ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERα 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 17 beta -estradiol, but at a concentration in the order of 10(5) to 10(7) higher than 17 beta -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 ER alpha and an increase in that of progesterone-receptor (PR), but the effects of these parabens were not as prominent as those of 17 beta -estradiol. Western blot analysis indicated that these parabens caused a slight decrease in expression of ER alpha protein. Competitive binding to human ER alpha and ER beta 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 ER alpha and ER beta. 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 17 beta -estradiol. (C) 2001 Elsevier Science Ltd. All rights reserved.