S11-01利用基于人体呼吸细胞的体外系统评估化学品的潜在毒性

IF 2.9 3区医学 Q2 TOXICOLOGY

Toxicology letters Pub Date : 2025-09-01 DOI:10.1016/j.toxlet.2025.07.075

N. Roldan , A.O. Stucki , M. Sharma , S. Verstraelen , A. Jacobs , K. Hollanders , J. Van Laer , S. Remy , E. Frijns , A.J. Clippinger

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引用次数: 0

摘要

表面活性剂是家用产品、个人护理用品和药品的基本成分。作为广泛使用的化学品，了解这些化学品的潜在毒性是监管机构关注的重点。为了评估这些化学物质的潜在呼吸毒性，将正常的人支气管上皮细胞系（BEAS-2B）和重建的人呼吸道上皮组织模型（RHRE; MucilAir™，瑞士上皮公司）暴露于两种表面活性剂：Triton X-100（非离子表面活性剂，CAS编号：9036-19-5）和油酰肌氨酸（阴离子表面活性剂，CAS编号：110-25-8）。测试系统以单次或重复暴露方式暴露于这两种表面活性剂（仅在MucilAir™中）。对于单次暴露，在暴露后约24小时（BEAS-2B和MucilAir™）和7天（评估恢复情况；MucilAir™），在顶侧移液（各30 μL），评估细胞效应。这些检测包括细胞毒性（乳酸脱氢酶（LDH）释放）、细胞活力（reazurin -based PrestoBlue®检测）、白细胞介素-6和-8的分泌（CXCL-8； MSD V-Plex检测），以及MucilAir™、经上皮电阻（TEER）、纤毛搏动频率（CBF）、平均活性面积（AAA）和组织学。对于重复液体暴露，将Mucil-Air™组织（顶端为30 μL）暴露于两种表面活性剂中，每天4小时，连续4天，恢复期为7天。每天及康复后评估细胞效应。将BEAS-2B细胞和MucilAir™组织单独暴露于这两种表面活性剂24小时后，观察细胞活力和炎症标志物的浓度依赖性影响。在MucilAir™组织中，两种表面活性剂在两个最高浓度（40和80 μg/cm2）下，细胞活力（25%）和TEER值显著降低，细胞毒性（70%）增加。这一观察结果与组织学一致，显示部分或全部细胞层破坏。5、10、20 μg/cm2均未见细胞活力变化。然而，暴露于20 μg/cm2的组织显示出两种化学物质的细胞毒性增加和TEER显著降低。7天后TEER值恢复，但油酰肌氨酸的细胞活力仍略有下降。初步重复暴露结果可能表明油酰肌氨酸存在累加效应（仅在测试的最高浓度，20 μg/cm2），而在暴露于Triton X-100后未观察到这种累加效应。本研究建立在INSPIRE（体外系统预测呼吸毒性）倡议的基础上，以帮助提高基于人类细胞的方法评估呼吸组织刺激的科学信心。这项研究的结果被用于MucilAir™细胞系统中大约20种化学物质的多实验室研究。其目的是建立一种标准化方法，作为满足与吸入毒性有关的各种信息需求的几种方法中的第一个。

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S11-01 Assessing the potential toxicity of chemicals using human respiratory cell-based in vitro systems

Surfactants are essential ingredients for household products, personal care items, and medicines. As widely used chemicals, understanding potential toxicity of these chemicals is a key focus for regulatory agencies. To evaluate potential respiratory toxicity of these chemicals, a normal human bronchial epithelial cell line (BEAS-2B) and a reconstructed human respiratory epithelial tissue model (RHRE; MucilAir™, Epithelix, Switzerland) were exposed to two surfactants: Triton X-100 (non-ionic surfactant; CAS Number: 9036-19-5) and oleoyl sarcosine (anionic surfactant; CAS Number: 110-25-8).

The test systems were exposed to the two surfactants as a single or repeated exposure (only in MucilAir™). For single exposures, the test chemicals were pipetted (30 μL each) on the apical side and cellular effects were assessed ~24 hours (BEAS-2B and MucilAir™) and seven days (to assess recovery; MucilAir™) after exposure. These included cytotoxicity (lactate dehydrogenase (LDH) release), cell viability (resazurin-based PrestoBlue® assay), secretion of interleukins-6 and -8 (CXCL-8; MSD V-Plex Assay), and additionally for MucilAir™, transepithelial electrical resistance (TEER), cilia beat frequency (CBF), average active area (AAA), and histology. For repeated liquid exposures, Mucil-Air™ tissues were exposed (30 μL, apically) to the two surfactants for 4 hours daily, consecutively for 4 days, with a 7-day recovery period. Cellular effects were assessed each day and after recovery.

Concentration-dependent effects in cell viability and inflammatory markers were observed after single exposure of BEAS-2B cells and MucilAir™ tissues to the two surfactants for 24 hours. In MucilAir™ tissues there was a significant decrease in cell viability (<25%) and TEER values, and an increase in cytotoxicity (>70%) at the two highest concentrations (40 and 80 μg/cm²) for both surfactants. This observation aligned with histology showing partial or full cell layer destruction. No change in cell viability was observed at 5, 10, and 20 μg/cm². However, tissues exposed to 20 μg/cm² showed increased cytotoxicity and a marked decrease in TEER for both chemicals. TEER values were restored after 7 days, but cell viability remained slightly decreased for oleoyl sarcosine. Preliminary repeat exposure results may indicate an additive effect in oleoyl sarcosine (only at the highest concentration tested, 20 μg/cm²) that was not observed after exposure to Triton X-100.

This study builds upon the INSPIRE (In vitro System to PredIct REspiratory toxicity) initiative to help increase scientific confidence in human cell-based methods to assess respiratory tissue irritation. The results from this study were used to inform a multi-laboratory study testing approximately 20 chemicals in the MucilAir™ cell system. The aim is to establish a standardized method that will serve as the first of several approaches to meet the diverse information needs related to inhalation toxicity.

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