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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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Related in: MedlinePlus

Tissue-specific expression of luciferase activity in uterus, ovary, vagina, mammary gland, pituitary gland, liver, kidney, and brain after SC exposure to CdCl2, EE2, or PBS for 3 consecutive days. Lines inside boxes represent median, boxes indicate 25th and 75th percentiles, and whiskers represent range.*p < 0.05, **p < 0.01, and #p < 0.001 compared with the PBS-treated control by Dunnett’s multiple comparison test.
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f2-ehp-118-1389: Tissue-specific expression of luciferase activity in uterus, ovary, vagina, mammary gland, pituitary gland, liver, kidney, and brain after SC exposure to CdCl2, EE2, or PBS for 3 consecutive days. Lines inside boxes represent median, boxes indicate 25th and 75th percentiles, and whiskers represent range.*p < 0.05, **p < 0.01, and #p < 0.001 compared with the PBS-treated control by Dunnett’s multiple comparison test.

Mentions: We measured luciferase activity in reproductive and nonreproductive organs to detect ER-mediated ERE-regulated gene expression (Figure 2). After EE2 exposure, uterus, vagina, pituitary gland, liver, kidney, and brain showed significantly increased luciferase activities compared with PBS controls (negative control). No significant alterations in luciferase activity were detected in any of the CdCl2-treated groups; however, nonsignificant decreases in luciferase activity were observed in several organs after exposure to the lowest dose of CdCl2 (5 μg/kg BW). Data on lung, heart, and WATs are not reported because luciferase activity levels in these tissues were not distinguishable from background in most of the vehicle- and CdCl2-treated animals. One of the EE2-treated animals showed very low levels of luciferase activity, which indicates a nonfunctional reporter. However, because the genotype of this mouse was confirmed, it was included in the statistical analysis.


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-specific expression of luciferase activity in uterus, ovary, vagina, mammary gland, pituitary gland, liver, kidney, and brain after SC exposure to CdCl2, EE2, or PBS for 3 consecutive days. Lines inside boxes represent median, boxes indicate 25th and 75th percentiles, and whiskers represent range.*p < 0.05, **p < 0.01, 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

f2-ehp-118-1389: Tissue-specific expression of luciferase activity in uterus, ovary, vagina, mammary gland, pituitary gland, liver, kidney, and brain after SC exposure to CdCl2, EE2, or PBS for 3 consecutive days. Lines inside boxes represent median, boxes indicate 25th and 75th percentiles, and whiskers represent range.*p < 0.05, **p < 0.01, and #p < 0.001 compared with the PBS-treated control by Dunnett’s multiple comparison test.
Mentions: We measured luciferase activity in reproductive and nonreproductive organs to detect ER-mediated ERE-regulated gene expression (Figure 2). After EE2 exposure, uterus, vagina, pituitary gland, liver, kidney, and brain showed significantly increased luciferase activities compared with PBS controls (negative control). No significant alterations in luciferase activity were detected in any of the CdCl2-treated groups; however, nonsignificant decreases in luciferase activity were observed in several organs after exposure to the lowest dose of CdCl2 (5 μg/kg BW). Data on lung, heart, and WATs are not reported because luciferase activity levels in these tissues were not distinguishable from background in most of the vehicle- and CdCl2-treated animals. One of the EE2-treated animals showed very low levels of luciferase activity, which indicates a nonfunctional reporter. However, because the genotype of this mouse was confirmed, it was included in the statistical analysis.

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