微囊藻毒素(MC)是由蓝藻水华产生的次级代谢产物,其中微囊藻毒素-LR(MC-LR)是水生环境中分布最广泛的变体。然而,MC-LR对结肠直肠的影响及其在促进结直肠肿瘤进展中的作用尚不清楚.因此,本研究旨在研究MC-LR对结肠炎相关性结直肠癌小鼠模型的影响,并阐明潜在的潜在分子机制.在这项研究中,我们使用AOM/DSS小鼠,并以40µg/kg或200µg/kg的剂量口服MC-LR。暴露于MC-LR会增加肿瘤负担,促进肿瘤生长,缩短的结肠大小,肠组织杯状细胞数量和紧密连接蛋白水平降低。此外,暴露于MC-LR诱导小鼠结肠肠道微生物群结构的改变,以大肠杆菌和志贺氏菌的相对丰度增加为特征,Akkermansia_muciniphila的相对丰度下降。转录组学分析显示,MC-LR暴露激活了小鼠结直肠组织中IL-17信号通路,并参与炎症调节和免疫反应。免疫荧光结果表明,暴露于MC-LR后,小鼠结肠直肠肿瘤中的T辅助细胞17(Th17)细胞水平增加。RT-qPCR结果显示MC-LR可诱导IL-6、IL-1β表达上调,IL-10,IL-17A,TNF-α,CXCL1、CXCL2、CXCL5和CCL20。这项研究的新颖性在于其全面的方法来理解MC-LR可能有助于CRC进展的机制。为建立有关饮用水中MC-LR的指导标准提供了新的观点和有价值的参考点。我们的研究结果表明,即使在指导值,MC-LR可以对易感小鼠产生深远的影响,强调需要重新评估指南价值,并更深入地了解环境毒素在癌症进展中的作用。
Microcystins (MCs) are secondary metabolites generated by cyanobacterial blooms, among which microcystin-LR (MC-LR) stands out as the most widely distributed variant in aquatic environments. However, the effects of MC-LR on the colorectum and its role in promoting colorectal tumor progression remain unclear. Therefore, this study aims to scrutinize the impact of MC-LR on a mice model of colitis-associated colorectal cancer and elucidate the potential underlying molecular mechanisms. In this study, we used AOM/DSS mice and orally administered MC-LR at doses of 40 µg/kg or 200 µg/kg. Exposure to MC-LR increased tumor burden, promoted tumor growth, shortened colon size, and decreased goblet cell numbers and tight junction protein levels in intestinal tissues. Additionally, exposure to MC-LR induced alterations in the structure of gut microbiota in the mouse colon, characterized by an increase in the relative abundance of Escherichia_coli and Shigella_sonnei, and a decline in the relative abundance of Akkermansia_muciniphila. Transcriptomic analysis revealed that MC-LR exposure activated the IL-17 signaling pathway in mouse colorectal tissues and participated in inflammation regulation and immune response. Immunofluorescence results demonstrated an increase in T-helper 17 (Th17) cell levels in mouse colorectal tumors following MC-LR exposure. The results from RT-qPCR revealed that MC-LR induced the upregulation of IL-6, IL-1β, IL-10, IL-17A, TNF-α, CXCL1, CXCL2, CXCL5 and CCL20. The novelty of this study lies in its comprehensive approach to understanding the mechanisms by which MC-LR may contribute to CRC progression, offering new perspectives and valuable reference points for establishing guidance standards regarding MC-LR in drinking water. Our findings suggest that even at guideline value, MC-LR can have profound effects on susceptible mice, emphasizing the need for a reevaluation of guideline value and a deeper understanding of the role of environmental toxins in cancer progression.