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The food contaminants bisphenol A and 4-nonylphenol act as agonists for estrogen receptor α in MCF7 breast cancer cells

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Abstract

Xenoestrogens are chemically distinct industrial products potentially able to disrupt the endocrine system by mimicking the action of endogenous steroid hormones. Among such compounds, the ubiquitous environmental contaminants bisphenol A (BPA) and 4-nonylphenol (NPH) may promote adverse effects in humans triggering estrogenic signals in target tissues. Following a research program on human exposure to endocrine disruptors, we found contamination of fresh food by BPA and NPH. More important, these contaminants were found to display estrogen-like activity using as a model system the estrogen-dependent MCF7 breast cancer cells (MCF7wt); its variant named MCF7SH, which is hormone-independent but still ERα-positive, and the steroid receptor-negative human cervical carcinoma HeLa cells. In transfection experiments BPA and NPH activated in a direct manner the endogenous ERα in MCF7 wt and MCF7SH cells, as the antiestrogen hydroxytamoxifen was able to reverse both responses. Moreover, only the hormone-binding domains of ERα and ERβ expressed by chimeric proteins in HeLa cells were sufficient to elicit the transcriptional activity upon BPA and NPH treatments. Transfecting the same cell line with ERα mutants, both contaminants triggered an estrogen-like response. These transactivation properties were interestingly supported in MCF7wt cells by the autoregulation of ERα which was assessed by RT-PCR for the mRNA evaluation and by immunoblotting and immunocytochemistry for the determination of protein levels. The ability of BPA and NPH to modulate gene expression was further confirmed by the upregulation of an estrogen target gene like pS2. As a biological counterpart, concentrations of xenoestrogens eliciting transcriptional activity were able to stimulate the proliferation of MCF7wt and MCFSH cells. Only NPH at a dose likely too high to be of any physiological relevance induced a severe cytotoxicity in an ERα-independent manner as ascertained in HeLa cells. The estrogenic effects of such industrial agents together with an increasing widespread human exposure should be taken into account for the potential influence also on hormone-dependent breast cancer disease.

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Authors and Affiliations

  1. Department of Pharmaco-Biology, University of Calabria, 87036, Rende (CS), Italy

    Adele Vivacqua, Anna Grazia Recchia, Giovanna Fasanella, Sabrina Gabriele, Daniela Bonofiglio &  Marcello Maggiolini

  2. Department of Cellular Biology, University of Calabria, 87036, Rende (CS), Italy

    Amalia Carpino & Vittoria Rago

  3. Department of Chemistry, University of Calabria, 87036, Rende (CS), Italy

    Maria Luisa Di Gioia, Antonella Leggio & Angelo Liguori

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  1. Adele Vivacqua
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Correspondence to Marcello Maggiolini.

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Vivacqua, A., Recchia, A.G., Fasanella, G. et al. The food contaminants bisphenol A and 4-nonylphenol act as agonists for estrogen receptor α in MCF7 breast cancer cells. Endocr 22, 275–284 (2003). https://doi.org/10.1385/ENDO:22:3:275

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