Cargando…

Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes

High systemic levels of oestrogens are cholestatic and primary biliary cholangitis (PBC)—which is characterized by hepatic ductular inflammation—is thought to be triggered by exposure to xenobiotics such as those around landfill sites. Xenoestrogens may be a component of this chemical trigger. We th...

Descripción completa

Detalles Bibliográficos
Autores principales: Meyer, Stephanie K., Probert, Philip M. E., Lakey, Anne K., Leitch, Alastair C., Blake, Lynsay I., Jowsey, Paul A., Cooke, Martin P., Blain, Peter G., Wright, Matthew C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356623/
https://www.ncbi.nlm.nih.gov/pubmed/28013213
http://dx.doi.org/10.1093/toxsci/kfw234
_version_ 1782515875972120576
author Meyer, Stephanie K.
Probert, Philip M. E.
Lakey, Anne K.
Leitch, Alastair C.
Blake, Lynsay I.
Jowsey, Paul A.
Cooke, Martin P.
Blain, Peter G.
Wright, Matthew C.
author_facet Meyer, Stephanie K.
Probert, Philip M. E.
Lakey, Anne K.
Leitch, Alastair C.
Blake, Lynsay I.
Jowsey, Paul A.
Cooke, Martin P.
Blain, Peter G.
Wright, Matthew C.
author_sort Meyer, Stephanie K.
collection PubMed
description High systemic levels of oestrogens are cholestatic and primary biliary cholangitis (PBC)—which is characterized by hepatic ductular inflammation—is thought to be triggered by exposure to xenobiotics such as those around landfill sites. Xenoestrogens may be a component of this chemical trigger. We therefore hypothesized that xenoestrogens are present at higher levels in the proximity of landfill sites. To test this hypothesis, soil samples were collected, extracts prepared and biological oestrogenic activity examined using cell-based reporter gene assays. Extracts from several sample sites around a landfill site contained a chemical(s) which activated the human ERα in a dose-dependent manner. Extracts from 3 separate control sampling sites were absent of any detectable activity. The mouse ERα and 2 variant mouse ERβ cDNAs were cloned and extracts from sample sites around a landfill site also activated these receptors. One variant murine ERβ was constitutively active when expressed in cholangiocytes, was readily inactivated by ICI182780 and activated in a dose-responsive, ICI182780-inhibitable manner by oestrogen. However, when this receptor was activated by extracts from landfill site soils, ICI182780 failed to antagonize activation. ERβ was readily detectable in murine cholangiocytes and exposing mice acutely to a pooled ER activating soil extracts also gave rise to a mild cholestatic injury. These data indicate that the environment around landfill sites may contain higher levels of xenoestrogens; that these chemicals have “super-activating” characteristics with a variant ERβ and therefore these chemicals could be a component of a xenobiotic insult that triggers PBC.
format Online
Article
Text
id pubmed-5356623
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-53566232017-03-30 Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes Meyer, Stephanie K. Probert, Philip M. E. Lakey, Anne K. Leitch, Alastair C. Blake, Lynsay I. Jowsey, Paul A. Cooke, Martin P. Blain, Peter G. Wright, Matthew C. Toxicol Sci Environmental Estrogens and Receptor Activation In Bile Duct Epithelium High systemic levels of oestrogens are cholestatic and primary biliary cholangitis (PBC)—which is characterized by hepatic ductular inflammation—is thought to be triggered by exposure to xenobiotics such as those around landfill sites. Xenoestrogens may be a component of this chemical trigger. We therefore hypothesized that xenoestrogens are present at higher levels in the proximity of landfill sites. To test this hypothesis, soil samples were collected, extracts prepared and biological oestrogenic activity examined using cell-based reporter gene assays. Extracts from several sample sites around a landfill site contained a chemical(s) which activated the human ERα in a dose-dependent manner. Extracts from 3 separate control sampling sites were absent of any detectable activity. The mouse ERα and 2 variant mouse ERβ cDNAs were cloned and extracts from sample sites around a landfill site also activated these receptors. One variant murine ERβ was constitutively active when expressed in cholangiocytes, was readily inactivated by ICI182780 and activated in a dose-responsive, ICI182780-inhibitable manner by oestrogen. However, when this receptor was activated by extracts from landfill site soils, ICI182780 failed to antagonize activation. ERβ was readily detectable in murine cholangiocytes and exposing mice acutely to a pooled ER activating soil extracts also gave rise to a mild cholestatic injury. These data indicate that the environment around landfill sites may contain higher levels of xenoestrogens; that these chemicals have “super-activating” characteristics with a variant ERβ and therefore these chemicals could be a component of a xenobiotic insult that triggers PBC. Oxford University Press 2017-03 2016-12-24 /pmc/articles/PMC5356623/ /pubmed/28013213 http://dx.doi.org/10.1093/toxsci/kfw234 Text en © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Environmental Estrogens and Receptor Activation In Bile Duct Epithelium
Meyer, Stephanie K.
Probert, Philip M. E.
Lakey, Anne K.
Leitch, Alastair C.
Blake, Lynsay I.
Jowsey, Paul A.
Cooke, Martin P.
Blain, Peter G.
Wright, Matthew C.
Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes
title Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes
title_full Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes
title_fullStr Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes
title_full_unstemmed Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes
title_short Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes
title_sort environmental xenoestrogens super-activate a variant murine er beta in cholangiocytes
topic Environmental Estrogens and Receptor Activation In Bile Duct Epithelium
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356623/
https://www.ncbi.nlm.nih.gov/pubmed/28013213
http://dx.doi.org/10.1093/toxsci/kfw234
work_keys_str_mv AT meyerstephaniek environmentalxenoestrogenssuperactivateavariantmurineerbetaincholangiocytes
AT probertphilipme environmentalxenoestrogenssuperactivateavariantmurineerbetaincholangiocytes
AT lakeyannek environmentalxenoestrogenssuperactivateavariantmurineerbetaincholangiocytes
AT leitchalastairc environmentalxenoestrogenssuperactivateavariantmurineerbetaincholangiocytes
AT blakelynsayi environmentalxenoestrogenssuperactivateavariantmurineerbetaincholangiocytes
AT jowseypaula environmentalxenoestrogenssuperactivateavariantmurineerbetaincholangiocytes
AT cookemartinp environmentalxenoestrogenssuperactivateavariantmurineerbetaincholangiocytes
AT blainpeterg environmentalxenoestrogenssuperactivateavariantmurineerbetaincholangiocytes
AT wrightmatthewc environmentalxenoestrogenssuperactivateavariantmurineerbetaincholangiocytes