Aflatoxin M1 and ochratoxin A induce a competitive endogenous RNA regulatory network of intestinal immunosuppression by whole-transcriptome analysis
Aflatoxin M1 and ochratoxin A induce a competitive endogenous RNA regulatory network of intestinal immunosuppression by whole-transcriptome analysis
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DOI：
10.1016/j.scitotenv.2022.158777
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发表时间：
2022-09-22
影响因子：
9.8
通讯作者：
Zheng, Nan
中科院分区：
文献类型：
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作者：
Gao, Ya-Nan;Wang, Zi-Wei;Zheng, Nan
黄曲霉毒素M1（AFM 1）和赭曲霉毒素A（OTA）是谷物食品和乳制品中常见的真菌毒素，对人体健康可能造成严重的负面影响。肠道对于免疫调节至关重要，因为它保护宿主的稳态健康免受外部污染物的影响;然而，AFM 1和OTA介导的肠道免疫毒性的潜在机制仍不清楚。在这项研究中，使用全转录组分析来表征暴露于单独和组合AFM 1和OTA [3.0 mg/kg体重（BW）] 28天的BALB/c小鼠肠道，以筛选关键的肠道免疫毒性相关差异表达mRNA（DEmRNAs）、差异表达microRNA（DEmiRNAs）、差异表达长非编码RNA（DElncRNAs）和相关的富集信号通路。然后在肠分化的Caco-2细胞中使用不同的抑制剂测定进行功能验证，以验证转录组的准确性和筛选的关键调控因子的重要性。体内实验结果显示，AFM 1和OTA暴露可破坏肠道，并产生肠道免疫抑制作用。与AFM 1相比，OTA在联合处理中具有更强的肠道毒性。对小鼠中竞争性内源性RNA（ceRNA）调控网络的进一步分析表明，AFM 1和OTA介导的肠道免疫抑制可解释如下：（i）毒素影响DEmRNA在细胞间的转移和转导机制（Csf 1、Csf 1 r、Cxcl 10、Cx 3cr 1和Irf 1），这些基因由关键DEmiRNAs调控（miR-106-x、miR-107-y和miR-124-y）和DElncRNA Rian，和（ii）毒素抑制转化生长因子-A-活化激酶1（TAK 1）/I-κ B激酶（IKK）/κ B α抑制剂（IxB α）/p65核因子-κ B（NF-κ B）信号传导磷酸化水平，这在分化的Caco-2细胞中使用TAK 1抑制剂（5 Z-7-oxozeaenol）验证。总之，我们从整个转录组的角度评估了共同暴露于AFM 1和OTA的风险以及相关的健康危害。
Aflatoxin M1 (AFM1) and ochratoxin A (OTA) are common mycotoxins in cereal foods and milk products, and may cause serious negative impacts on human health. The intestine is crucial for immune regulation as it protects host homeostatic health from external contaminants; however, the underlying mechanisms of AFM1 and OTA mediated intestinal immunotoxicity remain unclear. In this study, whole transcriptome analysis was used to characterize BALB/c mouse intestines exposed to individual and combined AFM1 and OTA [3.0 mg/kg body weight (BW)] for 28 days to screen for key intestinal immunotoxicity-related differentially expressed mRNAs (DEmRNAs), differentially expressed microRNAs (DEmiRNAs), differentially expressed long non-coding RNAs (DElncRNAs), and associated enriched signaling pathways. Functional validation was then conducted in intestinal differentiated Caco-2 cells using different inhibitor assays to verify the accuracy of transcriptome and the importance of the key screened regula-tory factors. In vivo data revealed that AFM1 and OTA exposure disrupted the intestines and exerted intestinal immu-nosuppression effects. When compared with AFM1, OTA had stronger intestinal toxicity in combined treatments. Further analyses of competitive endogenous RNA (ceRNA) regulatory networks in mice showed that AFM1 and OTA mediated-intestinal immunosuppression was putatively explained as follows: (i) toxins affected DEmRNAs regarding transfer and transduction mechanisms between cells (Csf1, Csf1r, Cxcl10, Cx3cr1, and Irf1), which were reg-ulated by key DEmiRNAs (miR-106-x, miR-107-y, and miR-124-y) and the DElncRNA Rian, and (ii) toxins inhibited transforming growth factor-A-activated kinase 1 (TAK1)/I-kappaB kinase (IKK)/inhibitor of kappa B alpha (IxB alpha)/p65 nuclear factor-kappa B (NF-kappa B) signaling phosphorylation levels, which was validated in differentiated Caco-2 cells using the TAK1 inhibitor (5Z-7-oxozeaenol). In conclusion, we evaluated the risk of co-exposure to AFM1 and OTA and associated health hazards from a whole transcriptome perspective.