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Experimental Biology and Medicine 229:383-392 (2004)
© 2004 Society for Experimental Biology and Medicine

MINIREVIEW

Endocrine Disruption by Cadmium, a Common Environmental Toxicant with Paradoxical Effects on Reproduction

Michael C. Henson1,* and P. Jorge Chedrese{dagger}

* Departments of Obstetrics and Gynecology, Physiology, Structural and Cellular Biology, and the Interdisciplinary Program in Molecular and Cellular Biology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112; and {dagger} Department of Obstetrics, Gynecology and Reproductive Sciences, University of Saskatchewan, Saskatoon, Saskatchewan S7N OW8, Canada

1To whom requests for reprints should be addressed at the Department of Obstetrics and Gynecology (SL-11), Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112-2699. E-mail: henson{at}tulane.edu


   Abstract
Top
 Abstract
Introduction
 Cd2+ Exposure and Reproduction
 Effects of Cd2+ in...
 Effects of Cd2+ During...
 Mechanism of Action of...
 Estrogenic Effects of Cd2+
 Conclusions
 References
 
Cadmium (Cd2+) is a common environmental pollutant and a major constituent of tobacco smoke. Exposure to this heavy metal, which has no known beneficial physiological role, has been linked to a wide range of detrimental effects on mammalian reproduction. Intriguingly, depending on the identity of the steroidogenic tissue involved and the dosage used, it has been reported to either enhance or inhibit the biosynthesis of progesterone, a hormone that is inexorably linked to both normal ovarian cyclicity and the maintenance of pregnancy. Thus, Cd2+ has been shown to exert significant effects on ovarian and reproductive tract morphology, with extremely low dosages reported to stimulate ovarian luteal progesterone biosynthesis and high dosages inhibiting it. In addition, Cd2+ exposure during human pregnancy has been linked to decreased birth weights and premature birth, with the enhanced levels of placental Cd2+ resulting from maternal exposure to industrial wastes or tobacco smoke being associated with decreased progesterone biosynthesis by the placental trophoblast. The stimulatory effects of Cd2+ on ovarian progesterone synthesis, as revealed by the results of studies using stable porcine granulosa cells, appear centered on the enhanced conversion of cholesterol to pregnenolone by the cytochrome P450 side chain cleavage (P450scc). However, in the placenta, the Cd2+-induced decline in progesterone synthesis is commensurate with a decrease in P450scc. Additionally, placental low-density lipoprotein receptor (LDL-R) mRNA declines in response to Cd2+ exposure, suggesting an inhibition in the pathway that provides cholesterol precursor from the maternal peripheral circulation. Potential mechanisms by which Cd2+ may affect steroidogenesis include interference with the DNA binding zinc (Zn2+)-finger motif through the substitution of Cd2+ for Zn2+ or by taking on the role of an endocrine disrupting chemical (EDC) that could mimic or inhibit the actions of endogenous estrogens. Divergent, tissue-specific (ovary vs. placenta) effects of Cd2+ also cannot be ruled out. Therefore, in consideration of the data currently available and in light of the potentially serious consequences of environmental Cd2+ exposure to human reproduction, we propose that priority should be given to studies dedicated to further elucidating the mechanisms involved.

Key Words: cadmium • placenta • stable granulosa cells • steroidogenesis • toxicology


   Introduction
Top
 Abstract
 Introduction
Cd2+ Exposure and Reproduction
 Effects of Cd2+ in...
 Effects of Cd2+ During...
 Mechanism of Action of...
 Estrogenic Effects of Cd2+
 Conclusions
 References
 
