Estrogenic activity of cadmium, copper and zinc in the yeast estrogen screen (original) (raw)
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Marine Environmental Research, 2008
Estrogenic potential of environmental samples is frequently assessed using receptor-based functional assays. Using the yeast estrogen screen (YES) developed by Routledge and Sumpter, we assessed the ability of cadmium to activate the estrogen receptor-mediated response. No induced transcriptional activity was observed with a range of CdCl 2 concentrations (1 nm-1 mM). But, when combining cadmium with the model compound 17b-estradiol, cadmium was able to significantly potentiate the induced estrogenic response for concentrations ranging from 15 nM to 1 lM. A maximal effect was observed at 0.5 lM with a ten fold reduction of the 17b-estradiol EC50.
Journal of Biological Chemistry, 1994
The effects of cadmium on estrogen receptor and other estrogen-regulated genes in the human breast cancer cell line MCF-7 were studied. Treatment of MCF-7 cells with 1 p~ cadmium decreased the level of estrogen receptor 58%. Cadmium induced a parallel decrease in estrogen receptor mRNA (62%). Progesterone receptor levels increased 3.2-fold after cadmium treatment. This induction was blocked by the anti-estrogen ICI-164,384. Progesterone receptor mRNA was also increased by cadmium, as well as cathepsin D mRNA. An in vitro nuclear transcription run-on assay showed that cadmium increased the transcription of the progesterone receptor and pS2 genes and decreased transcription of the estrogen receptor gene. These are not general effects of heavy metals, as zinc, 25 and 100 p~, did not affect progesterone receptor protein and mRNA levels. Cadmium stimulated pS2 and progesterone receptor mRNAs in a clone of MDA-MB-231 cells transfected with the human estrogen receptor, but had no effect in
Heavy Metals Acting as Endocrine Disrupters
2011
Last years researches focused on several natural and synthetic compounds that may interfere with the major functions of the endocrine system and were termed endocrine disrupters. Endocrine disrupters are defined as chemical substances with either agonist or antagonist endocrine effects in human and animals. These effects may be achieved by interferences with the biosynthesis or activity of several endogenous hormones. Recently, it was demonstrated that heavy metals such as cadmium (Cd), arsen (As), mercury (Hg), nickel (Ni), lead (Pb) and zinc (Zn) may exhibit endocrine-disrupting activity in animal experiments. Emerging evidence of the intimate mechanisms of action of these heavy metals is accumulating. It was revealed, for example, that the Zn atom from the Zn fingers of the estrogen receptor can be replaced by several heavy metal molecules such as copper, cobalt, Ni and Cd. By replacing the Zn atom with Ni or copper, binding of the estrogen receptor to the DNA hormone responsive elements in the cell nucleus is prevented. In both males and females, low-level exposure to Cd interferes with the biological effects of steroid hormones in reproductive organs. Arsen has the property to bind to the glucocorticoid receptor thus disturbing glucocorticoids biological effects. With regard to Hg, this may induce alterations in male and female fertility, may affect the function of the hypothalamo-pituitary-thyroid axis or the hypothalamo-pituitary-adrenal axis, and disrupt biosynthesis of steroid hormones.
Environmental Health Perspectives, 2010
Cadmium (Cd) is a widespread nephrotoxic food contaminant that accumulates and has a particularly long biological half-life in the liver and kidney (Amzal et al. 2009; Järup and Åkesson 2009). More recently, Cd was proposed to possess endocrine-disruptive properties. Several well-charac terized estrogenic responses were induced in rodents after intra peritoneal injection of low doses of Cd (Johnson et al. 2003). Effects included increased uterine weight, luminal epithelium
Evaluation of estrogenicity of major heavy metals
Science of The Total Environment, 2003
We have employed an estrogen receptor dependent transcriptional expression assay and E-Screen assay systems to evaluate the estrogenicity of various heavy metals and their species. Using the former, the following estrogenicity ranking was measured: bis(tri-n-butyltin))cadmium chloride)antimony chloride)barium chlorideschromium chloride)lithium hydroxide)sodium selenateslead acetate)stannous chloride. Using the latter, the following estrogenicity ranking was measured: bis(tri-n-butyltin))cadmium chloride)antimony chloride)lithium hydroxide)barium chloride)sodium selenate)chromium chloride. Especially, bis(tri-n-butyltin), cadmium chloride, antimony chloride, lithium hydroxide, barium chloride, and chromium chloride showed estrogenicity in both assay systems. Recent studies suggesting that bis(tri-n-butyltin), cadmium chloride, and lithium hydroxide have estrogenicities are compatible with the present findings. Furthermore, our studies are the first to suggest that antimony, barium, chromium may be estrogenic. A range of estrogenicity was observed for different species of the same heavy metal. The results demonstrate that an estrogen receptor dependent transcriptional expression assay and the E-Screen assay systems could serve as a useful method to assess the estrogenicity of heavy metals.
