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Fullerene and fullerene whisker are not carcinogenic to the lungs and pleura in rat long-term study after 2-week intra-tracheal intrapulmonary administration 大鼠气管内肺部给药 2 周后的长期研究表明,富勒烯和富勒烯晶须不会对肺部和胸膜产生致癌作用
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-13 DOI: 10.1007/s00204-024-03863-7
Asraful Nahar Sheema, Aya Naiki-Ito, Anna Kakehashi, Omnia Hosny Mohamed Ahmed, David B. Alexander, William T. Alexander, Takamasa Numano, Hiroyuki Kato, Yuko Goto, Hiroshi Takase, Akihiko Hirose, Takatsugu Wakahara, Kun’ichi Miyazawa, Satoru Takahashi, Hiroyuki Tsuda

Fullerene whiskers (FLW)s are thin rod-like structures composed of C60 and C70 fullerene (FL). The shape of FLWs suggests potential toxic effects including carcinogenicity to the lung and pleura, similar to effects elicited by asbestos and multi-walled carbon nanotubes (MWCNT)s. However, no long-term carcinogenic studies of FL or FLW have been conducted. In the present study we investigated the pulmonary and pleural carcinogenicity of FL and FLW. Twelve-week-old male F344 rats were administered 0.25 or 0.5 mg FL, FLW, MWCNT-7, and MWCNT-N by intra-tracheal intra-pulmonary spraying (TIPS). Acute lung lesions and carcinogenicity were analyzed at 1 and 104 weeks after 8 doses/15 days TIPS administration. At week 1, FLW, MWCNT-7, and MWCNT-N significantly increased alveolar macrophage infiltration. Expression of Ccl2 and Ccl3, reactive oxygen species production, and cell proliferation were significantly increased by administration of MWCNT-7 and MWCNT-N but not FL or FLW. At week 104, the incidence of bronchiolo-alveolar adenoma plus adenocarcinoma was significantly increased in the MWCNT-7 and MWCNT-N groups, and the incidence of mesothelioma was significantly increased in the MWCNT-7 group. No significant induction of pulmonary or pleural tumorigenesis was observed in the FL or FLW groups. The number of 8-OHdG-positive cells in the alveolar epithelium was significantly increased in the MWCNT-7 and MWCNT-N groups but not in the FL or FLW groups. FL and FLW did not exert pulmonary or pleural carcinogenicity in our study. In addition, oxidative DNA damage was implicated in MWCNT-induced lung carcinogenesis, suggesting that it may be a useful initial marker of carcinogenicity.

富勒烯晶须(FLW)是由 C60 和 C70 富勒烯(FL)组成的细棒状结构。富勒烯晶须的形状表明其具有潜在的毒性作用,包括对肺部和胸膜的致癌性,类似于石棉和多壁碳纳米管(MWCNT)的致癌作用。然而,目前尚未对 FL 或 FLW 进行长期致癌研究。在本研究中,我们调查了 FL 和 FLW 的肺部和胸膜致癌性。通过气管内肺内喷射(TIPS)给 12 周大的雄性 F344 大鼠注射 0.25 或 0.5 毫克 FL、FLW、MWCNT-7 和 MWCNT-N。在 8 次/15 天 TIPS 给药后的 1 周和 104 周,对急性肺部病变和致癌性进行了分析。在第 1 周,FLW、MWCNT-7 和 MWCNT-N 显著增加了肺泡巨噬细胞浸润。施用 MWCNT-7 和 MWCNT-N 能显著增加 Ccl2 和 Ccl3 的表达、活性氧的产生和细胞增殖,而 FL 或 FLW 则不能。在第 104 周,MWCNT-7 和 MWCNT-N 组的支气管肺泡腺瘤和腺癌发病率显著增加,MWCNT-7 组的间皮瘤发病率显著增加。FL 组和 FLW 组未观察到肺或胸膜肿瘤发生的明显诱导。肺泡上皮细胞中 8-OHdG 阳性细胞的数量在 MWCNT-7 组和 MWCNT-N 组中显著增加,而在 FL 组或 FLW 组中没有增加。在我们的研究中,FL 和 FLW 不具有肺或胸膜致癌性。此外,氧化 DNA 损伤与 MWCNT 诱导的肺癌发生有关,这表明它可能是致癌的一个有用的初始标记。
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引用次数: 0
The phytochemical plumbagin: mechanism behind its “pleiotropic” nature and potential as an anticancer treatment 植物化学物质 plumbagin:其 "多效性 "背后的机制及其作为抗癌疗法的潜力
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-13 DOI: 10.1007/s00204-024-03861-9
Shikshya Swarupa Panda, Bijesh Kumar Biswal

