Zearalenone (ZEA) is a mycotoxin that frequently occurs in agricultural crops and related products and seriously threatens both animal feed and human food safety. To identify key metabolites and regulators involved in ZEA toxicological processes, we performed metabolomic and transcriptomic analyses of porcine IPEC-J2 intestinal epithelial cells upon ZEA exposure using liquid chromatography-mass spectrometry (LC-MS)/MS and RNA-seq techniques. A total of 325 differential metabolites and 5646 differentially expressed genes were detected. Integrated analyses of metabolomic and transcriptomic data indicated that metabolic processes including lipid metabolism, amino acid metabolism, and carbohydrate metabolism were most affected. Exogenous addition of the key metabolite l-arginine significantly facilitated ZEA metabolism and ameliorated ZEA-induced reactive oxygen species levels and cell apoptosis. Furthermore, l -arginine contributed to the expression of phase II detoxification genes (SULT2B1, GSTA1, GSTM3, and GPX4). l-Arginine addition also increased the protein levels of LC3-II and Beclin 1, and downregulated p62/SQSTM1 levels, indicating its regulatory roles in autophagic flux activation upon ZEA exposure. This study provided global insights into metabolic and transcriptional changes as well as key metabolites and regulators underlying the cellular response to ZEA exposure, and paved the way for the identification of metabolic and molecular targets for biomonitoring and controlling contamination by ZEA.
Keywords: cytoprotective activity; l-arginine; metabolome; toxicity; transcriptome; zearalenone.