title: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Agnes L
authors.initials: AL
authors.lastname: Forgacs
authors.forename: Michael N
authors.initials: MN
authors.lastname: Kent
authors.forename: Meghan K
authors.initials: MK
authors.lastname: Makley
authors.forename: Bryan
authors.initials: B
authors.lastname: Mets
authors.forename: Nicholas
authors.initials: N
authors.lastname: DelRaso
authors.forename: Gary L
authors.initials: GL
authors.lastname: Jahns
authors.forename: Lyle D
authors.initials: LD
authors.lastname: Burgoon
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
authors.forename: Nicholas V
authors.initials: NV
authors.lastname: Reo
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D018955:CD36 Antigens / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D013045:Species Specificity; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D018955:CD36 Antigens; D005231:Fatty Acids, Unsaturated; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014280:Triglycerides; D002784:Cholesterol; D002794:Choline