Janssen Aafke W F, Jansen Holleboom Wendy, Rijkers Deborah, Louisse Jochem, Hoekstra Sjoerdtje A, Schild Sanne, Vrolijk Misha F, Hoogenboom Ron L A P, Beekmann Karsten
Wageningen Food Safety Research (WFSR), Wageningen University and Research, Wageningen, Netherlands.
European Food Safety Authority, Parma, Italy.
Front Toxicol. 2024 Mar 14;6:1347965. doi: 10.3389/ftox.2024.1347965. eCollection 2024.
Exposure to PFASs is associated to several adverse health effects, such as immunotoxicity. Immunotoxic effects of PFOA and PFOS, including a reduced antibody response in both experimental animals and humans, have been reported. However, there is limited understanding of the underlying mechanisms involved. Moreover, there is only a restricted amount of immunotoxicity data available for a limited number of PFASs. In the current study the effects of 15 PFASs, including short- and long-chain perfluorinated carboxylic and sulfonic acids, fluorotelomer alcohols, and perfluoralkyl ether carboxylic acids were studied on the expression of recombinant activating gene 1 () and in the Namalwa human B lymphoma cell line, and on the human IL-2 promotor activity in Jurkat T-cells. Concentration-response data were subsequently used to derive relative potencies through benchmark dose analysis. relative potency factors (RPFs) were obtained for 6 and 9 PFASs based on their effect on and gene expression in Namalwa B-cells, respectively, and for 10 PFASs based on their inhibitory effect on IL-2 promotor activity in Jurkat T-cells. The most potent substances were HFPO-TA for the reduction of and gene expression in Namalwa cells (RPFs of 2.1 and 2.3 respectively), and PFDA on IL-2 promoter activity (RPF of 9.1). RAG1 and RAG2 play a crucial role in V (D)J gene recombination, a process for acquiring a varied array of antibodies crucial for antigen recognition. Hence, the effects observed in Namalwa cells might indicate a PFAS-induced impairment of generating a diverse range of B-cells essential for antigen recognition. The observed outcomes in the Jurkat T-cells suggest a possible PFAS-induced reduction of T-cell activation, which may contribute to a decline in the T-cell dependent antibody response. Altogether, the present study provides potential mechanistic insights into the reported PFAS-induced decreased antibody response. Additionally, the presented models may represent useful tools for assessing the immunotoxic potential of PFASs and prioritization for further risk assessment.
接触全氟辛烷磺酸与多种不良健康影响相关，如免疫毒性。已有报道指出全氟辛酸和全氟辛烷磺酸的免疫毒性作用，包括在实验动物和人类中抗体反应降低。然而，对于其中涉及的潜在机制了解有限。此外，仅有数量有限的全氟辛烷磺酸的免疫毒性数据可供使用。在本研究中，研究了15种全氟辛烷磺酸，包括短链和长链全氟羧酸和磺酸、氟调聚物醇以及全氟烷基醚羧酸，对Namalwa人B淋巴瘤细胞系中重组激活基因1（RAG1）和RAG2表达的影响，以及对Jurkat T细胞中人白细胞介素-2启动子活性的影响。随后通过基准剂量分析利用浓度-反应数据得出相对效力。基于对Namalwa B细胞中RAG1和RAG2基因表达的影响，分别获得了6种和9种全氟辛烷磺酸的相对效力因子（RPFs），基于对Jurkat T细胞中白细胞介素-2启动子活性的抑制作用，获得了10种全氟辛烷磺酸的相对效力因子。在Namalwa细胞中，对RAG1和RAG2基因表达降低作用最强的物质是六氟环氧丙烷三聚体酸（HFPO-TA）（RPFs分别为2.1和2.3），对白细胞介素-2启动子活性作用最强的是全氟癸酸（PFDA）（RPF为9.1）。RAG1和RAG2在V（D）J基因重排中起关键作用，V（D）J基因重排是一个获取对抗原识别至关重要的多种抗体的过程。因此，在Namalwa细胞中观察到的效应可能表明全氟辛烷磺酸诱导了对抗原识别至关重要的多种B细胞生成受损。在Jurkat T细胞中观察到的结果表明全氟辛烷磺酸可能导致T细胞活化降低，这可能导致T细胞依赖性抗体反应下降。总之，本研究为所报道的全氟辛烷磺酸诱导的抗体反应降低提供了潜在的机制见解。此外，所呈现的模型可能是评估全氟辛烷磺酸免疫毒性潜力以及为进一步风险评估确定优先级的有用工具。
