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Enantiomeric methylsulfonyl-2,2',4',5,5',6-PCB; differences in biliary excretion but similar effects on the glucocorticoid-signalling pathway
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
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Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-89832OAI: oai:DiVA.org:uu-89832DiVA: diva2:161634
Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Interaction of Xenobiotics with the Glucocorticoid Hormone System in vitro
Open this publication in new window or tab >>Interaction of Xenobiotics with the Glucocorticoid Hormone System in vitro
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Persistent environmental pollutants were examined for their interaction with the glucocorticoid hormone system. The focus was placed on interference with the glucocorticoid synthesis and the glucocorticoid-signalling pathway in various in vitro test systems.

Several aryl methyl sulphones competitively inhibited CYP11B1 activity in mouse adrenocortical Y1 cells. The DDT metabolite, 3-methylsulphonyl-2,2’-bis(4-chlorophenyl)-1,1’-dichloroethene (3-MeSO2-DDE) had a higher affinity to the enzyme than the endogenous substrate, 11-deoxycorticosterone. In fact, 3-MeSO2-DDE (Ki 1.6 μM) was almost as potent as the drug metyrapone (Ki 0.8 μM), a well-known inhibitor of the enzyme. 3-MeSO2-DDE inhibited CYP11B1 activity in human adrenocortical H295R carcinoma cells, and at higher concentrations the CYP21 activity. The human H295R cell line seems to be a useful test system for studies of enzyme activities and could be used to screen endocrine disrupting chemicals interfering with the glucocorticoid hormone synthesis.

Several chiral PCB methyl sulphones and the fungicide tolylfluanid proved to be antagonists to the glucocorticoid receptor (GR) in rat hepatoma cells and/or Chinese hamster ovary cells stable transformed with a human GR and a responsive reporter vector. The 4-methylsulphonyl-2,3,6,2’,4’,5’-hexachlorobiphenyl (4-MeSO2-CB149) enantiomers had similar antagonistic effect on the GR. Co-exposure of substances led to additive inhibitory effects on glucocorticoid-regulated protein synthesis in rat hepatoma cells. In general, 4-substituted but not 3-substituted methylsulphonyl-PCBs interacted with the glucocorticoid hormone system.

In the environment, humans and wildlife are constantly exposed to a wide range of chemicals. Considering the effects of these substances via mechanisms of actions described in this thesis, interference of xenobiotics with the glucocorticoid hormone system deserves further attention. In conclusion, environmental pollutants can interact with the glucocorticoid hormone system in vitro, yet the effects of the tested substances on this hormone system remain to be established in vivo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 48 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 716
Keyword
Biology, DDT, PCB, tolylfluanid, adrenal, CYP11B1, glucocorticoid receptor, endocrine disrupter, Biologi
National Category
Biological Sciences
Research subject
Ecotoxicology
Identifiers
urn:nbn:se:uu:diva-2012 (URN)91-554-5321-X (ISBN)
Public defence
2002-05-24, Lindahlsalen, Uppsala, 09:15
Opponent
Available from: 2002-05-02 Created: 2002-05-02Bibliographically approved

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