Low-dose dioxins alter gene expression related to cholesterol biosynthesis, lipogenesis, and glucose metabolism through the aryl hydrocarbon receptor-mediated pathway in mouse liver

Toxicol Appl Pharmacol. 2008 May 15;229(1):10-9. doi: 10.1016/j.taap.2007.12.029. Epub 2008 Jan 17.


2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a common environmental contaminant. TCDD binds and activates the transcription factor aryl hydrocarbon receptor (AHR), leading to adverse biological responses via the alteration of the expression of various AHR target genes. Although small amounts of TCDD are consumed via contaminated daily foodstuffs and environmental exposures, the effects of low-dose TCDD on gene expression in animal tissues have not been clarified, while a number of genes affected by high-dose TCDD were reported. In this study, we comprehensively analyzed gene expression profiles in livers of C57BL/6N mice that were orally administered relatively low doses of TCDD (5, 50, or 500 ng/kg body weight (bw) day(-1)) for 18 days. The hepatic TCDD concentrations, measured by gas chromatography-mass spectrometry, were 1.2, 17, and 1063 pg toxicity equivalent quantity (TEQ)/g, respectively. The mRNA level of the cytochrome P450 CYP1A1 was significantly increased by treatment with only TCDD 500 ng/kg bw day(-1). DNA microarray and quantitative RT-PCR analyses revealed changes in the expression of genes involved in the circadian rhythm, cholesterol biosynthesis, fatty acid synthesis, and glucose metabolism in the liver with at all doses of TCDD employed. However, repression of expression of genes involved in energy metabolism was not observed in the livers of Ahr-null mice that were administered the same dose of TCDD. These results indicate that changes in gene expression by TCDD are mediated by AHR and that exposure to low-dose TCDD could affect energy metabolism via alterations of gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cholesterol / biosynthesis
  • Circadian Rhythm / physiology
  • Cytochrome P-450 CYP1A1 / drug effects
  • Cytochrome P-450 CYP1A1 / metabolism
  • Dose-Response Relationship, Drug
  • Environmental Pollutants / administration & dosage
  • Environmental Pollutants / toxicity*
  • Fatty Acids / biosynthesis
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Glucose / metabolism
  • Lipogenesis / drug effects
  • Liver / drug effects
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • Polychlorinated Dibenzodioxins / administration & dosage
  • Polychlorinated Dibenzodioxins / toxicity*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Receptors, Aryl Hydrocarbon / drug effects*
  • Receptors, Aryl Hydrocarbon / genetics
  • Reverse Transcriptase Polymerase Chain Reaction


  • Ahr protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Environmental Pollutants
  • Fatty Acids
  • Polychlorinated Dibenzodioxins
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Cholesterol
  • Cytochrome P-450 CYP1A1
  • Glucose