Academic journal article Environmental Health Perspectives

Irreversible Binding and Adrenocorticolytic Activity of the DDT Metabolite 3-Methylsulfonyl-DDE Examined in Tissue-Slice Culture

Academic journal article Environmental Health Perspectives

Irreversible Binding and Adrenocorticolytic Activity of the DDT Metabolite 3-Methylsulfonyl-DDE Examined in Tissue-Slice Culture

Article excerpt

The persistent adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE (Me[SO.sub.2]-DDE) was originally identified in Baltic grey seals, a population suffering from adrenocortical hyperplasia. In mice, Me[SO.sub.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 Me[SO.sub.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 Me[SO.sub.2]-[[sup.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 Me[SO.sub.2]-DDE (50 [micro]M) 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 Me[SO.sub.2]-DDE (50 [micro]M) for 24 hr. Our findings show that all effects of Me[SO.sub.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. Key words: adrenal cortex, DDT, endocrine disrupters, irreversible binding, 3-Me[SO.sub.2]-DDE, tissue-slice culture, toxicity. Environ Health Perspect 109:105-110 (2001). [Online 10 January 2001] http://ehpnet1.niehs.nih.gov/docs/2001/109p105-1101indhelabstract.html

The chlorinated insecticide DDT is a persistent environmental pollutant that undergoes long-range atmospheric transport and is biomagnified in food chains. Although its biological degradation in the environment is slow, DDT is biotransformed to numerous lipophilic and persistent metabolites that are found in human tissues and in wild mammals, birds, and fish. These degradation products include the dechlorinated metabolites DDD and DDE and the sulfur-containing DDE metabolite 3-methylsulfonyl-DDE (Me[SO.sub.2]-DDE). All metabolites have a capacity to interact with the endocrine system and have deleterious effects on humans and experimental and/or wild animals (1).

o,p'-DDD and p,p'-DDD are known to be tissue-selective toxicants following local metabolic activation and irreversible protein binding in the adrenal cortex in several species, including human (2), dog (3), and mink (4). By virtue of its tissue-selective toxicity, o,p'-DDD is currently used as an adrenocorticolytic drug to treat adrenocortical carcinoma and Cushing's disease (5).

Me[SO.sub.2]-DDE, along with a number of polychlorinated biphenyl (PCB)-derived methyl sulfones (Me[SO.sub.2]-PCBs), was originally identified in the blubber of Baltic grey seals (6). These persistent chemicals subsequently have been found in human breast milk, blood, and adipose tissue, as well as in adipose tissue of arctic polar bears (7-9). Several of these aryl methyl sulfones are characterized by their cell- and tissue-specific distribution patterns in the body. In the search for target cells of chlorinated aryl methyl sulfones it was found that [sup.14]C-labeled Me[SO.sub.2]-DDE produces a high and specific accumulation in the adrenal zona fasciculata in mice (10). Unlike the Me[SO.sub.2]-PCBs (polychlorinated biphenyls), which are irreversibly associated with specific PCB-binding proteins in their target cells (e. …

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