State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Collaborative Innovation Center of Food Safety and Quality Control, Jiangnan University, Wuxi, Jiangsu 214122, China; Yixing Institute of Food and Biotechnology Co., Ltd, Yixing 214200, China.
Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, GA, USA.
Toxicology. 2024 Nov;508:153928. doi: 10.1016/j.tox.2024.153928. Epub 2024 Aug 15.
Deoxynivalenol (DON) is a kind of widespread traditional Fusarium mycotoxins in the environment, and its intestinal toxicity has received considerable attention. Recently, the emerging Fusarium mycotoxin enniatins (ENNs) have also been shown to frequently coexist with DON in animal feed and food with large consumption. However, the mechanism of intestinal damage caused by the two mycotoxins co-exposure remains unclear. In this study, Caco-2 cell line was used to investigate the combined toxicity and potential mechanisms of four representative ENNs (ENA, ENA, ENB, and ENB) and DON. The results showed that almost all mixed groups showed antagonistic effects, particularly ENB at 1/4 IC (CI = 6.488). Co-incubation of ENNs mitigated the levels of signaling molecule levels disrupted by DON, including reactive oxygen species (ROS), calcium mobilization (Ca), adenosine triphosphate (ATP). The differentially expressed genes (DEGs) between the mixed and ENB groups were significantly enriched in the Ras/PI3K/Akt signaling pathway, including 28 up-regulated genes and 40 down-regulated genes. Quantitative real-time PCR further confirmed the lower expression of apoptotic gene in the mixed group, thereby reducing the cytotoxic effects caused by DON exposure. This study emphasizes that co-exposure of ENNs and DON reduces cytotoxicity by regulating the Ras/PI3K/Akt signaling pathway. Our results provide the first comprehensive evidence about the antagonistic toxicity of ENNs and DON on Caco-2 cells, and new insights into mechanisms investigated by transcriptomics.
脱氧雪腐镰刀菌烯醇（DON）是一种广泛存在于环境中的传统镰刀菌真菌毒素，其肠道毒性受到了相当多的关注。最近，新兴的镰刀菌真菌毒素恩镰菌素（ENNs）也被发现经常与 DON 一起存在于动物饲料和大量消费的食品中。然而，这两种真菌毒素共同暴露引起的肠道损伤机制仍不清楚。本研究采用 Caco-2 细胞系研究了四种代表性的 ENNs（ENA、ENA、ENB 和 ENB）和 DON 的联合毒性及其潜在机制。结果表明，几乎所有混合组都表现出拮抗作用，特别是在 1/4 IC（CI = 6.488）时的 ENB。ENNs 的共孵育减轻了 DON 破坏的信号分子水平，包括活性氧（ROS）、钙动员（Ca）和三磷酸腺苷（ATP）。混合组和 ENB 组之间差异表达基因（DEGs）显著富集在 Ras/PI3K/Akt 信号通路中，包括 28 个上调基因和 40 个下调基因。实时定量 PCR 进一步证实了混合组中凋亡基因的表达降低，从而降低了 DON 暴露引起的细胞毒性作用。本研究强调，ENNs 和 DON 的共同暴露通过调节 Ras/PI3K/Akt 信号通路降低了细胞毒性。我们的研究结果提供了关于 ENNs 和 DON 对 Caco-2 细胞的拮抗毒性的第一个全面证据，并为通过转录组学研究机制提供了新的见解。
