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Establishing relationships between particle-induced in vitro and in vivo inflammation endpoints to better extrapolate between in vitro markers and in vivo fibrosis. 建立颗粒诱导的体外和体内炎症终点之间的关系,以更好地推断体外标志物与体内纤维化之间的关系。
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-02-09 DOI: 10.1186/s12989-023-00516-y
Polly McLean, William Mueller, Ilse Gosens, Flemming R Cassee, Barbara Rothen-Rutishauser, Matthew Boyles, Lang Tran

Background: Toxicity assessment for regulatory purposes is starting to move away from traditional in vivo methods and towards new approach methodologies (NAM) such as high-throughput in vitro models and computational tools. For materials with limited hazard information, utilising quantitative Adverse Outcome Pathways (AOPs) in a testing strategy involving NAM can produce information relevant for risk assessment. The aim of this work was to determine the feasibility of linking in vitro endpoints to in vivo events, and moreover to key events associated with the onset of a chosen adverse outcome to aid in the development of NAM testing strategies. To do this, we focussed on the adverse outcome pathway (AOP) relating to the onset of pulmonary fibrosis.

Results: We extracted in vivo and in vitro dose-response information for particles known to induce this pulmonary fibrosis (crystalline silica, specifically α-quartz). To test the in vivo-in vitro extrapolation (IVIVE) determined for crystalline silica, cerium dioxide nanoparticles (nano-CeO2) were used as a case study allowing us to evaluate our findings with a less studied substance. The IVIVE methodology outlined in this paper is formed of five steps, which can be more generally summarised into two categories (i) aligning the in vivo and in vitro dosimetry, (ii) comparing the dose-response curves and derivation of conversion factors.

Conclusion: Our analysis shows promising results with regards to correlation of in vitro cytokine secretion to in vivo acute pulmonary inflammation assessed by polymorphonuclear leukocyte influx, most notable is the potential of using IL-6 and IL-1β cytokine secretion from simple in vitro submerged models as a screening tool to assess the likelihood of lung inflammation at an early stage in product development, hence allowing a more targeted investigation using either a smaller, more targeted in vivo study or in the future a more complex in vitro protocol. This paper also highlights the strengths and limitations as well as the current difficulties in performing IVIVE assessment and suggestions for overcoming these issues.

背景:用于监管目的的毒性评估正开始从传统的体内方法转向新的方法方法(NAM),如高通量体外模型和计算工具。对于危险信息有限的材料,在涉及不结盟运动的测试策略中利用定量的不良结果路径(AOPs)可以产生与风险评估相关的信息。这项工作的目的是确定将体外终点与体内事件联系起来的可行性,以及与选定的不良后果发生相关的关键事件,以帮助制定不结盟运动检测策略。为此,我们重点研究了与肺纤维化发病相关的不良结局通路(AOP)。结果:我们提取了已知可诱导肺纤维化颗粒(结晶二氧化硅,特别是α-石英)的体内和体外剂量反应信息。为了测试晶体二氧化硅的体内外推(IVIVE),二氧化铈纳米颗粒(纳米ceo2)被用作案例研究,使我们能够用较少研究的物质来评估我们的发现。本文概述的IVIVE方法由五个步骤组成,可以更笼统地概括为两类(i)体内和体外剂量测定的比对,(ii)剂量-反应曲线的比较和换算因子的推导。结论:我们的分析显示,通过多形核白细胞内流评估体外细胞因子分泌与体内急性肺部炎症的相关性,结果令人鼓舞,最值得注意的是,利用简单体外浸没模型的IL-6和IL-1β细胞因子分泌作为筛选工具,在产品开发的早期阶段评估肺部炎症的可能性,从而允许更有针对性的研究,使用较小的,更有针对性的体内研究或在未来更复杂的体外方案。本文还强调了目前进行IVIVE评估的优势和局限性,以及克服这些问题的建议。
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引用次数: 0
Acute phase response following pulmonary exposure to soluble and insoluble metal oxide nanomaterials in mice. 小鼠肺部暴露于可溶性和不溶性金属氧化物纳米材料后的急性期反应。
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-17 DOI: 10.1186/s12989-023-00514-0
Claudia Torero Gutierrez, Charis Loizides, Iosif Hafez, Anders Brostrøm, Henrik Wolff, Józef Szarek, Trine Berthing, Alicja Mortensen, Keld Alstrup Jensen, Martin Roursgaard, Anne Thoustrup Saber, Peter Møller, George Biskos, Ulla Vogel

Background: Acute phase response (APR) is characterized by a change in concentration of different proteins, including C-reactive protein and serum amyloid A (SAA) that can be linked to both exposure to metal oxide nanomaterials and risk of cardiovascular diseases. In this study, we intratracheally exposed mice to ZnO, CuO, Al2O3, SnO2 and TiO2 and carbon black (Printex 90) nanomaterials with a wide range in phagolysosomal solubility. We subsequently assessed neutrophil numbers, protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, Saa3 and Saa1 mRNA levels in lung and liver tissue, respectively, and SAA3 and SAA1/2 in plasma. Endpoints were analyzed 1 and 28 days after exposure, including histopathology of lung and liver tissues.

