title: 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Alters Lipid Metabolism and Depletes Immune Cell Populations in the Jejunum of C57BL/6 Mice.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor agonist that elicits dose-dependent hepatic fat accumulation and inflammation that can progress to steatohepatitis. To investigate intestine-liver interactions that contribute to TCDD-elicited steatohepatitis, we examined the dose-dependent effects of TCDD (0.01, 0.03, 0.1, 0.3, 1, 3, 10, or 30 µg/kg) on jejunal epithelial gene expression in C57BL/6 mice orally gavaged every 4 days for 28 days. Agilent 4x44K whole-genome microarray analysis of the jejunal epithelium identified 439 differentially expressed genes (|fold change| ≥ 1.5, P1(t) ≥ 0.999) across 1 or more doses, many related to lipid metabolism and immune system processes. TCDD-elicited differentially expressed genes were associated with lipolysis, fatty acid/cholesterol absorption and transport, the Kennedy pathway, and retinol metabolism, consistent with increased hepatic fat accumulation. Moreover, several major histocompatibility complex (MHC) class II genes (H2-Aa, H2-Ab1, H2-DMb1, Cd74) were repressed, coincident with decreased macrophage and dendritic cell levels in the lamina propria, suggesting migration of antigen-presenting cells out of the intestine. In contrast, hepatic RNA-Seq analysis identified increased expression of MHC class II genes, as well as chemokines and chemokine receptors involved in macrophage recruitment (Ccr1, Ccr5, Ccl5, Cx3cr1), consistent with hepatic F4/80 labeling and macrophage infiltration into the liver. Collectively, these results suggest TCDD elicits changes that support hepatic lipid accumulation, macrophage migration, and the progression of hepatic steatosis to steatohepatitis.
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824; Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824;
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Fader
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824; Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824;
authors.forename: Rance
authors.initials: R
authors.lastname: Nault
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824;
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Ammendolia
authors.affiliation: Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824; Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824;
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824;
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Williams
authors.affiliation: Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824; and.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Crawford
authors.affiliation: Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824; and.
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
authors.affiliation: Wellington Laboratories Inc., Guelph, Ontario N1G 3M5, Canada.
authors.forename: Dave
authors.initials: D
authors.lastname: Potter
authors.affiliation: Wellington Laboratories Inc., Guelph, Ontario N1G 3M5, Canada.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Sharratt
authors.affiliation: *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824; *Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824; tzachare@msu.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D018928:Immunity, Mucosal / Q000187:drug effects* / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007583:Jejunum / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins
keywords: MetS; NAFLD; TCDD; jejunum; macrophage; toxicogenomics