Chemotherapeutics are most often used to treat cancer, but side effects, drug resistance, and toxicity often compromise their effectiveness. In contrast, phytocompound plumbagin possesses a distinct pleiotropic nature, targeting multiple signaling pathways, such as ROS generation, cell death, cellular proliferation, metastasis, and drug resistance, and is shown to enhance the efficacy of chemotherapeutic drugs. Plumbagin has been shown to act synergistically with various chemotherapeutic drugs and enhance their efficacy in drug-resistant cancers. The pleiotropic nature is believed to be due to plumbagin's unique structure, which contains a naphthoquinone ring and a hydroxyl group responsible for plumbagin's various biological responses. Despite limitations such as restricted bioavailability and delivery, recent developments aim to address these challenges and harness the potential of plumbagin as an anticancer therapeutics. This review delves into the structural aspect of the plumbagin molecule contributing to its pleiotropic nature, explores the diverse mechanism that it targets, and discusses emerging strategies to overcome its limitations.

化疗药物最常用于治疗癌症,但副作用、耐药性和毒性往往会影响其疗效。相比之下,植物化合物 Plumbagin 具有明显的多效性,可针对多种信号通路,如 ROS 生成、细胞死亡、细胞增殖、转移和耐药性,并能增强化疗药物的疗效。研究表明,Plumbagin 能与各种化疗药物协同作用,增强它们对耐药性癌症的疗效。这种多效性被认为是由于 Plumbagin 的独特结构造成的,该结构包含一个萘醌环和一个羟基,羟基负责 Plumbagin 的各种生物反应。尽管存在生物利用度和给药方式受限等局限性,但最近的研究进展旨在应对这些挑战,并利用刺五加苷作为抗癌疗法的潜力。本综述深入探讨了造成 plumbagin 多效应性质的 plumbagin 分子结构方面的问题,探讨了 plumbagin 针对的各种机制,并讨论了克服其局限性的新策略。
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引用次数: 0
MicroRNAs in fluorosis pathogenesis: impact on dental, skeletal, and soft tissues 氟中毒发病机制中的微小核糖核酸:对牙齿、骨骼和软组织的影响
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-13 DOI: 10.1007/s00204-024-03853-9
Suryaa Manoharan, Syed Saadullah Ashfaq, Ekambaram Perumal

Fluoride-induced toxicity (fluorosis) poses a significant health concern globally, affecting millions of individuals. Understanding the molecular mechanisms underlying fluorosis, particularly the role of microRNAs (miRNAs), is crucial for developing effective preventive and therapeutic strategies. This review explores the pivotal role of miRNAs in the pathogenesis of fluorosis, particularly examining its impact on both hard (skeletal and dental) and soft (brain, liver, kidney, heart, and reproductive organs) tissues. Skeletal fluorosis manifests as abnormal bone mineralization and structure, while dental fluorosis affects enamel formation. In vitro and in vivo studies suggest a significant involvement of miRNAs in the progression of these conditions. For skeletal fluorosis, miR-124, miR-155, and miR-200c-3p have been identified as key regulators, while miR-296-5p and miR-214-3p are implicated in dental fluorosis. Moreover, soft tissue fluorosis encompasses a spectrum of adverse effects on various organs, including the brain, liver, kidneys, heart, and reproductive system. In soft tissues, miRNAs, such as miR-124, miR-200c-3p, miR-132, and miR-34b-5p, have been linked to cellular damage and dysfunction. Notably, miRNAs exert their effects through the modulation of critical pathways involved in fluorosis pathology, including Wnt signaling, apoptosis, cell cycle, and autophagy. Understanding the regulatory roles of miRNAs in fluorosis pathogenesis holds promise for identifying biomarkers and therapeutic targets. However, further research is needed to elucidate the molecular mechanisms underlying miRNA-mediated responses to fluoride exposure. Integration of miRNA research into fluorosis studies could facilitate the development of diagnostic tools and therapeutic interventions, thus mitigating the detrimental effects of fluorosis on both hard and soft tissues.

