{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:10:35Z","timestamp":1780337435352,"version":"3.54.1"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K15462, 22K12395, 19K12340, 15K00557, and 25740024"],"award-info":[{"award-number":["25K15462, 22K12395, 19K12340, 15K00557, and 25740024"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22221005 and 15H01741"],"award-info":[{"award-number":["22221005 and 15H01741"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health and Labour Sciences Research Grant for Research on the Risk of Chemical Substances from the Ministry of Health, Labor, and Welfare of Japan","award":["H20-Chemistry-General-003"],"award-info":[{"award-number":["H20-Chemistry-General-003"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    In the DNA complex of coactivator-bound estrogen receptor alpha (ER\u03b1), the N-terminal domain (NTD) and C-terminal ligand-binding domain (LBD) interact specifically. ER\u03b1-NTD and LBD constitute activation function 1 (AF-1) and activation function 2 (AF-2), respectively. We recently revealed that, despite the complete inactivity of ER\u03b1-NTD(AF-1), desNTD(AF-1)-ER\u03b1 exhibited approximately 65% of the activity of the natural estrogen 17\u03b2-estradiol (E2) for wild-type full-length ER\u03b1. It remains unclear how a deficiency of NTD(AF-1) influences the activity of desNTD(AF-1)-ER\u03b1 especially with respect to other estrogens and xenoestrogens. The major objective of this study is to evaluate the ligand specificity of desNTD(AF-1)-ER\u03b1 for a series of xenoestrogens, including bisphenol A (BPA), BPAF, and BPC, together with E2, and the antagonists 4-hydroxytamoxifen (4-OHT) and ICI 182,780 (ICI). The receptors were transiently expressed in HeLa cells, and receptor activation activity was evaluated by luciferase reporter gene assay. Antagonist activity was examined for ER\u03b1 and desNTD(AF-1)-ER\u03b1 using E2 as a reference agonist. E2 exhibited full agonist activity for both ER\u03b1 and desNTD(AF-1)-ER\u03b1, whereas 4-OHT and ICI were completely inactive and exhibited antagonist activity for E2 in both ER\u03b1 and desNTD(AF-1)-ER\u03b1. All bisphenols were active for full-length ER\u03b1. Surprisingly, however, BPAF and BPC were almost completely inactive for desNTD(AF-1)-ER\u03b1, whereas BPA was fully active. BPAF and BPC exhibited distinct antagonist activity for E2 in desNTD(AF-1)-ER\u03b1, with pA\n                    <jats:sub>2<\/jats:sub>\n                    values of 7.62 and 7.86, respectively. The present results revealed that the presence of the N-terminal NTD(AF-1) domain substantiates the agonist activity of halogen-containing BPAF and BPC in wild-type full-length ER\u03b1. ER\u03b1-NTD(AF-1) plays an essential role in determining the agonist\/antagonist activity of BPAF and BPC for estrogen receptor ER\u03b1.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0350499","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:41:02Z","timestamp":1780335662000},"page":"e0350499","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bisphenol BPAF and BPC are agonists for estrogen receptor ER\u03b1 but antagonists for N-terminal domain-lacking ER\u03b1"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3162-429X","authenticated-orcid":true,"given":"Xiaohui","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Shimohigashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyuki","family":"Shimohigashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"issue":"6","key":"pone.0350499.ref001","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.molcel.2015.01.025","article-title":"Structure of a biologically active estrogen receptor-coactivator complex on DNA","volume":"57","author":"P Yi","year":"2015","journal-title":"Mol Cell"},{"issue":"11","key":"pone.0350499.ref002","first-page":"1953","article-title":"Synergism between 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