Cadmium (Cd2+) is a heavy metal that is dispersed throughout the modern environment mainly as a result of pollution from a variety of sources. (1, 2).. Much of that released into the environment in recent years can be traced to occupational exposure and the wastes associated with mining, smelting, and electroplating as well as the intensive use of consumer products such as nickel/ Cd2+ batteries, pigments, and plastics (2, 3). Its high concentrations in the soil and water supply has made it easily detectable in meat, fish, and fruits, although tobacco smoke may be one of the most common sources of Cd2+ contamination in the general population (4). The metal has no known beneficial biological function and prolonged exposure to it has been linked to toxic effects in both humans and animals (3). Cd2+ has a long biological half-life of 15–30 years (5), mainly due to its low rate of excretion from the body, and accumulates over time in blood, kidney, and liver (1, 5–7) as well as in the reproductive organs, including the placenta, testis, and ovaries (3, 7–10). Specifically, human exposure to the metal is associated with increased incidences of renal disease, hypertension, osteoporosis, and leukemia, as well as cancers of the lung, kidney, urinary bladder, pancreas, breast, and prostate (11). The practically ubiquitous nature of Cd2+ and its deleterious effects on human health makes it a serious problem of worldwide scope and has lead, therefore, to numerous patient-based investigations by biomedical researchers throughout Asia (11–13), the Middle East (14), Australia (15), Europe (3, 7–9, 16), and the Americas (17–19).


   Cd2+ Exposure and Reproduction
Top
 Abstract
 Introduction
 Cd2+ Exposure and Reproduction
Effects of Cd2+ in...
 Effects of Cd2+ During...
 Mechanism of Action of...
 Estrogenic Effects of Cd2+
 Conclusions
 References
 
Various effects of Cd2+ on reproductive endocrinology have been described, but definitive conclusions about its actions on target tissues vary depending on the experimental model and the dosage employed. Exposure of rodents to the metal resulted in a down-regulation of pituitary hormones; including gonadotropins, prolactin, ACTH, growth hormone, and thyroid-stimulating hormone (20). Similarly, in pseudopregnant rats and in cultured granulosa cells from both rats and humans, Cd2+ inhibited progesterone synthesis (10, 21, 22). Because tobacco smoke is a source of Cd2+ contamination, the reproductive organs of smokers are generally considered to be at increased risk of exposure to toxic levels of Cd2+. Thus, enhanced Cd2+ concentrations and lower progesterone levels were evidenced in the follicular fluid and in the placentas of smokers compared with those of nonsmokers (4, 8), and exposure of hamsters to realistic environmental dosages of tobacco smoke had severe repercussions on reproductive structures. Exposure was linked to a decline in the number of corpora lutea, as well as a reduction in their vascular area. It caused blebbing of the ciliated cells in the oviductal epithelium and resulted in a decrease in the ratio of ciliated to secretory cells in the ampulla. Exposure also resulted in decreased uterine length and an increased number of uterine implantation sites (23). Although the results of studies conducted in cultured human trophoblast cells indicated that Cd2+ inhibited placental progesterone synthesis (24–26), some reports suggest that, in many instances, Cd2+ stimulates steroidogenesis. Thus, Cd2+ administrated to female rats during estrus and diestrus resulted in increased serum progesterone levels (10, 27) and stimulated progesterone synthesis in both cultured porcine granulosa cells (6) and JAr choriocarcinoma cells, a malignant trophoblast cell line (28). Therefore, although the results of many studies concur in suggesting a significant impact on reproduction, the specific mechanisms of action on steroidogenesis are still subject to conjecture.


   Effects of Cd2+ in the Ovary
Top
 Abstract
 Introduction
 Cd2+ Exposure and Reproduction
 Effects of Cd2+ in...
Effects of Cd2+ During...
 Mechanism of Action of...
 Estrogenic Effects of Cd2+
 Conclusions
 References
 