氟化物引起的毒性(氟中毒)是全球关注的一个重大健康问题,影响着数百万人。了解氟中毒的分子机制,尤其是微小核糖核酸(miRNA)的作用,对于制定有效的预防和治疗策略至关重要。本综述探讨了 miRNAs 在氟中毒发病机制中的关键作用,特别是研究了它对硬组织(骨骼和牙齿)和软组织(脑、肝、肾、心脏和生殖器官)的影响。骨骼氟中毒表现为骨骼矿化和结构异常,而牙齿氟中毒则影响牙釉质的形成。体外和体内研究表明,miRNA 在这些病症的发展过程中起着重要作用。在骨骼氟中毒中,miR-124、miR-155 和 miR-200c-3p 被认为是关键的调节因子,而 miR-296-5p 和 miR-214-3p 则与氟斑牙有关。此外,软组织氟中毒包括对大脑、肝脏、肾脏、心脏和生殖系统等各种器官的一系列不良影响。在软组织中,miRNA(如 miR-124、miR-200c-3p、miR-132 和 miR-34b-5p)与细胞损伤和功能障碍有关。值得注意的是,miRNAs 是通过调节氟中毒病理过程中的关键通路(包括 Wnt 信号转导、细胞凋亡、细胞周期和自噬)来发挥其作用的。了解 miRNA 在氟中毒发病机制中的调控作用,有望确定生物标志物和治疗靶点。然而,要阐明 miRNA 介导的氟暴露反应的分子机制,还需要进一步的研究。将 miRNA 研究纳入氟中毒研究可促进诊断工具和治疗干预措施的开发,从而减轻氟中毒对软硬组织的有害影响。
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引用次数: 0
Towards characterization of cell culture conditions for reliable proteomic analysis: in vitro studies on A549, differentiated THP-1, and NR8383 cell lines 为可靠的蛋白质组分析确定细胞培养条件的特征:A549、分化的 THP-1 和 NR8383 细胞系的体外研究
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-12 DOI: 10.1007/s00204-024-03858-4
Rico Ledwith, Tobias Stobernack, Antje Bergert, Aileen Bahl, Mario Pink, Andrea Haase, Verónica I. Dumit

Proteomic investigations result in high dimensional datasets, but integration or comparison of different studies is hampered by high variances due to different experimental setups. In addition, cell culture conditions can have a huge impact on the outcome. This study systematically investigates the impact of experimental parameters on the proteomic profiles of commonly used cell lines—A549, differentiated THP-1 macrophage-like cells, and NR8383—for toxicity studies. The work focuses on analyzing the influence at the proteome level of cell culture setup involving different vessels, cell passage numbers, and post-differentiation harvesting time, aiming to improve the reliability of proteomic analyses for hazard assessment. Mass-spectrometry-based proteomics was utilized for accurate protein quantification by means of a label-free approach. Our results showed that significant proteome variations occur when cells are cultivated under different setups. Further analysis of these variations revealed their association to specific cellular pathways related to protein misfolding, oxidative stress, and proteasome activity. Conversely, the influence of cell passage numbers on the proteome is minor, suggesting a reliable range for conducting reproducible biological replicates. Notable, substantial proteome alterations occur over-time post-differentiation of dTHP-1 cells, particularly impacting pathways crucial for macrophage function. This finding is key for the interpretation of experimental results. These results highlight the need for standardized culture conditions in proteomic-based evaluations of treatment effects to ensure reliable results, a prerequisite for achieving regulatory acceptance of proteomics data.

