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In vitro-in vivo correlations of pulmonary inflammogenicity and genotoxicity of MWCNT
Particle and Fibre Toxicology ( IF 7.2 ) Pub Date : 2021-07-23 , DOI: 10.1186/s12989-021-00413-2
Emilio Di Ianni 1 , Johanna Samulin Erdem 2 , Peter Møller 3 , Nicklas Mønster Sahlgren 1 , Sarah Søs Poulsen 1 , Kristina Bram Knudsen 1, 4 , Shan Zienolddiny 2 , Anne Thoustrup Saber 1 , Håkan Wallin 2 , Ulla Vogel 1, 5 , Nicklas Raun Jacobsen 1
Affiliation  

Multi-walled carbon nanotubes (MWCNT) have received attention due to extraordinary properties, resulting in concerns for occupational health and safety. Costs and ethical concerns of animal testing drive a need for in vitro models with predictive power in respiratory toxicity. The aim of this study was to assess pro-inflammatory response (Interleukin-8 expression, IL-8) and genotoxicity (DNA strand breaks) caused by MWCNT with different physicochemical properties in different pulmonary cell models and correlate these to previously published in vivo data. Seven MWCNT were selected; two long/thick (NRCWE-006/Mitsui-7 and NM-401), two short/thin (NM-400 and NM-403), a pristine (NRCWE-040) and two surface modified; hydroxylated (NRCWE-041) and carboxylated (NRCWE-042). Carbon black Printex90 (CB) was included as benchmark material. Human alveolar epithelial cells (A549) and monocyte-derived macrophages (THP-1a) were exposed to nanomaterials (NM) in submerged conditions, and two materials (NM-400 and NM-401) in co-cultures of A549/THP-1a and lung fibroblasts (WI-38) in an air-liquid interface (ALI) system. Effective doses were quantified by thermo-gravimetric-mass spectrometry analysis (TGA-MS). To compare genotoxicity in vitro and in vivo, we developed a scoring system based on a categorization of effects into standard deviation (SD) units (< 1, 1, 2, 3 or 4 standard deviation increases) for the increasing genotoxicity. Effective doses were shown to be 25 to 53%, and 21 to 57% of the doses administered to A549 and THP-1a, respectively. In submerged conditions (A549 and THP-1a cells), all NM induced dose-dependent IL-8 expression. NM-401 and NRCWE-006 caused the strongest pro-inflammatory response. In the ALI-exposed co-culture, only NM-401 caused increased IL-8 expression, and no DNA strand breaks were observed. Strong correlations were found between in vitro and in vivo inflammation when doses were normalized by surface area (also proxy for diameter and length). Significantly increased DNA damage was found for all MWCNT in THP-1a cells, and for short MWCNT in A549 cells. A concordance in genotoxicity of 83% was obtained between THP-1a cells and broncho-alveolar lavaged (BAL) cells. This study shows correlations of pro-inflammatory potential in A549 and THP-1a cells with neutrophil influx in mice, and concordance in genotoxic response between THP-1a cells and BAL cells, for seven MWCNT.

中文翻译:

