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Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
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2009 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 83, no 4, 389-396 p.Article in journal (Refereed) Published
Abstract [en]

The persistent environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo and causes decreased glucocorticoid production and cell death in the zona fasciculata. This study presents extended investigations of the cytotoxic and endocrine disrupting effects of 3-MeSO2-DDE and some structurally related molecules in the mouse adrenocortical cell line Y-1. Both 3-MeSO2-DDE and, to a lesser extent, 3,3'(bis)-MeSO2-DDE decreased corticosterone production and produced CYP11B1-dependent cytotoxicity in Y-1 cells. Neither 2-MeSO2-DDE nor p,p'-DDE had any significant effect on either cell viability or corticosterone production, indicating that the presence and position of the methylsulfonyl moiety of 3-MeSO2-DDE is crucial for its biological activity. The adrenocortical toxicant o,p'-DDD decreased corticosterone production but was not cytotoxic in this cell line. None of the compounds altered Cyp11b1 gene expression, indicating that 3-MeSO2-DDE inhibits CYP11B1 activity on the protein level.

Place, publisher, year, edition, pages
2009. Vol. 83, no 4, 389-396 p.
Keyword [en]
Adrenal cortex, Metabolic activation, Toxicity, Corticosterone, DDE, CYP11B1
National Category
Biological Sciences
Research subject
Ecotoxicology
Identifiers
URN: urn:nbn:se:uu:diva-100855DOI: 10.1007/s00204-008-0342-6ISI: 000264883800012PubMedID: 18651133OAI: oai:DiVA.org:uu-100855DiVA: diva2:211133
Available from: 2009-04-08 Created: 2009-04-08 Last updated: 2010-08-03Bibliographically approved
In thesis
1. In Vitro Studies of Adrenocorticolytic DDT Metabolites, with Special Focus on 3-methylsulfonyl-DDE
Open this publication in new window or tab >>In Vitro Studies of Adrenocorticolytic DDT Metabolites, with Special Focus on 3-methylsulfonyl-DDE
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO2-DDE) is bioactivated by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of mice and forms irreversibly bound protein adducts, reduces glucocorticoid secretion, and induces cell death selectively in cortisol-producing adrenocortical cells. 3-MeSO2-DDE has therefore been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) therapy.

The aims of this thesis were to (1) develop in vitro test systems based on murine and human adrenocortical cell lines and to (2) investigate the mechanisms behind 3-MeSO2-DDE toxicity in adrenocortical cells.

The cytotoxic and endocrine-modulating effects of 3-MeSO2-DDE were compared to those of o,p′-DDD (mitotane), the current ACC therapy, and to those of several structurally analogous compounds in both murine and human cell lines. 3-MeSO2-DDE bioactivation and cytotoxicity proceeded in a similar manner in the murine adrenocortical Y-1 cell line as in mice in vivo. The effects were highly structure-specific. Moreover, 3-MeSO2-DDE formed irreversibly bound protein adducts and caused cell death also in the human H295R cell line, and was slightly more cytotoxic than o,p′-DDD. However, 3-MeSO2-DDE toxicity in human cells was not affected by the CYP11B1 inhibitor etomidate, suggesting that bioactivation in human cells is performed by additional/other enzyme(s) than CYP11B1. 3-MeSO2-DDE generated biphasic responses in cortisol and aldosterone secretion and in expression levels of the steroidogenic genes CYP11B1, CYP11B2, and StAR. Such hormesis-like responses were not seen for o,p′-DDD or the precursor DDT metabolite p,p′-DDE.

In addition, the two o,p′-DDD enantiomers (R)-(+)-o,p′-DDD and (S)-(-)-o,p′-DDD exhibited slight differences in cytotoxic and endocrine-modulating activity in H295R cells.

In conclusion, this thesis  provides  extended  knowledge  on  the  mechanisms  of  action  of 3-MeSO2-DDE and points out important differences in effects between murine and human cells. Lead optimisation studies of 3-MeSO2-DDE using the herein presented in vitro test systems are ongoing.

 

Place, publisher, year, edition, pages
Uppsala, Sweden: Acta Universitatis Upsaliensis, 2010. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 744
Keyword
Toxicity, 3-methylsulfonyl-DDE, CYP, adrenal cortex, metabolic activation, steroid hormones, Y-1, H295R, mitotane, adrenocortical carcinoma
National Category
Pharmacology and Toxicology
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
urn:nbn:se:uu:diva-122721 (URN)978-91-554-7808-7 (ISBN)
Public defence
2010-06-01, Zootissalen, Evolutionsbiologiskt centrum (EBC), Villavägen 9, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2010-05-11 Created: 2010-04-16 Last updated: 2010-05-18Bibliographically approved

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