of BBP on Sertoli cells and the BTB in this study. C57BL/6 mice were administered BBP via oral gavage at doses ranging from 0 to 400 mg/kg/day for 60 consecutive days. A comprehensive investigation was performed to estimate testicular BBP levels, sperm parameters, histological alterations, functional permeability of the Sertoli cell–based BTB, and ferroptosis in mice. Isolated Sertoli cells were further used to explore and validate the role of ferroptosis in BBP-induced BTB disruption. The results showed that permeation of BBP into the testis induced reduction in sperm quantity and quality, accompanied by fractured BTB ultrastructure, compromised permeable ‘fence’ functions of BTB, decreased expressions of tight junction proteins (TJP1 and OCLN) and paracellular transepithelial electrical resistance (TER) of Sertoli cells. Moreover, BBP exposure significantly increased intracellular iron content, promoted lipid peroxidation, and activated ferroptosis in the testis of mice and primary Sertoli cells, which was involved in BBP-induced disruption of BTB integrity and function as confirmed by the ferroptosis inhibitors. In mechanism, BBP specifically downregulated the intracellular iron exporter ceruloplasmin (CP) level to inhibit Fe²⁺ export and the oxidization of Fe²⁺ into less toxic Fe³⁺, thus exacerbating ferroptosis in Sertoli cells. Overexpression of CP significantly suppressed ferroptosis and alleviated BBP-induced BTB disruption. These findings reveal the role of CP-mediated iron homeostasis in regulating Sertoli cell ferroptosis and BTB function, providing new insights into the mechanisms of BBP-related reproductive toxicity.

{"title":"Benzyl butyl phthalate promotes ferroptosis in Sertoli cells via disrupting ceruloplasmin-mediated iron balance","authors":"Yu Dong, Shuge Shu, Xiangyu Yu, Xinting Chen, Qiong Li, Xiaobing Shen, Yongquan Yu","doi":"10.1016/j.tox.2025.154078","DOIUrl":"10.1016/j.tox.2025.154078","url":null,"abstract":"<div><div>Widespread environmental contamination with benzyl butyl phthalate (BBP) has raised concerns due to its high potential for bioaccumulation and male reproductive toxicity. However, the mechanisms underlying BBP-induced male reproductive damage remain unclear. As the adjacent Sertoli cell-formed blood-testis barrier (BTB) creates a privileged niche for spermatogenesis and may serve as the first target of reproductive toxicants, we mainly focused on the detrimental effect of BBP on Sertoli cells and the BTB in this study. C57BL/6 mice were administered BBP via oral gavage at doses ranging from 0 to 400 mg/kg/day for 60 consecutive days. A comprehensive investigation was performed to estimate testicular BBP levels, sperm parameters, histological alterations, functional permeability of the Sertoli cell–based BTB, and ferroptosis in mice. Isolated Sertoli cells were further used to explore and validate the role of ferroptosis in BBP-induced BTB disruption. The results showed that permeation of BBP into the testis induced reduction in sperm quantity and quality, accompanied by fractured BTB ultrastructure, compromised permeable ‘fence’ functions of BTB, decreased expressions of tight junction proteins (TJP1 and OCLN) and paracellular transepithelial electrical resistance (TER) of Sertoli cells. Moreover, BBP exposure significantly increased intracellular iron content, promoted lipid peroxidation, and activated ferroptosis in the testis of mice and primary Sertoli cells, which was involved in BBP-induced disruption of BTB integrity and function as confirmed by the ferroptosis inhibitors. In mechanism, BBP specifically downregulated the intracellular iron exporter ceruloplasmin (CP) level to inhibit Fe<sup>2+</sup> export and the oxidization of Fe<sup>2+</sup> into less toxic Fe<sup>3+</sup>, thus exacerbating ferroptosis in Sertoli cells. Overexpression of CP significantly suppressed ferroptosis and alleviated BBP-induced BTB disruption. These findings reveal the role of CP-mediated iron homeostasis in regulating Sertoli cell ferroptosis and BTB function, providing new insights into the mechanisms of BBP-related reproductive toxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"512 ","pages":"Article 154078"},"PeriodicalIF":4.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349601","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

