Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, 48824, USA.
Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, USA.
Sci Rep. 2020 Sep 9;10(1):14831. doi: 10.1038/s41598-020-71795-0.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, induces steatosis that can progress to steatohepatitis with fibrosis, pathologies that parallel stages in the development of non-alcoholic fatty liver disease (NAFLD). Coincidently, one carbon metabolism (OCM) gene expression and metabolites are often altered during NAFLD progression. In this study, the time- and dose-dependent effects of TCDD were examined on hepatic OCM in mice. Despite AhR ChIP-seq enrichment at 2 h, OCM gene expression was not changed within 72 h following a bolus dose of TCDD. Dose-dependent repression of methionine adenosyltransferase 1A (Mat1a), adenosylhomocysteinase (Achy) and betaine-homocysteine S-methyltransferase (Bhmt) mRNA and protein levels following repeated treatments were greater at 28 days compared to 8 days. Accordingly, levels of methionine, betaine, and homocysteic acid were dose-dependently increased, while S-adenosylmethionine, S-adenosylhomocysteine, and cystathionine exhibited non-monotonic dose-dependent responses consistent with regulation by OCM intermediates and repression of glycine N-methyltransferase (Gnmt). However, the dose-dependent effects on SAM-dependent metabolism of polyamines and creatine could not be directly attributed to alterations in SAM levels. Collectively, these results demonstrate persistent AhR activation disrupts hepatic OCM metabolism at the transcript, protein and metabolite levels within context of TCDD-elicited 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，可诱导脂肪变性，进而发展为伴有纤维化的脂肪性肝炎，其病理变化与非酒精性脂肪性肝病（NAFLD）的发展阶段相平行。巧合的是，一碳代谢（OCM）基因表达和代谢物在 NAFLD 进展过程中经常发生改变。在本研究中，研究了 TCDD 在小鼠肝脏 OCM 中的时间和剂量依赖性作用。尽管 AhR ChIP-seq 在 2 小时时富集，但在 TCDD 单次剂量给药后 72 小时内，OCM 基因表达并未改变。重复处理后，甲硫氨酸腺苷转移酶 1A（Mat1a）、腺苷同型半胱氨酸酶（Achy）和甜菜碱-同型半胱氨酸 S-甲基转移酶（Bhmt）mRNA 和蛋白水平的剂量依赖性抑制在 28 天比 8 天时更为明显。相应地，蛋氨酸、甜菜碱和同型半胱氨酸酸的水平呈剂量依赖性增加，而 S-腺苷甲硫氨酸、S-腺苷同型半胱氨酸和胱硫醚的水平则表现出非单调剂量依赖性反应，与 OCM 中间产物的调节和甘氨酸 N-甲基转移酶（Gnmt）的抑制一致。然而，多胺和肌酸的 SAM 依赖性代谢的剂量依赖性影响不能直接归因于 SAM 水平的改变。综上所述，这些结果表明，持续的 AhR 激活会破坏 TCDD 诱导的脂肪变性向伴有纤维化的脂肪性肝炎进展过程中肝脏 OCM 代谢的转录、蛋白和代谢物水平。
