Comparative Metabolomic and Genomic Analyses of TCDD-Elicited Metabolic Disruption in Mouse and Rat Liver

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) elicits a broad spectrum of species-specific effects that have not yet been fully characterized. This study compares the temporal effects of TCDD on hepatic aqueous and lipid metabolite extracts from immature ovariectomized C57BL/6 mice and Sprague-Dawley rats using gas chromatography-mass spectrometry and nuclear magnetic resonance-based metabolomic approaches and integrates published gene expression data to identify species-specific pathways affected by treatment. TCDD elicited metabolite and gene expression changes associated with lipid metabolism and transport, choline metabolism, bile acid metabolism, glycolysis, and glycerophospholipid metabolism. Lipid metabolism is altered in mice resulting in increased hepatic triacylglycerol as well as mono- and polyunsaturated fatty acid (FA) levels. Mouse-specific changes included the induction of CD36 and other cell surface receptors as well as lipases- and FA-binding proteins consistent with hepatic triglyceride and FA accumulation. In contrast, there was minimal hepatic fat accumulation in rats and decreased CD36 expression. However, choline metabolism was altered in rats, as indicated by decreases in betaine and increases in phosphocholine with the concomitant induction of betaine-homocysteine methyltransferase and choline kinase gene expression. Results from these studies show that aryl hydrocarbon receptor-mediated differential gene expression could be linked to metabolite changes and species-specific alterations of biochemical pathways.

Comparison of TCDD-elicited genome-wide hepatic gene expression in Sprague–Dawley rats and C57BL/6 mice

“…Despite similarities in structural organization, amino acid sequence, and mode of action, as well as the conserved specificity of AhR binding to DREs (Bank et al, 1992; Denison et al, 1986, 2011; Hahn et al, 1997; Okey et al, 1994), a number of species-specific toxicogenomic, histopathological, and physiological responses are elicited by TCDD and related compounds (Black et al, 2012; Boutros et al, 2008; Boverhof et al, 2006; Carlson et al, 2009; Dere et al, 2011b; Forgacs et al, 2012, submitted for publication; Gonzalez and Shah, 2008; Maglich et al, 2002; Poland and Knutson, 1982; Silkworth et al, 2005). For example, acute high dose TCDD exposure induces hepatic steatosis in the mouse, with minimal hepatic fat accumulation in rats, while hepatocyte hyper-trophy is only reported in rat (Boverhof et al, 2006).…”

“…For example, acute high dose TCDD exposure induces hepatic steatosis in the mouse, with minimal hepatic fat accumulation in rats, while hepatocyte hyper-trophy is only reported in rat (Boverhof et al, 2006). Species-specific differences in choline metabolism (Forgacs et al, 2012) and serum clinical chemistry responses including alterations in serum alanine aminotransferase, cholesterol, free fatty acids, and triglycerides have also been reported (Boverhof et al, 2006; Forgacs et al, 2012). …”

“…In vivo genome-wide analysis showed that <20% of TCDD-responsive orthologs were conserved between rats and mice. Many of these differences were also reflected in species-specific hepatic metabolomic profiles (Forgacs et al, 2012). Similarly, >70% of the TCDD-elicited differentially expressed orthologs in rat H4IIE, mouse Hepa1c1c7, and human HepG2 hepatoma or HL1-1 liver stem-cell like cell lines were species-specific (Dere et al, 2011b; Kim et al, 2009).…”

The effects of early postnatal exposure to a low dose of decabromodiphenyl ether (BDE-209) on serum metabolites in male mice

“…Several toxicological studies of environmental contaminants have reported the metabolomic effects of BDE-209-like compounds (e.g., dioxins, PCBs, and organohalogen pesticides). Acylcarnitines, phospholipids, fatty acids, and some amino acids were reported as potential biomarkers of exposure to these compounds, which were related to amino acid and lipid metabolism (Lin et al, 2011;Forgacs et al, 2012;O'Kane et al, 2013;Moser et al, 2015). In the aryl hydrocarbon receptor (AhR) null mouse, 2,3,7,8-tetrachlorodibenzofuran (TCDF) treatment did not induce significant changes in glucose and lipid metabolite profiles from serum and liver extracts, indicating that the induced metabolic changes of these pathways by dioxin-like compounds might be mediated by AhR expression (Zhang et al, 2015).…”

Dioxin-Produced Alteration in the Profiles of Fecal and Urinary Metabolomes: A Change in Bile Acids and Its Relevance to Toxicity

“…It is, therefore, likely that such a change in metabolome is directly linked to the toxicity. To address this issue, many researchers have conducted comprehensive metabolomic analyses, the results of which have suggested that dioxins alter the levels of a number of compounds and components in the liver, [10][11][12] skeletal muscle, 12) hippocampus, 13) cerebellum, 14) blood, 15,16) and urine 17) in mice and rats, and in HepG2 cells. 18) However, in spite of these research findings, the component(s) contributing to dioxin toxicity appears to remain largely unidentified.…”