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Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
2001 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 109, no 2, 105-110 p.Article in journal (Refereed) Published
Abstract [en]

The persistent adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE (MeSO(2)-DDE) was originally identified in Baltic grey seals, a population suffering from adrenocortical hyperplasia. In mice, MeSO(2)-DDE induces mitochondrial degeneration and cellular necrosis in the adrenal zona fasciculata. In this study, we used precision-cut tissue slice culture to examine local CYP11B1-catalyzed irreversible binding of MeSO(2)-DDE in the murine adrenal cortex. We also examined effects on steroid hormone secretion, histology, and ultrastructure. As determined by microautoradiography, selective binding occurred in zona fasciculata of slices exposed to MeSO(2)-[(14)C]-DDE. Quantification of binding by phosphorautoradiography revealed a 3-fold reduction of binding in slices co-exposed to the CYP11B1 inhibitor metyrapone. As measured by HPLC, corticosterone and 11-deoxycorticosterone secretion to the medium increased linearly for at least 24 hr. Addition of the ACTH analog tetracosactide caused an 8-fold increase in corticosterone secretion. Addition of metyrapone reduced corticosterone secretion 4-fold. Exposure of slices to MeSO(2)-DDE (50 microM) reduced the rate of corticosterone secretion by 90% after 24 hr of incubation. As determined by electron microscopy, vacuolated mitochondria were present in zona fasciculata of slices exposed to MeSO(2)-DDE (50 microM) for 24 hr. Our findings show that all effects of MeSO(2)-DDE previously reported in vivo could be reproduced in adrenal slice culture ex vivo. This test system allows analysis of zone-specific irreversible binding and effects on steroid hormone secretion and target cell ultrastructure. We propose adrenal slice culture as a simple ex vivo test system with which to examine the adrenocorticolytic activity of xenobiotics in human and wild animal tissue.

Place, publisher, year, edition, pages
2001. Vol. 109, no 2, 105-110 p.
Keyword [en]
Adrenal Cortex/*drug effects/enzymology/secretion/ultrastructure, Animals, Autoradiography, Biotransformation, Corticosterone/secretion, Culture Techniques, Dichlorodiphenyl Dichloroethylene/analogs & derivatives/*metabolism/*toxicity, Female, Mice, Mice; Inbred C57BL, Microscopy; Electron, Rats, Rats; Sprague-Dawley, Steroid 11-beta-Hydroxylase/genetics/metabolism
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89543PubMedID: 11266318OAI: oai:DiVA.org:uu-89543DiVA: diva2:161116
Available from: 2001-11-22 Created: 2001-11-22 Last updated: 2013-06-13Bibliographically approved
In thesis
1. Adrenal Bioactivation and Toxicity of 3-MeSO2-DDE, o,p´-DDD and DMBA Investigated in Tissue Slice Culture
Open this publication in new window or tab >>Adrenal Bioactivation and Toxicity of 3-MeSO2-DDE, o,p´-DDD and DMBA Investigated in Tissue Slice Culture
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

I developed a precision-cut adrenal slice culture procedure to investigate cytochrome P450 (CYP) catalysed irreversible binding and adrenocorticolytic effects in human, rodent, and fish adrenal tissue, ex vivo. Autoradiography and radioluminography of exposed tissue slices showed that the potent adrenal toxicant 3-methylsulphonyl-2,2´-bis(4-chlorophenyl)-1,1´-dichloroethene (MeSO2-DDE) causes a selective metabolite binding in zona fasciculata (ZF), which is diminished by the CYP11B1 inhibitor metyrapone. MeSO2-DDE also reduces corticosterone secretion, increases 11-deoxycorticosterone secretion and causes mitochondrial degeneration in ZF cells in cultured mouse adrenal slices. ACTH treatment of mice induces CYP11B1 and increases irreversible MeSO2-DDE binding and toxicity in ZF cells. Metyrapone-sensitive binding of MeSO2-DDE is also observed in human zona fasciculata/reticularis (ZF/ZR) and 11-deoxycorti- sol/corticosterone secretion increases in MeSO2-DDE-exposed cultured human adrenal slices. The adrenocorticolytic drug 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichlorethane (o,p´- DDD, Mitotane®) is also bound in ZF/ZR but does not to impair hormone secretion in human adrenal slices at equimolar concentration. A targeted, presumably CYP1B1-catalysed irreversible binding of the adrenocorticolytic carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) in ZF/ZR occurs in rat adrenal slices, whereas presumably CYP1A1-catalysed irreversible binding in endothelial cells is observed in CYP1-induced rats and mice. The rat-specific adrenocorticolytic activity of DMBA may rely on two independent pathological processes resulting in cell death and haemorrhage in the adrenal cortex. In Atlantic cod, selective binding of o,p´-DDD is observed in interrenal cells in cultured anterior kidney slices.

In conclusion, precision-cut adrenal slice culture is a simple ex vivo test system with which to investigate CYP-catalysed metabolite binding, alteredsteroid hormone secretion and target cell ultrastructure in human, experimental and wild animal tissue. The results imply that organisms under stress could be at increased risk of MeSO2-DDE induced adrenal toxicity. MeSO2-DDE is an expected human adrenal toxicant, which should be evaluated as a possible alternative in the therapy of adrenocortical hypersecretion and tumour growth.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2001. 49 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 675
Keyword
Developmental biology, adrenal cortex, 3-MeSO2-DDE, o, p´-DDD, DMBA, bioactivation, binding, toxic, Utvecklingsbiologi
National Category
Developmental Biology
Research subject
Ecotoxicology
Identifiers
urn:nbn:se:uu:diva-1538 (URN)91-554-5185-3 (ISBN)
Public defence
2001-12-14, Lindahlsalen, Norbyv. 18A, Uppsala, 09:30
Opponent
Available from: 2001-11-22 Created: 2001-11-22Bibliographically approved

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