Metabolomic analysis of the effects of chronic arsenic exposure in a mouse model of diet-induced Fatty liver disease

Abstract

Arsenic is a widely distributed environmental component that is associated with a variety of cancer and non-cancer adverse health effects. Additional lifestyle factors, such as diet, contribute to the manifestation of disease. Recently, arsenic was found to increase inflammation and liver injury in a dietary model of fatty liver disease. The purpose of the present study was to investigate potential mechanisms of this diet-environment interaction via a high-throughput metabolomics approach. GC×GC-TOF MS was used to identify metabolites that were significantly increased or decreased in the livers of mice fed a Western diet (a diet high in fat and cholesterol) and co-exposed to arsenic-contaminated drinking water. The results showed that there are distinct hepatic metabolomic profiles associated with eating a high fat diet, drinking arsenic-contaminated water, and the combination of the two. Among the metabolites that were decreased when arsenic exposure was combined with a high fat diet were short-chain and medium-chain fatty acid metabolites and the anti-inflammatory amino acid, glycine. These results are consistent with the observed increase in inflammation and cell death in the livers of these mice and point to potentially novel mechanisms by which these metabolic pathways could be altered by arsenic in the context of diet-induced fatty liver disease.

Figure 1

Sample GC×GC-TOF MS chromatograms of metabolite extract from mouse liver. The x-axis is the first dimension retention time ¹t_R in seconds. The y-axis is the second dimension retention time ²t_R in seconds. The color bar shows the signal intensity of each peak plotted on the chromatogram in total ion current.

Figure 2

Abundance distribution of metabolite glycine in the liver samples of HFD+As group and HFD group. The abundance test (pairwise two-tail t-test) shows that the regulation of this metabolite in the HFD+As group is decreased with a fold change of 1.7 and a p-value of 5.0×10⁻³ comparing with HFD group.