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Mode of cell death induced by 3-methylsulphonyl-DDE in the mouse adrenal cortex
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
(English)Manuscript (Other (popular science, discussion, etc.))
URN: urn:nbn:se:uu:diva-96125OAI: oai:DiVA.org:uu-96125DiVA: diva2:170597
Available from: 2007-09-06 Created: 2007-09-06 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Adrenocorticolysis Induced by 3-MeSO2-DDE: Mechanisms of Action, Kinetics and Species Differences
Open this publication in new window or tab >>Adrenocorticolysis Induced by 3-MeSO2-DDE: Mechanisms of Action, Kinetics and Species Differences
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The DDT metabolite 3-methylsulphonyl-DDE (3-MeSO2-DDE) induces cell death specifically in the adrenal cortex of mice after a cytochrome P45011B1 (CYP11B1)-catalysed bioactivation. This substance is not only an environmental pollutant, but also a suggested lead compound for an improved chemotherapy of adrenocortical carcinoma (ACC). The aim of the thesis was to further investigate this compound in terms of kinetics, cell death mechanisms and species differences. The pharmacokinetics of 3-MeSO2-DDE and the current drug for ACC, o,p’-DDD, was studied during 6 months following a single dose in minipigs. The elimination was slower for 3-MeSO2-DDE than for o,p’-DDD, indicated by a lower clearance and longer t½ in plasma and subcutaneous fat. Both substances remained in fat tissue during the whole study period. Unlike o,p’-DDD, 3-MeSO2-DDE was retained also in liver. The adequacy of the murine adrenocortical cell line Y-1 was evaluated for studies of adrenotoxic compounds. The Y-1 cells proved to be an appropriate test system for future mechanism studies, since CYP-catalysed irreversible binding, inhibited corticosterone production induced by 3-MeSO2-DDE and o,p’-DDD were successfully demonstrated. Cell death of 3-MeSO2-DDE in the mouse adrenal cortex was implied to be necrotic. Early apoptotic signalling (i.e. up-regulation of caspase-9) was observed, although it seemed to be interrupted by ATP-depletion and anti-apoptotic actions by heat shock protein 70, resulting in lack of activation of caspase-3. Using cultured adrenal tissue slices, two not previously studied species were examined ex vivo regarding adrenal binding of 3-MeSO2-[14C]DDE. Binding was found in the hamster adrenal cortex and in assumed cortical cells in the medulla, while the guinea pig adrenal was devoid of binding. This emphasises the species specificity in bioactivation of 3-MeSO2-DDE. The thesis forms a basis for further investigations in the human adrenocortical cell line H295R and provides new knowledge of importance for toxicological risk assessment of 3-MeSO2-DDE.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 52 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 331
Toxicology, 3-methylsulphonyl-DDE, o, p'-DDD, CYP11B1, adrenal cortex, tissue-specific toxicity, bioactivation, kinetics, Y-1 cells, Toxikologi
National Category
Biological Sciences
urn:nbn:se:uu:diva-8180 (URN)978-91-554-6950-4 (ISBN)
Public defence
2007-09-29, Lindahlsalen, Evolutionsbiologiskt centrum (EBC), Norbyvägen 18 A, Uppsala, 10:00 (English)
Available from: 2007-09-06 Created: 2007-09-06 Last updated: 2011-01-20Bibliographically approved

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