title: A transgenic mouse model expressing an ERα folding biosensor reveals the effects of Bisphenol A on estrogen receptor signaling.
abstract: Estrogen receptor-α (ERα) plays an important role in normal and abnormal physiology of the human reproductive system by interacting with the endogenous ligand estradiol (E2). However, other ligands, either analogous or dissimilar to E2, also bind to ERα. This may create unintentional activation of ER signaling in reproductive tissues that can lead to cancer development. We developed a transgenic mouse model that constitutively expresses a firefly luciferase (FLuc) split reporter complementation biosensor (NFLuc-ER-LBDG521T-CFLuc) to simultaneously evaluate the dynamics and potency of ligands that bind to ERα. We first validated this model using various ER ligands, including Raloxifene, Diethylstilbestrol, E2, and 4-hydroxytamoxifen, by employing FLuc-based optical bioluminescence imaging of living mice. We then used the model to investigate the carcinogenic property of Bisphenol A (BPA), an environmental estrogen, by long-term exposure at full and half environmental doses. We showed significant carcinogenic effects on female animals while revealing activated downstream ER signaling as measured by bioluminescence imaging. BPA induced tumor-like outgrowths in female transgenic mice, histopathologically confirmed to be neoplastic and epithelial in origin. This transgenic mouse model expressing an ERα folding-biosensor is useful in evaluation of estrogenic ligands and their downstream effects, and in studying environmental estrogen induced carcinogenesis in vivo.
authors.affiliation: Departments of Radiology, and Bioengineering, the Bio-X Program, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155, Porter Drive, Palo Alto, CA 94304-1234, USA.
authors.forename: Thillai V
authors.initials: TV
authors.lastname: Sekar
authors.affiliation: Departments of Radiology, and Bioengineering, the Bio-X Program, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155, Porter Drive, Palo Alto, CA 94304-1234, USA.
authors.forename: Kira
authors.initials: K
authors.lastname: Foygel
authors.affiliation: Departments of Radiology, and Bioengineering, the Bio-X Program, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155, Porter Drive, Palo Alto, CA 94304-1234, USA.
authors.forename: Tarik F
authors.initials: TF
authors.lastname: Massoud
authors.affiliation: Departments of Radiology, and Bioengineering, the Bio-X Program, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155, Porter Drive, Palo Alto, CA 94304-1234, USA.
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.affiliation: Departments of Radiology, and Bioengineering, the Bio-X Program, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 3155, Porter Drive, Palo Alto, CA 94304-1234, USA.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Paulmurugan
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D015374:Biosensing Techniques / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity; D004781:Environmental Exposure; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D004967:Estrogens / Q000633:toxicity; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods; D008822:Mice, Transgenic; D057054:Molecular Imaging / Q000379:methods; D010636:Phenols / Q000633:toxicity*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D002273:Carcinogens; D047628:Estrogen Receptor alpha; D004967:Estrogens; D010636:Phenols; D020849:Raloxifene Hydrochloride; D011993:Recombinant Fusion Proteins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C016601:afimoxifene; C006780:bisphenol A; D000098826:Bisphenol A Compounds