Modulation of adrenal cell functions by cadmium salts: 2. Sites affected by CdCl2 during unstimulated steroid synthesis

Abstract

In previous studies cadmium chloride (CdCl2) nonlethally inhibited Y-1 adrenal mouse adrenal tumour cell 20-dihydroxyprogesterone (20DHP) secretion, affecting unstimulated and stimulated steroidogenic pathway sites differently. We studied CdCl2 effects on unstimulated steroidogenesis using Y-1 cells incubated 0.5 h in medium with or without cadmium (using the concentration that inhibited ACTH-stimulated steroid secretion by 50%). Exogenously added 20-hydroxycholesterol (20OHC), 22(R)-hydroxycholesterol (22OHC), 25-hydroxycholesterol (25OHC), pregnenolone (PREG), or progesterone (PROG) were used to bypass any rate-limited steroidogenic pathway sites that CdCl2 might inhibit. 25OHC is a biologically active nonpathway steroid, while 20OHC, 22OHC, PREG, and PROG are pathway steroids; each increased unstimulated 20DHP secretion nearly 10-fold. Although CdCl2 could not reduce dibutyryl cyclic AMP- (dbcAMP)-stimulated 20DHP secretion significantly, it did significantly reduce basal and 25OHC-induced 20DHP secretion 25% below untreated levels. When 20OHC, 22OHC, PREG, or PROG were incubated with unstimulated Y-1 cells, their synthesis into 20DHP was unaffected by cadmium. dbcAMP bypasses the plasma membrane enzyme complex that synthesizes intracellular cAMP during exogenous ACTH stimulation; dbcAMP was not inhibited by CdCl2. The rate-limited step accelerated by cAMP involves plasma membrane and/or cytoplasmic cholesterol transport to and through outer and inner mitochondrial membranes before the cholesterol is synthesized into pregnenolone by side-chain cleavage enzymes on the inner membrane matrix face. Little is known regarding the mechanisms controlling unstimulated steroidogenesis. Under unstimulated conditions the 25-, 20- and 22(R)-monohydroxyls of cholesterol facilitate plasma membrane, cytoplasm and inner and outer mitochondrial solubility, diffusion and/or transport to bypass rate-limited steps and augment unstimulated steroid synthesis. Since conversion of endogenous mitochondrial cholesterol and 25OHC, but not dbcAMP-mobilized cytoplasmic cholesterol, 20OHC or 22OHC conversion, to 20DHP is inhibited by CdCl2, this suggests that (a) control of mitochondrial cholesterol supplies is independent of the cAMP-regulated mitochondrial steps in the 20DHP steroid synthetic pathway, (b) CdCl2 specifically inhibited endogenous mitochondrial cholesterol and 25OHC utilization, (c) CdCl2 toxicity may affect adrenal, testicular, ovarian, and placental basal steroidogenic functions, and (d) 25OHC may be a useful compound to examine unstimulated steroid synthesis.

The Relations Between Levels of Cadmium and Thyroid Parameters in Hemodialysis Patients

“…As a result, data of Cd and ACTH and thyroid levels show that there are no relationships between each other. So that, when we focus on our data in the relation between ACTH and Cd, cannot cause an agreement on notice of relations of those parameters with the confirmation of Mgbonyebi et al [12][13]. The researchers mentioned that Cd toxicity in adrenal functions caused hyperactivity in ACTH stimulation and expression [12][13].…”

“…Furthermore, patients with end stage renal disease display a variety of endocrine disturbances [11]. Mgbonyebi et al [12][13], conclude that the toxicity of Cd in adrenal functions causes hyperactivity in ACTH stimulation and expression. Besides, disturbances in thyroid function are common among patients on renal replacement therapy [14].…”

Reversible, Non‐Denaturing Metal Substitution in Bovine Adrenodoxin and Spinach Ferredoxin and the Different Reactivities of [2Fe‐2S]‐Cluster‐Containing Proteins

“…Adx shares some of the features of SpI, in what is nuclear encoded and located in the adrenal cortex mitochondria, where it transfers electrons to the mitochondrial cytochromes P-450, which act as steroid hydroxylases. However, cadmium is known to interfere with both adrenal steroid hydroxylation [44,451 and renal calcidiol hydroxylation [46], the latter depending on a system consisting of a reductase, a [2Fe-2S]-ferredoxin, and a cytochrome P-450. As cadmium is an antimetabolite to iron and is able to change the membrane permeability, and thus the utilization of steroids, differential inhibitionhnactivation mechanisms may play a role in these systems.…”

Occupational, Environmental and Lifestyle Factors Associated With Spontaneous Abortion

“…Further, in the adrenal gland, heavy metals are deposited in the lipid-rich cortex and block various enzymatic pathways, causing hyperandrogenemia or partial hypoandrenalism. 88,89 Klages et al 90 reported that hypo- and hyperthyroidism could result from Pb and Cd exposure. These hormonal changes might be possible in human also due to environmental exposure to various environmental persistent chemicals including heavy metals and pesticides.…”