Identification of mouse metabolic variations related to patulin-induced acute and subacute hepatotoxicity by ultra-high-performance liquid chromatography high-resolution mass spectrometry

Abstract

Patulin (PAT), a toxin produced by molds in fruits and related products, has caused frequent food poisoning incidents worldwide. However, its potential mechanism of hepatotoxicity remains presently unclear. Herein, we intragastrically administered the C57BL/6J mice with 0, 1, 4, and 16 mg/kg b.wt of PAT on a single occasion (acute model), and 0, 50, 200, and 800 μg/kg b.wt of PAT daily over two weeks (subacute model). Assessments of histopathology and aminotransferase activities confirmed that significant hepatic damages were induced. Metabolic profiling on the liver using ultra-high-performance liquid chromatography high-resolution mass spectrometry discovered 43 and 61 differential metabolites in two models, respectively. Notably, acute and subacute models shared the common 18 differential metabolites, among which N-acetyl-leucine, inosine, 2-O-methyladenosine, PC 40:7, PC 38:6, and PC 34:2 could be regarded as the biomarkers indicative of PAT exposure. Moreover, analysis of metabolic pathways demonstrated that pentose phosphate pathway and purine metabolism were the main altered pathways in the acute model. Nevertheless, more pathways related to amino acids were affected in the subacute model. These results reveal the comprehensive influence of PAT on hepatic metabolism and provide a deeper understanding of the hepatotoxicity mechanism of PAT.

Keywords: Acute liver injury; Metabolic pathway; Nontargeted metabolomics; Patulin; Subacute liver injury; UHPLC-HRMS.