Pyrrolizidine alkaloid-induced transcriptomic changes in rat lungs in a 28-day subacute feeding study

Julia Buchmueller,Albert Braeuning,Stefanie Hessel-Pras,Otto Creutzenberg,Josef Daniel Rasinger,Johanna Ebmeyer,Jan G Hengstler,Heike Sprenger,Dirk Schaudien,Georgia Guenther

doi:10.1007/s00204-021-03108-x

Abstract

Pyrrolizidine alkaloids (PAs) are secondary plant metabolites synthesized by a wide range of plants as protection against herbivores. These toxins are found worldwide and pose a threat to human health. PAs induce acute effects like hepatic sinusoidal obstruction syndrome and pulmonary arterial hypertension. Moreover, chronic exposure to low doses can induce cancer and liver cirrhosis in laboratory animals. The mechanisms causing hepatotoxicity have been investigated previously. However, toxic effects in the lung are less well understood, and especially data on the correlation effects with individual chemical structures of different PAs are lacking. The present study focuses on the identification of gene expression changes in vivo in rat lungs after exposure to six structurally different PAs (echimidine, heliotrine, lasiocarpine, senecionine, senkirkine, and platyphylline). Rats were treated by gavage with daily doses of 3.3 mg PA/kg bodyweight for 28 days and transcriptional changes in the lung and kidney were investigated by whole-genome microarray analysis. The results were compared with recently published data on gene regulation in the liver. Using bioinformatics data mining, we identified inflammatory responses as a predominant feature in rat lungs. By comparison, in liver, early molecular consequences to PAs were characterized by alterations in cell-cycle regulation and DNA damage response. Our results provide, for the first time, information about early molecular effects in lung tissue after subacute exposure to PAs, and demonstrates tissue-specificity of PA-induced molecular effects.

Highlights

Pyrrolizidine alkaloids (PAs) are secondary plant metabolites occurring in approximately 3% of all flowering plants worldwide
Several studies were performed to evaluate the effect of PAs on gene expression patterns in the liver (Mei et al 2007; Ebmeyer et al 2020); the latter, presenting results of a whole-genome microarray analysis of the livers of the same animals examined in this study
After oral treatment of rats with six different PAs, each administered at a dose of 3.3 mg PA/kg body weight, we observed a change in transcription patterns in the lung especially for the PAs heliotrine and senkirkine (Fig. 3) that are completely different from the effects observed in the liver

Summary

Introduction

Pyrrolizidine alkaloids (PAs) are secondary plant metabolites occurring in approximately 3% of all flowering plants worldwide. The PA-parent compounds are not bioactive themselves They are metabolized and activated by cytochrome P450 monooxygenases (CYPs) (Stegelmeier et al 1999; Mattocks 1968). The currently existing risk assessment of PAs based on chronic, acute or subacute animal studies focuses predominantly on effects in the liver as the most affected organ (BfR 2020; EFSA 2011; Huang et al 2017; Mei et al 2007). Our study aimed to elucidate effects on the lung in a subacute rat study orally treated for 28 days with six structurally different PAs that were found to occur most frequently in spices and culinary herbs (Kaltner et al 2020). The PA representatives echimidine, heliotrine, lasiocarpine, senecionine, senkirkine, and platyphylline were used to monitor possible structure-specific PA effects

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