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 µg/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.

中文翻译：

---

一项为期28天的喂养研究表明，肝毒性吡咯烷嗪生物碱可诱导大鼠肝脏中的DNA损伤反应。

吡咯烷核生物碱（PA）是植物的次生代谢产物，可作为食物和饲料中的污染物。急性和亚急性PA中毒可导致人和动物的严重肝损伤，包括肝痛，肝肿大和由于肝窦窦闭塞引起的腹水发展（静脉闭塞性疾病）。长期暴露于低水平的PA会诱发肝硬化和肝癌。但是，尚不清楚PA诱导哪些转录变化，以及所有肝毒性PA，无论其结构如何，均诱导相似的应答。因此，进行了一项为期28天的亚急性大鼠摄食研究，使用了六种结构不同的PA乙酰肾上腺素，衣着亚idine胺，拉西卡洛平，senecionine，senkirkine和platyphylline，它们的急性毒性剂量为0.1至3.3 mg / kg体重。该剂量范围与人类有关，因为成年人食用受污染的茶可能导致〜8 µg / kg的剂量，并且据报道婴儿的剂量高达3 mg / kg体重时，被污染的食物摄入PA的情况。ALT和AST在所有治疗组中均未升高。全基因组微阵列分析揭示了高剂量治疗组中基因表达的显着影响，从而产生了36个共同调控的基因。但是，仅1，2-饱和的因此，因此推测为非肝毒性的PA茶碱没有引起明显的表达变化。被确定受高剂量治疗（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控。这些功能均受所有分析过的1,2-不饱和PA影响。2-不饱和肝毒性PA诱导的细胞周期调控过程与DNA损伤反应有关。对于所有肝毒性PA，观察到相似的作用。在不引起组织病理学改变且肝酶未增加的剂量范围内观察到效果。因此，转录组学研究确定了在最坏的情况下，与人类有关的PA剂量下，与基因毒性化合物反应相关的基因表达的变化。