The stimulatory and inhibitory effects of Cd2+ on progesterone synthesis (see Fig. 1Go) were recently investigated using the steroidogenically stable JC-410 porcine granulosa cell line (29), which was genetically modified with gene constructs containing the promoter region of the cytochrome P450 side chain cleavage (P450scc) gene linked to a luciferase reporter gene (30). P450scc is a hormonally regulated rate-limiting steroidogenic enzyme that catalyzes the conversion of cholesterol into pregnenolone, the immediate precursor of progesterone (31). It was observed that low (0.6–3 µM) and high (5 µM) concentrations of CdCl2 in the culture media had opposite effects on the P450scc promoter activity (32). Although these concentrations are somewhat arbitrary by nature, dosages were chosen from the lower ranges of previous in vivo and in vitro studies (as reviewed, 16). As illustrated in Figure 2Go, at low concentrations, CdCl2 stimulated P450scc gene promoter activity in a dose- and time-dependent fashion; while at high concentrations, it inhibited P450scc gene promoter activity. Low concentrations of CdCl2 increased P450scc mRNA levels and progesterone synthesis but did not affect cell count, protein content, or cellular morphology in cultured nontransfected JC-410 cells. High concentrations of CdCl2inhibited P450scc gene promoter activity and caused a reduction in cell number and cellular protein content as well as changes in cell morphology. Overall, results suggested that Cd2+ exerted a dual action in granulosa cells; low concentrations activated, while high concentrations inhibited expression of the P450scc gene. These studies were conducted in serum-free culture conditions in which CdCl2 stimulated expression of the P450scc gene and progesterone synthesis. Therefore, because synthesis of progesterone in JC-410 stable granulosa cells is entirely dependent on an intracellular source of cholesterol (33), it is reasonable to speculate that the effects of Cd2+ were independent of changes in the metabolism of low-density lipoprotein (LDL) or LDL receptor (LDL-R) function. This may explain why Cd2+ also elevates progesterone levels in estrous and diestrous rats (10, 27) in cultured porcine granulosa cells (6) and in choriocarcinoma cells (28). Effects in these studies were observed at Cd2+ concentrations that were dramatically lower than the concentrations (5–20 µM) reported to induce endocrine disruption in cultured human trophoblasts (24–26). Such lower concentrations may represent typical tissue burdens to which humans and animals are commonly exposed. Based on these results, therefore, it is reasonable to conclude that exposure to even low concentrations of Cd2+ is sufficient to significantly affect the steroidogenic pathway.



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  		Figure 1. The progesterone biosynthetic pathway. Low density lipoprotein (LDL)-cholesteryl linoleate is bound to a specific LDL receptor and internalized. Lysosomal proteolysis yields free cholesterol. Cytochrome P450 side chain cleavage (P450scc), on the inner mitochondrial matrix, converts it to pregnenolone. In the cytoplasm, pregnenolone is converted to progesterone by 3ß-hydroxysteroid dehydrogenase (3ß-HSD). Cholesterol may also be produced de novo from acetate in many cell types, although in the placental trophoblast, this mechanism is down-regulated.

 


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  		Figure 2. Effects of CdCl2 on JC-410 cells stably transfected with P450scc-2320-LUC. Cells were exposed to the indicated concentrations of CdCl2. After 24 hrs incubation, cells were collected and assayed for luciferase activity. (A) Data of relative light units (RLU) divided by (B) total protein content were expressed as a fold over mean control value for each treatment and analyzed by one-way ANOVA, followed by Fischer least significant difference test. Each point represents the mean ±SEM of three independent replications. Asterisk represents P < 0.05. Originally published in Smida et al., Biology of Reproduction 70:25–31, 2004.

 

   Effects of Cd2+ During Pregnancy and in the Placenta
Top
 Abstract
 Introduction
 Cd2+ Exposure and Reproduction
 Effects of Cd2+ in...
 Effects of Cd2+ During...
Mechanism of Action of...
 Estrogenic Effects of Cd2+
 Conclusions
 References
 
