Limits...
Estrogen-like effects of cadmium in vivo do not appear to be mediated via the classical estrogen receptor transcriptional pathway.

Ali I, Penttinen-Damdimopoulou PE, Mäkelä SI, Berglund M, Stenius U, Akesson A, Håkansson H, Halldin K - Environ. Health Perspect. (2010)

Bottom Line: We examined uterine weight and histology, vaginal opening, body and organ weights, Cd tissue retention, activation of mitogen-activated protein kinase (MAPK) pathways, and ERE-dependent luciferase expression.CdCl2 increased the height of the uterine luminal epithelium in a dose-dependent manner without increasing the uterine wet weight, altering the timing of vaginal opening, or affecting the luciferase activity in reproductive or nonreproductive organs.As we expected, EE2 advanced vaginal opening and increased uterine epithelial height, uterine wet weight, and luciferase activity in various tissues.

View Article: PubMed Central - PubMed

Affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

Background: Cadmium (Cd), a ubiquitous food contaminant, has been proposed to be an endocrine disruptor by inducing estrogenic responses in vivo. Several in vitro studies suggested that these effects are mediated via estrogen receptors (ERs).

Objective: We performed this study to clarify whether Cd-induced effects in vivo are mediated via classical ER signaling through estrogen responsive element (ERE)-regulated genes or if other signaling pathways are involved.

Methods: We investigated the estrogenic effects of cadmium chloride (CdCl2) exposure in vivo by applying the Organisation for Economic Co-operation and Development (OECD) rodent uterotrophic bioassay to transgenic ERE-luciferase reporter mice. Immature female mice were injected subcutaneously with CdCl2 (5, 50, or 500 µg/kg body weight) or with 17α-ethinylestradiol (EE2) on 3 consecutive days. We examined uterine weight and histology, vaginal opening, body and organ weights, Cd tissue retention, activation of mitogen-activated protein kinase (MAPK) pathways, and ERE-dependent luciferase expression.

Results: CdCl2 increased the height of the uterine luminal epithelium in a dose-dependent manner without increasing the uterine wet weight, altering the timing of vaginal opening, or affecting the luciferase activity in reproductive or nonreproductive organs. However, we observed changes in the phosphorylation of mouse double minute 2 oncoprotein (Mdm2) and extracellular signal-regulated kinase (Erk1/2) in the liver after CdCl2 exposure. As we expected, EE2 advanced vaginal opening and increased uterine epithelial height, uterine wet weight, and luciferase activity in various tissues.

Conclusion: Our data suggest that Cd exposure induces a limited spectrum of estrogenic responses in vivo and that, in certain targets, effects of Cd might not be mediated via classical ER signaling through ERE-regulated genes.

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Tissue Cd concentration (mean ± SD) in the liver and kidney after SC exposure to CdCl2, EE2, or PBS for 3 consecutive days.*p < 0.05, and #p < 0.001, compared with the PBS-treated control by Dunnett’s multiple comparison test.
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f1-ehp-118-1389: Tissue Cd concentration (mean ± SD) in the liver and kidney after SC exposure to CdCl2, EE2, or PBS for 3 consecutive days.*p < 0.05, and #p < 0.001, compared with the PBS-treated control by Dunnett’s multiple comparison test.

Mentions: To verify the effectiveness of dosing and to measure the internal dose of Cd after treatment, we analyzed liver and kidney Cd concentrations. Cd concentrations in liver and kidney samples increased in a dose-dependent manner (Figure 1). Among all treatment groups, the highest concentrations were found in liver compared with kidneys (about two to three times higher in liver than in kidneys). The Cd concentrations in liver were between 58 and 2,833 ng/g wet weight, whereas in kidneys the Cd concentrations from 36 to 1,109 ng/g wet weight. EE2-treated and PBS control animals showed very low Cd concentrations both in liver and in kidneys.


Estrogen-like effects of cadmium in vivo do not appear to be mediated via the classical estrogen receptor transcriptional pathway.

Ali I, Penttinen-Damdimopoulou PE, Mäkelä SI, Berglund M, Stenius U, Akesson A, Håkansson H, Halldin K - Environ. Health Perspect. (2010)

Tissue Cd concentration (mean ± SD) in the liver and kidney after SC exposure to CdCl2, EE2, or PBS for 3 consecutive days.*p < 0.05, and #p < 0.001, compared with the PBS-treated control by Dunnett’s multiple comparison test.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2957917&req=5

f1-ehp-118-1389: Tissue Cd concentration (mean ± SD) in the liver and kidney after SC exposure to CdCl2, EE2, or PBS for 3 consecutive days.*p < 0.05, and #p < 0.001, compared with the PBS-treated control by Dunnett’s multiple comparison test.
Mentions: To verify the effectiveness of dosing and to measure the internal dose of Cd after treatment, we analyzed liver and kidney Cd concentrations. Cd concentrations in liver and kidney samples increased in a dose-dependent manner (Figure 1). Among all treatment groups, the highest concentrations were found in liver compared with kidneys (about two to three times higher in liver than in kidneys). The Cd concentrations in liver were between 58 and 2,833 ng/g wet weight, whereas in kidneys the Cd concentrations from 36 to 1,109 ng/g wet weight. EE2-treated and PBS control animals showed very low Cd concentrations both in liver and in kidneys.

Bottom Line: We examined uterine weight and histology, vaginal opening, body and organ weights, Cd tissue retention, activation of mitogen-activated protein kinase (MAPK) pathways, and ERE-dependent luciferase expression.CdCl2 increased the height of the uterine luminal epithelium in a dose-dependent manner without increasing the uterine wet weight, altering the timing of vaginal opening, or affecting the luciferase activity in reproductive or nonreproductive organs.As we expected, EE2 advanced vaginal opening and increased uterine epithelial height, uterine wet weight, and luciferase activity in various tissues.

View Article: PubMed Central - PubMed

Affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

Background: Cadmium (Cd), a ubiquitous food contaminant, has been proposed to be an endocrine disruptor by inducing estrogenic responses in vivo. Several in vitro studies suggested that these effects are mediated via estrogen receptors (ERs).

Objective: We performed this study to clarify whether Cd-induced effects in vivo are mediated via classical ER signaling through estrogen responsive element (ERE)-regulated genes or if other signaling pathways are involved.

Methods: We investigated the estrogenic effects of cadmium chloride (CdCl2) exposure in vivo by applying the Organisation for Economic Co-operation and Development (OECD) rodent uterotrophic bioassay to transgenic ERE-luciferase reporter mice. Immature female mice were injected subcutaneously with CdCl2 (5, 50, or 500 µg/kg body weight) or with 17α-ethinylestradiol (EE2) on 3 consecutive days. We examined uterine weight and histology, vaginal opening, body and organ weights, Cd tissue retention, activation of mitogen-activated protein kinase (MAPK) pathways, and ERE-dependent luciferase expression.

Results: CdCl2 increased the height of the uterine luminal epithelium in a dose-dependent manner without increasing the uterine wet weight, altering the timing of vaginal opening, or affecting the luciferase activity in reproductive or nonreproductive organs. However, we observed changes in the phosphorylation of mouse double minute 2 oncoprotein (Mdm2) and extracellular signal-regulated kinase (Erk1/2) in the liver after CdCl2 exposure. As we expected, EE2 advanced vaginal opening and increased uterine epithelial height, uterine wet weight, and luciferase activity in various tissues.

Conclusion: Our data suggest that Cd exposure induces a limited spectrum of estrogenic responses in vivo and that, in certain targets, effects of Cd might not be mediated via classical ER signaling through ERE-regulated genes.

Show MeSH
Related in: MedlinePlus