Context

Urinary cadmium (Cd) excretion is associated with cancer and cardiovascular morbidity. A potential mechanism could be disturbance of steroidogenesis in gonads and adrenal glands.

Objective

We tested whether urinary excretion of Cd is correlated with that of cortico- and sex steroid metabolites in the general adult population.

Setting

The Swiss Kidney Project on Genes in Hypertension is a multicentric, family-based population study.

Measures

Urinary excretions of steroid hormone metabolites and Cd were measured with separate day and night collections. Associations were analyzed by mixed linear models.

Results

Urinary Cd and testosterone excretions in men were significantly correlated (respective day and night β values [standard error (SE)], 1.378 [0.242], P < 0.0005; and 1.440 [0.333], P < 0.0005), but not in women [0.333(0.257), P = 0.2; and 0.674 (0.361), P = 0.06]. Urinary Cd and cortisol excretions were positively associated in both sexes [day: β = 0.475 (SE, 0.157), P = 0.0025, and 0.877 (SE, 0.194), P < 0.0005, respectively; night: β = 0.875 (SE, 0.253), P < 0.0005 and 1.183 (SE, 0.277), P = 0.00002, respectively]. Cd excretion was correlated with mineralocorticoid metabolites excretion, except tetrahydroaldosterone, in both sexes (P < 0.01). There was an independent effect of Cd on sex hormone and corticosteroid synthesis and an interdependent effect on gluco- and mineralcorticoid production.

Conclusion

Our findings provide evidence for a global stimulating effect on steroid synthesis already at low-dose Cd exposure. These findings might explain the association of Cd with diseases such as steroid-sensitive cancers or metabolic disorders.

Urinary Cadmium Excretion Is Associated With Increased Synthesis of Cortico- and Sex Steroids in a Population Study.

Adrenocortical degenerative lesions can be induced by a wide range of structurally dissimilar and functionally unrelated compounds. A review of the literature indicates that the adrenal gland, particularly the cortex, is the endocrine organ most frequently affected by chemical injury (Ribelin 1984; Colby 1988). Examples of prototype adrenotoxicants associated with adrenocortical degeneration include glucocorticoids (Sasano et al. 1966; Purjesz et al. 1964), 7,12-dimethylbenzanthracene (Murad et al. 1973), aminoglutethimide (Camacho et al. 1967; Malendowicz 1972), spironolactone (Fischer and Horvat 1971), 2,2-bis (parachlorophenyl)-l,l dichlorethane (o,p’-DDD; Nelson and Woodward 1949; Hennigar et al. 1964), α-(l,4-dioxido-3-methyl-quinoxalin-2-yl)-N-methylnitrone (DMNM; Yarrington et al. 1981, 1985; Capen et al. 1991), amphenone (Hertz et al. 1955), and 1,1’ thiodiethylidene-ferrocene (MDL 80,478; Capen et al. 1991; Yarrington et al. 1983). With many of these compounds degenerative changes in the adrenal cortex occur, in conjunction with functional alterations in steroidogenesis.

Chemically Induced Adrenocortical Degenerative Lesions

Studies were done to investigate the actions of ACTH on the expression of CYP2D16 in the guinea pig adrenal cortex. Guinea pigs were treated with ACTH for 1, 3, or 7 days. In addition, some animals re

Downregulation of CYP2D16 by ACTH in the guinea pig adrenal cortex: time course, reversibility, and mechanism of action.

Studies were carried out to evaluate the effects of cadmium in vitro on microsomal steroid metabolism in the inner (zona reticularis) and outer (zona fasciculata and zona glomerulosa) zones of the guinea pig adrenal cortex. Microsomes from the inner zone have greater 21-hydroxylase than 17 alpha-hydroxylase activity, resulting in the conversion of progesterone primarily to 11-deoxycorticosterone and of 17 alpha-hydroxyprogesterone principally to its 21-hydroxylated metabolite, 11-deoxycortisol. Microsomes from the outer zones, by contrast, have far greater 17 alpha-hydroxylase and C17,20-lyase activities than 21-hydroxylase activity. As a result, progesterone is converted primarily to its 17-hydroxylated metabolite, 17 alpha-hydroxyprogesterone; and 17 alpha-hydroxyprogesterone is converted principally to delta 4-androstenedione, with only small amounts of 21-hydroxylated metabolites being produced. Addition of cadmium to incubations with inner zone microsomes causes concentration-dependent decreases in 21-hydroxylation and increases in 17 alpha-hydroxylase and C17,20-lyase activities, resulting in a pattern of steroid metabolism similar to that in normal outer zone microsomes. Cadmium similarly decreases 21-hydroxylation by outer zone microsomes but has no effect on the formation of 17-hydroxylated metabolites or on androgen (delta 4-androstenedione) production. In neither inner nor outer zone microsomes did cadmium affect cytochrome P-450 concentrations, steroid interactions with cytochrome(s) P-450, or NADPH-cytochrome P-450 reductase activities. The results indicate that cadmium produces both quantitative and qualitative changes in adrenal microsomal steroid metabolism and that the nature of the changes differs in the inner and outer adrenocortical zones. In inner zone microsomes, there appears to be a reciprocal relationship between 21-hydroxylase and 17 alpha-hydroxylase/C17,20-lyase activities which may influence the physiological function(s) of that zone.

J. H. Sherry

Papers

Effects of cadmium in vitro on microsomal steroid metabolism in the inner and outer zones of the guinea pig adrenal cortex