In human pregnancy, maternal exposure to Cd2+ is associated with low birth weight (34, 35) and an increased incidence of spontaneous abortion (36). Although pharmacokinetic studies have demonstrated that the metal does not readily reach the fetus, it accumulates in high concentrations in the placenta (8, 37–39). In both perfused human placentae (40) and in vivo rodent studies (41), observable symptoms of Cd2+ toxicity included lysosomal vesiculation, nuclear chromatin clumping, and mitochondrial calcification in trophoblast cells. In perfused human placentae, exposure to Cd2+ also precipitated a decline in the secretion of human chorionic gonadotropin (hCG; Ref. 40), a polypeptide hormone vital to early pregnancy maintenance. The placental trophoblast, which is the site of hCG synthesis, is also responsible for the production of progesterone (42), a steroid hormone that plays a vital role in pregnancy maintenance by promoting uterine myometrial quiescence (43). The potential for environmental Cd2+ to affect placental progesterone production by Cd2+ was evidenced by Piasek et al. (8), who determined an almost twofold increase in Cd2+ that was commensurate with an almost 50% decline in progesterone in the placentas of women who smoked during pregnancy. It is interesting to note, therefore, that maternal exposure to high levels of environmental Cd2+ led to a significant increase in the incidence of premature delivery in the Jinzu River basin in Japan, where itaiitai disease, the most severe manifestation of chronic Cd2+ poisoning is still reported (13). Indeed, older women with higher body burdens of the metal are at a greater risk for placental Cd2+ accumulation and subsequent adverse pregnancy effects, as maternal reserves may accumulate in placenta during pregnancy (16). Therefore, in a study investigating Cd2+ levels in maternal, umbilical cord, and newborn’s blood following environmental exposure, maternal and newborn blood Cd2+ levels were not correlated with one another, while cord levels (as an index of placental burden) were highly correlated with maternal Cd2+ concentrations, which were significantly elevated in smoking mothers (19). This phenomenon, which has been replicated in rodents that exhibited a 16% increase in placental Cd2+ burden following just 5 days of inhalation exposure to environmental tobacco smoke (44), may help to explain the increased incidence of premature delivery in smoking women. Indeed, high concentrations of placental Cd2+ that are directly related to maternal smoking have also been associated with an increase in trophoblast thickness, along with other quantifiable changes in placental morphology (17). In addition, Egawa et al. (45) determined that rats exposed to cigarette smoke between Days 14 and 16 of pregnancy exhibited an enhanced frequency of oxytocin-induced uterine myometrial contractions compared with rats breathing room air. The authors concluded that the effects of smoking on myometrial contractile activity could contribute to the increased risk of premature delivery reported in smoking mothers. With regard to this and related mechanisms, clinical studies have reported that both active (46) and passive exposure (47) to tobacco smoke during pregnancy constituted significant risk factors for preterm delivery, an effect that may be exacerbated among African Americans (48). In addition, tobacco smoke’s effects on the placenta via similar Cd2+-related mechanisms (36) might also be linked (49–51) to low birth weights and an enhanced incidence of intrauterine growth restriction (IUGR).

Collectively, therefore, clinical and experimental observations suggest that elevated concentrations of Cd2+ are at least one cause of the reduced levels of progesterone measured in the placentae of smokers, an effect that might contribute to premature delivery. Thus, it is possible that limited availability of cholesterol and/or inhibition of the steroidogenic genes could be mechanisms by which high Cd2+ concentrations contribute to inhibited progesterone synthesis, as described in the pseudopregnant rat model (21) and in cultured human (10) and rat (22) granulosa cells. To this end, we demonstrated that Cd2+ inhibited progesterone secretion in cultured human placental cells (5, 24) via a deleterious effect on LDL-R mRNA (25). However, because a number of steroidogenic enzymes are required for progesterone synthesis (see Fig. 1Go), it was quite possible that inhibition by Cd2+ might be multifaceted, affecting multiple sites in the steroidogenic pathway. Among the steroidogenic enzymes expressed by the primate placenta and involved in progesterone synthesis, P450scc and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) are vital components. P450scc catalyzes the conversion of cholesterol into pregnenolone, which is then converted into progesterone via 3ß-HSD (52). Syncytiotrophoblasts, formed in culture (as in vivo) from cytotrophoblast progenitors, adapt to facilitate this transition (53–55). Therefore, we continued our studies by investigating the influence of Cd2+ on the expression of the P450scc and 3ß-HSD genes, and their enzymatic activities, in cultured human placental cells.