蛋白质组学研究产生了高维数据集,但由于实验设置不同,差异很大,因此无法对不同研究进行整合或比较。此外,细胞培养条件也会对研究结果产生巨大影响。本研究系统地探讨了实验参数对常用细胞系--A549、分化的 THP-1 巨噬细胞样细胞和 NR8383--毒性研究蛋白质组谱的影响。这项工作的重点是分析不同容器、细胞通过数和分化后收获时间等细胞培养设置在蛋白质组水平上的影响,旨在提高用于危害评估的蛋白质组分析的可靠性。我们利用基于质谱仪的蛋白质组学,通过无标记方法对蛋白质进行了精确定量。我们的研究结果表明,在不同设置下培养细胞时,蛋白质组会发生显著变化。对这些变化的进一步分析表明,它们与蛋白质错误折叠、氧化应激和蛋白酶体活性相关的特定细胞通路有关。相反,细胞通过数对蛋白质组的影响很小,这表明进行可重复生物复制的范围是可靠的。值得注意的是,随着时间的推移,dTHP-1 细胞分化后的蛋白质组发生了重大改变,尤其是对巨噬细胞功能至关重要的通路产生了影响。这一发现是解释实验结果的关键。这些结果突出表明,在基于蛋白质组学的治疗效果评估中,需要标准化的培养条件,以确保结果的可靠性,这是蛋白质组学数据获得监管部门认可的前提条件。
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引用次数: 0
Methodological steps forward in toxicological in vitro screening of mineral wools in primary rat alveolar macrophages and normal rat mesothelial NRM2 cells 在原代大鼠肺泡巨噬细胞和正常大鼠间皮细胞 NRM2 中体外筛选矿棉毒理学的方法步骤
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-11 DOI: 10.1007/s00204-024-03855-7
Christina Ziemann, Florian Schulz, Christoph Koch, Mette Solvang, Annette Bitsch

Man-made vitreous fibers (MMVF) comprise diverse materials for thermal and acoustic insulation, including stone wool. Depending on dimension, durability, and dose, MMVF might induce adverse health effects. Therefore, early predictive in vitro (geno)toxicity screening of new MMVF is highly desired to ensure safety for exposed workers and consumers. Here, we investigated, as a starting point, critical in vitro screening determinants and pitfalls using primary rat alveolar macrophages (AM) and normal rat mesothelial cells (NRM2). A stone wool fiber (RIF56008) served as an exemplary MMVF (fibrous vs. ground to estimate impact of fiber shape) and long amosite (asbestos) as insoluble fiber reference. Materials were comprehensively characterized, and in vivo-relevant in vitro concentrations defined, based on different approaches (low to supposed overload: 0.5, 5 and 50 µg/cm2). After 4–48 h of incubation, certain readouts were analyzed and material uptake was investigated by light and fluorescence-coupled darkfield microscopy. DNA-strand break induction was not morphology-dependent and nearly absent in both cell types. However, NRM2 demonstrated material-, morphology- and concentration-dependent membrane damage, CINC-1 release, reduction in cell count, and induction of binucleated cells (asbestos > RIF56008 > RIF56008 ground). In contrast to NRM2, asbestos was nearly inactive in AM, with CINC-1 release solely induced by RIF56008. In conclusion, to define an MMVF-adapted, predictive in vitro (geno)toxicity screening tool, references, endpoints, and concentrations should be carefully chosen, based on in vivo relevance, and sensitivity and specificity of the chosen cell model. Next, further endpoints should be evaluated, ideally with validation by in vivo data regarding their predictivity.

