Cadmium-induced effects on cellular signaling pathways in the liver of transgenic estrogen reporter mice.
Estrogen-like effects of cadmium (Cd) have been reported in several animal studies, and recent epidemiological findings suggest increased risk of hormone-dependent cancers after Cd exposure. The mechanisms underlying these effects are still under investigation. Our aim was to study the effects of Cd on cellular signaling pathways in vivo with special focus on estrogen signaling and to perform benchmark dose analysis on the effects. Transgenic adult ERE-luciferase male mice were exposed subcutaneously to 0.5-500 μg CdCl(2) per kg body weight (bw) or 17α-ethinylestradiol (EE2) for 3 days. These doses had no effects on organ and bw or testicular histology, indicating subtoxic exposure levels. The transgene luciferase, reporting genomic estrogen response, was significantly increased by EE2 but not by Cd. However, Cd significantly affected kinase phosphorylation and endogenous gene expression. Interestingly, gene expression changes displayed a traditional dose-response relationship, with benchmark dose levels for the expression of Mt1, Mt2, p53, c-fos, and Mdm2 being 92.9, 19.9, 7.6, 259, and 25.9 μg/kg bw, respectively, but changes in kinase phosphorylation were only detected at low exposure levels. Phosphorylation of Erk1/2 was significantly increased even in the lowest dose group, 0.5 μg/kg bw, rendering pErk1/2 a more sensitive sensor of exposure than changes in gene expression. Collectively, our data suggest that the effects triggered by Cd in vivo are markedly concentration dependent. Furthermore, we conclude that the estrogen-like effects of Cd are likely to result from a mechanism different from steroidal estrogens.
Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden. imran.ali@ki.se
Imran
I
Ali
Pauliina
P
Damdimopoulou
Ulla
U
Stenius
Annika
A
Adamsson
Sari I
SI
Mäkelä
Agneta
A
Åkesson
Marika
M
Berglund
Helen
H
Håkansson
Krister
K
Halldin
D000818:Animals; D019256:Cadmium Chloride / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D020847:Estrogen Receptor Modulators / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004997:Ethinyl Estradiol / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D013737:Testis / Q000187:drug effects
D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D004997:Ethinyl Estradiol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019256:Cadmium Chloride