Pyrrolizidine alkaloid-induced transcriptomic changes in rat lungs in a 28-day subacute feeding study
Open Access
- 29 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Archives of Toxicology
- Vol. 95 (8), 2785-2796
- https://doi.org/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.Keywords
Funding Information
- Bundesinstitut für Risikobewertung (1322-624, 1329-554)
- Bundesinstitut für Risikobewertung (BfR)
This publication has 64 references indexed in Scilit:
- Whole Exome Sequencing to Identify a Novel Gene (Caveolin-1) Associated With Human Pulmonary Arterial HypertensionCirculation: Cardiovascular Genetics, 2012
- GOSemSim: an R package for measuring semantic similarity among GO terms and gene productsBioinformatics, 2010
- An Outbreak of Hepatic Veno-Occlusive Disease in Western Afghanistan Associated with Exposure to Wheat Flour Contaminated with Pyrrolizidine AlkaloidsJournal of Toxicology, 2010
- Gene expression changes induced by the tumorigenic pyrrolizidine alkaloid riddelliine in liver of Big Blue ratsBMC Bioinformatics, 2007
- Function of Kv1.5 channels and genetic variations ofKCNA5in patients with idiopathic pulmonary arterial hypertensionAmerican Journal of Physiology-Cell Physiology, 2007
- Short-Term Administration of a Cell-Permeable Caveolin-1 Peptide Prevents the Development of Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular HypertrophyCirculation, 2006
- Monocrotaline pyrrole targets proteins with and without cysteine residues in the cytosol and membranes of human pulmonary artery endothelial cellsProteomics, 2005
- Integrins: Bidirectional, Allosteric Signaling MachinesCell, 2002
- EMR4, a Novel Epidermal Growth Factor (EGF)-TM7 Molecule Up-regulated in Activated Mouse Macrophages, Binds to a Putative Cellular Ligand on B Lymphoma Cell Line A20Online Journal of Public Health Informatics, 2002
- Pyrrolizidine (Senecio) intoxication mimicking Reye syndromeThe Journal of Pediatrics, 1978