Results: All nanomaterials induced pulmonary inflammation after 1 day, and exposure to ZnO, CuO, SnO2, TiO2 and Printex 90 increased Saa3 mRNA levels in lungs and Saa1 mRNA levels in liver. Additionally, CuO, SnO2, TiO2 and Printex 90 increased plasma levels of SAA3 and SAA1/2. Acute phase response was predicted by deposited surface area for insoluble metal oxides, 1 and 28 days post-exposure.

Conclusion: Soluble and insoluble metal oxides induced dose-dependent APR with different time dependency. Neutrophil influx, Saa3 mRNA levels in lung tissue and plasma SAA3 levels correlated across all studied nanomaterials, suggesting that these endpoints can be used as biomarkers of acute phase response and cardiovascular disease risk following exposure to soluble and insoluble particles.

背景:急性期反应(APR)的特征是不同蛋白质的浓度变化,包括c反应蛋白和血清淀粉样蛋白a (SAA),它们可能与暴露于金属氧化物纳米材料和心血管疾病的风险有关。在这项研究中,我们气管内暴露于具有广泛吞噬溶酶体溶解度的ZnO, CuO, Al2O3, SnO2, TiO2和炭黑(Printex 90)纳米材料中。随后,我们评估了支气管肺泡灌洗液中中性粒细胞数量、蛋白质和乳酸脱氢酶活性、肺和肝组织中Saa3和Saa1 mRNA水平以及血浆中Saa3和Saa1 /2水平。分析暴露后1天和28天的终点,包括肺和肝组织病理学。结果:1 d后,所有纳米材料均引起肺部炎症,暴露于ZnO、CuO、SnO2、TiO2和Printex 90后,肺部Saa3 mRNA水平和肝脏Saa1 mRNA水平均升高。此外,CuO、SnO2、TiO2和Printex 90可提高血浆SAA3和SAA1/2水平。急性期反应可通过暴露后1天和28天不溶性金属氧化物的沉积表面积来预测。结论:可溶性和不溶性金属氧化物诱导APR呈剂量依赖性,且时间依赖性不同。中性粒细胞内流、肺组织中Saa3 mRNA水平和血浆Saa3水平在所有研究的纳米材料中都存在相关性,这表明这些终点可以用作暴露于可溶性和不溶性颗粒后急性期反应和心血管疾病风险的生物标志物。
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引用次数: 6
Short- and long-term polystyrene nano- and microplastic exposure promotes oxidative stress and divergently affects skin cell architecture and Wnt/beta-catenin signaling. 短期和长期接触聚苯乙烯纳米和微塑料会促进氧化应激,并对皮肤细胞结构和Wnt/ β -连环蛋白信号传导产生不同的影响。
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-16 DOI: 10.1186/s12989-023-00513-1
Anke Schmidt, Walison Augusto da Silva Brito, Debora Singer, Melissa Mühl, Julia Berner, Fariba Saadati, Christina Wolff, Lea Miebach, Kristian Wende, Sander Bekeschus

Nano- and microplastic particles (NMP) are strong environmental contaminants affecting marine ecosystems and human health. The negligible use of biodegradable plastics and the lack of knowledge about plastic uptake, accumulation, and functional consequences led us to investigate the short- and long-term effects in freshly isolated skin cells from mice. Using fluorescent NMP of several sizes (200 nm to 6 µm), efficient cellular uptake was observed, causing, however, only minor acute toxicity as metabolic activity and apoptosis data suggested, albeit changes in intracellular reactive species and thiol levels were observed. The internalized NMP induced an altered expression of various targets of the nuclear factor-2-related transcription factor 2 pathway and were accompanied by changed antioxidant and oxidative stress signaling responses, as suggested by altered heme oxygenase 1 and glutathione peroxide 2 levels. A highly increased beta-catenin expression under acute but not chronic NMP exposure was concomitant with a strong translocation from membrane to the nucleus and subsequent transcription activation of Wnt signaling target genes after both single-dose and chronic long-term NMP exposure. Moreover, fibroblast-to-myofibroblast transdifferentiation accompanied by an increase of α smooth muscle actin and collagen expression was observed. Together with several NMP-induced changes in junctional and adherence protein expression, our study for the first time elucidates the acute and chronic effects of NMP of different sizes in primary skin cells' signaling and functional biology, contributing to a better understanding of nano- and microplastic to health risks in higher vertebrates.

