ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERalpha and PR.
Estrogenic activities of the phenolic preservatives methylparaben, ethylparaben, propylparaben, butylparaben, isopropylparaben and isobutylparaben were examined by assaying estrogen-receptor (ER)-dependent proliferation of MCF-7 cells. All the compounds stimulated the proliferation to about the same level as the maximal cell yield attained with 3x10(-11) M 17beta-estradiol, but at a concentration in the order of 10(5) to 10(7) higher than 17beta-estradiol. The cell-proliferative effects of parabens were completely suppressed by anti-estrogen ICI 182,780. MCF-7 cells treated with butylparaben and isobutylparaben exhibited a decrease in gene expression of ERalpha and an increase in that of progesterone-receptor (PR), but the effects of these parabens were not as prominent as those of 17beta-estradiol. Western blot analysis indicated that these parabens caused a slight decrease in expression of ERalpha protein. Competitive binding to human ERalpha and ERbeta in vitro revealed that the parabens with longer side-chains showed greater affinity for estrogen receptors, and that they had similar relative binding affinity (RBA) values to both ERalpha and ERbeta. RBA values were much smaller than that of diethylstilbestrol. In conclusion, parabens have ER-dependent estrogenic activities, and their effects on the intracellular signaling pathway might be different from that of 17beta-estradiol.
Okubo
T
T
Department of Toxicology, The Tokyo Metropolitan Research Laboratory of Public Health, 3-24-1 Hyakunin-cho, Shinjuku-ku, 169-0073, Tokyo, Japan.
Yokoyama
Y
Y
Kano
K
K
Kano
I
I
D001667:Binding, Competitive; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal / Q000378:metabolism; D005260:Female; D005520:Food Preservatives / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D010226:Parabens / Q000378:metabolism / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D005520:Food Preservatives; D010226:Parabens; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol