Cargando…

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

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 e...

Descripción completa

Detalles Bibliográficos
Autores principales: Fling, Russell R., Doskey, Claire M., Fader, Kelly A., Nault, Rance, Zacharewski, Tim R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481292/
https://www.ncbi.nlm.nih.gov/pubmed/32908189
http://dx.doi.org/10.1038/s41598-020-71795-0
_version_ 1783580569722945536
author Fling, Russell R.
Doskey, Claire M.
Fader, Kelly A.
Nault, Rance
Zacharewski, Tim R.
author_facet Fling, Russell R.
Doskey, Claire M.
Fader, Kelly A.
Nault, Rance
Zacharewski, Tim R.
author_sort Fling, Russell R.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7481292
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-74812922020-09-11 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice Fling, Russell R. Doskey, Claire M. Fader, Kelly A. Nault, Rance Zacharewski, Tim R. Sci Rep Article 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. Nature Publishing Group UK 2020-09-09 /pmc/articles/PMC7481292/ /pubmed/32908189 http://dx.doi.org/10.1038/s41598-020-71795-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Fling, Russell R.
Doskey, Claire M.
Fader, Kelly A.
Nault, Rance
Zacharewski, Tim R.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice
title 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice
title_full 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice
title_fullStr 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice
title_full_unstemmed 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice
title_short 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice
title_sort 2,3,7,8-tetrachlorodibenzo-p-dioxin (tcdd) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481292/
https://www.ncbi.nlm.nih.gov/pubmed/32908189
http://dx.doi.org/10.1038/s41598-020-71795-0
work_keys_str_mv AT flingrussellr 2378tetrachlorodibenzopdioxintcdddysregulateshepaticonecarbonmetabolismduringtheprogressionofsteatosistosteatohepatitiswithfibrosisinmice
AT doskeyclairem 2378tetrachlorodibenzopdioxintcdddysregulateshepaticonecarbonmetabolismduringtheprogressionofsteatosistosteatohepatitiswithfibrosisinmice
AT faderkellya 2378tetrachlorodibenzopdioxintcdddysregulateshepaticonecarbonmetabolismduringtheprogressionofsteatosistosteatohepatitiswithfibrosisinmice
AT naultrance 2378tetrachlorodibenzopdioxintcdddysregulateshepaticonecarbonmetabolismduringtheprogressionofsteatosistosteatohepatitiswithfibrosisinmice
AT zacharewskitimr 2378tetrachlorodibenzopdioxintcdddysregulateshepaticonecarbonmetabolismduringtheprogressionofsteatosistosteatohepatitiswithfibrosisinmice