Oestrogenic activity of parabens in MCF7 human breast cancer cells

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 80; no. 1; pp. 49 - 60
• Main Authors: Byford, J.R, Shaw, L.E, Drew, M.G.B, Pope, G.S, Sauer, M.J, Darbre, P.D
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 2002; Elsevier Science
• Subjects: Animals; Binding Sites; Biological and medical sciences; Breast cancer cells; Breast Neoplasms - metabolism; Environmental oestrogen; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; Estrogen Receptor alpha; Estrogens - chemistry; Estrogens - metabolism; Female; Food Preservatives - chemistry; Food Preservatives - metabolism; Fulvestrant; Gene Expression Regulation, Neoplastic; Humans; Ligands; Models, Molecular; Molecular Structure; Parabens; Parabens - chemistry; Parabens - metabolism; Protein Binding; Proteins - genetics; Proteins - metabolism; Receptors, Estrogen - chemistry; Receptors, Estrogen - metabolism; Trefoil Factor-1; Tumor Cells, Cultured; Tumor Suppressor Proteins; Breast cancer cells; Environmental oestrogen; Parabens
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/S0960-0760(01)00174-1

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 [
3
H
]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 17β-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 (ERα) in place of 17β-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.