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

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.

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…Developmental exposure to environmental contaminants such as a mixture of polychlorinated biphenyls (PCBs) reduced the hepatic abundance of SAM and DNA methyltransferases in the rat [84]. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) also alters the hepatic one-carbon metabolism pathway and abundance of SAM in mice [85].…”

Genome-Wide ChIPseq Analysis of AhR, COUP-TF, and HNF4 Enrichment in TCDD-Treated Mouse Liver

“…The present study examined the effect of TCDD on AhR, HNF4α and COUP-TFII genomic binding with subsequent effects on the expression of genes associated with liver function and hepatocyte differentiation. As a potent AhR agonist, TCDD dysregulates a plethora of hepatic functions in rodents, including lipoprotein assembly and export metabolism [17,19], bile acid homeostasis [14,30], cholesterol metabolism [17,19], lipid metabolism [13,17,19], glucose metabolism [25,26,31], iron and heme homeostasis [32], one-carbon metabolism [33], and cobalamin-dependent reactions [34]. Previous studies have established that the activated AhR can bind to DNA motif as a heterodimer with ARNT and associated with other transcription factors such as COUP-TF, HIF, HNF4, LRH1, NRF1, PPAR, and RXR [3].…”

Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease

“…The same dose range (sesame oil vehicle and 0.01-30 µg/kg TCDD) and dosing regimen (every 4 days for 28 days) has been used in previous studies to examine TCDDelicited effects in mice relevant to NAFL D development and progression [9,[11][12][13][14][15]30,[76][77][78]. This model recapitulates similar NAFLD progression and pathologies with hepatocyte vacuolization at doses as low as 0.3 µg/kg TCDD.…”