Tributyl phosphate impairs the urea cycle and alters liver pathology and metabolism in mice after short-term exposure based on a metabonomics study

Abstract

As a newly emerging environmental contaminant, tributyl phosphate (TBP) is of increasing concern because of the environmental problems it can cause. Studies have suggested that TBP induces hepatocellular adenomas and has malignant potential for hepatocellular carcinoma. However, the mechanisms of its adverse effects are unclear. In this study, metabonomic techniques were used to identify differential endogenous metabolites, draw network metabolic pathways and conduct network analysis to elucidate the underlying mechanisms involved in TBP induced pathological changes of the liver. The metabonomics study showed that TBP altered endogenous metabolites in the plasma and liver. The number of categories of endogenous metabolites with a VIP >1 were 14 in plasma and 20 in liver. The results also showed that TBP impaired urea synthesis in the liver. In addition, results of both in vitro and in vivo experiments indicated that TBP activated nuclear receptor CAR and inhibited CYP3a11 and CYP2b10 activities in the liver of mice after short-term exposure. These effects may be the underlying causes leading to TBP induced hepatocellular adenomas. This study combined metabonomics and other technical methods to clarify the mechanism of TBP-induced liver tumorigenesis from a new perspective.

Keywords: Metabonomics; Tributyl phosphate; Tumorigenesis; Urea cycle.