Inhibition of the urea cycle by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin increases serum ammonia levels in mice

J Biol Chem. 2024 Jan;300(1):105500. doi: 10.1016/j.jbc.2023.105500. Epub 2023 Nov 25.


The aryl hydrocarbon receptor is a ligand-activated transcription factor known for mediating the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. TCDD induces nonalcoholic fatty liver disease (NAFLD)-like pathologies including simple steatosis that can progress to steatohepatitis with fibrosis and bile duct proliferation in male mice. Dose-dependent progression of steatosis to steatohepatitis with fibrosis by TCDD has been associated with metabolic reprogramming, including the disruption of amino acid metabolism. Here, we used targeted metabolomic analysis to reveal dose-dependent changes in the level of ten serum and eleven hepatic amino acids in mice upon treatment with TCDD. Bulk RNA-seq and protein analysis showed TCDD repressed CPS1, OTS, ASS1, ASL, and GLUL, all of which are associated with the urea cycle and glutamine biosynthesis. Urea and glutamine are end products of the detoxification and excretion of ammonia, a toxic byproduct of amino acid catabolism. Furthermore, we found that the catalytic activity of OTC, a rate-limiting step in the urea cycle was also dose dependently repressed. These results are consistent with an increase in circulating ammonia. Collectively, the repression of the urea and glutamate-glutamine cycles increased circulating ammonia levels and the toxicity of TCDD.

Keywords: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); ammonia; aryl hydrocarbon receptor (AHR); liver; toxicogenomics.

MeSH terms

  • Ammonia* / blood
  • Ammonia* / metabolism
  • Animals
  • Fibrosis
  • Glutamine / metabolism
  • Liver / metabolism
  • Male
  • Metabolic Networks and Pathways* / drug effects
  • Mice
  • Non-alcoholic Fatty Liver Disease* / chemically induced
  • Polychlorinated Dibenzodioxins* / toxicity
  • Receptors, Aryl Hydrocarbon / metabolism


  • Ammonia
  • Glutamine
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon