Hepatotoxic pyrrolizidine alkaloids induce DNA damage response in rat liver in a 28-day feeding study
Hepatotoxic pyrrolizidine alkaloids induce DNA damage response in rat liver in a 28-day feeding study
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DOI：
10.1007/s00204-020-02779-2
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发表时间：
2020-05-17
影响因子：
6.1
通讯作者：
Hessel-Pras, Stefanie
中科院分区：
文献类型：
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作者：
Ebmeyer, Johanna;Rasinger, Josef Daniel;Hessel-Pras, Stefanie
吡咯里西啶生物碱（PA）是植物次生代谢产物，作为食物和饲料污染物存在。急性和亚急性PA中毒可导致人类和动物的严重肝损伤，包括肝痛、肝肿大和由于肝窦闭塞（静脉闭塞性疾病）而产生腹水。长期暴露于低水平的PA可诱发肝硬化和肝癌。然而，目前还不清楚哪些转录变化是由PA诱导的，以及是否所有肝毒性PA，无论其结构如何，都诱导类似的反应。因此，以0.1 - 3.3 mg/kg体重的非急性毒性剂量，使用6种结构不同的PA天芥菜碱、艾咪定、毛果芸香碱、千里光碱、senkirkine和platyphylline进行了28天亚急性大鼠喂养研究。这一剂量范围与人类有关，因为饮用受污染的茶叶可能导致成人摄入8 μ g/kg的剂量，据报告，婴儿摄入受污染食物的PA剂量高达3 mg/kg体重。所有治疗组的ALT和AST均未升高。全基因组微阵列分析显示，高剂量治疗组对基因表达有明显影响，产生了一组36个常见的调控基因。然而，platyphylline，唯一的1，2-饱和，因此，推测非肝毒性PA，没有引起显着的表达变化。确定受高剂量处理（3.3 mg/kg体重）影响的生物学功能包括与DNA损伤反应相关的细胞周期调节。发现这些功能受到所有分析的1，2-不饱和PA的影响。总之，1，2-不饱和肝毒性PA诱导的细胞周期调控过程与DNA损伤反应。对所有肝毒性PA观察到类似的效果。在未引起组织病理学改变和肝酶升高的剂量范围内观察到效应。因此，转录组学研究确定了已知在最差情况暴露情景下参与对PA剂量下与人类相关的遗传毒性化合物反应的基因表达变化。
Pyrrolizidine alkaloids (PA) are secondary plant metabolites that occur as food and feed contaminants. Acute and subacute PA poisoning can lead to severe liver damage in humans and animals, comprising liver pain, hepatomegaly and the development of ascites due to occlusion of the hepatic sinusoids (veno-occlusive disease). Chronic exposure to low levels of PA can induce liver cirrhosis and liver cancer. However, it is not well understood which transcriptional changes are induced by PA and whether all hepatotoxic PA, regardless of their structure, induce similar responses. Therefore, a 28-day subacute rat feeding study was performed with six structurally different PA heliotrine, echimidine, lasiocarpine, senecionine, senkirkine, and platyphylline, administered at not acutely toxic doses from 0.1 to 3.3 mg/kg body weight. This dose range is relevant for humans, since consumption of contaminated tea may result in doses of 8 mu g/kg in adults and cases of PA ingestion by contaminated food was reported for infants with doses up to 3 mg/kg body weight. ALT and AST were not increased in all treatment groups. Whole-genome microarray analyses revealed pronounced effects on gene expression in the high-dose treatment groups resulting in a set of 36 commonly regulated genes. However, platyphylline, the only 1,2-saturated and, therefore, presumably non-hepatotoxic PA, did not induce significant expression changes. Biological functions identified to be affected by high-dose treatments (3.3 mg/kg body weight) comprise cell-cycle regulation associated with DNA damage response. These functions were found to be affected by all analyzed 1,2-unsaturated PA. In conclusion, 1,2-unsaturated hepatotoxic PA induced cell cycle regulation processes associated with DNA damage response. Similar effects were observed for all hepatotoxic PA. Effects were observed in a dose range inducing no histopathological alterations and no increase in liver enzymes. Therefore, transcriptomics studies identified changes in expression of genes known to be involved in response to genotoxic compounds at PA doses relevant to humans under worst case exposure scenarios.