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

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.

Analysis of potential risks of clinical application of Yi Dian Hong and its proprietary Chinese medicines: A review

“…Once present in the lungs, DHPA can lead to thrombus formation and thickening of the vessel walls, ultimately causing vessel occlusion and inflammation. [36,37] The combination of these effects triggers pulmonary arterial hypertension (PAH), which can subsequently lead to congestive heart failure. Culvenor et al’s study suggests that this phenomenon is associated with low levels of PAs (0.025 mmol/kg body weight) and prolonged exposure.…”

Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and Assessment of Non-Genotoxic Carcinogens

“…As already indicated, multiple durations of exposure and relevant concentrations should be investigated with transcriptomic assays to maximise the possibility to detect specific mechanisms of action and responses to potential NGTxCs. The integration of phenotypic in vitro assays or short term sub-acute/sub-chronic repeated dose toxicity studies might provide insights with respect to the doses/concentrations and/or durations of exposure to be investigated in the transcriptomic assays [ 30 , 115 , 116 , 117 , 118 ] as an intermediate step to facilitate the transition from in vivo assays to in vitro.…”

Comparative Pharmacokinetic Study of Two Pyrrolizidine Alkaloids Lasiocarpine and Heliotrine in Rats

“…Heliotrine (HEL) is a monoester ( Fig. 1 b ) and is classified as “not classifiable as to its carcinogenicity to humans” (Group 3) by IARC 23 , 24 , 25 . These two PAs were mainly found in Heliotropium genus plants, which belong to the Boraginaceae family 26 , 27 , 28 .…”