2,3,7,8-Tetrachlorodibenzo-p-dioxin elicited decreases in cobalamin inhibits methylmalonyl-CoA mutase activity redirecting propionyl-CoA metabolism to the β–oxidation-like pathway resulting in hepatic accumulation of the toxic intermediate acrylyl-CoA

Abstract

ABSTRACT2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant and the prototypical ligand for the aryl hydrocarbon receptor (AhR). AhR mediates the effects of TCDD and related compounds, including the reprograming of intermediate metabolism. Untargeted metabolomics analysis of hepatic extracts prepared from mice orally gavaged with TCDD every 4 days for 28 days identified the dose-dependent induction of acrylyl-CoA, a highly reactive toxic intermediate produced during the metabolism of propionyl-CoA in the cobalamin (Cbl)-independent β–oxidation-like pathway. Acrylyl-CoA is a biomarker of inborn errors of metabolism associated with propionic and methylmalonic acidemia associated with Cbl deficiency, transport and/or defects in Cbl-dependent methylmalonyl-CoA mutase (MUT). Although TCDD repressed gene expression for both the canonical Cbl-dependent carboxylase and the alternate Cbl-independent β–oxidation-like pathways, inhibition occurred only at 30 μg/kg TCDD while acrylyl-CoA levels increased at ~3 μg/kg. In contrast, TCDD decreased serum Cbl and hepatic cobalt levels at ~3 μg/kg TCDD consistent with the dosedependent increase in acrylyl-CoA levels. TCDD elicited negligible effects on the expression of genes associated with Cbl absorption, transport, trafficking and derivatization to 5’-deoxy-adenosylcobalamin (AdoCbl), the required MUT cofactor. In addition, TCDD induced the decarboxylation of cis-aconitate to itaconate by Acod1. Itaconate can then be activated to itaconyl-CoA, a MUT suicide inactivator that forms an adduct with AdoCbl, blocking MUT activity and reducing Cbl levels. Collectively, these results suggest MUT activity was impaired due to Cbl depletion by TCDD causing propionyl-CoA metabolism to be redirected to the alternate Cbl-independent β–oxidation-like pathway resulting in hepatic acrylyl-CoA accumulation.