纳米和微塑料颗粒(NMP)是影响海洋生态系统和人类健康的强环境污染物。可生物降解塑料的使用微不足道,对塑料的吸收、积累和功能后果缺乏了解,这促使我们研究了从小鼠新鲜分离的皮肤细胞中产生的短期和长期影响。使用几种尺寸的荧光NMP (200 nm至6µm),观察到有效的细胞摄取,然而,代谢活性和凋亡数据表明,尽管观察到细胞内活性物质和硫醇水平的变化,但仅引起轻微的急性毒性。内化NMP诱导了核因子2相关转录因子2途径的多种靶点的表达改变,并伴随着抗氧化和氧化应激信号反应的改变,如血红素加氧酶1和谷胱甘肽过氧化物2水平的改变。在急性而非慢性NMP暴露下,β -catenin表达的高度增加与单剂量和慢性长期NMP暴露后Wnt信号靶基因从膜到细胞核的强烈易位和随后的转录激活相伴随。此外,观察到成纤维细胞向肌成纤维细胞的转分化伴随着α平滑肌肌动蛋白和胶原蛋白表达的增加。结合几种NMP诱导的连接蛋白和粘附蛋白表达的变化,我们的研究首次阐明了不同大小的NMP对原代皮肤细胞信号传导和功能生物学的急性和慢性影响,有助于更好地理解纳米和微塑料对高等脊椎动物健康风险的影响。
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引用次数: 5
Polypropylene nanoplastic exposure leads to lung inflammation through p38-mediated NF-κB pathway due to mitochondrial damage. 聚丙烯纳米塑料暴露通过p38介导的NF-κB途径导致线粒体损伤导致肺部炎症。
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-10 DOI: 10.1186/s12989-022-00512-8
Jong-Hwan Woo, Hyeon Jin Seo, Jun-Young Lee, Iljung Lee, Kisoo Jeon, Bumseok Kim, Kyuhong Lee

Background: Polypropylene (PP) is used in various products such as disposable containers, spoons, and automobile parts. The disposable masks used for COVID-19 prevention mainly comprise PP, and the disposal of such masks is concerning because of the potential environmental pollution. Recent reports have suggested that weathered PP microparticles can be inhaled, however, the inhalation toxicology of PP microparticles is poorly understood.

Results: Inflammatory cell numbers, reactive oxygen species (ROS) production, and the levels of inflammatory cytokines and chemokines in PP-instilled mice (2.5 or 5 mg/kg) increased significantly compared to with those in the control. Histopathological analysis of the lung tissue of PP-stimulated mice revealed lung injuries, including the infiltration of inflammatory cells into the perivascular/parenchymal space, alveolar epithelial hyperplasia, and foamy macrophage aggregates. The in vitro study indicated that PP stimulation causes mitochondrial dysfunction including mitochondrial depolarization and decreased adenosine triphosphate (ATP) levels. PP stimulation led to cytotoxicity, ROS production, increase of inflammatory cytokines, and cell deaths in A549 cells. The results showed that PP stimulation increased the p-p38 and p-NF-κB protein levels both in vivo and in vitro, while p-ERK and p-JNK remained unchanged. Interestingly, the cytotoxicity that was induced by PP exposure was regulated by p38 and ROS inhibition in A549 cells.

Conclusions: These results suggest that PP stimulation may contribute to inflammation pathogenesis via the p38 phosphorylation-mediated NF-κB pathway as a result of mitochondrial damage.

背景:聚丙烯(PP)用于各种产品,如一次性容器、勺子和汽车零部件。用于新型冠状病毒防护的一次性口罩主要由PP材料组成,其处理可能会对环境造成污染,值得关注。最近的报道表明,风化的PP微粒可以被吸入,然而,PP微粒的吸入毒性尚不清楚。结果:与对照组相比,注射pp(2.5或5 mg/kg)小鼠的炎症细胞数量、活性氧(ROS)产生以及炎症细胞因子和趋化因子水平显著增加。pp刺激小鼠肺组织的组织病理学分析显示肺损伤,包括炎症细胞浸润到血管周围/实质间隙,肺泡上皮增生,泡沫状巨噬细胞聚集。体外研究表明,PP刺激引起线粒体功能障碍,包括线粒体去极化和三磷酸腺苷(ATP)水平下降。PP刺激导致A549细胞的细胞毒性、ROS产生、炎症细胞因子增加和细胞死亡。结果表明,PP刺激提高了体内和体外p-p38和p-NF-κB蛋白水平,而p-ERK和p-JNK保持不变。有趣的是,在A549细胞中,PP暴露诱导的细胞毒性受到p38和ROS抑制的调节。结论:这些结果表明,PP刺激可能通过p38磷酸化介导的NF-κB途径导致线粒体损伤,从而促进炎症发病。
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引用次数: 13
Putative adverse outcome pathways for silver nanoparticle toxicity on mammalian male reproductive system: a literature review. 银纳米颗粒毒性对哺乳动物雄性生殖系统的推定不良后果途径:文献综述。
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-05 DOI: 10.1186/s12989-022-00511-9
Ozge Kose, Paride Mantecca, Anna Costa, Marie Carrière

Background: Adverse outcome pathways (AOPs) are conceptual frameworks that organize knowledge about biological interactions and toxicity mechanisms. They present a sequence of events commencing with initial interaction(s) of a stressor, which defines the perturbation in a biological system (molecular initiating event, MIE), and a dependent series of key events (KEs), ending with an adverse outcome (AO). AOPs have recently become the subject of intense studies in a view to better understand the mechanisms of nanomaterial (NM) toxicity. Silver nanoparticles (Ag NPs) are one of the most explored nanostructures and are extensively used in various application. This, in turn, has increased the potential for interactions of Ag NPs with environments, and toxicity to human health. The aim of this study was to construct a putative AOPs (pAOP) related to reproductive toxicity of Ag NPs, in order to lay the groundwork for a better comprehension of mechanisms affecting both undesired toxicity (against human cell) and expected toxicity (against microorganisms).

Methods: PubMed and Scopus were systematically searched for peer-reviewed studies examining reproductive toxicity potential of Ag NPs. The quality of selected studies was assessed through ToxRTool. Eventually, forty-eight studies published between 2005 and 2022 were selected to identify the mechanisms of Ag NPs impact on reproductive function in human male. The biological endpoints, measurements, and results were extracted from these studies. Where possible, endpoints were assigned to a potential KE and an AO using expert judgment. Then, KEs were classified at each major level of biological organization.

Results: We identified the impairment of intracellular SH-containing biomolecules, which are major cellular antioxidants, as a putative MIE, with subsequent KEs defined as ROS accumulation, mitochondrial damage, DNA damage and lipid peroxidation, apoptosis, reduced production of reproductive hormones and reduced quality of sperm. These successive KEs may result in impaired male fertility (AO).

Conclusion: This research recapitulates and schematically represents complex literature data gathered from different biological levels and propose a pAOP related to the reproductive toxicity induced by AgNPs. The development of AOPs specific to NMs should be encouraged in order to provide new insights to gain a better understanding of NP toxicity.

背景:不良结果通路(AOPs)是组织生物相互作用和毒性机制知识的概念框架。它们呈现了一系列事件,始于应激源的初始相互作用(s),这定义了生物系统中的扰动(分子起始事件,MIE),以及一系列依赖的关键事件(KEs),以不利结果(AO)结束。为了更好地了解纳米材料(NM)的毒性机制,AOPs近年来成为研究的热点。银纳米粒子是目前研究最多的纳米结构之一,具有广泛的应用前景。这反过来又增加了银NPs与环境相互作用的可能性以及对人类健康的毒性。本研究旨在构建与银NPs生殖毒性相关的推定AOPs (pAOP),为更好地理解银NPs非期望毒性(对人体细胞)和预期毒性(对微生物)的影响机制奠定基础。方法:系统地检索PubMed和Scopus中同行评审的研究,研究Ag NPs的生殖毒性潜力。通过ToxRTool评估所选研究的质量。最终,我们选择了2005年至2022年间发表的48项研究来确定Ag NPs对人类男性生殖功能的影响机制。从这些研究中提取生物学终点、测量和结果。在可能的情况下,使用专家判断将端点分配给潜在的KE和AO。然后,在生物组织的各个主要水平上对ke进行分类。结果:我们发现细胞内含sh生物分子(主要的细胞抗氧化剂)的损伤是推定的MIE,随后的KEs定义为ROS积累、线粒体损伤、DNA损伤和脂质过氧化、细胞凋亡、生殖激素产生减少和精子质量下降。这些连续的KEs可能导致男性生育能力受损(AO)。结论:本研究从不同生物学水平收集的复杂文献资料进行了概括和图解,提出了AgNPs诱导的生殖毒性与pAOP有关。为了更好地了解NP毒性,应该鼓励开发针对NMs的AOPs。
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引用次数: 9
Correction: a systematic quality evaluation and review of nanomaterial genotoxicity studies: a regulatory perspective. 修正:纳米材料遗传毒性研究的系统质量评价和回顾:一个监管的角度。
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-12-28 DOI: 10.1186/s12989-022-00509-3
Kirsi M Siivola, Michael J Burgum, Blanca Suárez-Merino, Martin J D Clift, Shareen H Doak, Julia Catalán
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引用次数: 1
Pulmonary effects of exposure to indium and its compounds: cross-sectional survey of exposed workers and experimental findings in rodents. 暴露于铟及其化合物的肺部影响:暴露工人的横断面调查和啮齿动物的实验结果。
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-12-20 DOI: 10.1186/s12989-022-00510-w
Nan Liu, Yi Guan, Yan Yu, Gai Li, Ling Xue, Weikang Li, Xiaoyu Qu, Ning Li, Sanqiao Yao

Background: Many studies have shown that occupational exposure to indium and its compounds could induce lung disease. Although animal toxicological studies and human epidemiological studies suggest indium exposure may cause lung injury, inflammation, pulmonary fibrosis, emphysema, pulmonary alveolar proteinosis, and even lung cancer, related data collected from humans is currently limited and confined to single workplaces, and the early effects of exposure on the lungs are not well understood.

Objectives: This study combined population studies and animal experiments to examine the links of indium with pulmonary injury, as well as its mechanism of action. A cross-sectional epidemiological study of indium-exposed workers from China was conducted to evaluate associations between occupational indium exposure and serum biomarkers of early effect. This study also compares and analyzes the causal perspectives of changes in human serum biomarkers induced by indium compound exposure and indium exposure-related rat lung pathobiology, and discusses possible avenues for their recognition and prevention.

