title: Coexposure to phytoestrogens and bisphenol a mimics estrogenic effects in an additive manner.
abstract: 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 estrogen-induced 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.
authors.affiliation: * Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5056;
authors.forename: Anne
authors.initials: A
authors.lastname: Katchy
authors.forename: Caroline
authors.initials: C
authors.lastname: Pinto
authors.forename: Philip
authors.initials: P
authors.lastname: Jonsson
authors.forename: Trang
authors.initials: T
authors.lastname: Nguyen-Vu
authors.forename: Marchela
authors.initials: M
authors.lastname: Pandelova
authors.forename: Anne
authors.initials: A
authors.lastname: Riu
authors.forename: Karl-Werner
authors.initials: KW
authors.lastname: Schramm
authors.forename: Daniel
authors.initials: D
authors.lastname: Samarov
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Maria
authors.initials: M
authors.lastname: Bondesson
authors.forename: Cecilia
authors.initials: C
authors.lastname: Williams
mesh_terms: D001559:Benzhydryl Compounds / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D052244:Endocrine Disruptors / Q000302:isolation & purification / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D019833:Genistein / Q000302:isolation & purification / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D041943:Infant Formula / Q000737:chemistry; D007529:Isoflavones / Q000302:isolation & purification / Q000633:toxicity; D061986:MCF-7 Cells; D010636:Phenols / Q000633:toxicity*; D048789:Phytoestrogens / Q000302:isolation & purification / Q000633:toxicity*; D011485:Protein Binding; D041942:Soy Milk / Q000737:chemistry; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D019833:Genistein; D007529:Isoflavones; D010636:Phenols; D048789:Phytoestrogens; C506487:ESR1 protein, human; C013908:daidzin; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: bisphenol A; concentration addition.; estrogen receptor; phytoestrogens; proliferation; transcriptional activation