Progesterone secretion was reduced by coculture with CdCl2, both prior to and during differentiation of cytotrophoblasts into syncytiotrophoblasts, or following completion of the differentiation process (5, 24–26). Cytotrophoblasts progressed to syncytiotrophoblastic maturity regardless of treatment, while treatment with CdCl2 following differentiation inhibited 25-hydroxycholesterol (25-OHC)-stimulated progesterone secretion (26). Because 25-OHC readily traverses the plasma and mitochondrial membranes and taking into consideration that 3ß-HSD is not a rate-limiting step in the steroidogenic pathway, the conversion of 25-OHC to progesterone represents an index of P450scc activity. Therefore, results indicated that Cd2+ did not interfere with progesterone synthesis/secretion by simply inhibiting morphological change but rather by exerting a direct inhibitory effect on the biosynthetic pathway. Moreover, no significant differences were observed in cell protein or lactate dehydrogenase (LDH) activity, an enzyme that serves as an indicator of cell injury and death, as a result of coculture with CdCl2. These findings were reminiscent of our previous report of no significant Cd2+ induced decline in cell viability, as assessed by both DNA fragmentation assay and the conversion of 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) to formazan (25). Collectively, therefore, results suggested that Cd2+ suppression of progesterone synthesis in placental cell cultures could not be attributed to cell death by either apoptosis or necrosis. As illustrated in Figure 3Go, exposure to CdCl2 caused a dose-dependent decline in P450scc and 3ß-HSD mRNAs (26). Similarly, P450scc activity, as determined by the formation of progesterone from 25-OHC, was inhibited in cells cocultured with CdCl2, indicating that P450scc is one site at which Cd might interfere with placental progesterone synthesis (Fig. 4Go). In this respect, it must be recognized that the formation of progesterone from 25-OHC did not reflect P450scc activity entirely, as its biosynthesis also included the conversion of pregnenolone to progesterone by 3ß-HSD. However, in later experiments, basal progesterone synthesis was inhibited by the addition of aminoglutethimide, a potent inhibitor of P450scc (Fig. 5Go). Following the addition of 5 µg/ml pregnenolone over a short period, an approximately 500-fold increase in progesterone synthesis (i.e., 3ß-HSD activity) was observed in the presence of 90 µM aminoglutethimide. However, coculture with 20 µM CdCl2 had no significant effect on pregnenolone-stimulated progesterone synthesis, strongly suggesting that CdCl2 did not inhibit 3ß-HSD activity in cultured human trophoblasts.



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  		Figure 3. Effects of CdCl2 on (A) P450scc and (B) 3ß-HSD mRNA transcript abundance, as determined by competitive RT-PCR, in human trophoblasts cultured for 96 hrs. Values represent means ±SEM of four separate placental cultures. Different lowercase letters (a, b) indicate significant (P < 0.05) differences. Originally published in Kawai et al., Biology of Reproduction 67:178–183, 2002.

 


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  		Figure 4. Effects of CdCl2 on P450scc activity, as determined by the formation of progesterone from 25-hydroxycholesterol (25-OHC), in cultured human trophoblasts. Trophoblasts were incubated for 4 hrs (96–100 hrs in culture) with DMEM + 10% steroid-stripped FBS in the absence or presence of 20 µM CdCl2 and/or 20 µg/ml 25-OHC. Values represent the means ±SEM of four separate placental cultures. Different lowercase letters (a, b, c) indicate significant (P < 0.05) differences. Originally published in Kawai et al., Biology of Reproduction 67:178–183, 2002.

 


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  		Figure 5. Effects of CdCl2 on 3ß-HSD activity, as determined by the formation of progesterone from pregnenolone in cultured human trophoblasts. Trophoblasts were incubated for 4 hrs (96–100 hrs in culture) with DMEM + 10% steroid-stripped FBS and 90 µM aminoglutethimide in the absence or presence of CdCl2 and/or 5µg/ml pregnenolone. Values represent the means ±SEM of five separate placental cultures. Different lowercase letters (a, b, c) indicate significant (P < 0.05) differences. Originally published in Kawai et al, Biology of Reproduction 67:178–183, 2002.

 

   Mechanism of Action of Cd2+
Top
 Abstract
 Introduction
 Cd2+ Exposure and Reproduction
 Effects of Cd2+ in...
 Effects of Cd2+ During...
 Mechanism of Action of...
Estrogenic Effects of Cd2+
 Conclusions
 References
 
