整合分析揭示BPs对人体淋巴细胞免疫毒性机制

Integrated analysis reveals the immunotoxicity mechanism of BPs on human lymphocytes

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CHEMICO-BIOLOGICAL INTERACTIONS

影响因子:5.4

分区:医学2区 / 毒理学1区生化与分子生物学2区药学2区

发表日期:2024 Aug 25

作者: Qiujin Zhang, Mengzhen Li, Ping Wang, Xiao Lin, Keng Po Lai, Zhixiang Ding

DOI: 10.1016/j.cbi.2024.111148

摘要

双酚A（BPA）是一种广泛用于塑料制品的已被充分证实的内分泌干扰化学物质。除了其内分泌干扰作用外，BPA还表现出免疫毒性。由于其对人体健康的负面影响，许多国家已禁止使用BPA。近年来，许多化学品如双酚B（BPB）、双酚E（BPE）、双酚S（BPS）和双酚萘酚（BHPF）被用来替代BPA。由于这些替代化学品的化学结构与BPA相似，可能也会对人体健康造成危害。然而，它们的免疫毒性及其毒性背后的分子机制尚不完全清楚。本研究旨在通过将初级人类淋巴细胞暴露于BPA及其替代化学品中，探究其免疫毒性及其潜在机制。结果显示，BPA及其替代物影响淋巴细胞中白细胞介素（IL）和细胞因子的产生，如IL-1β、IL-5、IL-6、IL-8、干扰素α-2b（IFN-α2B）和肿瘤坏死因子α（TNF-α）。其中，BPA和BHPF的抑制作用更明显。通过比较转录组分析，进一步研究了BHPF暴露引起的生物过程和信号通路的变化。数据显示，免疫应答、T细胞功能和细胞因子-受体相互作用在人体淋巴细胞中发生了变异，表现为基因簇的失调。此外，智慧路径分析显示T淋巴细胞的分化、迁移和浸润功能受到抑制。首次揭示了BHPF在人类淋巴细胞中免疫毒性机制的具体过程。

Abstract

Bisphenol A (BPA) is a well-documented endocrine-disrupting chemical widely used in plastic products. In addition to its endocrine-disrupting effects, BPA exhibits immunotoxicity. Many countries have banned BPA because of its adverse effects on human health. In recent years, many chemicals such as bisphenol B (BPB), bisphenol E (BPE), bisphenol S (BPS), and bisphenol fluorene (BHPF) have been used to replace BPA. Because these replacement chemicals have chemical structures similar to that of BPA, they may also harm human health. However, their immunotoxicity and the molecular mechanisms underlying their toxicity remain largely unknown. The aim of this study was to investigate the immunotoxicity of BPA and its replacement chemicals, as well as the underlying mechanisms by exposing primary human lymphocytes to BPA and its replacement chemicals. Our results showed that exposure to BPA and its replacement chemicals altered the interleukin (IL) and cytokine production, such as IL-1b, IL-5, IL-6, IL-8, interferon alfa-2b (IFN-a2B), and tumor necrosis factor alpha (TNF-α), in the lymphocytes. Among these, BPA and BHPF caused a greater inhibition. Using comparative transcriptomic analysis, we further investigated the biological processes and signaling pathways altered by BHPF exposure. Our data highlighted alterations in the immune response, T cell function, and cytokine-cytokine receptor interactions in human lymphocytes through the deregulation of gene clusters. In addition, the results of ingenuity pathway analysis demonstrated the inhibition of T lymphocyte function, including differentiation, movement, and infiltration. Our results, for the first time, delineate the mechanisms underlying the immunotoxicity of BHPF in human lymphocytes.