Impact of pesticide exposure on auditory health: Mechanisms, efferent system disruption, and public health implications

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-05 DOI: 10.1016/j.tox.2025.154071

Gonzalo Terreros , Claudio Cifuentes-Cabello , Amanda D’Espessailles , Felipe Munoz

Pesticide exposure has been linked to adverse effects on auditory health, impacting both peripheral and central auditory systems. Studies suggest that organophosphate, carbamate, organochlorine, and pyrethroid pesticides disrupt auditory processing through oxidative stress, neuroinflammation, and interference with cholinergic signaling. These disruptions may compromise sensory hair cells, spiral ganglion neurons, and auditory pathways, impairing precise signal transmission. The auditory efferent system, responsible for cochlear protection and auditory signal modulation, appears particularly susceptible to pesticide-induced alterations. This system relies on cholinergic transmission to regulate cochlear amplification and selective attention, functions that may be disrupted by pesticide exposure. Evidence from epidemiological and experimental studies highlights the potential for long-term auditory dysfunction in populations exposed to pesticides, with agricultural workers and their families facing elevated risks due to prolonged contact with agrochemicals. This review integrates findings on pesticide exposure and its implications for auditory health, discussing potential peripheral and central ototoxicity pathways. The cumulative effects of chronic exposure are emphasized, including the gradual degradation of auditory processing capabilities. Additionally, the need for targeted interventions, such as audiological monitoring and enhanced safety protocols, is addressed. Further research is critical to elucidate the mechanisms underlying pesticide-induced auditory damage and identify protective strategies. Such investigations can inform evidence-based policies to mitigate the public health impact of pesticide exposure while maintaining agricultural productivity. A multidisciplinary approach is essential to safeguard auditory health in vulnerable populations exposed to these environmental hazards.

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引用次数: 0

Airway exposure to lithium nickel manganese cobalt oxide particles induces alterations in lung microenvironment and potential kidney and liver damage in mice 气道暴露于锂镍锰钴氧化物颗粒可引起小鼠肺微环境的改变和潜在的肾和肝损伤。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2024.154036

Junyi Wang , Xin Fang , Ruirui Wu , Ziyu Liu , Gang Wang , Yuxin Hu , Huihui Wang , Jingbo Pi , Yuanyuan Xu

With the increasing use of lithium-ion batteries, the exposure and health effects of lithium nickel manganate cobalt (NMC), a popular cathode material for the battery, have attracted widespread attention. However, the main absorption routes and target organs of NMC are unknown. This study aims to systematically investigate the main absorption routes and target organs of NMC. Male adult C57BL/6 J mice were subjected to acute exposure to NMC particles (Ni: Mn: Co = 5: 3: 2, mass median geometric diameter 9.15 μm) by intragastric administration, transdermal drug delivery, and oropharyngeal aspiration (OPA). The OPA group showed a significant increase in NMC metal levels in organs and blood compared to the other exposure routes. After OPA treatment (0.5 or 2 mg, once per day, 3 days), significantly increased metal levels were found in the lung, liver and kidney, but there was no dose-response effect. In the lung, obvious inflammation, and significant elevation of white blood cells, neutrophils and eosinophils in bronchoalveolar lavage fluid were observed, all of which showed a dose-response effect. Reduced urine output and renal tubular cell loss, as well as dysregulated metabolic and immune functions as indicated by the hepatic transcriptome, were observed in NMC-exposed mice. Respiratory exposure is the main exposure route of NMC. Short-term respiratory exposure to NMC results in potential damage to the kidney and liver in addition to severe inflammation in the lung.