人造玻璃纤维(MMVF)包括各种用于隔热和隔音的材料,其中包括岩棉。根据尺寸、耐久性和剂量的不同,人造玻璃纤维可能会对健康产生不良影响。因此,我们非常需要对新型 MMVF 进行早期预测性体外(基因)毒性筛选,以确保接触这些材料的工人和消费者的安全。在此,我们以原代大鼠肺泡巨噬细胞(AM)和正常大鼠间皮细胞(NRM2)为起点,研究了体外筛选的关键决定因素和陷阱。石羊毛纤维(RIF56008)作为示范性 MMVF(纤维状与磨碎状,以估计纤维形状的影响),长铁石棉(石棉)作为不溶性纤维参考。根据不同的方法(从低负荷到假定超负荷:0.5、5 和 50 µg/cm2),对材料进行了全面的特征描述,并确定了体内相关的体外浓度。培养 4-48 小时后,分析了某些读数,并通过光和荧光耦合暗视野显微镜研究了材料吸收情况。DNA 链断裂诱导与形态无关,在两种细胞中几乎都不存在。然而,NRM2 表现出了与材料、形态和浓度相关的膜损伤、CINC-1 释放、细胞数量减少以及双核细胞诱导(石棉> RIF56008 >RIF56008地面)。与 NRM2 相反,石棉在 AM 中几乎没有活性,CINC-1 的释放仅由 RIF56008 诱导。总之,要确定一种与 MMVF 相适应的、具有预测性的体外(基因)毒性筛选工具,应根据所选细胞模型的体内相关性、敏感性和特异性,仔细选择参考点、终点和浓度。接下来,应评估进一步的终点,最好能通过体内数据验证其预测性。
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引用次数: 0
Interleukin-9 promotes EMT-mediated PM2.5-induced pulmonary fibrosis by activating the STAT3 pathway 白细胞介素-9通过激活STAT3通路促进EMT介导的PM2.5诱导的肺纤维化
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-11 DOI: 10.1007/s00204-024-03864-6
Yuxuan Li, Yi Zhong, Chenwen Li, Zhixia Han, Yan Cui, Renjiang He, Yingyi Liu, Qinlin Cui, Daping He, Zhengquan Hu, Qingbi Zhang, Jun Bai

This study investigated the impact of PM2.5 on promoting EMT in PM2.5-induced pulmonary fibrosis (PF) development and explored molecular mechanisms of the IL-9/STAT3/Snail/TWIST1 signaling pathway in PF owing to PM2.5. Four groups of male SD rats were formed: control (0 mg/kg.bw), low (1 mg/kg.bw), medium (5 mg/kg.bw), and high-dose (25 mg/kg.bw) PM2.5 groups. Experimental rats were subjected to PM2.5 exposure via intratracheal instillation, given once weekly for 16 weeks. 24 h after the final exposure, blood, BALF, and lung tissues were collected. Pulmonary epithelial cells underwent cultivation and exposure to varying PM2.5 concentrations with/without inhibitors for 24 h, after which total protein was extracted for relevant protein assays. The findings demonstrated that PM2.5 damaged lung tissue to different degrees and led to PF in rats. Rats subjected to PM2.5 exposure exhibited elevated concentrations of IL-9 protein in both serum and BALF, and elevated levels of IL-9 and its receptor, IL-9R, in lung tissues, compared to control counterparts. Furthermore, PM2.5-exposed groups demonstrated significantly augmented protein levels of p-STAT3, Snail, TWIST1, Vimentin, COL-I, and α-SMA, while displaying notably diminished levels of E-Cadherin compared to control group. The same findings were observed in PM2.5-treated cells. In BEAS-2B cells co-treated with Stattic (STAT3 inhibitor) and PM2.5, the opposite results occurred. Similar results were obtained for cells co-treated with IL-9-neutralizing antibody and PM2.5. Our findings suggest PM2.5 mediates PF development by promoting IL-9 expression, leading to STAT3 phosphorylation and upregulation of Snail and TWIST1 expression, triggering EMT occurrence and progression in lung epithelial cells.

本研究探讨了PM2.5对促进PM2.5诱导的肺纤维化(PF)发展中EMT的影响,并探索了PM2.5导致的PF中IL-9/STAT3/Snail/TWIST1信号通路的分子机制。雄性SD大鼠分为四组:对照组(0 mg/kg.bw)、低剂量组(1 mg/kg.bw)、中剂量组(5 mg/kg.bw)和高剂量组(25 mg/kg.bw)。实验鼠通过气管内灌注接触 PM2.5,每周一次,持续 16 周。最终暴露 24 小时后,收集血液、BALF 和肺组织。培养肺上皮细胞并将其暴露于不同浓度的PM2.5(含/不含抑制剂)中24小时,然后提取总蛋白进行相关蛋白检测。研究结果表明,PM2.5 对大鼠的肺组织造成了不同程度的损伤,并导致了 PF。与对照组相比,暴露于PM2.5的大鼠血清和BALF中的IL-9蛋白浓度升高,肺组织中的IL-9及其受体IL-9R水平升高。此外,与对照组相比,PM2.5 暴露组的 p-STAT3、Snail、TWIST1、Vimentin、COL-I 和 α-SMA 蛋白水平明显升高,而 E-Cadherin 水平明显降低。在 PM2.5 处理的细胞中也观察到了同样的结果。在用 Stattic(STAT3 抑制剂)和 PM2.5 联合处理的 BEAS-2B 细胞中,出现了相反的结果。用 IL-9 中和抗体和 PM2.5 联合处理的细胞也得到了类似的结果。我们的研究结果表明,PM2.5通过促进IL-9的表达,导致STAT3磷酸化、Snail和TWIST1表达上调,引发肺上皮细胞EMT的发生和发展,从而介导PF的发展。
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引用次数: 0
Escaping the cohort of concern: in vitro experimental evidence supports non-mutagenicity of N-nitroso-hydrochlorothiazide 逃离关注人群:体外实验证据支持 N-亚硝基-氢氯噻嗪的非突变性
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-11 DOI: 10.1007/s00204-024-03859-3
R. D. Gandhi, S. Hickert, Y. Hoevelmann, C. D. Mee, J. Schlingemann, A. Adams, A. Blanazs, S. Simon, J. Elloway, L. Rigger, A. Teasdale, C. V. Beaumont, L. Wright, A. Doherty