Cadmium as an Endocrine Disruptor in the Reproductive System
Immunology‚ Endocrine & Metabolic Agents in Medicinal Chemistry, 2006
Cadmium is a heavy metal that has no known beneficial biological role. Although naturally occurring, it owes its presence in today's environment mainly to contamination from consumer goods (electric batteries, paints, etc.), industrial wastes, and soil fertilizers. Cadmium is a constituent of foods (seafood, grains, vegetables) and tobacco smoke, which are its main sources of exposure to the general population. Human exposure has been linked to a vast array of ill effects ranging from those affecting lung, kidney and bone, to those affecting reproductive organs and specific cell functions. By virtue of its demonstrated capacity to alter the rates of ovarian and placental steroidogenesis, thereby adversely impacting normal reproduction in both humans and animals, cadmium has been added to the list of acknowledged endocrine disrupting chemicals (EDCs). Extensive evidence suggests direct effects on specific components of the steroidogenic pathway, including the low density lipoprotein (LDL)-cholesterol receptor and P450 side chain cleavage enzyme. In addition to exerting its effects via both transcriptional and post-transcriptional mechanisms, cadmium may also regulate hormone binding and intracellular second messenger pathways. Women may be at increased risk for the reproductive anomalies associated with exposure and, as demonstrated in numerous studies, the metal may also function as a potent nonsteroidal agent; a xenoestrogen, that can mimic or block the effects of endogenous estrogens. The effects of cadmium on reproduction, combined with its abundance in the human environment, continue to call for more detailed studies dedicated to elucidating the mechanisms that control the metal's influence as an EDC.
Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland
Nature Medicine, 2003
It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor 1,2 . The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.
Cadmium on estrogen receptor of levels and estrogen-induced responses in human breast cancer cells
Journal of Biological Chemistry
The effects of cadmium on estrogen receptor and other estrogen-regulated genes in the human breast cancer cell line MCF-7 were studied. Treatment of MCF-7 cells with 1 p~ cadmium decreased the level of estrogen receptor 58%. Cadmium induced a parallel decrease in estrogen receptor mRNA (62%). Progesterone receptor levels increased 3.2-fold after cadmium treatment. This induction was blocked by the anti-estrogen ICI-164,384. Progesterone receptor mRNA was also increased by cadmium, as well as cathepsin D mRNA. An in vitro nuclear transcription run-on assay showed that cadmium increased the transcription of the progesterone receptor and pS2 genes and decreased transcription of the estrogen receptor gene. These are not general effects of heavy metals, as zinc, 25 and 100 p~, did not affect progesterone receptor protein and mRNA levels. Cadmium stimulated pS2 and progesterone receptor mRNAs in a clone of MDA-MB-231 cells transfected with the human estrogen receptor, but had no effect in MDA-MB-231 cells transfected with antisense estrogen receptor. Cadmium also stimulated an estrogen response element in transient transfection experiments. These data suggest that the effects of cadmium are mediated by the estrogen receptor independent of estradiol. In addition to its effect on gene expression, cadmium induced the growth of MCF-7 cells 5.6-fold.
Inhibition of Rainbow Trout (Oncorhynchus mykiss) Estrogen Receptor Activity by Cadmium
Biology of Reproduction, 2000
This study was conducted to determine if the cadmium-mediated inhibition of vitellogenesis observed in fish collected from contaminated areas or undergoing experimental exposure to cadmium correlated with modification in the transcriptional activity of the estrogen receptor. A recombinant yeast system expressing rainbow trout (Oncorhynchus mykiss) estradiol receptor or human estradiol receptor was used to evaluate the direct effect of cadmium exposure on estradiol receptor transcriptional activity. In recombinant yeast, cadmium reduced the estradiolstimulated transcription of an estrogen-responsive reporter gene. In vitro-binding assays indicated that cadmium did not affect ligand binding to the receptor. Yeast one-and two-hybrid assays showed that estradiol-induced conformational changes and receptor dimerization were not affected by cadmium; conversely, DNA binding of the estradiol receptor to its cognate element was dramatically reduced in gel retardation assay. This study provides mechanistic data supporting the idea that cadmium is an important endocrine disrupter through a direct effect on estradiol receptor transcriptional activity and may affect a number of estrogen signaling pathways.