Methods: This is a study of 57 exposed (at least 6 h per day for one year) workers from an indium ingot production plant, and 63 controls. Indium concentration in serum, urine, and airborne as exposure indices were measured by inductively coupled plasma-mass spectrometry. Sixteen serum biomarkers of pulmonary injury, inflammation, and oxidative stress were measured using ELISA. The associations between serum indium and 16 serum biomarkers were analyzed to explore the mechanism of action of indium on pulmonary injury in indium-exposed workers. Animal experiments were conducted to measure inflammatory factors levels in bronchoalveolar lavage fluid (BALF) and lung tissue protein expressions in rats. Four different forms of indium compound-exposed rat models were established (intratracheal instillation twice per week, 8 week exposure, 8 week recovery). Model I: 0, 1.2, 3, and 6 mg/kg bw indium tin oxide group; Model II: 0, 1.2, 3, and 6 mg/kg bw indium oxide (In2O3) group; Model III: 0, 0.523, 1.046, and 2.614 mg/kg bw indium sulfate (In2(SO4)3) group; Model IV: 0, 0.065, 0.65, and 1.3 mg/kg bw indium trichloride (InCl3) group. Lung pathological changes were assessed by hematoxylin & eosin, periodic acid Schiff, and Masson's staining, transmission electron microscopy, and the protein changes were determined by immunohistochemistry.

Results: In the production workshop, the airborne indium concentration was 78.4 μg/m3. The levels of serum indium and urine indium in indium-exposed workers were 39.3 μg/L and 11.0 ng/g creatinine. Increased lung damage markers, oxidative stress markers, and inflammation markers were found in indium-exposed workers. Serum indium levels were statistically and positively ass

背景:许多研究表明,职业性接触铟及其化合物可诱发肺部疾病。虽然动物毒理学研究和人类流行病学研究表明,接触铟可能导致肺损伤、炎症、肺纤维化、肺气肿、肺泡蛋白沉积症,甚至肺癌,但目前从人类收集的相关数据有限,而且仅限于单一工作场所,接触对肺部的早期影响尚未得到很好的了解。目的:本研究采用群体研究和动物实验相结合的方法,探讨铟与肺损伤的关系及其作用机制。对来自中国的铟暴露工人进行了一项横断面流行病学研究,以评估职业性铟暴露与早期影响的血清生物标志物之间的关系。本研究还比较和分析了铟化合物暴露引起的人血清生物标志物变化和铟暴露相关大鼠肺部病理生物学的因果关系,并探讨了可能的识别和预防途径。方法:这是一项对来自铟锭生产厂的57名暴露工人(每天至少6小时,持续一年)和63名对照工人的研究。采用电感耦合等离子体质谱法测定血清、尿液和空气中铟浓度作为暴露指标。采用ELISA法检测肺损伤、炎症和氧化应激的16种血清生物标志物。分析血清铟与16种血清生物标志物的相关性,探讨铟对暴露工人肺损伤的作用机制。采用动物实验方法测定大鼠支气管肺泡灌洗液(BALF)中炎症因子水平及肺组织蛋白表达。建立4种不同形式的铟化合物暴露大鼠模型(每周气管内注射2次,暴露8周,恢复8周)。型号一:0、1.2、3、6 mg/kg bw氧化铟锡组;模型II: 0、1.2、3和6 mg/kg bw氧化铟(In2O3)组;模型三:0、0.523、1.046、2.614 mg/kg bw硫酸铟(In2(SO4)3)组;模型四:0、0.065、0.65和1.3 mg/kg bw三氯化铟(InCl3)组。采用苏木精伊红染色、周期性席夫染色、马松染色、透射电镜观察肺组织病理变化,免疫组织化学检测肺组织蛋白变化。结果:生产车间空气中铟浓度为78.4 μg/m3。铟暴露工人血清铟和尿铟水平分别为39.3 μg/L和11.0 ng/g。在暴露于铟的工人中发现肺损伤标志物、氧化应激标志物和炎症标志物增加。血清铟水平与血清SP-A、IL-1β、IL-6水平呈正相关。其中SP-A表现出持续-反应模式。动物实验结果显示,随着剂量的增加,各模型组大鼠血清中镉、肺中镉水平显著升高,IL - 1β、IL -6、IL - 10、TNF - α的BALF水平显著升高,SP-A、SP-D、KL-6、GM-CSF、NF-κB p65、HO-1蛋白表达上调。透射电镜显示,In2(SO4)3和InCl3是可溶的,在肺组织中没有发现颗粒,而不溶性化合物(ITO和In2O3)则相反。在In2(SO4)3和InCl3暴露组的肺组织中未发现pas染色阳性物质,而ITO和In2O3大鼠模型支持人类铟肺病中肺泡蛋白沉积和间质纤维化的发现。ITO和InCl3可加速间质纤维化。我们的体内研究结果表明,表面活性剂的肺泡内积聚(免疫组织化学)和铟肺病的特征性胆固醇裂口肉芽肿(PAS染色)是由一种特定形式的铟(ITO和In2O3)引发的。结论:在暴露于铟的工人中,生物标志物发现表明肺损伤、氧化应激和炎症反应。在工作场所遇到的四种形式的铟的大鼠模型中,生物标志物对所有化合物的反应总体上与人类一致。此外,在大鼠模型中,暴露于氧化铟锡和氧化铟后发现肺泡蛋白沉积,暴露于氧化铟锡和三氯化铟后发现间质纤维化,支持先前关于人类疾病的报道。血清SP-A水平与铟暴露呈正相关,可能被认为是暴露工人暴露和影响的潜在生物标志物。
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引用次数: 1
Grouping of orally ingested silica nanomaterials via use of an integrated approach to testing and assessment to streamline risk assessment. 通过使用综合测试和评估方法对口服二氧化硅纳米材料进行分组,以简化风险评估。
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-12-02 DOI: 10.1186/s12989-022-00508-4
Luisana Di Cristo, Victor C Ude, Georgia Tsiliki, Giuseppina Tatulli, Alessio Romaldini, Fiona Murphy, Wendel Wohlleben, Agnes G Oomen, Pier P Pompa, Josje Arts, Vicki Stone, Stefania Sabella