随着锂离子电池使用的不断增加，锂镍锰酸钴（NMC）作为一种流行的电池正极材料，其暴露及其对健康的影响引起了广泛关注。然而，NMC的主要吸收途径和靶器官尚不清楚。本研究旨在系统探讨NMC的主要吸收途径和靶器官。以成年雄性C57BL/6J小鼠为研究对象，通过灌胃、经皮给药和口咽吸三种方式急性暴露于NMC颗粒（Ni: Co: Mn = 5:3:2，质量中位几何直径9.15 μm）。与其他暴露途径相比，OPA组器官和血液中的NMC金属水平显着增加。OPA治疗后（0.5或2mg，每天1次，3 d）肺、肝、肾中金属含量明显升高，但无剂量效应。肺内可见明显炎症反应，支气管肺泡灌洗液白细胞、中性粒细胞、嗜酸性粒细胞明显升高，呈剂量反应效应。在nmc暴露的小鼠中观察到尿量减少和肾小管细胞损失，以及肝脏转录组所显示的代谢和免疫功能失调。呼吸道暴露是NMC的主要暴露途径。短期呼吸接触NMC会导致肾脏和肝脏的潜在损害，以及肺部的严重炎症。

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引用次数: 0

C-C motif chemokine ligand 5 contributes to radon exposure-induced lung injury by recruiting dendritic cells to activate effector T helper cells C-C基序趋化因子配体5通过招募树突状细胞激活效应T辅助细胞参与氡暴露诱导的肺损伤。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2024.154044

Liping Ma , Yilong Wang , Junwang Guo , Xuewen Zhang , Shuang Xing , Benbo Liu , Guo Chen , Xu Wang , Jiyao Hu , Ge Li , Gencheng Han , Maoxiang Zhu

Radon (²²²Rn) is a naturally occurring radioactive gas, ionizing radiation emitted by the radon induces oxidative stress and the up-regulation of inflammatory proteins, which may cause lung damage or cancer. However, the underlying pathogenesis remains to be determined. Effector T helper cells are key in mediating the host’s protection and immune homeostasis. In this study we revealed that, accompanied by the activation of effector T helper cells, there is a significant increase in C-C motif chemokine ligand 5 (Ccl5) in the lung of mice after cumulative inhalation of radon at 3, 9, 21, 45, 90, and 180 working level months (WLM). In vitro experiments showed that Ccl5 attracts DC migration and promotes the activation of effector T helper cells in the Ccl5-DC and T cells co-culture model. Of particular interest, Ccl5 neutralization in vivo inhibited the migration of DC cells and the subsequent activation of effector T helper cells, which finally protected mice from radon-induced lung damage and inflammatory response. Ultimately, transcriptome sequencing and western blot analysis showed that Ccl5 activates the CCR5/PI3K/AKT/Nr4a1 pathway to increase the secretion of IL-12 and IFN-γ by DC cells, which then promotes the activation of effector T helper cells. Overall, these results indicate that Ccl5 significantly contributes to the progression of radon-induced lung damage by modulating DC to activate effector T helper cells.

氡（222Rn）是一种天然存在的放射性气体，氡释放的电离辐射可诱导氧化应激和炎症蛋白上调，从而可能导致肺损伤或癌症。然而，潜在的发病机制仍有待确定。效应T辅助细胞是介导宿主保护和免疫稳态的关键。在这项研究中，我们发现，在累积吸入氡3、9、21、45、90和180个工作水平月（WLM）后，伴随着效应T辅助细胞的激活，小鼠肺中C-C基序趋化因子配体5 （Ccl5）显著增加。体外实验表明，在Ccl5-DC和T细胞共培养模型中，Ccl5吸引DC迁移，促进效应T辅助细胞的激活。特别有趣的是，体内Ccl5中和抑制DC细胞的迁移和随后的效应T辅助细胞的激活，最终保护小鼠免受氡诱导的肺损伤和炎症反应。最终，转录组测序和western blot分析显示，Ccl5激活CCR5/PI3K/AKT/Nr4a1通路，增加DC细胞分泌IL-12和IFN-γ，进而促进T辅助效应细胞的激活。总体而言，这些结果表明Ccl5通过调节DC激活效应T辅助细胞，显著促进氡诱导肺损伤的进展。