The mechanisms by which Cd2+ affects cell function and gene expression were recently reviewed by Bhttacharyya et al. (1). Cd2+ can easily enter into the cells through the L-type voltage Ca2+ channels (56) and receptor-mediated Ca2+ channels (57) because both cations have similar radii size and charge (Ca2+ = 0.97 A ° , Cd2+ = 0.99 Å). Cd2+ can also displace Ca2+ from its normal binding to calmodulin and protein kinase-C (PKC; Ref. 58). Calmodulin activates several enzymes of the second messenger pathways that regulate gene expression, including Ca2+/calmodulin-dependent kinase, phosphodiesterase, and the myosin light-chain kinase (58). PKC is a family of Ser/Thr kinases that depends on Ca2+ and phospholipids to be activated (59). Cd2+ can activate PKC directly with a constant 5000-fold smaller than that of Ca2+ (60). Cd2+ concentrations between 0.1 and 5 µM interfere with the Ca2+-ATPase pumps, leading to an immediate, transient, but substantial increase in intracellular Ca2+ (61, 62). This increase in Ca2+ results in the formation of inositol triphosphate (IP), which triggers the PKC signal cascade (63). It is known that an increase in the uptake of extracellular Ca2+ potentiates the effects of FSH and 8-Br-cAMP on transcription of the P450scc gene and progesterone synthesis in primary cultures of porcine granulosa cells (64). Therefore, it is reasonable to speculate that the low concentrations of Cd2+ may be sufficient to mimic the effects of Ca2+, resulting in stimulation of the steroidogenic pathway and synthesis of progesterone.

The results of our studies in stable granulosa cells suggested that the effect of Cd2+ was specific in stimulating the promoter of the P450scc gene (Fig. 2Go) because CdCl2 did not affect luciferase activity in cells transiently transfected with the promoterless version of the plasmid vector used in these experiments and had no effect on expression of the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Ref. 32). Moreover, CdCl2 also stimulated activity of a construct containing only the first 100 base pairs of the promoter; suggesting that a cis-acting element located in the proximity of the transcription start site may be involved in the CdCl2-stimulated expression of the porcine P450scc gene (30). They include consensus sequence motifs for the proto-oncogenes c-jun and c-fos, the cAMP regulatory element binding protein (CREB), the activator protein-1 (AP-1), and the specific protein-1 (Sp1). Exposure to Cd2+ activates these transcription factors in a variety of experimental models. In rat L6-myoblasts, 1 µM Cd2+ induces transcription of c-jun and c-fos through mechanisms mediated by PKC (65). It is known that, on stimulation, c-jun and c-fos form heterodimers that bind to AP-1 sites in several PKC-activated genes (66). Therefore, it is reasonable to speculate that PKC stimulation by Cd2+ may lead to activation of the P450scc genes through the AP-1 sites located in its promoter. Sp1 is a zinc-finger transcription factor originally defined in the promoter of the simian virus SV40 (67). Sp1 plays an essential role in eukaryotic gene expression, maintenance of homeostasis, cell cycle control, terminal differentiation, and apoptosis. The Sp1 binding motif was also found in other gene promoters, including those that are highly regulated by Cd2+, such as human metallothionein IIA (68). Further investigation needs to be conducted to determine the mechanisms by which transcription factors mediate the effects of Cd2+ on the P450scc gene.

While it must be acknowledged that post-transcriptional regulation might also be at work, the apparent dose-dependent reduction in the abundance of P450scc mRNA transcripts in response to Cd2+ suggested an effect on transcriptional regulation. In this capacity, the hormonal regulation and developmental pattern of P450scc expression are specific to individual steroidogenic tissues. Thus, hormone receptor binding activates a G protein that increases intracellular cAMP, which in turn activates transcription of the P450scc gene (69, 70). Ringler et al. (71) reported that cAMP regulates progesterone synthesis in normal human trophoblasts, at least in part, by regulating the abundance of P450scc mRNA. Therefore, it is believed that human placental P450scc is regulated mainly at the level of gene expression and so it is possible that, in the trophoblast, Cd2+ inhibits progesterone synthesis by a direct interference with transcription.

Although a decline in 3ß-HSD mRNA levels was also observed following coculture with CdCl2, 3ß-HSD activity was not significantly affected (26). Therefore, perhaps because of the typically high concentration of 3ß-HSD within human trophoblasts (72), coculture with CdCl2 exerted no significant effects on activity. It is also possible that 3ß-HSD protein could be regulated at both transcriptional and post-transcriptional levels. In this capacity, treatment of human trophoblasts with progesterone and estradiol increased 3ß-HSD RNA evels, but had no significant effect on protein levels (73), suggesting that 3ß-HSD steady-state mRNA levels in human placenta could be regulated after transcription. A similar post-transcriptional regulatory mechanism has been suggested in respect to follicle-stimulating hormone-induced gene expression in rat granulosa cells (74). Therefore, Cd2+ may exert a direct effect on 3ß-HSD transcript abundance but not on a post-transcriptional regulatory mechanism.

