Metabolomic Analysis Reveals the Mechanisms of Hepatotoxicity Induced by Aflatoxin M1 and Ochratoxin A.
Metabolomic Analysis Reveals the Mechanisms of Hepatotoxicity Induced by Aflatoxin M1 and Ochratoxin A.
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DOI：
10.3390/toxins14020141
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发表时间：
2022-02-15
期刊：
影响因子：
4.2
通讯作者：
Zheng N
中科院分区：
文献类型：
--
作者：
Gao YN;Wu CQ;Wang JQ;Zheng N
黄曲霉毒素M1（AFM 1）是牛奶中唯一有最高残留限量的毒素，而赭曲霉毒素A（OTA）是谷类食品中常见的毒素。在环境中发现这两种毒素的共同存在是很常见的。然而，这些毒素对肝毒性的相互作用及其潜在机制仍不清楚。暴露于3.5 mg/kg b.w.个体AFM 1的小鼠的肝脏和血清代谢组学，OTA剂量为3.5 mg/kg b.w.，本研究采用UPLC-MS法进行了35 d的联合用药。随后对人肝细胞肝癌（Hep G2）细胞进行代谢组学研究，以缩小关键代谢物的范围。对肝脏重量和血清指标（如总胆红素和谷氨酰转移酶）的表型结果显示，组合毒素比单独毒素具有更严重的不良反应，表明AFM 1和OTA组合对肝损伤具有协同作用。通过肝脏和血清中的代谢分析，我们发现（i）组合毒素具有协同效应，因为组合处理时差异表达的代谢物数量高于单个毒素，（ii）OTA在AFM 1和OTA联合诱导的肝毒性中发挥主导作用，以及（iii）溶血磷脂酰胆碱（LysoPC），尤其是LysoPC（16：1），被确定为受AFM 1和OTA影响最大的代谢物。这些发现为确定AFM 1和OTA肝毒性的潜在生物标志物提供了新的见解。
Aflatoxin M1 (AFM1) is the only toxin with the maximum residue limit in milk, and ochratoxin A (OTA) represents a common toxin in cereals foods. It is common to find the co-occurrence of these two toxins in the environment. However, the interactive effect of these toxins on hepatoxicity and underlying mechanisms is still unclear. The liver and serum metabolomics in mice exposed to individual AFM1 at 3.5 mg/kg b.w., OTA at 3.5 mg/kg b.w., and their combination for 35 days were conducted based on the UPLC-MS method in the present study. Subsequent metabolome on human hepatocellular liver carcinoma (Hep G2) cells was conducted to narrow down the key metabolites. The phenotypic results on liver weight and serum indicators, such as total bilirubin and glutamyltransferase, showed that the combined toxins had more serious adverse effects than an individual one, indicating that the combined AFM1 and OTA displayed synergistic effects on liver damage. Through the metabolic analysis in liver and serum, we found that (i) a synergistic effect was exerted in the combined toxins, because the number of differentially expressed metabolites on combination treatment was higher than the individual toxins, (ii) OTA played a dominant role in the hepatoxicity induced by the combination of AFM1, and OTA and (iii) lysophosphatidylcholines (LysoPCs), more especially, LysoPC (16:1), were identified as the metabolites most affected by AFM1 and OTA. These findings provided a new insight for identifying the potential biomarkers for the hepatoxicity of AFM1 and OTA.
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