Parabens (4-
hydroxybenzoic acid esters) have been recently reported to have oestrogenic activity in yeast cells and animal models. Since the human population is exposed to
parabens through their widespread use as preservatives in foods,
pharmaceuticals and
cosmetics, we have investigated here whether oestrogenic activity of these compounds can also be detected in oestrogen-sensitive human cells. We report on the oestrogenic effects of four
parabens (
methylparaben,
ethylparaben, n-
propylparaben, n-
butylparaben) in oestrogen-dependent MCF7 human
breast cancer cells. Competitive inhibition of [3H]
oestradiol binding to MCF7 cell oestrogen receptors could be detected at 1,000,000-fold molar excess of n-
butylparaben (86%), n-
propylparaben (77%),
ethyl-paraben (54%) and
methylparaben (21%). At concentrations of 10(-6)M and above,
parabens were are able to increase expression of both transfected (ERE-CAT reporter gene) and endogenous (pS2) oestrogen-regulated genes in these cells. They could also increase proliferation of the cells in monolayer culture, which could be inhibited by the
antiestrogen ICI 182,780, indicating that the effects were mediated through the oestrogen receptor. However, no antagonist activity of
parabens could be detected on regulation of cell proliferation by
17 beta-oestradiol at 10(-10)M. Molecular modelling has indicated the mode by which
paraben molecules can bind into the
ligand binding pocket of the crystal structure of the
ligand binding domain (LBD) of the oestrogen receptor alpha (
ERalpha) in place of 17beta-
oestradiol; it has furthermore shown that two
paraben molecules can bind simultaneously in a mode in which their phenolic
hydroxyl groups bind similarly to those of the meso-hexoestrol molecule. Future work will need to address the extent to which
parabens can accumulate in hormonally sensitive tissues and also the extent to which their weak oestrogenic activity can add to the more general environmental oestrogen problem.