Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture.

Abstract

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.

Stress and immune responses of nestling tree swallows (Tachycinet bicolor) and eastern bluebirds (Sialia sialis) exposed to nonpersistent pesticides and p,p′‐dichlorodiphenyldichloroethylene in apple orchards of southern ontario, canada

“…Our findings are consistent with observations of other wildlife exposed to organochlorine contaminants [29,30]. Results from laboratory studies have established that DDT metabolites are potent toxicants in the adrenal cortex in birds [15] and mammals [31]. The lipid‐rich cortical tissue of the avian adrenal has a high affinity for metabolites of DDT; the primary metabolite in adrenal tissue of chickens dosed with DDT was p,p′ ‐DDE [25].…”

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

“…The binding of mitotane to mitochondrial adrenal cells was partially reversed by metyrapone, a known inhibitor of CYP11B1. 36,37 These data suggest that CYP11B1 activity on mitotane binding also results in the formation of reactive species or molecules such as DDAC. CYP11B1 is localized in the mitochondrial inner membrane and is involved in the conversion of progesterone to cortisol in the adrenal cortex.…”

“…51 The reaction for the covalent bond is mediated through a specific CYP450 responsible for steroidogenesis in adrenal cells, such as CYP11A1 (see section 3.2). 52 The binding was also partially reversed by metyrapone, a known inhibitor of CYP11B1, 36,37 suggesting that both CYP11A1 and CYP11B1 are involved in the formation of the DDAC.…”

“…35 Mitotane labelled with 14 C was localized mainly in the zona fasciculata and zona reticularis in human adrenocortical tumour and mouse adrenal tissue. 36,37 Mitotane is distributed by binding with chylomicrons and lipoproteins, with most of the compound bound to lipoproteins 38 ; thus, the pharmacological activity of mitotane is exerted by unbound mitotane particles. 39 Under normolipidaemic conditions, a substantial amount of mitotane is bound to high-density lipoproteins and albumin, whereas under hypertriglyceridaemic conditions, mitotane is bound mainly to chylomicrons and to very low-density lipoproteins.…”

Mechanisms of Endocrine System Function

“…For example, the DDT (dichlorodiphenyltrichloroethane) metabolite methylsulfonyl-DDE (MeSO 2 -DDE), a highly potent and tissue-specific toxicant, induced degeneration and necrosis in the adrenal cortex of laboratory mice following a single dose (Lindhe et al, 2001). Because of its high blood supply and lipid content, a variety of persistent environmental contaminants and other chemicals are selectively taken up and retained in the adrenal cortex, both in adults and fetuses.…”