In recent years, nitrosamine impurities in pharmaceuticals have been subject to intense regulatory scrutiny, with nitrosamine drug substance-related impurities (NDSRIs) treated as cohort of concern impurities, regardless of predicted mutagenic potential. Here, we describe a case study of the NDSRI N-nitroso-hydrochlorothiazide (NO-HCTZ), which was positive in the bacterial reverse mutation (Ames) test but is unstable under the test conditions, generating formaldehyde among other products. The mutagenic profile of NO-HCTZ was inconsistent with that expected of a mutagenic nitrosamine, exhibiting mutagenicity in the absence of metabolic activation, and instead aligned well with that of formaldehyde. To assess further, a modified Ames system including glutathione (3.3 mg/plate) to remove formaldehyde was developed. Strains used were S. typhimurium TA98, TA100, TA1535, and TA1537, and E. coli WP2 uvrA/pKM101. In this system, formaldehyde levels were considerably lower, with a concomitant increase in levels of S-(hydroxymethyl)glutathione (the adduct formed between glutathione and formaldehyde). Upon retesting NO-HCTZ in the modified system (1.6–5000 µg/plate), a clear decrease in the mutagenic response was observed in the strains in which NO-HCTZ was mutagenic in the original system (TA98, TA100, and WP2 uvrA/pKM101), indicating that formaldehyde drives the response, not NO-HCTZ. In strain TA1535, an increase in revertant colonies was observed in the modified system, likely due to a thiatriazine degradation product formed from NO-HCTZ under Ames test conditions. Overall, these data support a non-mutagenic designation for NO-HCTZ and demonstrate the value of further investigation when a positive Ames result does not align with the expected profile.

近年来,药品中的亚硝胺杂质受到了监管部门的严格审查,亚硝胺药物物质相关杂质(NDSRI)被视为一组关注杂质,而不管预测的致突变潜力如何。在这里,我们描述了一项关于 NDSRI N-亚硝基-氢氯噻嗪(NO-HCTZ)的案例研究,该物质在细菌反向突变(艾姆斯)试验中呈阳性,但在试验条件下不稳定,会产生甲醛等产物。NO-HCTZ 的致突变特征与亚硝胺的致突变特征不一致,在没有新陈代谢活化的情况下表现出致突变性,而与甲醛的致突变特征非常一致。为了进一步评估,开发了一种改进的阿姆斯系统,其中包括谷胱甘肽(3.3 毫克/板)来清除甲醛。所用菌株为伤寒杆菌 TA98、TA100、TA1535 和 TA1537 以及大肠杆菌 WP2 uvrA/pKM101。在这一系统中,甲醛含量大大降低,S-(羟甲基)谷胱甘肽(谷胱甘肽与甲醛之间形成的加合物)的含量也随之增加。在改良系统(1.6-5000 微克/板)中重新测试 NO-HCTZ 后,在原始系统中 NO-HCTZ 具有诱变作用的菌株(TA98、TA100 和 WP2 uvrA/pKM101)中观察到诱变反应明显降低,这表明是甲醛而不是 NO-HCTZ 驱动了诱变反应。在菌株 TA1535 中,改良系统中观察到返祖菌落增加,这可能是由于 NO-HCTZ 在艾姆斯试验条件下形成了噻嗪降解产物。总之,这些数据支持NO-HCTZ的非致畸性命名,并证明了当阿姆斯试验的阳性结果与预期结果不一致时,进一步调查的价值。
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引用次数: 0
The food-borne carcinogenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) disrupts circadian rhythms and ameliorated by pterostilbene (PSB) in Caenorhabditis elegans 食源性致癌物 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶(PhIP)会扰乱草履虫的昼夜节律,而紫檀芪(PSB)可改善其昼夜节律
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-10 DOI: 10.1007/s00204-024-03857-5
Chun-Han Chang, Pei-Ling Yen, Min-Hsiung Pan, Vivian Hsiu-Chuan Liao

