Coexposure to phytoestrogens and bisphenol a mimics estrogenic effects in an additive manner

Anne Katchy, Caroline Pinto, Philip Jonsson, Trang Nguyen-vu, Marchela Pandelova, Anne Riu, Karl Werner Schramm, Daniel Samarov, Jan Åke Gustafsson, Maria Bondesson, Cecilia Williams

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogeninduced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer.

Original languageEnglish (US)
Article numberkft271
Pages (from-to)21-35
Number of pages15
JournalToxicological Sciences
Issue number1
StatePublished - Mar 2014


  • Bisphenol A
  • Concentration addition
  • Estrogen receptor
  • Phytoestrogens
  • Proliferation
  • Transcriptional activation

ASJC Scopus subject areas

  • Toxicology


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