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


CONCLUSIONS
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.
Ali
Imran
I
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Penttinen-Damdimopoulou
Pauliina E
PE
Mäkelä
Sari I
SI
Berglund
Marika
M
Stenius
Ulla
U
Akesson
Agneta
A
Håkansson
Helen
H
Halldin
Krister
K
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D052244:Endocrine Disruptors / Q000633:toxicity*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
D052244:Endocrine Disruptors; D004967:Estrogens; D011960:Receptors, Estrogen; D002104:Cadmium