Toxic effects of chronic low-dose exposure of thioacetamide on rats based on NMR metabolic profiling.

Thioacetamide (TAA) is a well-known toxicant and its long term exposure could induce liver fibrosis and cirrhosis. A liver fibrosis rat model was established by consecutive injection of TAA solution for 7 weeks. Serum and urine samples were collected weekly for NMR based metabolomic study. Clinical biochemistry of serum samples revealed liver impairment and fibrosis. Histopathological inspections disclosed severe liver fibrosis and cirrhosis formation, and pathological changes in kidney by long-term TAA administration. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied on serum and urine samples to excavate differential metabolites associated with TAA induced impairment and explore the time-dependent metabolic event associated with this xenobiotic perturbation. Integration of metabolomics results with serum biochemical revealed several potential biomarkers for liver fibrosis (2-hydroxybutyrate, 3-hydroxybutyrate and adipate in urine, and phenylalanine, N,N-dimethyl glycine, O-acetyl glycoprotein, N-acetyl glycoprotein and choline in serum). Pathway analysis revealed disturbed pathways concerning tricarboxylic acid (TCA) cycle, pyruvate metabolism, starch and sucrose metabolism, glycolysis or gluconeogenesis, degradation of ketone bodies, butanoate metabolism, and biosynthesis of BCAAs (valine, leucine and isoleucine) and AAAs (phenylalanine, tyrosine and tryptophan). This integrative study should help to develop a systematic understanding of liver fibrosis-related diseases and their metabolic events.