title: Understanding the molecular basis for differences in responses of fish estrogen receptor subtypes to environmental estrogens.
abstract: Exposure to endocrine disrupting chemicals (EDCs) can elicit adverse effects on development, sexual differentiation, and reproduction in fish. Teleost species exhibit at least three subtypes of estrogen receptor (ESR), ESR1, ESR2a, and ESR2b; thus, estrogenic signaling pathways are complex. We applied in vitro reporter gene assays for ESRs in five fish species to investigate the ESR subtype-specificity for better understanding the signaling pathway of estrogenic EDCs. Responses to bisphenol A, 4-nonylphenol, and o,p'-DDT varied among ESR subtypes, and the response pattern of ESRs was basically common among the different fish species. Using a computational in silico docking model and through assays quantifying transactivation of the LBD (using GAL-LBD fusion proteins and chimera proteins for the ESR2s), we found that the LBD of the different ESR subtypes generally plays a key role in conferring responsiveness of the ESR subtypes to EDCs. These results also indicate that responses of ESR2s to EDCs cannot necessarily be predicted from the LBD sequence alone, and an additional region is required for full transactivation of these receptors. Our data thus provide advancing understanding on receptor functioning for both basic and applied research.
authors.affiliation: †Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.|‡Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Tohyama
authors.affiliation: ‡Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Anke
authors.initials: A
authors.lastname: Lange
authors.affiliation: ‡Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Ogino
authors.affiliation: ‡Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: ∥Center for Environmental Risk Research, National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Tatarazako
authors.affiliation: ⊥Department of Biological Sciences, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Katsu
authors.affiliation: #Research Center for Environmental Quality Management, Kyoto University, Otsu, Shiga 520-0811, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ihara
authors.affiliation: #Research Center for Environmental Quality Management, Kyoto University, Otsu, Shiga 520-0811, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: ∇Department of Life Environmental Conservation, Faculty of Agriculture, Ehime University, Matsuyama, Ehime 790-8566, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishibashi
authors.affiliation: †Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Charles R
authors.initials: CR
authors.lastname: Tyler
authors.affiliation: ‡Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan.
authors.forename: Taisen
authors.initials: T
authors.lastname: Iguchi
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D003198:Computer Simulation; D003634:DDT / Q000633:toxicity; D052244:Endocrine Disruptors / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000633:toxicity*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D009990:Oryzias / Q000235:genetics*; D010636:Phenols / Q000633:toxicity; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D000098826:Bisphenol A Compounds
chemical_list: D000596:Amino Acids; D001559:Benzhydryl Compounds; D003634:DDT; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D004958:Estradiol; D004967:Estrogens; D008024:Ligands; D010636:Phenols; D011960:Receptors, Estrogen; C016340:o,p'-DDT; C041594:4-nonylphenol; C006780:bisphenol A; D000098826:Bisphenol A Compounds