The food-borne 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potential human carcinogen abundant in cooked meat. While circadian rhythms are crucial biological oscillations, the negative impact of PhIP on circadian systems and the potential of mitigation remain underexplored. We investigated the effects of PhIP on circadian rhythms and the mitigating effects of the phytochemical antioxidant pterostilbene (PSB) in Caenorhabditis elegans. We show that exposure to 10 μM PhIP disrupts the 24-h circadian rhythms of C. elegans, an effect mitigated by co-exposure to 100 μM PSB. In addition, PhIP-induced circadian disruption can be linked to defective oxidative stress resistance, which is associated with the DAF-16/FOXO pathway and is modulated by PSB. Molecular docking suggested that PhIP and PSB bind similarly to DAF-16. Moreover, 10 μM PhIP abolished the rhythmic expression of the core clock gene prdx-2, which is restored by 100 μM PSB. Findings from this study provide novel insight of how food-borne contaminant like PhIP may contribute to the disruption of circadian rhythms and suggest potential for PSB to mitigate these effects in higher organisms.

食源性 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶(PhIP)是一种潜在的人类致癌物质,在熟肉中含量丰富。昼夜节律是重要的生物振荡,但 PhIP 对昼夜节律系统的负面影响和缓解潜力仍未得到充分探索。我们研究了 PhIP 对草履虫昼夜节律的影响以及植物化学抗氧化剂紫檀芪(PSB)的缓解作用。我们的研究表明,暴露于 10 μM PhIP 会扰乱秀丽隐杆线虫的 24 小时昼夜节律,而同时暴露于 100 μM PSB 会减轻这种影响。此外,PhIP 诱导的昼夜节律紊乱可能与氧化应激抗性缺陷有关,而氧化应激抗性缺陷与 DAF-16/FOXO 通路有关,并受到 PSB 的调节。分子对接表明,PhIP 和 PSB 与 DAF-16 的结合方式相似。此外,10 μM PhIP 会抑制核心时钟基因 prdx-2 的节律性表达,而 100 μM PSB 则会恢复这种表达。这项研究的结果提供了一个新的视角,揭示了食源性污染物(如 PhIP)可能如何导致昼夜节律紊乱,并提出了 PSB 在高等生物中减轻这些影响的潜力。
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引用次数: 0
Elevated risk of adverse effects from foodborne contaminants and drugs in inflammatory bowel disease: a review 炎症性肠病患者受到食源性污染物和药物不良影响的风险升高:综述。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-09 DOI: 10.1007/s00204-024-03844-w
Tom Walraven, Mathias Busch, Jingxuan Wang, Joanne M. Donkers, Marjolijn Duijvestein, Evita van de Steeg, Nynke I. Kramer, Hans Bouwmeester

The global burden of Inflammatory bowel disease (IBD) has been rising over the last decades. IBD is an intestinal disorder with a complex and largely unknown etiology. The disease is characterized by a chronically inflamed gastrointestinal tract, with intermittent phases of exacerbation and remission. This compromised intestinal barrier can contribute to, enhance, or even enable the toxicity of drugs, food-borne chemicals and particulate matter. This review discusses whether the rising prevalence of IBD in our society warrants the consideration of IBD patients as a specific population group in toxicological safety assessment. Various in vivo, ex vivo and in vitro models are discussed that can simulate hallmarks of IBD and may be used to study the effects of prevalent intestinal inflammation on the hazards of these various toxicants. In conclusion, risk assessments based on healthy individuals may not sufficiently cover IBD patient safety and it is suggested to consider this susceptible subgroup of the population in future toxicological assessments.

