Lack of activity of cadmium in in vitro estrogenicity assays.
Prompted by reports about strong estrogenic effects of cadmium, attempts were made to reproduce these observations using the yeast estrogen screen (YES) and the E-Screen assays. For the first time, possible activation of the Src/MAPK pathway was also investigated. In the YES, only a slight activation (10% of a maximal effect) of the estrogen receptor alpha (ERalpha) was observed at cadmium concentrations between 5 x 10(-7) M and 5 x 10(-6) M. In the E-Screen assay, carried out by two laboratories, the heavy metal was without observable cell proliferative effects when tested in the range between 6 x 10(-11) M and 1 x 10(-5) M. However, in both assays, cadmium led to a reduction of the effects of 17beta-estradiol (E2). Treatment of MCF-7 human breast cancer cells with 1 x 10(-7) M cadmium failed to induce phosphorylation of Src and the MAP kinases Erk1 and Erk2-effects shown to occur with E2 and epidermal growth factor (EGF). In summary, we were unable to confirm the strong estrogenicity of cadmium reported recently by a number of laboratories. This apparent absence of effects in our hands is not due to a lack of uptake of the metal or to effective protection against cadmium by high levels of glutathione or metallothionein, since toxicity and an antagonism of E2 responses were observed both in the YES and the E-Screen.
Silva
Elisabete
E
Centre for Toxicology, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK. elisabete.silva@pharmacy.ac.uk
Lopez-Espinosa
Maria José
MJ
Molina-Molina
José-Manuel
JM
Fernández
Marieta
M
Olea
Nicolas
N
Kortenkamp
Andreas
A
D015153:Blotting, Western; D019256:Cadmium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015003:Yeasts / Q000737:chemistry / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004958:Estradiol; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D019256:Cadmium Chloride