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Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells

View ORCID ProfileRobin Mesnage, Alexia Phedonos, Matthew Arno, Sucharitha Balu, J. Christopher Corton, Michael N Antoniou
doi: https://doi.org/10.1101/112862
Robin Mesnage
1Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom
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  • ORCID record for Robin Mesnage
Alexia Phedonos
1Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom
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Matthew Arno
2Genomics Centre, King's College London, Waterloo Campus, 150 Stamford Street, London SE1 9NH, United Kingdom
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Sucharitha Balu
2Genomics Centre, King's College London, Waterloo Campus, 150 Stamford Street, London SE1 9NH, United Kingdom
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J. Christopher Corton
3Integrated Systems Toxicology Division, National Health and Environmental Effects Research Lab, US Environmental Protection Agency, 109 T.W. Alexander Dr MD-B143-06, Research Triangle Park, NC 27711. Fax: (919) 541-0694
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Michael N Antoniou
1Gene Expression and Therapy Group, King's College London, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, 8th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom
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  • For correspondence: michael.antoniou@kcl.ac.uk
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Abstract

Background Plasticizers with estrogenic activity, such as bisphenol A (BPA), have been reported to have potential adverse health effects in humans. Due to mounting evidence of these health effects and public pressure, BPA is being phased out by the plastics manufacturing industry and replaced by other bisphenol variants in “BPA-free” products.

Objectives We have compared estrogenic activity of BPA to 6 bisphenol analogues (bisphenol S, BPS; bisphenol F, BPF; bisphenol AP, BPAP; bisphenol AF, BPAF; bisphenol Z, BPZ; bisphenol B, BPB) in three human breast cancer cell lines.

Methods Estrogenicity was assessed by cell growth in an estrogen receptor (ER)-mediated cell proliferation assay, and by the induction of estrogen response element (ERE)-mediated transcription in a luciferase assay. Gene expression profiles were determined in MCF-7 human breast cancer cells by microarray analysis and confirmed by Illumina-based RNA sequencing.

Results All bisphenols showed estrogenic activity in promoting cell growth and inducing ERE-mediated transcription. BPAF was the most potent bisphenol, followed by BPB > BPZ ~ BPA > BPF ~ BPAP > BPS. The addition of ICI 182,780 antagonized the activation of ERs by bisphenols. Data mining of ToxCast high-throughput screening assays confirms our results but also shows divergence in the sensitivities of the assays. The comparison of transcriptome profile alterations resulting from BPA alternatives with an ERα gene expression biomarker further indicates that all BPA alternatives act as ERα agonists in MCF-7 cells. These results were confirmed by RNA sequencing.

Conclusion In conclusion, BPA alternatives are not necessarily less estrogenic in a human breast cancer cell model. Three bisphenols (BPAF, BPB, and BPZ) were more estrogenic than BPA. The relevance of human exposure to BPA alternatives in hormone-dependent breast cancer risk should be investigated.

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Posted March 02, 2017.
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Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells
Robin Mesnage, Alexia Phedonos, Matthew Arno, Sucharitha Balu, J. Christopher Corton, Michael N Antoniou
bioRxiv 112862; doi: https://doi.org/10.1101/112862
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Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells
Robin Mesnage, Alexia Phedonos, Matthew Arno, Sucharitha Balu, J. Christopher Corton, Michael N Antoniou
bioRxiv 112862; doi: https://doi.org/10.1101/112862

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