Modulation of adrenal cell functions by cadmium salts. 1. Cadmium chloride effects on basal and ACTH-stimulated steroidogenesis

Abstract

Cultured Y-1 mouse adrenal tumor cells, which secrete 20-alpha-hydroxy-4-pregnen-3-one (20-DHP), were used to investigate the acute nonlethal effects of incremental cadmium chloride (CdCl2) concentrations on basal and maximally stimulated steroid secretion. In addition, cumulative CdCl2 effects during 4-hr incubations, effect reversibility, and viability were determined. Cells were incubated in 1 ml serum-free Eagle's Minimal Essential Medium (FMEM) with or without 0.5 IU (ca. 1.5 microM) adrenocorticotropin (ACTH) in the presence or absence of CdCl2. Following incubation, cell viability was quantitated using trypan blue exclusion. The 20-DHP secreted into the experimental incubation medium was measured by radioimmunoassay. CdCl2 levels of 10.0 micrograms/ml or greater significantly inhibited basal 30 min steroid secretion in a dose-dependent manner; ACTH-stimulated steroid secretion was significantly inhibited by levels 5.0 micrograms/ml or greater. At least 80% of all control and stimulated cells in the presence or absence of cadmium ions excluded trypan blue. The reduction in ACTH-stimulated steroid secretion was greater than the reduction in basal steroid secretion at any cadmium concentration level. The CdCl2 concentration that reduced stimulated steroid hormone secretion by 50% (IC50) was 45.0 micrograms/ml. Exposing Y-1 cells to either 5.0, 10.0, 45.0 or 500.0 micrograms CdCl2/ml FMEM for periods ranging from 0.5 to 4 hr inhibited ACTH-stimulated steroid secretion in a time-dependent manner. After 30 min exposure to 10.0, 45.0 or 500.0 micrograms CdCl2/ml FMEM with or without ACTH, cadmium inhibition was irreversible. When 5.0 micrograms CdCl2/ml was used, basal and stimulated inhibition was reversible by reincubating in medium containing ACTH alone. The relatively greater cadmium effects on ACTH stimulated steroidogenesis might suggest that cadmium modulated the rate-limited transducing system between the ACTH plasma membrane receptor complex and cholesterol side-chain cleaving mitochondrial enzymes. However, cadmium influences on basal secretion indicated effects on the non-rate-limited steroidogenic pathway.

Chromogranin A processing and secretion: specific role of endogenous and exogenous prohormone convertases in the regulated secretory pathway.

“…1). Although Cd 2ϩ may be cytotoxic at high dosage (50,51), in these experiments Cd 2ϩ did not impair two crucial functions of wild-type AtT-20 cells: prohormone processing (Figs. 3-6) and regulated secretion (Fig.…”

Responsiveness of the interrenal tissue of yellow perch (Perca flavescens) from contaminated sites to an ACTH challenge test in vivo

“…The specific cellular mechanisms responsible for this endocrine disruption are not yet understood. Xenobiotics can directly alter the HPI axis by cytotoxic effects (Ilan and Yaron 1983), they may interfere with the bioactivity of ACTH (Bestervelt et al 1993), or they may inhibit the steroidogenic pathways in adrenal cells (Mgbonyebi et al 1993). Increased clearance rates of plasma cortisol could also explain the lower cortisol levels in chronically stressed fish (Schreck et al 1985).…”

Cadmium up-regulates transcription of the steroidogenic acute regulatory protein (StAR) gene through phosphorylated CREB rather than SF-1 in K28 cells

“…It was shown that cadmium interfered with normal gonadal function, as a significant reduction was observed in hormonal levels in vivo (Piasek and Laskey, 1994;Paksy et al, 1997;Piasek et al, 2002;Sen Gupta et al, 2004a) as well as in vitro (Mgbonyebi et al, 1998;Piasek and Laskey, 1999;Piasek et al, 2002). Cadmium has also been shown to stimulate the synthesis of ovarian luteal progesterone at low doses; however, at high doses, the synthesis was inhibited (Henson and Chedrese, 2004).…”