过去几十年来,全球炎症性肠病(IBD)的发病率不断上升。IBD 是一种病因复杂且大多不明的肠道疾病。该病的特点是胃肠道长期发炎,间歇性加重和缓解。这种受损的肠道屏障可导致、增强甚至促成药物、食源性化学物质和微粒物质的毒性。本综述讨论了随着 IBD 在社会中发病率的上升,是否有必要在毒理学安全性评估中将 IBD 患者作为一个特殊的人群来考虑。文中讨论了各种体内、体外和体外模型,这些模型可以模拟 IBD 的特征,并可用于研究普遍存在的肠道炎症对各种毒物危害的影响。总之,基于健康人的风险评估可能不足以涵盖 IBD 患者的安全,建议在未来的毒理学评估中考虑到这一易感人群。
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引用次数: 0
Predictive biomarkers for embryotoxicity: a machine learning approach to mitigating multicollinearity in RNA-Seq 胚胎毒性的预测性生物标志物:减轻 RNA-Seq 中多重共线性的机器学习方法。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-06 DOI: 10.1007/s00204-024-03852-w
Yixian Quah, Soontag Jung, Jireh Yi-Le Chan, Onju Ham, Ji-Seong Jeong, Sangyun Kim, Woojin Kim, Seung-Chun Park, Seung-Jin Lee, Wook-Joon Yu

Multicollinearity, characterized by significant co-expression patterns among genes, often occurs in high-throughput expression data, potentially impacting the predictive model’s reliability. This study examined multicollinearity among closely related genes, particularly in RNA-Seq data obtained from embryoid bodies (EB) exposed to 5-fluorouracil perturbation to identify genes associated with embryotoxicity. Six genes—Dppa5a, Gdf3, Zfp42, Meis1, Hoxa2, and Hoxb1—emerged as candidates based on domain knowledge and were validated using qPCR in EBs perturbed by 39 test substances. We conducted correlation studies and utilized the variance inflation factor (VIF) to examine the existence of multicollinearity among the genes. Recursive feature elimination with cross-validation (RFECV) ranked Zfp42 and Hoxb1 as the top two among the seven features considered, identifying them as potential early embryotoxicity assessment biomarkers. As a result, a t test assessing the statistical significance of this two-feature prediction model yielded a p value of 0.0044, confirming the successful reduction of redundancies and multicollinearity through RFECV. Our study presents a systematic methodology for using machine learning techniques in transcriptomics data analysis, enhancing the discovery of potential reporter gene candidates for embryotoxicity screening research, and improving the predictive model's predictive accuracy and feasibility while reducing financial and time constraints.

高通量表达数据中经常会出现多共线性现象,其特征是基因之间存在显著的共表达模式,这可能会影响预测模型的可靠性。本研究研究了密切相关基因之间的多重共线性,特别是暴露于5-氟尿嘧啶扰动的类胚体(EB)的RNA-Seq数据,以确定与胚胎毒性相关的基因。基于领域知识,六个基因-Dppa5a、Gdf3、Zfp42、Meis1、Hoxa2 和 Hoxb1 成为候选基因,并在受到 39 种测试物质干扰的 EB 中使用 qPCR 进行了验证。我们进行了相关性研究,并利用方差膨胀因子(VIF)检查了基因之间是否存在多重共线性。通过交叉验证的递归特征消除法(RFECV),Zfp42 和 Hoxb1 在所考虑的七个特征中排名前两位,被确定为潜在的早期胚胎毒性评估生物标记物。结果,评估该双特征预测模型统计意义的 t 检验得出的 p 值为 0.0044,证实通过 RFECV 成功地减少了冗余和多重共线性。我们的研究提出了一种在转录组学数据分析中使用机器学习技术的系统方法,有助于发现胚胎毒性筛选研究中潜在的候选报告基因,提高预测模型的预测准确性和可行性,同时减少资金和时间限制。
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引用次数: 0
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Archives of Toxicology
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