Background: Nanomaterials can exist in different nanoforms (NFs). Their grouping may be supported by the formulation of hypotheses which can be interrogated via integrated approaches to testing and assessment (IATA). IATAs are decision trees that guide the user through tiered testing strategies (TTS) to collect the required evidence needed to accept or reject a grouping hypothesis. In the present paper, we investigated the applicability of IATAs for ingested NFs using a case study that includes different silicon dioxide, SiO2 NFs. Two oral grouping hypotheses addressing local and systemic toxicity were identified relevant for the grouping of these NFs and verified through the application of oral IATAs. Following different Tier 1 and/or Tier 2 in vitro methods of the TTS (i.e., in vitro dissolution, barrier integrity and inflammation assays), we generated the NF datasets. Furthermore, similarity algorithms (e.g., Bayesian method and Cluster analysis) were utilized to identify similarities among the NFs and establish a provisional group(s). The grouping based on Tier 1 and/or Tier 2 testing was analyzed in relation to available Tier 3 in vivo data in order to verify if the read-across was possible and therefore support a grouping decision.

Results: The measurement of the dissolution rate of the silica NFs in the oro-gastrointestinal tract and in the lysosome identified them as gradually dissolving and biopersistent NFs. For the local toxicity to intestinal epithelium (e.g. cytotoxicity, membrane integrity and inflammation), the biological results of the gastrointestinal tract models indicate that all of the silica NFs were similar with respect to the lack of local toxicity and, therefore, belong to the same group; in vivo data (although limited) confirmed the lack of local toxicity of NFs. For systemic toxicity, Tier 1 data did not identify similarity across the NFs, with results across different decision nodes being inconsistent in providing homogeneous group(s). Moreover, the available Tier 3 in vivo data were also insufficient to support decisions based upon the obtained in vitro results and relating to the toxicity of the tested NFs.

Conclusions: The information generated by the tested oral IATAs can be effectively used for similarity assessment to support a grouping decision upon the application of a hypothesis related to toxicity in the gastrointestinal tract. The IATAs facilitated a structured data analysis and, by means of the expert's interpretation, supported read-across with the available in vivo data. The IATAs also supported the users in decision making, for example, reducing the testing when the grouping was well supported by the evidence and/or moving forward to advanced testing (e.g., the use of more suitable cellular models or chronic exposure) to improve the confidence level of the data and obtain more focused information.