It has been proposed that accumulation of P450scc mRNA is mainly controlled by the cAMP-dependent pathway in human trophoblasts (72, 75). Thus, the human P450scc gene promoter contains consensus sequences that match known positive cAMP-responsive elements (76, 77). However, in our study (26), the cAMP analog, 8-bromo-cAMP, was not effective in blunting the decline in progesterone secretion elicited by Cd2+. In addition, coculture with CdCl2 did not influence the cAMP content in cultured cells, suggesting that cAMP in human trophoblasts may not be involved with the Cd2+-induced inhibition of progesterone secretion. The possibility still exists, however, that Cd2+ interferes with the downstream cascade of the cAMP-protein kinase A-dependent pathway. Kostrzewska and Sobieszek (78) reported that higher Cd2+ concentrations inhibited the phosphorylation of myosin light chain kinase in the smooth muscle myosin, suggesting that Cd2+ interferes with the phosphorylation of protein kinases. An additional possibility is that the metal may directly affect transcription of the P450scc gene by interfering with the DNA binding zinc-finger motif through the substitution of Cd2+ for Zn2+ (79). Moreover, cations such as Cd2+ have been reported to alter the structure of nucleic acids (DNA, tRNA) and certain enzymes by reacting with their sulfydryl groups (80, 81). Therefore, it is possible that Cd2+ interferes with progesterone biosynthesis by one or more of the described mechanisms affecting transcription of the P450scc gene.


   Estrogenic Effects of Cd2+
Top
 Abstract
 Introduction
 Cd2+ Exposure and Reproduction
 Effects of Cd2+ in...
 Effects of Cd2+ During...
 Mechanism of Action of...
 Estrogenic Effects of Cd2+
Conclusions
 References
 
Endocrine-disrupting chemicals (EDCs) are natural or synthetic agents that can mimic, enhance, or inhibit the action of endogenous hormones (82). The most commonly reported EDCs that affect reproduction are the pesticides that reproduce the effects of estrogens (83), and recent reports have also highlighted the potential of Cd2+ to mimic the effects of estrogen in various tissues. The first of these observations was made by Garcia-Morales et al. (84), in MCF-7 human breast cancer cells, who found that 1 pm Cd2+ mimicked the effect of estrogens by decreasing the level of estrogen receptor (ER) mRNA and transcription of the ER gene and increasing transcription of the progesterone receptor (PR) gene. The changes in steady-state levels of protein and mRNA of these genes were due to changes in transcription that were blocked by the antiestrogen, ICI-164384, thereby supporting the concept of an ER-mediated effect of the metal. Moreover, these estrogenic actions were not mimicked by Zn2+, suggesting the existence of Cd2+-specific effects on transcription (84). More recently, it was demonstrated that Cd2+ activates the ER-{alpha} through an interaction with the hormone-binding domain of the receptor, in which it binds with high affinity, blocking the binding of estradiol (85). The interaction of Cd2+ with the receptor appeared to involve several amino acids in the hormone-binding pocket of the receptor, suggesting that the metal may form a coordination complex with the hormone-binding domain and thereby activate the receptor (85). Similarly, in vivo studies conducted in rats showed that Cd2+ precipitated early puberty onset, increased uterine weight, and enhanced mammary development. Moreover, Cd2+ induced hormone-regulated genes in ovariectomized animals, including the PR and complement component C3 (86). In the mammary gland, Cd2+ promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PR, and C3. Female offspring, exposed in utero to Cd2+, experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary glands. Therefore, it might be concluded that Cd2+ mimics the effects of estrogens and that its effects cannot be extended to other heavy metals. To this end, the effects of Cd2+ appear to be mediated by the ER{alpha} and are independent of estrogen binding (87). Overall, the information presented provides strong evidence that Cd2+ is a potent nonsteroidal estrogen in vivo and in vitro.


