2,3,7,8-Tetrachlorodibenzo-p-Dioxin Alters Lipid Metabolism and Depletes Immune Cell Populations in the Jejunum of C57BL/6 Mice

Toxicol Sci. 2015 Dec;148(2):567-80. doi: 10.1093/toxsci/kfv206. Epub 2015 Sep 16.


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.

Keywords: MetS; NAFLD; TCDD; jejunum; macrophage; toxicogenomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Environmental Pollutants / toxicity*
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation
  • Genes, MHC Class II
  • Immunity, Mucosal / drug effects*
  • Immunity, Mucosal / genetics
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Jejunum / drug effects*
  • Jejunum / immunology
  • Jejunum / metabolism
  • Jejunum / pathology
  • Lipid Metabolism / drug effects*
  • Lipid Metabolism / genetics
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / chemically induced*
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / immunology
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Polychlorinated Dibenzodioxins / toxicity*
  • Risk Assessment
  • Time Factors


  • Environmental Pollutants
  • Polychlorinated Dibenzodioxins