The interaction of cadmium‐binding proteins (Cd‐bp) and progesterone in cadmium‐induced tissue and embryo toxicity

Abstract

Previous work indicates that a dimer of Cd-thionein (Cd-bp-D, 19,000 MW) is involved in the hereditary resistance to Cd-embryotoxicity seen in the inbred NAW/Pr (NAW) mouse strain. Cd-bp-D is not detected in virgin females after Cd exposure and is detected only after the first 24 hours of exposure to Cd in an inbred strain (C57BL/10ChPr) susceptible to Cd-induced embryotoxicity (Wolkowski, '74; Wolkowski-Tyl, '78). Since progesterone (P) is critical for maintenance of pregnancy in mice, we have studied the possible relationship between this hormone and Cd-bp-D production. As a model system, was examined effects of Cd treatment on Cd-bp synthesis in NAW males. It was anticipated that this model could provide information bearing not only on the relationship between P and Cd-bp-D production, but also on that between Cd-bp-D and Cd toxicity, since a single sc injection of CdCl2 causes typical testicular hemorrhagic necrosis in NAW males, and these animals make only metallothionein and not Cd-bp-D. NAW males were, therefore, given P (0.1 g/Kg bw) and then exposed to Cd. Sephadex gel chromatography (G-200) of liver cytosol from animals killed 24 hours later detected only Cd-bp-D. Testes of these males did not show hemorrhagic necrosis. Since the adrenals of male mammals release P in response to stress, NAW males were stressed by repeated sesame oil or propylene glycol injections (5 ml/Kg bw), or the adrenal was stimulated directly with injections of ACTH (100 IU/Kg bw) for seven days prior to Cd exposure. All methods tested which significantly elevated serum P levels (as confirmed by radioimmunoassay), also resulted in production of Cd-bp-D and absence of testicular hemorrhage in Cd-treated NAW males. Suppression of P release by injection of dexamethazone or corticosterone or by adrenalectomy resulted in testicular hemorrhage and production of only metalicthionein after Cd exposure. The relevance of the interaction between P, Cd-bp-D and protection against Cd-induced toxicity seen in the model system was supported by analysis of serum P levels in pregnant females; elevated levels were seen in resistant (NAW dams on day 10 of gestation and significantly lower levels seen in dams from a Cd-sensitive strain.

Effect of Progesterone Pretreatment on Cadmium Toxicity in Male Fischer (F344/NCr) and Wistar (WF/NCr) Rats

“…Gunn et al (1) reported that estrogen and stilbestrol protected CD-1 mouse testes against injury from cadmium, although estrogens did not modify cadmium accumulation in the testes (2). Wolkowoski-Tyl and Preston (3) reported that progesterone pretreatment prevented the necrotizing effects of cadmium in NAW mouse testes, but corticosterone and dexamethasone were without effect. That study suggested that progesterone induced a dimer of cadmiumthionein ('Cd-bp-D', 19,000 mw) in liver that may have an important role in resis-tance to cadmium-induced testicular necrosis (3).…”

“…Wolkowoski-Tyl and Preston (3) reported that progesterone pretreatment prevented the necrotizing effects of cadmium in NAW mouse testes, but corticosterone and dexamethasone were without effect. That study suggested that progesterone induced a dimer of cadmiumthionein ('Cd-bp-D', 19,000 mw) in liver that may have an important role in resis-tance to cadmium-induced testicular necrosis (3). However, these authors did not show whether progesterone induced cadmium-binding proteins in the testes, and cadmium content in testes was actually increased by prior progesterone treatment.…”

Hepatoprotective Effects of Cyproterone Acetate in Mice; Minimal Role of Metallothionein

“…Similarly, Maekawa and Hosoyama (1965) reported that testosterone or progesterone pretreatments in rats reduced Cd-induced testicular toxicity. In contrast, testosterone pretreatment in mice (Gunn et al, 1965a), as well as corticosterone or dexamethasone pretreatments (Wolkowoski-Tyl & Preston, 1979), had little or no effect on Cd toxicity. Progesterone pretreatment appears to be quite effective in reducing Cd toxicity in mice (Wolkowoski-Tyl & Preston, 1979).…”

“…In contrast, testosterone pretreatment in mice (Gunn et al, 1965a), as well as corticosterone or dexamethasone pretreatments (Wolkowoski-Tyl & Preston, 1979), had little or no effect on Cd toxicity. Progesterone pretreatment appears to be quite effective in reducing Cd toxicity in mice (Wolkowoski-Tyl & Preston, 1979). In marked contrast, in more recent studies our laboratory has found that pretreatment with progesterone greatly increased Cd toxicity in vivo in rat liver (Shiraishi et al, 1993) and in vitro in rat liver cells (Shimada et al, 1997a).…”

“…Several studies indicate that Cd toxicity can be modi ed by steroid hormones including estradiol, progesterone, and testosterone (Gunn et al, 1965a(Gunn et al, , 1965bMaekawa & Hosoyama, 1965;Wolkowoski-Tyl & Preston, 1979;Shiraishi et al, 1993;Shimada et al, 1997a;Shimada & Waalkes, 1998a). For instance, in early studies Gunn et al (1965a) found that estradiol and stilbestrol protected the mouse testes against injury from Cd.…”