   Conclusions
Top
 Abstract
 Introduction
 Cd2+ Exposure and Reproduction
 Effects of Cd2+ in...
 Effects of Cd2+ During...
 Mechanism of Action of...
 Estrogenic Effects of Cd2+
 Conclusions
References
 
We propose that, at low concentrations, Cd2+ stimulates transcription of the P450scc gene and the steroidogenic pathway in the ovary. We also propose that, at high concentrations, Cd2+ inhibits activity of the P450scc gene and progesterone synthesis in the ovary and facilitates changes in cell morphology and cell death. The effect of Cd2+ appears to be mediated via a cis-acting element located 100 bp upstream of the P450scc gene transcription start site. Conversion of cholesterol into pregnenolone by P450scc is an obligated step in the steroidogenic pathway. Therefore, the changes induced by Cd2+ on the expression of the P450scc gene in granulosa cells could affect the synthesis of all steroid hormones in the ovary. We also propose that cholesterol sequestration via the LDL-R and the conversion of cholesterol into pregnenolone by P450scc are two sites at which Cd2+ can interfere with progesterone production in cultured human trophoblasts. Further study is called for to definitively determine the collective mechanisms by which Cd2+ interferes with placental progesterone biosynthesis in vivo and to better understand their ramifications with respect to smoking, environmental exposure, normal placental function, and pregnancy maintenance.

Intriguingly, Cd2+ has been reported to affect steroido-genesis directly, both in vivo and in vitro, although differences in experimental methods and the concentrations tested may be responsible for variations in results (10, 21, 88, 89). With this in mind, the results of recent studies support the concept that, depending on its concentration, Cd2+ exerts dual effects on steroidogenesis. At low doses, Cd2+ stimulates DNA synthesis, cell multiplication, and malignant transformation (90, 91). Cd2+ administered in the mM range is toxic and can be associated with diminished DNA synthesis, apoptosis, and chromosome aberrations (92). When used in concentrations over 2–5 µM, Cd2+ induces apoptosis, partially via activation of the caspase-9 in HL-60 cells (93). Therefore, it is possible that the reduction in cell number, the cellular protein content, and the changes in cell morphology observed in our experiments with ovarian cells (32) were due to the apoptotic effects of high concentrations of CdCl2. However, this does not appear to be the case in placenta, as trophoblast cells may possess an enhanced resistance to Cd2+-induced cell death (9, 24–26).

To date, studies have been directed toward experiments to explain the paradoxical, dosage-dependent effects of Cd2+ on steroidogenesis; in the view that low doses up-regulate, while comparatively high doses downregulate progesterone synthesis. Although when we consider that women with lower placental Cd2+ burdens also have lower placental progesterone levels and are prone to premature delivery, a negative effect of low Cd2+ concentrations on placental progesterone synthesis is suggested. In this capacity, therefore, it might be that the higher Cd2+ concentrations used in placental cell cultures for up to 96 hrs simply compensate for the lower placental Cd2+ burdens typically observed in vivo, to which the trophoblast is exposed for many months. Results might then be said to suggest a tissue-specific effect of Cd2+, ovary versus placenta, on steroidogenesis. If this were the case, the most important question would become: Is the effect of Cd2+ on steroidogenesis really paradoxical at all?


   Acknowledgments
 
We thank April G. O’Quinn, M.D., Gabriella Pridjian, M.D., Kenneth F. Swan, M.S., and Elease Bradford, M.S.P.H., of the Tulane University Health Sciences Center, Department of Obstetrics and Gynecology, for their support of studies conducted in the laboratory of MCH. The authors also gratefully acknowledge Mrs. Nathlynn Dellande and Mrs. Christine Meaden for their assistance in manuscript preparation.


   Footnotes
 
This work was supported by the Tulane Department of Obstetrics and Gynecology for studies in the laboratory of MCH and by the Canadian Network of Toxicology Centers, the Natural Sciences and Engineering Research Council of Canada, the Saskatchewan Agricultural Development Fund, a J. Murray Research Grant, and a Clinical Teaching and a Research Grant from the College of Medicine, University of Saskatchewan, for support of studies conducted in the laboratory of P.J.C.


   References
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 Abstract
 Introduction
 Cd2+ Exposure and Reproduction
 Effects of Cd2+ in...
 Effects of Cd2+ During...
 Mechanism of Action of...
 Estrogenic Effects of Cd2+
 Conclusions
 References
 

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