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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice.

Scientific reports (2020-09-11)
Russell R Fling, Claire M Doskey, Kelly A Fader, Rance Nault, Tim R Zacharewski
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
1,4-Diaminobutane, 99%
Supelco
Amino acid standards, physiological, analytical standard, acidics, neutrals, and basics
Sigma-Aldrich
Cell Free Amino Acid Mixture - 13C,15N, 98 atom % 15N, 98 atom % 13C, ~5-100 mM in water
Supelco
DL-Homocysteine, analytical standard
Sigma-Aldrich
L-Homocysteic acid
Supelco
N,N-Dimethylglycine, for HPLC derivatization, LiChropur, ≥99% (NT)