背景:纳米材料可以以不同的纳米形式存在。他们的分组可以通过假设的制定来支持,这些假设可以通过测试和评估的综合方法进行询问(IATA)。iata是指导用户通过分层测试策略(TTS)来收集接受或拒绝分组假设所需的证据的决策树。在本文中,我们通过一个包括不同二氧化硅、SiO2纳米颗粒的案例研究,研究了iata对摄取纳米颗粒的适用性。确定了与这些NFs分组相关的两种针对局部和全身毒性的口服分组假设,并通过口服iata的应用进行了验证。根据不同的TTS 1级和/或2级体外方法(即体外溶出,屏障完整性和炎症分析),我们生成了NF数据集。此外,利用相似性算法(如贝叶斯方法和聚类分析)识别NFs之间的相似性并建立临时组。将基于Tier 1和/或Tier 2测试的分组与可用的Tier 3体内数据进行分析,以验证是否可能进行解读,从而支持分组决策。结果:测定了二氧化硅纳米颗粒在口腔胃肠道和溶酶体中的溶出率,确定其为逐渐溶解的生物持久性纳米颗粒。对于肠上皮的局部毒性(如细胞毒性、膜完整性和炎症),胃肠道模型的生物学结果表明,所有二氧化硅NFs在缺乏局部毒性方面相似,因此属于同一组;体内数据(尽管有限)证实了NFs没有局部毒性。对于系统毒性,Tier 1数据没有确定NFs之间的相似性,在提供同质组时,不同决策节点的结果不一致。此外,现有的3级体内数据也不足以支持基于获得的体外结果和与所测试NFs毒性相关的决策。结论:经测试的口服iata产生的信息可以有效地用于相似性评估,以支持在应用与胃肠道毒性相关的假设时进行分组决策。IATAs促进了结构化的数据分析,并通过专家的解释,支持对现有体内数据的解读。国际航空运输协会还为用户的决策提供支持,例如,在证据充分支持分组的情况下减少测试和/或推进高级测试(例如,使用更合适的细胞模型或慢性暴露),以提高数据的置信度并获得更集中的信息。
{"title":"Grouping of orally ingested silica nanomaterials via use of an integrated approach to testing and assessment to streamline risk assessment.","authors":"Luisana Di Cristo,&nbsp;Victor C Ude,&nbsp;Georgia Tsiliki,&nbsp;Giuseppina Tatulli,&nbsp;Alessio Romaldini,&nbsp;Fiona Murphy,&nbsp;Wendel Wohlleben,&nbsp;Agnes G Oomen,&nbsp;Pier P Pompa,&nbsp;Josje Arts,&nbsp;Vicki Stone,&nbsp;Stefania Sabella","doi":"10.1186/s12989-022-00508-4","DOIUrl":"https://doi.org/10.1186/s12989-022-00508-4","url":null,"abstract":"<p><strong>Background: </strong>Nanomaterials can exist in different nanoforms (NFs). Their grouping may be supported by the formulation of hypotheses which can be interrogated via integrated approaches to testing and assessment (IATA). IATAs are decision trees that guide the user through tiered testing strategies (TTS) to collect the required evidence needed to accept or reject a grouping hypothesis. In the present paper, we investigated the applicability of IATAs for ingested NFs using a case study that includes different silicon dioxide, SiO<sub>2</sub> NFs. Two oral grouping hypotheses addressing local and systemic toxicity were identified relevant for the grouping of these NFs and verified through the application of oral IATAs. Following different Tier 1 and/or Tier 2 in vitro methods of the TTS (i.e., in vitro dissolution, barrier integrity and inflammation assays), we generated the NF datasets. Furthermore, similarity algorithms (e.g., Bayesian method and Cluster analysis) were utilized to identify similarities among the NFs and establish a provisional group(s). The grouping based on Tier 1 and/or Tier 2 testing was analyzed in relation to available Tier 3 in vivo data in order to verify if the read-across was possible and therefore support a grouping decision.</p><p><strong>Results: </strong>The measurement of the dissolution rate of the silica NFs in the oro-gastrointestinal tract and in the lysosome identified them as gradually dissolving and biopersistent NFs. For the local toxicity to intestinal epithelium (e.g. cytotoxicity, membrane integrity and inflammation), the biological results of the gastrointestinal tract models indicate that all of the silica NFs were similar with respect to the lack of local toxicity and, therefore, belong to the same group; in vivo data (although limited) confirmed the lack of local toxicity of NFs. For systemic toxicity, Tier 1 data did not identify similarity across the NFs, with results across different decision nodes being inconsistent in providing homogeneous group(s). Moreover, the available Tier 3 in vivo data were also insufficient to support decisions based upon the obtained in vitro results and relating to the toxicity of the tested NFs.</p><p><strong>Conclusions: </strong>The information generated by the tested oral IATAs can be effectively used for similarity assessment to support a grouping decision upon the application of a hypothesis related to toxicity in the gastrointestinal tract. The IATAs facilitated a structured data analysis and, by means of the expert's interpretation, supported read-across with the available in vivo data. The IATAs also supported the users in decision making, for example, reducing the testing when the grouping was well supported by the evidence and/or moving forward to advanced testing (e.g., the use of more suitable cellular models or chronic exposure) to improve the confidence level of the data and obtain more focused information.</p>","PeriodicalId":19847,"journal":{"name":"Particle and Fibre Toxicology","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2022-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9719179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10500180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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: 3
A comprehensive understanding of ambient particulate matter and its components on the adverse health effects based from epidemiological and laboratory evidence. 根据流行病学和实验室证据,全面了解环境颗粒物及其成分对健康的不利影响。
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-11-29 DOI: 10.1186/s12989-022-00507-5
Tianyu Li, Yang Yu, Zhiwei Sun, Junchao Duan

The impacts of air pollution on public health have become a great concern worldwide. Ambient particulate matter (PM) is a major air pollution that comprises a heterogeneous mixture of different particle sizes and chemical components. The chemical composition and physicochemical properties of PM change with space and time, which may cause different impairments. However, the mechanisms of the adverse effects of PM on various systems have not been fully elucidated and systematically integrated. The Adverse Outcome Pathway (AOP) framework was used to comprehensively illustrate the molecular mechanism of adverse effects of PM and its components, so as to clarify the causal mechanistic relationships of PM-triggered toxicity on various systems. The main conclusions and new insights of the correlation between public health and PM were discussed, especially at low concentrations, which points out the direction for further research in the future. With the deepening of the study on its toxicity mechanism, it was found that PM can still induce adverse health effects with low-dose exposure. And the recommended Air Quality Guideline level of PM2.5 was adjusted to 5 μg/m3 by World Health Organization, which meant that deeper and more complex mechanisms needed to be explored. Traditionally, oxidative stress, inflammation, autophagy and apoptosis were considered the main mechanisms of harmful effects of PM. However, recent studies have identified several emerging mechanisms involved in the toxicity of PM, including pyroptosis, ferroptosis and epigenetic modifications. This review summarized the comprehensive evidence on the health effects of PM and the chemical components of it, as well as the combined toxicity of PM with other air pollutants. Based on the AOP Wiki and the mechanisms of PM-induced toxicity at different levels, we first constructed the PM-related AOP frameworks on various systems.

空气污染对公众健康的影响已成为全世界关注的焦点。环境颗粒物(PM)是一种主要的空气污染,由不同粒径和化学成分的非均匀混合物组成。PM的化学成分和理化性质随时间和空间的变化而变化,可能造成不同程度的损伤。然而,PM对各种系统的不良影响的机制尚未得到充分阐明和系统整合。采用不良结果通路(Adverse Outcome Pathway, AOP)框架,全面阐述PM及其成分不良反应的分子机制,阐明PM引发的各系统毒性的因果机制关系。讨论了公共健康与PM相关性的主要结论和新见解,特别是在低浓度下,为未来进一步研究指明了方向。随着对其毒性机制研究的深入,发现PM在低剂量暴露下仍可引起不良健康影响。世界卫生组织将PM2.5推荐水平调整为5 μg/m3,这意味着需要探索更深入、更复杂的机制。传统上认为,氧化应激、炎症、自噬和细胞凋亡是PM有害作用的主要机制。然而,最近的研究已经确定了几种涉及PM毒性的新机制,包括焦亡,铁亡和表观遗传修饰。本文综述了关于PM及其化学成分对健康影响的综合证据,以及PM与其他空气污染物的联合毒性。基于AOP Wiki和不同层次的pm诱导毒性机制,我们首先在不同的系统上构建了与pm相关的AOP框架。
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引用次数: 14
Concentration-dependent increase in symptoms due to diesel exhaust in a controlled human exposure study. 在一项对照人体暴露研究中,柴油废气引起的浓度依赖性症状增加
IF 1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-11-23 DOI: 10.1186/s12989-022-00506-6
Juma Orach, Christopher Francis Rider, Agnes Che Yan Yuen, Christopher Carlsten

Background: Traffic-related air pollution (TRAP) exposure causes adverse effects on wellbeing and quality of life, which can be studied non-invasively using self-reported symptoms. However, little is known about the effects of different TRAP concentrations on symptoms following controlled exposures, where acute responses can be studied with limited confounding. We investigated the concentration-response relationship between diesel exhaust (DE) exposure, as a model TRAP, and self-reported symptoms.

Methods: We recruited 17 healthy non-smokers into a double-blind crossover study where they were exposed to filtered air (FA) and DE standardized to 20, 50, 150 µg/m3 PM2.5 for 4 h, with a ≥ 4-week washout between exposures. Immediately before, and at 4 h and 24 h from the beginning of the exposure, we administered visual analog scale (VAS) questionnaires and grouped responses into chest, constitutional, eye, neurological, and nasal categories. Additionally, we assessed how the symptom response was related to exposure perception and airway function.

Results: An increase in DE concentration raised total (β ± standard error = 0.05 ± 0.03, P = 0.04), constitutional (0.01 ± 0.01, P = 0.03) and eye (0.02 ± 0.01, P = 0.05) symptoms at 4 h, modified by perception of temperature, noise, and anxiety. These symptoms were also correlated with airway inflammation. Compared to FA, symptoms were significantly increased at 150 µg/m3 for the total (8.45 ± 3.92, P = 0.04) and eye (3.18 ± 1.55, P = 0.05) categories, with trends towards higher values in the constitutional (1.49 ± 0.86, P = 0.09) and nasal (1.71 ± 0.96, P = 0.08) categories.

Conclusion: DE exposure induced a concentration-dependent increase in symptoms, primarily in the eyes and body, that was modified by environmental perception. These observations emphasize the inflammatory and sensory effects of TRAP, with a potential threshold below 150 µg/m3 PM2.5. We demonstrate VAS questionnaires as a useful tool for health monitoring and provide insight into the TRAP concentration-response at exposure levels relevant to public health policy.

背景:与交通相关的空气污染(TRAP)暴露会对健康和生活质量产生不利影响,这可以使用自我报告的症状进行无创研究。然而,不同浓度的TRAP对受控暴露后症状的影响知之甚少,在这种情况下,急性反应可以在有限混淆的情况下进行研究。我们调查了柴油废气(DE)暴露(作为模型TRAP)与自我报告症状之间的浓度-反应关系。方法:我们招募了17名健康的非吸烟者进行双盲交叉研究,让他们暴露于标准为20、50、150µg/m3 PM2.5的过滤空气(FA)和DE中4小时,两次暴露之间有≥4周的洗脱期。在暴露开始前、4小时和24小时,我们进行了视觉模拟量表(VAS)问卷调查,并将反应分为胸部、体质、眼睛、神经系统和鼻腔类别。此外,我们评估了症状反应与暴露感知和气道功能的关系。结果:DE浓度升高使总症状(β±标准误差= 0.05±0.03,P = 0.04)、体质症状(0.01±0.01,P = 0.03)和眼睛症状(0.02±0.01,P = 0.05)升高,温度、噪音和焦虑的感觉改善。这些症状也与气道炎症有关。与FA相比,当浓度为150µg/m3时,总类别(8.45±3.92,P = 0.04)和眼部类别(3.18±1.55,P = 0.05)的症状显著增加,其中体质类别(1.49±0.86,P = 0.09)和鼻腔类别(1.71±0.96,P = 0.08)的症状有升高趋势。结论:DE暴露引起症状的浓度依赖性增加,主要是在眼睛和身体,这是由环境感知改变。这些观察结果强调了TRAP的炎症和感官效应,其潜在阈值低于150µg/m3 PM2.5。我们证明了VAS问卷是健康监测的有用工具,并提供了与公共卫生政策相关的暴露水平下TRAP浓度反应的见解。
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引用次数: 1
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Particle and Fibre Toxicology
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