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引用次数: 0

Non-dioxin-like polychlorinated biphenyls (PCB 101, 153, and 180) and adipocyte lipid dysfunctions: Involvement of glycerol and role of aquaglyceroporins in mature 3T3-L1 cells 非二恶英样多氯联苯（PCB 101、153和180）和脂肪细胞脂质功能障碍：成熟3T3-L1细胞中甘油的参与和水甘油孔蛋白的作用

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology

Pub Date : 2025-02-01 DOI: 10.1016/j.tox.2025.154050

F. Del Piano , A. Monnolo , A. Lama , C. Pirozzi , F. Comella , S. Melini , C. Naccari , A. Pelagalli , R. Meli , M.C. Ferrante

Non-dioxin-like polychlorinated biphenyls (NDL-PCBs), as well as dioxin-like PCBs, are endocrine disruptors that persist in human and animal tissues worldwide. Due to their lipophilicity and resistance to enzymatic degradation, PCBs accumulate in fat deposits contributing to the onset of endocrine and metabolic diseases. Aquaporins (AQPs) are transmembrane channel proteins that allow the transport of water and small solutes. In particular, the aquaglyceroporins AQP3, AQP7, and AQP9 mediate the release and the uptake of glycerol in adipose tissue. Here, we investigate the modulation of these AQPs by NDL-PCBs and the following effects on lipid metabolism in mature 3T3-L1 adipocytes exposed for 48 h to PCB 101, 153, or 180 (1 μM). NDL-PCBs modulated protein expression of AQP3 and AQP7, involved in glycerol release, and AQP9, implicated in glycerol uptake. This modulation induced a greater accumulation of glycerol in treated adipocytes indirectly evaluated by its reduction in the culture media. Interestingly, only PCB 153 altered the expression of enzymes involved in glycerol metabolism and lipid accumulation (i.e. Pparg, Fabp4, Gyk, Dgat1, and Agpat9). These modifications indicated an increase of adipocyte lipid accumulation confirmed by Oil Red O staining. The role of AQPs in the increased cellular accumulation of glycerol was confirmed using phloretin, an AQP9 inhibitor, that reverted the PCB 153 effect. Our results show the involvement of AQPs in PCB 153-induced dysfunction of glycerol metabolism and lipid storage in adipocytes, contributing to better defining the mechanisms underlying its known obesogenic effect.

非二恶英样多氯联苯（NDL-PCBs）以及二恶英样多氯联苯是存在于世界各地人类和动物组织中的内分泌干扰物。由于多氯联苯的亲脂性和抗酶降解性，多氯联苯在脂肪沉积物中积累，导致内分泌和代谢疾病的发生。水通道蛋白（AQPs）是一种跨膜通道蛋白，允许水和小溶质的运输。特别是，AQP3、AQP7和AQP9介导脂肪组织中甘油的释放和摄取。在这里，我们研究了ndl -多氯联苯对这些AQPs的调节以及暴露于PCB 101、153或180 （1μM）下48小时成熟3T3-L1脂肪细胞脂质代谢的后续影响。ndl -多氯联苯调节了参与甘油释放的AQP3和AQP7以及参与甘油摄取的AQP9的蛋白表达。这种调节诱导了甘油在处理过的脂肪细胞中更大的积累，通过其在培养基中的减少间接评估。有趣的是，只有PCB 153改变了参与甘油代谢和脂质积累的酶的表达（即Pparg， Fabp4, Gyk， Dgat1和Agpat9）。这些修饰表明脂肪细胞脂质积累增加，油红O染色证实。利用一种AQP9抑制剂根皮素证实了AQPs在增加甘油细胞积累中的作用，这种抑制剂可以逆转PCB 153的作用。我们的研究结果表明，AQPs参与了PCB 153诱导的甘油代谢和脂肪细胞脂质储存功能障碍，有助于更好地定义其已知致肥作用的机制。

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引用次数: 0