多壁碳纳米管肺致炎性和遗传毒性的体外-体内相关性

多壁碳纳米管 (MWCNT) 因其非凡的特性而受到关注,导致对职业健康和安全的担忧。动物试验的成本和伦理问题推动了对具有呼吸毒性预测能力的体外模型的需求。本研究的目的是评估在不同肺细胞模型中由具有不同理化特性的 MWCNT 引起的促炎反应(白细胞介素 8 表达,IL-8)和基因毒性(DNA 链断裂),并将这些与先前发表的体内数据相关联。 . 7个MWCNT被选中;两个长/厚(NRCWE-006/Mitsui-7 和 NM-401),两个短/薄(NM-400 和 NM-403),一个原始(NRCWE-040)和两个表面改性;羟基化 (NRCWE-041) 和羧化 (NRCWE-042)。炭黑 Printex90 (CB) 被列为基准材料。人类肺泡上皮细胞 (A549) 和单核细胞衍生的巨噬细胞 (THP-1a) 在浸没条件下暴露于纳米材料 (NM),以及 A549/THP-1a 共培养物中的两种材料(NM-400 和 NM-401)气液界面 (ALI) 系统中的肺成纤维细胞 (WI-38)。有效剂量通过热重质谱分析 (TGA-MS) 进行量化。为了比较体外和体内的基因毒性,我们开发了一个评分系统,该评分系统基于将影响分类为标准偏差 (SD) 单位(< 1、1、2、3 或 4 个标准偏差增加)以增加基因毒性。显示有效剂量分别为 A549 和 THP-1a 给药剂量的 25% 至 53% 和 21% 至 57%。在淹没条件下(A549 和 THP-1a 细胞),所有 NM 均诱导剂量依赖性 IL-8 表达。NM-401 和 NRCWE-006 引起最强的促炎反应。在暴露于 ALI 的共培养物中,只有 NM-401 导致 IL-8 表达增加,并且没有观察到 DNA 链断裂。当剂量按表面积(也代表直径和长度)归一化时,在体外和体内炎症之间发现了很强的相关性。发现 THP-1a 细胞中所有 MWCNT 和 A549 细胞中短 MWCNT 的 DNA 损伤显着增加。在 THP-1a 细胞和支气管肺泡灌洗 (BAL) 细胞之间获得了 83% 的遗传毒性一致性。这项研究显示了 A549 和 THP-1a 细胞的促炎潜力与小鼠中性粒细胞流入的相关性,以及 THP-1a 细胞和 BAL 细胞之间基因毒性反应的一致性,对于 7 个 MWCNT。只有 NM-401 导致 IL-8 表达增加,并且没有观察到 DNA 链断裂。当剂量按表面积(也代表直径和长度)归一化时,在体外和体内炎症之间发现了很强的相关性。发现 THP-1a 细胞中所有 MWCNT 和 A549 细胞中短 MWCNT 的 DNA 损伤显着增加。在 THP-1a 细胞和支气管肺泡灌洗 (BAL) 细胞之间获得了 83% 的遗传毒性一致性。这项研究显示了 A549 和 THP-1a 细胞的促炎潜力与小鼠中性粒细胞流入的相关性,以及 THP-1a 细胞和 BAL 细胞之间基因毒性反应的一致性,对于 7 个 MWCNT。只有 NM-401 导致 IL-8 表达增加,并且没有观察到 DNA 链断裂。当剂量按表面积(也代表直径和长度)归一化时,在体外和体内炎症之间发现了很强的相关性。发现 THP-1a 细胞中所有 MWCNT 和 A549 细胞中短 MWCNT 的 DNA 损伤显着增加。在 THP-1a 细胞和支气管肺泡灌洗 (BAL) 细胞之间获得了 83% 的遗传毒性一致性。这项研究显示了 A549 和 THP-1a 细胞的促炎潜力与小鼠中性粒细胞流入的相关性,以及 THP-1a 细胞和 BAL 细胞之间基因毒性反应的一致性,对于 7 个 MWCNT。当剂量按表面积(也代表直径和长度)归一化时,在体外和体内炎症之间发现了很强的相关性。发现 THP-1a 细胞中所有 MWCNT 和 A549 细胞中短 MWCNT 的 DNA 损伤显着增加。在 THP-1a 细胞和支气管肺泡灌洗 (BAL) 细胞之间获得了 83% 的遗传毒性一致性。这项研究显示了 A549 和 THP-1a 细胞的促炎潜力与小鼠中性粒细胞流入的相关性,以及 THP-1a 细胞和 BAL 细胞之间基因毒性反应的一致性,对于 7 个 MWCNT。当剂量按表面积(也代表直径和长度)归一化时,在体外和体内炎症之间发现了很强的相关性。发现 THP-1a 细胞中所有 MWCNT 和 A549 细胞中短 MWCNT 的 DNA 损伤显着增加。在 THP-1a 细胞和支气管肺泡灌洗 (BAL) 细胞之间获得了 83% 的遗传毒性一致性。这项研究显示了 A549 和 THP-1a 细胞的促炎潜力与小鼠中性粒细胞流入的相关性,以及 THP-1a 细胞和 BAL 细胞之间基因毒性反应的一致性,对于 7 个 MWCNT。
更新日期:2021-07-23
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