2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that induces diverse biological and toxic effects, including reprogramming intermediate metabolism, mediated by the aryl hydrocarbon receptor. However, the specific reprogramming effects of TCDD are unclear. Here, we performed targeted LC-MS analysis of hepatic extracts from mice gavaged with TCDD. We detected an increase in S-(2-carboxyethyl)-L-cysteine, a conjugate from the spontaneous reaction between the cysteine sulfhydryl group and highly reactive acrylyl-CoA, an intermediate in the cobalamin (Cbl)-independent β–oxidation-like metabolism of propionyl-CoA. TCDD repressed genes in both the canonical Cbl-dependent carboxylase and the alternate Cbl-independent β–oxidation-like pathways as well as inhibited methylmalonyl-CoA mutase (MUT) at lower doses. Moreover, TCDD decreased serum Cbl levels and hepatic cobalt levels while eliciting negligible effects on gene expression associated with Cbl absorption, transport, trafficking, or derivatization to 5′-deoxy-adenosylcobalamin (AdoCbl), the required MUT cofactor. Additionally, TCDD induced the gene encoding aconitate decarboxylase 1 (Acod1), the enzyme responsible for decarboxylation of cis-aconitate to itaconate, and dose-dependently increased itaconate levels in hepatic extracts. Our results indicate MUT inhibition is consistent with itaconate activation to itaconyl-CoA, a MUT suicide inactivator that forms an adduct with adenosylcobalamin. This adduct in turn inhibits MUT activity and reduces Cbl levels. Collectively, these results suggest the decrease in MUT activity is due to Cbl depletion following TCDD treatment, which redirects propionyl-CoA metabolism to the alternate Cbl-independent β–oxidation-like pathway. The resulting hepatic accumulation of acrylyl-CoA likely contributes to TCDD-elicited hepatotoxicity and the multihit progression of steatosis to steatohepatitis with fibrosis.

2,3,7,8-四氯二苯并-对-二恶英 (TCDD) 是一种持久性环境污染物，可诱导多种生物和毒性效应，包括由芳烃受体介导的重编程中间代谢。然而，TCDD 的具体重编程效应尚不清楚。在这里，我们对用 TCDD 灌胃的小鼠的肝提取物进行了靶向 LC-MS 分析。我们检测到 S-(2-羧乙基)-L-半胱氨酸的增加，这是半胱氨酸巯基与高反应性丙烯酰辅酶 A 之间自发反应的结合物，是钴胺素 (Cbl) 非依赖性 β-氧化样的中间体丙酰辅酶A的代谢。TCDD 抑制经典 Cbl 依赖性羧化酶和替代 Cbl 非依赖性 β-氧化样途径中的基因，并在较低剂量下抑制甲基丙二酰辅酶 A 变位酶 (MUT)。而且，TCDD 降低了血清 Cbl 水平和肝钴水平，同时对与 Cbl 吸收、转运、运输或衍生为 5'-脱氧腺苷钴胺素 (AdoCbl)（所需的 MUT 辅助因子）相关的基因表达的影响可忽略不计。此外，TCDD 诱导了编码乌头酸脱羧酶 1 (Acod1) 的基因，该酶负责将顺式乌头酸脱羧为衣康酸，并剂量依赖性地增加肝提取物中的衣康酸水平。我们的结果表明 MUT 抑制与衣康酸盐对衣康酰辅酶 A 的激活一致，衣康酰辅酶 A 是一种与腺苷钴胺素形成加合物的 MUT 自杀灭活剂。这种加合物反过来抑制 MUT 活性并降低 Cbl 水平。总的来说，这些结果表明 MUT 活性的降低是由于 TCDD 治疗后 Cbl 耗尽，它将丙酰辅酶 A 代谢重定向到替代的 Cbl 非依赖性 β-氧化样途径。由此产生的丙烯酰辅酶 A 在肝脏中的积累可能导致 TCDD 引起的肝毒性和脂肪变性向纤维化脂肪性肝炎的多重打击进展。